NZ788873A - Anti-B7-H3 antibodies and antibody drug conjugates - Google Patents

Abstract

The invention relates to B7 homology 3 protein (B7-H3) antibodies and antibody drug conjugates (ADCs), including compositions and methods of using said antibodies and ADCs.

Description

ANTI-B7-H3 DIES AND ANTIBODY DRUG CONJUGATESRELATED APPLICATIONSThis ation claims priority to U.S. Provisional Application No. 62/347,476, filed on 8June 2016, and to U.S. Provisional Application No. 62/366,511, filed on 25 July 2016. The presentapplication is a divisional application of application No. 749155, which is the New d NationalPhase application of . The entire contents of the foregoing applications areexpressly incorporated herein by reference.

SEQUENCE LISTINGThe instant application contains a Sequence Listing which has been submitted electronicallyin ASCII format and is hereby orated by reference in its entirety. Said ASCII copy, created onJune 7, 2017, is named -12620_ST25.txt and is 159,744 bytes in size.

BACKGROUND OF THE IONThe B7 homology 3 protein (B7-H3) (also known as CD276 and B7RP-2, and referred toherein as “B7-H3”) is a type I transmembrane glycoprotein of the immunoglobulin superfamily.

Human B7-H3 contains a putative signal peptide, V-like and C-like Ig domains, a transmembraneregion and a cytoplasmic domain. Exon duplication in humans results in the expression of two B7-H3isoforms having either a single IgV-IgC-like domain (2IgB7-H3 isoform) or a IgV-IgC-IgV-IgC-likedomain (4IgB7-H3 isoform) containing several conserved cysteine residues. The predominant B7-H3isoform in human tissues and cell lines is the 4IgB7-H3 isoform (Steinberger et al., J. Immunol.172(4): 2352-9 (2004)).

B7-H3 has been reported as having both co-stimulatory and co-inhibitory ing functions(see, e.g., Chapoval et al., Nat. Immunol. 2: 269-74 (2001); Suh et al., Nat. Immunol. 4: 899-906(2003); Prasad et al., J. Immunol. 173: 2500-6 ; and Wang et al., Eur. J. Immunol. 35: 428-38(2005)). For e, in vitro studies have shown B7-H3’s co-stimulatory function since B7-H3 wasable to increase proliferation of xic hocytes (CTLs) and upregulate interferon gamma(IFN-γ) production in the presence of anti-CD3 antibody to mimic the T cell receptor signal(Chapoval et al., 2001). Moreover, in vivo studies using cardiac afts in B7-H3 -/- mice showeddecreased production of key cytokine, chemokine and chemokine receptor mRNA transcripts (e.g.,IL-2, IFN-γ, monocyte chemoattractant protein (MCP-1) and IFN-inducible protein (IP)-10) ased to wild-type control (Wang et al., 2005). In contrast, B7-H3 co-inhibitory function hasbeen observed, for example, in mice where B7-H3 protein inhibited T-cell activation and orcytokine production (Suh et al., 2003). Although no ligands have been identified for human B7-H3,murine B7-H3 has been found to bind to the triggering receptor expressed on myeloid cells (TREM-)like transcript 2 (TLT-2), a modulator of adaptive an innate immunity ar responses. Binding ofmurine B7-H3 to TLT-2 on CD8+ T-cells enhances T-cell effector functions such as proliferation,117813-12620cytotoxicity and cytokine production (Hashiguchi er al., Proc. Nat’l. Acad. Sci. U.S.A. 105(30):10495-500 (2008)).

B7-H3 is not constitutively expressed in many immune cells (e.g., natural killer (NK) cells, T-cells, and antigen-presenting cells (APCs)), however, its expression can be d. Further, theexpression of B7-H3 is not restricted to immune cells. B7-H3 transcripts are expressed in a variety ofhuman tissues ing colon, heart, liver, placenta, prostate, small intestine, testis, and uterus, aswell as osteoblasts, fibroblasts, epithelial cells, and other cells of non-lymphoid lineage, potentiallyindicating immunological and non-immunological functions (Nygren er al. Front Biosci. 3:989-93(2011)). r, protein expression in normal tissue is typically maintained at a low level and thus,may be subject to post-transcriptional regulation.

B7-H3 is also expressed in a variety of human s, including prostate cancer, clear cellrenal cell carcinoma, glioma, melanoma, lung cancer, non-small cell lung cancer (NSCLC), small celllung cancer, atic cancer, gastric cancer, acute myeloid leukemia (AML), non-Hodgkin'slymphoma (NHL), ovarian cancer, colorectal cancer, colon cancer, renal cancer, hepatocellularcarcinoma, kidney cancer, head and neck cancer, hypopharyngeal us cell carcinoma,glioblastoma, neuroblastoma, breast cancer, trial , and urothelial cell carcinoma.

Although the role of B7-H3 in cancer cells is unclear, its expression may trate signaling eventsthat may protect cancer cells from innate and adaptive immune responses. For e, B7-H3 isoverexpressed in high-grade prostatic intraepithelial neoplasia and adenocarcinomas of the prostate,and high expression levels of B7-H3 in these cancerous cells is associated with an increased risk ofcancer progression after surgery (Roth et al. Cancer Res. 67(16): 7893-900 (2007)). Further, tumorB7-H3 expression in NSCLC inversely correlated with the number of infiltrating lymphocytesand significantly correlated with lymph node metastasis (Sun et al. Lung Cancer 53(2): 143-51(2006)). The level of circulating soluble B7-H3 in NSCLC patients has also been associated withhigher tumor stage, tumor size, lymph node metastasis, and distant metastasis (Yamato er al., Br. J.

Cancer 101(10):1709-16 (2009)).

B7-H3 may also play an important role in T-cell-mediated antitumor responses in a contextdependent manner. For example, gastric cancer tumor cell expression of B7-H3 positively correlatedwith survival time, infiltration depth, and tissue type (Wu et al., World J. Gastroenterol. 12(3): 457-9(2006)). r, high expression of B7-H3 in atic tumor cells was associated with patiental after surgical resection and significantly correlated with the number of tumor-infiltratingCD8+ T-cells (Loos er al., BMC Cancer 9:463 (2009).

Antibody drug conjugates (ADC) represent a relatively new class of therapeutics comprisingan antibody conjugated to a cytotoxic drug via a chemical linker. The therapeutic concept of ADCs isto combine binding capabilities of an antibody with a drug, where the antibody is used to deliver thedrug to a tumor cell by means of binding to a target surface antigen, including target e nsthat are overexpressed in the tumor cells.

MEl 24985843V.1 2117813-12620There remains a need in the art for anti-B7-H3 antibodies and anti-B7-H3 ADCs that can beused for therapeutic purposes in the treatment of cancer.

SUMMARY OF THE INVENTIONIn certain aspects, the t invention provides for antibodies and antibody drug conjugates(ADCs) that specifically bind to human B7-H3. In certain aspects, the present invention providesnovel ADCs that can ively deliver Bcl-XL inhibitors to target cancer cells, e.g., B7-H3expressing cells.

In one aspect, the present invention provides an antoi-B7-H3 antibody, or n bindingportion thereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or antigen bindingportion thereof, comprises a heavy chain variable region comprising a CDR3 having the amino acidsequence of SEQ ID NO: 12 and a light chain variable region comprising a CDR3 having the aminoacid sequence of SEQ ID NO: 15.

In one embodiment, the anti-B7-H3 antibody, or antigen binding portion f, comprises aheavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 140and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:In one embodiment, the anti-B7-H3 antibody, or antigen binding portion thereof, comprises aheavy chain le region sing a CDRl having the amino acid sequence of SEQ ID NO: 10and a light chain variable region comprising a CDRl having the amino acid sequence of either SEQID NO: 136 or 138.

In one aspect, the present ion provides an anti- B7-H3 antibody, or antigen gportion thereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or antigen bindingn thereof, comprises a heavy chain variable region comprising a CDR3 having the amino acidsequence of SEQ ID NO: 35 and a light chain variable region comprising a CDR3 having the aminoacid sequence of SEQ ID NO: 39.

In one embodiment, the anti-B7-H3 antibody, or antigen binding portion thereof, comprises aheavy chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO: 34,and a light chain variable region comprising a CDR2 having the amino acid sequence of SEQ ID NO:38.

In one embodiment, the anti-B7-H3 antibody, or antigen binding portion thereof, comprises aheavy chain variable region sing a CDRl having the amino acid ce of SEQ ID NO: 33and a light chain variable region sing a CDRl having the amino acid ce of either SEQID NO: 37.

In one embodiment, the anti-B7-H3 antibody, or antigen binding n thereof, is an IgGisotype.

MEl 24985843V.1 3117813-12620In one embodiment, the anti-B7-H3 antibody, or antigen binding n thereof, is an IgGlor an IgG4 isotype.

In one embodiment, the anti-B7-H3 antibody, or antigen binding n thereof, has a KD of1.5 X 10'8 or less as determined by surface plasmon resonance.

In one aspect, the present invention provides an anti-B7-H3 antibody, or antigen-bindingportion thereof, that binds to hB7-H3, said dy, or n-binding portion thereof, comprisingeither (i) a heavy chain variable region comprising a CDR set of SEQ ID NOs: 10, 11, and 12, and alight chain le region comprising a CDR set of SEQ ID NOs: 14, 7, and 15, or (ii) a heavy chainvariable region comprising a CDR set of SEQ ID NOs: 33, 34, and 35, and a light chain variableregion comprising a CDR set of SEQ ID NOs: 37, 38, and 39.

In one aspect, the present invention provides an anti-B7-H3 antibodythat binds to human B7-H3 (hB7-H3), wherein the dy comprises a heavy chain variable region sing a CDR3having the amino acid ce of SEQ ID NO: 12 and a light chain variable region comprising aCDR3 having the amino acid sequence of SEQ ID NO: 15.

In one embodiment, the anti-B7-H3 antibody comprises a heavy chain variable regioncomprising a CDR2 having the amino acid sequence of SEQ ID NO: 140 and a light chain variableregion comprising a CDR2 having the amino acid sequence of SEQ ID NO: 7.

In one embodiment, the anti-B7-H3 antibody comprises a heavy chain variable regioncomprising a CDR1 having the amino acid sequence of SEQ ID NO: 10 and a light chain variableregion comprising a CDR1 having the amino acid ce of either SEQ ID NO: 136 or 138.

In one aspect, the present invention provides an anti- B7-H3 dy that binds to humanB7-H3 (hB7-H3), wherein the antibody, or antigen binding n thereof, comprises a heavy chainvariable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a lightchain variable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

In one embodiment, the anti-B7-H3 antibody comprises a heavy chain variable regioncomprising a CDR2 having the amino acid sequence of SEQ ID NO: 34, and a light chain variableregion comprising a CDR2 having the amino acid sequence of SEQ ID NO: 38.

In one embodiment, the anti-B7-H3 antibody comprises a heavy chain variable regioncomprising a CDR1 having the amino acid sequence of SEQ ID NO: 33 and a light chain variableregion comprising a CDR1 having the amino acid sequence of either SEQ ID NO: 37.

In one ment, the anti-B7-H3 antibody is an IgG isotype.

In one embodiment, the anti-B7-H3 antibody is an IgGl or an IgG4 isotype.

In one embodiment, the anti-B7-H3 antibody has a KD of 1.5 X 10'8 or less as determined bysurface plasmon resonance.

In one aspect, the present invention provides an anti-B7-H3 antibody that binds to hB7-H3,said antibody comprising either (i) a heavy chain variable region sing a CDR set of SEQ IDNOs: 10, 11, and 12, and a light chain variable region comprising a CDR set of SEQ ID NOs: 14, 7,MEl 24985843V.1 4117813-12620and 15, or (ii) a heavy chain variable region comprising a CDR set of SEQ ID NOs: 33, 34, and 35,and a light chain variable region comprising a CDR set of SEQ ID NOs: 37, 38, and 39.

In one embodiment, the anti-B7-H3 antibody, or antigen binding portion thereof, ishumanized.

In one embodiment, the anti-B7-H3 dy, or antigen binding portion thereof, furthercomprises a human acceptor framework. In one ment, the human acceptor frameworkcomprises an amino acid sequence selected from the group ting of SEQ ID Nos: 155,156, 164,165, 166, and 167. In one embodiment, the human acceptor framework comprises at least oneframework region amino acid substitution. In one embodiment, the amino acid ce of theframework is at least 65% identical to the sequence of said human acceptor framework and comprisesat least 70 amino acid residues cal to said human acceptor framework.

In one ment, the human acceptor framework comprises at least one framework regionamino acid substitution at a key residue, said key e selected from the group ting of aresidue adjacent to a CDR; a glycosylation site residue; a rare residue; a residue e of interactingwith human B7-H3; a residue capable of interacting with a CDR; a canonical e; a contacte between heavy chain variable region and light chain variable region; a residue within aVernier zone; and a residue in a region that overlaps between a Chothia-defined variable heavy chainCDR1 and a Kabat-defined first heavy chain framework. In one embodiment, the key residue isselected from the group ting of 48H, 67H, 69H, 71H, 73H, 94H, and 2L. In one embodiment,the key residue substitution is in the variable heavy chain region and is selected from the groupconsisting of M48I, V67A, I69L, A71V, K73R, and R94G. In one embodiment, the key residuesubstitution is in the variable light chain region and is I2V.

In one aspect, the present invention provides an anti-B7-H3 antibody, or antigen-bindingportion thereof, that binds to hB7-H3 comprising a heavy chain variable region comprising a CDR setof SEQ ID NOs: 25, 26, and 27, and a light chain variable region comprising a CDR set of SEQ IDNOs: 29, 30, and 31. In one embodiment, the anti-B7-H3 antibody, or antigen binding portionthereof, is humanized. In one embodiment, the anti-B7-H3 antibody, or antigen binding portionf, further comprises a human acceptor framework.

In one embodiment, the human acceptor framework comprises an amino acid ceselected from the group consisting of SEQ ID NOs: 155 to 158. In one embodiment, the humanacceptor framework comprises at least one framework region amino acid substitution. In oneembodiment, the amino acid sequence of the framework is at least 65% identical to the sequence ofsaid human acceptor framework and comprises at least 70 amino acid residues identical to said humanacceptor framework. In one embodiment, the amino acid sequence of the framework is at least85% cal, 90% identical, 95% identical, 96% identical, 97% identical, 98% cal, or99% identical to the sequence of the human acceptor framework and comprises at least 70, atMEl 24985843V.1 5117813-12620least 75, at least 80, or at least 85 amino acid residues identical to the human acceptorIn one embodiment, the human acceptor framework comprises at least one framework regionamino acid substitution at a key residue, said key residue selected from the group consisting of: aresidue adjacent to a CDR; a glycosylation site residue; a rare residue; a residue capable of interactingwith human B7-H3; a residue capable of interacting with a CDR; a canonical residue; a contactresidue n heavy chain variable region and light chain variable region; a residue within aVernier zone; and a residue in a region that overlaps between a Chothia-defined variable heavy chainCDRl and a Kabat-defined first heavy chain framework. In one embodiment, the key residue isselected from the group ting of 69H, 46L, 47L, 64L, and 71L. In one ment, the keyresidue substitution is in the variable heavy chain region and is L691. In one embodiment, the keyresidue substitution is in the le light chain region and is selected from the group consisting ofL46P, L47W, G64V, and F7lH.

In one aspect, the present invention provides an anti-hB7-H3 antibody, or antigen-bindingportion thereof, sing a heavy chain CDRl comprising an amino acid sequence as set forth inSEQ ID NO: 10, a heavy chain CDR2 comprising an amino acid sequence as set forth in SEQ ID NO:140, a heavy chain CDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 12, a lightchain CDRl comprising an amino acid sequence as set forth in SEQ ID NO: 136 or 138, a light chainCDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 7, and a light chain CDR3comprising an amino acid sequence as set forth in SEQ ID NO: 15.

In another aspect, the present invention provides an anti-hB7-H3 antibody, or antigen-bindingn f, comprising a heavy chain CDRl comprising an amino acid sequence as set forth inSEQ ID NO: 33, a heavy chain CDR2 sing an amino acid sequence as set forth in SEQ ID NO:34, a heavy chain CDR3 comprising an amino acid ce as set forth in SEQ ID NO: 35, a lightchain CDRl comprising an amino acid sequence as set forth in SEQ ID NO: 37, a light chain CDR2comprising an amino acid sequence as set forth in SEQ ID NO: 38, and a light chain CDR3comprising an amino acid sequence as set forth in SEQ ID NO: 39.

In one embodiment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, sesa heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 139 and alight chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 135.

In one embodiment, the anti-hB7-H3 antibody, or n-binding portion thereof, comprisesa heavy chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 139, and/or a light chain comprising an amino acid sequence having at least90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 135.

MEl 24985843V.1 6117813-12620In one embodiment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, comprisesa heavy chain variable domain sing an amino acid sequence set forth in SEQ ID NO: 139 and alight chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 137.

In one ment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, comprisesa heavy chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 139, and/or a light chain comprising an amino acid sequence having at least90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 137.

In one embodiment, the B7-H3 antibody, or antigen-binding portion thereof, comprisesa heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 147 and alight chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 144.

In one embodiment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, comprisesa heavy chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 147, and/or a light chain sing an amino acid sequence having at least90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 144.

In one aspect, the present invention provides an anti-hB7-H3 antibody comprising a heavychain CDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 10, a heavy chain CDR2sing an amino acid ce as set forth in SEQ ID NO: 140, a heavy chain CDR3 comprisingan amino acid sequence as set forth in SEQ ID NO: 12, a light chain CDR1 comprising an amino acidsequence as set forth in SEQ ID NO: 136 or 138, a light chain CDR2 comprising an amino acidsequence as set forth in SEQ ID NO: 7, and a light chain CDR3 comprising an amino acid sequenceas set forth in SEQ ID NO: 15.

In another aspect, the present invention provides an anti-hB7-H3 antibody comprising a heavychain CDR1 comprising an amino acid ce as set forth in SEQ ID NO: 33, a heavy chain CDR2sing an amino acid ce as set forth in SEQ ID NO: 34, a heavy chain CDR3 singan amino acid sequence as set forth in SEQ ID NO: 35, a light chain CDR1 comprising an amino acidsequence as set forth in SEQ ID NO: 37, a light chain CDR2 comprising an amino acid sequence asset forth in SEQ ID NO: 38, and a light chain CDR3 comprising an amino acid sequence as set forthin SEQ ID NO: 39.

In one embodiment, the anti-hB7-H3 antibody comprises a heavy chain variable domaincomprising an amino acid sequence set forth in SEQ ID NO: 139 and a light chain variable domaincomprising an amino acid sequence set forth in SEQ ID NO: 135.

In one embodiment, the anti-hB7-H3 antibody ses a heavy chain comprising an aminoacid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 139, and/ora light chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 135.

MEl 24985843V.1 7117813-12620In one ment, the anti-hB7-H3 antibody comprises a heavy chain variable domaincomprising an amino acid sequence set forth in SEQ ID NO: 139 and a light chain variable domaincomprising an amino acid ce set forth in SEQ ID NO: 137.

In one embodiment, the anti-hB7-H3 antibody ses a heavy chain comprising an aminoacid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 139, and/ora light chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 137.

In one embodiment, the anti-hB7-H3 antibody comprises a heavy chain variable domaincomprising an amino acid sequence set forth in SEQ ID NO: 147 and a light chain variable domaincomprising an amino acid sequence set forth in SEQ ID NO: 144.

In one ment, the anti-hB7-H3 antibody comprises a heavy chain sing an aminoacid ce having at least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 147, and/ora light chain comprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 144.

In one embodiment, the anti-hB7-H3 antibody, or antigen-binding n thereof, comprisesa heavy chain CDR set corresponding to antibody huAb13v1, and a light chain CDR setcorresponding to dy v1. In one embodiment, the anti-hB7-H3 antibody, or n-binding portion f, comprises a heavy chain variable region corresponding to antibodyhuAb13v1, and a light chain variable region corresponding to antibody huAb13v1.

In one embodiment, the anti-hB7-H3 antibody, or antigen-binding n thereof, comprisesa heavy chain CDR set corresponding to antibody huAb3v2.5, and a light chain CDR setcorresponding to antibody huAb3v2.5. In one embodiment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, comprises a heavy chain variable region corresponding to antibodyhuAb3v2.5, and a light chain variable region corresponding to antibody huAb3v2.5.

In one embodiment, the dy, or antigen binding portion thereof, binds cynomolgus B7-In one embodiment, the antibody, or antigen binding portion thereof, has a dissociationconstant (KD) to hB7-H3 selected from the group consisting of: at most about 10'7 M; at most about'8 M; at most about 10'9 M; at most about 10'10 M; at most about 10'11 M; at most about 10'12 M; andat most 10'13 M.

In one embodiment, the antibody, or antigen binding portion thereof, comprises a heavy chainimmunoglobulin constant domain of a human IgM constant domain, a human IgG1 constant domain,a human IgG2 constant domain, a human IgG3 constant domain, a human IgG4 constant domain, ahuman IgA constant domain, or a human IgE constant domain.

In one embodiment, the antibody is an IgG having four polypeptide chains which are twoheavy chains and two light .

MEl 24985843V.1 8-12620In one embodiment, the antibody, or antigen-binding portion thereof, comprises the heavychain globulin constant region domain is a human IgG1 constant domain. In oneembodiment, the human IgG1 constant domain comprises an amino acid sequence of SEQ ID NO:159 or SEQ ID NO: 160.

In one aspect, the present invention provides an ed antibody, or antigen g portionthereof, that binds to human B7-H3 3), wherein the antibody, or antigen binding portionthereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 168 and a lightchain comprising the amino acid ce of SEQ ID NO: 169.

In one aspect, the present invention provides an isolated antibody, or antigen binding portionthereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or antigen g portionthereof, comprises a heavy chain comprising the amino acid ce of SEQ ID NO: 170 and a lightchain comprising the amino acid sequence of SEQ ID NO: 171.

In one , the present invention provides an isolated antibody, or antigen binding nthereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or n binding portionthereof, comprises a heavy chain comprising the amino acid sequence of SEQ ID NO: 172 and a lightchain comprising the amino acid sequence of SEQ ID NO: 173.

In one embodiment, the antibody, or antigen binding portion thereof, further comprises a lightchain immunoglobulin constant domain comprising a human Ig kappa constant domain or a human Iglambda constant domain.

In one embodiment, the anti-hB7-H3 antibody, or antigen-binding portion thereof, competeswith the antibody, or antigen binding portion thereof, of any one of the anti-hB7-H3 antibodies, orantigen-binding portions thereof, disclosed herein.

In one aspect, the present invention provides a pharmaceutical ition comprising theanti-hB7-H3 antibody, or antigen binding n thereof, as disclosed , and a ceuticallyacceptable carrier.

In another , the present invention provides an anti-hB7-H3 Antibody Drug Conjugate(ADC) comprising an anti-hB7-H3 antibody disclosed herein conjugated to a drug via a linker. In oneembodiment, the drug is an auristatin or a pyrrolobenzodiazepine (PBD). In one embodiment, thedrug is a Bcl-XL inhibitor.

In one aspect, the present invention provides an anti-hB7-H3 antibody drug conjugate (ADC)comprising a drug linked to an anti-human B7-H3 (hB7-H3) antibody by way of a linker, wherein thedrug is a Bcl-XL inhibitor according to structural formula (11a), (11b), (11c), or (IId):MEl 24985843V.1 9-12620(Ila)(11b)(IIC)(11d)wherein:MEI 24985843V.1 10117813-1262033 N\N/ Z,and and is optionally substituted with one or more substituents independentlyselected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C1,4alkoxy, amino, cyano andhalomethyl;copdqqrmAr2 is selected from -wE1,11 gm {EH} g;|\ g/N/W N/N/fi //\N\N 9V”: NW”; 15/91mm ""m and I or an e thereof, and isoptionally substituted with one or more substituents independently selected from halo, hydroxy, nitro,lower alkyl, lower heteroalkyl, C1,4alkoxy, amino, cyano and thyl, wherein the Rlz-ZZb-, R’-2213-, #-N(R4)-R13-ZZb-, or #-R’-ZZb- substituents are attached to Ar2 at any Ar2 atom capable of beingsubstituted; Z1 is selected from N, CH, C-halo, C-CH3 and C—CN; 223 and 22b are each , independentlyfrom one another, ed from a bond, NR6, CRGaRéb, O, S, S(O), S(O)2, -NR6C(O)-,-NR63C(O)NR6b-, and O)O-;ls alvxflpaxf or $Xfipaym§ wherein #, where attached to R’, is attachedto R’ at any R’ atom capable of being substituted; X’ is selected at each occurrence from -N(R10)--N(R10)C(O)-, -N(R10)S(O)2-, -S(O)2N(R10)-, and -O-; n is selected from 0-3; R10 is independentlyselected at each occurrence from hydrogen, lower alkyl, heterocycle, aminoalkyl, G-alkyl, and-(CH2)2-O-(CH2)2-O-(CH2)2-NH2; G at each occurrence is independently selected from a polyol, apolyethylene glycol with between 4 and 30 repeating units, a salt and a moiety that is charged atphysiological pH; SPa is independently ed at each occurrence from oxygen, N(H)-,-N(H)S(O)2-, -N(H)C(O)-, -C(O)N(H) -, -N(H)- and optionally substituted, arylene, heterocyclene,ene; wherein methylene is optionally substituted with one or more of -NH(CH2)2G, NHZ, C1,MEl 24985843V.l 11117813-12620, and carbonyl; m2 is selected from 0-12; R1 is selected from hydrogen, methyl, halo,thyl, ethyl, and cyano; R2 is selected from hydrogen, methyl, halo, halomethyl and cyano; R3 isselected from hydrogen, methyl, ethyl, halomethyl and haloethyl; R4 is selected from hydrogen, loweralkyl and lower alkyl or is taken together with an atom of R13 to form a cycloalkyl orcyclyl ring having between 3 and 7 ring atoms; R6, R6a and R61) are each, independent from oneanother, selected from hydrogen, optionally substituted lower alkyl, optionally substituted lowerheteroalkyl, optionally substituted cycloalkyl and optionally substituted heterocyclyl, or are takentogether with an atom from R4 and an atom from R13 to form a lkyl or heterocyclyl ring havingbetween 3 and 7 ring atoms; R“a and R11b are each, ndently of one another, selected fromhydrogen, halo, methyl, ethyl, thyl, hydroxyl, methoxy, CN, and SCH3; R12 is optionally R’ oris selected from en, halo, cyano, optionally substituted alkyl, optionally substituted alkyl,optionally substituted heterocyclyl, and optionally substituted cycloalkyl; R13 is selected fromoptionally substituted CH; alkylene, optionally tuted heteroalkylene, optionally substitutedheterocyclene, and optionally substituted cycloalkylene; and # represents a point of attachment to alinker; and wherein the anti-hB7-H3 antibody binds to B7-H3 (SEQ ID NO: 149) with a dissociationconstant (Kd) of about 1 X 10'6 M or less. In a further embodiment, the antibody comprises a heavychain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 147 and a lightchain variable domain comprising the amino acid sequence set forth in SEQ ID NO: 144; binds to B7-H3 (SEQ ID NO: 149) with a dissociation constant (Kd) of about 1 X 10'6 M or less, as determined bysurface plasmon resonance; and/or ts tumor growth in an in viva human small-cell lungcarcinoma (SCLC) xenograft assay with a tumor growth inhibition % (TGI%) of at least about 50%relative to a human IgG antibody which is not specific for B7-H3, wherein the human IgG antibody isadministered in the SCLC xenograft assay at the same dose and frequency as the anti-hB7-H3antibody.

In one embodiment, the ADC is a compound according to structural formula (I):(I) ( D—L—LKfiAbwherein D is the Bcl-XL inhibitor drug of a (11a), (11b), (11c) or (IId); L is the linker; Abis the anti-hB7-H3 antibody; LK represents a covalent linkage linking the linker (L) to the anti-hB7-H3 dy (Ab); and m is an integer ranging from 1 to 20.

In one embodiment, G at each ence is a salt or a moiety that is charged at physiologicalpH.

In one embodiment, G at each occurrence is a salt of a carboxylate, a sulfonate, aphosphonate, or ammonium.

MEl 24985843V.l 12117813-12620In one ment, G at each occurrence is a moiety that is charged at physiological pHselected from the group consisting of carboxylate, a sulfonate, a phosphonate, and an amine.

In one ment, G at each occurrence is a moiety ning a polyethylene glycol withbetween 4 and 30 repeating units, or a polyol.

In one embodiment, the polyol is a sugar.

In one embodiment, the ADC is of the formula (IIa) or formula (11d), and R’ es at leastone substitutable nitrogen suitable for attachment to a linker.

In one embodiment, G is selected at each occurrence from:OH OHOH OHO o HO OH HO OHEOMfiom,)L/|:O I. OH /CH3oH ,20 ,zoo,0 (EH3OM IPI N\CH /N\CHit/|M\OM El/IH 3'31 I 3 /|N\H N I:OH E0 Hs CH3 H ,7’1/ ,X0”ifri3 5C L”OHi5. OH ,andwll ,wherein M is hydrogen or a positively charged counterion.

In one embodiment, R’ is selected from ENNWONOQKOH' # O E OH/\/N\/\S”:O.91 [i] \\S,/O 'zfi/V| km W\ \/(}S\\O OHOH HO OOH, 54? OHEL/VN HO OH NJ:OH 51am OHOH OH HOMEl 24985843V.l 13117813-12620W“NUf1 WWNSOO HO OH \\ ,OH# OHo 0 #IO #EL /\/N\/\/OP\OH 5"; OHCH3 NHzl/VNW Q0 ui/VNWQOE/OH §:OH OE/VOV\N/\/\Ig,,OHO # OHif HO OHCH3 NH O $71/\/N\/\O OH‘1 OH K/oWu“# 00 CH3 OH5H N/#N QEN HN O /\/N OHO OH HO O OMEI 24985843V.1 14117813-12620H HN’# OHOH ,8:/\/NW8, 0 /\/N\¢\O /\/H OHa ‘5 a w Wo # o5E HO\S//O:0PH ,#S\ # H HN ON CFO N 0EN \/\N/\/ \/\g/OHQ N'z‘Z/\/N\/\)J\OH EN WOH# H o O‘CH3I o‘31/\/ (\OH ENNwN/V/SboN HI HO HOOH # OHOH 0 o0“ 3NNHO OHOH OH5HO\ ”O N\#H O g IO \N —\—N“ENN\/\l}l/\)J\OH 8 §—\_N/\/\M/# 7:# JM \5 5 #5J/o o So o o S S S [O oo o o ' OHL [I HO OHHN o oo o/H N\me N N/# EWfifiNMEI 24985843V.1 15117813-12620HO OHOH OHN O# ‘N| \ //N N \#wHO OHi 0H—/—N OH\ “Lil/\/ MOI-IE # OH5HO OH#\H OH OHN OHH WAKE/Km“?l”E OH OH OH #5O\/? N CH\S\/\/#\N/ CH OH3 O |39% VL OH /\/N[ll H OH 1L1 WOHM # OH5 50 OHOO0 0 HO OHOH 1*”EA/N OHHO OH ENNWO OOH O,andiii Oo/OEdi/NWS/the ADCs of a (IIb) or (110) or the point of attachment in the Bel-XL inhibitor drug of the ADCsof formula (Ila) or (11d) to a linker L.

MEl 24985843V.l 16117813-12620N N\ / \ /In one embodiment, Ar1 is selected from<—:—> and and is optionallysubstituted with one or more substituents independently selected from halo, cyano, methyl, andhalomethyl.

In one embodiment, Ar1 is {—2—}.

In one embodiment, Ar2 is substituted with one or more, optionallysubstituents.ad 91,rim,In one embodiment, Ar2 is ed from w(or; /” I“\ “/T ;\ x G9 CON \:s sW ,W 5m, 5% 5m|| N’CN/WNme" Kit-w and ”1% ; and is optionally tuted with one or more tuents.

In one embodiment, Ar2 is substituted with one or more solubilizing groups.

In one embodiment, each solubilizing group is, independently of the others, selected from amoiety containing a polyol, a polyethylene glycol with between 4 and 30 repeating units, a salt, or amoiety that is charged at physiological pH.

In one embodiment, Ar2 is substituted with one or more solubilizing groups.

In one ment, each solubilizing group is, independently of the others, ed from amoiety containing a polyol, a polyethylene glycol with n 4 and 30 repeating units, a salt, or amoiety that is charged at physiological pH.

In one embodiment, Z1 is N.

In one embodiment, Z2a is O.

In one embodiment, R1 is methyl or chloro.

In one embodiment, R2 is hydrogen or methyl.

MEl 24985843V.l 17117813-12620In one embodiment, R2 is hydrogen.

In one embodiment, 22b is O.

In one ment, 22b is NH or CH2.

In one embodiment, the ADC is a compound according to structural formula (IIa).

In one embodiment, the ADC is a compound according to structural formula (IIa) whichincludes a core selected from ures (C. l)-(C.21):(C.l)MEl 24985843V.1 18-12620MEI 24985843V.1 19-12620(C.8)(C.10)(C.11)MEI 24985843V.1 20-12620(C.12)(C.13)(C.14)(C.15)MEI 24985843V.1 21-12620(C.16)MW 0XV/ N N\ OH/ 0};(017) Hi 0 \N 8 "'3C(C.18)N N\ OH\/ o}?(C.19) "i 0 \N/ S H3C6 CH3MEI 24985843V.1 22-12620HN ,NN 8 "'3C(C21) H)N\ ,NN / S H3C6 CH3In one embodiment, the ADC is a compound according to structural formula (Hal):(Hal)wherein Y is optionally substituted C1-C8 alkylene; r is 0 or 1; and s is l, 2 or 3.

In one embodiment, the ADC is a compound according to structural formula (IIa.2):MEl 24985843V.l 23117813-12620wherein U is selected from N, O and CH, with the proviso that when U is 0, then Va and R21aare ; R20 is selected from H and C1-C4 alkyl; R21a and R21b are each, independently from oneanother, absent or ed from H, C1-C4 alkyl and G, where G is selected from a polyol, PEG4-30, asalt and a moiety that is charged at physiological pH; Va and Vb are each, independently from oner, absent or selected from a bond, and an optionally substituted alkylene; R20 is selected from Hand C1-C4 alkyl; and s is 1,2 or 3.

In one embodiment, the ADC is a compound according to structural formula (IIa.3):12/22b OOH (,3N\ R2‘Ija (”Rb/ \ 1 sN—T—N\#HN o \ /(IIa.3)wherein Rb is selected from H, C1-C4 alkyl and Jb-G or is optionally taken er with ana and Jbatom of T to form a ring haVing between 3 and 7 atoms; J are each, independently from oneanother, selected from optionally substituted C1-C8 alkylene and optionally substituted phenylene; T isselected from optionally tuted C1-C8 alkylene, CHZCHZOCHZCHZOCHZCHZ,CH2CHZOCH2CHZOCH2CHZOCH2 and a polyethylene glycol containing from 4 to 10 ethylene glycolunits; G is selected from a polyol, 0, a salt and a moiety that is charged at physiological pH;ands is l, Zor 3.

In one embodiment, the ADC is a compound according to structural formula (IIb).

In one ment, the ADC is a compound according to structural formula (11b. 1):G\‘7: a22b 0N 2 1’ ‘\ R\ 2<\/O>Y\ IR4 a/ \Z1 r N‘#HN o \ IR’I’lb1)wherein Y is optionally substituted C1-C8 alkylene; G is selected from a polyol, PEG4-30, asalt and a moiety that is charged at physiological pH; r is 0 or 1; and s is l, 2 or 3.

In one embodiment, the ADC is a compound according to structural formula (IIc).

MEl 24985843V.l 24117813-12620In one embodiment, the ADC is a compound ing to structural formula (IIc. l):(IIc. 1)wherein Ya is optionally substituted C1-C8 alkylene; Yb is optionally substituted C1-C8alkylene; R23 is selected from H and C1-C4 alkyl; and G is selected from a polyol, PEG4-30, a salt anda moiety that is charged at physiological pH.

In one ment, the ADC is a compound according to structural formula (IIc.2):\ r‘xN‘Yla/Z\2b O# 9 OH ‘YbR2 /2a/\/N\ ’R23z1 YHN X \N/ ‘\,_-R25(IIc.2)wherein Ya is ally substituted C1-C8 alkylene; Yb is optionally substituted C1-C8alkylene;YC is optionally substituted C1-C8 alkylene; R23 is selected from H and C1-C4 alkyl; R25 isYb-G or is taken together with an atom of YC to form a ring haVing 4-6 ring atoms; and G is selectedfrom a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH.

In one embodiment, the Bcl-XL inhibitor is selected from the group consisting of thefollowing compounds modified in that the hydrogen corresponding to the # position of structuralformula (11a), (11b), (11c), or (IId) is not present forming a monoradical:1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-[l-({3-[2-({2-[2-(carboxymethoxy)ethoxy]ethyl } amino)ethoxy] -5 ,7-dimethyltricyclo[3.3. l . ec- l -yl } methyl)methyl-lH-pyrazolyl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-{ l- [(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]—5-methyl-lH-pyrazolyl inecarboxylic acid;MEl 24985843V.l 25117813-126202-{ [(2-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carb0xypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl thyl] amino } ethyl)sulfonyl] amino } dcoxy-D-gluc0pyranosc;1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1 { 2-[(4-{ [(3R,4R,SS ,6R)-3 ,4,5-trihydr0xy(hydr0xymcthy1)tctrahydr0-2H-pyrany1]mcthy1 } benzyl)amino] cthoxy } 10[3.3. 1.13,7]dccyl)mcthyl]—5-mcthyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(3-su1f0pr0pyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2,3-dihydroxypropyl)amino] cthoxy } -5 ,7-dimcthyltricyc10 [3 . 3. 1 . 13’7] dccy1)methyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;2-({ [4-({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } methyl)phcnyl] sulfonyl } amin0)dcoxy-bcta-D-g1uc0pyranosc;8-(1,3 -bcnz0thiaz01y1carbam0y1) { 6-carb0xy [1 -( { 3- [2-( { 2- [1 -D-glucopyranuronosyl)-1H-1,2,3-triaz01yl]cthyl}amino)cth0xy]-5,7-dimcthyltricyc10[3.3.1.13’7]dcc-1-y1 }mcthyl)-5 -mcthy1-1H-pyraz01yl]pyridinyl}-1 ,2,3,4-tctrahydr0isoquinolinc;3-[1-({ 3-[2-(2-{ [4-(bcta-D-allopyranosyloxy)bcnzyl] amino}cth0xy)cth0xy] -5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}mcthyl)mcthyl-1H-pyraz01y1]—6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-dimcthy1(2-{2-[(2-sulfocthyl)amin0]cthoxy}cthoxy)tricyc10[3.3.1.13’7]dccyl]mcthyl}mcthy1-1H-pyraz01y1)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1 { phosph0nocthyl)amin0]cthoxy}tricyc10[3.3. 1.13’7]dccyl)mcthyl]-5 -mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthyl{2-[methy1(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthy1]—5-mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthyl{2-[(3-phosph0n0pr0py1)amin0]cthoxy}tricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthyl-1H-1y1 }pyridinccarb0xylic acid;MEI 24985843V.1 26117813-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-dimcthyl(2- { 2- [(3-phosph0n0pr0pyl)amino] cthoxy } cthoxy)tricyc10[3 . 3. 1 . 13’7]dcc-1 -yl] methyl } methyl- 1 H-pyraz01yl)pyridinccarboxylic acid;3-{ 1-[(3-{2-[L-alpha-aspartyl(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl] mcthy1-1H-pyraz01y1 } [8-(1 ,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;6-{4-[({2-[2-(2-aminocthoxy)cthoxy]ethyl} [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl]amin0)mcthyl]bcnzyl}-2,6-anhydr0-L-c acid;4-({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbam0yl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-ypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } methyl)phcnyl hcxopyranosiduronic acid;6-[ 1 -(1 z0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3,5-dimcthy1-(2-phosph0nocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01yl inccarb0xylic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3,5-dimcthy1-7-{2-[mcthyl(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 ,3]thiaz010[5 ,4-b]pyridinylcarbam0yl)-3 ydr0isoquin01in-2( 1 H) -yl]pyridine-z-carboxylic acid;3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 ,3]thiaz010[4,5-b]pyridinylcarbam0yl)-3 ,4-dihydr0isoquin01in-2( 1 H) -yl]pyridine-z-carboxylic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 -tctrahydr0quin01iny1] { 1-[(3,5-dimcthy1-7-{2-[(2-sulfocthyl)amino]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1 { 2-[(3 -phosph0n0pr0pyl)(pipcridinyl)amino]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;3-{ 1-[(3-{2-[D-a1pha-asparty1(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3. 1 -. 13’7]dcc- 1y1)mcthyl] mcthy1-1H-pyraz01y1 } [8-(1 ,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;MEI 24985843V.1 27117813-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [1-(carboxymcthyl)pipcridinyl]amino } cthoxy)-5 ,7-dimcthyltricyc10[3.3. 1 . ccyl] methyl } methyl- 1 H-pyraz01yl)pyridinccarboxylic acid;N-[(SS)amin0{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3. 1 . ccy1 } oxy)cthyl] (methyl)amino } 0X0hcxyl] -N,N-dimcthylmcthanaminium;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 5-y1{2-[pipcridinyl(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-5 -(3-phosph0n0pr0poxy)-3 ,4-dihydr0isoquin01in-2(1H)-y1]—3-[1-({3,5-dimcthy1[2-(mcthylamin0)cth0xy]tricyc10[3.3.1.13’7]dccyl}mcthyl)methyl- 1 H-pyraz01yl]pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [N-(2-carboxycthyl)-L-alpha-aspartyl] amino } cthoxy)-5 cthyltricyc10[3 . 3. 1 . 13’7]dccyl] methyl } methyl- 1 H-pyraz01yl)pyridinccarboxylic acid;3-{ 1-[(3-{2-[(2-aminocthyl)(2-sulfocthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dcc-1-y1)mcthyl]mcthy1-1H-pyraz01y1} [8-(1 z0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;6-[5-(2-aminocthoxy)(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-[1-({3,5-dimcthy1[2-(mcthy1amin0)cth0xy]tricyc10[3.3.1.13’7]dccy1}mcthyl)mcthyl-1H-pyraz01yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3,5-dimcthyl { 2-[(3-sulfopropyl)amino]cth0xy }tricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl)(pipcridinyl)amin0]cthoxy} -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(3-su1f0-L-alanyl)(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[ { 2-[(2-carboxycthyl)amin0]cthyl}(2-sulfocthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl] hy1-1H-pyraz01y1 }pyridinccarb0xylic acid;3-{ 1-[(3,5-dimcthy1{2-[(3-phosph0n0pr0pyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;MEI 24985843V.1 28117813-126203-{1-[(3,5-dimcthy1{2-[(3-phosph0n0pr0pyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[8-([1,3]thiaz010[5,4-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;1,3-bcnz0thiazolylcarbamoyl)-5 -(carb0xymcth0xy)-3,4-dihydr0isoquin01in-2(1H)-y1][1-({3,5-dimcthy1[2-(mcthylamin0)cth0xy]tricyc10[3.3.1.13’7]dccyl}mcthyl)mcthyl-1H-1yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-carboxypropyl)(pipcridinyl)amino] cthoxy } -5 ,7-dimcthyltricyc10 [3 . 3. 1 -. 13 ’7] dccyl)methyl] -5methyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3,5-dimcthyl { 2-[(2-thyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;3-{ 1-[(3-{2-[L-alpha-aspartyl(2-sulfocthyl)amin0]cthoxy} -5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{2-[(1,3-dihydroxypropan-z-yl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[5-(2-aminocthoxy)(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-{ 1-[(3,5-dimcthy1{2-[methy1(2-su1focthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl){2-[(2-sulfocthyl)amino]cth0xy}-3,4-dihydroisoquinolin-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{ 2-[mcthy1(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl){2-[(2-sulfocthyl)amin0]ethyl}amin0]cth0xy}tricyclo[3.3.1.13’7]dccy1)mcthyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;1,3-bcnz0thiazolylcarbamoyl){2-[(2-carb0xycthyl)amin0]cthoxy}-3,4-dihydroisoquinolin-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{ hy1(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;3-{ 1-[(3,5-dimcthy1 { 2-[(3-phosph0n0pr0pyl)(pipcridinyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01yl}[8-([1 ,3]thiaz010[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]pyridine-Z-carboxylicacid;MEI 24985843V.1 29117813-126201,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0-2H-1,4-bcnz0xazinyl]—3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyclo[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-5 -(3-su1f0pr0p0xy)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-[1-({3,5-dimcthy1[2-(mcthy1amin0)cth0xy]tricyc10[3.3.1.13’7]dccy1}mcthyl)mcthyl-1H-pyraz01yl]pyridine-Z-carboxylic acid;3-{ 5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl}[1-([1,3]thiaz010[4,5-b]pyridinylcarbam0yl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 az010[4,5-b]pyridinylcarbamoyl)naphthalcnyl]pyridine-2-carb0xylic acid;(1§)({2-[5-(1-{ [3-(2-aminocthoxy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthy1}methyl-1H-pyraz01yl)carb0xypyridinyl] ( 1 ,3-bcnz0thiaz01ylcarbam0y1)- 1 2,3,4-tctrahydroisoquinolin-S-yl }mcthy1)- 1 ,5 -anhydr0-D-glucit01;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-carboxypropyl)amin0]cth0xy} -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccy1)mcthyl]—5-mcthyl-lH-pyrazol-4-y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3,5-dimcthyl { 2-[(3-phosphonopropyl)amin0]cthoxy}tricyc10[3.3.1. 13’7]dcc-1 -y1)mcthyl] -5 -mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [4-(bcta-D-glucopyranosyloxy)bcnzyl] amino } )-5 ,7-dimcthyltricyc10[3.3. 1 -. 13’7]dccyl]mcthy1 }-mcthyl- 1 H-pyraz01yl)pyridinccarb0xylic acid;3-(1-{ [3 -(2-{ [4-(bcta-D-a110pyran0syloxy)benzyl] amino}cth0xy)-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl]mcthy1}mcthy1-1H-pyraz01y1)[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;3-{ 1-[(3-{2-[azctidiny1(2-su1focthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl] hy1-1H-pyraz01y1 } [8-(1 ,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;3-{ 1 -[(3-{2-[(3-amin0pr0pyl)(2-sulfocthy1)amin0]cthoxy } -5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3- { 2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;MEI 24985843V.1 3O117813-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(N6,N6-dimcthy1-L-lysyl)(mcthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]-1H-pyraz01yl }pyridinccarb0xylic acid;3-{ 1-[(3-{2-[(3-amin0pr0pyl)(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[1-(1,3-bcnz0thiaz01ylcarbamoyl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;3-{ 1-[(3-{2-[azctidiny1(mcthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3. ]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[1-(1,3-bcnz0thiaz01ylcarbamoyl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;N6-(37-0X0-2,5,8,11,14,17,20,23,26,29,32,35-d0dccaOXahcptatriacontanyl)-L-lysyl-N-[2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carb0xypyridin-3-y1}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1]—L-alaninamidc;methyl 6- [4-(3-{ [2-( { 3- [(4- { 6- [8 -(1,3 -bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]—5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl]amin0}pr0pyl)-1H-1,2,3-triazoly1]—6-dcoxy-bcta-L-glucopyranosidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3- { 2-[(2-ycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[5-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[4-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[5-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3-{2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[1-(1,3-bcnz0thiazolylcarbamoyl)-5,6-dihydr0imidaz0[1,5-a]pyrazin-7(8H)-yl]{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 inccarb0xylic acid;8-(1,3 -bcnz0thiaz01y1carbam0y1) { 6-carb0xy [1 -( { 3- [2-( { 3- [1 -(bcta-D-glucopyranuronosyl)-1H-1,2,3-triaz01yl]pr0pyl}amino)cth0xy]—5,7-dimcthyltricyc10[3.3.1.13’7]dcc-1-y1 }mcthyl)-5 -mcthy1-1H-pyraz01yl]pyridinyl}-1 -tctrahydr0isoquinolinc;MEI 24985843V.1 3 1117813-126206-[7-(1 ,3-bcnz0thiazolylcarbamoyl)-1H-ind01yl] { 1-[(3,5-dimcthy1 { 2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridincylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)[3-(mcthylamin0)pr0pyl]-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amino]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]--mcthyl-1H-pyraz01yl }pyridinccarb0xylic acid;-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } -5 -dcoxy-D-arabinit01;1-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } -1 ,2-didcoxy-D-arabino-hcxitol;6-[4-(1 ,3-bcnz0thiazolylcarbam0y1)isoquin01inyl]{ 1-[(3,5-dimcthyl { 2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [3-hydroxy(hydr0xymcthyl)pr0pyl]amino } cthoxy)-5 cthyltricyc10[3 . 3. 1 -. 13 ’7]dcc-1 -yl] methyl }-mcthyl- 1 H-pyraz01yl)pyridinccarb0xylic acid;1-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } -1 ,2-didcoxy-D-crythr0-pcntit01;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-y1(2-{ S)-2,3,4-trihydr0xybutyl]amino}cth0xy)tricyc10[3.3.1.13’7]dccyl]mcthyl}methyl- 1 H-pyraz01yl)pyridinccarboxylic acid;6-[8 -( 1 ,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-y1] (1 -{ [3-(2-{[(2S,3S,4R,5R,6R)-2,3,4,5,6,7-hcxahydr0xyhcptyl] amino}cth0xy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthyl}-5 -mcthy1- 1H-pyraz01y1)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[({ 3-[(1,3-dihydr0xypr0panyl)amin0]pr0pyl } sulfonyl)amino]cthoxy} -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-{ [1 ,3-dihydr0xy(hydroxymcthyl)propan-z-yl]amino } 0X0pr0pyl)amin0]cthoxy} -5 ,7-dimcthyltricyc10[3.3. ]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl](1-{ [3-(2-{ [(35)-hydr0xybutyl]amino}cthoxy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthyl}mcthy1-1H—pyraz01yl)pyridinccarb0xylic acid;MEI 24985843V.1 32117813-126204-({ [2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—2-carboxypyridinyl}methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl }oxy)ethyl] amino } methyl)phenyl beta-D-glucopyranosiduronic acid;3-{ [2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl }oxy)ethyl]amino }propyl beta-D-glucopyranosiduronic acid;6-[4-(1 ,3-benzothiazolylcarbamoyl)oxidoisoquinolinyl] [l -( { 3 ,5 -dimethyl [2-(methylamino)ethoxy] tricyclo[3 . 3. l . 13’7] dec-l -yl } methyl)methyl- 1 H-pyrazolyl]pyridinecarboxylic acid;6-{ 8-[(l ,3-benzothiazolyl)carbamoyl] -3,4-dihydroisoquinolin-2(lH)-yl } { l-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]acetamido}tricyclo[3.3. l.13’7]decan-l-yl)methyl]—5-methyl-lH-pyrazolyl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3 ,5-yl({2-[(2-sulfoethyl)amino]ethyl}sulfanyl)tricyclo[3.3.l.13’7]dec-l-yl]methyl}methyl-azolyl)pyridinecarboxylic acid; and6-{ 8-[(l zothiazolyl)carbamoyl] -3,4-dihydroisoquinolin-2(lH)-yl } { l- [(3,5-dimethyl { 3-[(2-sulfoethyl)amino]propyl}tricyclo[3.3. l . 13’7]decan-l -yl)methyl]—5-methyl- 1H-pyrazolyl }pyridinecarboxylic acid.

In one embodiment, the linker is cleavable by a lysosomal enzyme. In one embodiment, thelysosomal enzyme is Cathepsin B.

In one ment, the linker comprises a segment according to ural formula (IVa),(IVb), (IVc), or (IVd):MEl 24985843V.l 33117813-126200/n%:\O/\I\/\T@\O an?a o/ lnmv/=\OE U>W_ /21%:me >N_I Ex I> majflfixz mm 259381o O 02I \/¢¥ NZ_21%_58/__\F/z\ASE 95: 82V 90>:TymfiwmwflumMun—2117813-12620wherein peptide represents a peptide (illustrated N—>C, wherein peptide includes the aminoand carboxy “termini”) a cleavable by a lysosomal enzyme; T represents a polymer sing one ormore ne glycol units or an alkylene chain, or combinations thereof;Ra is selected from en, C16 alkyl, SO3H and CHZSO3H; Ry is hydrogen or C14 alkyl-(O)r-(C1,4 alkylene)S-G1 or C14 alkyl-(N)-[(C1,4 ne)-G1]2; RZ is C14 alkyl-(O)r-(C1,4 alkylene)S-G2;G1 is SO3H, COZH, PEG 4-32, or sugar moiety; G2 is SO3H, COZH, or PEG 4-32 moiety; r is 0 or 1; sis 0 or 1; p is an integer ranging from 0 to 5; ‘3q is 0 or 1; X is 0 or 1; y is 0 or 1; represents the pointof attachment of the linker to the Bcl-XL inhibitor; and * represents the point of attachment to theremainder of the linker.

In one embodiment, the peptide is selected from the group consisting of Val-Cit; Cit-Val;Ala-Ala; t; Cit-Ala; Asn-Cit; n; Cit-Cit; Val-Glu; l; Ser-Cit; Cit-Ser; Lys-Cit;Cit-Lys; t; Cit-Asp; Ala-Val; Val-Ala; Phe-Lys; Lys-Phe; Val-Lys; Lys-Val; Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu-Cit; Cit-Leu; Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; p; and Trp-Cit.

In one embodiment, the lysosomal enzyme is B-glucuronidase or B-galactosidase.

In one embodiment, the linker comprises a segment according to structural formula (Va),(Vb), (Vc), (Vd), or (Ve):jalko //CIDH OHO/’I,I, \\\\OH(Vb) O (3j‘filko /MEl 24985843V.l 3 5117813-12620>41 X0 /OH OH020,], ““0H0 OA o /&0 /OH OHwherein q is 0 0r 1; r is 0 0r 1; X1 is CH2, 0 or NH; ‘9! ents the point of attachment ofthe linker t0 the drug; and * represents the point of attachment to the remainder of the linker.

MEI 24985843V.1 36-12620In one embodiment, the linker comprises a segment according to ural formula (VIIIa),(VIIIb), or ):/ RqfivOMo(VIIIa) (hydrolyzed form)(hydrolyzed form)(VIIIb)““4 oO O H02c\/\/\fooN f HNo N ON_>\._*(VIIIc) RW RW (hydrolyzed form)or a yzed tive thereof, wherein: Rq is H or —O-(CH2CH20)11-CH3; X is 0 or 1; y is0 or 1; G3 is —CH2CH2CHZSO3H or —CH2CHZO-(CH2CH20)11-CH3; RW is —O-CH2CHZSO3H or —NH(CO)-CH2CHZO-(CH2CH20)12-CH3; * represents the point of attachment to the remainder of thelinker; and 9’; represents the point of attachment of the linker to the antibody.

In one embodiment, the linker comprises a polyethylene glycol segment haVing from 1 to 6ethylene glycol units.

In one embodiment, m is 2, 3 or 4.

In one embodiment, linker L is selected from IVa or IVb.

In one embodiment, linker L is selected from the group consisting of IVa.l-IVa.8, IVb. l-IVb.l9, IVc.l-IVc.7, IVd.l-IVd.4, Va.l-Va.12, Vb.l-Vb.10, Vc.l-Vc.ll, Vd.l-Vd.6, Ve.l-Ve.2,VIa.l, VIc. l-Vlc.2, VId.l-VId.4, VIIa.l-VIIa.4, VIIb. l-VIIb.8, VIIc.l-VIIc.6 in either the closed oropen form.

In one embodiment, the linker L is ed from the group consisting of IVb.2, IVc.5, IVc.6,IVc.7, IVd.4, Vb.9, VIIa.l, VIIa.3, , VIIc.4, and VIIc.5, wherein the maleimide of each linkerMEl 24985843V.l 37117813-12620has reacted with the antibody Ab, forming a covalent attachment as either a succinimide (closed form)or succinamide (open form).

In one ment, the linker L is selected from the group consisting of IVb.2, IVc.5, IVc.6,IVd.4, VIIa.l, VIIa.3, VIIc.l, VIIc.4, VIIc.5, wherein the maleimide of each linker has reacted withthe antibody Ab, g a covalent attachment as either a succinimide (closed form) or amide(open form).

In one embodiment, the linker L is selected from the group ting of IVb.2, VIIa.3, IVc.6,and VIIc.l, wherein 5‘1: is the attachment point to drug D and @ is the attachment point to the LK,wherein when the linker is in the open form as shown below, @ can be either at the a-position or [5-position of the carboxylic acid next to it:H2NYO””k KY”3 O\/©/ rat EDI/\jjé VIIa.3 (closed form)I OHZNYOHNK Q V021VHa.3 (open form)“fN ”t;@O O0:8; VIIc.1 (closed form)0 OHMEl 24985843V.l 3 8117813-1262022!: 11:1,], 0IVc.6 d form).5 ON :7p” NHIVc.6 (open form)OYNHZIVb.2 (closed form)MEI 24985843V.1 39117813-12620Oz—/{Z NI/_\ oH HW3N02$IZ NWfl<COZH0 @IVb.2 (open form)In one embodiment, LK is a e formed with an amino group on the anti-hB7H3 antibodyIn one embodiment, LK is an amide or a thiourea.

In one embodiment, LK is a linkage formed with a sulfhydryl group on the anti-hB7-H3antibody Ab.

In one ment, LK is a her.

In one embodiment, LK is selected from the group consisting of amide, thiourea andthioether; and m is an integer g from 1 to 8.

In one embodiment, D is a Bcl-XL inhibitor as bed herein; L is selected from the groupting of linkers IVa.l-IVa.8, IVb.l-IVb.l9, IVc.l-IVc.7, IVd.l-IVd.4, Va.l-Va.12, Vb.l-Vb.10,Vc.l-Vc.l l, Vd.l-Vd.6, Ve.l-Ve.2, VIa.l, VIc.l-Vlc.2, VId.4, VIIa.l-VIIa.4, VIIb.l-VIIb.8,and VIIc. l -VIIc.6, wherein each linker has reacted with the antibody, Ab, forming a covalentattachment; LK is thioether; and m is an integer g from 1 to 8.

In one embodiment, D is the Bcl-XL inhibitor selected from the group consisting of thefollowing nds modified in that the hydrogen corresponding to the # position of structuralformula (11a), (11b), (He), or (IId) is not present, forming a monoradical:6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-{ l-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]—5-methyl-lH-pyrazolyl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-{ l-[(3- { 2-[(2-carboxyethyl)amino]ethoxy} -5 ,7-dimethyltricyclo[3.3. l . 13’7] decyl)methyl] methyl- l H-pyrazol-4-yl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{ l-[(3,5-dimethyl { 2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]methyl-lH-pyrazolyl}pyridinecarboxylic acid;l-{ [2-({ 3 -[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—2-carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-lyl}oxy)ethyl] amino } -l ,2-dideoxy-D-arabino-hexitol;MEl 24985843V.l 4O117813-126206-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3-(2-{ [3-hydroxy(hydroxymethyl)propyl]amino } ethoxy)-5 ,7-dimethyltricyclo[3 . 3. l -. 13’7]dec-l -yl] methyl }-methyl-lH-pyrazolyl)pyridinecarboxylic acid; and1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]-3 -(l-{ [3 -(2-{ [(35)-3 ,4-dihydroxybutyl] amino } ethoxy)-5 ,7-dimethyltricyclo[3.3. l . 13’7] decyl]methyl } -5 -methyl- 1H-pyrazolyl)pyridinecarboxylic acid;L is selected from the group ting of linkers IVb.2, IVc.5, IVc.6, IVc.7, IVd.4, Vb.9,Vc. ll, VIIa.l, VIIa.3, VIIc.l, VIIc.4, and VIIc.5 in either closed or open forms;LK is thioether; andm is an r ranging from 2 to 4.

In one embodiment, the ADC is selected from the group consisting of formulae i-Vi:MEl 24985843V.l 41-1262024985843V.1-12620.95 66IO 2/.‘2 :0 2/,Zo o/ \ /z_ \_o Om mz_._4 JZ\I\z 2TymfiwmwflumMun—2-12620TymfiwmwflumMun—2117813-12620wherein m is an integer from 1 to 6. In one embodiment, Ab is an anti-hB7-H3 antibody,n the anti-hB7-H3 antibody comprises a heavy chain CDR3 domain comprising the amino acidce set forth in SEQ ID NO: 35, a heavy chain CDR2 domain comprising the amino acidsequence set forth in SEQ ID NO: 34, and a heavy chain CDR1 domain comprising the amino acidsequence set forth in SEQ ID NO: 33; and a light chain CDR3 domain sing the amino acidsequence set forth in SEQ ID NO: 39, a light chain CDR2 domain comprising the amino acidsequence set forth in SEQ ID NO: 38, and a light chain CDR1 domain comprising the amino acidsequence set forth in SEQ ID NO: 37. In one embodiment, the Ab is an anti-hB7-H3 antibody,wherein the anti-hB7H3 antibody comprises a heavy chain variable region sing the amino acidsequence set forth in SEQ ID NO: 147, and a light chain variable region comprising the amino acidsequence set forth in SEQ ID NO: 144. In one embodiment, Ab is an anti-hB7-H3 antibody, whereinthe B7-H3 dy ses a heavy chain constant region comprising the amino acidsequence set forth in SEQ ID NO: 160 and/or a light chain constant region comprising the amino acidsequence set forth in SEQ ID NO: 161. In one embodiment, Ab is an anti-hB7-H3 antibody, whereinthe anti-hB7-H3 dy comprises a heavy chain comprising the amino acid sequence set forth inSEQ ID NO: 168, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 169.

In one embodiment, Ab is an B7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136. In onement, the Ab is an anti-hB7-H3 antibody, wherein the anti-hB7H3 antibody comprises a heavychain variable region comprising the amino acid sequence set forth in SEQ ID NO: 139, and a lightchain le region sing the amino acid sequence set forth in SEQ ID NO: 135. In oneembodiment, Ab is an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavychain constant region comprising the amino acid sequence set forth in SEQ ID NO: 160 and/or a lightchain constant region comprising the amino acid sequence set forth in SEQ ID NO: 161. In oneembodiment, Ab is an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavychain comprising the amino acid sequence set forth in SEQ ID NO: 170, and a light chain comprisingthe amino acid sequence set forth in SEQ ID NO: 171.

In one embodiment, m is an integer from 2 to 6. In one embodiment, m is 2.

In one embodiment, the ADC comprises an anti-hB7-H3 antibody comprising a heavy chainCDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavy chain CDR2domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavy chain CDR1MEl 24985843V.1 45-12620domain comprising the amino acid sequence set forth in SEQ ID NO: 10; a light chain CDR3 domaincomprising the amino acid sequence set forth in SEQ ID NO: 15, a light chain CDR2 domaincomprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chain CDR1 domaincomprising the amino acid sequence set forth in SEQ ID NO: 136 or 138.

In one embodiment, the ADC comprises an antibody comprising a heavy chain variableregion comprising the amino acid sequence set forth in SEQ ID NO: 139, and a light chain variableregion comprising the amino acid ce set forth in SEQ ID NO: 135.

In one embodiment, the ADC comprises an the antibody comprising a heavy chain variableregion comprising the amino acid sequence set forth in SEQ ID NO: 139, and a light chain variableregion comprising the amino acid sequence set forth in SEQ ID NO: 137.

In one embodiment, the ADC comprises an antibody comprising a light chain CDR3 domaincomprising the amino acid sequence set forth in SEQ ID NO: 39, a light chain CDR2 domaincomprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chain CDR1 domaincomprising the amino acid sequence set forth in SEQ ID NO: 37; and a heavy chain CDR3 domaincomprising the amino acid sequence set forth in SEQ ID NO: 35, a heavy chain CDR2 domaincomprising the amino acid ce set forth in SEQ ID NO: 34, and a heavy chain CDR1 domaincomprising the amino acid sequence set forth in SEQ ID NO: 33.

In one embodiment, the ADC comprises an antibody comprising a heavy chain variableregion sing the amino acid ce set forth in SEQ ID NO: 147, and a light chain variableregion sing the amino acid sequence set forth in SEQ ID NO: 144.

In one embodiment, the ADC is selected from the group consisting of huAb3v2.5-CZ,huAb3v2.5-TX, huAb3v2.5-TV, huAb3v2.5-YY, huAb3v2.5-AAA, huAb3v2.5-AAD, huAb3v2.6-CZ, huAb3v2.6-TX, huAb3v2.6-TV, 2.6-YY, huAb3v2.6-AAD, huAb13v1-CZ, huAb13v1-TX, huAb13v1-TV, v1-YY, huAb13v1-AAA, huAb13v1-AAD, wherein CZ, TX, TV, YY,AAA, and AAD are synthons disclosed in Table B, and wherein the ated synthons are either inopen or closed form.

In one aspect, the present invention provides a ceutical composition comprising aneffective amount of an ADC described herein, and a pharmaceutically acceptable r.

In another aspect, the present invention provides a pharmaceutical composition comprising anADC mixture comprising a plurality of ADCs described herein, and a pharmaceutically acceptablecarrier.

In one embodiment, the ADC mixture has an average drug to antibody ratio (DAR) of 1.5 toIn one embodiment, the ADC mixture comprises ADCs each having a DAR of 1.5 to 8.

In one aspect, the present invention provides a method for treating cancer, comprisingadministering a therapeutically effective amount of an ADC described herein to a subject in needthereof.

MEl 24985843V.1 46117813-12620In one embodiment, the cancer is selected from the group consisting of small cell lungcancer, non small cell lung cancer, breast cancer, ovarian cancer, a glioblastoma, prostate cancer,pancreatic cancer, colon cancer, gastric , melanoma, hepatocellular carcinoma, head and neckcancer, kidney cancer, leukemia, e. g., acute myeloid leukemia (AML), and lymphoma, e. g., non-Hodgkin's lymphoma (NHL).

In one embodiment, the cancer is a squamous cell carcinoma. In one embodiment, thesquamous cell carcinoma is squamous lung cancer or us head and neck .

In one embodiment, the cancer is triple negative breast cancer.

In one embodiment, the cancer is non-small cell lung .

In one embodiment, the cancer is characterized as having an activating EGFR mutation. Inone embodiment, the activating EGFR mutation is selected from the group consisting of an exon 19deletion mutation, a single-point substitution mutation L858R in exon 21, a T790M point mutation,and combinations thereof.

In one aspect, the present invention provides a method for inhibiting or decreasing solidtumor growth in a subject having a solid tumor, said method comprising administering an effectiveamount of an ADC described herein to the subject having the solid tumor, such that the solid tumorgrowth is inhibited or decreased.

In one embodiment, the solid tumor is a all cell lung carcinoma.

In one embodiment, the ADC is stered in ation with an additional agent or anadditional therapy.

In one embodiment, the additional agent is selected from the group consisting of an anti-PDlantibody (e. g. pembrolizumab), an anti-PD-Ll antibody (e.g., izumab), an anti-CTLA-4antibody (e. g. ipilimumab), a MEK inhibitor (e. g. trametinib), an ERK inhibitor, a BRAF inhibitor(e. g. dabrafenib), osimertinib, erlotinib, gefitinib, sorafenib, a CDK9 inhibitor (e.g. dinaciclib), aMCL-l inhibitor, temozolomide, a Bcl-2 tor (6.g. venetoclax), a Bcl-XL inhibitor, ibrutinib, amTOR inhibitor (e.g. everolimus), a PI3K inhibitor (e.g. buparlisib), duvelisib, idelalisib, an AKTtor, a HER2 inhibitor (e. g. lapatinib), a taxane (e.g. xel, paclitaxel, nab-paclitaxel), anADC comprising an auristatin, an ADC comprising a PBD (e.g. rovalpituzumab tesirine), an ADCcomprising a maytansinoid (e. g. TDMl), a TRAIL agonist, a proteasome inhibitor (e. g. omib),and a nicotinamide oribosyltransferase (NAMPT) tor.

In one embodiment, the anti-B7-H3 ADCs of the invention are administered in ationwith venetoclax to a human subject for the treatment of small cell lung cancer (SCLC).

In one embodiment, the additional therapy is radiation.

In one embodiment, the additional agent is a chemotherapeutic agent.

MEl 24985843V.l 47117813-12620In one aspect, the present invention provides a process for the preparation of an ADCaccording to structural formula (I):(I) ( D—L—LKfiAbwherein:D is the Bcl-XL inhibitor drug of formula (11a), (11b), (11c), or (IId) as disclosed herein;L is the linker as disclosed herein;Ab is an hB7-H3 antibody, wherein the hB7-H3 antibody comprises the heavy and light chainCDRs of huAb3v2.5, huAb3v2.6, or huAb13v1;LK represents a covalent linkage linking linker L to antibody Ab; andm is an integer g from 1 to 20;the process comprising:treating an antibody in an aqueous solution with an ive amount of a disulfide reducingagent at 30-40 CC for at least 15 minutes, and then g the antibody solution to 20-27 C’C;adding to the reduced antibody solution a solution of dimethyl ide comprising asynthon selected from the group of 2.1 to 2.176 (Table B);adjusting the pH of the solution to a pH of 7.5 to 8.5;allowing the reaction to run for 48 to 80 hours to form the ADC;wherein the mass is shifted by 18 i 2 amu for each hydrolysis of a imide to asuccinamide as measured by on spray mass spectrometry; andwherein the ADC is optionally purified by hydrophobic interaction chromatography.

In one embodiment, m is 2.

In another aspect, the present invention provides an ADC prepared by the process asdescribed above.

BRIEF DESCRIPTION OF THE DRAWINGSFigure 1 is a graphical representation of the epitope grouping of murine anti-B7-H3hybridoma antibodies as determined by pair-wise g assays.

Figure 2 depicts an antibody ion, modification with a maleimide derivative to give athiosuccinimide intermediate, and subsequent hydrolysis of thiosuccinimide moietyFigure 3 depicts the structure of an antibody-maleimidocaproyl-vc-PABA-MMAE ADC.

Figure 4 s the structure of a PBD dimer (SGD-1882) ated to an antibody (Ab)via a maleimidocaproyl-valine-alanine linker (collectively referred to as SGD-1910).

MEl 24985843V.1 48117813-12620Figure 5 depicts the MS characterization of light chain and heavy chain of huAbl3vl 1) priorto conjugation, 2) after conjugation to a maleimide derivative to give a ccinimide intermediateand 3) post pH 8-mediated hydrolysis of the thiosuccinimide ring.

DETAILED DESCRIPTION OF THE INVENTIONs aspects of the invention relate to anti-B7-H3 antibodies and antibody fragments, anti-B7-H3 ADCs, and pharmaceutical compositions thereof, as well as nucleic acids, recombinantexpression s and host cells for making such antibodies and nts. Methods of using theantibodies, fragments, and ADCs described herein to detect human B7-H3, to t human B7-H3activity (in vitro or in viva), and to treat cancers are also assed by the invention. In certainments, the invention provides anti-B7-H3 ADCs, including ADCs comprising Bcl-xLinhibitors, synthons useful for sizing the ADCs, compositions comprising the ADCs, methodsof making the ADCs, and various methods of using the ADCs.

As will be appreciated by skilled artisans, the ADCs disclosed herein are “modular” in nature.

Throughout the instant disclosure, various specific ments of the various es” comprisingthe ADCs, as well as the ns useful for synthesizing the ADCs, are described. As specific non-ng examples, specific ments of antibodies, s, and Bcl-xL inhibitors that maycomprise the ADCs and synthons are described. It is intended that all of the specific embodimentsdescribed may be combined with each other as though each specific combination were explicitlydescribed individually.

It will also be appreciated by skilled artisans that the various ADCs and/or ADC synthonsdescribed herein may be in the form of salts, and in certain embodiments, particularlypharmaceutically acceptable salts. The compounds of the present disclosure that possess a sufficientlyacidic, a sufficiently basic, or both functional groups, can react with any of a number of inorganicbases, and inorganic and organic acids, to form a salt. Alternatively, compounds that are inherentlycharged, such as those with a quaternary nitrogen, can form a salt with an appropriate counterion, e.g.,a halide such as a bromide, chloride, or fluoride.

Acids commonly employed to form acid addition salts are inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, oric acid, and the like, andorganic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, ophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, etc. Base addition salts e those derivedfrom inorganic bases, such as ammonium and alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like.

In the disclosure below, if both structural diagrams and nomenclature are included and if thenomenclature conflicts with the structural diagram, the structural diagram controls.

An outline of the Detailed Description of the Invention is provided below:MEl 24985843V.l 49117813-12620I. DefinitionsII. Anti-B7-H3 AntibodiesII.A. Anti-B7-H3 Chimeric AntibodiesII.B. Humanized Anti-B7-H3 AntibodiesIII. Anti-B7-H3 Antibody Drug Conjugates (ADCs)III.A. Anti-B7-H3 / Bcl-xL Inhibitor ADCsIII.A.l. Bcl-xL InhibitorsIII.A.2 Bcl-xL LinkersCleavable LinkersNon-Cleavable LinkersGroups Used to Attach Linkers to Anti-B7-H3 AntibodiesLinker Selection ConsiderationsIII.A.3. Bcl-xL ADC SynthonsIII.A.4 Methods of sis of Bcl-xL ADCsIII.A.5. General Methods for Synthesizing Bcl-xL InhibitorsIII.A.6. General Methods for Synthesizing nsIII.A.7. General s for Synthesizing Anti-B7-H3 ADCsIII.B. Anti-B7-H3 ADCs: Other Exemplary Drugs for ConjugationIII.C. Anti-B7-H3 ADCs: Other Exemplary LinkersIV. Purification of Anti-B7-H3 ADCsV. Uses of Anti-B7-H3 Antibodies and 7-H3 ADCsVI. Pharmaceutical Compositions1. DefinitionsIn order that the invention may be more readily understood, n terms are first d. Inaddition, it should be noted that whenever a value or range of values of a parameter are recited, it isintended that values and ranges intermediate to the recited values are also intended to be part of thisinvention.

The term “anti-B7-H3 antibody” refers to an antibody that specifically binds to B7-H3. Anantibody “which binds” an antigen of interest, i.e., B7-H3, is one capable of g that antigen withsufficient affinity such that the antibody is useful in targeting a cell sing the antigen. In apreferred embodiment, the antibody specifically binds to human B7-H3 (hB7-H3). Examples of anti-B7-H3 antibodies are disclosed in the examples below. Unless otherwise indicated, the term “anti-B7-H3 dy” is meant to refer to an antibody which binds to wild type B7-H3 (e.g., a 4IgB7-H3isoform of B7-H3) or any variant of B7-H3. The amino acid sequence of wild type human B7-H3 isprovided below as SEQ ID NO: 149, where the signal peptide (amino acid residues 1-28) isunderlined.

MEl 24985843V.l 50117813-12620LQRQGSPGMGVIVGAAKGAKWECKIGAKfiVQVP£3?VVALVGTDATLCCSFSPVPGFSKAQKNK"WQLTDT{QLVHSFAEGQDQGSAYAWRTALF?DLLAQGWASLRLQQVQVADjGSEICEVS"QDEGSAAVSLQVAA?YSKPSMTLEPNKDLR?GDTVTITCSSYQGY?fiAfiVEWQDGQGV?LTGWVTTSQ ANEQGLFDV{SILQVVLGANGTYSCLVQN?VLQQDA{SSVT:T?Q?S?lGAVfiVQV?£3?VVAWVGTDATLQCSFSPVPGFSKAQKNK"WQKTDT{QLVISFTEGQDQGSAYAWRTALF?DLLAQGWASLRLQQVQVADEGSFTCFVSIQDFGSAAVSLQVAA?YS<?SMTLE?WKDLR?GDTVTITCSSYRGY?fiAfiVEWQDGQGV?LTGNVTTSQ ANEQGLFDVHSVLQVVLGANGTYSCLVQN?VLQQDAHGSVIulGQ?MlEP?jALWVIVGLSVCLIALLVALAFVCWRK KQSCfiflfiNAGAfiDQDGfiGfiGSKIALQ?LKHSDS{fiDDGQfi A (SfiQ DNO: 149)Thus, in one embodiment of the invention, the antibody or ADC binds human B7-H3 as defined inSEQ ID NO: 149. The ellular domain (ECD) of human B7-H3 is provided in SEQ ID NO: 152(inclusive of a His tag). As such, in one embodiment of the invention, the antibody of ADC binds theECD of human B7-H3 as described in the ECD of SEQ ID NO: 152.

The terms “specific binding” or “specifically binding”, as used herein, in reference to theinteraction of an antibody or an ADC with a second chemical species, mean that the interaction isdependent upon the presence of a particular structure (6. g., an antigenic determinant or epitope) on thechemical s; for example, an antibody recognizes and binds to a specific protein structure ratherthan to proteins generally. If an antibody or ADC is specific for epitope “A”, the presence of amolecule containing epitope A (or free, unlabeled A), in a reaction containing d “A” and theantibody, will reduce the amount of labeled A bound to the antibody or ADC. By way of example, anantibody "binds specifically" to a target if the antibody, when d, can be competed away from itstarget by the corresponding non-labeled antibody. In one embodiment, an antibody specifically bindsto a target, e.g., B7-H3, if the antibody has a KD for the target of at least about 10'4 M, 10'5 M, 10'6 M,10-7 M, 10'8 M, 10'9 M, 10'10 M, 10'11 M, 10'12 M, or less (less meaning a number that is less than 10'12, e. g. 1013). In one embodiment, the term “specific binding to B7-H3” or “specifically binds to B7-H3,” as used herein, refers to an antibody or an ADC that binds to B7-H3 and has a dissociationconstant (KD) of 1.0 x 10'7 M or less, as determined by surface plasmon resonance. It shall betood, however, that the antibody or ADC may be capable of specifically binding to two or morens which are related in sequence. For example, in one ment, an antibody can specificallybind to both human and a non-human (e.g., mouse or man primate) orthologs of B7-H3.

The term “antibody” refers to an immunoglobulin le that specifically binds to anantigen and comprises a heavy (H) chain(s) and a light (L chain(s). Each heavy chain is comprised ofa heavy chain variable region (abbreviated herein as HCVR or VH) and a heavy chain constantregion. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Eachlight chain is comprised of a light chain variable region viated herein as LCVR or VL) and alight chain constant region. The light chain constant region is comprised of one domain, CL. The VHand VL regions can be further subdivided into regions of ariability, termed complementarityining regions (CDR), interspersed with s that are more conserved, termed framework40 regions (FR). Each VH and VL is composed of three CDRs and four FRs, ed from amino-MEl 24985843V.l 5 1-12620terminus to y-terminus in the following order: FRI, CDRl, FR2, CDR2, FR3, CDR3, FR4. Anantibody can be of any type (e.g., IgG, IgE, IgM, IgD, IgA and IgY) and class (e.g., IgGl, IgG2, IgG3, IgG4, IgAl and IgA2) or subclass.

While the term ody” is not intended to include antigen binding portions of an antibody (definedbelow), it is intended, in certain embodiments, to e a small number of amino acid deletions fromthe carboxy end of the heavy s). In one embodiment, an dy comprises a heavy chainhaving l-5 amino acid deletions the carboxy end of the heavy chain. In one embodiment, an antibodyis a monoclonal antibody which is an IgG, having four polypeptide chains, two heavy (H) chains, andtwo light (L chains) that can bind to hB7-H3. In one embodiment, an antibody is a monoclonal IgGantibody comprising a lambda or a kappa light chain.

The term en binding portion” or “antigen binding fragment” of an antibody (or simply“antibody portion” or “antibody fragment”), as used herein, refers to one or more fragments of anantibody that retain the ability to specifically bind to an antigen (e.g., hB7-H3). It has been shownthat the antigen binding function of an antibody can be performed by fragments of a full-lengthantibody. Such antibody embodiments may also be bispecific, dual specific, or multi-specificformats; specifically binding to two or more different ns. Examples of binding fragmentsencompassed within the term “antigen binding portion” of an antibody e (i) a Fab fragment, amonovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, abivalent nt comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii)a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL andVH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 3412544-546, Winter et al., PCT publication WO 90/05144 Al herein incorporated by reference), whichcomprises a single variable domain; and (vi) an isolated complementarity determining region (CDR).rmore, although the two domains of the Fv nt, VL and VH, are coded for by separategenes, they can be joined, using recombinant methods, by a synthetic linker that enables them to bemade as a single protein chain in which the VL and VH regions pair to form lent molecules(known as single chain Fv (scFv); see e. g., Bird et al. (1988) Science 3-426; and Huston et al.(1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended tobe encompassed within the term “antigen binding portion” of an antibody. In certain ments ofthe invention, scFv les may be incorporated into a fusion protein. Other forms of single chainantibodies, such as diabodies are also encompassed. Diabodies are bivalent, bispecific antibodies inwhich VH and VL domains are expressed on a single polypeptide chain, but using a linker that is tooshort to allow for pairing between the two domains on the same chain, thereby forcing the domains topair with complementary domains of another chain and creating two antigen binding sites (see e. g.,Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, R.J., et al. (1994)MEI 24985843V.l 52117813-12620Structure 2:1121-1123). Such antibody binding portions are known in the art (Kontermann and Dubeleds., Antibody Engineering (2001) Springer-Verlag. New York. 790 pp. (ISBN 41354-5).

An IgG is a class of antibody comprising two heavy chains and two light chains arranged in aY-shape. An IgG constant domain refers to a heavy or light chain constant domain. Exemplaryhuman IgG heavy chain and light chain constant domain amino acid sequences are known in the artand represented below in Table A.

Table A: Se uences of human I G heav chain constant domains and li ht chain constant domainsProtein Sequence SequenceIdentifier<GPSVF9LAPSSKSTSGGTAALGCLVKDYIg gamma—l IOL—'"COED-<51WL—HTJD>4 AKm@10<'UU) mLLJH 9VTVSWWSGALTSGVHTFPAVLQSSGLYS constant region 'u‘<}m VVTV9SSSLGTQTY__CWVNH 9SWTKVDKU/U‘UUALLJ9KSCD<T 99C9API 9SVFLF9PDlT.M S9 LLVlCVVV 13PL'VKhWWDV_LViWA <99L' TVL2LWG<EY <VSW<AT._ L<l SKA<GT.99S9LL lKVQVSLTCLVKGFY1 L'SWGQ9EWWYKTT9PVLDSDGSFFD<S9WQQGWVFSCSVMiEALHNHYTA <GPSVF9LAPSS{STSGGTAALGCLVKDYIg gamma—l Fconstant 'U<}U)'UU) (DHH 9VTVSWWSGALTSGVHTFPAVLQSSGLYS region L VVTV9SSSLGTQTY..CWVNH< 9SWTKVDKK (DU/:J‘IUUALLJ9KSC D<THTC99C9AP_EAAGG9SVFLF9P mutantK DlTM S9lP. lCVVV KEWWY G)<1.LViWAKl L'.'QYWSlY9VVSVLTVLH WLWG<I <AT.9A9 L<l SKA<GQ EPQVY . '11 LTCLVKGFYP AVLW .3WWYKTT9PVLDSDGSFFL {LTV {SRWQQGWVFSCSVMiEALHNHYTQAF<m-u£>< SLSLS9G_ u __ LQLKSGTASVVCLLNWF22g Kappa : '_ I , 4:8Vl41QDSKJScons van o region I {HKVYACEVT {QGLSS:g Lambda : ; 9SVlLF)) :2. {ATLVCLIISDFconsvanv region ; 9GAVTVAW<A, <AGVETTTPS<QSNWLSLTPI {RSYSCQVLHLIGSLVZKTVAPTECSAn “isolated antibody”, as used herein, is intended to refer to an dy that is substantiallyfree of other dies having different antigenic specificities (e. g., an isolated antibody thatspecifically binds B7-H3 is substantially free of antibodies that specifically bind antigens other thanB7-H3). An isolated antibody that specifically binds B7-H3 may, however, have cross-reactivity toother antigens, such as B7-H3 molecules from other s. Moreover, an isolated antibody may besubstantially free of other cellular al and/or chemicals.

MEl 24985843V.l 53117813-12620The term “humanized antibody” refers to antibodies which comprise heavy and light chainvariable region sequences from a nonhuman species (e. g., a mouse) but in which at least a n ofthe VH and/or VL sequence has been altered to be more “human-like”, i.e., more similar to humangermline variable sequences. In particular, the term “humanized antibody” is an antibody or a variant,derivative, analog or fragment thereof which immunospecifically binds to an antigen of interest andwhich comprises a framework (FR) region having substantially the amino acid ce of a humanantibody and a complementary determining region (CDR) having substantially the amino acidsequence of a non-human antibody. As used herein, the term “substantially” in the context of a CDRrefers to a CDR having an amino acid sequence at least 80%, preferably at least 85%, at least 90%, atleast 95%, at least 98% or at least 99% identical to the amino acid sequence of a non-human antibodyCDR. A humanized antibody comprises substantially all of at least one, and typically two, variables (Fab, Fab', F(ab')2, FabC, Fv) in which all or ntially all of the CDR regions correspondto those of a non-human immunoglobulin (i.e., donor antibody) and all or substantially all of theframework regions are those of a human immunoglobulin consensus sequence. Preferably, ahumanized antibody also comprises at least a portion of an immunoglobulin constant region (Fc),typically that of a human immunoglobulin. In some embodiments, a humanized antibody containsboth the light chain as well as at least the variable domain of a heavy chain. The antibody also mayinclude the CH1, hinge, CH2, CH3, and CH4 regions of the heavy chain. In some embodiments, ahumanized antibody only contains a humanized light chain. In other embodiments, a humanizeddy only contains a humanized heavy chain. In specific embodiments, a humanized antibodyonly contains a humanized variable domain of a light chain and/or zed heavy chain.

The humanized antibody can be selected from any class of immunoglobulins, ing IgM,IgG, IgD, IgA and IgE, and any isotype, including t limitation IgGl, IgG2, IgG3 and IgG4. Thehumanized antibody may se ces from more than one class or isotype, and particularconstant s may be ed to optimize desired effector functions using techniques well-knownin the art.

The terms “Kabat numbering,” “Kabat definitions,” and “Kabat labeling” are usedinterchangeably herein. These terms, which are recognized in the art, refer to a system of numberingamino acid residues which are more variable (i.e., ariable) than other amino acid residues in theheavy and light chain variable regions of an antibody, or an antigen binding portion thereof (Kabat etal. (1971) Ann. NYAcad, Sci. 190:382-391 and, Kabat, E.A., et al. (1991) Sequences ofProteins oflogical Interest, Fifth Edition, US. Department of Health and Human es, NIHPublication No. 91-3242). For the heavy chain variable region, the hypervariable region ranges fromamino acid positions 31 to 35 for CDRl, amino acid positions 50 to 65 for CDR2, and amino acidpositions 95 to 102 for CDR3. For the light chain variable region, the hypervariable region rangesfrom amino acid positions 24 to 34 for CDRl, amino acid positions 50 to 56 for CDR2, and aminoacid positions 89 to 97 for CDR3.

MEl 24985843V.l 54117813-12620As used herein, the term “CDR” refers to the complementarity determining region withinantibody variable sequences. There are three CDRs in each of the variable regions of the heavy chain(HC) and the light chain (LC), which are designated CDRl, CDR2 and CDR3 (or ically HCCDRl, HC CDR2, HC CDR3, LC CDRl, LC CDR2, and LC CDR3), for each of the variable regions.

The term “CDR set” as used herein refers to a group of three CDRs that occur in a single variableregion capable of binding the antigen. The exact boundaries of these CDRs have been defineddifferently according to different systems. The system described by Kabat (Kabat et al., Sequences ofProteins of Immunological Interest (National utes of Health, Bethesda, Md. (1987) and (1991))not only provides an unambiguous residue numbering system applicable to any variable region of anantibody, but also provides precise residue boundaries defining the three CDRs. These CDRs may bereferred to as Kabat CDRs. a and ers (Chothia &Lesk, J. Mol. Biol. 1-917 (1987)and Chothia et al., Nature 342:877-883 (1989)) found that n sub- portions within Kabat CDRsadopt nearly identical e backbone mations, despite having great diversity at the level ofamino acid sequence. These sub-portions were designated as L1, L2 and L3 or H1, H2 and H3 wherethe “L” and the “H” designates the light chain and the heavy chains regions, respectively. Theseregions may be referred to as Chothia CDRs, which have boundaries that overlap with Kabat CDRs.

Other boundaries defining CDRs overlapping with the Kabat CDRs have been described by Padlan(FASEB J. 9:133-139 (1995)) and MacCallum (J. Mol. Biol. 262(5):732-45 (1996)). Still other CDRboundary definitions may not strictly follow one of the above s, but will nonetheless overlapwith the Kabat CDRs, although they may be ned or lengthened in light of prediction orexperimental findings that particular es or groups of residues or even entire CDRs do notsignificantly impact antigen binding. The methods used herein may utilize CDRs defined according toany of these systems, although red embodiments use Kabat or Chothia defined CDRs.

As used herein, the term “framework” or “framework ce” refers to the remainingsequences of a variable region minus the CDRs. Because the exact definition of a CDR sequence canbe determined by different systems, the g of a framework sequence is subject tocorrespondingly different interpretations. The six CDRs (CDR-Ll, CDR-L2, and CDR-L3 of lightchain and CDR-H1, CDR-H2, and CDR-H3 of heavy chain) also divide the framework regions on thelight chain and the heavy chain into four sub-regions (FRl, FR2, FR3 and FR4) on each chain, inwhich CDRl is positioned n FRl and FR2, CDR2 between FR2 and FR3, and CDR3 betweenFR3 and FR4. Without specifying the particular sub-regions as FRl, FR2, FR3 or FR4, a frameworkregion, as referred by others, represents the combined FR's within the variable region of a single,naturally occurring immunoglobulin chain. As used herein, a FR represents one of the four sub-regions, and FRs ents two or more of the four sub- regions constituting a framework region.

The framework and CDR regions of a humanized antibody need not correspond precisely tothe parental sequences, 6. g., the donor dy CDR or the consensus framework may bemutagenized by substitution, insertion and/or deletion of at least one amino acid residue so that theMEl 24985843V.l 5 5117813-12620CDR or framework e at that site does not correspond to either the donor antibody or theconsensus framework. In a preferred embodiment, such ons, however, will not be extensive.

Usually, at least 80%, preferably at least 85%, more preferably at least 90%, and most ably atleast 95% of the humanized antibody residues will correspond to those of the parental FR and CDR” refers to the framework region in thesequences. As used herein, the term “consensus frameworconsensus immunoglobulin sequence. As used herein, the term “consensus globulinsequence” refers to the sequence formed from the most frequently occurring amino acids (ornucleotides) in a family of related immunoglobulin ces (See e.g., er, From Genes toClones (Verlagsgesellschaft, Weinheim, Germany 1987). In a family of globulins, eachon in the sus sequence is occupied by the amino acid occurring most frequently at thatposition in the . If two amino acids occur equally frequently, either can be included in theconsensus sequence.

The term “human acceptor framework”, as used herein, is meant to refer to a ork of andy or antibody fragment thereof comprising the amino acid sequence of a VH or VL frameworkderived from a human antibody or antibody fragment thereof or a human consensus sequenceframework into which CDR's from a non-human species may be incorporated.

“Percent (%) amino acid sequence identity” with respect to a peptide or polypeptide sequenceis defined as the percentage of amino acid residues in a candidate sequence that are identical with theamino acid residues in the specific peptide or polypeptide sequence, after aligning the sequences andintroducing gaps, if necessary, to achieve the maximum percent sequence identity, and notconsidering any conservative substitutions as part of the sequence identity. Alignment for purposes ofdetermining percent amino acid sequence identity can be achieved in various ways that are within theskill in the art, for ce, using publicly available computer software such as BLAST, BLAST-2,ALIGN or Megalign AR) software. Those skilled in the art can ine appropriateparameters for measuring alignment, including any algorithms needed to achieve maximal alignmentover the full length of the sequences being compared. In one embodiment, the invention includes anamino acid sequence having at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, atleast 97%, at least 98%, or at least 99% identity to an amino acid ce set forth in any one ofSEQ ID NOs: l to 148.

The term “multivalent antibody” is used herein to denote an antibody comprising two or moreantigen binding sites. In certain embodiments, the multivalent antibody may be engineered to have thethree or more antigen binding sites, and is generally not a naturally occurring antibody.

The term “multispecific antibody” refers to an dy capable of binding two or moreunrelated antigens. In one embodiment, the multispecific antibody is a bispecific antibody that iscapable of binding to two unrelated antigens, e.g., a bispecific antibody, or antigen-binding portionthereof, that binds B7-H3 and CD3.

MEl 24985843V.l 56117813-12620The term “dual variable domain” or “DVD,” as used hangeably herein, are antigenbinding proteins that comprise two or more antigen binding sites and are tetravalent or multivalentg proteins. Such DVDs may be ecific, i.e., capable of g one antigen ormultispecific, Le. capable of binding two or more antigens. DVD binding proteins comprising twoheavy chain DVD polypeptides and two light chain DVD polypeptides are referred to a DVD Ig.

Each half of a DVD Ig comprises a heavy chain DVD polypeptide, and a light chain DVDpolypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variabledomain and a light chain variable domain with a total of 6 CDRs involved in antigen binding perantigen binding site. In one embodiment, the CDRs described herein are used in an anti-B7-H3 DVD.

The term "chimeric antigen receptor" or "CAR" refers to a recombinant protein comprising atleast (1) an antigen-binding region, e.g., a variable heavy or light chain of an antibody, (2) atransmembrane domain to anchor the CAR into a T cell, and (3) one or more intracellular signalingdomains.

The term “activity” includes activities such as the g specificity/affinity of an antibodyor ADC for an antigen, for example, an anti-hB7-H3 antibody that binds to an hB7-H3 antigen and/orthe neutralizing potency of an antibody, for example, an anti-hB7-H3 antibody whose binding to hB7-H3 inhibits the biological activity of hB7-H3, e. g., inhibition of proliferation of B7-H3 expressing celllines, e.g., human H146 lung carcinoma cells, human H1650 lung carcinoma cells, or human EBCllung carcinoma cells.

The term “non cell lung carcinoma (NSCLC) xenograft assay,” as used herein, refers toan in vivo assay used to determine whether an anti-B7-H3 antibody or ADC, can inhibit tumor growth(6. g., further ) and/or decrease tumor growth resulting from the transplantation of NSCLC cellsinto an immunodeficient mouse. An NSCLC xenograft assay includes transplantation of NSCLCcells into an immunodeficient mouse such that a tumor grows to a desired size, 6. g., 200-250 mm3,whereupon the antibody or ADC is administered to the mouse to determine r the antibody orADC can inhibit and/or decrease tumor growth. In certain embodiments, the activity of the antibodyor ADC is determined ing to the percent tumor growth inhibition (%TGI) relative to a controldy, 6. g., a human IgG antibody (or collection f) which does not specifically bind tumorcells, e.g., is ed to an antigen not associated with cancer or is obtained from a source which iscerous (e.g., normal human serum). In such embodiments, the antibody (or ADC) and thecontrol antibody are administered to the mouse at the same dose, with the same frequency, and via thesame route. In one embodiment, the mouse used in the NSCLC xenograft assay is a severe combineddeficiency (SCID) mouse and/or an athymic CD-l nude mouse. Examples of NSCLC cellsthat may be used in the NSCLC xenograft assay include, but are not limited to, H1299 cells (NCI-H1299 [H-1299] (ATCC® CRL-5803)), H1975 cells (NCI-H1975 cells ] (ATCC® CRL-5908TM)), and EBC-l cells.

MEl 24985843V.l 57117813-12620The term “small-cell lung carcinoma (SCLC) xenograft assay,” as used herein, refers to an invivo assay used to determine whether an anti-B7-H3 antibody or ADC, can inhibit tumor growth (e.g.,further growth) and/or se tumor growth resulting from the lantation of SCLC cells into animmunodeficient mouse. An SCLC xenograft assay includes transplantation of SCLC cells into andeficient mouse such that a tumor grows to a desired size, e.g., 200-250 mm3, whereupon theantibody or ADC is administered to the mouse to determine r the antibody or ADC can inhibitand/or decrease tumor growth. In certain embodiments, the activity of the antibody or ADC isined according to the t tumor growth inhibition (%TGI) relative to a control antibody,e.g., a human IgG antibody (or collection thereof) which does not specifically bind tumor cells, 6. g., isdirected to an n not ated with cancer or is obtained from a source which is noncancerous(e. g., normal human serum). In such embodiments, the antibody (or ADC) and the control antibodyare administered to the mouse at the same dose, with the same frequency, and via the same route. Inone embodiment, the mouse used in the NSCLC xenograft assay is a severe combinedimmunodeficiency (SCID) mouse and/or an athymic CD-l nude mouse. Examples of SCLC cells thatmay be used in the SCLC xenograft assay include, but are not limited to, H146 cells (NCI-Hl46 cells[H146] (ATCC® HTB-173TM)), and H847 cells (NCI-H847 [H847] (ATCC® CRL-5846TM)). Theterm “epitope” refers to a region of an antigen that is bound by an antibody or ADC. In certainembodiments, epitope determinants include chemically active surface groupings of les such asamino acids, sugar side chains, phosphoryl, or sulfonyl, and, in certain embodiments, may havespecific three dimensional structural characteristics, and/or specific charge teristics. In certainembodiments, an antibody is said to ically bind an antigen when it preferentially recognizes itstarget antigen in a complex mixture of proteins and/or macromolecules.

The term “surface plasmon resonance”, as used herein, refers to an optical phenomenon thatallows for the analysis of real-time biospecific interactions by detection of alterations in proteinconcentrations within a biosensor matrix, for e using the BIAcore system (PharmaciaBiosensor AB, Uppsala, Sweden and Piscataway, NJ). For further descriptions, see Jonsson, U., et al.(1993) Ann. Biol. Clin. 51:19-26; Jonsson, U., et al. (1991) Biotechniques 112620-627; Johnsson, B.,et al. (1995) J. Mol. Recognit. 8:125-131; and Johnnson, B., et al. (1991) Anal. Biochem. 198:268-277. In one embodiment, surface plasmon nce is determined according to the methodsdescribed in Example 2.

The term“ km,” or “ ka”, as used herein, is intended to refer to the on rate constant forassociation of an antibody to the antigen to form the antibody/antigen complex.

The term “koff” or “ kd”, as used herein, is intended to refer to the off rate constant foriation of an antibody from the antibody/antigen complex.

The term “KD”, as used herein, is intended to refer to the equilibrium dissociation constant ofa particular antibody-antigen interaction (e.g., huAbl3 dy and B7-H3). KD is calculated by ka/MEl 24985843v.l 5 8117813-12620The term “competitive binding”, as used herein, refers to a situation in which a first antibodycompetes with a second antibody, for a binding site on a third molecule, e.g., an antigen. In oneembodiment, competitive binding between two antibodies is determined using FACS analysis.

The term “competitive binding assay” is an assay used to determine whether two or moredies bind to the same epitope. In one ment, a itive binding assay is a competitionfluorescent activated cell sorting (FACS) assay which is used to determine whether two or moreantibodies bind to the same epitope by determining whether the fluorescent signal of a dantibody is reduced due to the introduction of a non-labeled antibody, where ition for the sameepitope will lower the level of fluorescence.

The term “labeled antibody” as used herein, refers to an antibody, or an antigen bindingportion thereof, with a label incorporated that provides for the identification of the binding protein,e.g., an antibody. Preferably, the label is a detectable marker, e.g., incorporation of a radiolabeledamino acid or attachment to a ptide of biotinyl moieties that can be detected by marked avidin(e. g., streptavidin containing a fluorescent marker or enzymatic ty that can be ed byoptical or colorimetric methods). Examples of labels for polypeptides include, but are not limited to,the following: radioisotopes or radionuclides (e.g., 3H, 14C, 35S, 90Y, 99Tc, 111In, 125I, 131I, 177Lu, 166Ho,or 153Sm); fluorescent labels (e.g., FITC, rhodamine, nide phosphors), enzymatic labels (6. g.,horseradish peroxidase, luciferase, alkaline phosphatase); chemiluminescent s; biotinylgroups; ermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipperpair sequences, binding sites for secondary antibodies, metal binding domains, epitope tags); andic agents, such as gadolinium chelates.

The term "antibody-drug-conjugate” or “ADC” refers to a binding protein, such as anantibody or antigen binding fragment thereof, chemically linked to one or more chemical drug(s) (alsoreferred to herein as agent(s), warhead(s), and payload(s)) that may ally be therapeutic orcytotoxic agents. In a preferred embodiment, an ADC includes an antibody, a drug, (6. g. a cytotoxicdrug), and a linker that enables attachment or conjugation of the drug to the dy. An ADCtypically has re from 1 to 8 drugs conjugated to the antibody, including drug loaded species of2, 4, 6, or 8. Non-limiting examples of drugs that may be ed in the ADCs are mitotic inhibitors,antitumor antibiotics, immunomodulating agents, vectors for gene therapy, alkylating agents,giogenic agents, antimetabolites, boron-containing agents, chemoprotective agents, hormones,antihormone agents, corticosteroids, photoactive therapeutic agents, oligonucleotides, radionuclideagents, topoisomerase inhibitors, kinase inhibitors (e.g., TEC-family kinase inhibitors andserine/threonine kinase inhibitors), and radiosensitizers. In one embodiment, the drug is a Bcl-xLThe terms “anti-B7-H3 antibody drug conjugate” or “anti-B7-H3 ADC”, usedinterchangeably herein, refer to an ADC comprising an dy that specifically binds to B7-H3,y the antibody is conjugated to one or more chemical agent(s). In one embodiment, the anti-MEl 24985843V.l 59117813-12620B7-H3 ADC comprises antibody vl, huAb3v2.5, or huAb3v2.6 conjugated to an auristatin,e.g., MMAE or MMAF. In one embodiment, the anti-B7-H3 ADC ses antibody huAbl3vl,huAb3v2.5, or huAb3v2.6 conjugated to a Bcl-xL inhibitor. In a preferred embodiment, the anti-B7-H3 ADC binds to human B7-H3 (hB7-H3).

The term “Bcl-xL inhibitor”, as used herein, refers to a compound which antagonizes Bcl-xLactivity in a cell. In one embodiment, a Bcl-xL inhibitor promotes sis of a cell by inhibitingBcl-xL activity.

The term “auristatin”, as used herein, refers to a family of antimitotic agents. Auristatinderivatives are also included within the definition of the term “auristatin”. Examples of auristatinsinclude, but are not limited to, auristatin E (AE), monomethylauristatin E (MMAE),monomethylauristatin F (MMAF), and synthetic analogs of dolastatin. In one embodiment, an anti-B7-H3 antibody bed herein is conjugated to an auristatin to form an anti-B7-H3 ADC.

As used herein, the term “Ab-chMAE” is used to refer to an ADC comprising an antibodyconjugated to monomethylauristatin E (MMAE) via a maleimidocaproyl valine citrulline p-aminobenzyloxycarbamyl (PABA) linker.

As used herein the term “mcMMAF” is used to refer to a linker/drug combination ofmaleimidocaproyl-monomethylauristatin F (MMAF).

The term “drug-to-antibody ratio” or “DAR” refers to the number of drugs, 6. g., Bcl-xLinhibitor, attached to the antibody of the ADC. The DAR of an ADC can range from 1 to 8, ghhigher loads, 6. g., 20, are also le depending on the number of linkage site on an antibody. Theterm DAR may be used in reference to the number of drugs loaded onto an individual antibody, or,alternatively, may be used in reference to the average or mean DAR of a group of ADCs.

The term ired ADC species”, as used herein, refers to any drug loaded species which isto be separated from an ADC species having a different drug load. In one embodiment, the termundesired ADC species may refer to drug loaded species of 6 or more, i.e., ADCs with a DAR of 6 ormore, including DAR6, DAR7, DAR8, and DAR greater than 8 (i.e., drug loaded species of 6, 7, 8, orgreater than 8). In a separate embodiment, the term undesired ADC species may refer to drug loadedspecies of 8 or more, i.e., ADCs with a DAR of 8 or more, including DAR8, and DAR r than 8(i.e., drug loaded s of 8, or greater than 8).

The term “ADC mixture”, as used , refers to a ition containing a heterogeneousDAR distribution of ADCs. In one ment, an ADC mixture ns ADCs having adistribution of DARs of l to 8, e.g., 1.5, 2, 4, 6, and 8 (i.e., drug loaded species of 2, 4, 6, and 8).

Notably, degradation products may result such that DARs of l, 3, 5, and 7 may also be included in themixture. Further, ADCs within the mixture may also have DARs greater than 8. The ADC mixtureresults from interchain disulfide reduction followed by conjugation. In one embodiment, the ADCmixture ses both ADCs with a DAR of 4 or less (i.e., a drug loaded species of 4 or less) andADCs with a DAR of 6 or more (i.e., a drug loaded species of 6 or more).

MEl 24985843V.l 6O117813-12620The term a “xenograft assay”, as used herein, refers to a human tumor xenograft assay,wherein human tumor cells are transplanted, either under the skin or into the organ type in which thetumor ated, into immunocompromised mice that do not reject human cells.

The term “cancer” is meant to refer to or describe the logical condition in sthat is typically characterized by unregulated cell growth. Examples of cancer include, but are notlimited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid malignancies. Moreparticular examples of such cancers include glioblastoma, acute myeloid leukemia (AML), non-Hodgkin's lymphoma (NHL), non-small cell lung cancer, lung , colon cancer, colorectal cancer,head and neck cancer, breast cancer (e. g., triple negative breast cancer), pancreatic , squamouscell tumors, squamous cell carcinoma (e. g., squamous cell lung cancer or squamous cell head andneck cancer), anal cancer, skin cancer, and vulvar cancer. In one embodiment, the dies orADCs of the invention are administered to a patient having a tumor(s) that overexpresses B7-H3. Inone embodiment, the antibodies or ADCs of the invention are administered to a t having a solidtumor which is likely to over-express B7-H3. In one embodiment, the antibodies or ADCs of theinvention are administered to a patient having squamous cell non-small cell lung cancer (NSCLC). Inone embodiment, the antibodies or ADCs of the invention are administered to a patient having solidtumors, including ed solid tumors. In one ment, the antibodies or ADCs of theinvention are administered to a patient having te cancer. In one embodiment, the antibodies orADCs of the invention are administered to a t having non-small cell lung cancer. In oneembodiment, the dies or ADCs of the invention are administered to a patient having aglioblastoma. In one embodiment, the antibodies or ADCs of the invention are administered to apatient having colon . In one embodiment, the antibodies or ADCs of the invention areadministered to a patient having head and neck cancer. In one embodiment, the antibodies or ADCsof the invention are administered to a patient having kidney cancer. In one embodiment, theantibodies or ADCs of the invention are administered to a patient having clear cell renal cellcarcinoma. In one embodiment, the antibodies or ADCs of the invention are administered to a thaving glioma. In one embodiment, the antibodies or ADCs of the invention are administered to apatient having melanoma. In one ment, the dies or ADCs of the invention areadministered to a patient having pancreatic cancer. In one embodiment, the dies or ADCs ofthe invention are administered to a patient having gastric cancer. In one embodiment, the antibodiesor ADCs of the invention are administered to a patient having ovarian cancer. In one embodiment,the dies or ADCs of the invention are administered to a patient having ctal cancer. In oneembodiment, the antibodies or ADCs of the invention are administered to a patient having renalcancer. In one embodiment, the antibodies or ADCs of the invention are administered to a thaving small cell lung cancer. In one embodiment, the antibodies or ADCs of the invention areadministered to a patient having hepatocellular carcinoma. In one embodiment, the antibodies orADCs of the invention are administered to a patient having hypopharyngeal squamous cell carcinoma.

MEl 24985843V.l 61117813-12620In one embodiment, the antibodies or ADCs of the invention are administered to a patient havingneuroblastoma. In one embodiment, the antibodies or ADCs of the invention are stered to apatient having breast cancer. In one embodiment, the dies or ADCs of the ion areadministered to a patient having endometrial cancer. In one embodiment, the antibodies or ADCs ofthe invention are administered to a patient having urothelial cell carcinoma. In one embodiment, theantibodies or ADCs of the invention are administered to a patient having acute myeloid leukemia(AML). In one embodiment, the antibodies or ADCs of the invention are administered to a patienthaving non-Hodgkin's lymphoma (NHL).

The term “B7-H3 expressing tumor,” as used herein, refers to a tumor which expresses B7-H3protein. In one embodiment, B7-H3 expression in a tumor is determined using histochemicalstaining of tumor cell membranes, where any immunohistochemical staining above ound levelin a tumor sample indicates that the tumor is a B7-H3 sing tumor. Methods for detectingexpression of B7-H3 in a tumor are known in the art, and include immunohistochemical assays. Inst, a “B7-H3 negative tumor” is defined as a tumor having an absence of B7-H3 membranestaining above background in a tumor sample as ined by immunohistochemical techniques.

The terms “overexpress,93 “overexpression,” or xpressed” interchangeably refer to agene that is transcribed or translated at a detectably greater level, usually in a cancer cell, incomparison to a normal cell. Overexpression therefore refers to both pression of protein andRNA (due to increased transcription, post transcriptional sing, translation, post translationalprocessing, altered stability, and altered protein degradation), as well as local overexpression due toaltered protein c patterns (increased nuclear localization), and augmented functional activity, 6. g.,as in an increased enzyme hydrolysis of substrate. Thus, overexpression refers to either n orRNA levels. Overexpression can also be by 50%, 60%, 70%, 80%, 90% or more in comparison to anormal cell or ison cell. In certain embodiments, the anti-B7-H3 dies or ADCs of theinvention are used to treat solid tumors likely to overexpress B7-H3.

The term “gene amplification”, as used herein, refers to a cellular process characterized by theproduction of multiple copies of any particular piece of DNA. For example, a tumor cell may amplify,or copy, somal segments as a result of cell signals and sometimes environmental events. Theprocess of gene amplification leads to the production of additional copies of the gene. In oneembodiment, the gene is B7-H3, i.e., “B7-H3 amplification.” In one embodiment, the compositionsand methods disclosed herein are used to treat a subject having B7-H3 amplified cancer.

The term “administering” as used herein is meant to refer to the delivery of a substance (6. g.,an anti-B7-H3 antibody or ADC) to achieve a therapeutic objective (e.g., the ent of a B7-H3-associated disorder). Modes of administration may be parenteral, enteral and topical. Parenteraladministration is usually by injection, and includes, without limitation, intravenous, intramuscular,intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,MEl 24985843V.l 62117813-12620transtracheal, subcutaneous, subcuticular, intraarticular, sular, subarachnoid, intraspinal andintrasternal injection and infusion.

The term “combination therapy” or “combination” in the context of a therapeutic method(e. g., a treatment method), as used herein, refers to the administration of two or more therapeuticsubstances, e.g., an anti-B7-H3 antibody or ADC and an additional therapeutic agent. The additionaltherapeutic agent may be administered concomitant with, prior to, or following the stration ofthe anti-B7-H3 antibody or ADC.

As used herein, the term “effective amount” or “therapeutically effective amount” refers tothe amount of a drug, e.g., an antibody or ADC, which is sufficient to reduce or ameliorate thety and/or duration of a disorder, e.g., cancer, or one or more symptoms thereof, prevent theadvancement of a disorder, cause regression of a disorder, prevent the recurrence, development, onsetor progression of one or more symptoms associated with a disorder, detect a disorder, or enhance orimprove the prophylactic or therapeutic effect(s) of r therapy (e.g., prophylactic or therapeuticagent). The effective amount of an antibody or ADC may, for example, inhibit tumor growth (6. g.,inhibit an increase in tumor volume), se tumor growth (e.g., decrease tumor volume), reducethe number of cancer cells, and/or relieve to some extent one or more of the symptoms associatedwith the cancer. The ive amount may, for example, improve disease free survival (DFS),e overall survival (OS), or decrease hood of recurrence.s chemical tuents are defined below. In some instances, the number of carbonatoms in a substituent (e.g., alkyl, alkanyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl, andaryl) is indicated by the prefix “CX-Cy” or “CH” wherein x is the minimum and y is the maximumnumber of carbon atoms. Thus, for e, “C1-C6 alkyl” refers to an alkyl ning from 1 to 6carbon atoms. Illustrating further, “C3-C8 cycloalkyl” means a saturated hydrocarbyl ring containingfrom 3 to 8 carbon ring atoms. If a substituent is bed as being “substituted,” a hydrogen atomon a carbon or nitrogen is replaced with a non-hydrogen group. For example, a substituted alkylsubstituent is an alkyl substituent in which at least one hydrogen atom on the alkyl is replaced with anon-hydrogen group. To illustrate, monofluoroalkyl is alkyl tuted with a fluoro radical, anddifluoroalkyl is alkyl tuted with two fluoro radicals. It should be recognized that if there is morethan one substitution on a substituent, each substitution may be identical or different (unless otherwisestated). If a substituent is described as being “optionally substituted”, the substituent may be either (1)not tuted or (2) substituted. le substituents include, but are not limited to, C1-C6 alkyl,C2-C6 alkenyl, C2-C6 alkynyl, aryl, cycloalkyl, heterocyclyl, aryl, halogen, C1-C6 haloalkyl, oxo,-CN, N02, -ORxa, -OC(O)R"Z, -OC(O)N(Rxa)2, -SRxa, -S(O)2Rxa, N(Rxa)2, -C(O)Rxa, -C(O)ORxa,-C(O)N(R"a)2, -C(O)N(R"a)S(O)2R"Z, -N(R"a)2, -N(R"a)C(O)R"Z, -N(R"a)S(O)2R"Z, -N(R"a)C(O)O(R"Z),-N(R"a)C(O)N(R"a)2, -N(R"a)S(O)2N(R"a)2, -(C1-C6 alkylenyl)-CN, -(C1-C6 alkylenyl)-OR"a, -(C1-C6alkylenyl)-OC(O)RXZ, -(C1-C6 alkylenyl)-OC(O)N(Rxa)2, -(C1-C6 alkylenyl)-SRxa, -(C1-C6alkylenyl)-S(O)2Rxa, -(C1-C6 alkylenyl)-S(O)2N(Rxa)2, -(C1-C6 alkylenyl)-C(O)Rxa, -(C1-C6MEl 24985843V.l 63117813-12620alkylenyl)-C(O)OR"a, -(C1-C6 alkylenyl)-C(O)N(R"a)2, -(C1-C6 alkylenyl)-C(O)N(R"a)S(O)2R"Z,-(C1-C6 alkylenyl)-N(R"a)2, -(C1-C6 alkylenyl)-N(R"a)C(O)R"Z, -(C1-C6 alkylenyl)-N(R"a)S(O)2R"Z,-(C1-C6 alkylenyl)-N(R"a)C(O)O(R"Z), -(C1-C6 alkylenyl)-N(R"a)C(O)N(R"a)2, or -(C1-C6alkylenyl)-N(Rxa)S(O)2N(Rxa)2; wherein R”, at each occurrence, is independently hydrogen, aryl,cycloalkyl, heterocyclyl, heteroaryl, C1-C6 alkyl, or C1-C6 haloalkyl; and R”, at each occurrence, isindependently aryl, cycloalkyl, heterocyclyl, heteroaryl, C1-C6 alkyl or C1-C6 haloalkyl.

Various ADCs, synthons and Bcl-XL inhibitors comprising the ADCs and/or synthons aredescribed in some embodiments herein by reference to structural formulae including substituents. It isto be tood that the various groups comprising substituents may be combined as valence andstability permit. Combinations of substituents and les envisioned by this disclosure are onlythose that result in the formation of stable compounds. As used herein, the term “stable” refers tocompounds that possess stability ient to allow manufacture and that maintain the integrity of thecompound for a sufficient period of time to be useful for the purpose detailed herein.

As used herein, the following terms are intended to have the following meanings:The term “alkoxy” refers to a group of the formula —OR"a, where Rm is an alkyl group.entative alkoxy groups include methoxy, , propoxy, tert-butoxy and the like.

The term “alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may berepresented by the general a —RbORm where Rb is an alkylene group and Rm is an alkyl group.

The term “alkyl” by itself or as part of another substituent refers to a saturated or unsaturatedbranched, straight-chain or cyclic monovalent hydrocarbon radical that is derived by the l ofone hydrogen atom from a single carbon atom of a parent alkane, alkene or . Typical alkylgroups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, l; propyls such aspropan- l -yl, propanyl, cyclopropan-l -yl, prop-l -enyl, prop-l yl, propen-l -yl,cyclopropenyl; cyclopropen-l -yl, prop-l -yn- l -yl etc., propyn-l -yl, ; butyls such asbutan-l-yl, butanyl, 2-methyl-propan-l-yl, 2-methyl-propanyl, cyclobutan-l-yl, en-l-yl,butenyl, yl-prop-l -enyl, buten- l -yl buta- l ,3-dien-l -yl,, butenyl,buta-l ,3-dienyl, ut- l -en-l -yl, cyclobut-l yl, cyclobuta- l ,3-dien-l -yl, butyn- l -yl,but-l-yn-3 -yl, but-3 -yn-l-yl, etc; and the like. Where specific levels of saturation are intended, thenomenclature “alkanyl,” “alkenyl” and/or “alkynyl” are used, as defined below. The term “loweralkyl” refers to alkyl groups with l to 6 carbons.

The term “alkanyl” by itself or as part of another tuent refers to a ted branched,straight-chain or cyclic alkyl derived by the removal of one hydrogen atom from a single carbon atomof a parent alkane. Typical alkanyl groups e, but are not limited to, methyl; ethanyl; propanylssuch as propan-l-yl, propanyl (isopropyl), cyclopropan-l-yl, eta; butanyls such as butan-l-yl,2-yl (sec-butyl), 2-methyl-propan-l-yl (isobutyl), 2-methyl-propanyl (t—butyl),cyclobutan-l -yl, etc; and the like.

MEl 24985843V.l 64117813-12620The term “alkenyl” by itself or as part of another substituent refers to an ratedbranched, straight-chain or cyclic alkyl having at least one carbon-carbon double bond derived by theremoval of one en atom from a single carbon atom of a parent alkene. Typical alkenyl groupsinclude, but are not limited to, ethenyl; propenyls such as prop-l-en-l-yl , prop-l-enyl,propen-l -yl, propenyl, cycloprop- l -en-l -yl; cyclopropen- l -yl ; butenyls such asbut-l-en-l-yl, but-l-enyl, 2-methyl-prop-l-en-l-yl, buten-l-yl, butenyl,buta-l,3-dien-l-yl, buta-l,3-dienyl, cyclobut-l-en-l-yl, cyclobut-l-enyl,cyclobuta-l ,3-dien-l-yl, etc.; and the like.

The term “alkynyl” by itself or as part of another substituent refers to an ratedbranched, straight-chain or cyclic alkyl having at least one carbon-carbon triple bond derived by thel of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groupsinclude, but are not limited to, ethynyl; propynyls such as prop-l-yn-l-yl , propyn-l-yl, etc.;butynyls such as but-l-yn-l-yl, but-l-ynyl, butyn-l-yl and the like., etc.;The term “alkylamine” refers to a group of the formula -NHRm and “dialkylamine” refers to agroup of the formula —NRxaRxa, where each Rm is, independently of the others, an alkyl group.

The term “alkylene” refers to an alkane, alkene or alkyne group having two terminallent radical centers derived by the removal of one hydrogen atom from each of the twoterminal carbon atoms. Typical alkylene groups include, but are not limited to, methylene; andsaturated or unsaturated ethylene; ene; butylene; and the like. The term “lower alkylene” refersto alkylene groups with l to 6 carbons.

The term “heteroalkylene” refers to a divalent ne having one or more -CH2- groupsreplaced with a thio, oxy, or -NR"3- where RX3 is selected from en, lower alkyl and lowerheteroalkyl. The heteroalkylene can be linear, branched, cyclic, bicyclic, or a combination f andcan include up to 10 carbon atoms and up to 4 heteroatoms. The term “lower alkylene” refers toalkylene groups with l to 4 carbon atoms and l to 3 heteroatoms.

The term “aryl” means an aromatic carbocyclyl containing from 6 to 14 carbon ring atoms.

An aryl may be monocyclic or polycyclic (i.e., may contain more than one ring). In the case ofpolycyclic ic rings, only one ring the polycyclic system is required to be aromatic while theremaining ring(s) may be saturated, partially ted or unsaturated. Examples of aryls include, naphthalenyl, indenyl, indanyl, and tetrahydronaphthyl.

The term “arylene” refers to an aryl group having two monovalent radical centers d bythe removal of one hydrogen atom from each of the two ring carbons. An ary arylene group isa phenylene.

An alkyl group may be substituted by a “carbonyl” which means that two hydrogen atomsfrom a single alkanylene carbon atom are removed and replaced with a double bond to an oxygenatom.

MEl 24985843V.l 65117813-12620The prefix “halo” indicates that the substituent which includes the prefix is substituted withone or more independently selected halogen radicals. For example, haloalkyl means an alkyltuent in which at least one hydrogen radical is replaced with a n radical. Typical halogenradicals include chloro, fluoro, bromo and iodo. Examples of haloalkyls e methyl, l-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, and l,l,l-trifluoroethyl. It should berecognized that if a substituent is substituted by more than one halogen radical, those halogen radicalsmay be cal or different (unless otherwise stated).

The term “haloalkoxy” refers to a group of the formula —ORC, where RC is a haloalkyl.

The terms “heteroalkyl,” “heteroalkanyl,” “heteroalkenyl,” “heteroalkynyl,” and“heteroalkylene” refer to alkyl, alkanyl, alkenyl, alkynyl, and alkylene groups, respectively, in whichone or more of the carbon atoms, 6. g., l, 2 or 3 carbon atoms, are each independently ed withthe same or different heteroatoms or heteroatomic groups. Typical atoms and/or heteroatomicgroups which can replace the carbon atoms include, but are not limited to, -O-, -S-, -S-O-, -NRC-, -PH,-S(O)-, -S(O)2-, -S(O)NRC-, -S(O)2NRC-, and the like, including combinations thereof, where each RCis independently hydrogen or C1-C6 alkyl. The term “lower heteroalkyl” refers to between 1 and 4carbon atoms and between 1 and 3 atoms.

The terms alkyl” and “heterocyclyl” refer to cyclic versions of “alkyl” andoalkyl” groups, tively. For heterocyclyl groups, a heteroatom can occupy the positionthat is attached to the remainder of the molecule. A cycloalkyl or heterocyclyl ring may be a single-ring (monocyclic) or have two or more rings (bicyclic or polycyclic).clic cycloalkyl and heterocyclyl groups will typically contains from 3 to 7 ring atoms,more typically from 3 to 6 ring atoms, and even more typically 5 to 6 ring atoms. Examples ofcycloalkyl groups include, but are not d to, cyclopropyl; cyclobutyls such as cyclobutanyl andcyclobutenyl; cyclopentyls such as cyclopentanyl and cyclopentenyl; cyclohexyls such ascyclohexanyl and cyclohexenyl; and the like. Examples of monocyclic heterocyclyls include, but arenot limited to, oxetane, furanyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydropyranyl, thiophenyl(thiofuranyl), dihydrothiophenyl, tetrahydrothiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, pyrazolyl, linyl, pyrazolidinyl, triazolyl, tetrazolyl, oxazolyl,oxazolidinyl, isoxazolidinyl, isoxazolyl, thiazolyl, isothiazolyl, thiazolinyl, isothiazolinyl,thiazolidinyl, isothiazolidinyl, azolyl, zolyl (including oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furazanyl), or l,3,4-oxadiazolyl), oxatriazolyl (including l,2,3,4-oxatriazolyl or l,2,3,5-oxatriazolyl), dioxazolyl (including l,2,3-dioxazolyl, l,2,4—dioxazolyl, 1,3,2-dioxazolyl, or l,3,4-dioxazolyl), l,4-dioxanyl, dioxothiomorpholinyl, oxathiazolyl, olyl,oxathiolanyl, pyranyl, dihydropyranyl, thiopyranyl, tetrahydrothiopyranyl, pyridinyl (azinyl),piperidinyl, diazinyl (including pyridazinyl (l,2-diazinyl), dinyl (l,3-diazinyl), or pyrazinyl(l,4-diazinyl)), piperazinyl, triazinyl (including l,3,5-triazinyl, 1,2,4-triazinyl, and l,2,3-triazinyl)),oxazinyl (including l,2-oxazinyl, l,3-oxazinyl, or l,4-oxazinyl)), oxathiazinyl (including 1,2,3-MEl 24985843V.l 66117813-12620oxathiazinyl, oxathiazinyl, 1,2,5-oxathiazinyl, or l,2,6-oxathiazinyl)), oxadiazinyl (including1,2,3-oxadiazinyl, 1,2,4-oxadiazinyl, 1,4,2-oxadiazinyl, or l,3,5-oxadiazinyl)), linyl, azepinyl,oxepinyl, thiepinyl, diazepinyl, pyridonyl (including pyrid-2(lH)-onyl and pyrid-4(lH)-onyl), furan-2(5H)-onyl, donyl (including pyramid-2(lH)-onyl and pyramid-4(3H)-onyl), oxazol-2(3H)-onyl, lH-imidazol-2(3H)-onyl, pyridazin-3(2H)-onyl, and pyrazin-2(lH)-onyl.

Polycyclic cycloalkyl and cyclyl groups contain more than one ring, and bicycliccycloalkyl and heterocyclyl groups contain two rings. The rings may be in a bridged, fused or spiroorientation. Polycyclic cycloalkyl and cyclyl groups may include combinations of d,fused and/or spiro rings. In a spirocyclic cycloalkyl or heterocyclyl, one atom is common to twodifferent rings. An example of a spirocycloalkyl is spiro[4.5]decane and an example of aspiroheterocyclyls is a spiropyrazoline.

In a bridged cycloalkyl or heterocyclyl, the rings share at least two common j acentatoms. Examples of bridged cycloalkyls include, but are not limited to, adamantyl and norbornanylrings. Examples of bridged heterocyclyls include, but are not limited to, 2-cyclo[3.3.1.13’7]decanyl.

In a fused-ring cycloalkyl or heterocyclyl, two or more rings are fused together, such that tworings share one common bond. Examples of fused-ring cycloalkyls e decalin, ylene,tetralin, and anthracene. Examples of fused-ring heterocyclyls containing two or three rings includeimidazopyrazinyl (including imidazo[l,2-a]pyrazinyl), imidazopyridinyl (including imidazo[l,2-a]pyridinyl), imidazopyridazinyl (including imidazo[l,2-b]pyridazinyl), thiazolopyridinyl (includingthiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl), indolizinyl, pyrrolyl, 4H-quinolizinyl, purinyl, naphthyridinyl, pyridopyridinylding pyrido[3,4-b]—pyridinyl, pyrido[3,2-b]—pyridinyl, or pyrido[4,3-b]-pyridinyl), andpteridinyl. Other examples of fused-ring heterocyclyls include fused heterocyclyls, such asdihydrochromenyl, tetrahydroisoquinolinyl, indolyl, isoindolyl (isobenzazolyl, pseudoisoindolyl),indoleninyl (pseudoindolyl), isoindazolyl (benzpyrazolyl), benzazinyl (including quinolinyl (lbenzazinyl) or isoquinolinyl (2-benzazinyl)), phthalazinyl, quinoxalinyl, quinazolinyl, benzodiazinyl(including cinnolinyl (1,2-benzodiazinyl) or quinazolinyl (l,3-benzodiazinyl)), yranyl(including chromanyl or isochromanyl), benzoxazinyl (including 1,3,2-benzoxazinyl, 1,4,2-benzoxazinyl, 2,3,l-benzoxazinyl, or 3,1,4-benzoxazinyl), d]thiazolyl, and benzisoxazinyl(including 1,2-benzisoxazinyl or l,4-benzisoxazinyl).

The term “cycloalkylene” refers to a cycloalkyl group haVing two monovalent radical centersderived by the removal of one hydrogen atom from each of two ring carbons. arycycloalkylene groups e: 2A5’zQs EOEMEl 24985843V.l 67117813-12620The term “heteroaryl” refers to an aromatic heterocyclyl containing from 5 to 14 ring atoms.

A heteroaryl may be a single ring or 2 or 3 fused rings. Examples of heteroaryls e 6-memberedrings such as pyridyl, pyrazyl, pyrimidinyl, pyridazinyl, and 1,3,5-, 1,2,4- or 1,2,3-triazinyl; 5-membered ring substituents such as triazolyl, pyrrolyl, imidazyl, furanyl, thiophenyl, pyrazolyl,oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5-, or 1,3,4-oxadiazolyl and isothiazolyl; 6/5-membered fused ring tuents such as imidazopyrazinyl (including imidazo[l,2-a]pyrazinyl)imidazopyridinyl (including imidazo[l,2-a]pyridinyl), opyridazinyl (includingimidazo[l ,2-b]pyridazinyl), thiazolopyridinyl (including thiazolo[5,4-c]pyridinyl, thiazolo[5,4-b]pyridinyl, thiazolo[4,5-b]pyridinyl, and thiazolo[4,5-c]pyridinyl), benzo[d]thiazolyl,benzothiofuranyl, benzisoxazolyl, benzoxazolyl, purinyl, and anthranilyl; and 6/6-membered fusedrings such as benzopyranyl, quinolinyl, isoquinolinyl, inyl, quinazolinyl, and benzoxazinyl.

Heteroaryls may also be heterocycles having aromatic (4N+2 pi electron) resonance contributors suchas pyridonyl (including pyrid-2(lH)-onyl and pyrid-4(lH)-onyl), pyrimidonyl (including pyramid-2(lH)-onyl and pyramid-4(3H)-onyl), pyridazin-3(2H)-onyl and n-2(lH)-onyl.

The term “sulfonate” as used herein means a salt or ester of a sulfonic acid.

The term “methyl sulfonate” as used herein means a methyl ester of a sulfonic acid group.

The term xylate” as used herein means a salt or ester of a carboxylic acid.

The term “polyol”, as used herein, means a group containing more than two hydroxyl groupsindependently or as a portion of a monomer unit. Polyols e, but are not limited to, reduced C2-C6 carbohydrates, ne glycol, and glycerin.

The term “sugar” when used in context of “G1” includes O-glycoside, N—glycoside, S-glycoside and C-glycoside (C-glycoslyl) ydrate derivatives of the monosaccharide anddisaccharide classes and may originate from naturally-occurring sources or may be tic in origin.

For example “sugar” when used in context of cludes derivatives such as but not limited to thosederived from onic acid, galacturonic acid, galactose, and glucose among others. Suitable sugarsubstitutions include but are not limited to hydroxyl, amine, carboxylic acid, sulfonic acid,phosphonic acid, esters, and ethers.

The term “NHS ester” means the N-hydroxysuccinimide ester derivative of a carboxylic acid.

The term “amine” includes primary, secondary and tertiary aliphatic amines, including cyclicversions.

The term salt when used in context of “or salt f” include salts commonly used to formalkali metal salts and to form addition salts of free acids or free bases. In general, these salts llymay be ed by conventional means by reacting, for example, the riate acid or base with acompound of the inventionWhere a salt is intended to be administered to a patient (as opposed to, for example, being inuse in an in vitro context), the salt preferably is pharmaceutically able and/or physiologicallycompatible. The term "pharmaceutically acceptable" is used adjectivally in this patent application toMEl 24985843V.l 68-12620mean that the modified noun is riate for use as a pharmaceutical product or as a part of apharmaceutical product. The term “pharmaceutically acceptable salt” includes salts commonly usedto form alkali metal salts and to form addition salts of free acids or free bases. In l, these saltstypically may be prepared by conventional means by reacting, for example, the appropriate acid orbase with a compound of the invention.

Various s of the invention are described in further detail in the following subsections.

II. Anti-B7-H3 diesOne aspect of the invention provides anti-B7-H3 antibodies, or antigen binding portionsthereof. In one embodiment, the present invention provides chimeric anti-B7-H3 antibodies, orantigen binding portions f. In yet another embodiment, the present invention provideszed anti-B7-H3 antibodies, or antigen binding portions thereof. In another aspect, theinvention features antibody drug conjugates (ADCs) comprising an anti-B7-H3 antibody describedherein and at least one drug(s), such as, but not limited to, a Bcl-xL tor or an auristatin. Theantibodies or ADCs of the invention have characteristics including, but not limited to, binding to wild-type human B7-H3 in vitro, g to wild-type human B7-H3 on tumor cells expressing B7-H3, anddecreasing or inhibiting aft tumor growth in a mouse model.

One aspect of the invention features an anti-human B7-H3 (anti-hB7-H3) Antibody DrugConjugate (ADC) comprising an anti-hB7-H3 antibody conjugated to a drug via a linker, wherein thedrug is a Bcl-xL inhibitor. Exemplary 7-H3 antibodies (and sequences thereof) that can be usedin the ADCs are bed herein.

The anti-B7-H3 antibodies described herein provide the ADCs of the invention with theability to bind to B7-H3 such that the cytotoxic Bcl-xL drug attached to the antibody may be deliveredto the B7-H3-expressing cell, particularly a B7-H3 expressing cancer cell.

While the term “antibody” is used throughout, it should be noted that antibody fragments (i.e.,antigen-binding portions of an anti-B7-H3antibody) are also included in the invention and may beincluded in the embodiments (methods and compositions) described hout. For example, ananti-B7-H3antibody fragment may be conjugated to the Bcl-xL inhibitors described herein. Thus, it iswithin the scope of the invention that in certain embodiments, antibody fragments of the anti-B7-H3antibodies bed herein are conjugated to Bcl-xL inhibitors (including those described below inSection III.A) via linkers (including those described below in Section III.A). In certain embodiments,the anti-B7-H3 antibody binding portion is a Fab, a Fab’, a F(ab’)2, a Fv, a disulfide linked Fv, anscFv, a single domain antibody, or a diabody.

II.A. Anti-B7-H3 Chimeric AntibodiesA chimeric antibody is a molecule in which different portions of the antibody are derivedfrom different animal s, such as antibodies having a le region derived from a murinemonoclonal dy and a human immunoglobulin constant . Methods for producing chimericMEl 24985843V.l 69117813-12620antibodies are known in the art. See e. g., Morrison, Science 229: 1202 ; Oi et al., BioTechniqaes4:214 (1986); Gillies et al., (1989) J. Immunol. Methods 1-202; US Pat. Nos. 5,807,715;4,816,567; and 4,816,397, which are incorporated herein by reference in their entireties. In addition,techniques ped for the production of "chimeric antibodies” (Morrison et al., 1984, Proc. Natl.

Acad. Sci. 81:851-855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature314:452-454, each of which are incorporated herein by reference in their entireties) by splicing genesfrom a mouse antibody molecule of appropriate antigen specificity together with genes from a humanantibody le of appropriate biological activity can be used.

As described in Example 3, eighteen anti-B7-H3 murine antibodies were fied havinghigh specific binding activity t human and cynomolgus B7-H3. Chimeric antibodies, in thecontext of a human immunoglobulin nt region, were generated from these eighteen antibodies.

Thus, in one aspect, the present invention is directed to an anti-B7-H3 dy, or n-binding portion thereof, having a heavy chain variable region including an amino acid sequence setforth in SEQ ID NOs: 1, 9, 16, 24, 32, 40, 48, 56, 64, 72, 80, 87, 95, 101, or 108; and/or a light chainle region including an amino acid sequence set forth in SEQ ID NOs: 5, 13, 20, 28, 36, 44, 52,60, 68, 76, 84, 91, 98, 105, or 112.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 1, and a light chain variable region including an amino acid sequence set forth inSEQ ID NO: 5.

In another aspect, the present invention is ed to an anti-B7-H3 antibody, or antigen-g portion f, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 2; (b) a CDR2 having an amino acid sequence as setforth in SEQ ID NO: 3; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 4;and a light chain variable region including (a) a CDRl having an amino acid sequence as set forth inSEQ ID NO: 6; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 7; and (c) aCDR3 having an amino acid sequence as set forth in SEQ ID NO: 8.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 9, and a light chain variable region including an amino acid sequence set forth inSEQ ID NO: 13.

In another aspect, the present ion is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 11; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 12; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 14 (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 7;MEl 24985843V.1 7O117813-12620and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 16, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 20.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 17; (b) a CDR2 having an amino acid ce asset forth in SEQ ID NO: 18; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 19; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 21; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 22;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 23.

In another aspect, the present invention is directed to an anti-B7-H3 dy, or n-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 24, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 28.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region ing (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 25; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 26; and (c) a CDR3 having an amino acid ce as set forth in SEQ IDNO: 27; and a light chain variable region including (a) a CDRl having an amino acid ce as setforth in SEQ ID NO: 29; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 30;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 31.

In another aspect, the t invention is directed to an anti-B7-H3 antibody, or n-g portion thereof, having a heavy chain le region including an amino acid sequence as setforth in SEQ ID NO: 32, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 36.

In another aspect, the t invention is ed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 33; (b) a CDR2 having an amino acid ce asset forth in SEQ ID NO: 34; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 35; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 37; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 38;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 182.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setMEl 24985843V.l 71117813-12620forth in SEQ ID NO: 40, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 44.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 41; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 42; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 43; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 45; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 46;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 47.

In another aspect, the present ion is directed to an 7-H3 dy, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 48, and a light chain variable region including an amino acid ce set forthin SEQ ID NO: 52.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding n thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 49; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 50; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 51; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 53; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 54;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 55.

In r , the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid ce as setforth in SEQ ID NO: 56, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 60.

In another aspect, the present invention is directed to an anti-B7-H3 dy, or antigen-binding portion f, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 57; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 58; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 59; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 61; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 62;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 63.

In another aspect, the present invention is directed to an 7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 64, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 68.

In another aspect, the present ion is directed to an anti-B7-H3 antibody, or n-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anMEl 24985843V.l 72117813-12620amino acid sequence as set forth in SEQ ID NO: 65; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 66; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 67; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 69; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 70;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 71.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or n-g portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 72, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 76.

In another aspect, the present invention is directed to an anti-B7-H3 dy, or n-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 73; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 74; and (c) a CDR3 having an amino acid ce as set forth in SEQ IDNO: 75; and a light chain variable region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 77; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 78;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 79.

In another aspect, the present invention is directed to an 7-H3 dy, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 80, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 84.

In another aspect, the present ion is directed to an anti-B7-H3 antibody, or antigen-binding n thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 81; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 82; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 83; and a light chain le region including (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 85; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 7;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 86.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 87, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 91.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or n-binding portion thereof, having a heavy chain variable domain region including (a) a CDRl having anamino acid sequence as set forth in SEQ ID NO: 88; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 89; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 90; and a light chain variable region ing (a) a CDRl having an amino acid sequence as setforth in SEQ ID NO: 92; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 93;MEl 24985843V.l 73117813-12620and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 94.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid ce as setforth in SEQ ID NO: 95, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 98.

In another aspect, the t invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1 having anamino acid sequence as set forth in SEQ ID NO: 49; (b) a CDR2 having an amino acid ce asset forth in SEQ ID NO: 96; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 97; and a light chain variable region including (a) a CDR1 having an amino acid sequence as setforth in SEQ ID NO: 99; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 93;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 100.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 101, and a light chain variable region including an amino acid sequence set forthin SEQ ID NO: 105.

In another , the present invention is directed to an anti-B7-H3 antibody, or antigen-g portion f, having a heavy chain variable domain region including (a) a CDR1 having anamino acid sequence as set forth in SEQ ID NO: 102; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 103; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 104; and a light chain variable region including (a) a CDR1 having an amino acid sequence as setforth in SEQ ID NO: 106; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO: 46;and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 107.

In another , the t invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable region including an amino acid sequence as setforth in SEQ ID NO: 108, and a light chain variable region including an amino acid ce set forthin SEQ ID NO: 112.

In r aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1 having anamino acid sequence as set forth in SEQ ID NO: 109; (b) a CDR2 having an amino acid sequence asset forth in SEQ ID NO: 110; and (c) a CDR3 having an amino acid sequence as set forth in SEQ IDNO: 111; and a light chain variable region including (a) a CDR1 having an amino acid sequence as setforth in SEQ ID NO: 113; (b) a CDR2 having an amino acid sequence as set forth in SEQ ID NO:114; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 115.

MEl 24985843V.1 74117813-12620II.B. Humanized Anti-B7-H3 AntibodiesThe chimeric antibodies disclosed herein may be used in the tion of humanized anti-B7-H3 antibodies. For example, ing the generation and characterization of chimeric anti-B7-H3 antibodies chAbl-chAb18, antibodies chAb3, chAb13, and chAb18 were ed forhumanization. Specifically, six different humanized antibodies were created based on chAb3red to herein as huAb3V1, huAb3V2, huAb3V3, huAb3V4, huAb3V5, and huAb3V6 (seees 12 and 13), nine different humanized dies were created based on chAb13 (referred toherein as huAb13V1, huAb13V2, huAb13V3, huAb13V4, huAb13V5, huAb13V6, huAb13V7,huAb13V8, huAb13V9), and ten different humanized antibodies were d based on chAb18(referred to herein as huAb18V1, huAb18V2, huAb18V3, huAb18V4, huAb18V5, huAb18V6,huAb18V7, huAb18V8, huAb18V9, and huAb18V10 (see Examples 9 and 10)). Tables 8, 12, 16, 18,and 19 provide the amino acid sequences of CDR, VH and VL regions of zed chAb3, chAb13,and chAb18, respectively.

Generally, humanized antibodies are antibody molecules from man species antibodythat binds the desired antigen haVing one or more complementarity determining regions (CDRs) fromthe non-human species and framework regions from a human immunoglobulin molecule. Knownhuman Ig sequences are disclosed, e.g., www.ncbi.nlm.nih.gov/entrez- /query.fcgi;www.atcc.org/phage/hdb.html; www.sciquest.coml; www.abcam.coml;www.antibodyresource.com/onlinecomphtml;www.public.iastate.edu/.about.pedro/research_tools.html; en.uni-heidelberg.de/SD/IT/IT.html; www.whfreeman.com/immunology/CH- 05/kuby05.htm;www.library.thinkquest.org/12429/Immune/Antibodyhtml;www.hhmi.org/grants/lectures/1996/Vlab/; www.path.cam.ac.ukl.about.mrc7/m— ikeimageshtml;www.antibodyresourcecoml; mcb.harvard.edu/BioLinks/Immuno-tml.www.immunologylink.com/; x.wustl.edu/.about.hcenter/index.- html;www.biotech.ufl.edu/.about.hcl/; www.pebio.com/pa/340913/340913.html- ;www.nal.usda.gov/awic/pubs/antibody/; www.m.ehime-u.acjp/.about.yasuhito- /Elisa.html;www.biodesigncom/table.asp; www.icnet.uk/axp/facs/daVies/lin- ks.html;www.biotech.ufl.edu/.about.fccl/protocol.html; www.isac-net.org/sites_geo.html; aximtl.imt.uni-marburg.de/.about.rek/AEP- Start.html; baserV.uci.kun.nl/.about.jraats/linksl.html; www.recab.uni-hd.de/immuno.bme.nwu.edu/; www.mrc-cpe.cam.ac.uk/imt-doc/pu- blic/INTROhtml;www.ibt.unam.mx/Vir/V_mice.html; imgt.cnusc.fr:8104/;www.biochem.ucl.ac.uk/.about.martin/abs/index.html; antibody.bath.ac.ukl;abgen.cvm.tamu.edu/lab/wwwabgenhtml; www.unizh.ch/.about.honegger/AHOsem-lideOl .html; www.cryst.bbk.ac.ukl.about.ubcg07s/;www.nimr.mrc.ac.uk/CC/ccaewg/ccaewghtm; th.cam.ac.uk/.about.mrc7/h-umanisation/TAHHPhtml; www.ibt.unam.mx/Vir/structure/stat_aim.html;MEl 24985843V.1 75117813-12620www.biosci.missouri.edu/smithgp/index.html; www.cryst.bioc.cam.ac.uk/.abo- ut.fmolina/Web-pages/Pept/spottech.html; www.jerini.de/fr roducts.htm; www.patents.ibm.com/ibm.html.Kabat et al.,Sequences of Proteins of Immunological Interest, US. Dept. Health (1983), each entirely incorporatedherein by reference. Such ed sequences can be used to reduce immunogenicity or reduce,enhance or modify binding, affinity, on-rate, off-rate, avidity, specificity, half-life, or any othersuitable characteristic, as known in the art.

Framework residues in the human framework regions may be substituted with thecorresponding residue from the CDR donor antibody to alter, preferably improve, antigen binding.

These framework tutions are identified by s well known in the art, e. g., by modeling ofthe interactions of the CDR and framework residues to fy ork residues important forantigen binding and sequence comparison to identify unusual framework residues at particularpositions. (See, e.g., Queen et al., US. Pat. No. 5,585,089; Riechmann et al., Nature 332:323 (1988),which are incorporated herein by reference in their entireties.) Three-dimensional immunoglobulinmodels are commonly available and are familiar to those skilled in the art. Computer programs areavailable which illustrate and display le three-dimensional conformational ures ofselected candidate immunoglobulin sequences. Inspection of these displays permits analysis of thelikely role of the residues in the functioning of the candidate immunoglobulin sequence, i. e., theanalysis of residues that influence the ability of the candidate immunoglobulin to bind its antigen. Inthis way, FR residues can be selected and combined from the consensus and import sequences so thatthe desired antibody characteristic, such as increased affinity for the target antigen(s), is achieved. Inl, the CDR residues are directly and most substantially ed in influencing antigen binding.

Antibodies can be humanized using a y of techniques known in the art, such as but not limited tothose described in Jones et al., Nature 321 :522 (1986); Verhoeyen et al., Science 239: 1534 (1988)),Sims et al., J. Immunol. 151: 2296 (1993); Chothia and Lesk, J. Mol. Biol. 196:901 (1987), Carter etal., Proc. Natl. Acad. Sci. USA. 89:4285 (1992); Presta et al., J. Immunol. 151:2623 (1993), Padlan,Molecular Immunology 28(4/5):489-498 (1991); Studnicka et al., Protein Engineering 05-814(1994); Roguska. et al. , PNAS 91:969-973 (1994); PCT publication WO 91/09967, PCT/2US98/16280, US96/18978, US91/09630, US91/05939, US94/01234, GB89/01334, GB91/01134,GB92/01755; WO90/14443, WO90/14424, WO90/14430, EP 229246, EP 592,106; EP 519,596, EP239,400, US. Pat. Nos. 5,565,332, 5,723,323, 5,976,862, 5,824,514, 5,817,483, 6, 5763192,5723323, 5,766886, 352, 6,204,023, 370, 5,693,762, 5,530,101, 5,585,089, 5,225,539;4,816,567, each entirely incorporated herein by nce, included references cited therein.zed 7-H3 antibodies d from chAb3Six humanized antibodies based on chAb3 were created. The sequences of each are asfollows:MEl 24985843V.1 76117813-12620A) huAb3v1 (VH amino acid sequence set forth in SEQ ID NO: 125 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 128 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively);B) 2 (VH amino acid ce set forth in SEQ ID NO: 127 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 128 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively);C) huAb3v3 (VH amino acid ce set forth in SEQ ID NO: 126 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid ce set forth in SEQ ID NO: 129 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively);D) huAb3v4 (VH amino acid sequence set forth in SEQ ID NO: 125 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 130 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively);E) huAb3v5 (VH amino acid sequence set forth in SEQ ID NO: 127 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid ce set forth in SEQ ID NO: 130 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively); andF) huAb3v6 (VH amino acid ce set forth in SEQ ID NO: 126 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 11, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 130 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 14, 7, and 15, respectively).

Of the six humanized versions of chAb3, huAb3v2 was selected for further modified in orderto remove potential deamidation or isomerization sites in the light chain CDR1 or in the heavy chainCDR2. Nine variants of the humanized antibody huAb3v2 were generated, and are referred to hereinas huAb3v2.1, huAb3v2.2, huAb3v2.3, 2.4, huAb3v2.5, huAb3v2.6, huAb3v2.7, huAb3v2.8,and huAb3v2.9 (CDR and variable domain sequences are provided in Table 16). The nine variants ofthe 2 antibody include the following:A) huAb3v2.1 (VH amino acid sequence set forth in SEQ ID NO: 131 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 132, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 133 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 134, 7, and 15, respectively);B) huAb3v2.2 (VH amino acid sequence set forth in SEQ ID NO: 131 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 132, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 135 and VL CDR1, CDR2, and CDR3 amino acidMEl 24985843V.1 77117813-12620sequences set forth in SEQ ID NOs: 136, 7, and 15, respectively);C) huAb3v2.3 (VH amino acid sequence set forth in SEQ ID NO: 131 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 132, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 137 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 138, 7, and 15, respectively);D) huAb3v2.4 (VH amino acid sequence set forth in SEQ ID NO: 139 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 140, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 133 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 134, 7, and 15, respectively);E) huAb3v2.5 (VH amino acid sequence set forth in SEQ ID NO: 139 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 140, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 135 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 136, 7, and 15, respectively);F) huAb3v2.6 (VH amino acid sequence set forth in SEQ ID NO: 139 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 140, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 137 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 138, 7, and 15, respectively);G) huAb3v2.7 (VH amino acid sequence set forth in SEQ ID NO: 141 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 142, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 133 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 134, 7, and 15, respectively);H) huAb3v2.8 (VH amino acid sequence set forth in SEQ ID NO: 141 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 142, and 12, respectively; and VLamino acid ce set forth in SEQ ID NO: 135 and VL CDR1, CDR2, and CDR3 amino acidces set forth in SEQ ID NOs: 136, 7, and 15, respectively); andI) huAb3v2.9 (VH amino acid sequence set forth in SEQ ID NO: 141 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 10, 142, and 12, respectively; and VLamino acid sequence set forth in SEQ ID NO: 137 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 138, 7, and 15, tively).

Thus, in one aspect, the present invention provides antibodies comprising variable and/orCDR sequences from a zed antibody derived from chAb3. In one embodiment, the inventionfeatures anti-B7-H3 antibodies which are derived from Ab3 have improved characteristics, e.g.,improved binding affinity to isolated B7-H3 n and improved binding to B7-H3 expressing cells,as described in the Examples below. Collectively these novel antibodies are referred to herein as“Ab3 variant antibodies.” Generally, the Ab3 variant dies retain the same epitope specificity asAb3. In various embodiments, anti-B7-H3 antibodies, or n g fragments thereof, of theinvention are capable of modulating a ical function of B7-H3.

MEl 24985843V.1 78117813-12620In one aspect, the present invention es a humanized antibody, or antigen bindingn thereof, having a heavy chain variable region including an amino acid sequence set forth inSEQ ID NOs: 125, 126, 127, 131, 139, or 141; and/or a light chain variable region including an aminoacid sequence set forth in SEQ ID NOs: 128, 129, 130, 133, 135, or 137.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigenbinding portion thereof, of the invention comprises a heavy chain le region comprising a CDR1domain comprising an amino acid ce as set forth in SEQ ID NO: 10; a CDR2 domaincomprising an amino acid sequence as set forth in SEQ ID NO: 11, 132, 140, or 142; and a CDR3domain comprising an amino acid sequence as set forth in SEQ ID NO: 12; and a light chain variableregion comprising a CDR1 domain comprising an amino acid ce as set forth in SEQ ID NO:14, 134, 136, or 138; a CDR2 domain comprising an amino acid ce as set forth in SEQ ID NO:7; and a CDR3 domain comprising an amino acid sequence as set forth in SEQ ID NO: 15.

In one , the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 125, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 128.

In one aspect, the present invention is ed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 127, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 128.

In one aspect, the present invention is directed to an anti-B7-H3 dy, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 126, and a light chain le region including an amino acid sequence set forth in SEQID NO: 129.

In one aspect, the present invention is directed to an 7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 125, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 130.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 127, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 130.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 126, and a light chain le region including an amino acid sequence set forth in SEQID NO: 130.

MEl 24985843V.1 79117813-12620In another aspect, the present invention is ed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 11; and (c) a CDR3 having an amino acid ce as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 14; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one aspect, the present invention is ed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 131, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 133.

In r aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 132; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 131, and a light chain le region including an amino acid sequence set forth in SEQID NO: 135.

In another aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain le domain region including (a) a CDR1having an amino acid ce as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 132; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid ce as set forth in SEQ ID NO: 15.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 131, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 137.

In another aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain le domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 132; and (c) a CDR3 having an amino acid sequence as set forthMEl 24985843V.1 80117813-12620in SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 138; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one aspect, the t invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid ce as set forth inSEQ ID NO: 139, and a light chain variable region ing an amino acid sequence set forth in SEQID NO: 133.

In r aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 140; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region ing (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one , the present ion is directed to an anti-B7-H3 dy, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 139, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 135.

In another aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 140; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid ce as set forth in SEQ ID NO: 15.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or n-binding n thereof, having a heavy chain comprising the amino acid sequence of SEQ ID NO:170 and a light chain comprising the amino acid sequence of SEQ ID NO: 171.

In one aspect, the present ion is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 139, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 137.

In another aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 140; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidMEl 24985843V.1 81-12620sequence as set forth in SEQ ID NO: 138; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In another aspect, the present invention is directed to an 7-H3 antibody, or antigen-binding portion thereof, having a heavy chain comprising the amino acid sequence of SEQ ID NO:172 and a light chain comprising the amino acid sequence of SEQ ID NO: 173. In one aspect, thet invention is directed to an anti-B7-H3 antibody, or antigen-binding portion thereof, having aheavy chain variable region including an amino acid sequence as set forth in SEQ ID NO: 141, and alight chain variable region including an amino acid sequence set forth in SEQ ID NO: 133.

In another aspect, the present invention is directed to a zed anti-B7-H3 antibody, orantigen-binding portion f, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 142; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region ing (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one , the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 141, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 135.

In another aspect, the t ion is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 142; and (c) a CDR3 having an amino acid ce as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

In one , the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 141, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 137.

In another aspect, the present invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 10; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 142; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 12; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 138; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 15.

MEl 24985843V.1 82117813-12620Humanized anti-B7-H3 antibodies derived from chAb13The nine different humanized antibodies created based on chAb13 include the ing:A) huAb13v1 (VH amino acid sequence set forth in SEQ ID NO: 147 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 144 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);B) huAb13v2 (VH amino acid sequence set forth in SEQ ID NO: 146 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 143 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);C) huAb13v3 (VH amino acid sequence set forth in SEQ ID NO: 146 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, tively; and VLamino acid sequence set forth in SEQ ID NO: 144 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);D) huAb13v4 (VH amino acid sequence set forth in SEQ ID NO: 146 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 145 and VL CDR1, CDR2, and CDR3 amino acidces set forth in SEQ ID NOs: 37, 38, and 39, tively);E) huAb13v5 (VH amino acid sequence set forth in SEQ ID NO: 147 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 143 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);F) huAb13v6 (VH amino acid sequence set forth in SEQ ID NO: 147 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 145 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, tively);G) huAb13v7 (VH amino acid sequence set forth in SEQ ID NO: 148 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, tively; and VLamino acid sequence set forth in SEQ ID NO: 143 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);H) huAb13v8 (VH amino acid sequence set forth in SEQ ID NO: 148 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 144 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 37, 38, and 39, respectively);I) huAb13v9 (VH amino acid ce set forth in SEQ ID NO: 148 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 33, 34, and 35, respectively; and VLamino acid sequence set forth in SEQ ID NO: 145 and VL CDR1, CDR2, and CDR3 amino acidMEl 24985843v.1 83117813-12620sequences set forth in SEQ ID NOs: 37, 38, and 39, respectively).

Thus, in one aspect the present invention provides antibodies comprising variable and/or CDRsequences from a humanized antibody derived from chAb13. In one embodiment, the inventionfeatures 7-H3 dies which are derived from chAb13 have improved characteristics, e.g.,improved binding affinity to ed B7-H3 protein and improved binding to B7-H3 sing cells,as described in the Examples below. Collectively these novel antibodies are referred to herein as“Ab13 variant antibodies.” Generally, the Ab13 variant antibodies retain the same epitope specificityas Ab13. In various embodiments, anti-B7-H3 antibodies, or antigen binding fragments thereof, ofthe invention are capable of modulating a ical function of B7-H3.

In one aspect, the present ion provides a humanized antibody, or antigen bindingportion thereof, having a heavy chain variable region including an amino acid sequence set forth inSEQ ID NOs: 146, 147, or 148; and/or a light chain variable region including an amino acid sequenceset forth in SEQ ID NOs: 143, 144, or 145.

In another aspect, the present invention is directed to an anti-B7-H3 antibody, or antigenbinding portion thereof, of the invention comprises a heavy chain le region comprising a CDR1domain comprising an amino acid sequence as set forth in SEQ ID NO: 33; a CDR2 domaincomprising an amino acid sequence as set forth in SEQ ID NO: 34; and a CDR3 domain comprisingan amino acid sequence as set forth in SEQ ID NO: 35; and a light chain variable region comprising aCDR1 domain comprising an amino acid ce as set forth in SEQ ID NO: 37; a CDR2 domaincomprising an amino acid sequence as set forth in SEQ ID NO: 38; and a CDR3 domain comprisingan amino acid sequence as set forth in SEQ ID NO: 39.

In one aspect, the present ion is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 147, and a light chain variable region ing an amino acid sequence set forth in SEQID NO: 144. In one embodiment, the invention provides an anti-B7H3 antibody comprising the CDRsequences set forth in the le regions of huAb13v1 (SEQ ID NOs. 144 and 147).

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen gportion thereof, having a heavy chain comprising the amino acid sequence of SEQ ID NO: 168 and alight chain comprising the amino acid sequence of SEQ ID NO: 169.

In one aspect, the present ion is directed to an 7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 146, and a light chain variable region including an amino acid ce set forth in SEQID NO: 143.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 146, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 144.

MEl 24985843V.1 84117813-12620In one aspect, the t invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 146, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 145.

In one , the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 147, and a light chain variable region ing an amino acid sequence set forth in SEQID NO: 143.

In one aspect, the t invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 147, and a light chain variable region ing an amino acid sequence set forth in SEQID NO: 145.

In one aspect, the present invention is ed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 148, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 143.

In one , the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 148, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 144.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or n-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 148, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 145.

Humaniged anti-B7-H3 antibodies derived from chAb18The ten different humanized antibodies created based on chAb18 include the following:A) v1 (VH amino acid sequence set forth in SEQ ID NO: 116 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 120 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);B) huAb18v2 (VH amino acid sequence set forth in SEQ ID NO: 118 and VH CDR1, CDR2,and CDR3 amino acid ces set forth in SEQ ID NOs: 25, 119, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 120 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);C) huAb18v3 (VH amino acid sequence set forth in SEQ ID NO: 117 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27, tively; and VLMEl 24985843V.1 85117813-12620amino acid sequence set forth in SEQ ID NO: 121 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);D) huAb18v4 (VH amino acid sequence set forth in SEQ ID NO: 118 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 119, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 121 and VL CDR1, CDR2, and CDR3 amino acidces set forth in SEQ ID NOs: 29, 30, and 31, respectively);E) huAb18v5 (VH amino acid sequence set forth in SEQ ID NO: 116 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 123 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);F) huAb18v6 (VH amino acid sequence set forth in SEQ ID NO: 118 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 119, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 123 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);G) huAb18v7 (VH amino acid sequence set forth in SEQ ID NO: 118 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 119, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 124 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively);H) huAb18v8 (VH amino acid sequence set forth in SEQ ID NO: 117 and VH CDR1, CDR2,and CDR3 amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 122 and VL CDR1, CDR2, and CDR3 amino acidces set forth in SEQ ID NOs: 29, 30, and 31, respectively);I) v9 (VH amino acid sequence set forth in SEQ ID NO: 117 and VH CDR1, CDR2,and CDR3 amino acid ces set forth in SEQ ID NOs: 25, 26, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 124 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively); andJ) huAb18v10 (VH amino acid sequence set forth in SEQ ID NO: 118 and VH CDR1, CDR2,and CDR3 amino acid ces set forth in SEQ ID NOs: 25, 119, and 27, respectively; and VLamino acid sequence set forth in SEQ ID NO: 122 and VL CDR1, CDR2, and CDR3 amino acidsequences set forth in SEQ ID NOs: 29, 30, and 31, respectively).

Thus, in one aspect the present invention es antibodies comprising variable and/or CDRsequences from a humanized antibody derived from chAb18. In one embodiment, the ionfeatures anti-B7-H3 antibodies which are derived from Ab18 have improved characteristics, 6. g.,ed binding affinity to isolated B7-H3 protein and ed binding to B7-H3 expressing cells,as described in the Examples below. Collectively these novel antibodies are referred to herein as“Ab18 variant antibodies.” Generally, the Ab18 variant antibodies retain the same epitope specificityMEl 24985843V.1 86117813-12620as Ab18. In various embodiments, anti-B7-H3 antibodies, or antigen binding fragments thereof, ofthe invention are capable of modulating a biological function of B7-H3.

In one , the present invention provides a humanized antibody, or antigen bindingportion f, having a heavy chain variable region including an amino acid sequence set forth inSEQ ID NOs: 116, 117, or 118; and/or a light chain variable region including an amino acid sequenceset forth in SEQ ID NOs: 120, 121, 122, 123 or 124.

In another aspect, the t invention is directed to an 7-H3 antibody, or nbinding portion thereof, of the invention comprises a heavy chain variable region comprising a CDR1domain comprising an amino acid sequence as set forth in SEQ ID NO: 25; a CDR2 domaincomprising an amino acid ce as set forth in SEQ ID NO: 26 or 119; and a CDR3 domaincomprising an amino acid sequence as set forth in SEQ ID NO: 27; and a light chain variable regioncomprising a CDR1 domain comprising an amino acid sequence as set forth in SEQ ID NO: 29; aCDR2 domain comprising an amino acid ce as set forth in SEQ ID NO: 30; and a CDR3domain comprising an amino acid sequence as set forth in SEQ ID NO: 31.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 116, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 120.

In another aspect, the t invention is directed to a humanized anti-B7-H3 antibody, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid ce as set forth in SEQ ID NO: 25; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 26; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 27; and a light chain variable region ing (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 29; (b) a CDR2 having an amino acid ce as set forth inSEQ ID NO: 30; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 31.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 118, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 120.

In another aspect, the present invention is directed to a zed anti-B7-H3 dy, orantigen-binding portion thereof, having a heavy chain variable domain region including (a) a CDR1having an amino acid sequence as set forth in SEQ ID NO: 25; (b) a CDR2 having an amino acidsequence as set forth in SEQ ID NO: 119; and (c) a CDR3 having an amino acid sequence as set forthin SEQ ID NO: 27; and a light chain variable region including (a) a CDR1 having an amino acidsequence as set forth in SEQ ID NO: 29; (b) a CDR2 having an amino acid sequence as set forth inSEQ ID NO: 30; and (c) a CDR3 having an amino acid sequence as set forth in SEQ ID NO: 31.

MEl 24985843V.1 87117813-12620In one aspect, the present invention is directed to an 7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 117, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 121.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or n-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 118, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 121.

In one aspect, the present ion is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain le region including an amino acid sequence as set forth inSEQ ID NO: 116, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 123.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 118, and a light chain le region including an amino acid sequence set forth in SEQID NO: 123.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 118, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 124.

In one , the t invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion thereof, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 117, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 122.

In one aspect, the present invention is ed to an anti-B7-H3 dy, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 117, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 124.

In one aspect, the present invention is directed to an anti-B7-H3 antibody, or antigen-bindingportion f, having a heavy chain variable region including an amino acid sequence as set forth inSEQ ID NO: 118, and a light chain variable region including an amino acid sequence set forth in SEQID NO: 122.

In one , the present invention provides a humanized antibody, or antigen bindingportion thereof, having a heavy chain variable region including an amino acid sequence set forth inSEQ ID NOs: 116,117,118,146,147,148,125,126,127,131,139,or141;and/or alight chainvariable region ing an amino acid sequence set forth in SEQ ID NOs: 120, 121, 122, 123, 124,143, 144, 145, 128, 129, 130, 133, 135, or 137.

MEl 24985843V.1 88117813-12620In another , the present invention is directed to an anti-B7-H3 antibody, or antigenbinding portion thereof, of the invention comprises a heavy chain variable region sing a CDR1domain comprising an amino acid sequence as set forth in SEQ ID NO: 10, 25, or 33; a CDR2 domaincomprising an amino acid ce as set forth in SEQ ID NO: 11, 26, 34, 119, 132, 140, or 142; anda CDR3 domain comprising an amino acid sequence as set forth in SEQ ID NO: 12, 27, or 35; and alight chain variable region comprising a CDR1 domain sing an amino acid sequence as setforth in SEQ ID NO: 14, 29, 37, 134, 136, or 138; a CDR2 domain comprising an amino acidsequence as set forth in SEQ ID NO: 7, 30, or 38; and a CDR3 domain comprising an amino acidsequence as set forth in SEQ ID NO: 15, 31 or 39.

In another aspect, the ion provides an anti-B7-H3 antibody, or antigen binding fragmentthereof, that specifically competes with an anti-B7-H3 antibody, or fragment thereof, as describedherein, wherein said ition can be ed in a competitive binding assay using said antibody,the human B7-H3 polypeptide, and the anti-B7-H3 antibody or fragment thereof.

In ular embodiments, the competing antibody, or antigen binding portion thereof, is anantibody, or antigen binding portion f, that competes with huAb3v2.5, 2.6, orhuAb13v1.

In one embodiment, the anti-B7-H3 antibodies, or antigen binding portions thereof, of theinvention bind to the ellular domain of human B7-H3 (SEQ ID NO: 152) with a dissociationconstant (KD) of about 1 X 10'6 M or less, as determined by e plasmon resonance. Alternatively,the antibodies, or antigen binding portions thereof, bind to human B7-H3 with a KD of between about1 X 10'6 M and about 1 X 10'11 M, as determined by surface plasmon resonance. In a furtheralternative, antibodies, or antigen binding portions thereof, bind to human B7-H3 with a KD ofbetween about 1 X 10'6 M and about 1 X 10'7 M, as determined by surface plasmon resonance.

Alternatively, dies, or antigen binding ns thereof, of the invention binds to human B7-H3with a KD of between about 1 X 10'6 M and about 5 X 10'11 M, about 1 X 10'6 M and about 5 X 10'10M;a KD of between about 1 X 10'6 M and about 1 X 10'9 M; a KD of between about 1 X 10'6 M and about 5X 10'9 M; a KD of between about 1 X 10'6 M and about 1 X 10'8 M; a KD of between about 1 X 10'6 Mand about 5 X 10'8 M; a KD of between about 1 X 10'7 M and about 3.4 X 10'11 M; a KD of betweenabout 5.9 X 10'7 M; and about 2.2 X 10'7 M, as determined by surface plasmon resonance.

In one embodiment, the antibodies, or antigen binding portions thereof, of the invention bindto human B7-H3 (SEQ ID NO: 149) with a KD of about 1 X 10'6 M or less, as determined by surfacen resonance. Alternatively, the antibodies, or antigen binding portions thereof, of the inventionbind to human B7-H3 (SEQ ID NO: 149) with a KD of between about 8.2 X 10'9 M and about 6.3 X 10'M; a KD of between about 8.2 X 10'9 M and about 2.0 X 10'9 M; a KD of between about 2.3 X 10'9 Mand about 1.5 X 10'10 M, as determined by surface plasmon resonance.

MEl 24985843V.1 89117813-12620The foregoing establish a novel family of B7-H3 binding proteins, isolated in ance withthis invention, and including antigen binding polypeptides that se the CDR sequences listed inthe Sequence Table provided herein.

Anti-B7-H3 antibodies ed herein may comprise a heavy chain variable regioncomprising CDRl, CDR2 and CDR3 sequences and a light chain le region comprising CDRl,CDR2 and CDR3 sequences, wherein one or more of these CDR sequences comprise specified aminoacid sequences based on the antibodies described herein (e. g., huAbl3vl or huAb3v2.5), orvative cations thereof, and n the antibodies retain the desired onal propertiesof the anti-B7-H3antibodies described herein. Accordingly, the anti-B7—H3 antibody, or antigenbinding portion thereof, may comprise a heavy chain variable region comprising CDRl, CDR2, andCDR3 sequences and a light chain variable region sing CDRl, CDR2, and CDR3 sequences,n: (a) the heavy chain variable region CDR3 sequence comprises SEQ ID NO: 12 or 35, andconservative modifications thereof, e. g., l, 2, 3, 4, 5, l-2, 1-3, l-4 or l-5 conservative amino acidsubstitutions; (b) the light chain variable region CDR3 sequence comprises SEQ ID NO: 15 or 39, andconservative modifications thereof, e. g., l, 2, 3, 4, 5, l-2, 1-3, l-4 or l-5 conservative amino acidsubstitutions; (c) the antibody specifically binds to B7-H3, and (d) the antibody exhibits l, 2, 3, 4, 5,6, or all of the following onal properties described herein, e.g., g to soluble human B7-H3.

In a one embodiment, the heavy chain variable region CDR2 sequence comprises SEQ ID NO: 140 or34, and conservative modifications thereof, e.g., l, 2, 3, 4, 5, l-2, 1-3, l-4 or l-5 conservative aminoacid substitutions; and the light chain variable region CDR2 sequence comprises SEQ ID NO: 7 or 38,and conservative modifications thereof, e.g., l, 2, 3, 4, 5, l-2, 1-3, l-4 or l-5 conservative amino acidsubstitutions. In another preferred embodiment, the heavy chain variable region CDRl sequencecomprises SEQ ID NO: 10 or 33, and conservative modifications thereof, e. g., l, 2, 3, 4, 5, l-2, 1-3,l-4 or l-5 conservative amino acid substitutions; and the light chain variable region CDRl sequenceses SEQ ID NO: 136, 138, or 37, and conservative modifications thereof, e.g., l, 2, 3, 4, 5, l-2,1-3, l-4 or l-5 conservative amino acid substitutions.

Conservative amino acid substitutions may also be made in portions of the antibodies otherthan, or in addition to, the CDRs. For example, conservative amino acid modifications may be madein a ork region or in the Fc region. A variable region or a heavy or light chain may comprise l,2, 3, 4, 5, l-2, 1-3, l-4, l-5, l-lO, l-15, l-20, l-25, or l-50 conservative amino acid tutionsrelative to the anti-B7-H3 antibody sequences provided herein. In certain ments, the anti-B7-H3antibody comprises a combination of conservative and non-conservative amino acid modification.

To generate and to select CDRs having preferred B7-H3 binding and/or neutralizing activitywith respect to hB7-H3, standard methods known in the art for generating antibodies, or antigenbinding portions thereof, and assessing the B7-H3 binding and/or neutralizing characteristics of thoseMEl 24985843V.l 90-12620antibodies, or antigen binding portions thereof, may be used, including but not limited to thosespecifically described herein.

In certain embodiments, the antibody comprises a heavy chain constant region, such as anIgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM, or IgD constant region. In certain embodiments, the anti-B7-H3 antibody, or antigen binding portion thereof, comprises a heavy chain immunoglobulin constantdomain selected from the group consisting of a human IgG constant domain, a human IgM constantdomain, a human IgE nt domain, and a human IgA constant domain. In further embodiments,the antibody, or antigen binding portion thereof, has an IgGl heavy chain constant region, an IgG2heavy chain constant region, an IgG3 constant region, or an IgG4 heavy chain constant .

Preferably, the heavy chain constant region is an IgGl heavy chain constant region or an IgG4 heavychain constant region. Furthermore, the antibody can comprise a light chain constant region, either akappa light chain constant region or a lambda light chain constant region. Preferably, the dycomprises a kappa light chain constant region. Alternatively, the antibody portion can be, forexample, a Fab fragment or a single chain Fv fragment.

In certain embodiments, the anti-B7-H3 antibody g portion is a Fab, a Fab’, a F(ab’)2, aFv, a disulfide linked Fv, an scFv, a single domain antibody, or a diabody.

In certain embodiments, the anti-B7-H3 antibody, or antigen binding n thereof, is amultispecific antibody, 6. g. a bispecific antibody.

Replacements of amino acid residues in the Fc portion to alter antibody effector function havebeen described (Winter, er al. US Patent Nos. 5,648,260 and 5,624,821, incorporated by reference). The Fc n of an dy mediates several important effector functions 6. g. cytokineinduction, ADCC, phagocytosis, complement dependent cytotoxicity (CDC) and half-life/ ncerate of antibody and n-antibody complexes. In some cases these effector functions are desirablefor eutic antibody but in other cases might be unnecessary or even rious, depending on thetherapeutic objectives. Certain human IgG isotypes, particularly IgG1 and IgG3, mediate ADCC andCDC via binding to FcyRs and complement Clq, tively. Neonatal Fc receptors (FcRn) are thecritical components determining the circulating half-life of dies. In still another embodiment atleast one amino acid residue is replaced in the constant region of the antibody, for example the Fcregion of the antibody, such that effector functions of the antibody are altered.

One embodiment of the invention includes a recombinant chimeric antigen receptor (CAR)comprising the binding regions of the antibodies described herein, e.g., the heavy and/or light chainCDRs of vl. A recombinant CAR, as described herein, may be used to redirect T cellspecificity to an antigen in a human yte n (HLA)-independent fashion. Thus, CARs ofthe invention may be used in immunotherapy to help engineer a human subject’s own immune cells torecognize and attack the subject’s tumor (see, e.g., US. Pat. Nos. 319; 8,389,282; 8,822,647;8,906,682; 8,911,993; 8,916,381; 8,975,071; and US. Patent Appln. Publ. No. US20140322275, eachMEl 24985843V.l 91117813-12620of which is incorporated by reference herein with respect to CAR technology). This type ofimmunotherapy is called ve cell transfer (ACT), and may be used to treat cancer in a subject inneed thereof.

An anti-B7-H3 CAR of the invention ably contains a extracellular antigen-bindingdomain specific for B7-H3, a transmembrane domain which is used to anchor the CAR into a T cell,and one or more ellular signaling domains. In one embodiment of the invention, the CARincludes a transmembrane domain that comprises a transmembrane domain of a protein selected fromthe group consisting of the alpha, beta or zeta chain of the T-cell receptor, CD28, CD3 epsilon, CD45,CD4, CD5, CD8, CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137 andCD154. In one embodiment of the invention, the CAR comprises a costimulatory domain, e.g., acostimulatory domain comprising a functional signaling domain of a protein selected from the groupting of 0X40, CD2, CD27, CD28, CD5, ICAM-1, LFA-l (CD11a/CD18), ICOS (CD278), and4-1BB (CD137). In certain ments of the invention, the CAR comprises an scFv comprisingthe CDR or variable regions described herein 6. g., CDRs or le regions from the huAb13v1antibody, a transmembrane domain, a co-stimulatory domain (6. g., a functional ing domain fromCD28 or 4-1BB), and a signaling domain comprising a functional signaling domain from CD3 (e.g.,CD3-zeta).

In certain embodiments, the invention incudes a T cell comprising a CAR (also referred to asa CAR T cell) comprising antigen g regions, 6. g. CDRs, of the antibodies described herein or anscFv described .

In certain ments of the invention, the CAR comprises a heavy chain le regioncomprising a CDR1 domain comprising an amino acid sequence as set forth in SEQ ID NO: 10, 25, or33; a CDR2 domain sing an amino acid sequence as set forth in SEQ ID NO: 11, 26, 34, 119,132, 140, or 142; and a CDR3 domain comprising an amino acid sequence as set forth in SEQ ID NO:12, 27, or 35; and a light chain variable region comprising a CDR1 domain comprising an amino acidsequence as set forth in SEQ ID NO: 14, 29, 37, 134, 136, or 138; a CDR2 domain comprising anamino acid sequence as set forth in SEQ ID NO: 7, 30, or 38; and a CDR3 domain comprising anamino acid sequence as set forth in SEQ ID NO: 15, 31 or 39.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 11; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 14; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aMEl 24985843V.1 92117813-12620CDR2 having an amino acid sequence as set forth in SEQ ID NO: 132; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR ses a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 132; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion ing (a) a CDR1 having an amino acid ce as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid ce as set forth in SEQ ID NO: 132; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 138; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid ce as set forth in SEQ ID NO: 140; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 140; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain le region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain le domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 140; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aMEl 24985843V.1 93117813-12620CDR1 having an amino acid sequence as set forth in SEQ ID NO: 138; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion ing (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid ce as set forth in SEQ ID NO: 142; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 134; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 142; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 136; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 10; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 142; and (c) a CDR3 having anamino acid sequence as set forth in SEQ ID NO: 12; and a light chain variable region including (a) aCDR1 having an amino acid ce as set forth in SEQ ID NO: 138; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 7; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 15.

In certain embodiments of the invention, the CAR ses a heavy chain variable regioncomprising a CDR1 domain sing an amino acid sequence as set forth in SEQ ID NO: 33; aCDR2 domain comprising an amino acid sequence as set forth in SEQ ID NO: 34; and a CDR3domain comprising an amino acid sequence as set forth in SEQ ID NO: 35; and a light chain variableregion sing a CDR1 domain comprising an amino acid sequence as set forth in SEQ ID NO:37; a CDR2 domain comprising an amino acid sequence as set forth in SEQ ID NO: 38; and a CDR3domain comprising an amino acid sequence as set forth in SEQ ID NO: 39.

In certain ments of the invention, the CAR comprises a heavy chain variable regioncomprising a CDR1 domain comprising an amino acid sequence as set forth in SEQ ID NO: 25; aCDR2 domain comprising an amino acid sequence as set forth in SEQ ID NO: 26 or 119; and a CDR3domain comprising an amino acid sequence as set forth in SEQ ID NO: 27; and a light chain variableregion comprising a CDR1 domain comprising an amino acid sequence as set forth in SEQ ID NO:29; a CDR2 domain comprising an amino acid sequence as set forth in SEQ ID NO: 30; and a CDR3MEl 24985843V.1 94117813-12620domain comprising an amino acid ce as set forth in SEQ ID NO: 31.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 25; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 26; and (c) a CDR3 having anamino acid ce as set forth in SEQ ID NO: 27; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 29; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 30; and (c) a CDR3 having an amino acid sequence as setforth in SEQ ID NO: 31.

In certain embodiments of the invention, the CAR comprises a heavy chain variable domainregion including (a) a CDR1 having an amino acid sequence as set forth in SEQ ID NO: 25; (b) aCDR2 having an amino acid sequence as set forth in SEQ ID NO: 119; and (c) a CDR3 having anamino acid ce as set forth in SEQ ID NO: 27; and a light chain variable region including (a) aCDR1 having an amino acid sequence as set forth in SEQ ID NO: 29; (b) a CDR2 having an aminoacid sequence as set forth in SEQ ID NO: 30; and (c) a CDR3 having an amino acid ce as setforth in SEQ ID NO: 31.

One embodiment of the invention includes a labeled anti-B7-H3 dy, or antibody portionthereof, where the antibody is derivatized or linked to one or more functional molecule(s) (e.g.,another peptide or protein). For example, a d dy can be derived by functionally linking anantibody or antibody portion of the invention (by chemical coupling, genetic fusion, noncovalentassociation or otherwise) to one or more other molecular entities, such as another antibody (e.g., aific antibody or a diabody), a detectable agent, a pharmaceutical agent, a protein or e thatcan mediate the association of the antibody or antibody portion with another molecule (such as astreptavidin core region or a polyhistidine tag), and/or a cytotoxic or therapeutic agent selected fromthe group consisting of a mitotic inhibitor, an antitumor antibiotic, an immunomodulating agent, avector for gene therapy, an alkylating agent, an antiangiogenic agent, an antimetabolite, a boron-containing agent, a rotective agent, a hormone, an antihormone agent, a corticosteroid, aphotoactive therapeutic agent, an oligonucleotide, a radionuclide agent, a topoisomerase inhibitor, akinase inhibitor, a radiosensitizer, and a combination thereof.

Useful detectable agents with which an antibody or dy portion thereof, may bederivatized e fluorescent nds. Exemplary fluorescent detectable agents includefluorescein, cein isothiocyanate, rhodamine, 5-dimethylaminenapthalenesulfonyl chloride,phycoerythrin and the like. An antibody may also be derivatized with detectable enzymes, such asalkaline phosphatase, horseradish dase, glucose oxidase and the like. When an antibody isderivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme usesto produce a detectable reaction product. For e, when the detectable agent horseradishperoxidase is present the addition of hydrogen peroxide and diaminobenzidine leads to a coloredMEl 24985843V.1 95117813-12620reaction product, which is able. An antibody may also be derivatized with biotin, and detectedthrough indirect measurement of avidin or streptavidin binding.

In one embodiment, the antibody of the invention is conjugated to an imaging agent.

Examples of imaging agents that may be used in the compositions and s described hereininclude, but are not limited to, a radiolabel (e.g., ), an enzyme, a fluorescent label, aluminescent label, a bioluminescent label, a magnetic label, and biotin.

In one ment, the antibodies or ADCs are linked to a radiolabel, such as, but not limitedto, indium ( In). 111 Indium may be used to label the antibodies and ADCs described herein for use inidentifying B7-H3 positive tumors. In a certain embodiment, anti-B7-H3 antibodies (or ADCs)described herein are labeled with 111 I via a bifunctional chelator which is a bifunctional cyclohexyldiethylenetriaminepentaacetic acid (DTPA) chelate (see US Patent Nos. 5,124,471; 287; and,286,850, each of which is incorporated herein by reference).

Another embodiment of the invention provides a glycosylated binding protein wherein theanti-B7-H3 antibody or antigen binding portion thereof comprises one or more carbohydrate residues.

Nascent in viva protein production may undergo further processing, known as post-translationalmodification. In particular, sugar (glycosyl) es may be added enzymatically, a process knownas glycosylation. The resulting proteins bearing covalently linked oligosaccharide side chains areknown as glycosylated proteins or glycoproteins. Antibodies are glycoproteins with one or morecarbohydrate residues in the Fc domain, as well as the variable domain. Carbohydrate residues in theFc domain have important effect on the effector function of the Fc domain, with minimal effect onantigen binding or half-life of the antibody (R. Jefferis, Biotechnol. Prog. 21 (2005), pp. 11—16). Incontrast, glycosylation of the variable domain may have an effect on the n g activity ofthe antibody. Glycosylation in the variable domain may have a negative effect on antibody bindingaffinity, likely due to steric nce (Co, M.S., er al., Mol. Immunol. (1993) 1- 1367), orresult in increased ty for the antigen (Wallick, S.C., et al., Exp. Med. (1988) 168: 1099-1 109;, A., et al., EMBO J. (1991) 10:2717-2723).

One aspect of the invention is ed to ting glycosylation site mutants in which theO- or ed glycosylation site of the binding protein has been mutated. One skilled in the art cangenerate such mutants using standard well-known logies. Glycosylation site mutants that retainthe biological activity, but have increased or decreased binding activity, are another object of theinvention.

In still another embodiment, the glycosylation of the anti-B7-H3 dy or antigen bindingportion of the invention is modified. For example, an slated antibody can be made (i.e., theantibody lacks glycosylation). Glycosylation can be altered to, for example, se the affinity ofthe antibody for antigen. Such carbohydrate modifications can be accomplished by, for example,altering one or more sites of glycosylation within the antibody sequence. For example, one or moreamino acid substitutions can be made that result in elimination of one or more variable regionMEl 24985843V.1 96117813-12620glycosylation sites to thereby ate glycosylation at that site. Such aglycosylation may increasethe affinity of the antibody for antigen. Such an approach is described in further detail in PCTPublication W02003016466A2, and US. Pat. Nos. 5,714,350 and 6,350,861, each of which isincorporated herein by reference in its entirety.

Additionally or alternatively, a modified anti-B7-H3 antibody of the invention can be madethat has an altered type of glycosylation, such as a hypofucosylated antibody having d amountsof fucosyl residues or an antibody having increased bisecting GlcNAc structures. Such alteredglycosylation patterns have been demonstrated to increase the ADCC y of dies. Suchcarbohydrate modifications can be accomplished by, for example, expressing the antibody in a hostcell with d glycosylation machinery. Cells with altered glycosylation machinery have beendescribed in the art and can be used as host cells in which to express recombinant antibodies of theion to thereby produce an antibody with d glycosylation. See, for e, Shields, R. L.et al. (2002) J. Biol. Chem. 277:26733-26740; Umana et al. (1999) Nat. Biotech. 17:176-1, as well as,European Patent No: EP 1,176,195; PCT Publications WO 03/035835; WO 99/54342 80, each ofwhich is incorporated herein by reference in its ty.

Protein glycosylation depends on the amino acid sequence of the protein of interest, as well asthe host cell in which the protein is expressed. ent organisms may e entglycosylation enzymes (6. g., glycosyltransferases and glycosidases), and have different substrates(nucleotide sugars) available. Due to such factors, protein glycosylation pattern, and composition ofglycosyl residues, may differ depending on the host system in which the particular protein isexpressed. Glycosyl residues useful in the invention may include, but are not limited to, glucose,galactose, mannose, fucose, n-acetylglucosamine and sialic acid. Preferably the glycosylated bindingprotein comprises glycosyl residues such that the glycosylation pattern is human.

Differing protein glycosylation may result in differing protein characteristics. For instance,the cy of a therapeutic protein produced in a microorganism host, such as yeast, andglycosylated utilizing the yeast endogenous pathway may be reduced compared to that of the sameprotein expressed in a mammalian cell, such as a CHO cell line. Such glycoproteins may also beimmunogenic in humans and show reduced half-life in viva after administration. Specific receptors inhumans and other animals may recognize specific glycosyl residues and e the rapid clearanceof the protein from the bloodstream. Other adverse effects may e changes in n folding,solubility, susceptibility to ses, cking, transport, compartmentalization, secretion,recognition by other ns or factors, antigenicity, or allergenicity. Accordingly, a practitioner mayprefer a therapeutic protein with a specific composition and pattern of glycosylation, for exampleglycosylation composition and pattern identical, or at least similar, to that produced in human cells orin the species-specific cells of the intended subject animal.

Expressing ylated proteins different from that of a host cell may be achieved bygenetically modifying the host cell to express heterologous glycosylation enzymes. UsingMEl 24985843V.1 97117813-12620recombinant techniques, a practitioner may generate antibodies or antigen binding ns thereofexhibiting human protein glycosylation. For example, yeast strains have been genetically modified toexpress non-naturally occurring glycosylation enzymes such that glycosylated proteins(glycoproteins) produced in these yeast strains exhibit protein glycosylation cal to that of animalcells, especially human cells (US. patent Publication Nos. 18590 and 20020137134 and PCTpublication WO2005 100584 A2).

Antibodies may be produced by any of a number of techniques. For example, expressionfrom host cells, wherein expression vector(s) encoding the heavy and light chains is (are) transfectedinto a host cell by standard ques. The various forms of the term “transfection” are intended toencompass a wide variety of techniques commonly used for the introduction of exogenous DNA intoa yotic or eukaryotic host cell, e.g., electroporation, calcium-phosphate precipitation, DEAE-dextran transfection and the like. Although it is possible to s antibodies in either prokaryotic oreukaryotic host cells, expression of antibodies in otic cells is preferable, and most preferable inmammalian host cells, because such eukaryotic cells (and in particular mammalian cells) are morelikely than prokaryotic cells to assemble and secrete a properly folded and immunologically activeantibody.

Preferred mammalian host cells for expressing the recombinant antibodies of the inventioninclude Chinese r Ovary (CHO cells) (including dhfr- CHO cells, bed in Urlaub andChasin, (1980) Proc. Natl. Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker, e.g.,as described in R]. Kaufman and PA. Sharp (1982) Mol. Biol. 159:601-621), NSO myeloma cells,COS cells and SP2 cells. When recombinant expression vectors encoding antibody genes areintroduced into mammalian host cells, the antibodies are ed by culturing the host cells for aperiod of time sufficient to allow for sion of the antibody in the host cells or, more preferably,secretion of the antibody into the culture medium in which the host cells are grown. dies canbe recovered from the culture medium using standard protein purification s.

Host cells can also be used to produce functional antibody fragments, such as Fab fragmentsor scFv molecules. It will be understood that variations on the above procedure are within the scopeof the ion. For example, it may be ble to transfect a host cell with DNA encodingfunctional fragments of either the light chain and/or the heavy chain of an antibody of this invention.

Recombinant DNA technology may also be used to remove some, or all, of the DNA ng eitheror both of the light and heavy chains that is not necessary for binding to the antigens of interest. Themolecules expressed from such truncated DNA molecules are also encompassed by the antibodies ofthe invention. In addition, bifunctional antibodies may be ed in which one heavy and one lightchain are an antibody of the invention and the other heavy and light chain are specific for an antigenother than the antigens of interest by crosslinking an antibody of the invention to a second antibody bystandard chemical crosslinking methods.

MEl 24985843V.l 98117813-12620In a preferred system for recombinant expression of an antibody, or n binding nthereof, a recombinant expression vector encoding both the antibody heavy chain and the antibodylight chain is uced into dhfr- CHO cells by calcium phosphate-mediated transfection. Withinthe recombinant expression vector, the antibody heavy and light chain genes are each operativelylinked to CMV enhancer/AdMLP promoter regulatory elements to drive high levels of transcription ofthe genes. The recombinant sion vector also carries a DHFR gene, which allows for selectionof CHO cells that have been transfected with the vector using methotrexate selection/amplification.

The selected transformant host cells are cultured to allow for expression of the antibody heavy andlight chains and intact antibody is recovered from the culture . Standard molecular biologytechniques are used to prepare the recombinant expression vector, transfect the host cells, select fortransformants, culture the host cells and recover the antibody from the culture medium. Still furtherthe invention es a method of synthesizing a recombinant antibody of the invention by culturinga host cell in a suitable culture medium until a recombinant antibody is synthesized. Recombinantdies of the invention may be produced using nucleic acid molecules ponding to the aminoacid sequences disclosed herein The method can further comprise isolating the recombinant antibodyfrom the culture medium.

The N- and C-termini of antibody polypeptide chains of the t invention may differ fromthe ed sequence due to commonly observed post-translational modifications. For example, C-terminal lysine residues are often missing from antibody heavy chains. Dick et al. (2008) Biotechnol.. 100:1132. N-terminal glutamine residues, and to a lesser extent glutamate residues, arefrequently converted to pyroglutamate residues on both light and heavy chains of therapeuticantibodies. Dick et al. (2007) Biotechnol. Bioeng. 97:544; Liu et al. (2011) JBC 28611211; Liu et al.(2011) J. Biol. Chem. 286211211.111. Anti-B7-H3 Antibody Drug Conjugates (ADCs)Anti-B7-H3 antibodies described herein may be conjugated to a drug moiety to form an anti-B7-H3 Antibody Drug Conjugate (ADC). Antibody-drug conjugates (ADCs) may increase thetherapeutic efficacy of antibodies in treating disease, 6. g., cancer, due to the ability of the ADC toively deliver one or more drug moiety(s) to target tissues, such as a associated antigen,e.g., B7-H3 expressing tumors. Thus, in certain embodiments, the invention es anti-B7-H3ADCs for therapeutic use, e.g., treatment of .

Anti-B7-H3 ADCs of the invention comprise an anti-B7-H3 antibody, i.e., an antibody thatspecifically binds to B7-H3, linked to one or more drug moieties. The icity of the ADC isdefined by the specificity of the antibody, i.e., anti-B7-H3. In one embodiment, an anti-B7-H3antibody is linked to one or more cytotoxic drug(s) which is delivered internally to a transformedcancer cell sing B7-H3.

MEl 24985843V.1 99117813-12620Examples of drugs that may be used in the anti-B7-H3 ADC of the invention are providedbelow, as are linkers that may be used to conjugate the antibody and the one or more drug(s). Theterms 93 “agent,” and “drug moiety” are used interchangeably herein. The terms “linked” and“conjugated” are also used hangeably herein and indicate that the antibody and moiety arecovalently linked.

In some embodiments, the ADC has the following formula (formula I):(I) ( D—L—LKfiAbwherein Ab is the dy, e.g., anti-B7-H3 antibody huAb13v1, huAb3v2.5, or huAb3v2.6, and (L)is a linker, (D) is a drug, and LK represents a covalent linkage linking linker L to antibody Ab; and mis an integer g from 1 to 20. D is a drug moiety having, for example, cytostatic, xic, orotherwise eutic activity against a target cell, e.g., a cell expressing B7-H3. In someembodiments, mranges from 1 to 8, 1 to 7, 1 to 6, 2 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2, 1.5 to 8, 1.5 to 7,1.5 to 6, 1.5 to 5, 1.5 to 4, 2 to 6, 1 to 5, 1 to 4, 1 to 3, 1 to 2,or 2 to 4. The DAR ofan ADC isequivalent to the “m” referred to in a I. In one embodiment, the ADC has a formula of Ab-(LK-L-D)m, n Ab is an anti-B7-H3 antibody, e.g.huAb13v1, huAb3v2.5, or huAb3v2.6, L is alinker, D is a drug, 6. g., a Bcl-xL inhibitor or an atin such as MMAF or MMAE, and m is 2 to 4(equivalent to a DAR of 2-4). Additional details regarding drugs (D of Formula I) and linkers (L ofFormula I) that may be used in the ADCs of the invention, as well as alternative ADC structures, aredescribed below.111. A. Anti-B7—H3 ADCs: Bcl-xL Inhibitors, Linkers, Synthons, and Methods of Making SameDysregulated apoptotic pathways have also been implicated in the pathology of cancer. Theimplication that down-regulated apoptosis (and more particularly the Bcl-2 family of proteins) isinvolved in the onset of cancerous malignancy has revealed a novel way of targeting this still elusivedisease. Research has shown, for example, the anti-apoptotic proteins, Bcl 2 and Bcl-xL, are over-expressed in many cancer cell types. See, Zhang, 2002, Nature Reviews/Drug Discovery 1:101;Kirkin et al., 2004, Biochimica Biophysica Acta 1644:229-249; and on et al., 2000, CancerResearch 60:6101-6110. The effect of this lation is the survival of altered cells which wouldotherwise have undergone apoptosis in normal conditions. The repetition of these defects associatedwith unregulated proliferation is thought to be the starting point of cancerous ion.

Aspects of the disclosure concern anti-hB7-H3 ADCs sing an anti-hB7-H3 antibodyconjugated to a drug via a , wherein the drug is a Bcl-xL inhibitor. In specific embodiments, theADCs are compounds according to structural a (I) below, or a pharmaceutically acceptable saltthereof, wherein Ab represents the anti-hB7-H3 antibody, D represents a Bcl-xL inhibitor drug (i.e., aMEl 24985843V.1 100117813-12620compound of formula (11a), (11b), (11c), or (IId) as shown below), L represents a linker, LK entsa covalent linkage g the linker (L) to the anti-hB7-H3 antibody (Ab) and m represents thenumber of D-L-LK units linked to the antibody, which is an integer ranging from 1 to 20. In certainembodiments, m is 2, 3 or 4. In some embodiments, m ranges from 1 to 8, l to 7, l to 6, 2 to 6, l to 5,lto4,2to4,lto3,lt02,oris l.

(I) ( D—L—LKfiAbSpecific embodiments of s Bcl-XL inhibitors per se, and various Bcl-XL inhibitors (D),linkers (L) and anti-B7-H3 antibodies (Ab) that can comprise the ADCs described herein, as well asthe number of Bcl-XL inhibitors linked to the ADCs, are bed in more detail below.es of Bcl-XL inhibitors that may be used in the anti-B7-H3 ADC of the invention areprovided below, as are linkers that may be used to conjugate the antibody and the one or more Bcl-XLinhibitor(s). The terms “linked” and “conjugated” are also used interchangeably herein and indicatethat the antibody and moiety are covalently linked.

III.A.1. Bcl-XL InhibitorsOne aspect of the instant disclosure concerns Bcl-XL inhibitors that have low cellbility. The compounds are generally heterocyclic in nature and include one or moresolubilizing groups that impart the compounds with high water solubility and low cell permeability.

The solubilizing groups are generally groups that are capable of en g, forming dipole-dipole interactions, and/or that include a polyethylene glycol polymer containing from 1 to 30 units,one or more polyols, one or more salts, or one or more groups that are charged at physiological pH.

The Bcl-XL inhibitors may be used as compounds or salts per se in the various methodsdescribed herein, or may be included as a component part of an ADC.

Specific embodiments of Bcl-XL tors that may be used in unconjugated form, or thatmay be included as part of an ADC include compounds according to structural formulae (11a), (11b),(11c), or (IId). In the present ion, when the Bcl-XL inhibitors are included as part of an ADC, #shown in structural formula (11a), (11b), (11c), or (IId) below represents a point of attachment to alinker, which indicates that they are represented in a dical form.

MEl 24985843V.1 101-12620(Ila)(11b)(IIC)(11d)or a pharmaceutically acceptable salt thereof, wherein:MEI 24985843V.1 102117813-12620— — NN / \ N \ /Ar1 is selected from6 \ / / \N N \ /I du'vvNANH NANH NJ\\C} N<\ /> < \NN \ /and and is optionally substituted with one or more substituents, ,independently selected from halo, hydroxy, nitro, lower alkyl, lower alkyl, C1,4alkoxy, amino,cyano and halomethyl;Ar2 is selected COCKQEDEURECKCEA’army?“N/fi N/FN/fi / \and is optionally substituted with one or more substituents independently selected from halo, hydroxy,nitro, lower alkyl, lower heteroalkyl, C1,4alkoxy, amino, cyano and halomethyl, wherein the Rlz-ZZb-,R’-ZZb-, #-N(R4)-R13-ZZb-, or #-R’-ZZb- tuents are attached to Ar2 at any Ar2 atom capable ofbeing substituted;Z1 is selected from N, CH, C-halo, C-CH3 and C-CN;223 and ZZbare each, independently from one another, ed from a bond, NR6, CRGaRéb, O,3, 3(0), 3(0)2, -NR6C(O)-,-NR63C(O)NR6b-, and —NR6C(O)O-;R’ is a alkylene, heteroalkylene, lkylene, heterocyclene, aryl or heteroarylndently substituted at one or more carbon or heteroatoms with a solubilizing moiety containinga group selected from a polyol, a polyethylene glycol containing from 4 to 30 ethylene glycol units, asalt, and a group that is charged at logical pH and combinations f, wherein #, whereattached to R’, is attached to R’ at any R’ atom capable of being substituted;R1 is selected from hydrogen, methyl, halo, halomethyl, ethyl, and cyano;R2 is selected from hydrogen, methyl, halo, halomethyl and cyano;R3 is selected from hydrogen, methyl, ethyl, halomethyl and haloethyl;R4 is selected from hydrogen, lower alkyl and lower heteroalkyl or is taken together with anatom of R13 to form a cycloalkyl or heterocyclyl ring haVing between 3 and 7 ring atoms;R6, R6" and R61) are each, independent from one another, selected from hydrogen, optionallysubstituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted cycloalkyl andMEI 24985843V.1 103117813-12620optionally substituted heterocyclyl, or are taken together with an atom from R4 and an atom from R13to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms;R11a and R11b are each, independently of one another, selected from hydrogen, halo, methyl,ethyl, halomethyl, hydroxyl, methoxy, CN, and SCH3;R12 is optionally R’ or is selected from hydrogen, halo, cyano, ally tuted alkyl,ally substituted heteroalkyl, optionally substituted heterocyclyl, and optionally substitutedcycloalkyl;R13 is selected from optionally tuted CH; alkylene, optionally substituted heteroalkylene,optionally substituted heterocyclene, and optionally substituted cycloalkylene; and# represents the point of attachment to a linker L.

One embodiment of Bcl-XL inhibitors that may be used in unconjugated form, or that may beincluded as part of an ADC include compounds according to ural formulae (Ila), (11b), (11c), or(11d):(Ila)(11b)(IIc)MEl 24985843V.1 104-12620(11d)NANH NJ\\N / \ /Nand and is optionally substituted with one or more substituents independentlyselected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C1,4alkoxy, amino, cyano andhalornethyl;N, (U CO {I}r T a a T s‘Ar2 is selected from W ww ww WW, , 5 5(,1), gag, @: (gr/A,0 /N N/ N\| | //N/1 NCN/m N//\N \u x :3 XV? / «1mm “"m W‘s» and ”7‘” or an N-oxide thereof, and is,optionally substituted with one or more substituents independently selected from halo, y, nitro,lower alkyl, lower heteroalkyl, C1,4alkoxy, amino, cyano and halornethyl, wherein the Rlz-ZZb-, R’-ZZb-, #-N(R4)-R13-ZZb-, or #-R’-ZZb- substituents are ed to Ar2 at any Ar2 atom e of beingsubstituted;Z1 is selected from N, CH, C-halo, C-CH3 and C-CN;Z2a and ZZbare each, independently from one another, selected from a bond, NR6, CRGaRéb, O,3, 3(0), S(O)2, -NR6C(O)-,-NR63C(O)NR6b-, and —NR6C(O)O-;MEI 24985843V.1 105117813-12620R, is Elyxlifibpaxg or $X9F§P3X§ wherein #, where attached to R’, is attachedto R’ at any R’ atom e of being tuted;X’ is selected at each occurrence from -N(R10)-, -N(R10)C(O)-, -N(R10)S(O)2-, -S(O)2N(R10)-,and -O-;n is selected from 0-3;R10 is independently selected at each occurrence from hydrogen, lower alkyl, heterocycle,aminoalkyl, G-alkyl, and -(CH2)2-O-(CH2)2-O-(CH2)2-NH2;G at each occurrence is independently selected from a polyol, a polyethylene glycol withbetween 4 and 30 repeating units, a salt and a moiety that is d at physiological pH;SPa is independently selected at each occurrence from , -S(O)2N(H)-, -N(H)S(O)2-,-N(H)C(O)-, (H) -, -N(H)- and optionally substituted methylene;, arylene, heterocyclene,wherein ene is optionally substituted with one or more of -NH(CH2)2G, NHZ, C1,8alkyl, andcarbonyl;m2 is selected from 0-12;R1 is selected from hydrogen, methyl, halo, halomethyl, ethyl, and cyano;R2 is selected from hydrogen, , halo, halomethyl and cyano;R3 is selected from hydrogen, methyl, ethyl, halomethyl and haloethyl;R4 is selected from hydrogen, lower alkyl and lower heteroalkyl or is taken together with anatom of R13 to form a cycloalkyl or heterocyclyl ring haVing between 3 and 7 ring atoms;R6, R6" and R61) are each, independent from one another, selected from hydrogen, optionallysubstituted lower alkyl, ally substituted lower heteroalkyl, optionally substituted cycloalkyl andoptionally substituted heterocyclyl, or are taken er with an atom from R4 and an atom from R13to form a cycloalkyl or heterocyclyl ring haVing between 3 and 7 ring atoms;R113 and R11b are each, independently of one another, selected from hydrogen, halo, methyl,ethyl, halomethyl, hydroxyl, methoxy, CN, and SCH3;R12 is optionally R’ or is selected from hydrogen, halo, cyano, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl, and optionally tutedcycloalkyl;R13 is selected from optionally substituted CH; alkylene, ally substituted alkylene,optionally substituted heterocyclene, and optionally substituted cycloalkylene; and# represents the point of attachment to a linker L.

When a Bcl-XL inhibitor of structural formulae (IIa)-(IId) is not a component of an ADC, # informulae (IIa)-(IId) represents the point of attachment to a hydrogen atom. When the Bcl-XL inhibitoris a component of an ADC, # in formulae (IIa)-(IId) ents the point of attachment to the linker.

MEI 24985843V.1 106117813-12620When a Bcl-xL inhibitor is a component of an ADC, the ADC may comprise one or more Bcl-xLinhibitors, which may be the same or different, but are typically the same.

In n embodiments, R’ is a C2-C8 alkylene substituted with one or more moietiescontaining a salt and/or a group that is charged at physiological pH. The salt may be selected, forexample, from the salt of a carboxylate, a sulfonate, a phosphonate, and an ammonium ion. Forexample, the salt may be the sodium or potassium salt of a ylate, sulfonate or phosphonate orthe chloride salt of an ammonium ion. The group that is charged at physiological pH may be anygroup that is charged at a physiological pH, including, by way of e and not limitation, azwitterionic group. In certain embodiments a group that is a salt is a dipolar moiety such as, but notd to, N-oxides of amines including certain heterocyclyls such as, but not limited to, ne andine. In specific embodiments the group that is charged at physiological pH is selectedindependently at each occurrence, from carboxylate, sulfonate, phosphonate, and amine.

In certain embodiments, R’ is a C2-C8 heteroalkylene substituted with one or more moietiescontaining polyethylene glycol or a polyol such as a diol or a sugar moiety.

In certain embodiments, R’ may be tuted with groups in addition to a lizingmoiety. For example, R’ may be substituted with one or more of the same or different alkyl,heteroalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or halo groups.

In certain embodiments, R’ is represented by the formula:iii/Vxlifiépaxgor a pharmaceutically acceptable salt thereof, wherein:X‘ is selected at each occurrence from -N(R10)- and -O-;n is selected from 1-3;R10 is indiVidually selected at each ence from hydrogen, alkyl, heterocycle, aminoalkyl,G-alkyl, heterocycle, and -(CH2)2-O-(CH2)2-O-(CH2)2-NH2;G at each occurrence is independently selected from a polyol, a polyethylene glycol withbetween 4 and 30 repeating unit (referred to herein as PEG4-30), a salt and a moiety that is charged atphysiological pH;SPa is independently selected at each occurrence from , amide, arylene,heterocyclene, and optionally tuted methylene; wherein methylene is optionally tuted withone or more of —NH(CH2)2G, amine and carbonyl; andm2 is selected from 0-6,wherein there is at least one substitutable nitrogen in R’ that is attached to a linker or ahydrogen atom at a substitutable nitrogen atom of R’.

In certain embodiments, R’ is Elyxlflmfi or $X'flpif;MEl 24985843V.1 107117813-12620X’ is selected at each occurrence from -N(R10)-, -N(R10)C(O)-, )S(O)2-, -S(O)2N(R10)-,and -O-;n is selected from 0-3;R10 is independently selected at each occurrence from en, alkyl, heterocycle,aminoalkyl, G-alkyl, heterocycle, and -(CH2)2-O-(CH2)2-O-(CH2)2-NH2;G at each ence is independently selected from a polyol, a polyethylene glycol withbetween 4 and 30 repeating units, a salt and a moiety that is charged at physiological pH;SPa is independently selected at each occurrence from -S(O)2N(H)-, -N(H)S(O)2-,-N(H)C(O)-, -C(O)N(H) -, -N(H)- and optionally substituted methylene;, arylene, heterocyclene,n methylene is optionally substituted with one or more of —NH(CH2)2G, amine, alkyl, andcarbonyl;m2 is selected from 0-12, and#, where attached to R’, is attached to R’ at any R’ atom capable of being substituted.

In certain embodiments, G at each occurrence is a salt or a moiety that is d atlogical pH.

In certain embodiments, G at each occurrence is a salt of a carboxylate, a sulfonate, aphosphonate, or ammonium.

In certain embodiments, G at each occurrence is a moiety that is charged at physiological pHselected from the group consisting of carboxylate, a sulfonate, a phosphonate, and an amine.

In certain embodiments, G at each ence is a moiety containing a polyethylene glycolwith n 4 and 30 repeating units, or a polyol.

In certain ments, the polyol is a sugar.

In certain ments, R’ of formula (IIa) or (IId) includes at least one substitutablenitrogen suitable for attachment to a linker.

In certain embodiments, G is selected independently at each occurrence from:OH OHO OiLL)J\OM 0”(I O ’1‘ Horji'OH HTIOHEL 0 “a; 0 0/0"35 5 5 5OH 0 CH3 OHJOH OM H Ha 0 NW a/WIO OM CH3 and gym wherein M is hydrogenor a positively charged counterion. In certain embodiments, M is Na+, K+ or Li+. In certainembodiments, M is hydrogen. In particular embodiments, G is SO3H.

MEl 24985843V.1 108117813-12620In certain embodiments, G is selected independently at each ence from:OH OHOH OHo HO OH HO OHA g\o O0M5E5M5/ \ “’71 OH /CH z, 3OH 53 535 00 5aim—III OHOM IFI’ N:/P\OM 5EICH3/I \CH3 E/I\CH3/| I:0 51‘" IM CH3 537“ ifwherein M is hydrogen or a positively charged counterion. In certain embodiments, M is hydrogen.

In particular embodiments, G is SO3H.

In certain embodiments, R’ is selected from:O H o/N\/\O/\/O\)I\OHH /N\/\ ”—EgoH HO“ ,O wZL/\/ N N CHS/ \/\”S\\/E bH OHHO 0“st/VN HHO OH NJ:OH EN OHENme/fio OHO O\\S,OHOH 'ZLL/\/ WNW \\OO OMEl 24985843V.1 109117813-12620H ,0 o‘771/\/ \/\P’_OH H \‘P/OHOH 51%” W\ OHEH3 NH2 |CSIJOH NH2 §,0HH o'771/\/ W \\0 31m \n)\/ O\ II,OH\O 31/\/ \/\H/\/\IlaO O OH5 5HO OHCH3 NH2 01i/\/ OH K/OO \/\NH20 HQL)” HHO OH O O N OH \ /OH‘zLL/\/NH OH EN \/\n/O EA/NWROHH (EH3 NH2 CH3 Q 00 CH3 OHH QLL‘L/\/N (\NHZILA/N\/\S:’O 31/\/ \/\n/N OHO / \O OH HO O5 0\\ No HO *771/\/5 5“@520 HO\ 00MEI 24985843V.1 1 10117813-12620o O‘CH3 0 OHOH OHHO HOOH OH5Hos/,0:OkgO 0 OH H OHENN HO OH ”EA/NwNVkOHOH and H or a salt thereof.

,When Bcl-XL inhibitors of this embodiment are included in an ADC, the linker of the ADC is linkedto the nitrogen atom of an available primary or secondary amine group.

In certain embodiments, R’ is selected from:“st/VN HHO OH NJ:OH EN OHOH /VséOO O H5H o“ti/WNWP’LOH H QED/OHOH 53;” W\ OHEH3 NH2 ICSIJOH NH2 §,0HH oill/V W \\O 551/\/ \n)\/ \\O Emowmmllé’OI-IO O OHMEI 24985843V.1 1 1 1117813-12620HO OHCH3 NH2 0 N OH/ OH |\/OO \/\NH2H 9H3 NH2 CH3 €21| O||,/ON\)J\OH §0 CH3 OHO H /\/NO 05%Ho\s”:0 HO\ 00H 820NH2 0 H H OEA/ NOHN 2"N OH HENNwN/VROO OH H HO5 5“WI :NN\ N\31m H\/\/[\’N N NO wZL/\/0 ‘CH3 0 OHOH OHHO HOOH OHMEI 24985843V.1 1 12117813-12620HO\ //0 o 0amNHQHO OH ENNwNVLOH 8OH H MI0 o So o o S S S [O oL0 E0 O 'HN o ofE o E M —\_'L H_\_N NH2 ‘5 f\/\M NH2\ NH 0HO OHHO OH0/ 0N N\ o\ IN H \ UNH N' N%(\¢r EKNN/NHO OHWVHO OH_/—NH ” 0H HH3 E OHOH OHN OHOH OH OHMEI 24985843V.1 1 13117813-12620are included in an ADC, the linker of the ADC is linked to the en atom of an available primaryor secondary amine group.1'?! OIn certain embodiments, R’ is selected from ‘SZ/VN\/\O/\/O\)J\OH/\/N #.777. HO OH EA/N'J:OH OH00 #, ,MEl 24985843V.1 1 14117813-12620CH3 NHENNWHVE/OH §:OH O“\O wi/VNWQO ENO$NMIIDIOHO # OHif HO OHCH3 NH O /\/N\/\ OH.771 OO HOH /N\ OH N Pam # \/\([)]/531W W \OH 50 CH3OH5/\/N Q51L HN O N OHO OH HO O05 5HO\|I/OH HN,# P”NNWKK/SI O H/\/N\O/\ /\/N OHx ‘5 a w Wo # o5E HO\ ”(3,OH H‘0 # CYSQO E HN O/\/ \/\ /\/N \/\[C5)/OH ‘25-H ENNMOH'73/\/N OHMEI 24985843V.1 1 15117813-12620HOJD #\«/\V/fl: NN S:0 N rEN O0 \CH3N HEN HOH /\/N\/\E /\/,S§ OH$ OHO HOOH # OH# N. I‘N o‘7’1/\/N N,0“ NHO OHHO EKA\/OH OH5HO\ ”O N\#(J O E—q\—NI o \NAAOH 8 §_\_N/\/\N’# EN# NW \5 5 ‘#5J/o o LW0 o o S S S [O oo o o 'J; E J/ HO OHHN o oo o/H N‘fV\N N N/#H H EJNINO ”EL/V 5HO OHMEI 24985843V.1 1 16117813-12620HO OH#\H OH OHN OHH HOWNN‘;3% IOH OH OH #KWNVL N| H OOHH EA/ \/\(\OHM” # OH5 50 OH#\/O/0 0 HO OHOH ifN OHOH O and,lit 0“ 40‘J‘JJv NWS\OH wherein # represents either a hydrogen atom in the Bel-XL inhibitor drug ofthe ADCs of formula (IIb) or (110) or the point of attachment in the Bel-XL inhibitor drug of the ADCsof a (Ila) or (11d) to a linker L.

MEl 24985843V.1 1 17117813-12620and is optionally tuted with one or more substituents independently selected from halo,N Scyano, methyl, and halomethyl. In particular embodiments, Ar1 is 6.

In certain embodiments, Ar2 is optionally substituted with one or moresubstituents, wherein the b-, R’-ZZb-, #-N(R4)-R13-ZZb-, or Zb- substituents are attached toAr2 at any Ar2 atom capable of being tuted.

In certain embodiments, Ar2 is selected N; ::N \e‘é @{g,wlw"L‘s, and "“4, and is optionally substituted with one or more substituents,wherein the Rlz-ZZb-, R’-ZZb-, #-N(R4)-R13-ZZb-, or #-R’-ZZb- substituents are attached to Ar2 at anyAr2 atom capable of being substituted. In certain embodiments, Ar2 is selected from: wlw”rhododco9Ué,/N/W N/ NFN/W\ e, KN),"‘1' NW and WW, ; and is ally substituted with one ormore substituents, wherein the Rlz-ZZb-, R’-ZZb-, #-N(R4)-R13-ZZb-, or #-R’-ZZb- substituents areattached to Ar2 at any Ar2 atom capable of being substituted. In certain embodiments, Ar2 issubstituted with one or more solubilizing group. In certain embodiments, the each solubilizing groupMEl 24985843V.1 1 18-12620is, ndently of the others, selected from a moiety containing a polyol, a polyethylene glycol withbetween 4 and 30 repeating units, a salt, or a moiety that is charged at physiological pH.

In certain ments, Z1 of formulae (IIa)-(IId) is N.

In n embodiments, Z2a of ae (IIa)-(IId) is O. In certain embodiments, Z2a offormulae (IIa)-(IId) is CRéaRéb. In certain embodiments, Z2a of formulae (IIa)-(IId) is S. In nments, Z2a of formulae (IIa)-(IId) is —NR6C(O)-. In particular embodiments, R6 is hydrogen.

In certain embodiments, 22b of formulae (IIa)-(IId) is O. In certain embodiments, 22b offormulae (IIa)-(IId) is NH or CH2.

In certain embodiments, R1 of formulae (IId) is selected from methyl and chloro.

In certain embodiments, R2 of formulae (IIa)-(IId) is selected from hydrogen and methyl. Inparticular embodiments, R2 is hydrogen.

In certain embodiments the Bcl-XL inhibitor is a compound of formula (IIa). In certainembodiments in which the Bcl-XL inhibitor is a compound of formula (IIa), the compound has thestructural formula (11a. 1),R12’Z\2b O@ OH 3‘1 ZaQVOWN:Yr s #HN NIZQ R11a(11a. 1)or salts f, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R113, Rllb, R12’ G and # are defined as above;Y is optionally substituted C1-C8 alkylene;r is 0 or 1; ands is l, 2 or 3.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), r is 0and s is 1.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), r is 0and s is 2.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), r is land s is 2.

In certain ments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), Z2a isselected from O, NH, CH2 and S. In particular embodiments, Z2a is O. In certain embodiments, Z2a offormula (IIa.l) is -CR63R6b-. In n embodiments, Z2a of formula (11a. 1) is CH2. In certainMEl 24985843V.1 1 19117813-12620embodiments, Z2a of formula (Ila. l) is S .

In certain embodiments, Z2a of formula ) is-NR6C(O)-.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), Y isselected from ethylene, ene and butylene. In particular embodiments, Y is selected fromethylene and propylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), G isO O 0 CH3|| ||)KOM Ii]:E/§=o 11/ FI’\0M 21/ I CH3selected from ‘3‘- OM OM and CH3 n M is hydrogen or a, , ,'771/ |positively charged counterion. In particular embodiments, G is OM. In particular embodiments,G is SO3H.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), Ar2 isselected fromWN/fi >/\N/fil ,Q3}; Elva;N 0and (film;"m m m’ wherein the b- substituent isattached to Ar2 at any Ar2 atom capable of being substituted.

In n embodiments in which the Bcl-XL inhibitor is a compound of formula (11a. 1), Ar2 isselected from(WIDE; kK/N\jPN/fi )PN/fi:/ N\@5 @195I IN O4W}, [11% [1mg’ n the Rlz-ZZb-substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

MEl 24985843V.1 120117813-12620In particular embodiments in which the Bcl-XL inhibitor is a compound of formula (Ha. 1), Ar2is w . In particular embodiments in which the Bcl-XL inhibitor is a compound offormula , Ar2 is wIn certain embodiments in which the Bcl-XL inhibitor is a compound of formula (Ha. 1), 22b-R12 is selected from H, F, CN, OCH3, OH, NHZ, OCHZCHZOCH3, N(CH3)C(=O)CH3,CH2N(CH3)C(=O)CH3SCH3, C(=O)N(CH3)2 and OCHZCH2N(CH3)(C(=O)CH3). In particularembodiments, ZZb-R12 is selected from H, F and CN. In particular embodiments, ZZb-R12 is H.

In embodiments where ZZb-R12 is substituted with hydroxyl (OH), the oxygen can serve as thepoint of attachment to a g group (See Section 4.4.1.1).

In certain embodiments in which the Bcl-XL inhibitor is a compound of a (Ha. 1), Ar1 isIn certain ments in which the Bcl-XL inhibitor is a compound of a (Ha. 1), thezzalvoi‘flN:Y| r #group Mww bonded to the adamantane ring is selected from:i} (WCOZH1,2 fiPO3H21,2O/\/N\ O/\/N\# O/\/N\# O/\/N\#W'w # ’, w'w '«JM «Jet ,H038 H038 H038 H0383 H038S/\/N\ /N\ O:‘S/\/N\\HZC/\/N\# HI}! NI 7 m,1 JV'V'V # .1va # .Iva # l#MEl 24985843V.1 121117813-12620In certain embodiments, a compound of formula ) may be converted into the compoundof formula IIa.l.l, wherein n is selected from 1-3:11a. 1 .1In certain embodiments, the compound of formula l can be converted into a compoundof formula IIa.l.2, wherein L represents a linker and LK represents a linkage formed between areactive onal group on linker L and a complementary functional group on antibody.

IIa.l.2In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa), thecompound has the structural formula ),(IIa.2)or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R113, Rllb, R12 and # are defined as above;U is selected from N, O and CH, with the o that when U is 0, then Va and R21a areabsent;R20 is selected from H and C1-C4 alkyl;MEl 24985843V.1 122117813-12620R21a and R21b are each, independently from one another, absent or selected from H, C1-C4alkyl and G, where G is selected from a polyol, 0, a salt and a moiety that is charged atphysiological pH;Va and Vb are each, independently from one another, absent or selected from a bond, and anoptionally substituted alkylene;R20 is selected from H and C1-C4 alkyl; ands is l, 2 or 3.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), s is 2.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), Z2a isselected from O, NH, CH2 and S. In ular embodiments, Z2a is O. In certain embodiments, Z2a offormula (IIa.2) is CRGaRéb. In certain embodiments, Z2a of formula (IIa.2) is CH2. In certainembodiments, Z2a of formula ) is S. In certain embodiments, Z2a of formula (IIa.2) is-NR6C(O)-.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), U isselected from N and O. In particular embodiments, U is O.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), Va isa bond, R21a is a C1-C4 alkyl group, Vb is selected from methylene and ethylene and R21b is G. Inparticular embodiments, Va is a bond, R21a is a methyl group and Vb is selected from methylene andethylene and R21b is G.

In n embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), Va ised from methylene and ethylene, R21a - is G, Vb is selected from methylene and ethylene and R21bis G. In particular embodiments, Va is ethylene, R21a is G, Vb is selected from methylene and ethyleneand R21b is G.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), G isO O 0 CH3II II)LOM Ii]:'7??- E/§=o D\OM 21/ I CH3selected from OM OM and CH3 wherein M is hydrogen or a, , ,31/ |vely charged counterion. In particular embodiments, G is OM. In particularembodiments, G is SO3H.

In certain ments in which the Bcl-XL inhibitor is a compound of formula ), R20 ised from hydrogen and a methyl group.

MEl 24985843V.1 123117813-12620In certain ments in which the Bcl-XL inhibitor is a nd of formula ), Ar2 isselected from(0590::F3C.90gm (“:0 and£;1CiI’ wherein the Rlz-Z2b- substituent isattached to Ar2 at any Ar2 atom capable of being substituted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), Ar2 isselected from39$nyF3C 933CI mafim7 wherein theRlz-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

In particular embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), Ar2 iswlw wherein the Rlz-Z2b- substituent is attached to Ar2 at any Ar2 atom capable of beingsubstituted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.2), 22b-R12 is selected from H, F, CN, OCH3, OH, NHZ, OCHZCHZOCH3, N(CH3)C(=O)CH3,CH2N(CH3)C(=O)CH3SCH3, C(=O)N(CH3)2 and OCHZCH2N(CH3)(C(=O)CH3). In particularembodiments, ZZb-R12 is selected from H, F and CN. In particular embodiments, ZZb-R12 is H. InN Scertain embodiments in which the Bcl-XL inhibitor is a compound of a (IIa.2), Ar1 is 6.

In particular embodiments in which the Bcl-XL inhibitor is a compound of formula ), Ar2 isMEl 24985843V.1 124117813-12620-w wherein the Rlz-Z2b- substituent is attached to Ar2 at any Ar2 atom capable of beingtuted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa), thecompound has the structural formula (IIa.3),12/22b OOH (I3N\ R2\ Zag ‘F (”Eb/ \ 1 SN—T—N\#HN \ o /or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R113, Rllb, R12 and # are defined as above;Rb is selected from H, C1-C4 alkyl and Jb-G or is optionally taken together with an atom of Tto form a ring having between 3 and 7 atoms;Ja and J are each, independently from one another, selected from optionally substituted C1-C8ne and ally substituted phenylene;T is selected from optionally substituted C1-C8 ne, CHZCHZOCHZCHZOCHZCHZ,CHZCHZOCHZCHZOCHZCHZOCHZ and a polyethylene glycol containing from 4 to 10 ethylene glycolunits;G is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH;s is l, 2 or 3.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), s is 1.

In certain embodiments in which the Bcl-XL tor is a compound of formula (IIa.3), s is 2.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Z2a isselected from 0, CH2 and S. In particular embodiments, Z2a is O. In certain embodiments, Z2a offormula (IIa.3) is CRGaRéb. In certain embodiments, Z2a of formula (IIa.3) is CH2. In certainembodiments, Z2a of formula (IIa.3) is S. In certain embodiments, Z2a of a (IIa.3) is —NR6C(O)-In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Ja isselected from methylene and ethylene and Rh is Jb-G, wherein Jb is ene or ethylene. In someMEl 24985843V.1 125117813-12620such embodiments, T is ethylene. In other such embodiments, T is CHZCHZOCHZCHZOCHZCHZ. Inother such embodiments, T is a polyethylene glycol containing from 4 to 10 ethylene glycol units.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Ja isselected from methylene and ne and Rh is taken together with an atom of T to form a ringhaVing 4-6 ring atoms.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Ja isselected from methylene and ethylene and Rh is H or alkyl. In some such embodiments, T is ethylene.

In other such embodiments, T is CHZCHZOCHZCHZOCHZCHZ.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), G isO 0 CH3|| ||)LOM Ii]:‘(TTO “Li/I'D\OM 21/ I CH3selected from ‘3‘- OM OM and CH3 n M is hydrogen or a, , ,31/ \O|positively charged rion. In particular embodiments, G is OM. In ular embodiments,G is SO3H.

In n embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), R20 isselected from hydrogen and a methyl group.

In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIa.3), Ar2 isselected fromPN/fi >/\N/fi] .

N 0go (go, Ego,wherein the R12 2b‘ -Z - substituent isattached to Ar2 at any Ar2 atom capable of being substituted.

In particular embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Ar2- ,where1n the R- 12 2bis w -Z - substituent is attached to Ar2 at any Ar2 atom capable ofbeing substituted. In certain embodiments in which the Bcl-XL inhibitor is a compound of formula), Ar2 is selected fromMEl 24985843V.1 126117813-12620®fi\sfv¥F3C EEG"be,/NMEH:IlamE;1©E7 wherein the Rlz-ZZb-substituent is attached to Ar2 at any Ar2 atom capable of being substituted. In ular embodimentsin which the Bcl-XL inhibitor is a compound of formula ), Ar2 is -w wherein theRlz-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), 22b-R12 is selected from H, F, CN, OCH3, OH, NHZ, OCHZCHZOCH3, N(CH3)C(=O)CH3,CH2N(CH3)C(=O)CH3SCH3, C(=O)N(CH3)2 and OCHZCH2N(CH3)(C(=O)CH3). In particularembodiments, ZZb-R12 is selected from H, F and CN. In particular embodiments, ZZb-R12 is H.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), Ar1 isIn n embodiments in which the Bcl-XL inhibitor is a compound of formula (IIa.3), theJa K‘RbI . I22a 3 N—T—N\MNva #group is selected from:HSOSH josH H803H 503,4and (IO/\/N\/\ /#N O/\/N\/\ /# /\/NN O T O/\/NAN AN mi” N l\# NW N\H020 ’ Hogs ’ #.

In certain embodiments in which the Bcl-XL tor is a compound of formula (IIa.3), theJail Rb22a "TNMIL/W8group is selected from:MEl 24985843V.1 127117813-12620HSO3H ‘jOgH ,jOgH 803H/\/N /# /\/N /# /\/NAN A” A” N\ “1”# N\COZH $03HPO3H2l/l/ CO2H $03H KISO3HO/\/ /\/N:11 73 O/\/ \/\/| #w U a)” ”u/N va HIn certain ments the Bcl-XL inhibitor is a compound of formula (IIb). In certainembodiments in which the Bcl-XL tor is a compound of formula (IIb), the compound has thestructural formula (IIb.l),(1113.1)or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R4, R113, R111) and # are defined as above;Y is optionally substituted C1-C8 alkylene;G is selected from a polyol, 0, a salt and a moiety that is charged at physiological pH;r is 0 or 1; ands is l, 2 or 3.

In certain embodiments in which the Bcl-XL tor is a compound of formula (IIb.l), s is l.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), s is 2. Incertain embodiments in which the Bcl-XL inhibitor is a compound of formula (11b. 1), s is 3.

In certain embodiments in which the Bcl-XL tor is a compound of formula (IIb.l), Z2a isselected from 0, CH2, NH and S. In particular embodiments, Z2a is O. In certain embodiments, Z2a offormula (11b. 1) is CRGaRéb. In n embodiments, Z2a of formula (11b. 1) is CH2. In certainembodiments, Z2a of formula (IIb.l) is S. In certain embodiments, Z2a of formula (IIb.l) is —MEl 24985843V.1 128117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), 22bselected from 0, CH2, NH, NCH3 and S. In particular embodiments, 22b is O. In particularembodiments, 22b is NH. In particular embodiments, 22b is NCH3.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), Y isethylene and r is 0.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula (IIb.l), Y isethylene and r is 1.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula ), R4 isH or methyl. In particular embodiments, R4 is methyl. In other ments, R4 is H.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), R4 istaken together with an atom of Y to form a ring having 4-6 ring atoms. In particular embodiments,the ring is a cyclobutane ring. In other embodiments, the ring is a piperazine ring. In otherments, the ring is a morpholine ring.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula (IIb.l), G is0 IO E C+H3SI: \ Hselected from $0M ‘24MOE/(Fl;MOM 2/2. 03 . .an H3 where1n M is hydrogen or aE/|\Opositively d counterion. In particular embodiments, G is OM. In other embodiments, Gis SO3H. In particular embodiments, G is NHZ. In other embodiments, G is PO3H2. In particularembodiments, G is NHZ. In particular embodiments, G is C(O)OH. In particular embodiments, G ispolyol.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), Ar2is selected from031 go”? NEON?Q0 [”11 111011‘ wherein the G-(CH2)S-ZZb- tuentis attached to Ar2 at any Ar2 atom capable of being substituted.

MEl 24985843V.1 129117813-12620In ular embodiments in which the Bcl-XL tor is a compound of formula (IIb.l),Ar2 is -|w wherein the G-(CH2)S-ZZb- tuent is attached to Ar2 at any Ar2 atomcapable of being substituted. In certain embodiments in which the Bcl-XL tor is a compound offormula (IIb.l), Ar2 is selected fromCafe»???F3C EEG/“JEHIJCE mgr;7 n theG-(CH2)S-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted. In particularembodiments in which the Bcl-XL inhibitor is a compound of formula (11b. 1), Ar2 iswherein the G-(CH2)S-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), Ar1 isIn certain embodiments in which the Bcl-XL inhibitor is a compound of formula ), theS .group is selected from:HOfO PO H /30 H H2N HOK3/:0 3 \L and O’ “'w’ OH 'In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIb.l), theI’ /\R4r ‘#group -v' is selected from:MEl 24985843V.1 130117813-12620| HO/\/N\ o/\/N\# and. # MV7 'N‘l’vONOWIIVWW IIn certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIb.l), theza‘<\/ -I” ~\0 Y> \Nr ,Rgroup m is selected from:H29/VN\# /\/C/Njfi A): j '11. Q Q T WENR4\ /#I 0 F34H2C’N\# R4\ / #«INN \N/U\/\/N‘#.Am l MA, 50 1l \ /N \\flaw Or f f/N /NR4 1 j and E jo \N N\N/go \N/KO \N/KOIn certain embodiments the Bcl-XL inhibitor is a compound of formula (IIc). In nments in which the Bcl-XL inhibitor is a compound of formula (IIc), the compound has thestructural formula (IIc. l)\N ,_[I /Zzbx Ya- \ G#’ OH ‘R2 N/Y2a/\/ *R23(IIc.l)or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R4, Rlla’ R1113 and # are defined as above;Ya is optionally substituted C1-C8 alkylene;Yb is optionally substituted C1-C8 alkylene;R23 is selected from H and C1-C4 alkyl; andG is selected from a , PEG4-30, a salt and a moiety that is charged at physiological pH;MEl 24985843V.1 131117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIc. l), Z2a isselected from 0, CH2, NH and S. In particular ments, Z2a is O. In certain embodiments, Z2a offormula (IIc.l) is CRGaRéb. In certain ments, Z2a of formula (IIc. l) is S. In certainembodiments, Z2a of formula (IIc. l) is —NR6C(O)-.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), 22b isselected from 0, CH2, NH, NCH3 and S. In particular embodiments, 22b is O. In particularembodiments, 22b is NH. In particular embodiments, 22b is NCH3.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula (IIc. 1), 22b isa bond. In some such embodiments Ya is methylene or ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), 22b isO. In some such ments Ya is ene, ethylene, or propylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), 22b isNR6, where R6 is defined as above. In some such embodiments, R6 is taken together with an atomfrom Ya to form a cycloalkyl or heterocyclyl ring having n 3 and 7 ring atoms. In some suchembodiments, the ring has 5 atoms.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ya isethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ya ismethylene.

In certain ments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ya ispropylene.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula (IIc. l), R4 isH or methyl. In particular embodiments, R4 is H.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Yb isne or propylene. In particular embodiments, Yb is ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. l), R23 ismethyl.

In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIc. l), R23 isIn certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. l), G isO o 0|| II)LOM [If31/Ito E/FI)\OM “91/ I \CH3selected from at OM OM and CH3 wherein M is hydrogen or a, , ,31/ \O|positively d counterion. In particular embodiments, G is OM. In particular embodiments,G isSO3H.

MEl 24985843V.1 132117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ar2 ised from(05%”?F3C.90cm (“:0 andE;JCiE’ wherein the #-N(R4)-Ya-ZZb-substituent is ed to Ar2 at any Ar2 atom capable of being substituted.

In particular embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ar2ENDK;is wlw wherein the #-N(R4)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atom capableof being substituted. In certain embodiments in which the Bcl-XL inhibitor is a compound of formula(IIc.l), Ar2 is selected from$nyF3C (P3/NMEHFCE"but, andEjCE7 wherein the)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted. Inparticular embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. 1), Ar2 iswherein the #-N(R4)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atom capableof being substituted.

In certain ments in which the Bcl-XL inhibitor is a compound of a (IIc. 1), Ar1 isMEl 24985843V.1 133117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc. l), theZza/\/ ‘R23group «ml/vw is selected from:H038 H033S (fi‘COZH12 (WPO3H21,2 S(ID/\/N\ (ID/\/N\ (ID/\/N\ (ID/\/N\ and HZC/\/N\M .AAA. MA MA, .1vaIn other ments in which the Bcl-XL inhibitor is a compound of formula (IIc.l), theZza/\/ ‘R23group «ml/vw is selected from:H038 Hogs Hogs HogsN uc HN/u\/\NIn certain ments in which the Bcl-XL inhibitor is a nd of formula (IIc), thecompound has the structural formula (IIc.2),#xN‘Y'a/or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, R4, Rlla’ R1113 and # are defined as above;Ya is optionally substituted C1-C8 alkylene;Yb is optionally substituted C1-C8 alkylene;YC is optionally substituted C1-C8 alkylene;R23 is selected from H and C1-C4 alkyl;R25 is Yb-G or is taken together with an atom of YC to form a ring haVing 4-6 ring atoms; andG is selected from a , 0, a salt and a moiety that is charged at physiological pH.

MEl 24985843V.1 134117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIc.2), Z2a isselected from 0, CH2, NH and S. In ular embodiments, Z2a is O. In certain embodiments, Z2a ofa (IIc.2) is CRGaRéb. In certain embodiments, Z2a of formula (IIc.2) is S . In certainembodiments, Z2a of formula (IIc.2) is —NR6C(O)-.In certain embodiments in which the Bcl-XLinhibitor is a compound of formula (IIc.2), 22b is selected from 0, CH2, NH, NCH3 and S. Inular embodiments, 22b is O. In particular embodiments, 22b is NH. In ular ments,22b is NCH3.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), 22b isa bond. In some such embodiments Ya is methylene or ethylene.

In certain ments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), 22b isNR6, where R6 is defined as above. In some such embodiments, R6 is taken together with an atomfrom Ya to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms. In some suchembodiments, the ring has 5 atoms.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), Ya isethylene.

In certain embodiments in which the Bcl-XL inhibitor is a nd of formula (IIc.2), Ya ismethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), R4 isH or methyl.

In certain ments in which the Bcl-XL inhibitor is a compound of formula ), Yb isethylene or propylene. In particular embodiments, Yb is ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IIc.2), YC isethylene or ene. In particular embodiments, Yb is ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), R25 istaken together with an atom of YC to form a ring having 4 or 5 ring atoms.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), R23 ismethyl.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), G isO 0 CH3II II '+)L S: P\O N\CH52!. /| ’11 OM/| OM ‘771/I 3selected from OM, I, OM ,and CH3 wherein M is hydrogen or aE/§:Opositively charged counterion. In particular embodiments, G is OM. In ularembodiments, G is SO3H.

MEl 24985843V.1 135117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), Ar2 isselected from(Tm NEON? N93?CW}; [:03qu’lr (:11;W m’ wherein the )-Ya-ZZb-substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

In ular ments in which the Bcl-XL inhibitor is a compound of formula (IIc.2),Ar2 is w n the #-N(R4)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atomcapable of being substituted. In certain embodiments in which the Bcl-XL inhibitor is a nd offormula (IIc.2), Ar2 is selected from03k few V“? $0m andrjm’ wherein the #-N(R4)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted. In particularembodiments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), Ar2 iswherein the #-N(R4)-Ya-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of beingsubstituted.

MEl 24985843V.1 136117813-12620In certain embodiments in which the Bcl-XL tor is a compound of formula (IIc.2), Ar1In n ments in which the Bcl-XL inhibitor is a compound of formula (IIc.2), the2aNN\ ’R23HIM YC_N\group is selected from:803H SO3H SO3H SO3Hl/‘ (I H and l/'O/\/N\/\N/ O/\/N\/\N/ O/\/Nl I OWN?IH020 H038In certain ments in which the Bcl-XL inhibitor is a compound of formula (IId), thecompound has the structural formula (IId.l),(IId.l)or salts thereof, wherein:Arl, Arz, 21, 223, 22b, R1, R2, Rlla’ R1113 and # are defined as above;Ya is optionally substituted alkylene;Yb is optionally substituted alkylene;R23 is selected from H and C1-C4 alkyl;Ga is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH;Gb is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiologicalIn certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), s is l.

In n embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), s is 2.

MEl 24985843V.1 137117813-12620In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), Z2a isselected from O, NH, CH2 and S. In particular embodiments, Z2a is O. In certain embodiments, Z2a offormula (11d. 1) is CRGaRéb. In certain ments, Z2a of formula (11d. 1) is S. In certainembodiments, Z2a of a (IId.l) is —NR6C(O)-.

In n embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), 22b isselected from O, NH, CH2 and S. In particular embodiments, 22b is O.

In certain embodiments in which the Bcl-XL inhibitor is a compound of a (IId.l), Ya isselected from ethylene, propylene and butylene. In ular embodiments, Y is ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), Ya isselected from ne, propylene and butylene. In particular embodiments, Y is ethylene.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), Ga isO O 0|| ||)LOM Ii]:E/§=o “Li/I'D\OM 21/ I CH3selected from ‘3‘- OM OM and CH3 wherein M is hydrogen or a, , ,uLL/ \OIpositively charged counterion. In particular embodiments, Ga is OM. In particularembodiments, Ga is SO3H. In particular embodiments, Ga is COZH.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), Gb isO O 0 CH3|| ||)LOM Ii]:E/§=o 11/ FI’\0M 21/ I CH3selected from 51‘- OM OM and CH3 n M is hydrogen or a, , ,positively charged counterion... . . . ,. {i=0In particular embodiments, G .is OM. In particularembodiments, Gb is SO3H. In particular embodiments, Gb is COZH.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), R23 ismethyl.

In certain embodiments in which the Bcl-XL tor is a nd of formula (IId.l), Ar2is selected fromMEl 24985843V.1 13 8-12620WN/fi >/\N/fil ,N 0Q3}? Elm; and Kim;’ wherein the Ga-Ya-N(#)-(CH2)S-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted.

In particular embodiments in which the Bcl-XL inhibitor is a nd of formula (IId.l),Ar2 is wlw wherein the Ga-Ya-N(#)-(CH2)S-ZZb- substituent is attached to Ar2 at any Ar2atom capable of being tuted. In certain embodiments in which the Bcl-XL inhibitor is acompound of formula (11d. 1), Ar2 is selected from(Eng: :Z’?\/N\;PN/fi )PN/fi [ I 1:m N}; NE;l .am; {if};N {if};0i wherein the Ga-Ya-CH2)S-ZZb- substituent is attached to Ar2 at any Ar2 atom capable of being substituted. Inparticular embodiments in which the Bcl-XL inhibitor is a nd of formula (IId.l), Ar2 isNW wherein the Ga-Ya-N(#)-(CH2)S-ZZb- substituent is attached to Ar2 at any Ar2 atomcapable of being substituted.

In certain embodiments in which the Bcl-XL inhibitor is a compound of formula (IId.l), Ar1 isIn certain embodiments, R11a and R11b of formulae (IIa)-(IId) are the same. In a particularembodiment, R11a and R11b are each methyl.

MEl 24985843V.1 139117813-12620In certain embodiments, the compounds of formulae (IId) include one of the followingcores (C.l)-(C.21):(C.l)MEl 24985843V.1 140-12620((15)(C16)(C17)((18)MEI 24985843V.1 141-12620(C. 10)(C. 12)MEI 24985843V.1 142-12620(C. 13)(C. 14)(C. 15)(C. 16)ME1 24985843V.1 143-12620(C.17)(C.18)(C. 19)(C20)MEI 24985843V.1 144117813-12620(C21) HNNAS "'3C6 CH3Exemplary Bcl-XL inhibitors according to structural formulae (IIa)-(IId) that may be used inthe methods described herein in ugated form and/or included in the ADCs described hereininclude the following compounds, and/or salts thereof:MEl 24985843V.1 145-12620App EX. N0. —BCl-XL Inhibitor Cmpd N0—W231MEI 24985843V.1 146117813-12620Notably, when the Bcl-XL inhibitor of the present application is in ated form, thehydrogen corresponding to the # position of structural formulae (IIa)-(IId) is not present, forming amonoradical. For example, compound W2.01 (Example 1.1) is 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({ 3-[2-({2-[2-(carboxymethoxy)ethoxy]ethyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1. 13 ,7]decyl } methyl)-1H-pyrazolyl]pyridinecarboxylic acid.

When it is in unconjugated form, it has the following ure:N’ \[i OWN/VOWON \ / \ NWhen the same compound is included in the ADCs as shown in structural formula (Ila) or(11b), the hydrogen corresponding to the # on is not present, forming a monoradical.

MEl 24985843V.1 147117813-12620nggifigggfiwmfi“In certain embodiments, the Bcl-XL inhibitors according to structural ae (IIa)-(IId) areselected from the group consisting of W201, W202, W203, W204, W205, W206, W207, W208,W209, W210, W211, W212, W213, W214, W215, W216, W217, W218, W219, W220,W221, W222, W223, W224, W225, W226, W227, W228, W229, W230, W231, W232,W233, W234, W235, W236, W237, W238, W239, W240, W241, W242, W243, W244,W245, W246, W247, W248, W249, W250, W251, W252, W253, W254, W255, W256,W257, W258, W259, W260, W261, W262, W263, W264, W265, W266, W267, W268,W269, W270, W271, W272, W273, W274, W275, W276, W277, W278, W279, W280,W281, W282, W283, W284, W285, W286, W287, W288, W289, W290, and W291, orpharmaceutically acceptable salts thereof.

In certain embodiments, the ADC, or a pharmaceutically acceptable salt thereof, comprises adrug linked to an antibody by way of a linker, wherein the drug is a Bcl-XL inhibitor selected from thegroup consisting of W201, W202, W203, W204, W205, W206, W207, W208, W209, W210,W211, W212, W213, W214, W215, W216, W217, W218, W219, W220, W221, W222,W223, W224, W225, W226, W227, W228, W229, W230, W231, W232, W233, W234,W235, W236, W237, W238, W239, W240, W241, W242, W243, W244, W245, W246,W247, W248, W249, W250, W251, W252, W253, W254, W255, W256, W257, W258,W259, W260, W261, W262, W263, W264, W265, W266, W267, W268, W269, W270,W271, W272, W273, W274, W275, W276, W277, W278, W279, W280, W281, W282,W283, W284, W285, W286, W287, W288, W289, W290, and W291.

In certain embodiments, the ADC, or a pharmaceutically able salt thereof, the Bcl-XLinhibitor is selected from the group consisting of the following compounds modified in that thehydrogen corresponding to the # position of structural formula (IIa), (IIb),(IIc), or (IId) is not presentforming a monoradical;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-[l-({3-[2-({2-[2-(carboxymethoxy)ethoxy]ethyl } amino)ethoxy] -5 ethyltricyclo[3.3. l . 13’7]dec- l -yl } methyl)methyl-lH-pyrazolyl]pyridinecarboxylic acid;MEl 24985843V.1 148117813-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-y1{2-[(2-sulfocthyl)amin0]cthoxy}tricyclo[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;2-{ [(2-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carb0xypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } ethyl)sulfonyl] amino } dcoxy-D-gluc0pyranosc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-{ 1-[(3 ,5-dimcthy1 { 2- [(4-{ [(3R,4R,SS,6R) -3 ,4,5-trihydr0xy(hydr0xymcthyl)tctrahydro—2H-pyrany1]mcthy1 } benzyl)amino] cthoxy } tricyc10[3.3. 1.13’7]dccyl)mcthyl]—5-mcthyl-1H—pyraz01yl }pyridinccarb0xylic acid1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(3-su1f0pr0pyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 3-oxypropyl)amino] cthoxy } -5 ,7-dimcthyltricyc10 [3 . 3. 1 . 13’7] dccy1)methyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;2-({ [4-({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } methyl)phcnyl] sulfonyl } amin0)dcoxy-bcta-D-g1uc0pyranosc;8-(1,3 -bcnz0thiaz01y1carbam0y1) { 6-carb0xy [1 -( { 3- [2-( { 2- [1 -(bcta-D-glucopyranuronosyl)-1H-1,2,3-triaz01yl]cthyl}amino)cth0xy]-5,7-dimcthyltricyc10[3.3.1.13’7]dcc-1-y1 }mcthyl)-5 -mcthy1-1H-pyraz01yl]pyridinyl}-1 ,2,3,4-tctrahydr0isoquinolinc;3-[1-({ 3-[2-(2-{ ta-D-allopyranosyloxy)bcnzyl] amino}cth0xy)cth0xy] -5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}mcthyl)mcthyl-1H-pyraz01y1]—6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-y1(2-{2-[(2-sulfocthyl)amin0]cthoxy}cthoxy)tricyc10[3.3.1.13’7]dccyl]mcthyl}mcthy1-1H-pyraz01y1)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1 { 2-[(2-phosph0nocthyl)amin0]cthoxy}tricyc10[3.3. 1.13’7]dccyl)mcthyl]-5 1-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthyl{2-[methy1(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthy1]—5-mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthyl{2-[(3-phosph0n0pr0py1)amin0]cthoxy}tricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;MEI 24985843V.1 149117813-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-dimcthyl(2- { 2- [(3-phosph0n0pr0pyl)amino] cthoxy } cthoxy)tricyc10[3 . 3. 1 . 13’7]dcc-1 -yl] methyl } - 1 H-pyraz01yl)pyridinccarboxylic acid;3-{ 1-[(3-{2-[L-alpha-aspartyl(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dcchyl] mcthy1-1H-pyraz01y1 } [8-(1 ,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;6-{4-[({2-[2-(2-aminocthoxy)cthoxy]ethyl} [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl]amin0)mcthyl]bcnzyl}-2,6-anhydr0-L-gulonic acid;4-({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbam0yl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] amino } methyl)phcnyl hcxopyranosiduronic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3,5-dimcthy1-7-{2-[(2-phosph0nocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 5-dimcthy1-7-{2-[mcthyl(3-su1f0-L-alanyl)amin0]cthoxy}tricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 ,3]thiaz010[5 ,4-b]pyridinylcarbam0yl)-3 ,4-dihydr0isoquin01in-2( 1 H) ridine-z-carboxylic acid;3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 az010[4,5-b]pyridinylcarbam0yl)-3 ,4-dihydr0isoquin01in-2( 1 H) -yl]pyridine-z-carboxylic acid;6-[ 1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3,5-dimcthy1-(2-sulfocthyl)amino]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. ccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1 { 2-[(3 -phosph0n0pr0pyl)(pipcridinyl)amino]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;MEI 24985843V.1 150117813-126203-{ l-[(3 - { 2-[D-alpha-aspartyl(methyl)amino] ethoxy } -5 ,7-dimethyltricyclo[3 . 3. l -. 13’7]dec- lyl)methyl] hyl- l H-pyrazolyl } [8-(l ,3-benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]pyridinecarb0xylic acid;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl](l-{[3-(2-{[1-(carboxymethyl)piperidinyl]amino } ethoxy)-5 ,7-dimethyltricyclo[3 .3 . l -. 13’7] decyl] methyl } -5methyl- 1 H-pyrazolyl)pyridinecarboxylic acid;N- [(SS)-5 -amin0{ [2-({ 3- [(4- { 6- [8 -( l ,3 -benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carboxypyridinyl } methyl- 1 H-pyrazol-l -yl)methyl] -5 ,7 -dimethyltricyclo[3.3. l . 13’7]dec- l -yl } hyl] (methyl)amino } 0X0hexyl] -N,N-dimethylmethanaminium;1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl]—3-{ l- [(3,5-dimethyl { 2-[piperidinyl(2-sulfoethyl)amino]ethoxy } tricyclo [3 . 3 . l 3 ’7] decyl)methyl] -5methyl- 1 H-pyrazolyl inecarb0xylic acid;6- [ 8 -(l ,3 -benz0thiazolylcarbamoyl) -5 -(3-phosph0n0pr0poxy)-3 ,4-dihydr0isoquinolin-2( l H) -yl] -3 -[l-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3. l.13’7]dec-l-yl}methyl)-5 -methyl- 1 H-pyrazolyl]pyridinecarboxylic acid;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl](l-{ [3-(2-{ [N-(2-carboxyethyl)-L-alpha-aspartyl] amino } ethoxy)-5 ,7-dimethyltricyclo [3 . 3 . l 3 ’7] decyl] methyl } -5methyl- 1 zolyl)pyridinecarboxylic acid;3-{ l-[(3 -{2-[(2-amin0ethyl)(2-sulf0ethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl)methyl] methyl- l H-pyrazolyl } [8 -( l ,3 -benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl]pyridinecarb0xylic acid;6- [5-(2-amin0eth0xy)-8 -(l ,3-benz0thiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2( l H) -yl] -3-[1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.l.13’7]dec-l-yl}methyl)methyl-1H-pyrazolyl]pyridine-Z-carboxylic acid;1,3-benz0thiazolylcarbamoyl)naphthalenyl]{ l- [(3 ,5 -dimethyl { 2- [(3-sulfopropyl)amino]ethoxy }tricyclo[3 . 3. l.13’7]dec-l-yl)methyl]methyl- 1 H-pyrazolyl }pyridinecarboxylic acid;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl]—3-{ l- [(3- { 2-[(2-carboxyethyl)(piperidinyl)amino]ethoxy} -5 ,7-dimethyltricyclo[3 . 3. ]dec-l-yl)methyl]-5 -methyl- 1 H-pyrazolyl }pyridinecarb0xylic acid;1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl]—3-{ l- [(3,5-dimethyl { 2-[(3 -sulf0-L-alanyl)(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.l.13’7]dec-l-yl)methyl]methyl- 1 H-pyrazolyl }pyridinecarb0xylic acid;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl]—3-{ l- [(3- { 2-[ { 2- [(2-carboxyethyl)amino]ethyl } (2-sulf0ethyl)amino]ethoxy } -5 ,7-dimethyltricyclo[3.3.1.13’7]dec-lyl)methyl] methyl- 1 H-pyrazolyl }pyridinecarboxylic acid;MEI 24985843V.1 151117813-126203-{1-[(3,5-dimcthy1{2-[(3-phosph0n0pr0pyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;3-{ 1-[(3,5-dimcthy1{2-[(3-phosph0n0pr0pyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[8-([1,3]thiaz010[5,4-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-5 -(carb0xymcth0xy)-3,4-dihydr0isoquin01in-2(1H)-y1][1-({3,5-dimcthy1[2-(mcthylamin0)cth0xy]tricyc10[3.3.1.13’7]dccyl}mcthyl)mcthyl-1H-pyraz01yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-carboxypropyl)(pipcridinyl)amino] cthoxy } -5 ,7-dimcthyltricyc10 [3 . 3. 1 -. 13 ’7] dccyl)methyl] -5methyl-1H-pyraz01yl }pyridinccarb0xylic acid;1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3,5-dimcthyl { 2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;3-{ 1-[(3-{2-[L-alpha-aspartyl(2-sulfocthyl)amin0]cthoxy} -5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{2-[(1,3-dihydroxypropan-z-yl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[5-(2-aminocthoxy)(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-{ 1-[(3,5-dimcthy1{2-[methy1(2-su1focthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;1,3-bcnz0thiazolylcarbamoyl){2-[(2-sulfocthyl)amino]cth0xy}-3,4-dihydroisoquinolin-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{ 2-[mcthy1(2-thyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl){2-[(2-sulfocthyl)amin0]ethyl}amin0]cth0xy}tricyclo[3.3.1.13’7]dccy1)mcthyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl){2-[(2-carb0xycthyl)amin0]cthoxy}-3,4-oisoquinolin-2(1H)-y1]—3-{ 1-[(3,5-dimcthy1{ hy1(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;3-{ 1-[(3,5-dimcthy1 { 2-[(3-phosph0n0pr0pyl)(pipcridinyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01yl}[8-MEI 24985843V.1 152117813-12620([1 az010[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]pyridine-Z-carboxylicacid;6-[4-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0-2H-1,4-bcnz0xazinyl]—3-{ 1-[(3,5-dimcthyl{2-[(2-sulfocthyl)amin0]cthoxy}tricyclo[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-5 -(3-su1f0pr0p0xy)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-[1-({3,5-dimcthy1—7-[2-(mcthy1amin0)cth0xy]tricyc10[3.3.1.13’7]dccy1}mcthyl)mcthyl-1H-pyraz01yl]pyridine-Z-carboxylic acid;3-{ 1-[(3,5-dimcthy1—7-{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl}[1-([1,3]thiaz010[4,5-b]pyridinylcarbam0yl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;3-{ 1-[(3,5-dimcthy1—7-{2-[(2-sulfocthyl)amin0]cthoxy}tricyc10[3.3.1.13’7]dccyl)mcthyl]methyl- 1 H-pyraz01yl } [8 -( [1 ,3]thiaz010[4,5-b]pyridinylcarbamoyl)naphthalcnyl]pyridine-0xylic acid;(1§)({2-[5-(1-{ [3-(2-aminocthoxy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthy1}methyl-1H-pyraz01yl)carb0xypyridinyl] ( 1 ,3-bcnz0thiaz01—2-ylcarbam0y1)- 1 2,3,4-tctrahydroisoquinolin-S-yl }mcthy1)- 1 ,5 -anhydr0-D-glucit01;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-carboxypropyl)amin0]cth0xy} -5 ,7-dimcthyltricyc10[3.3. ]dccy1)mcthyl]—5-mcthyl-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3,5-dimcthyl { 2-[(3-phosphonopropyl)amin0]cthoxy}tricyc10[3.3.1. 13’7]dcc-1 -y1)mcthyl] -5 -mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [4-D-glucopyranosyloxy)bcnzyl] amino } cthoxy)-5 ,7-dimcthyltricyc10[3.3. 1 -. 13’7]dccyl]mcthy1 }-mcthyl- 1 H-pyraz01yl)pyridinccarb0xylic acid;3-(1-{ [3 -(2-{ [4-(bcta-D-a110pyran0syloxy)benzyl] amino}cth0xy)-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl]mcthy1}mcthy1—1H-pyraz01y1)[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;3-{ 1-[(3-{2-[azctidiny1(2-su1focthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[8-(1,3-bcnz0thiazoly1carbam0yl)-3,4-dihydroisoquinolin-2(1H)-y1]pyridinecarb0xylic acid;3-{ 1 -[(3-{2-[(3-amin0pr0pyl)(2-sulfocthy1)amin0]cthoxy } -5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]pyridine-Z-carboxylic acid;MEI 24985843V.1 153117813-126206-[1 -(1 ,3-bcnz0thiazolylcarbamoyl)-1 ,2,3,4-tctrahydr0quin01iny1] { 1-[(3- { 2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-yridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(N6,N6-dimcthy1-L-lysyl)(mcthyl)amin0]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]methyl-1H-pyraz01yl }pyridinccarb0xylic acid;3-{ 1-[(3-{2-[(3-amin0pr0pyl)(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[1-(1,3-bcnz0thiaz01ylcarbamoyl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;3-{ 1-[(3-{2-[azctidinyl(mcthyl)amino]cthoxy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01y1}[1-(1,3-bcnz0thiaz01ylcarbamoyl)-12,3,4-tctrahydroquinoliny1]pyridinccarb0xylic acid;N6-(37-0X0-2,5,8,11,14,17,20,23,26,2932,35-d0dccaOXahcptatriacontanyl)-L-lysyl-N-[2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carb0xypyridin-3-y1}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1]—L-alaninamidc;methyl 6- [4-(3-{ [2-( { 3- [(4- { 6- [8 -(1,3 -bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]—5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl]amin0}pr0pyl)-1H-1,2,3-triazoly1]—6-dcoxy-bcta-L-glucopyranosidc;1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]{ 1-[(3- { 2-[(2-carboxycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[5-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[4-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3,5-dimcthy1{2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridinccarboxylic acid;6-[5-(1,3-bcnz0thiazolylcarbam0y1)quin01iny1]{ 1-[(3-{2-[(2-ycthyl)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3.1. 13’7]dccyl)mcthyl]mcthy1-1H-pyraz01-4-y1}pyridinccarb0xylic acid;6-[1-(1,3-bcnz0thiazolylcarbamoyl)-5,6-dihydr0imidaz0[1,5-a]pyrazin-7(8H)-yl]{ 1-dimcthy1{2-[(2-sulfocthyl)amin0]cthoxy}tricyclo[3.3.1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01y1 }pyridinccarb0xylic acid;MEI 24985843V.1 154-126208-(1 ,3-bcnz0thiazoly1carbam0y1) { 0xy [1 -( { 3- [2-( { 3- [1 -(bcta-D-glucopyranuronosyl)-1H-1,2,3-triaz01y1]pr0pyl}amino)cth0xy]—5,7-dimcthyltricyc10[3.3.1.13’7]dcc-1-y1}mcthyl)-5 -mcthy1-1H-pyraz01y1]pyridiny1}-1,2,3,4-tctrahydr0is0quinolinc;1,3-bcnz0thiazolylcarbamoyl)-1H-ind01y1]{ 1-[(3,5-dimcthy1 { 2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthy1]mcthy1-1H-pyraz01y1}pyridinccarboxylic acid;1 ,3-bcnz0thiazolylcarbamoyl)[3-(mcthy1amin0)pr0py1] -3 ,4-dihydr0isoquin01in-2(1H)-y1] { 1-[(3,5-dimcthy1{2-[(2-su1focthyl)amino]cth0xy}tricyc10[3.3. 1 -. 1 cyl)mcthy1]-mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;5-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01y1)mcthy1]-5,7-dimcthy1tricyc10[3.3.1. 13’7]dccyl }oxy)cthy1] amino } -5 -dcoxy-D-arabinit01;1-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01y1)mcthy1]-5,7-dimcthy1tricyc10[3.3.1. 13’7]dccyl }oxy)cthy1] amino } -1 ,2-didcoxy-D-arabino-hcxitol;6-[4-(1,3-bcnz0thiazolylcarbam0y1)isoquin01iny1]{ 1-[(3,5-dimcthy1 { 2-[(2-sulfocthyl)amin0]cth0xy}tricyc10[3.3.1.13’7]dccy1)mcthy1]mcthy1-1H-pyraz01y1}pyridinccarboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [3-hydroxy(hydr0xymcthyl)pr0py1]amino } cthoxy)-5 ,7-dimcthyltricyc10[3 . 3. 1 -. 13 ’7]dcc-1 -y1] methyl }-mcthy1- 1 H-pyraz01yl)pyridinccarb0xy1ic acid;1-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01y1)mcthy1]-5,7-dimcthy1tricyc10[3.3.1. 13’7]dccyl }oxy)cthy1] amino } -1 ,2-didcoxy-D-crythr0-pcntit01;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3,5-y1(2-{ [(2S,3S)-2,3,4-trihydr0xybuty1]amino}cth0xy)tricyc10[3.3.1. 13’7]dccy1]mcthy1}methyl-1H-pyrazolyl)pyridinccarb0xy1ic acid;6-[8 -(1,3-bcnz0thiazoly1carbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]—3-(1-{ [3-(2-{[(28,3S,4R,5R,6R)-2,3,4,5,6,7-hcxahydr0xyhcpty1]amin0}cthoxy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1]mcthyl}-5 -mcthy1- 1 H-pyraz01y1)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[({ 3-[(1,3-dihydr0xypr0panyl)amin0]pr0py1 } sulfonyl)amino]cthoxy} -5 ,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1)mcthy1]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-{ [1 ,3-dihydr0xy(hydroxymcthyl)propan-z-yl]amino } 0X0pr0pyl)amin0]cthoxy} -5 ,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1)mcthy1]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;MEI 24985843V.1 155-126206-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3-(2-{ [(35)-3 ,4-dihydroxybutyl] amino } ethoxy)-5 ,7-dimethyltricyclo[3.3. l . 13’7] decyl]methyl } -5 -methyl-1H-pyrazolyl)pyridinecarboxylic acid;4-({ [2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—2-carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl thyl]amino}methyl)phenyl beta-D-glucopyranosiduronic acid;3-{ [2-({ 3 -[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridin-3 -yl}methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl }oxy)ethyl]amino l beta-D-glucopyranosiduronic acid;6-[4-(1 ,3-benzothiazolylcarbamoyl)oxidoisoquinolinyl] [l -( { 3 ,5 -dimethyl [2-(methylamino)ethoxy] tricyclo[3 . 3. l . 13’7]dec-l -yl } methyl)methyl- l H-pyrazolyl]pyridinecarboxylic acid;(1,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2(lH)-yl}{ l-[(3,5-dimethyl { 2-[(2-sulfoethyl)amino]acetamido }tricyclo[3.3. l . 13’7]decan-l -yl)methyl]—5-methyl- 1H-pyrazolyl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3 -( l -{ [3 ,5-dimethyl( { 2-[(2-sulfoethyl)amino]ethyl } yl)tricyclo[3 . 3. l . 13’7]dec-l -yl] methyl } hyl-lH-pyrazolyl)pyridinecarboxylic acid; and6-{ 8 -[(l ,3-benzothiazolyl)carbamoyl] -3 ,4-dihydroisoquinolin-2(1H)-yl } { l- [(3 ,5-dimethyl { 3 -[(2-sulfoethyl)amino]propyl } tricyclo[3.3. l . 13’7]decan-l -yl)methyl] methyl- 1H-pyrazolyl }pyridinecarboxylic acid;and a ceutically acceptable salt thereof.

The Bcl-xL inhibitors bind to and t anti-apoptotic Bcl-xL proteins, inducing apoptosis.

The ability of specific Bcl-xL inhibitors according to structural formulae (IIa)-(IId) to bind to andinhibit Bcl-xL activity may be confirmed in standard binding and activity assays, including, forexample, the TR-FRET Bcl-xL binding assays described in Tao er al., 2014, ACS Med. Chem. Lett.,: 093. A specific TR-FRET Bcl-xL binding assay that can be used to confirm Bcl-xL bindingis provided in Example 4, below. Typically, Bcl-xL inhibitors useful as tors per se and in theADCs described herein will exhibit a K, in the binding assay of Example 5 of less than about 1 nM,but may exhibit a significantly lower K, for example a K, of less than about 1, 0.1, or even 0.01 nM.

Bcl-xL tory activity may also be confirmed in rd cell-based cytotoxicity assays,such as the FL5.12 cellular and Molt-4 cytotoxicity assays described in Tao er al., 2014, ACS Med.

Chem. Lett., 5: 093. A specific Molt-4 cellular cytotoxicity assay that may be used to confirmBcl-xL inhibitory activity of specific Bcl-xL inhibitors that are able to permeate cell membranes isprovided in Examples 5 and 6, below. Typically, such cell-permeable Bcl-xL inhibitors will exhibitan ECSO of less than about 500 nM in the Molt-4 cytotoxicity assay of Examples 5 and 6, but mayMEI 24985843V.1 156117813-12620exhibit a significantly lower EC50, for example an ECSO of less than about 250, 100, 50, 20, 10 or evennM.

Owing to the presence of solubilizing groups, many of the Bcl-xL tors described hereinare expected to exhibit low or very low cell bility, and therefore will not yield significantactivity in n cellular assays due to the ity of the compound to se the cell membrane,including the Molt-4 cellular toxicity assay of Examples 5 and 6. Bcl-xL inhibitory activity ofcompounds that do not freely traverse cell membranes may be confirmed in cellular assays withpermeabilized cells. The process of mitochondrial outer-membrane permeabilization (MOMP) iscontrolled by the Bcl-2 family proteins. Specifically, MOMP is promoted by the pro-apoptotic Bcl-2family proteins Bax and Bak which, upon activation oligomerize on the outer ondrialne and form pores, leading to release of cytochrome c (cyt c). The release of cyt c triggersformulation of the apoptosome which, in turn, results in e activation and other events thatcommit the cell to undergo programmed cell death (see, Goldstein et al., 2005, Cell Death andDiflerentiation 122453-462). The oligomerization action of Bax and Bak is antagonized by the anti-apoptotic Bcl-2 family members, including Bcl-2 and Bcl-xL. Bcl-xL inhibitors, in cells that dependupon Bcl-xL for survival, can cause activation of Bax and/or Bak, MOMP, release of cyt c anddownstream events g to apoptosis. The s of cyt c release can be measured via westernblot of both mitochondrial and cytosolic fractions of cells and used as a proxy measurement ofapoptosis in cells.

As a means of detecting Bcl-xL inhibitory activity and consequent release of cyt c for Bcl-xLinhibitors with low cell permeability, the cells can be treated with an agent that causes selective poreformation in the plasma, but not mitochondrial, membrane. Specifically, the cholesterol/phospholipidratio is much higher in the plasma membrane than the mitochondrial ne. As a result, shortincubation with low concentrations of the cholesterol-directed detergent digitonin selectivelypermeabilizes the plasma membrane without significantly affecting the mitochondrial membrane.

This agent forms insoluble complexes with cholesterol leading to the segregation of cholesterol fromits normal phospholipid g sites. This action, in turn, leads to the formation of holes about 40-50A wide in the lipid bilayer. Once the plasma membrane is permeabilized, cytosolic components ableto pass over nin-formed holes can be washed out, including the cytochrome C that was releasedfrom mitochondria to cytosol in the apoptotic cells s, 2006, Cytometry A 69(6):515-523).

Typically, Bcl-xL tors will yield an ECSO of less than about 10 nM in the Molt-4 cellpermeabilized cyt c assay of Examples 5 and 6, although the compounds may exhibit significantlylower ECSOs, for example, less than about 5, l, or even 0.5 nM. As demonstrated in Example 6,Bcl-xL inhibitors having low or very low cell permeability that do not exhibit activity in the standardMolt-4 cellular toxicity assay with rmeablized cells exhibit potent functional activity, asmeasured by release of cyt c, in cellular xicity assays with permeabilized cells. In addition tocytochrome c release, mitochondria undergoing apoptosis frequently lose their transmembraneMEI 24985843V.1 157117813-12620mitochondrial membrane potential (Bouchier-Hayes et al., 2008, Methods 44(3): 222-228). JC—l is acationic carbocyanine dye that accumulates in mitochondria and fluoresces red when mitochondria arehealthy and is lost when the mitochondrial membrane is compromised (percentage depolarization;Smiley et al., 1991, Proc. Natl. Acad. Sci. USA, 88: 675; Reers et al., 1991: Biochemistry, 30:4480-4486). This loss in signal can be detected in permeabilized cells using a fluorimeter (excitation545 nm and emission of 590 nm) and is therefore fully quantitative, enhancing both reproducibilityand throughput. Typically, Bcl-xL inhibitors will yield an EC50 of less than about 10 nM in theMolt-4 cell permeabilized JC-l assay of es 5 and 6, although the compounds may exhibitsignificantly lower EC50s, for e, less than about 5, l, 0.5 or even 0.05 nM. As demonstrated ine 6, Bcl-xL inhibitors having low or very low cell permeability that do not exhibit activity inthe standard Molt-4 cellular toxicity assay with non-permeablized cells exhibit potent functionalactivity, as measured by their loss of transmembrane mitochondrial membrane potential in the JC-lassay, in cellular cytotoxicity assays with permeabilized cells. Low permeability Bcl-xL inhibitorsalso exhibit potent ty when administered to cells in the form of ADCs (see, e.g., Example 8).

Although many of the Bcl-xL inhibitors of structural formulae (IIa)-(IId) ively orically inhibit Bcl-xL over other anti-apoptotic Bcl-2 family proteins, selective and/or specificinhibition of Bcl-xL is not necessary. The Bcl-xL tors and ADCs comprising the compoundsmay also, in addition to inhibiting Bcl-xL, inhibit one or more other anti-apoptotic Bcl-2 familyproteins, such as, for e, Bcl-2. In some embodiments, the Bcl-xL inhibitors and/or ADCs areselective and/or specific for Bcl-xL. By specific or selective is meant that the particular Bcl-xLinhibitor and/or ADC binds or ts Bcl-xL to a greater extent than Bcl-2 under equivalent assayconditions. In specific embodiments, the Bcl-xL inhibitors and/or ADCs exhibit in the range of about-fold, 100-fold, or even greater specificity or selectivity for Bcl-xL than Bcl-2 in binding assays.

III.A.2.Bcl-xL LinkersIn the ADCs described herein, the Bcl-xL inhibitors are linked to the antibody by way oflinkers. The linker linking a Bcl-xL inhibitor to the antibody of an ADC may be short, long,hydrophobic, hydrophilic, e or rigid, or may be composed of ts that each independentlyhas one or more of the above-mentioned properties such that the linker may include segments havingdifferent properties. The s may be polyvalent such that they ntly link more than oneBcl-xL inhibitor to a single site on the antibody, or monovalent such that covalently they link a singleBcl-xL inhibitor to a single site on the antibody.

As will be appreciated by skilled artisans, the linkers link the Bcl-xL inhibitors to theantibody by forming a covalent linkage to the Bcl-xL inhibitor at one location and a covalent linkageto antibody at r. The covalent linkages are formed by reaction between onal groups onthe linker and functional groups on the inhibitors and antibody. As used herein, the expression“linker” is intended to include (i) unconjugated forms of the linker that include a onal groupcapable of covalently g the linker to a Bcl-xL inhibitor and a functional group capable ofMEl 24985843V.1 15 8117813-12620covalently linking the linker to an antibody; (ii) partially conjugated forms of the linker that include afunctional group capable of covalently linking the linker to an antibody and that is covalently linkedto a Bcl-xL inhibitor, or vice versa; and (iii) fully conjugated forms of the linker that is covalentlylinked to both a Bcl-xL tor and an dy. In some specific ments of intermediatesynthons and ADCs described herein, moieties comprising the functional groups on the linker andcovalent linkages formed between the linker and antibody are ically illustrated as R’C and LK,respectively.

The s are ably, but need not be, chemically stable to conditions outside the cell,and may be designed to cleave, immolate and/or ise specifically degrade inside the cell.

Alternatively, s that are not designed to specifically cleave or degrade inside the cell may beused. A wide variety of linkers useful for linking drugs to antibodies in the context of ADCs areknown in the art. Any of these linkers, as well as other linkers, may be used to link the Bcl-xLinhibitors to the antibody of the ADCs described herein.

Exemplary polyvalent s that may be used to link many Bcl-xL inhibitors to an antibodyare described, for example, in US. Patent No 8,399,512; US. Published Application No.2010/0152725; US. Patent No. 8,524,214; US. Patent No. 8,349,308; US. Published Application No.2013/189218; U.S. hed Application No. 17265;example, the Fleximer® linker technology developed by Mersana er al. has the potential to enablehigh-DAR ADCs with good physicochemical properties. As shown below, the Fleximer® linkertechnology is based on incorporating drug molecules into a solubilizing poly-acetal backbone via asequence of ester bonds. The methodology renders highly-loaded ADCs (DAR up to 20) whilstmaintaining good physicochemical properties. This methodology could be utilized with Bcl-xLinhibitors as shown in the Scheme below.

MEI 24985843V.1 159-12620linkerFleximeradd 24985843V.1117813-12620To utilize the er® linker technology depicted in the scheme above, an aliphatic alcoholcan be present or introduced into the Bcl-xL inhibitor. The alcohol moiety is then conjugated to analanine moiety, which is then synthetically orated into the Fleximer® linker. Liposomalprocessing of the ADC in vitro releases the parent alcohol —containing drug.

Additional examples of dendritic type linkers can be found in US 2006/1 16422; US2005/271615; de Groot et al., (2003) Angew. Chem. Int. Ed. 42:4490-4494; Amir et al., (2003)Angew. Chem. Int. Ed. 4-4499; Shamis et al., (2004) J. Am. Chem. Soc. 126:1726-1731 ; Sunet al., (2002) Bioorganic & Medicinal Chemistry Letters 12:2213-2215; Sun et al., (2003) Bioorganic& Medicinal Chemistry 11:1761-1768; King et al., (2002) Tetrahedron Letters 43:1987-1990.

Exemplary monovalent linkers that may be used are described, for example, in Nolting, 2013,Antibody-Drug Conjugates, s in Molecular Biology 1-100; Kitson et al., 2013,CROs/CMOs - Chemica Oggi — Chemistry Today 31(4): 30-36; Ducry et al., 2010, BioconjugateChem. 21:5-13; Zhao et al., 2011, J. Med. Chem. 54:3606-3623; US. Patent No. 7,223,837; US.

Patent No. 8,568,728; US. Patent No. 8,535,678; and 010957, the content of each of whichis incorporated herein by reference in their entireties.

By way of example and not limitation, some cleavable and noncleavable linkers that may beed in the ADCs described herein are described below.

Cleavable LinkersIn certain embodiments, the linker selected is cleavable in vitro and in viva. Cleavable linkersmay include chemically or enzymatically unstable or degradable linkages. Cleavable linkers generallyrely on processes inside the cell to liberate the drug, such as reduction in the cytoplasm, exposure toacidic conditions in the lysosome, or cleavage by specific proteases or other enzymes within the cell.

Cleavable linkers generally orate one or more chemical bonds that are either chemically orenzymatically cleavable while the remainder of the linker is noncleavable.

In certain embodiments, a linker comprises a ally labile group such as hydrazoneand/or disulfide groups. Linkers sing chemically labile groups exploit differential propertiesbetween the plasma and some cytoplasmic compartments. The intracellular conditions to facilitatedrug release for hydrazone containing linkers are the acidic enVironment of endosomes andmes, while the disulfide containing linkers are d in the cytosol, which contains high thiolconcentrations, e. g., glutathione. In certain embodiments, the plasma stability of a linker singa chemically labile group may be increased by ucing steric hindrance using substituents near theally labile group.abile groups, such as hydrazone, remain intact during systemic circulation in theblood’s neutral pH enVironment (pH 7.3-7.5) and undergo hydrolysis and release the drug once theADC is internalized into mildly acidic endosomal (pH 5.0-6.5) and lysosomal (pH 4.5-5.0)compartments of the cell. This pH dependent release mechanism has been associated with cificMEl 24985843V.1 161117813-12620release of the drug. To increase the stability of the one group of the linker, the linker may bevaried by chemical cation, 6. g., substitution, allowing tuning to achieve more efficient ein the lysosome with a minimized loss in circulation.

Hydrazone-containing linkers may contain onal cleavage sites, such as additional acid-labile ge sites and/or enzymatically labile cleavage sites. ADCs including exemplaryone-containing linkers include the following structures:,N S\/\)LD n(1h) JN WN 8 AbD Q n(Ii) H3CZI AbO nwherein D and Ab represent the drug and Ab, respectively, and n represents the number of drug-linkers linked to the antibody. In certain linkers such as linker (Ig), the linker comprises twocleavable groups — a disulfide and a hydrazone . For such linkers, effective release of theunmodified free drug requires acidic pH or disulfide reduction and acidic pH. Linkers such as (lb)and (Ii) have been shown to be effective with a single one cleavage site.

Other acid-labile groups that may be included in linkers include cis-aconityl-containinglinkers. cis-Aconityl chemistry uses a carboxylic acid juxtaposed to an amide bond to accelerateamide hydrolysis under acidic conditions.

Cleavable linkers may also include a disulfide group. Disulfides are thermodynamicallystable at physiological pH and are designed to release the drug upon internalization inside cells,wherein the cytosol provides a significantly more reducing environment compared to the extracellularenvironment. Scission of disulfide bonds generally requires the presence of a cytoplasmic thiolMEI 24985843V.1 162117813-12620cofactor, such as (reduced) glutathione (GSH), such that disulfide-containing linkers are reasonablestable in circulation, selectively ing the drug in the cytosol. The intracellular enzyme proteinide ase, or similar enzymes capable of cleaving disulfide bonds, may also contribute tothe preferential cleavage of disulfide bonds inside cells. GSH is reported to be present in cells in theconcentration range of 05-10 mM compared with a significantly lower concentration of GSH orne, the most abundant low-molecular weight thiol, in circulation at approximately 5 uM. Tumorcells, where irregular blood flow leads to a hypoxic state, result in enhanced activity of reductiveenzymes and therefore even higher glutathione concentrations. In certain embodiments, the in vivostability of a disulfide-containing linker may be ed by chemical modification of the , e.g.,use of steric hindrance adjacent to the disulfide bond.

ADCs including exemplary disulfide-containing linkers include the ing ures:R R H(Ij) D\/R><R8\ MN AbO n(1k) D\/\S/S Ab(11) DMS’S Abwherein D and Ab represent the drug and antibody, respectively, n represents the number of drug-linkers linked to the antibody and R is independently selected at each occurrence from hydrogen oralkyl, for example. In certain embodiments, increasing steric hindrance adjacent to the disulfide bondincreases the stability of the linker. Structures such as (Ij) and (11) show increased in vivo stabilitywhen one or more R groups is selected from a lower alkyl such as methyl.r type of linker that may be used is a linker that is specifically cleaved by an enzyme.

Such s are typically peptide-based or include peptidic s that act as substrates for enzymes.

Peptide based linkers tend to be more stable in plasma and extracellular milieu than chemically labilelinkers. Peptide bonds generally have good serum stability, as lysosomal proteolytic enzymes haveMEI 24985843v.1 163117813-12620very low ty in blood due to nous inhibitors and the unfavorably high pH value of bloodcompared to mes. Release of a drug from an antibody occurs specifically due to the action oflysosomal ses, e. g., cathepsin and plasmin. These proteases may be present at elevated levels incertain tumor tissues. In certain embodiments, the linker is cleavable by a lysosomal enzyme. Incertain ments, the linker is cleavable by a mal enzyme, and the lysosomal enzyme isCathepsin B. . In certain embodiments, the linker is cleavable by a lysosomal enzyme, and themal enzyme is B-glucuronidase or B-galactosidase. In n embodiments, the linker iscleavable by a lysosomal enzyme, and the lysosomal enzyme is B-glucuronidase. In certainembodiments, the linker is cleavable by a lysosomal enzyme, and the lysosomal enzyme isB-galactosidase.

Those skilled in the art recognize the importance of cleavable linkers that are stable to plasma,yet are readily d by a lysosomal enzyme. sed herein, in certain ments, are linkers,cleavable by the lysosomal enzymes B-glucuronidase or B-galactosidase, that show improved plasmastability and reduced non-specific release of small molecule drug.

In exemplary embodiments, the cleavable peptide is selected from tetrapeptides such as Gly-Phe-Leu-Gly, Ala-Leu-Ala-Leu or dipeptides such as t, Val-Ala, and Phe-Lys. In certainembodiments, dipeptides are preferred over longer polypeptides due to hydrophobicity of the longerpeptides.

A variety of dipeptide-based cleavable linkers useful for linking drugs such as doxorubicin,mitomycin, camptothecin, tallysomycin and auristatin/auristatin family members to antibodies havebeen described (see, Dubowchik et al., 1998, J. Org. Chem. 67:1866-1872; Dubowchik et al., 1998,Bioorg. Med. Chem. Lett. 83341-3346; Walker et al., 2002, Bioorg. Med. Chem. Lett. 12:217-219;Walker et al., 2004, Bioorg. Med. Chem. Lett.14:4323-4327; and Francisco et al., 2003, Blood102: 1458-1465, the contents of each of which are incorporated herein by reference). All of thesedipeptide linkers, or modified versions of these dipeptide linkers, may be used in the ADCs bedherein. Other dipeptide linkers that may be used include those found in ADCs such as SeattleGenetics’ Brentuximab Vendotin SGN-35 (AdcetrisTM), Seattle Genetics SGN-75 (anti-CD-70, MC-monomethyl atin F(MMAF), Celldex Therapeutics glembatumumab (CDX-011) (anti-NMB,Val-Cit- monomethyl atin E(MMAE), and Cytogen PSMA-ADC (PSMA-ADC-1301) (anti-PSMA, Val-Cit-MMAE).

Enzymatically cleavable linkers may e a self-immolative spacer to spatially separate thedrug from the site of enzymatic cleavage. The direct attachment of a drug to a peptide linker canresult in proteolytic release of an amino acid adduct of the drug, thereby impairing its activity. Theuse of a self-immolative spacer allows for the elimination of the fully active, ally unmodifieddrug upon amide bond hydrolysis.

One self-immolative spacer is the bifunctional minobenzyl alcohol group, which islinked to the e through the amino group, forming an amide bond, while amine containing drugsMEl 24985843V.1 164117813-12620may be attached through carbamate functionalities to the benzylic hydroxyl group of the linker (togive a p-amidobenzylcarbamate, PABC). The resulting prodrugs are activated upon protease-mediated cleavage, leading to a l,6-elimination reaction releasing the unmodified drug, carbondioxide, and remnants of the linker group. The following scheme depicts the ntation of p-amidobenzyl carbamate and e of the drug:MEI 24985843v.1 165117813-12620omeoEA|OE1258TymfiwmwflumMun—2117813-12620wherein X-D represents the unmodified drug. Heterocyclic variants of this self-immolative grouphave also been described. See US. Patent No. 7,989,434.

In certain embodiments, the tically cleavable linker is a B-glucuronic acid-basedlinker. Facile e of the drug may be realized through cleavage of the B-glucuronide glycosidicbond by the lysosomal enzyme B-glucuronidase. This enzyme is present abundantly within lysosomesand is pressed in some tumor types, while the enzyme activity outside cells is low. I?)-Glucuronic acid-based linkers may be used to circumvent the tendency of an ADC to undergoaggregation due to the hilic nature of B-glucuronides. In certain embodiments, B-glucuronicacid-based linkers are preferred as linkers for ADCs linked to hydrophobic drugs. The followingscheme depicts the release of the drug from and ADC containing a B-glucuronic acid-based linker::*g)LD i[3-g—Iucuronidase Hogo \2 1 6-elimination 0g“W 3e: w . mA variety of cleavable uronic ased linkers useful for linking drugs such asauristatins, camptothecin and doxorubicin analogues, CBI minor-groove binders, and rin toantibodies have been described (see, Jeffrey et al., 2006, Bioconjug. Chem. 172831-840; Jeffrey et al.,Bioorg. Med. Chem. Lett. 172278-2280; and Jiang et al., 2005, J. Am. Chem. Soc. 127:11254-11255,the contents of each of which are incorporated herein by nce). All of these B-glucuronic acid-based linkers may be used in the ADCs described herein. In certain embodiments, the enzymaticallyble linker is a B-galactoside-based linker. B-Galactoside is present abundantly withinmes, while the enzyme ty outside cells is low. Additionally, Bcl-XL inhibitors containinga phenol group can be covalently bonded to a linker through the phenolic oxygen. One such linker,described in US. Published App. No. 318668, relies on a methodology in which a diamino-ethane “SpaceLink” is used in conjunction with traditional “PAB O”-based self-immolative groups todeliver phenols. The cleavage of the linker is depicted schematically below using a Bcl-XL inhibitorof the disclosure.

MEl 24985843V.1 167117813-12620representative linkerwith PABO unitHO 0HOB/El "8paceLink"HO O-: /U\| lysosomalO — K enzymeSpaceLink‘s ultimatefate is a cyclic ureable linkers may include avable portions or segments, and/or cleavable segmentsor portions may be included in an otherwise non-cleavable linker to render it cleavable. By way ofexample only, polyethylene glycol (PEG) and related polymers may include cleavable groups in thepolymer backbone. For example, a polyethylene glycol or polymer linker may include one or moreble groups such as a disulfide, a hydrazone or a dipeptide.

Other degradable linkages that may be included in linkers include ester linkages formed bythe reaction of PEG carboxylic acids or activated PEG carboxylic acids with alcohol groups on aically active agent, n such ester groups lly hydrolyze under physiologicalconditions to release the biologically active agent. Hydrolytically degradable es include, but arenot limited to, carbonate linkages; imine linkages resulting from reaction of an amine and analdehyde; phosphate ester linkages formed by reacting an alcohol with a phosphate group; acetallinkages that are the reaction product of an aldehyde and an alcohol; orthoester linkages that are theon product of a formate and an alcohol; and oligonucleotide linkages formed by aphosphoramidite group, ing but not limited to, at the end of a polymer, and a 5' hydroxyl groupof an oligonucleotide.

In certain embodiments, the linker comprises an enzymatically cleavable peptide moiety, fore, a linker comprising structural formula (IVa), (IVb), (IVc) or (IVd):MEI 24985843V.1 168117813-12620Ry oR61 0H q oJl<91(IVa) N\N TH peptide~m_y XRy 0(Nb) qWp e~N HRy oW0%peptide‘NW0”;HRy oR2 oq oie‘i(IVd) /N\TJ\peptide~M'or a pharmaceutically able salt thereof, wherein:peptide represents a peptide (illustrated N—>C, wherein peptide includes the amino andcarboxy ni”) cleavable by a lysosomal enzyme;T represents a r comprising one or more ethylene glycol units or an alkylene chain, orcombinations thereof;Ra is selected from hydrogen, C16 alkyl, SO3H and CHZSO3H;Ry is hydrogen or C14 alkyl-(O)r-(C1,4 alkylene)S-G1 or C14 alkyl-(N)-[(C1,4 alkylene)-G1]2;RZ is C14 alkyl-(O)r-(C1,4 alkylene)S-G2;G1 is SO3H, COZH, PEG 4-32, or sugar moiety;G2 is SO3H, COZH, or PEG 4-32 moiety;r is 0 or 1;sis00rl;MEI 24985843V.1 169117813-12620p is an integer ranging from 0 to 5;q is 0 or 1;X is 0 or 1;yis00rl;represents the point of attachment of the linker to the Bcl-XL inhibitor; and* represents the point of attachment to the remainder of the .

In certain embodiments, the linker comprises an tically cleavable peptide moiety, forexample, a linker comprising structural formula (IVa), (IVb), (IVc), or (IVd), or a pharmaceuticallyacceptable salt f.

In n embodiments, the peptide is selected from a tripeptide or a dipeptide. In particularembodiments, the dipeptide is selected from: Val-Cit; Cit-Val; Ala-Ala; Ala-Cit; Cit-Ala; Asn-Cit;Cit-Asn; Cit-Cit; u; Glu-Val; Ser-Cit; Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; l;Val-Ala; Phe-Lys; Lys-Phe; Val-Lys; Lys-Val; Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu-Cit; Cit-Leu;Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; p; and Trp-Cit; or a pharmaceutically able salt thereof.

Exemplary embodiments of linkers according to structural formula (IVa) that may be includedin the ADCs described herein include the linkers illustrated below (as rated, the linkers include agroup suitable for covalently linking the linker to an antibody):MEl 24985843V.1 170117813-12620"”4I OO/\©\ MyZI 002$ _<0 I/_\2 oIZ zNI IZI OO/:\/\ O flQfQ\ j>14¥<0§030§03jw<2 I mO Iow//\/O\/\ zingzo OZI OOJ J? OZ O /gut/C NZ;V ETymfiwmwflum-12620IIIII$.35 GEE 6.36Tymfiwmwflum-12620936 $.36Tymfiwmwflum117813-12620Exemplary embodiments of linkers according to structural formula (IVb), (IVc), or (IVd) thatmay be included in the ADCs bed herein include the linkers illustrated below (as illustrated, thelinkers include a group le for covalently linking the linker to an antibody):(IVb.1) oo 1OAWH2/ o o DAOJifiiNWLN N\:)LNH(IVb.2) Ho o jHH2N oO OJJ?‘(IVb.3) NM HN NO H HO 5o O O OJLi‘NVLN NgLNH(IVb.4) \ H = Ho 1oékNH2MEl 24985843V.1 174117813-12620NH2 ONAANLF0 o O is:\ 9193”"(IVb.5) OO 1(IVb.6)(IVb.8)MEI 24985843V.1 175117813-12620(IVb.9) gomxg¢<rkoékNH2(IVb.11)(IVb.12)MEI 24985843V.1 176-12620(IVb.13)(IVb.14)(IVb.15)(IVb.16)\/ OOWNHNWWNW OMEI 24985843V.1 177117813-12620(IVb.17)O O0 QNO _(IVb.19)MEI 24985843V.1 178117813-12620g?“\/\O/\/O\)J\NO ON9L”/©/\OJL5€(IVc. 1) o o \L(IVc.2) H O: H Héwovg $5523)?N N NHN1 0 O(IVc.3) oH 3 HQW1mmN \sin/O O OO /OHO /‘OS/H \=/ O0 HN K/S \(IVc.4) oMEI 24985843V.1 179-12620O[\1/\n/N\E)OJ\NJfifN A/\O/\/O\/\O/\/O\}(IVc.5)O O /-\ WML\0/\/0\/\O/\/0\}H0 3030H 2D‘OH(IVC.6) 000;:NH : 00:5:‘ NNijLN \JLNDADAD}?(IVc.7) = HMEI 24985843V.1 180117813-12620O/\/O\/\O/\/O\/\O/\/O\(IVd.1)N\n/\/N\/\o/\/O\/\O/\/Oj0 O/\/O\/\O/\/0\/\OK/Owo/(IVd.2) 0II IHN\n/:\NHO /\/o\/\O/\/ojO O/\/O\/\o/\/O\/\O“0%0/Y\/N\/\O/\/0\/\O/\/Oj(IVd.3) O/\/O\/\O/\/O\/\OK/Owo/VOV\O{Ck/\OA/OWOA/OO/\/O\/\O/\/O\/\OMEI 24985843V.1 181117813-12620H Z: H 0 O(IVd.4) WOfiNffiTVN—kg}In certain ments, the linker comprises an enzymatically cleavable sugar moiety, forexample, a linker comprising structural formula (Va), (Vb), (Vc), (Vd), or (Ve):Jake /OH OH021/,” ‘\\\\OH(Vb) o 5)9.le /MEI 24985843V.1 182-12620231 X0 /A O /Jelly) /or a pharmaceutically acceptable salt thereof, wherein:q is 0 0r 1;r is 0 0r 1;X1 is CH2, 0 or NH;MEI 24985843V.1 183117813-12620represents the point of attachment of the linker to the drug; and* represents the point of attachment to the remainder of the linker.

Exemplary embodiments of s according to structural formula (Va) that may be includedin the ADCs described herein include the linkers illustrated below (as illustrated, the linkers include agroup le for covalently linking the linker to an antibody):(Va. 1)oYEA,(Va.2) 0 0 ONJl\/\NJJ\/\NH H /OYEA.

O \(V33) O/\/O\/\HMpMEl 24985843V.1 184-12620$.36 $.36Tymfiwmwflum-126206.36 936Tymfiwmwflum-12620$.36 8.36Tymfiwmwflum-12620833 3.36Tymfiwmwflum117813-12620Exemplary embodiments of linkers according to structural formula (Vb) that may be includedin the ADCs described herein include the linkers illustrated below (as illustrated, the linkers include agroup suitable for covalently g the linker to an antibody):(Vb.1)(Vb.2)MEI 24985843V.1 189117813-12620(Vb.3)HN HO(Vb.5) HOII.

O OO\/\0(Vb.6)MEI 24985843V.1 190117813-12620HO 9H 0\. OHHO‘ O 0(Vb.7) O NO Ho:<ai‘HO : OO \(Vb.8) //©/\’\Nk/1;?o OH(W9) 0 OHMEI 24985843V.1 191117813-12620(Vb.10) MN 0H ;Exemplary embodiments of s according to structural formula (Vc) that may be includedin the ADCs bed herein include the linkers illustrated below (as illustrated, the linkers include agroup suitable for covalently linking the linker to an antibody):MEI 24985843V.1 192-12620(V0.1) C ?\O/\/Offi\/\N)\\/\N /V0.2 O3—,.“ OO O COZHO/\/\NH o1% oMEI 24985843V.1 193-12620O “Whfi(V0.4) ”H OO OHNJVNFEW/O\ 0% /O\/\O/\/NH sogH(V0.5)0 \”if" 0% O(V0.6) O\/\O/\/NH SO3HMEI 24985843V.1 194117813-12620(V0.7)(V0.8) O\/\N O/\/\/N\5’44O o OOWNH sogH(V09)MEI 24985843V.1 195-12620(Vc. 10)(Vc.ll)ary embodiments of linkers according to structural formula (Vd) that may be includedin the ADCs described herein include the linkers illustrated below (as illustrated, the linkers include agroup suitable for covalently linking the linker to an antibody):MEI 24985843V.1 196-12620(Vd.1)(Vd.2)(Vd.3)MEI 24985843V.1 197117813-12620oZ<J_/—>L| N(Vd.4)(Vd.5)(Vd.6) W0 9Hary embodiments of linkers according to structural formula (Ve) that may be includedin the ADCs bed herein include the linkers illustrated below (as illustrated, the linkers include agroup suitable for covalently linking the linker to an antibody):MEI 24985843V.1 198117813-1262005/2,(Val)OH NAVNJWNH HO oHO "”’OHO O(V6.2)H HOH N/U\/\N)\/O\/\N OH Ho ““‘N\n/\/O\/\O/\/O\/\O/\/NO H\\ OHO "”’OH O NO OOH UNon-Cleavable LinkersAlthough cleavable linkers may provide certain advantages, the linkers comprising the ADCdescribed herein need not be cleavable. For noncleavable s, the drug release does not depend onthe differential properties n the plasma and some cytoplasmic compartments. The release ofthe drug is postulated to occur after alization of the ADC via antigen-mediated endocytosis anddelivery to lysosomal compartment, where the antibody is degraded to the level of amino acidsthrough intracellular proteolytic degradation. This process releases a drug derivative, which is formedby the drug, the linker, and the amino acid residue to which the linker was covalently attached. Theamino-acid drug metabolites from conjugates with noncleavable linkers are more hydrophilic andgenerally less membrane permeable, which leads to less bystander effects and less nonspecifictoxicities compared to conjugates with a cleavable linker. In l, ADCs with noncleavables have greater stability in circulation than ADCs with ble linkers. Non-cleavable linkersmay be alkylene , or maybe ric in natures, such as, for example, based uponpolyalkylene glycol polymers, amide polymers, or may e segments of alkylene chains,polyalkylene glycols and/or amide polymers. In n embodiments, the linker comprises apolyethylene glycol segment having from 1 to 6 ethylene glycol units.

A variety of non-cleavable linkers used to link drugs to antibodies have been described. (See,Jeffrey et al., 2006, Bioconjug. Chem. l7;83l-840; Jeffrey et al., 2007, Bioorg. Med. Chem. Lett.

MEI 24985843V.1 199117813-1262017:2278-2280; and Jiang et al., 2005, J. Am . Chem. Soc. 127:11254-11255, the contents of which areincorporated herein by reference). All of these linkers may be ed in the ADCs described herein.

In certain embodiments, the linker is non-cleavable in viva, for example a linker ing toural formula (VIa), (VIb), (VIc) or (VId) (as illustrated, the linkers include a group suitable forcovalently linking the linker to an antibody:0 OWaywm(VIb) 311W0/]E/O\/\04%;:o 0(VIC) RX/mmmm(VId) AWRXor a pharmaceutically acceptable salt thereof, wherein:Ra is selected from hydrogen, alkyl, sulfonate and methyl sulfonate;R’C is a moiety including a functional group capable of covalently linking the linker toan antibody; and9‘5represents the point of attachment of the linker to the Bcl-XL tor.

Exemplary embodiments of linkers according to structural formula (VIa)-(VId) that may beincluded in the ADCs described herein include the s illustrated below (as illustrated, the linkersMEI 24985843V.1 200117813-12620include a group suitable for covalently linking the linker to an dy, and “ “ represents the pointof attachment to a Bcl-XL inhibitor):(VIa. 1)(VIc. 1)(VIc.2)(VId.1)(VId.2)(was)(VId.4)MEl 24985843V.1 201117813-12620Groups Used to Attach Linkers to Anti-B7-H3 AntibodiesAttachment groups can be electrophilic in nature and include: maleimide groups, tedides, active esters such as NHS esters and HOBt esters, haloformates, acid halides, alkyl andbenzyl halides such as haloacetamides. As discussed below, there are also emerging technologiesrelated to “self-stabilizing” maleimides and “bridging disulfides” that can be used in accordance withthe disclosure.

Loss of the drug-linker from the ADC has been observed as a result of a maleimide exchangeprocess with albumin, cysteine or glutathione (Alley et al., 2008, Bioconjugate Chem. 19: 759-769).

This is particularly ent from highly solvent-accessible sites of conjugation while sites that arelly accessible and have a positively charged environment promote maleimide ring hydrolysis(Junutula et al., 2008, Nat. Biotechnol. 26: 925-932). A recognized solution is to hydrolyze thesuccinimide formed from conjugation as this is resistant to deconjugation from the antibody, therebymaking the ADC stable in serum. It has been reported previously that the succinimide ring willundergo hydrolysis under alkaline conditions (Kalia et al., 2007, Bioorg. Med. Chem. Lett. 17: 6286-6289). One example of a stabilizing” maleimide group that hydrolyzes spontaneously underantibody conjugation conditions to give an ADC s with improved stability is depicted in thetic below. See US. Published Application No. 2013/0309256, International ApplicationPublication No. WO 73337, Tumey et al., 2014, Bioconjugate Chem. 25: 1871-1880, andLyon et al., 2014, Nat. hnol. 32: 1059-1062. Thus, the maleimide attachment group is reactedwith a sulflqydryl of an antibody to give an intermediate succinimide ring. The hydrolyzed form ofthe ment group is resistant to deconjugation in the presence of plasma proteins.

MEI 24985843V.1 202117813-12620o ZNIo 2: 9.: memE5k? «E: :2 IO E$>o v0:zJAl\|\VO 0 mU_E_:_oo=w $3.3m_.mwo_ m94E”6 2m«Zn... 9E2 9E2Z 32H O 0 20 O :2283 o2n. ZNI kuzegc 85293g< w 0. 21v IOQ,<Em OmEmma £an A| Hmé?IZ 5.? I2 msomcmanm Alo o (R::2o 2“:o o 928E603 9Ez z0 o o om 85:82E m a?w56596 $286.9:”899$ ac:fictoz 8 86:80TymfiwmwflumMun—2117813-12620As shown above, the maleimide ring of a linker may react with an antibody Ab, forming acovalent attachment as either a succinimide (closed form) or succinamide (open form).erics has disclosed a method for bridging a pair of sulflaydryl groups derived fromreduction of a native hinge disulfide bond. See, Badescu et al., 2014, Bioconjugate Chem. 25: l 124-1136. The reaction is depicted in the schematic below. An advantage of this methodology is theability to synthesize homogenous DAR4 ADCs by full reduction of IgGs (to give 4 pairs ofsulfhydryls) followed by reaction with 4 equivalents of the ting agent. ADCs containing“bridged disulfides” are also claimed to have sed stability.

MEl 24985843V.1 204117813-12620\\ $14“92:86zm zovEswfiE ‘| vomvtnrmNo N0m\TymfiwmwflumMun—2117813-12620Similarly, as depicted below, a maleimide derivative that is capable of bridging a pair ofdryl groups has been developed. See US. Published Application No. 2013/0224228.

In certain embodiments the ment moiety comprises the structural formulae (VIIa),(VIIb), or (VIIc):q 0 /(VIIa) oRq 1 0(VIIb)g o o(VIIc) “1}"or a pharmaceutically acceptable salt thereof, wherein:Rq is H or —O-(CH2CH20)11-CH3;X is 0 or 1;yisOorl;MEl 24985843v.1 206117813-12620G3 is —CH2CH2CHZSO3H or —CH2CHzO-(CH2CHZO)11-CH3;RW is CH2$O3H 01‘ —NH(CO)'CHchzo-(CHchzo)12-CH3; and* represents the point of attachment to the remainder of the linker.

In certain embodiments, the linker comprises a segment according to structural formulae(VIIIa), (VIIIb), or (VIIIc):mob/OVO/(VIIIa) (hydrolyzed form)) O(hydrolyzed form)4“” oo o Hogs/W700N f HNo N NO> *(VIIIc) RW RW (hydrolyzed form)or a hydrolyzed derivative or a pharmaceutically acceptable salt thereof, wherein:Rq is H or —O-(CH2CH20)11-CH3;X is 0 or 1;y is 0 or 1;G3 is —CH2CH2CHZSO3H or —CH2CHzO-(CH2CHZO)11-CH3;RW is —O-CH2CHZSO3H or —NH(CO)-CH2CHZO-(CH2CHZO)lz-CH3;* represents the point of attachment to the remainder of the linker; andrepresents the point of attachment of the linker to the antibody.

Exemplary ments of linkers according to structural formula (VIIa) and (VIIb) that maybe included in the ADCs described herein e the linkers illustrated below (as illustrated, thelinkers e a group suitable for covalently g the linker to an antibody):MEl 24985843V.1 207-126200 \(VIIa.1) o o No HN 0{Okoxo 0/ BHHofo/—\ _/—o/—\o—/—O0(V11a.2) 0MEI 24985843V.1 208-126209.3:: TymfiwmwflumMun—2-12620z/.\=/z O/©/O\/\O/\/O\/\O/\/O\/\O/\/O\/\O/\/O\/\O/\/O\/\O/ Oz/,\=/zIO :02$.35 TymfiwmwflumMun—2117813-12620f0)\0/\/O\/\O/\/O\/\O/ O\/\O/\/O\/\O/\/O\/\OL flu fO\/\O/\/O\/\O/\/O\/\O/ \/O\/\O/\/O\/\O \Wm z o/¥Z\/lez O:2 OWM IZNI HO z/Xfiz:o£5 Gets TymfiwmwflumMun—2-12620o Oz:z z:Zz 2 \/ /z zw H/Moo :0 ou mu0Am I::¥/Z muoAmer/V 225V TymfiwmwflumMun—2-12620Ger/V TymfiwmwflumMun—2117813-12620/\/O\/\O/\/O\/\O/ o\/\o/\/o\/\o/\/o\/o\o/LzA356 Amer/V TymfiwmwflumMun—2-12620Exemplary embodiments of linkers according to structural formula (VIIc) that may beed in the ADCs described herein include the linkers illustrated below (as illustrated, the linkersinclude a group suitable for covalently linking the linker to an antibody):MEl 24985843V.1 215117813-12620(VIIC.1)O/\/O\/\O/\/O\/\0/\/o\o/\O/\/O\/\O/\/O\/\O\/O\/\O/\/O(V1102)O ON\[]/\NN \o/’S\MEI 24985843V.1 216-12620O/\/o\/\O/\/o\/\O/\/O\O/\O/\/O\/\0/\/O\/\Oifo 9O\/\O/\/O\/\O/\/O(V1103)O O OHN11% NY”N \o oO\\/rO//S\\DNVNT71””H _(VIIC.4){(0 o o N?(V1105)MEI 24985843V.1 217117813-12620(VIIc.6)In certain embodiments, L is selected from the group consisting of IVa.l-IVa.8, IVb. l-, IVc.7, IVd.l-IVd.4, Va.l-Va.12, Vb.l-Vb.10, Vc.l-Vc.ll, Vd.l-Vd.6, Ve.l-Ve.2,VIa. 1, VIC. l-Vlc.2, VId. l -VId.4, VIIa. l -VIIa.4, VIIb. l-VIIb. 8, VIIc. l 6 in either the closed oropen form, and a pharmaceutically acceptable salt thereof.

In certain ments, L is selected from the group ting of IVb.2, IVc.5, IVc.6, IVc.7,IVd.4, Vb.9, VIIa.l, VIIa.3, VIIc.l, VIIc.4, and VIIc.5, wherein the maleimide of each linker hasreacted with the antibody Ab, forming a covalent attachment as either a succinimide (closed form) orsuccinamide (open form),and a pharmaceutically acceptable salt thereof.

In certain embodiments, L is selected from the group consisting of IVb.2, IVc.5, IVc.6, IVd.4,VIIa.l, VIIa.3, VIIc.l, VIIc.4, VIIc.5, n the maleimide of each linker has reacted with theantibody Ab, forming a covalent attachment as either a succinimide (closed form) orsuccinamide(open form), and a pharmaceutically acceptable salt thereof.

In certain embodiments, L is selected from the group consisting of IVb.2, VIIa.3, IVc.6, andVIIc.l, wherein 5‘4 is the ment point to drug D and @ is the attachment point to the LK,wherein when the linker is in the open form as shown below, @ can be either at the a-position or [5-position of the ylic acid next to it:H2NY0””1 Q0W2—“? O\/©/ Wyn/[i r33? VIIa.3 (closed form)I OMEl 24985843V.1 218117813-12620ch.6 d form)MEI 24985843V.1 219117813-12620w,“ NHIVc.6 (open form)NW35@IVb.2 (closed form)W0 rm Maw@lVb.2 (open form)Bcl-xL Linker Selection ConsiderationsAs is known by skilled artisans, the linker selected for a particular ADC may be influenced bya variety of factors, ing but not limited to, the site of attachment to the antibody (e. g., lys, cys orother amino acid residues), structural constraints of the drug pharmacophore and the lipophilicity ofthe drug. The specific linker selected for an ADC should seek to balance these different factors forthe specific antibody/drug combination. For a review of the factors that are ced by choice oflinkers in ADCs, see Nolting, Chapter 5 “Linker logy in dy-Drug Conjugates,” In:Antibody-Drug Conjugates: Methods in Molecular Biology, vol. 1045, pp. , Laurent Ducry(Ed), Springer Science & Business Medica, LLC, 2013.

For example, ADCs have been observed to effect killing of der antigen-negative cellspresent in the Vicinity of the antigen-positive tumor cells. The mechanism of bystander cell killing byMEl 24985843V.1 220117813-12620ADCs has indicated that metabolic products formed during ellular processing of the ADCs mayplay a role. Neutral cytotoxic metabolites ted by metabolism of the ADCs in antigen-positivecells appear to play a role in bystander cell killing while charged metabolites may be prevented fromdiffusing across the membrane into the medium and therefore cannot affect bystander killing. Inn embodiments, the linker is selected to attenuate the bystander killing effect caused by cellularmetabolites of the ADC. In certain ments, the linker is ed to increase the bystanderkilling effect.

The properties of the linker may also impact aggregation of the ADC under conditions of useand/or storage. Typically, ADCs reported in the literature contain no more than 3-4 drug moleculesper antibody molecule (see, e. g., Chari, 2008, Acc Chem Res 41 :98-107). Attempts to obtain higherdrug-to-antibody ratios (“DAR”) often , particularly if both the drug and the linker werehydrophobic, due to aggregation of the ADC (see King et al., 2002, J Med Chem 45:4336-4343;Hollander et al., 2008, Bioconjugate Chem 19:358-361; Burke et al., 2009 jugate Chem: 1242-1250). In many instances, DARs higher than 3-4 could be beneficial as a means ofincreasing potency. In instances where the Bcl-xL inhibitor is hydrophobic in , it may bedesirable to select linkers that are relatively hydrophilic as a means of reducing ADC aggregation,especially in instances where DARS greater than 3-4 are desired. Thus, in certain embodiments, thelinker incorporates chemical moieties that reduce aggregation of the ADCs during storage and/or use.

A linker may incorporate polar or hydrophilic groups such as charged groups or groups that becomecharged under physiological pH to reduce the aggregation of the ADCs. For example, a linker mayincorporate charged groups such as salts or groups that deprotonate, e. g., carboxylates, or protonate,e. g., amines, at physiological pH.

Exemplary polyvalent linkers that have been ed to yield DARs as high as 20 that maybe used to link us Bcl-xL inhibitors to an antibody are described in US. Patent No 8,399,512;US. Published Application No. 2010/0152725; US. Patent No. 8,524,214; US. Patent No. 8,349,308;US. Published Application No. 2013/189218; U.S. Published Application No. 2014/017265; WO2014/093379;nce in their entireties.

In particular ments, the aggregation of the ADCs during storage or use is less thanabout 40% as ined by size-exclusion chromatography (SEC). In ular embodiments, theaggregation of the ADCs during storage or use is less than 35%, such as less than about 30%, such asless than about 25%, such as less than about 20%, such as less than about 15%, such as less than about%, such as less than about 5%, such as less than about 4%, or even less, as determined by size-exclusion chromatography (SEC).

III.A.3. Bcl-xL ADC SynthonsAntibody-Drug Conjugate synthons are synthetic intermediates used to form ADCs. Thesynthons are generally compounds according to structural formula (III):MEl 24985843V.l 221117813-12620(III) D—L RXor a pharmaceutically able salt thereof, wherein D is a Bcl-XL inhibitor as previously described,L is a linker as previously bed, and R’C is a reactive group suitable for linking the synthon to anantibody.

In specific embodiments, the intermediate synthons are compounds ing to uralformulae (IIIa), (IIIb), (IIIc) and (IIId), below, or a pharmaceutically acceptable salt thereof, Wherethe various substituents Arl, Arz, 21, 223, 2%, R’, R1, R2, R4, R113, Rllb, R12 and R13 are as previouslydefined for structural formulae (Ila), (11b), (11c) and (11d), respectively, L is a linker as previouslydescribed and R’C is a functional group as described above:(IIIa)/R1\ / L \ RX(IIIb) R’4R1 1 b(IIIc)MEl 24985843V.1 222117813-12620(111d)To synthesize an ADC, an intermediate synthon according to structural formula (III), or a saltthereof, is contacted with an antibody of st under conditions in which onal group R’C reactswith a “complementary” functional group on the antibody, F", to form a covalent linkage.

(III) D—L—RX + Ab —> (I) [D—L—LK-l-AbThe identities of groups R’C and FC will depend upon the chemistry used to link the synthon tothe dy. Generally, the chemistry used should not alter the ity of the antibody, for exampleits ability to bind its . Preferably, the binding properties of the conjugated antibody will closelyresemble those of the unconjugated antibody. A variety of chemistries and techniques for conjugatingmolecules to biological molecules such as antibodies are known in the art and in particular toantibodies, are well-known. See, e. g., Amon et al., “Monoclonal Antibodies For Immunotargeting OfDrugs In Cancer Therapy,” in: Monoclonal dies And Cancer Therapy, Reisfeld et al. Eds., AlanR. Liss, Inc., 1985; Hellstrom et al., odies For Drug Delivery,” in: lled Drug Delivery,Robinson et al., Eds., Marcel Dekker, Inc., 2nd Ed. 1987; Thorpe, “Antibody Carriers Of xicAgents In Cancer Therapy: A Review,” in: Monoclonal Antibodies ’84: Biological And ClinicalApplications, Pinchera et al., Eds., 1985; “Analysis, Results, and Future Prospective of theTherapeutic Use of Radiolabeled Antibody In Cancer Therapy,” in: Monoclonal Antibodies ForCancer Detection And Therapy, Baldwin et al., Eds., ic Press, 1985; Thorpe et al., 1982,Immunol. Rev. 62: 1 19-58; PCT publication W0 89/12624. Any of these chemistries may be used tolink the synthons to an antibody.

Typically, the synthons are linked to the side chains of amino acid residues of the antibody,including, for example, the primary amino group of accessible lysine residues or the sulflaydryl groupof accessible cysteine residues. Free sulflaydryl groups may be obtained by reducing interchaindisulfide bonds. In n embodiments, LK is a linkage formed with an amino group on the anti-hB7-H3 antibody Ab. In certain embodiments, LK is an amide, thioether, or thiourea. In certainembodiments, LK is an amide or thiourea. In certain embodiments, LK is a linkage formed with asulflaydryl group on the anti-hB7-H3 dy Ab. In certain ments, LK is a thioether. Incertain embodiments, LK is an amide, thioether, or thiourea; and m is an integer ranging from 1 to 8.

MEI 24985843V.1 223117813-12620A number of functional groups R’C and chemistries useful for g synthons to accessiblelysine residues are known, and include by way of example and not limitation NHS-esters andisothiocyanates.

A number of functional groups R’C and chemistries useful for linking synthons to accessiblefree sulflaydryl groups of cysteine residues are known, and include by way of e and notlimitation haloacetyls and maleimides.

However, conjugation chemistries are not limited to available side chain groups. Side chainssuch as amines may be converted to other useful groups, such as hydroxyls, by linking an appropriatesmall molecule to the amine. This strategy can be used to increase the number of available linkingsites on the antibody by ating unctional small molecules to side chains of ibleamino acid residues of the antibody. Functional groups R’C suitable for covalently linking the synthonsto these “converted” functional groups are then included in the synthons.

The antibody may also be engineered to include amino acid residues for conjugation. Anapproach for ering antibodies to include non-genetically encoded amino acid residues useful forconjugating drugs in the context of ADCs is described in Axup er al., 2003, Proc Natl Acad Sci101-16106 and Tian er al., 2014, Proc Natl Acad Sci lll:l776-l77l as are chemistries andonal groups useful for linking synthons to the non-encoded amino acids.

Exemplary synthons useful for making ADCs described herein include, but are not limited to,the following synthons listed below in Table B.

MEl 24985843V.1 224-1262033955:cfigmm 350Baa—8mm— .cZm Tymfiwmwflum2an Mm:-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ TymfiwmwflumMun—2-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955553% 350 NW OmBaa—amm— .cZ—— TymfiwmwflumMun—2117813-1262033955553% 350m— .cZ TymfiwmwflumMun—2117813-1262033955553% 350 >m 06m— .c Z——TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-12620Synthon>> Codem No.m 24985843V.1117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955553% 350 CE mmBaa—amm— .cZ—— TymfiwmwflumMun—2117813-1262033955553% 350m— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955553% 350 w: Em— .cZ—— TymfiwmwflumMun—2-12620Synthon CodeExample N0. 24985843V.1-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum-1262033955:cfigmm 350 mH DHBaa—8mm— .cZ——TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955553% 350 n: v:Baa—amm— .cZ—— TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-12620Synthon>> Codem No.m 24985843V.1117813-1262033955553% 350 DE mmm— .cZ—— TymfiwmwflumMun—2117813-1262033955553% 350 BE NEm— .cZ—— TymfiwmwflumMun—2-1262033955553% 350 WI m:Baa—amm— .cZ—— TymfiwmwflumMun—2117813-12620Structure>> Codem No.m 24985843V.1-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum117813-1262033955553% 350m— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955553% 350m— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum-12620Synthon CodeExample N0. 24985843V.1117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2117813-12620n CodeExample N0. 24985843V.1-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350 mmBaa—8mm— .cZ TymfiwmwflumMun—2-12620Synthon CodeExample N0. 24985843V.1117813-12620Synthon>> Codem No.m 24985843V.1117813-1262033955553% 350m— .cZ MEN TymfiwmwflumMun—2-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-12620SynthonExample 24985843V.1117813-1262033955553% 350 BBm— .cZ :fid TymfiwmwflumMun—2-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2117813-1262033955553% 350m— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350 Wm MEm— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350 MEm— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955:cfigmm 350 NH <3Baa—8mm— .cZ TymfiwmwflumMun—2117813-12620n CodeExample N0. 24985843V.1-1262033955:cfigmm 350 DDBaa—8mm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350 >3Baa—8mm— .cZ TymfiwmwflumMun—2117813-12620Synthon Codee N0. 24985843V.1-1262033955:cfigmm 350 0>Baa—8mm— .cZ TymfiwmwflumMun—2117813-12620/O\/\O/\/O\/\O/\/O\/\O O/\/O\/\O/\/O\/\O/\.Ox33955 w553% Io::cfigmm 350 m>m— .cZ TymfiwmwflumMun—2-1262033955 /O\/\O/\/O\/\Ol\/O\/\O:cfigmm 350 H> >>Baa—8mm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350 :5Baa—8mm— .cZ TymfiwmwflumMun—2117813-12620O/\/O\/\O/\/O\ /O\/\O/\/\Z0302?)ongogogo/33955 Ed :0553% \AZ\_m/\/43szI/O.\OO553% 350Baa—8mm— Tymfiwmwflum-1262033955:cfigmm 350 ONBaa—8mm— .cZ TymfiwmwflumMun—2117813-12620xOx/xO/\/O o \/o\/\o/\/2\/\_rz O\/\O/\lO\/\Ol\/Z\/\=/Z Ol\/O\/\Ol\/O\/\O\O/\/O\J\/\O/\/ O33955 I:cfigmm 350 MN 15mBaa—8mm— .cZ DAN TymfiwmwflumMun—2-1262033955 Z W/ogogogo/Io.553% 350Baa—amm— .cZ TymfiwmwflumMun—2-1262033955553% 350 m>Baa—amm— .cZ NQN TymfiwmwflumMun—2-12620Z-Z \\O/\IO\/\OI\/O\/\OI\IO\33955TymfiwmwflumMun—2-12620”logo/\zogol\/O\/\O/33955:cfigmm 350 >> 3%Baa—8mm— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum-1262033955553% 350Baa—amm— .cZ TymfiwmwflumMun—2-12620o\/\o/\/o\/\o/\/z\/\FflO/\/O\/\O/\/O\/\(O/\/O\/\O/\/O\NO\/\O/\/O\/\O/\/O/\/o\/\o/\/o\/\ou o\O33955553% 350Baa—amm— .cZ TymfiwmwflumMun—2117813-1262033955553% 350 <<<m— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ Tymfiwmwflum117813-1262033955553% 350 Um< qm<m— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350 Zm< m<<Baa—8mm— .cZ TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ Tymfiwmwflum117813-1262033955:cfigmm 350 §m<m— .cZ TymfiwmwflumMun—2117813-12620O\/\O/\/O\/\O/\/Z\/\=/Z O/\/O\/\O/\/O\/\O \JO33955:cfigmm 350 Dm< >m<Baa—8mm— .cZ TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ 5:.N 98:88 mid 98:88 TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ aid 98:88 TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ GEN 98:88 MEN 98:88 TymfiwmwflumMun—2-1262033955:cfigmm 350Baa—8mm— .cZ Nwfim 98:88 TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ mmfim 98:88 TymfiwmwflumMun—2117813-1262033955:cfigmm 350m— .cZ wwfid 98:88 mmfim 98:88 TymfiwmwflumMun—2-12620In certain embodiments, the synthon is ed from the group consisting of synthones 2.1, 2.2, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 2.10, 2.11, 2.12, 2.13, 2.14, 2.15, 2.16, 2.17, 2.18, 2.19,2.20, 2.21, 2.22, 2.23, 2.24, 2.25, 2.26, 2.27, 2.28, 2.29, 2.30, 2.31, 2.32, 2.33, 2.34, 2.35, 2.36, 2.37,2.38, 2.39, 2.40, 2.41, 2.42, 2.43, 2.44, 2.45, 2.46, 2.47, 2.48, 2.49, 2.50, 2.51, 2.52, 2.53, 2.54, 2.55,2.56, 2.57, 2.58, 2.59, 2.60, 2.61, 2.62, 2.63, 2.64, 2.65, 2.66, 2.67, 2.68, 2.69, 2.77, 2.78, 2.79, 2.80,2.81, 2.82, 2.83, 2.84, 2.85, 2.86, 2.87, 2.88, 2.89, 2.90, 2.91, 2.92, 2.93, 2.94, 2.95, 2.96, 2.97, 2.98,2.101, 2.102, 2.103, 2.104, 2.105, 2.106, 2.107, 2.108, 2.109, 2.110, 2.111, 2.112, 2.113, 2.114, 2.115,2.116, 2.117, 2.118, 2.119, 2.120, 2.121, 2.122, 2.123, 2.124, 2.125, 2.126, 2.127, 2.128, 2.129, 2.130,2.131, 2.132, 2.133, 2.134, 2.135, 2.136, 2.137, 2.138, 2.139, 2.140, 2.141, 2.142, 2.143, 2.144, 2.145,2.146, 2.147, 2.148, 2.149, 2.150, 2.151, 2.152, 2.153, 2.154, 2.155, 2.156, 2.157, 2.158, 2.159, 2.160,2.161, 2.162, 2.163, 2.164, 2.166, 2.167, 2.168, 2.169, 2.170, 2.171, 2.172, 2.173, 2.174, 2.175, and2. 176, or a pharmaceutically acceptable salt thereof. The compound names of these synthon areprovided below:N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l -yl)hexanoyl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl](2-sulfoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l -yl)hexanoyl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl](3-sulfopropyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l -yl)hexanoyl]-L-Valyl-N-[4-({ [{2-[2-( { 3-[(4- { 6-[8-(l,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] boxypyridin-3 -yl } -5 -methyl- 1 zol- l -yl)methyl] -5 ,7-dimethyltricyclo[3 . 3. l . ec- l -yl } oxy)ethoxy] ethyl } (2-sulfoethyl)carbamoyl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;methyl 6- { [2-( { 3- [(4- { 6- [8 -( l ,3 -benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2(1H)-yl] carboxypyridinyl } methyl-lH-pyrazol-l -yl)methyl]—5,7-dimethyltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl]({ [4-({N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-lyl)hexanoyl] -L-Valyl-N5-carbamoyl-L-ornithyl } amino)benzyl] oxy } carbonyl)amino }propyl)- l H- l ,2,3 -l-l -yl] deoxy-beta-L-glucopyranoside;N-[6-(2,5-dioxo-2,5-dihydro-lH-pyrrol- l -yl)hexanoyl]-L-Valyl-N-(4-{ [([2-( { 3-[(4- { 6-[8-(1 ,3-benzothiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carboxypyridinyl } -5 -methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl] {3-[1-(beta-D-glucopyranuronosyl)-1H- l ,2,3 -triazolyl]propyl } carbamoyl) oxy]methyl }phenyl)-N5-carbamoyl-L-ornithinamide;MEl 24985843V.1 315117813-12620N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [(2R){ [2-({ 3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1. 13’7]decy1 } oxy)ethyl] (methyl)amino } -1-0X0-3 -su1f0pr0panyl]carbamoyl } oxy)methyl]phenyl } -L-alaninamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}oxy)ethyl][4-(beta-D-glucopyranosyloxy)benzyl]carbamoyl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [4-(beta-D-allopyranosyloxy)benzyl] [2-({ 3 -[(4-{6-[8-(1,3 thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}methyl-1H-pyraz01y1)methyl]—5,7-dimethyltricyclo[3.3. 1.13’7]decy1}oxy)ethyl]carbam0yl}0xy)methyl]phenyl}-N5-carbam0y1-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] b0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-phosphonoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-phosphonoethyl)carbamoyl } oxy)methyl]phenyl } ninamide;2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](3-phosphonopropyl)carbamoyl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [(2R){ [2-({ 3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl]amin0}0X0sulfopropan-z-yl] carbamoyl } oxy)methyl]phenyl } ninamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-Valyl-N-[4-({ -({ 3-[(4-{ 6-[8-(1 z0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)eth0xy]ethyl}(3-phosphonopropyl)carbamoyl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-Valyl-N-[4-({ [{2-[2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)eth0xy]ethyl}(3-phosphonopropyl)carbamoyl]oxy } methyl)phenyl] -L-alaninamide;MEI 24985843V.1 316117813-12620N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)carbamoyl } oxy)methyl]phenyl } -L-alaninamide;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3-(2-{ [(28)-3-carb0xy({ [(4-{ [(2S){ [(2S){ 5-diox0-2,5-dihydr0-lH-pyrrol-l -yl)hexan0yl]amin0 } methylbutanoyl] amino }pr0pan0yl]amino } benzyl)0xy]carbonyl } amin0)pr0pan0yl] (methyl)amino } ethoxy)-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl]methyl}methyl-lH-pyrazolyl)pyridinecarboxylic acid;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl][4-(beta-D-glucopyranuronosyloxy)benzyl]carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[ l -enz0thiazolylcarbamoyl)-l ,2,3 ,4-tetrahydr0quinolinyl] carb0xypyridinyl } methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl](2-phosphonoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]-L-Valyl-N5-carbam0yl-N- { 4-[({ [2-4-{2-carb0xy[8-([ l ,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinyl}methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl }oxy)ethyl] (2-sulf0ethyl)carbam0yl } oxy)methyl]phenyl } -L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l xan0yl]—L-valyl-N- { 4-[({ l -{ [2-({ 3-[(4-{6-[ l -(l ,3-benz0thiazolylcarbamoyl)-l ,2,3,4-tetrahydr0quinolinyl] carb0xypyridin-3 -yl } methyl- 1 H-pyrazol- l thyl] -5 ,7-dimethyltricyclo[3 . 3. l -. 13’7]dec- l -yl } hyl] (methyl)amino }l-0X0-3 -sulf0pr0panyl]carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [(2R)-l -{ [2-({ 3-[(4-{6-[ l -(l ,3-benz0thiazolylcarbamoyl)-l ,2,3,4-tetrahydr0quinolinyl] carb0xypyridin-3 -yl } methyl- 1 H-pyrazol- l -yl)methyl] -5 ,7-dimethyltricyclo[3 . 3. l -. 13’7]dec- l -yl } hyl] (methyl)amino }l-0X0-3 -sulf0pr0panyl]carbamoyl } oxy)methyl]phenyl } -L-alaninamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l xan0yl]-L-Valyl-N5-carbam0yl-N- { 4-[({ [2-({3-[(4-{2-carb0xy[8-([ l ,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-idinyl}methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl }oxy)ethyl] (2-sulf0ethyl)carbam0yl } oxy)methyl]phenyl } -L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[ l -(l,3-benz0thiazolylcarbamoyl)-l ,2,3 ,4-tetrahydr0quinolinyl] carb0xypyridinyl } methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}oxy)ethyl](2-sulfoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;MEl 24985843V.1 317117813-12620N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 --lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-carboxyethyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ { 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] b0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-yethyl)carbamoyl } oxy)methyl]phenyl } -L-alaninamide;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1](1-{ [3-(2-{ [(2R)-0xy({ [(4-{ [(2S){ [(2S){ [6-(2,5-diox0-2,5-dihydr0-1H-pyrr01-1 -y1)hexan0yl]amin0 } methylbutanoyl] amino }pr0pan0yl]amino } benzyl)0xy]carbonyl } amin0)pr0pan0yl] (methyl)amino } ethoxy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methy1-1H-pyraz01yl)pyridinecarboxylic acid;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1. 13’7]decy1}oxy)ethyl] [1-(carboxymethyl)piperidinyl]carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;(S)((2-((3 -((4-(6-(8-(benz0[d] thiazoly10arbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)carboxypyridin-3 -y1)-5 -methy1-1H-pyraz01yl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)(methyl)amin0)((((4-((S)((S)(6-(2,5-diOX0-2,5-dihydr0-lH-pyrrol-l -yl)hexanamid0)-3 -methylbutanamid0)ureid0pentanamid0)benzyl)0xy)carb0nyl)amino)-N,N,N-trimethy10X0hexan-l-aminium salt;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-sulfoethyl)carbam0yl } oxy)methyl]phenyl } -L-a1aninamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-Valyl-N-[4-({ [(4-{ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-sulfoethyl)amino }piperidin-1 -y1)carb0nyl]oxy } methyl)phenyl] -N5-carbamoyl-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-5 -(3-phosph0n0pr0poxy)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carboxypyridinyl}methy1-1H-pyraz01yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl }oxy)ethyl] (methyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0yl-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-Valyl-N-[4-({ [(4-{ [2-({ { 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](3-MEl 24985843V.1 318117813-12620phosphonopropyl)amino }piperidin- l -yl)carb0nyl]oxy } )phenyl] -N5-carbamoyl-L-inamide;N-[6-(2,5-di0X0-2,5 -dihydr0- l H-pyrrol- l -yl)hexan0yl] -L-Valyl-N- { 4- [({ [2-({ 3 -[(4- { 6-[8-(1,3-benz0thiazolylcarbamoyl)naphthalenyl] carboxypyridin-3 -yl } methyl- 1 H-pyrazol- l -yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)carbamoyl } oxy)methyl]phenyl } -N5-carbam0yl-L-0rnithinamide;N-[6-(2,5-di0X0-2,5 -dihydr0- l ol- l -yl)hexan0yl] -L-Valyl-N-[4-({ [(4-{ [2-( { 3- [(4- { 6- [8 -(1,3-benz0thiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2( l H) -yl] carb0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](2-carboxyethyl)amino }piperidin- l -yl)carb0nyl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-di0X0-2,5 -dihydr0- l H-pyrrol- l -yl)hexan0yl] -L-Valyl-N5-ca.rbam0yl-N- { 4-[({ [2-( { 3-[(4-{ 2-carboxy[8-([ l azolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-lyl}oxy)ethyl] (3-phosph0n0pr0pyl)carbamoyl } oxy)methyl]phenyl } -L-0rnithinamide;2,5-di0X0-2,5 -dihydr0- l H-pyrrol- l -yl)hexan0yl] -L-Valyl-N5-ca.rbam0yl-N- { 4-[({ [2-( { 3-[(4-{ 2-carboxy[8-([ l ,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl }oxy)ethyl] (3-phosph0n0pr0pyl)carbamoyl } oxy)methyl]phenyl } -L-0rnithinamide;N- { 6- [(chloroacetyl)amino]hexan0yl } -L-Valyl-N- { 4-[({ [2-( { 3 -[(4- { 6- [8 -( l ,3 thiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2( l H)-yl] carboxypyridinyl } methyl- 1 H-pyrazol- l -yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2—sulfoethyl)carbamoyl } oxy)methyl]phenyl } -L-alaninamide;N-[6-(2,5-di0X0-2,5 r0- l H-pyrrol- l -yl)hexan0yl] yl-N- { 4- [({ [2-({ 3 -[(4- { 6-[8-(1,3-benz0thiazolylcarbamoyl)-5 -(carb0xymeth0xy)-3 ,4-dihydr0isoquinolin-2( lH) -yl] carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl }oxy)ethyl] (methyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-di0X0-2,5 -dihydr0- l H-pyrrol- l -yl)hexan0yl] -L-Valyl-N-[4-({ [(2-{ [2-( { 3- [(4- { 6- [8 -(1,3-benz0thiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2( l H) -yl] carb0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](2-sulfoethyl)amino } ethyl)(2-carboxyethyl)carbamoyl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(lH)-yl][l-({3-[2-({(2S)-2-[{ [(4-{ [(2S)(carbam0ylamin0){ [(2S){ 5-di0X0-2,5-dihydr0- l H-pyrrol-l -yl)hexan0yl] amino } methylbutan0yl] amino }pentan0yl]amino } )0xy]carbonyl } (2-yethyl)amino] carb0xypr0pan0yl } amino)eth0xy] -5 ,7-dimethyltricyclo[3 . 3. 1.13’7]dec-l-yl } ) -5 -methyl- 1 H-pyrazolyl]pyridinecarboxylic acid;MEl 24985843V.1 319-126206-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3-(2-{ [(28)-2-({ [(4-{ [(2S)(carbam0ylamin0){ [(2S){ [6-(2,5-diox0-2,5-dihydr0-lH-pyrrol-l -yl)hexan0yl] amino } methylbutan0yl] amino }pentan0yl]amino } )0xy]carb0nyl } amin0)carboxypropanoyl] (2-sulf0ethyl)amino } ethoxy)-5 ,7-dimethyltricyclo[3 . 3. l . 13’7]dec- l -yl] methyl } methyl- 1 H-pyrazolyl)pyridinecarboxylic acid;2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]-L-Valyl-N-[4-({ [(4-{ [2-( { 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] b0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](3-carboxypropyl)amino }piperidin- l -yl)carb0nyl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;4-[(lE)({ -[(4-{6-[8-(1,3-benz0thiazolylcarbam0yl)(carb0xymeth0xy)-3,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridinyl } methyl- l H-pyrazol-l -yl)methyl] -5 ,7-dimethyltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl](methyl)carbam0yl}oxy)pr0p-l-en-l-yl]({N-[6-(2,5-diox0-2,5 -dihydr0- l H-pyrrol- l -yl)hexan0yl] -beta-alanyl } amin0)phenyl beta-D-glucopyranosiduronic acid;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N- { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)naphthalenyl] carb0xypyridin-3 -yl } methyl- l H-pyrazol- l -yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2—sulfoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol-l-yl)hexan0yl]-L-Valyl-N-[4-({ [(2-{ [8-(1 ,3-benzothiazolylcarbam0yl)(6-carb0xy{ l- [(3 ,5-dimethyl { 2-[methyl(2-sulfoethyl)amin0]eth0xy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]methyl-lH-pyrazolyl}pyridinyl)- l ,2,3 ,4-tetrahydroisoquinolin-5 -yl] oxy } ethyl)carbam0yl]0xy } methyl)phenyl] -N5-carbam0yl-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol-l-yl)hexan0yl]-L-Valyl-N-[4-({ [(2-{ [8-(1 ,3-benzothiazolylcarbam0yl)(6-carb0xy{ l- [(3 ,5-dimethyl { 2-[methyl(2-sulfoethyl)amin0]eth0xy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]methyl-lH-pyrazolyl}pyridinyl)- l ,2, 3 ,4-tetrahydroisoquinolin-5 -yl] oxy } ethyl)(2-sulf0ethyl)carbamoyl]oxy } methyl)phenyl] -N5-oyl-L-ornithinarnide;N-[6-(2,5-diox0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]-L-Valyl-N-[4-({ [(2-{ [2-( { 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)-3 ydroisoquinolin-2( l H)-yl] carb0xypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](2-sulfoethyl)amino } ethyl)(2-sulf0ethyl)carbamoyl]oxy } )phenyl] -N5-carbamoyl-L-ornithinamide;N-{6-[(chloroacetyl)amino]hexan0yl}-L-Valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3 ,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridinyl } methyl- l H-pyrazol- l -yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2—sulfoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-0rnithinamide;MEl 24985843V.1 320117813-12620N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)hcxan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[4-(1 z0thiaz01y1carbamoyl)-3,4-dihydr0-2H-1 ,4-bcnz0xazinyl]carb0xypyridin-3 -y1 } methyl-lH-pyrazolyl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-thyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)hcxan0yl]-L-Valyl-N-[4-({ [(2-{ [ES-(1,3-bcnzothiazoly1carbam0yl)(6-carb0xy{ 1- [(3 ,5-dimcthy1 { 2-[mcthy1(2-thyl)amin0]cth0xy}tricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl}pyridiny1)-1,2,3,4-tctrahydr0isoquin01in-5 -yl] oxy } (2-carboxycthyl)carbamoyl]oxy } methyl)phcnyl] -N5-carbamoyl-L-ornithinamidc;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)hcxan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-5 -(3-su1f0pr0p0xy)-3,4-dihydr0isoquin01in-2(1H)-y1] carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] (methyl)carbam0yl } thyl]phcnyl } -N5-carbam0yl-L-0rnithinamidc;N-[3 -(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)propan0yl]-L-Valyl-N-{4-[({ [2-( { 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-[(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)accty1]—L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridiny1}-5 -mcthy1-1H-pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } thyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [(28)-2-({ [(4-{ [(2S,3R,4S,SS,6S)carb0xy-3,4,5-trihydr0xytctrahydr0-2H-pyranyl]oxy } [(3-{ [6-(2,5-di0X0-2,5 -dihydr0-1H-pyrr01y1)hcxan0yl] amino }propan0y1)amin0]benzyl)0xy] carbonyl } amin0)-3 -sulfopropanoyl] (methyl)amin0 } cthoxy)-5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthyl}-5 -mcthyl-1H-pyraz01y1)pyridinccarb0xylic acid;4-[(1E)({ [2-({3-[(4-{2-carb0xy[8-([1,3]thiaz010[5,4-b]pyridin-Z-ylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]pyridiny1} -5 -mcthy1-lH-pyrazolyl)mcthyl]—5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)pr0pcnyl]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0y1]-bcta-alanyl}amin0)phcny1 beta-D-glucopyranosiduronic acid;)({ [2-({3-[(4-{2-carb0xy[8-([1,3]thiaz010[4,5-b]pyridin-Z-ylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]pyridiny1} -5 -mcthy1-lH-pyrazolyl)mcthyl]—5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)pr0pcnyl]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0y1]-bcta-alanyl}amin0)phcny1 -glucopyranosiduronic acid;MEI 24985843V.1 321-126204-[(1E)({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]—5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)pr0pcnyl]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0y1]-bcta-alanyl}amin0)phcny1 beta-D-glucopyranosiduronic acid;4-[(1E)({ [2-({3-[(4-{2-carb0xy[8-([1,3]thiaz010[5,4-b]pyridin-Z-ylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]pyridiny1} -5 -mcthy1-lH-pyrazolyl)mcthyl]—5,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1}oxy)cthyl](3-phosph0n0pr0pyl)carbamoyl}oxy)pr0pcn-1 -y1]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0yl]-bcta-alany1}amin0)phcny1 beta-D-glucopyranosiduronic acid;4-[(1E)({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbam0yl)(3-phosph0n0pr0poxy)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](methyl)carbam0yl}oxy)pr0pcny1]—2-({N-[6-(2,5-di0X0-2,5 -dihydr0-1H-pyrr01yl)hcxan0y1]-bcta-alany1}amin0)phcnyl -glucopyranosiduronic acid;4-[(1E)({[2-({3-[(4-{6-[8-(1,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydr0isoquin01in-y1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]—5,7-dimcthyltricyc10[3.3. 1 . ccy1}oxy)cthyl](3-phosph0n0pr0pyl)carbamoyl}oxy)pr0pcn-1 -y1]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0yl]-bcta-alany1}amin0)phcny1 beta-D-yranosiduronic acid;4-[({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl] [2-(2-{ [3-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)pr0pan0yl] amino}cth0xy)cth0xy]phcnyl beta-D-gluc0pyranosidur0nic acid;4-[(1E)({ [2-({3-[(4-{2-carb0xy[8-([1,3]thiaz010[4,5-b]pyridin-Z-ylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]pyridiny1} -5 1-lH-pyrazolyl)mcthyl]—5,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1}oxy)cthyl](3-phosph0n0pr0pyl)carbamoyl}oxy)pr0pcn-1 -y1]—2-({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1 -y1)hcxan0yl]-bcta-alany1}amin0)phcny1 beta-D-glucopyranosiduronic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl)({ [(2E)(4-{ [(28,3R,4S,SS,6S)carb0xy-3 ,4,5-trihydr0xytctrahydr0-2H-pyrany1]0xy } [(3-{ [6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)hcxan0yl] amino }pr0pan0yl)amin0]phcnyl)pr0pcn-1 -yl]oxy } carbonyl)amino]cthoxy } -5 ,7 -dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl){ [(4-{ [(2S,3R,4S,SS,6S)carboxy-3,4,5-trihydr0xytctrahydr0-2H-pyrany1]oxy} [2-(2-{ [3-(2,5-di0X0-2,5-dihydr0-1H-pyrr01MEI 24985843V.1 322117813-12620yl)pr0pan0yl] amino } cthoxy)cth0xy]benzyl)0xy] carbonyl } amino] cthoxy} -5 ,7-yltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;N-[6-(cthcnylsulf0nyl)hcxanoyl]-L-Valyl-N-{4-[({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;4-[(1E){ [(4-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-y1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]—5,7-dimcthyltricyc10[3.3. 1 -. 13’7]dccy1 } oxy)cthyl] (3-phosph0n0pr0pyl)amino }pipcridin-1yl)carb0nyl]0xy}pr0pcnyl]({N-[6-(2,5-di0X0-2,5-dihydr0-lH-pyrrolyl)hcxan0yl]—bcta-alanyl } amin0)phcny1 beta-D-gluc0pyranosidur0nic acid;4-[(1E){ [(4-{ [2-({3-[(4-{2-carboxy[8-([1,3]thiazolo[4,5-b]pyridin-Z-ylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]pyridiny1} -5 1-lH-pyrazolyl)mcthyl]—5,7-dimcthyltricyc10[3.3. 1 -. 13’7]dccy1 } oxy)cthyl] (3-phosph0n0pr0pyl)amino }pipcridin-1yl)carb0nyl]0xy}pr0pcnyl]({N-[6-(2,5-di0X0-2,5-dihydr0-lH-pyrrolyl)hcxan0yl]—bcta-alanyl } amin0)phcny1 beta-D-gluc0pyranosidur0nic acid;)({[2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbam0y1)naphthalcnyl]carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)pr0pcnyl]({N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrrol-l -y1)hcxan0yl]-bcta-alany1}amin0)phcnyl beta-D-g1uc0pyranosidur0nic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1][1-({3-[2-({N-[6-(2,5-di0X0-2,5 -dihydr0-1H-pyrr01yl)hcxan0y1]su1f0-L-alany1}amin0)cth0xy]—5,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1}mcthyl)mcthy1-1H-pyraz01yl]pyridinecarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-[1-({3-[2-(2-{ [6-(2,5-di0X0-2,5 -dihydr0-1H-pyrr01yl)hcxan0y1](2-sulfocthyl)amin0}cth0xy)cth0xy]-5,7-dimcthyltricyc10[3.3. 1 . ccy1}mcthyl)mcthy1-1H-pyraz01yl]pyridinecarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [6-i0X0-2,5 -dihydr0-1H-pyrr01yl)hcxan0y1](2-sulfocthyl)amin0}cth0xy)-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl]mcthyl}-5 -mcthy1- 1H-pyraz01y1)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{ [1-(2,5-di0X0-2,5-dihydr0-lH-pyrrolyl)0X0(2-sulfocthyl)-3,6,9,12,15,18-hcxa0xaazatctracosanyl]oxy}-5,7-dimcthyltricyclo[3.3.1.13’7]dccy1)mcthyl]mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{ [1-(2,5-di0X0-2,5-dihydr0-lH-pyrrolyl)0X0(2-sulfocthyl)-3,6,9,12,15,18,25-hcpta0xaazahcptacosanyl]0xy}-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01yl }pyridinccarb0xylic acid;MEI 24985843V.1 323-126206-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1](1-{ [3-(2-{ [6-(cthcnylsulfonyl)hcxanoyl] focthyl)amino } cthoxy)-5 ,7-dimcthyltricyc10 [3 . 3. 1.13’7]dccy1]mcthy1} -5 l- 1H-pyraz01yl)pyridinccarb0xylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[ { 6-r0acctyl)amin0]hexanoyl } focthyl)amino] cthoxy } -5 ,7-dimcthyltricyc10[3 . 3. 1 -. 13’7]dcc-1y1)mcthyl] mcthy1-1H-pyraz01y1 }pyridinccarb0xylic acid;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)hcxan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1] carb0xypyridin-3 -y1} -5 --lH-pyrazolyl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](3-carboxypropyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-{ 6-[(bromoacctyl)amin0]hexanoyl}-L-Va1y1-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] (3-carboxypr0pyl)carbam0yl } oxy)mcthyl] [2-(2-{ [3 -(2,5 -di0X0-2,5-dihydr0-1H-pyrrol-l -y1)pr0pan0yl] amino } cthoxy)cth0xy]phcnyl beta-D-gluc0pyranosidur0nic acid;4-({ [(4-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl}oxy)cthyl](3-carboxypr0pyl)amin0}pipcridiny1)carb0ny1]0xy}mcthyl)-3 -[2-(2-{ [3-(2,5-di0x0-2, 5 -dihydr0-1H-pyrr01-1 -y1)pr0pan0yl] amino } cthoxy)cth0xy]phenyl beta-D-gluc0pyranosidur0nicacid;4-[({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] f0pr0py1)carbam0yl } oxy)mcthyl] [2-(2-{ [3-(2,5-di0X0-2,5-dihydr0-1H-pyrr01-1-y1)pr0pan0yl] amino } cthoxy)cth0xy]phcnyl beta-D-gluc0pyranosidur0nic acid;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)hcxan0yl]-L-Valyl-N-[4-({ [(3-{ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-lH-pyrazolyl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)amino } azctidiny1)carb0nyl] oxy } methyl)phcnyl] -N5-carbamoyl-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{ [26-(2,5-di0X0-2,5-dihydr0-lH-pyrroly1)-8,24-di0x0-3 -(2-sulfocthy1)-1 1,14,17,20-tctra0xa-3,7,23-triazahcxacos—1-y1]0xy}-5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1)mcthyl]—5-mcthyl-1H-pyraz01yl }pyridinccarb0xylic acid;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)hcxan0yl]-L-Valyl-N-[4-({ [(3-{ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1] carb0xypyridin-3 -y1} -5 -MEI 24985843V.1 324117813-12620methyl-1H-pyraz01— 1 -yl)mcthyl] -5,7-dimcthyltricyc10[3.3. 1 . 13’7]dccy1}0xy)cthyl] (2-thyl)amino }pr0pyl)carbamoyl]oxy } methyl)phcnyl] -N5-carbamoyl-L-0rnithinamidc;N- { 6-[(iodoacctyl)amin0]hexanoyl } -L-Va1y1-N- { 4-[({ [2-( { 3-[(4- { 6-[8-( 1 ,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-{6-[(cthcnylsulfonyl)amin0]hexanoyl}-L-Va1y1-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridiny1}-5 -mcthy1-1H-pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-{6-[(cthcnylsulfonyl)amin0]hexanoyl}-L-Va1y1-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridiny1}-5 -mcthy1-1H-pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(3-{ [6-(cthcnylsulfonyl)hcxanoyl]amino }propyl)(2-sulfocthyl)amin0]cthoxy } -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;N-[3-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)pr0pan0yl]-L-Valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[1-cnz0thiazoly1carbam0yl)-1,2,3,4-tctrahydr0quin01iny1]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthy1tricyc10[3.3.1. 13’7]dccyl}oxy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[(2-carboxycthyl){ [(2-{ R,4S,SS,6S)carboxy-3,4,5-trihydr0xytctrahydr0-2H-pyrany1]oxy} { [3-(2,5-di0X0-2,5-dihydr0-1H-pyrr01pan0yl] amino } cthoxy)cth0xy]benzyl)0xy] carbonyl } amino] cthoxy} -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01— 1 -yl)hcxan0yl]sulfo-L-a1any1-L-va1y1—N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl]—2-carb0xypyridin-3-y1}mcthyl-1H-pyraz01—1-yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-carboxycthyl)carbam0yl } oxy)mcthyl]phcnyl } -N5-carbam0y1-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3-{ [(438,46S)({ [(4-{ [(2S){ [(2S){ 5-di0X0-2,5-dihydr0-1H-pyrr01—1-yl)hcxan0yl]amin0}-3-mcthylbutan0yl] amino n0yl]amino } bcnzyl)oxy] carbonyl } amino)mcthyl-37,44,47-tri0x0-11,14,17,20,23,26,29,32,35-d0dcca0xa-38,45,48-triazapcntac0ntanyl]oxy}-5,7-dimcthyltricyc10[3.3. 1.13’7]dccyl)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;N-[6-(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)hcxan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[1-(1,3-bcnz0thiazoly1carbam0yl)-1,2,3,4-tctrahydr0quin01iny1]carb0xypyridinyl}mcthyl-MEI 24985843V.1 325117813-126201H-pyraz01y1)methy1]-5,7-dimethyltricyclo[3.3.1. ecy1}oxy)ethy1](2-carboxyethyl)carbam0yl } thy1]phenyl } rbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)naphthalenyl]carb0xypyridin-3 -y1}methy1-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—yethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;6-[8-(1,3-benz0thiazolylcarbamoyl)naphthalenyl]{ 1- [(3- { 2- [(2-carboxyethyl){ [(2-{[(2R,3S,4R,5R,6R)carb0xy-3,4,5-trihydroxytetrahydro-zH-pyrany1]oxy } [2-(2-{ [6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1] amino } ethoxy)eth0xy] benzyl)0xy] carbonyl } amino]eth0xy } -5 ,7-dimethyltricyclo[3.3. 1.13’7]decyl)methyl]methy1-1H-pyraz01y1}pyridinecarb0xylic acid;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[5-(1 ,3-benz0thiaz01ylcarbam0y1)quinoliny1]carb0xypyridinyl}methy1-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—sulfoethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[4-(1 ,3-benz0thiaz01ylcarbam0y1)quinolinyl]carb0xypyridinyl}methy1-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—yethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[4-(1 ,3-benz0thiaz01ylcarbam0y1)quinolinyl]carb0xypyridinyl}methy1-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—sulfoethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[5-(1 ,3-benz0thiaz01ylcarbam0y1)quinoliny1]carb0xypyridinyl}methy1-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—carboxyethyl)carbam0yl } thy1]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[1-(1 ,3-benz0thiaz01ylcarbamoyl)-5,6-dihydroimidaz0[1 ,5-a]pyrazin-7(8H)-yl]carb0xypyridinyl } -5 -methy1-1H-pyraz01yl)methy1] -5,7-dimethyltricyclo[3.3. 1 . 13’7]dec-1 -y1}0xy)ethy1] (2-sulfoethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[7-(1 ,3-benz0thiazolylcarbam0yl)-1H-ind01y1] carb0xypyridinyl } methy1-1H-pyraz01-1 -y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—sulfoethyl)carbam0yl } oxy)methy1]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0y1]-L-Va1y1-N-[4-({ [{3-[8-(1,3-benzothiazol-Z-ylcarbam0yl)(6-carb0xy{ 1- [(3 ,5-dimethy1 { 2-[(2-MEI 24985843V.1 326117813-12620sulfoethyl)amin0]eth0xy}tricyclo[3.3. 1.13’7]decyl)methyl]methy1-1H-pyraz01yl}pyridiny1)-1,2,3,4-tetrahydroisoquinoliny1]pr0pyl } l)carbam0yl] oxy } methyl)phenyl] -N5-carbam0yl-L-ornithinamide;N-(6-{ [(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)acetyl]amin0}hexan0y1)-L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carb0xypyridin-3-y1}methyl-1H-pyraz01yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-sulfoethyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-benz0thiaz01ylcarbamoyl)naphthalenyl]carb0xypyridin-3 -y1}methyl-1H-pyraz01y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl] [3-(beta-L-glucopyranuronosyloxy)pr0pyl] carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[4-(1 ,3-benz0thiaz01ylcarbam0y1)isoquinolinyl] carb0xypyridin-3 -y1} -5 -methy1-1H-pyraz01hyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethy1](2—sulfoethyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-alpha-glutamyl-L-Valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carb0xypyridin-3-y1}methyl-1H-pyraz01yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decy1}0xy)ethyl](2-sulfoethyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;N-[(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)acetyl]-L-a1pha-glutamyl-L-valyl-N-{4-[({ [2-({ 3-[(4-{6-[8-(1,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl } -5 -methy1-1H-pyraz01yl)methyl] imethyltricyclo[3.3. 1 . 13’7]dec-1 y)ethyl] (2-sulfoethyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0y1-L-0rnithinamide;1-{ [2-({3-[(4-{6-[8-(1,3-benz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carboxypyridinyl}methy1-1H-pyraz01yl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]({[4-({N-[6-(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0yl]-D-Va1y1-N5-carbam0yl-D-ornithyl } amino)benzyl] oxy } carbonyl)amino } -1 ,2-dideoxy-D-arabino-hexitol;2,5-diox0-2,5-dihydr0-1H-pyrr01y1)hexan0y1]—L-valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[4-( 1 ,3-benz0thiaz01ylcarbamoyl)0Xidoisoquinoliny1] b0xypyridin-3 -y1} -5 -methyl-1H-pyrazol-l-y1)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl }oxy)ethyl] (methyl)carbam0yl } oxy)methyl]phenyl } -N5-carbam0yl-L-0rnithinamide;N-({ (3S,SS)-3 -(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)0X0[(2-sulfoethoxy)methyl]pyrrolidiny1}acetyl)-L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbam0y1)naphthalenyl]carb0xypyridinyl}methyl-1H-pyraz01-1 -y1)methy1]—5,7-yltricyclo[3.3. 1.13’7]decy1}oxy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide;MEI 24985843V.1 327117813-12620N-{(28)(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l-y1)[4-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyloxy)phcnyl]pr0pan0yl } -L-Valyl-N- { 4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazoly1carbamoyl)naphthalcnyl]carb0xypyridin-3 -y1}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } rbam0y1-L-0rnithinamidc;N-({ (3S,SS)-3 -(2,5-di0X0-2,5-dihydr0-1H-pyrr010X0[(2-sulfocthoxy)mcthyl]pyrrolidiny1}acctyl)-L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-{(28)(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l-y1)[4-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyloxy)phcnyl]pr0pan0yl } -L-Valyl-N- { 4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridiny1}-5 -mcthy1-1H-pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-oisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-yltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]({N-[(2,5-di0X0-2,5-dihydr0- 1 H-pyrrolyl)acctyl] y1-L-alany1 } amin0)phcny1 } cthyl)-L-gu10nic acid;3-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbamoyl)naphthalcnyl]carb0xypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl]({[4-(4-{[6-(2,5-di0X0-2,5 -dihydr0-1H-pyrr01yl)hcxan0y1]amin0}buty1)(bcta-D-glucopyranuronosyloxy)bcnzyl]oxy } carbonyl)amin0 }pr0py1 beta-D-gluc0pyranosidur0nic acid;N-{ [(3S,SS)(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)(mcth0xymcthyl)0X0pyrr01idin-1-y1]accty1}-L-Valyl-N-{4-[({ [2-({ 3-[(4-{ 6-[8-(1 ,3-bcnz0thiaz01y1carbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]phcnyl}-N5-carbamoyl-L-ornithinamidc;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]—5-({N-[6-(2,5-di0X0-2,5-dihydr0-lH-pyrrolyl)hcxan0yl]-L-Valyl-L-alanyl}amin0)phcny1}cthyl)-L-gu10nic acid;2-[({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl thyl](2-sulfocthyl)carbam0yl}oxy)mcthyl] (4-{ [3 -(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)pr0pan0yl]amin0}butyl)phcny1 beta-D-gluc0pyranosidur0nic acid;MEI 24985843V.1 328117813-126202-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazoly1carbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl] [4-({ (28)(2,5-di0X0-2,5-dihydr0-lH-pyrrol-1-y1)[4-(2,5,8,11,14,17,20,2326,29,32-undcca0xatctratriac0ntanyloxy)phcnyl]pr0pan0yl}amin0)butyl]phcny1 beta-D-gluc0pyranosidur0nic acid;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]—5-[(N-{(28)(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)[4-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyloxy)phcnyl]pr0pan0yl } -L-Valyl-L-alanyl)amin0]phcny1 } ethyl)-L-gulonic acid;6-(8-(bcnz0[d]thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-yl)(1-((3-(2-((((2-(2-((2S,3R,4R,SS,6S)carb0xy-3,4,5-trihydr0xytctrahydr0-2H-pyranyl)cthyl)((S)((S)(2-((38,5S)(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -0X0((2-sulfocthoxy)mcthyl)pyrr01idiny1)acctamid0)methylbutanamid0)pr0panamid0)benzyl)0xy)carbonyl)(2-sulfocthyl)amino)cth0xy)-,7-dimcthy1adamantanyl)mcthyl)-5 -mcthy1-1H-pyrazolyl)pic01inic acid;bcnz0[d]thiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-yl)(1-((3-(2-((((2-(((ZS,3R,4S,SS,6S)carb0xy-3,4,5-trihydroxytctrahydro-zH-pyranyl)0xy)(4-(2-((3S,SS)(2,5-di0X0-2,5 r0-1H-pyrr01yl)0X0-5 -((2-sulfocthoxy)methyl)pyrr01idintamido)butyl)bcnzyl)oxy)carb0nyl)(2-sulfocthyl)amino)cth0xy)-5 ,7-dimcthyladamantany1)mcthyl)mcthy1-1H-pyrazolyl)pic01inic acid;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] (2-sulfocthyl)carbam0yl } oxy)mcthyl] (4-{ [(2,5 -di0X0-2,5 -dihydr0-1H-pyrr01y1)acctyl]amin0}butyl)phcnyl beta-D-gluc0pyranosidur0nic acid;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]carb0xypyridinyl } -5 -mcthy1-1H-pyraz01yl)mcthyl] -5,7-dimcthyltricyc10[3.3. 1 . 13’7]dcc-1 -y1}0xy)cthyl] (2-sulfocthyl)carbam0yl } oxy)mcthyl] (4-{ [(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)acctyl]amin0}butyl)phcnyl -gluc0pyranosidur0nic acid;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)naphthalcnyl]carb0xypyridinyl } -5 -mcthy1-1H-pyraz01yl)mcthyl] imcthyltricyc10[3.3. 1 . 13’7]dcc-1 -y1}0xy)cthyl] (2-sulfocthyl)carbam0yl}oxy)mcthyl] [4-( { (28)(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -y1)[4-(258,11,14,17,20,23,26,29,32-undcca0xatctratriac0ntanyloxy)phcnyl]pr0pan0yl}amin0)butyl]phcny1 beta-D-gluc0pyranosidur0nic acid;N-[(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)accty1]—L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]carb0xypyridiny1}-5 -mcthy1-1H-MEl 24985843V.1 329117813-12620pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl } oxy)mcthyl] (4-carb0xybutyl)phcnyl } -L-alaninamidc;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl] (3-{ [(2,5-di0X0-2,5-dihydr0-1H-pyrr01tyl] amino }pr0pyl)phcnyl beta-D-gluc0pyranosidur0nic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1]—3-{ 1-[(3- { 2-[({ [2-3R,4S,SS,6S)carb0xy-3,4,5-trihydr0xytctrahydr0-2H-pyrany1]oxy} (4-{ [(2,5-di0X0-2,5-dihydro- 1 H-pyrrolyl)acctyl] amino } butyl)bcnzyl]0xy } carbonyl)(3-{ [1,3 -dihydr0xyxymcthyl)pr0pany1] amino } -3 -0x0pr0py1)amin0]cth0xy}-5,7-dimcthyltricyc10[3.3. 1 . 13’7]dcc-1-y1)mcthyl]mcthy1-1H-pyraz01y1}pyridinccarb0xylic acid;6-(8-(bcnz0[d]thiazolylcarbam0y1)naphthalcnyl)(1 -((3 -(2-((((2-(((2S,3R,4S,SS,6S)-6-carb0xy-3 ,4,5-trihydr0xytctrahydr0-2H-pyranyl)0xy)(4-(2-((3S,SS)-3 -(2,5-di0X0-2,5 -dihydr0-1H-pyrr01yl)0X0-5 -((2-sulfocthoxy)methyl)pyrr01idintamido)butyl)bcnzyl)oxy)carb0nyl)(2-sulfocthyl)amino)cth0xy)-5 ,7-dimcthyladamantany1)mcthyl)mcthy1-1H-pyrazolyl)pic01inic acid;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl] [3-hydr0xy(hydroxymcthyl)pr0pyl] carbamoyl } oxy)methyl] -5 -(3 -{ [(2,5-di0X0-2,5 -dihydro-1H-pyrr01yl)acctyl]amin0}pr0pyl)phcnyl beta-D-gluc0pyranosidur0nic acid;N-({ (3S,SS)-3 -(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)0X0[(2-sulfocthoxy)mcthyl]pyrrolidiny1}acctyl)-L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hcptadccaoxatripcntacont-S2-yny1)phcnyl}-L-alaninamidc;N-({ (3S,SS)-3 -(2,5-di0X0-2,5-dihydr0-1H-pyrr010X0[(2-sulfocthoxy)mcthyl]pyrrolidiny1}acctyl)-L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydr0isoquin01in-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]-3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-hcptadcca0xatripcntacontany1)phcnyl}-L-alaninamidc;2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0yl)-3,4-dihydr0isoquin01in-2(1H)-y1]—2-carboxypyridinyl}mcthy1-1H-pyraz01yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl thyl] 3,4-dihydr0xybutyl]carbamoyl}oxy)mcthyl] -5 -(3-{ [(2,5-di0x0-2,5-dihydr0-1H-pyrrol-l -y1) acctyl] amino }pr0pyl)phcnyl beta-D-g1uc0pyranosidur0nic acid;MEI 24985843V.1 330117813-126201-{ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01—1-yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl]({ [4-(4-{ [(2,5-diox0-2,5-dihydr0-1H-pyrr01—1-yl)acctyl]amin0}butyl)(bcta-D-glucopyranuronosyloxy)bcnzyl]oxy } carbonyl)amino } - 1 ,2-didcoxy-D-arabino-hcxitol;1-{ -[(4-{6-[8-(1,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]—2-carboxypyridinyl}mcthy1-1H-pyraz01—1-yl)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccyl }oxy)cthyl]({ [4-(4-{ [(2,5-diox0-2,5-dihydr0-1H-pyrr01—1-yl)acctyl]amin0}butyl)(bcta-D-glucopyranuronosyloxy)bcnzyl]oxy } carbonyl)amino } - 1 ,2-didcoxy-D-crythr0-pcntit01;N-[(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)accty1]—L-valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazoly1carbamoyl)naphthalcnyl]carb0xypyridin-3 -y1}mcthyl-1H-pyraz01—1-y1)mcthyl]-5,7-dimcthyltricyclo[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]-3-[27-(2,5,8,11,14,1720,23-0cta0xahcxacosanyl)-2,5,8,11,14,17,20,23-0cta0xaazatriac0ntan--y1]phcny1}-L-alaninamidc;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01-1 -y1)mcthy1]—5,7-yltricyclo[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]—5-({N-[(2S)[3,4-bis(2,5,8,1 1,14,17,20,23,26,29,32-undcca0xatctratriacontany10xy)phcnyl](2,5-diOX0-2,5-dihydro- 1 H-pyrrolyl)pr0pan0y1] yl-L-alany1 } amin0)phcny1 } cthyl)-L-gu10nic acid;N-[(2,5-diOX0-2,5-dihydr0-1H-pyrr01—1-y1)accty1]—N-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyl)-bcta-alany1—L-valy1-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyclo[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]-3-(2,5,8,1 1,14,17,20,23,26,29,32,35,38,41,44,47,50-hcptadccaoxatripcntacontany1)phcnyl}-L-alaninamidc;N-[(2,5-diOX0-2,5-dihydr0-1H-pyrr01—1-y1)accty1]—N-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyl)-bcta-alany1—L-valy1-N-{4-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}mcthyl-1H-pyraz01y1)mcthyl]-5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}0xy)cthy1](2—sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-[(2,5-diox0-2,5-dihydr0-1H-pyrr01y1)accty1]—L-valyl-N-{4-[({ -[(4-{6-[8-(1,3-benzothiazoly1carbam0yl)-3,4-dihydroisoquinolin-2( ] carb0xypyridinyl } -5 -mcthy1-1H-pyrazol-l-y1)mcthyl]-5,7-dimcthyltricyclo[3.3.1.13’7]dccy1}0xy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl][27-(2,5,8,11,14,1720,23-0cta0xahcxacosanyl)-2,5,8,1 1,14,1720,23-0ctaoxaazatriac0ntanyl]phenyl}-L-alaninamidc;N-{(3S)(2,5-diox0-2,5-dihydr0-1H-pyrr01—1-y1)[1-(2,5,8,11,14,17,20,23,26,29,32,35-oxahcptatriacontanyl)-1H-1,2,3-triaz01yl]pr0pan0yl}-L-Valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-y1] carb0xypyridin-3 -y1} -5 -MEI 24985843V.1 3 31117813-12620methyl-1H-pyraz01— 1 -yl)mcthyl] -5,7-dimcthyltricyc10[3.3. 1 . ccy1}0xy)cthyl] (2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;N-{(3R)(2,5-di0X0-2,5-dihydr0-1H-pyrr01—1-y1)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodccaoxahcptatriacontanyl)-1H-1,2,3-triaz01yl]pr0pan0yl}-L-Valyl-N-{4-[({ [2-({3-[(4-{6-[8-(1 ,3-bcnz0thiaz01ylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1] carb0xypyridin-3 -y1} -5 -methyl-1H-pyraz01— 1 -yl)mcthyl] imcthyltricyc10[3.3. 1 . 13’7]dccy1}0xy)cthyl] (2-sulfocthyl)carbam0yl } oxy)mcthyl]phenyl } -N5-carbam0y1-L-0rnithinamidc;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1][1-({3-[2-({ [(2-{2-[(2S,3R,4R,SS,6S)carb0xy-3,4,5-trihydr0xytctrahydr0-2H-pyranyl]ethyl } { [(2S){ [(28)-2-{ [(2,5-di0X0-2,5-dihydr0-1H-pyrrol-l -y1)acctyl]amin0 } methylbutanoyl] amino }pr0pan0yl]amino } benzyl)0xy]carb0nyl} [(3R,4S,5R)-3 ,4,5,6-tctrahydroxyhcxyl] amino)cth0xy] -5 ,7-dimcthyltricyc10[3.3. 1.13’7]dccyl}mcthyl)-5 -mcthy1-1H-1yl]pyridine-Z-carboxylic acid;6-[8-(1,3-bcnz0thiazolylcarbamoyl)-3,4-dihydr0isoquin01in-2(1H)-y1][1-({3-[2-({ [(2-{2-[(2S,3R,4R,SS,6S)carb0xy-3,4,5-trihydr0xytctrahydr0-2H-pyranyl]ethyl } { [(2S)( { (28)-2-[({(3S,SS)(2,5-di0X0-2,5-dihydr0-1H-pyrr01y1)0X0[(2-sulfocthoxy)methyl]pyrr01idinyl}accty1)amin0]—3 lbutan0y1 } amin0)pr0pan0yl] amino } bcnzyl)oxy] carbonyl} [(3R,4S,5R)-3 ,4,5,6-tctrahydr0xyhcxyl] amino)cth0xy] -5 ,7-dimcthyltricyc10[3 . 3. 1.13’7]dccyl}mcthyl)-5 -mcthy1-1H-pyraz01yl]pyridine-Z-carboxylic acid;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01-1 -y1)mcthy1]—5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}oxy)mcthyl]({N-[(2,5-di0X0-2,5-dihydr0-1H-pyrr01—1-yl)acctyl]—N-(2,5,8,11,14,17,20,23,26,29,32-undccaoxatctratriacontanyl)-bcta-a1any1—L-valy1-L-alanyl } phcnyl } cthyl)-L-gu10nic acid;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01-1 -y1)mcthy1]—5,7-dimcthyltricyc10[3.3.1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]—5-[(N-{2-(2,5-di0X0-2,5-dihydr0-1H-pyrr01yl)[1-(2,5,8,11,14,17,20,23,2629,32,35-d0dcca0xahcptatriacontan-37-y1)-1H-1,2,3-triaz01—4-yl]pr0pan0yl}-L-Valyl-L-alanyl)amin0]phcnyl}cthy1)-L-gu10nic acid;(6S)-2,6-anhydr0(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-oisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01-1 -y1)mcthy1]—5,7-yltricyc10[3.3. 1.13’7]dccy1}oxy)cthyl](2-sulfocthyl)carbam0yl}0xy)mcthyl]—5-[(N-{(3S)(2,5-di0X0-2,5-dihydr0-1H-pyrr01—1-y1)[1-(2,5,8,1 1,14,17,20,23,26,29,32,35-dodccaoxahcptatriacontanyl)-1H-1,2,3 -triaz01yl]pr0pan0yl } -L-Valyl-L-alanyl)amin0]phcnyl }cthy1)-L-gu10nic acid;(6S)-2,6-anhydr0(2-{2-[({ -[(4-{6-[8-(1,3-bcnz0thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-y1]carb0xypyridinyl}mcthyl-1H-pyraz01-1 -y1)mcthy1]—5,7-MEl 24985843V.1 332117813-12620dimethyltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl](2-sulf0ethyl)carbam0yl}oxy)methyl][(N-{(3R)(2,5-di0x0-2,5-dihydr0-lH-pyrrol- l -yl)[l -(2,5,8,l l,l4,l7,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)- l H-1 23 -triazolyl]pr0pan0yl } -L-Valyl-L-alanyl)amin0]phenyl } ethyl)-L-gulonic acid;(6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridinyl } methyl- l H-pyrazol-l -yl)methyl] -5 ,7-yltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]—5-[(N-{(3S)i0X0-2,5-dihydr0-lH-pyrrol- l -yl)[l -(3-sulf0pr0pyl)-1H- l ,2,3-triazolyl]propanoyl } -L-valyl-L-alanyl)amin0]phenyl } ethyl)-L-gulonic acid;(6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridinyl } methyl- l zol-l -yl)methyl] -5 ,7-dimethyltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl](2-sulf0ethyl)carbam0yl}oxy)methyl][(N-{(3R)(2,5-di0X0-2,5-dihydr0-lH-pyrrol- l -yl)[l lf0pr0pyl)-1H- l ,2,3-triazolyl]propanoyl } -L-valyl-L-alanyl)amin0]phenyl } ethyl)-L-gulonic acid;(6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( l H)-yl] carb0xypyridinyl } methyl- l H-pyrazol-l -yl)methyl] -5 ,7-dimethyltricyclo[3.3. l.13’7]dec-l-yl}oxy)ethyl](2-sulf0ethyl)carbam0yl}oxy)methyl]({N-[(2,5-di0X0-2,5-dihydr0- l ol- l -yl)acetyl] -N-[2-(2-sulf0ethoxy)ethyl] -beta-alanyl-L-valyl-L-alanyl } phenyl } ethyl)-L-gulonic acid;6-{ 8-[(l ,3-benz0thiazolyl)carbamoyl] -3,4-dihydr0isoquinolin-2(lH)-yl } [ l -( { 3-[2-({ [(2-{2-[(2S,3R,4R,SS,6S)carb0xy-3,4,5-trihydr0xy0xanyl]ethyl } { [(2S){ 2-{ [(ZS)(2,5-di0X0-2,5-dihydr0-lH-pyrrol- l -yl){4-[(2,5,8, l l ,l4,17,20,23,26,29,32-undecaoxatetratriacontan-34-yl)0xy]phenyl }propanoyl]amino } methylbutanoyl] amino }propanoyl]amino }phenyl)meth0xy]carb0nyl} S,5R)-3 ,4,5,6-tetrahydroxyhexyl] amino)eth0xy] -5 ,7-dimethyltricyclo[3.3. ]decan-l-yl}methyl)-5 -methyl- 1H-pyrazolyl]pyridine-Z-carboxylic acid;4-{ [({2-[(3-{ [4-(6-{ 8-[( l ,3-benz0thiazolyl)carbamoyl]-3,4-dihydr0is0quinolin-2(lH)-yl } -0xypyridin-3 -yl)methyl- l H-pyrazol-l -yl] methyl } -5 ,7-dimethyltricyclo[3.3. 1.13’7]decan-lyl)0xy]ethyl} 3 ,4-dihydr0xybutyl] carbamoyl)0xy] methyl } (2- { 2-[2-(2,5-di0X0-2,5-dihydr0-lH-pyrrol- l -yl)acetamido]ethoxy } ethoxy)phenyl beta-D-gluc0pyranosidur0nic acid;2,6-anhydr0[2-({ [{2-[(3-{ [4-(6-{ 8-[(l ,3-benz0thiazolyl)carbamoyl] -3,4-dihydroisoquinolin-2( l H)-yl } carb0xypyridin-3 -yl)methyl- l H-pyrazol-l -yl] methyl } -5 ,7-dimethyltricyclo[3.3. l.13’7]decan-l-yl)0xy]ethyl}(2-sulf0ethyl)carbam0yl]oxy}methyl){[(79S,82$)[(2,5-di0x0-2,5-dihydr0-lH-pyrrol- l -yl)acetyl]methyl-77,80,83-tri0X0(propanyl)-2,5,8,l 1,14, 17,20,23,26,29,32,35,38,4l,44,47,50,53,56,59,62,65,68,7 l -tetracosaoxa-74,78,8 l -triazatri0ctac0ntanyl] amino }phenyl] -7,8 -dide0xy-L-glycer0-L-gulo-0ct0nic acid;MEl 24985843V.1 333117813-126206- { 8-[(l ,3-benz0thiazolyl)carbamoyl] -3,4-dihydr0isoquinolin-2(lH)-yl } { l-[(3- { 2-[{ [(4-{ S)[3 -(carbam0ylamin0)pr0pyl] 2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -yl)acetyl]—0x0-5 anyl)- l 5-sulf0- l 3-oxa-3,6,lO-triazapentadecanan-l -oyl] amino }phenyl)meth0xy] carbonyl } (2-sulf0ethyl)amin0]eth0xy} -5 ,7-dimethyltricyclo[3.3. l.13’7]decan-l-yl)methyl]—5-methyl-lH-pyrazolyl}pyridinecarb0xylic acid;6-(8-(benz0[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(lH)-yl)(l -((3 -(2-((((2-(2-((2S,3R,4R,SS,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)((S)((S)(2-((3S,SS)(2,5-di0X0-2,5-dihydr0- l H-pyrrol-l -yl)0X0((2-sulfoethoxy)methyl)pyrrolidin- l -yl)acetamid0)methylbutanamido)propanamido)benzyl)0xy)carb0nyl)((S)-3 ,4-dihydroxybutyl)amino)eth0xy)-5 ,7-dimethyladamantan- l -yl)methyl)methyl- 1 H-pyrazolyl)picolinic acid;2,6-anhydr0(2-{ [( { { [4-(6-{ 8-[(l ,3-benz0thiazolyl)carbamoyl] -3,4-dihydroisoquinolin-2( l H)-yl } carb0xypyridin-3 -yl)methyl- l H-pyrazol-l -yl] methyl } -5 ,7-dimethyltricyclo[3.3. l . 13’7]decan-l -yl)0xy]ethyl} [(3S)-3 ydr0xybutyl]carbamoyl)0xy] methyl } {[(2S)({ (ZS)[2-(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -yl)acetamid0]—3-methylbutanoyl } amin0)pr0pan0yl]amino }phenyl)-7,8-dideoxy-L-glycero-L-gulo-octonic acid;2-{ [({2-[(3-{ [4-(6-{ 8-[( l ,3-benz0thiazolyl)carbamoyl]-3,4-dihydr0is0quinolin-2(lH)-yl } -2-carb0xypyridin-3 -yl)methyl- l H-pyrazol-l -yl] methyl } -5 ethyltricyclo[3.3. 1.13’7]decan-lyl)0xy]ethyl} [(3S)-3,4-dihydr0xybutyl]carbamoyl)0xy]methyl } { 4-[2-(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -yl)acetamido] butyl }phenyl -gluc0pyranosidur0nic acid;6-{ 8-[(l ,3-benz0thiazolyl)carbamoyl] -3,4-dihydr0isoquinolin-2(lH)-yl } { l-[(3- { 2-[{ [(4-{ [(2S)(carbam0ylamin0){ [(2S){ [6-(2,5-di0X0-2,5-dihydr0-lH-pyrrol-l -yl)hexan0yl] amino } methylbutan0yl] amino }pentanoyl]amino }phenyl)meth0xy] carbonyl } (2-sulfoethyl)amin0]acetamid0}-5,7-dimethyltricyclo[3.3.l.13’7]decan-l-yl)methyl]—5-methyl-lH-pyrazolyl }pyridinecarb0xylic acid;2,5-di0x0-2,5-dihydr0-lH-pyrrol- l -yl)hexan0yl]—L-valyl-N— { 4-[({ [2-({ 3-[(4- { 6-[8-(l,3-benz0thiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2(lH)-yl] carb0xypyridin-3 -yl } -5 -methyl-1H-pyrazol- l -yl)methyl] -5 ,7-dimethyltricyclo[3 . 3. l . 13’7]dec- l -yl } sulfanyl)ethyl] (2-sulfoethyl)carbamoyl } oxy)methyl]phenyl } -N5-carbamoyl-L-ornithinamide;2,5-di0X0-2,5-dihydr0-lH-pyrrol-l-yl)hexan0yl]-L-Valyl-N-[4-({ [(3-{ 3-[(4-{ 6-[8-(1 ,3-benzothiazolylcarbamoyl)-3 ,4-dihydr0isoquinolin-2( lH)-yl] carb0xypyridinyl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}pr0pyl)(2-sulfoethyl)carbam0yl]oxy } methyl)phenyl] -N5-carbamoyl-L-ornithinamide;2-[({ [2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(lH)-yl]—2-carboxypyridinyl}methyl-lH—pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl }oxy)ethyl] [(3S)-3,4-dihydr0xybutyl]carbamoyl}oxy)methyl] { 4-[({ (3S,SS)(2,5-di0X0-2,5-MEl 24985843V.1 334117813-12620dihydro-1H-pyrrolyl)oxo-5 -[(2-sulfoethoxy)methyl]pyrrolidinyl } acetyl)amino] butyl }phenylbeta-D-glucopyranosiduronic acid;2,6-anhydro[2-({ [{2-[(3-{ [4-(6-{ 8-[(1,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl }carboxypyridin-3 -yl)methyl- 1H-pyrazol-1 -yl] methyl } -5 ,7-dimethyltricyclo[33.1.13’7]decanyl)oxy]ethyl}(2-sulfoethyl)carbamoyl]oxy}methyl){ [N-( { (3R,SS)(2,5-dioxo-2,5-dihydro- 1H-pyrrol-1 -yl)oxo [(2-sulfoethoxy)methyl]pyrrolidin-1 -yl }acetyl)-L-Valyl-L-alanyl] amino }phenyl] -7,8-dideoxy-L-glycer0-L-gul0-octonic acid;hydro{2-({ [{2-[(3-{ [4-(6-{ 8-[(1,3-benzothiazolyl)carbamoyl]-3,4-oisoquinolin-2(1H)-yl rboxypyridin-3 -yl)methyl- 1H-pyrazol-1 -yl] methyl } -5 ,7-dimethyltricyclo[33.1.13’7]decanyl)oxy]ethyl}(2-sulfoethyl)carbamoyl]oxy}methyl)[(N—{ [(3R,SS)(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)oxo(41-oxo-11,14,17,20,23,26,29,32,35,38-tridecaoxaazatritetracontanyl)pyrrolidinyl]acetyl}-L-valyl-L-alanyl)amino]phenyl } ideoxy-L-glycer0-L-gul0-octonic acid;(6S)-2,6-anhydro(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H—pyrazolyl)methyl]-5,7-dimethyltricyclo[33.1.13’7]decyl}oxy)ethyl][(3S)-3,4-dihydroxybutyl]carbamoyl}oxy)methyl]({N-[(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetyl]—N—(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyl)-b-alanyl-L-valyl-L-alanyl } amino)phenyl } ethyl)-L-gulonic acid; and(6S)-2,6-anhydro(2-{2-[({ [2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H—pyrazolyl)methyl]-5,7-dimethyltricyclo[33.1.13’7]decyl}oxy)ethyl][(3S)-3,4-dihydroxybutyl]carbamoyl}oxy)methyl]({N—[(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetyl]-N—[2-(2-sulfoethoxy)ethyl]-b-alanyl-L-valyl-L-alanyl } amino)phenyl } -L-gulonic acid.

In certain embodiments, the ADC, or a pharmaceutically acceptable salt thereof,D is the Bcl-XL inhibitor selected from the group consisting of the following compoundsmodified in that the hydrogen corresponding to the # on of structural formula (Ila), (11b), (11c),or (Ed) is not present, forming a monoradical:W201, W202, W203, W204, W205, W206, W207, W208, W209, W210, W211,W212, W213, W214, W215, W216, W217, W218, W219, W220, W221, W222, W223,W224, W225, W226, W227, W228, W229, W230, W231, W232, W233, W234, W235,W236, W237, W238, W239, W240, W241, W242, W243, W244, W245, W246, W247,W248, W249, W250, W251, W252, W253, W254, W255, W256, W257, W258, W259,W260, W261, W262, W263, W264, W265, W266, W267, W268, W269, W270, W271,W272, W273, W274, W275, W276, W277, W278, W279, W280, W281, W282, W283,W284, W285, W286, W287, W288, W289, W290, and W291, and a pharmaceutically acceptablesalt thereof;MEl 24985843V.1 335117813-12620L is selected from the group consisting of linkers IVa. l-IVa.8, IVb. l-IVb.l9, IVc. l-IVc.7,IVd.l-IVd.4, Va.l-Va.12, Vb.l-Vb.10, Vc.l-Vc.ll, Vd.l-Vd.6, e.2, VIa.l, VIc.l-Vlc.2,VId. l -VId.4, VIIa. l -VIIa.4, VIIb. l-VIIb.8, VIIc. l 6, wherein each linker has reacted with theantibody, Ab, forming a covalent attachment;LK is thioether; andm is an integer ranging from 1 to 8.

In certain embodiments, the ADC, or a pharmaceutically able salt thereof,D is the Bcl-XL inhibitor selected from the group consisting of the following compoundsmodified in that the en corresponding to the # position of structural formula (Ila), (11b), (11c),or (Ed) is not present, forming a monoradical:6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-{ l-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]—5-methyl-lH-pyrazolyl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—3-{ l-[(3- { 2-[(2-carboxyethyl)amino]ethoxy} -5 ,7-dimethyltricyclo[3.3. l . 13’7] dec- 1 thyl] methyl- l H-pyrazol-4-yl }pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{ 5-dimethyl { 2-[(2-thyl)amino]ethoxy}tricyclo[3.3. l.13’7]dec-l-yl)methyl]methyl-lH-pyrazolyl}pyridinecarboxylic acid;l-{ [2-({ 3 -[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl]—2-carboxypyridin-3 -yl } -5 -methyl-lH-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl }oxy)ethyl] amino } -l eoxy-D-arabino-hexitol;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl](l-{ [3-(2-{ [3-hydroxy(hydroxymethyl)propyl]amino } ethoxy)-5 ethyltricyclo[3 . 3. l -. 13’7]dec-l -yl] methyl }5-methyl-lH-pyrazolyl)pyridinecarboxylic acid;6-[8-(1 ,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2( lH)-yl] -3 -( l -{ [3 -(2-{ [(35)-3 ,4-dihydroxybutyl] amino } ethoxy)-5 ,7-dimethyltricyclo[3.3. l . 13’7] dec- 1 thyl } -5 -methyl- lH-lyl)pyridinecarboxylic acid;and pharmaceutically acceptable salts thereof;L is selected from the group consisting of linkers IVb.2, IVc.5, IVc.6, IVc.7, IVd.4, Vb.9,Vc. ll, VIIa.l, VIIa.3, VIIc.l, VIIc.4, and VIIc.5 in either closed or open forms and apharmaceutically acceptable salt thereof;LK is thioether; andm is an integer ranging from 2 to 4.

To form an ADC, the maleimide ring of a synthon (for example, the synthons listed in TableB) may react with an antibody Ab, forming a covalent attachment as either a succinimide (closedMEl 24985843V.1 336117813-12620form) or succinamide(open form). Similarly, other functional groups, e. g. acetyl halide or vinylsulfone may react with an antibody, Ab, forming a covalent attachment.

In certain embodiments, the ADC, or a pharmaceutically acceptable salt thereof, is edfrom the group consisting of AbA-CZ, AbA-TX, AbA-TV, , AbA-AAA, AbA-AAD, AbB-CZ, AbB-TX, AbB-TV, , D, AbG-CZ, AbG-TX, AbG-TV, , A,AbG-AAD, AbK-CZ, AbK-TX, AbK-TV, AbK-YY, AbK-AAA, AbK-AAD, wherein CZ, TX, TV,YY, AAA, and AAD are synthons disclosed in Table B, and wherein the conjugated ns areeither in open or closed form.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:o§[,NH2 AbNH 3Q L I; mH OVQ/ rHiWNN—\( 0/\/ owherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid ce set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 144; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid ce set forth in SEQ ID NO:168, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 169.

MEl 24985843V.1 337117813-12620In one embodiment, the ADC, or a ceutically acceptable salt thereof, is:OYNHZ Ab«firfiwwherein m is 2, Ab is either an anti-hB7-H3 dy, wherein the anti-hB7-H3 antibody ses aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain sing the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:170, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 171.

MEl 24985843V.1 338117813-12620In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(ii),n m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chainCDR2 domain sing the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain sing the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 144; or an anti-hB7-H3 dy, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain sing the amino acid sequence set forth in SEQ ID NO: 169.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:o NH2Y Ab0‘\ LQ‘s/OH O HOZCAiR H 3 H HN O\n/\H WNo oWW 0(ii),MEl 24985843V.1 339117813-12620wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid ce set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain sing the amino acid sequence set forth in SEQ ID NO: 136; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain le region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:170, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 171.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:0 SO m“if” N?O 25’ OO OH(iii),wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain sing the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chainCDR2 domain sing the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 144; or an B7-H3 dy, wherein the B7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 169.

MEl 24985843V.1 340117813-12620In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(iii),wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 dy comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid ce set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136; or an anti-hB7-H3antibody, n the anti-hB7H3 antibody comprises a heavy chain le region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:170, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 171.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(1V),wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain sing the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chainMEl 24985843V.1 341117813-12620CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain le region comprising theamino acid sequence set forth in SEQ ID NO: 144; or an B7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 169.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(1V),wherein m is 2, Ab is either an anti-hB7-H3 antibody, n the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136; or an B7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an B7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid ce set forth in SEQ ID NO:170, and a light chain comprising the amino acid ce set forth in SEQ ID NO: 171.

MEl 24985843V.1 342117813-12620In one ment, the ADC, or a pharmaceutically acceptable salt thereof, is:wherein m is 2, Ab is either an B7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 39, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain sing the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 144; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 169.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:n m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 dy comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a light chainMEl 24985843V.1 343117813-12620CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136; or an anti-hB7-H3antibody, wherein the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:170, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 171.

In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(Vi),wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody comprises aheavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 33; and a lightchain CDR3 domain comprising the amino acid ce set forth in SEQ ID NO: 39, a light chainCDR2 domain sing the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain sing the amino acid sequence set forth in SEQ ID NO: 37; or an anti-hB7-H3antibody, n the anti-hB7H3 antibody comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 147, and a light chain variable region sing theamino acid sequence set forth in SEQ ID NO: 144; or an B7-H3 antibody, wherein the anti-hB7-H3 antibody comprises a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:168, and a light chain sing the amino acid sequence set forth in SEQ ID NO: 169.

MEl 24985843V.1 344117813-12620In one embodiment, the ADC, or a pharmaceutically acceptable salt thereof, is:(Vi),wherein m is 2, Ab is either an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody ses aheavy chain CDR3 domain comprising the amino acid ce set forth in SEQ ID NO: 12, a heavychain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 140, and a heavychain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 10; and a lightchain CDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 15, a light chainCDR2 domain sing the amino acid sequence set forth in SEQ ID NO: 7, and a light chainCDR1 domain comprising the amino acid ce set forth in SEQ ID NO: 136; or an B7-H3antibody, wherein the anti-hB7H3 dy comprises a heavy chain variable region comprising theamino acid sequence set forth in SEQ ID NO: 139, and a light chain le region comprising theamino acid sequence set forth in SEQ ID NO: 135; or an anti-hB7-H3 antibody, wherein the anti-hB7-H3 antibody ses a heavy chain comprising the amino acid sequence set forth in SEQ ID NO:170, and a light chain comprising the amino acid sequence set forth in SEQ ID NO: 171.

Bcl—xL inhibitors, including warheads and synthons, and methods of making thesame, are described in US 2016/0339117 (Abeie Inc.), which is incorporated by referenceIII.A.4. Methods of Synthesis of Bcl-xL ADCsThe Bcl-xL inhibitors and synthons described herein may be synthesized using standard,known techniques of c chemistry. General schemes for synthesizing Bcl-xL inhibitors andsynthons that may be used as-is or modified to synthesize the full scope of Bcl-xL inhibitors andsynthons described herein are provided below. Specific methods for synthesizing exemplary Bcl-xLinhibitors and synthons that may be useful for guidance are provided in the Examples section. ADCsmay likewise be prepared by standard methods, such as methods ous to those bed inHamblett er al., 2004, “Effects of Drug Loading on the Antitumor Activity of a MonoclonalAntibody Drug Conjugate”, Clin. Cancer Res. 10:7063-7070; Doronina er al., 2003, “Development ofpotent and highly efficacious monoclonal antibody auristatin conjugates for cancer therapy,” Nat.

Biotechnol. 21(7):778-784; and Francisco et al., 2003, Blood 102:1458-1465. For example, ADCswith four drugs per antibody may be prepared by partial reduction of the antibody with an excess of aMEl 24985843V.1 345117813-12620reducing reagent such as DTT or TCEP at 37 CC for 30 min, then the buffer exchanged by elutionthrough SEPHADEX® G—25 resin with 1 mM DTPA in DPBS. The eluent is diluted with furtherDPBS, and the thiol concentration of the antibody may be measured using ithiobis(2-nitrobenzoic acid) [Ellman’s reagent]. An excess, for example , of a -drug synthon isadded at 4 CC for 1 hr, and the conjugation reaction may be quenched by addition of a ntialexcess, for example 20-fold, of cysteine. The resulting ADC mixture may be purified onSEPHADEX G-25 equilibrated in PBS to remove unreacted synthons, desalted if desired, and purifiedby size-exclusion chromatography. The resulting ADC may then be then e filtered, for example,through a 0.2 um filter, and lyophilized if desired for storage. In certain embodiments, all of thehain cysteine disulfide bonds are replaced by linker-drug conjugates. One embodiment pertainsto a method of making an ADC, comprising contacting a synthon described herein with an antibodyunder conditions in which the synthon covalently links to the antibodyExamples of the foregoing Bcl-xL inhibtors, linkers, and synthons thereof, as well asmethods of making the same, can be found in US Patent Publication No. US 339117, the entirets of which are incorporated by reference herein.

Specific s for synthesizing ary ADCs that may be used to synthesize the fullrange of ADCs described herein are provided in the Examples section.

III.A.5. General Methods for Synthesizing Bcl-xL InhibitorsIn the schemes below, the various substituents Arl, Arz, 21, R4, R10, R11a and R are asdefined in the Detailed Description section..1.1. Synthesis of Compound (6)MEl 24985843V.1 346-12620\ /H ‘|osmium flEm\ / ‘| 5HOE ER£3 Z,fiN 02\ /am TymfiwmwflumMun—2117813-12620The synthesis of an intermediate (6) is described in Scheme 1. Compound (1) can be d withBH3- THF to provide compound (2). The reaction is typically performed at ambient temperature in asolvent, such as, but not limited to, tetrahydrofuran. Compound (3) can be prepared by treatingcompound (2) with L/NH in the presence of ethylenetributylphosphorane. The reaction istypically performed at an elevated temperature in a solvent such as, but not limited to, toluene.

Compound (3) can be treated with ethane-1,2-diol in the ce of a base such as, but not limited to,triethylamine, to provide nd (4). The reaction is typically performed at an elevatedtemperature, and the reaction may be performed under microwave conditions. nd (4) can betreated with a strong base, such as, but not limited to, n-butyllithium, followed by the addition ofiodomethane, to e compound (5). The addition and on is typically performed in a tsuch as, but not limited to, tetrahydrofuran, at a reduced temperature before warming up to ambienttemperature for work up. Compound (5) can be treated with N-iodosuccinimide to provide compound(6). The reaction is typically performed at ambient temperature is a solvent such as, but not limitedto, N,N-dimethylformamide..1.2. Synthesis of Compound (12)MEl 24985843V.1 348-12620osmiumTymfiwmwflum117813-12620The synthesis of intermediate (12) is described in Scheme 2. Compound (3) can be treated with tri-n-butyl-allylstannane in the presence of ZnClz- EtZO or N, N'—azoisobutyronitrile (AIBN) to providecompound (10) (Yamamoto et al., 1998, Heterocycles 472765-780). The reaction is typicallyperformed at -78 CC in a solvent, such as, but not limited to dichloromethane. Compound (10) can betreated under standard ions known in the art for hydroboration/oxidation to provide compound(1 1). For example, treatment of compound (10) with a reagent such as BH3-THF in a t such as,but not limited to, tetrahydrofuran followed by treatment of the intermediate alkylborane adduct withan oxidant such as, but not limited to, hydrogen peroxide in the presence of a base such as, but notlimited to, sodium hydroxide would provide compound (1 1) (Brown et al., 1968, J. Am. Chem. Soc.86:397). lly the addition of BH3-THF is med at low temperature before warming toambient temperature, which is followed by the addition of hydrogen peroxide and sodium hydroxideto te the alcohol product. nd (12) can be generated according to Scheme 1, aspreviously described for compound (6).5.1.3. Synthesis of Compound (15)MEl 24985843V.1 350-12620osmium IO\/\ EOEnfiOwZTymfiwmwflum117813-12620The synthesis of intermediate (15) is described in Scheme 3. Compound (3) can be reactedwith thiourea in a solvent mixture of acetic acid and 48% aqueous HBr solution at 100 CC to yield anintermediate that can be subsequently treated with sodium hydroxide in a solvent mixture such as, butnot limited to, 20% v/v ethanol in water to provide compound (13). Compound (13) can be reactedwith roethanol in the presence of a base such as, but not limited to, sodium de to providend (14). The reaction is typically performed at ambient or elevated temperatures in a solventsuch as, but not limited to, ethanol. nd (15) can be generated according to Scheme 1, aspreviously described for compound (6).5.1.4. Synthesis of Compound (22)MEl 24985843V.1 352-12620oz ccom: 20 mHDEOmmv 20 oosmium mo cums:Q megwmvmI Q: _N\fix IQ,com: £&moo£ 02 8s"35 2EI 6:TymfiwmwflumMun—2117813-12620The synthesis of compound (22) is described in Scheme 4. nd (16) can be reacted withiodomethane in the presence of a base such as, but not limited to, potassium carbonate to providecompound (17). The reaction is typically conducted at ambient or elevated temperature in a solventsuch as, but not limited to, acetone or N,N-dimethylformamide. Compound (17) can be reacted underphotochemical conditions with tosyl cyanide in the presence of benzophenone to provide nd(18) (see Kamijo er al., 2011, Org. Lett., 13:5928-5931). The reaction is typically run at ambienttemperature in a solvent such as, but not d to, acetonitrile or benzene using a Riko 100Wmedium pressure mercury lamp as the light source. Compound (18) can be d with lithiumhydroxide in a solvent system such as, but not limited to, es of water and tetrahydrofuran orwater and methanol to provide compound (19). Compound (19) can be treated with BH3-THF toprovide compound (20). The on is lly performed at ambient temperature in a solvent, suchas, but not limited to, tetrahydrofuran. Compound (21) can be prepared by treating compound (20)with L<NH in the presence of cyanomethylenetributylphosphorane. The reaction is typicallyperformed at an elevated ature in a solvent such as, but not limited to, toluene. Compound (21)can be d with N-iodosuccinimide to e compound (22). The reaction is typicallyperformed at ambient temperature is a solvent such as, but not limited to, N,N-dimethylformamide..1.5. sis of Compound (24)Scheme 5. EtzONRHa R1 lb —> NRlla R] lb —> R] lb(22) (23) NRlla (24)The synthesis of pyrazole compound (24), is described in Scheme 5. Compound (22) canbe treated with a reducing agent such as, but not limited to, lithium aluminum hydride in a solventsuch as, but not limited to, diethyl ether or tetrahydrofuran to provide compound (23). Typically thereaction is performed at 0 CC before warming to ambient or elevated temperature. Compound (23)can be reacted with di-tert-butyl dicarbonate under standard conditions described herein or in theliterature to provide compound (24).

MEl 24985843V.1 354117813-12620.1.6. Synthesis of nd (24a)Scheme6CN COZH:‘N Rllb Rllb1 R11a (22a) NR'1a (23a)Rllb—>IJ/\<NR11a (24a)The synthesis of intermediate (24a) is bed in Scheme 6. Compound (22a) can behydrolyzed using conditions described in the literature to provide compound (23a). Typically theon is run in the presence of potassium hydroxide in a solvent such as, but not d to, ethyleneglycol at ed temperatures (see Roberts et al., 1994, J. Org. Chem. 59:6464-6469; Yang et al,2013, Org. Lett., 152690-693). Compound (24a) can be made from compound (23a) by Curtiusrearrangement using conditions described in the literature. For example, compound (23a) can bereacted with sodium azide in the presence of tetrabutylammonium bromide, zinc(II) triflate and di-tert-butyl dicarbonate to provide compound (24a) (see Lebel et al., Org. Lett., 2005, 7:4107-4110).lly the reaction is run at elevated temperatures, preferably from 40-50°C, in a solvent such as,but not limited to, tetrahydrofuran.5.1.7. Synthesis of Compound (29)Scheme7FifiOk(26) 3242O’B‘H\o (25)0 ONdO0J< EE:Nd3:As shown in Scheme 7, compounds of formula (27) can be ed by reactingcompounds of formula (25) with tert—butyl 3-br0m0flu0r0picolinate (26) in the presence of a base,such as, but not limited to, N,N-diisopropylethylamine, 0r triethylamine. The reaction is typicallyperformed under an inert atmosphere at an elevated temperature in a solvent, such as, but not limitedto, dimethyl sulfoxide. nds of formula (27) can be reacted with 4,4,5,5-tetramethyl-l,3,2-dioxaborolane (28), under borylation ions described herein or in the literature to providecompounds of formula (29).

MEl 24985843V.1 355117813-12620.1.8. Synthesis of Compound (38)Scheme 80 )4 O K—, N N —. N N| 09 O| NU/ O/\/ ‘S/ / O/\/Scheme 8 describes a method to make intermediates which contain -Nu (nucleophile) tethered to anadamantane and picolinate ted as a l ester. Compound (30) can be reacted withcompound (31) under Suzuki ng conditions described herein or in the literature to emethyl compound (32). Compound (32) can be treated with a base such as but not limited totriethylamine, followed by methanesulfonyl chloride to provide compound (33). The addition istypically performed at low temperature before warming up to ambient temperature in a solvent, suchas, but not limited to, dichloromethane. Compound (33) can be d with a nucleophile (Nu) ofa (34) to provide compound (35). Examples of nucleophiles include, but are not limited to,sodium azide, methylamine, ammonia and di-tert-butyl iminodicarbonate. Compound (17) can bereacted with m hydroxide to provide compound (36). The reaction is typically performed atambient temperature in a solvent such as but not limited to tetrahydrofuran, methanol, water, ormixtures thereof. Compound (36) can be reacted with nd (37) under amidation conditionsdescribed herein or readily available in the literature to provide compounds of formula (38).

MEl 24985843V.1 356117813-12620.1.9. sis of Compounds (42) and (43)Scheme 9o 1,NHl \,211) ffi’o‘aO.Et TFA2) TMSBr“s"OOH(42) (43)Scheme 9 shows entative methods used to make solubilized Bcl-xL inhibitors. Bcl-xL inhibitors can be synthesized using the general approach of modifying a primary amine with asolubilizing group and then attaching the resulting secondary amine to a linker as described in laterschemes. For example, compound (41) can be prepared by reacting compound (39) with nd(40). The reaction is lly performed at ambient temperature in a solvent such as but not dto N,N-dimethylf0rmamide. Compound (41) can be reacted with trifluoroacetic acid to providecompound (43). The reaction is typically performed at ambient temperature in a solvent such as butnot limited to dichloromethane. Another example shown in Scheme 9 is the on of compound(39) with diethyl vinylphosphonate, followed by reaction with bromotrimethylsilane andallyltrimethylsilane to provide compound (42). Other examples to introduce solubilizing groups onthe Bcl-xL inhibitors described herein include, but are not limited to, reductive amination reactions,alkylations, and amidation ons.

MEl 24985843V.1 357117813-12620.1.10. Synthesis of nd (47)Scheme 10O \O O0 Arz N\ WSOHY OH 3| (N ArllNH \| \Z1I Oo o NH2OYAF2 N\ KOH SO3H| —> NHAr1/ (N\l \,Z1 OScheme 10 shows introduction of a solubilizing group by amidation reaction. Bcl-XLinhibitors can be synthesized using the general approach of modifying a primary or secondary aminewith a solubilizing group and then attaching the resulting amine to a linker as described in laterschemes. For e, compound (45) can be d sequentially with HATU and compound (44),to provide compound (46). Compound (46) can be treated with diethylamine in solvents such as, butnot limited to, N,N-dimethylf0rmamide to give compound (47).

MEl 24985843V.1 358117813-12620.1.11. Synthesis of Compound (51)Scheme 11O x l O0 Ar2 N 0 Ar2 N X QY \ O Ell) Y \ ONHI |/ (NHz 1,NH /| \/Z1 (48) Ar (N.HO l \IZ1N —> NTDBPS ”3°C0 0 <3*s\ 0 Ar2 N QW O J<Y \ O| N O~TDBPS(40) Arl’NH / TFA\ ( \——\ ’l 21 S OI o l/\\N 00 —’Ar2 N QCY \ OH| N,NH /Ar1 \ </ \—\| NZ1 ,0 d§bOHScheme 11 shows representative methods to make solubilized Bcl-XL inhibitors. Bcl-XLtors can be synthesized using the general approach of modifying a primary amine with a spacerto give a differentially protected diamine. The unprotected secondary amine can be modified with asolubilizing group. Deprotection of a protected amine them reveals a site for linker attachment, asdescribed in later s. For example, compound (39) can be ively ted with reagentssuch as, but not limited to tert-butyl 4-0X0piperidine-l-carb0xylate (48), under conditions known inthe art, to provide a secondary amine (49). Compound (50) can be prepared by ng compound(49) with 4-((tert—butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (40). The reaction istypically performed at ambient temperature in a solvent such as but not limited to N,N-dimethylformamide. Compound (40) can be d with trifluoroacetic acid to provide compound(51). The reaction is typically performed at ambient temperature in a solvent such as but not limitedto romethane..1.12. Synthesis of Compound (61)MEl 24985843V.1 359117813-12620@mo A|OO @6:om/\0 Al VjflU/\N\/Zm\/\N\/NIZ\/\OV1 0m.__/\/Z\/\ 0N2 so2 324%?2.29mmmw/O £212 ARV_N IO\z,Q93_0 W.©/\N> Q/Oj/@330 m/\/Z\/\OEO\/\O AomV ifOM/\O/Z\o/\oAmmV AGVEVjo .N/Z \ ANmV6 “m9Tymfiwmwmfim117813-12620Scheme 12 describes a method to synthesize solubilized Bcl-XL inhibitors. Compound (52) can bed with methanesulfonyl chloride, in the presence of a base, such as, but not limited to,triethylamine, to provide compound (53). The reaction is typically med at a low temperature ina solvent such as but not limited to dichloromethane. Compound (53) can be d with ammonia inol to provide nd (54). The reaction is typically performed at an elevated temperature,and the reaction may be performed under microwave conditions. nd (56) can be ed byreacting compound (55) in the presence of a base such as but not limited to N,N-diisopropylethylamine. The reaction is typically performed at ambient temperature in a solvent suchas but not limited to N,N-dimethylformamide. Compound (56) can be treated with di-t-butyldicarbonate and 4-(dimethylamino)pyridine to provide compound (57). The reaction is typicallyperformed at ambient ature in a solvent such as but not limited to tetrahydrofuran. Compound(59) can be prepared by reacting compound (57) with a boronate ester (or the equivalent boronic acid)of formula (58), under Suzuki Coupling conditions described herein or in the literature. Bis(2,5-dioxopyrrolidin-l-yl) carbonate can be reacted with compound (37), followed by reaction withcompound (59), to provide compound (60). The reaction is typically med at ambienttemperature in a solvent such as, but not limited to, acetonitrile. nd (61) can be prepared bytreating compound (60) with trifluoroacetic acid. The reaction is typically performed at ambientature in a solvent such as but not limited to dichloromethane..1.13. Synthesis of Compound (70)MEl 24985843V.1 361-12620z 932.39mTymfiwmwflum117813-12620Scheme 13 describes the synthesis of 5-hydroxy tetrahydroisoquinoline intermediates. Compound(63) can be prepared by treating compound (62) with N-bromosuccinimide. The reaction is typicallyperformed at ambient temperature is a solvent such as, but not limited to, N,N-dimethylformamide.

Compound (63) can be reacted with benzyl bromide in the presence of a base, such as, but not limitedto, potassium carbonate, to provide compound (64). The on is typically med at anelevated temperature, in a t such as, but not limited to, acetone. Compound (64) can be dwith carbon monoxide and methanol in the ce of a base, such as, but not limited to,triethylamine, and a catalyst, such as, but not limited to, compound (65). The reaction is llyperformed at an elevated temperature under an inert atmosphere. Compound (65) can be treated withan acid, such as, but not d to, hydrochloric acid in dioxane, to provide compound (66). Thereaction is lly performed at ambient temperature in a solvent, such as, but not d to,tetrahydrofuran. Compound (67) can be prepared by reacting compound (66) with tert—butyl 3-bromofluoropicolinate in the presence of a base, such as, but not limited to, triethylamine. Theon is typically performed under an inert atmosphere at an elevated temperature in a solvent, suchas, but not limited to, dimethyl sulfoxide. Compound (67) can be d with a boronic acid offormula (68), wherein Ad is the methyladamantane moiety of the compounds of the disclosure (e.g.,the compounds of formulae (IIa)-(IId)), under Suzuki Coupling conditions described herein or in theture to provide compound (69). Compound (70) can be prepared by reacting compound (69)with hydrogen in the presence of Pd(OH)2. The reaction is typically performed at an elevatedtemperature in a solvent such as, but not limited to tetrahydrofuran..1.14. Synthesis of Compound (75)MEI 24985843V.1 363-12620Scheme HOTOOJ (37)< 24985843V.1117813-12620Scheme 14 shows representative methods used to make solubilized Bcl-xL inhibitors. Bcl-xLinhibitors can be synthesized using the general approach of modifying an Ar2 tuent with asolubilizing group and then ing an amine to a linker as described in later schemes. For example,compound (71) can be reacted with utyl 2-bromoacetate in the presence of a base such as, butnot limited to, potassium carbonate in a solvent such as, but not limited, to N,N-dimethylformamide.

Compound (72) can be treated with s lithium hydroxide in a solvent such as, but not limited to,methanol, tetrahydrofuran or mixtures thereof to provide compound (73). Compound (74) can beobtained by amidation of compound (73) with compound (37) under ions previously described.

Compound (74) can be treated with acids such as, but not limited to trifluoroacetic acid or HCl, toprovide a Bcl-xL inhibitor of the formula (75). The reaction is typically performed at ambienttemperature in solvents such as, but not limited to, romethane or 1,4-dioxane.

III.A.6. l Methods for Synthesizing Bcl-xL SynthonsIn the schemes below, the various substituents Arl, Arz, 21, Y, G, R11a and R11b are as defined in theDetailed Description section.5.2.1. Synthesis of Compound (89)MEl 24985843V.1 365-12620IANV<<“Wadi.GaO €<< 0__+2O; \00 mod=3...27% I:CaJ: ‘| :0 €<<o z€<m Amwv:3:z 8% o2 fZNI oszW/zLAQK/WWVcesium \ o OH 22‘| EZ\I z, 22o O z\ /ZIO O 50an :0/ \ $33% , 0:0 am mm 0 Z\IZ Ni#4O o Z:§<<fo Qooo0 :Zm£5 a);£2 EaOI awfw IAC<MLA:m\/z\ TymfiwmwflumAnn—2117813-12620As shown in scheme 15, compounds of formula (77), wherein PG is an appropriate baselabile protecting group and AA(2) is Cit, Ala, or Lys, can be reacted with 4-(aminophenyl)methanol(78), under amidation ions described herein or readily available in the literature to providecompound (79). Compound (80) can be prepared by reacting compound (79) with a base such as, butnot limited to, diethylamine. The reaction is typically performed at ambient temperature in a tsuch as but not d to N,N-dimethylformamide. Compound (81), wherein PG is an appropriatebase or acid labile protecting group and AA(1) is Val or Phe, can be reacted with compound (80),under amidation conditions described herein or readily available in the literature to provide compound(82). Compound (83) can be prepared by treating compound (82) with diethylamine or trifluoroaceticacid, as appropriate. The on is typically performed at ambient temperature in a solvent such asbut not limited to dichloromethane. Compound (84), wherein Sp is a spacer, can be reacted withcompound (83) to provide compound (85). The reaction is typically performed at ambienttemperature in a solvent such as but not d to N,N-dimethylformamide. Compound (85) can bereacted with bis(4-nitrophenyl) carbonate (86) in the presence of a base such as, but not limited toN,N-diisopropylethylamine, to provide compounds (87). The reaction is typically performed att ature in a solvent such as but not limited to N,N-dimethylformamide. Compounds(87) can be reacted with compound (88) in the ce of a base such as, but not limited to, N,N-diisopropylethylamine, to provide compound (89). The on is typically performed at ambienttemperature in a t such as, but not limited to, N,N-dimethylformamide.5.2.2. Synthesis of Compounds (94) and (96)MEl 24985843V.1 367117813-12620/ \ / \_ _\W:7”1< <NOZ o :039Q A|LAW Nox/Q/ CmE O:5 2: a? ::szFZ S<<$2 I2 oO 33m fi>n€<< Jana:I41/2\ooEm o/=\z ANQ o3 o\>/z\/\o :0 fl,N\z2.39m o 0oIO/fifi A3Tymfiwmwflum117813-12620Scheme 16 describes the installment of alternative mAb-linker attachments to dipeptide Synthons.

Compound (88) can be reacted with compound (90) in the ce of a base such as, but not limitedto, N,N-diisopropylamine to provide compound (91). The reaction is typically performed at ambientature in a solvent such as but not limited to N,N-dimethylformamide. Compound (92) can beprepared by reacting compound (91) with diethylamine. The reaction is typically performed atambient temperature in a solvent such as but not limited to methylformamide. Compound (93),wherein X1 is Cl, Br, or I, can be reacted with nd (92), under amidation conditions describedherein or readily available in the ture to provide compound (94). Compound (92) can be reactedwith compounds of formula (95) under amidation conditions described herein or readily available inthe ture to provide compound (96)..2.3. Synthesis of Compound (106)MEl 24985843V.1 369-12620:0 IOcesium770 OOV/mmxle£5O 0Tymfiwmwflum117813-12620Scheme 17 bes the synthesis of vinyl glucuronide linker intermediates and synthons.(2R,3R,4S,5S,6S)Bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (97) canbe treated with silver oxide, followed by 4-bromonitrophenol (98) to provide (2S,3R,4S,5S,6S)monitrophenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (99). Thereaction is typically performed at ambient temperature in a solvent, such as, but not limited to,acetonitrile. (2S,3R,4S,5S,6S)(4-Bromonitrophenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (99) can be reacted with (E)-tert—butyldimethyl((3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)allyl)oxy)silane (100) in the presence of a base such as, but not limited to,sodium carbonate, and a catalyst such as but not limited to tris(dibenzylideneacetone)dipalladiumba)3), to e (2S,3R,4S,5S,6S)(4-((E)((tert—butyldimethylsilyl)oxy)prop-l-en-l-yl)nitrophenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (101). The reaction istypically med at an elevated temperature in a solvent, such as, but not limited to,tetrahydrofuran. (2S,3R,4S,58,6S)(2-amino((E)hydroxyprop-l -en-l -yl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (102) can be prepared by reacting(2S,3R,4S ,5S -(4-((E)-3 -((tert—butyldimethylsilyl)oxy)propenyl)nitrophenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (101) with zinc in the presence of an acidsuch as, but not limited to, hydrochloric acid. The addition is typically performed at low temperaturebefore warming to ambient temperature in a solvent such as, but not limited to, tetrahydrofuran, water,or mixtures thereof. (2S,3R,4S,5S,6S)(2-amino((E)hydroxyprop-l-en-l-yl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (102) can be reacted with (9H-fluorenyl)methyl oro-3 -oxopropyl)carbamate (103), in the presence of a base such as, but not limitedto, N,N-diisopropylethylamine, to e (2S,3R,4S,5S,6S)(2-(3-((((9H-fluorenyl)methoxy)carbonyl)amino)propanamido)((E)hydroxypropenyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl tate (104). The addition is typicallyperformed at low temperature before warming to ambient temperature in a solvent such as, but notlimited to, romethane. Compound (88) can be reacted with (2S,3R,4S,5S,6S)(2-(3-((((9H-fluorenyl)methoxy)carbonyl)amino)propanamido)((E)-3 -hydroxyprop- l -en-l -yl)phenoxy)xycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (104) in the presence of a base such as,but not limited to, N-ethyl-N-isopropylpropanamine, followed by work up and reaction withcompound (105) in the presence of a base such as, but not limited to, N,N-diisopropylethylamine toprovide compound (106). The reactions are typically performed at ambient ature in a solventsuch as, but not limited to N,N- dimethylformamide..2.4. Synthesis of Compound (115)MEI 24985843V.1 371117813-12620ooELIZ O\/\O/\/O \\ IOSE 0:O OIOI Z/ oI N\O x zIz;<LM: IZI> o2.3% ,0meE. HamTymfiwmwflum117813-12620Scheme 18 bes the synthesis of a representative 2-ether glucuronide linkerintermediate and synthon. ,4S,5S,6S)Bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (97) can be reacted with 2,4-dihydroxybenzaldehyde (107) in the presence ofsilver carbonate to provide (2S,3R,4S,5S,6S)(4-formyl-3 -hydroxyphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (108). The reaction is llyperformed at an elevated temperature in a solvent, such as, but not limited to, acetonitrile.(2S,3R,4S,5S,6S)(4-Formylhydroxyphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl tate (108) can be treated with sodium borohydride to e (2S,3R,4S,5S,6S)(3-hydroxy(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate(109). The addition is typically performed at low temperature before warming to t temperaturein a solvent such as but not limited to tetrahydrofuran, methanol, or mixtures thereof.(2S,3R,4S,5S,6S)(4-(((tert—butyldimethylsilyl)oxy)methyl)hydroxyphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (110) can be prepared by reacting(2S,3R,4S,5S,6S)(3-hydroxy(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-3,4,5-triyl triacetate (109) with tert—butyldimethylsilyl chloride in the presence of imidazole.

The reaction is typically performed at low temperature in a solvent, such as, but not limited to,dichloromethane. (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)(((tert—butyldimethylsilyl)oxy)methyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (111) can be ed by reacting(2S,3R,4S,5S,6S)(4-(((tert—butyldimethylsilyl)oxy)methyl)hydroxyphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (110) with (9H-fluorenyl)methyl (2-(2-hydroxyethoxy)ethyl)carbamate in the presence of triphenylphosphine and a azodicarboxylate suchas, but not limited to, t—butyl diazene-l,2-dicarboxylate. The on is typically performed atambient temperature in a solvent such as but not limited to toluene. (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)(((tert—imethylsilyl)oxy)methyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (111) can be treated with acetic acid to provide (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-fluoren-9-yl)methoxy)carbonyl)amino)ethoxy)ethoxy)(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (112). The reaction is typicallyperformed at ambient temperature in a solvent such as but not limited to water, tetrahydrofuran, ormixtures f. (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (113) can be prepared by reacting(2S,3R,4S,5S,6S)(3-(2-(2-((((9H-fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (112) withbis(4-nitrophenyl) carbonate in the presence of a base such as but not limited to N-ethyl-N-MEl 24985843V.1 373117813-12620isopropylpropanamine. The reaction is typically med at ambient temperature in a solventsuch as but not limited to N,N-dimethylformamide. (2S,3R,4S,SS,6S)(3-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (113) can be treated with compound (88)in the presence of a base such as but not limited to N-ethyl-N-isopropylpropanamine, followed bytreatment with lithium hydroxide to provide a compound (114). The reaction is typically performed atambient temperature in a t such as but not limited to N,N-dimethylformamide, tetrahydrofuran,ol, or mixtures thereof. Compound (115) can be prepared by reacting compound (114) withcompound (84) in the presence of a base such as but not d to N-ethyl-N-isopropylpropanamine. The reaction is typically performed at ambient temperature in a solvent such as but not limitedto N,N-dimethylformamide..2.5. sis of Compound (119)MEI 24985843V.1 374-126202.39mTymfiwmwflum117813-12620Scheme 19 describes the uction of a second solubilizing group to a sugar linker.

Compound (116) can be reacted with (R)((((9H-fluorenyl)methoxy)carbonyl)amino)sulfopropanoic acid (117), under amidation conditions described herein or readily available in theliterature, ed by treatment with a base such as but not limited to diethylamine, to ecompound (118). Compound (118) can be reacted with compound (84), wherein Sp is a spacer, underamidation conditions described herein or readily available in the literature, to provide compound(119).

MEl 24985843V.1 376117813-12620.2.6. Synthesis of Compound (129)Scheme 20Br OACO H O H fiOACo ”I,0 H OH OH COZCH3Br/\/O\/\BrOH (124)(121) ( 123) é —> (122)—>0 0(120)OH \L IO OH H=0 OAc O OAc0 0,, 0:00A 0GAO C QAC0 Ar2 N0 / =O‘N Arl’ 0 OHsm \ \zlI N_, , 800 N 0 00 OHSp: spacer—> \L 0 \(129) 0Scheme 20 describes the synthesis of 4-ether glucuronide linker intermediates andsynthons. 4-(2-(2-Br0moeth0xy)ethoxy)hydr0xybenzaldehyde (122) can be prepared by reacting2,4-dihydr0xybenzaldehyde (120) with l-br0m0(2-br0moethoxy)ethane (121) in the presence of abase such as, but not limited to, potassium carbonate. The on is typically med at anMEl 24985843V.1 377117813-12620elevated ature in a solvent such as but not limited to acetonitrile. 4-(2-(2-Bromoethoxy)ethoxy)hydroxybenzaldehyde (122) can be treated with sodium azide to provide 4-(2-(2-azidoethoxy)ethoxy)hydroxybenzaldehyde (123). The reaction is lly performed atambient temperature in a solvent such as but not limited to N,N-dimethylformamide.(2S,3R,4S,5S,6S)(5-(2-(2-Azidoethoxy)ethoxy)formylphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (125) can be prepared by ng 4-(2-(2-azidoethoxy)ethoxy)hydroxybenzaldehyde (123) with (3R,4S,5S,6S)bromoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (124) in the presence of silver oxide.

The on is typically performed at ambient temperature in a solvent such as, but not limited to,acetonitrile. Hydrogenation of (2S,3R,4S,5S,6S)(5-(2-(2-azidoethoxy)ethoxy)formylphenoxy)-6-(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (125) in the presence of Pd/C willprovide (2S,3R,4S,5S,6S)(5-(2-(2-aminoethoxy)ethoxy)(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (126). The reaction is typicallyperformed at ambient temperature in a solvent such as, but not limited to, tetrahydrofuran.,4S,5S,6S)(5-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (127) canbe prepared by treating ,4S,5S,6S)(5-(2-(2-aminoethoxy)ethoxy)(hydroxymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (126) with(9H-fluorenyl)methyl carbonochloridate in the presence of a base, such as, but not limited to, N-ethyl-N-isopropylpropanamine. The reaction is typically performed at low temperature in a solventsuch as, but not limited to, dichloromethane. Compound (88) can be reacted with (2S,3R,4S,5S,6S)-2-(5-(2-(2-((((9H-Fluorenyl)methoxy)carbonyl)amino)ethoxy)ethoxy)xymethyl)phenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (127) in thepresence of a base, such as, but not limited to, l-N-isopropylpropanamine, followed bytreatment with m hydroxide to provide compound (128). The reaction is typically performed atlow temperature in a solvent such as, but not limited to, N,N-dimethylformamide. Compound (129)can be prepared by ng compound (128) with compound (84) in the presence of a base such as,but not limited to, N-ethyl-N-isopropylpropanamine. The reaction is typically performed atambient temperature in a solvent such as but not limited to N,N-dimethylformamide.

MEl 24985843V.1 378117813-12620.2.7. Synthesis of Compound (139)Scheme 21OH “0/7;er3 OH' —. 133 ( )HZN (130) HzN (132) HzNQAOTBSOH O\/\O/\/N3 \/N30 HO\ JKEIDJ/OH0 4/ —>AcO‘ ’OAC/\/ \/\0 00A0 0 0/\/O\/\N3 O N3(134)\ 0 0 NH\0 0 OTNH 0(135) \g’ (136)me” mm? ACO‘ ’OACo 0N1.—O0T0 00 O ONOszOzN N02 0 0 NHfl \0 \n’ (137)ACO ”'OAQ51:1 ‘\ 0E lN INI \ I,G 0 N- - /HN.Y HO // 0 TYHON \N/lf(88) Ar2O ArzllN,Ar1 0(138) N.ArlHO OYNHH0“‘ ”'01?0 0% l0 SmOIjb. NI N" O O \ lO (84) O N. /Y Y HO\ / O—’pSpaceS : r 0 N0 ArZMN'ArI0 0 NH kH0 \11/ (139)H0“‘ "'01? if}Scheme 21 describes the synthesis of carbamate glucuronide intermediates and synthons.2-Amin0(hydr0xymethyl)phenol (130) can be treated with sodium hydride and then reacted with 2-(2-azidoethoxy)ethyl 4-methylbenzenesulf0nate (131) to provide (4-amin0-3 -(2-(2-azidoethoxy)ethoxy)phenyl)methanol (132). The reaction is typically med at an edtemperature in a solvent such as, but not limited to N,N-dimethylf0rmamide. 2-(2-(2-MEl 24985843V.1 379117813-12620Azidoethoxy)ethoxy)(((tert-butyldimethylsilyl)oxy)methyl)aniline (133) can be prepared byreacting no-3 -azidoethoxy)ethoxy)phenyl)methanol (132) with tertbutyldimethylchlorosilanein the presence of imidazole. The reaction is typically performed atambient temperature in a solvent such as, but not limited to tetrahydrofuran. 2-(2-(2-Azidoethoxy)ethoxy)(((tert-butyldimethylsilyl)oxy)methyl)aniline (133) can be treated withphosgene, in the presence of a base such as but not d to triethylamine, followed by reaction with(3R,4S,5S,6S)hydroxy(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (134) in thece of a base such as but not limited to triethylamine, to provide 2S,3R,4S,5S,6S)(((2-(2-(2-azidoethoxy)ethoxy)(((tert-butyldimethylsilyl)oxy)methyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (135). The reaction is typicallyperformed in a solvent such as, but not limited to, e, and the additions are typically performed atlow temperature, before g up to ambient temperature after the phosgene addition and heatingat an ed temperature after the (3R,4S,5S,6S)hydroxy(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (134) addition. (2S,3R,4S,SS,6S)(((2-(2-(2-Azidoethoxy)ethoxy)(hydroxymethyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (136) can be ed by reacting 2S,3R,4S,SS,6S)(((2-(2-(2-azidoethoxy)ethoxy)(((tert-butyldimethylsilyl)oxy)methyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (135) with p-toluenesulfonic acid monohydrate. The reaction is typicallyperformed at t temperature in a solvent such as, but not limited to methanol.(2S,3R,4S,5S,6S)(((2-(2-(2-Azidoethoxy)ethoxy)(hydroxymethyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (136) can be reacted with bis(4-nitrophenyl)carbonate in the presence of a base such as, but not limited to, N,N-diisopropylethylamine, to provide (2S,3R,4S,SS,6S)(((2-(2-(2-azidoethoxy)ethoxy)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl tate (137). The reaction is typically performed at ambient temperature in asolvent such as, but not limited to, N,N-dimethylformamide. (2S,3R,4S,5S,6S)(((2-(2-(2-Azidoethoxy)ethoxy)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)carbamoyl)oxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (137) can be reacted with nd inthe presence of a base such as, but not limited to, N,N-diisopropylethylamine, followed by treatmentwith aqueous lithium hydroxide, to provide compound (138). The first step is typically conducted atambient temperature in a solvent such as, but not limited to N,N-dimethylformamide, and the secondstep is typically ted at low temperature in a solvent such as but not limited to methanol.nd (138) can be treated with tris(2-carboxyethyl))phosphine hydrochloride, followed byreaction with compound (84) in the presence of a base such as, but not limited to, N,N-diisopropylethylamine, to provide compound (139). The on with tris(2-carboxyethyl))phosphinehydrochloride is typically med at ambient temperature in a solvent such as, but not limited to,tetrahydrofuran, water, or mixtures thereof, and the reaction with N-succinimidyl 6-MEl 24985843V.1 380117813-12620maleimidohexanoate is typically performed at ambient temperature in a solvent such as, but notd to, N,N-dimethylf0rmamide..2.8. Synthesis of Compound (149)MEl 24985843V.1 3 81117813-12620O OEO 58%‘ZU o ‘|QEQSUWTymfiwmwflum117813-12620Scheme 22 describes the synthesis of galactoside linker intermediates and synthons.(28,3R,4S,SS,6R)(Acetoxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl cetate (140) can betreated with HBr in acetic acid to provide (2R,3S,4S,5R,6S)(acetoxymethyl)bromotetrahydro-an-3,4,5-triyl triacetate (141). The reaction is typically med at ambient temperatureunder a nitrogen atmosphere. (2R,3S,4S,5R,6S)(Acetoxymethyl)(4-formylnitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (143) can be prepared by treating(2R,3S,4S,5R,6S)(acetoxymethyl)bromotetrahydro-2H-pyran-3,4,5-triyl triacetate (141) with(I) oxide in the presence of 4-hydroxy-3 -nitrobenzaldehyde (142). The reaction is typicallyperformed at ambient temperature in a solvent such as, but not limited to, itrile.(2R,3S,4S,5R,6S)(Acetoxymethyl)(4-formylnitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyltriacetate (143) can be d with sodium borohydride to provide (2R,3S,4S,5R,6S)(acetoxymethyl)(4-(hydroxymethyl)nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate(144). The reaction is typically performed at low temperature in a solvent such as but not limited totetrahydrofuran, methanol, or es thereof. (2R,3S,4S,5R,6S)(Acetoxymethyl)(2-amino(hydroxymethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (145) can be prepared by ng(2R,3S,4S,5R,6S)(acetoxymethyl)(4-(hydroxymethyl)nitrophenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (144) with zinc in the presence of hloric acid. The reaction is typicallyperformed at low temperature, under a nitrogen atmosphere, in a solvent such as, but not limited to,tetrahydrofuran. (ZS,3R,4S,SS,6R)(2-(3-((((9H-Fluorenyl)methoxy)carbonyl)amino)propanamido)(hydroxymethyl)phenoxy)(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (146) can be prepared by reacting(2R,3S,4S,5R,6S)(acetoxymethyl)(2-amino(hydroxymethyl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate (145) with (9H-fluorenyl)methyl (3-chlorooxopropyl)carbamate (103) inthe presence of a base such as, but not limited to, N,N-diisopropylethylamine. The reaction istypically performed at low temperature, in a solvent such as, but not d to, dichloromethane.(28,3R,4S,SS,6R)(2-(3-((((9H-Fluorenyl)methoxy)carbonyl)amino)propanamido)xymethyl)phenoxy)(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (146) can bereacted with bis(4-nitrophenyl)carbonate in the presence of a base such as, but not limited to, N,N-diisopropylethylamine, to provide (28,3R,4S,SS,6R)(2-(3-((((9H-fluorenyl)methoxy)carbonyl)amino)propanamido)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (147). The reaction is typically performedat low temperature, in a solvent such as, but not limited to, N,N-dimethylformamide.(2S,3R,4S,SS,6R)(2-(3-((((9H-Fluorenyl)methoxy)carbonyl)amino)propanamido)((((4-nitrophenoxy)carbonyl)oxy)methyl)phenoxy)(acetoxymethyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (147) can be reacted with compound (88) in the presence of a base such as, but not dto N,N-diisopropylethylamine, followed by treatment with lithium hydroxide, to e compoundMEl 24985843V.1 383117813-12620(148). The first step is typically performed at low temperature, in a solvent such as, but not limited to,methylformamide, and the second step is typically performed at ambient temperature, in asolvent such as, but not limited to, methanol. Compound (148) can be treated with compound (84),wherein Sp is a spacer, in the presence of a base, such as, but not d to N,N-diisopropylethylamine, to provide compound (149). The reaction is typically performed at ambienttemperature, in a solvent such as, but not limited to, N,N-dimethylformamide.

III.A.7. General Methods for Synthesizing Anti-B7-H3 ADCsThe present invention also discloses a process to prepare an anti-B7-H3 ADC ing tostructural formula (I):(I) ( agAbwherein D, L, LK, Ab and m are as defined in the Detailed Description section. The processcomprises:treating an antibody in an aqueous solution with an effective amount of a disulfide reducingagent at 30-40 CC for at least 15 minutes, and then cooling the dy solution to 20-27 C’C;adding to the reduced antibody solution a solution of water/dimethyl sulfoxide comprising asynthon selected from the group of 2.1 to 2.176 (Table B);adjusting the pH of the on to a pH of 7.5 to 8.5;allowing the on to run for 48 to 80 hours to form the ADC;wherein the mass is shifted by 18 i 2 amu for each hydrolysis of a succinimide to asuccinamide as measured by electron spray mass spectrometry; andn the ADC is optionally purified by hydrophobic interaction chromatography.

In certain embodiments, the antibody is an hB7-H3 dy, wherein the hB7-H3 antibodycomprises the heavy and light chain CDRs of huAb3v2.5, huAb3v2.6, or huAbl3vl.

The present invention is also directed to an anti-B7-H3 ADC prepared by the above-describedprocess.

In n embodiments, the anti-B7-H3 ADC disclosed in the present ation is formedby contacting an antibody that binds an hB7-H3 cell surface receptor or tumor associated antigenexpressed on a tumor cell with a drug-linker synthon under ions in which the drug-linkersynthon covalently links to the antibody through a maleimide moiety as shown in ae (He) and(Hf), or through an acetyl halide as shown in(IIg), or through a vinyl sulfone as shown in (Kb).

D—L -NH1 /D_L1_N "at“3: 6(He) 0, (Ht) 002“,MEl 24985843V.1 384117813-12620D—Ll-NH D_L1_N!_,Vi xS/\/ I0’ \\(11g) 0 (11h) 0wherein D is the Bcl-xL tor drug according to structural a (11a), (11b), (11c) or (IId) asdescribed above and L1 is the portion of the linker not formed from the maleimide, acetyl halide orvinyl sulfone upon attachment of the synthon to the antibody; and wherein the drug-linker synthon isselected from the group consisting of synthon examples 2.1 to 2.176 (Table B), or a pharmaceuticallyacceptable salt thereof.

In certain embodiments, the ting step is carried out under conditions such that the anti-B7-H3 ADC has a DAR of 2, 3 or 4.

III.B. Anti-B7-H3 ADCs: Other Exemplary Drugs for ConjugationAnti-B7-H3 antibodies may be used in ADCs to target one or more drug(s) to a cell of interest,e.g., a cancer cell expressing B7-H3. The anti-B7-H3 ADCs of the invention provide a edtherapy that may, for example, reduce the side effects often seen with anti-cancer therapies, as the oneor more ) is delivered to a specific cell.atinsAnti-B7-H3 antibodies of the invention, e.g., the huAbl3vl, huAb3v2.5, or huAb3v2.6antibody, may be conjugated to at least one auristatin. Auristatins represent a group of dolastatinanalogs that have generally been shown to possess anticancer activity by interfering with microtubuledynamics and GTP hydrolysis, y ting cellular division. For example, auristatin E (US.

Patent No. 5,635,483) is a synthetic analogue of the marine natural t dolastatin 10, a compoundthat inhibits tubulin polymerization by binding to the same site on tubulin as the anticancer drugvincristine (G. R. Pettit, Prog. Chem. Org. Nat. Prod, 70: 1-79 (1997)). Dolastatin 10, auristatin PE,and auristatin E are linear peptides having four amino acids, three of which are unique to thedolastatin class of compounds. Exemplary embodiments of the auristatin subclass of mitoticinhibitors include, but are not limited to, thyl auristatin D (MMAD or auristatin Dtive), monomethyl auristatin E (MMAE or auristatin E tive), monomethyl auristatin F(MMAF or auristatin F derivative), auristatin F phenylenediamine (AFP), auristatin EB (AEB),auristatin EFP (AEFP), and 5-benzoylvaleric acid-AE ester (AEVB). The sis and structure ofauristatin derivatives are described in US. Patent Application Publication Nos. 2003-0083263, 2005-0238649 and 009751; International Patent Publication No. WO 04/010957, International PatentPublication No. WO 02/088172, and US. Pat. Nos. 6,323,315; 6,239,104; 6,034,065; 5,780,588;,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024;,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414, each of which isincorporated by reference .

MEI 24985843V.1 385117813-12620In one embodiment, anti-B7-H3 antibodies of the invention, 6. g., huAbl3vl, huAb3v2.5, or2.6, are conjugated to at least one MMAE (mono-methyl auristatin E). Monomethyl auristatinE (MMAE, vedotin) inhibits cell division by blocking the polymerization of tubulin. However, due toits super toxicity, auristatin E cannot be used as a drug itself. Auristatin E can be linked to amonoclonal antibody (mAb) that recognizes a ic marker expression in cancer cells and directsMMAE to the cancer cells. In one embodiment, the linker linking MMAE to the anti-B7-H3 antibodyis stable in extracellular fluid (i.e., the medium or environment that is external to , but is cleavedby cathepsin once the ADC has bound to the specific cancer cell antigen and entered the cancer cell,thus releasing the toxic MMAE and activating the potent anti-mitotic mechanism.

In one embodiment, an anti-B7-H3 antibody described herein, 6. g., huAbl3vl, huAb3v2.5, orhuAb3v2.6, is ated to at least one MMAF (monomethylauristatin F). thyl auristatin F(MMAF) inhibits cell division by blocking the polymerization of tubulin. It has a charged C-terminalphenylalanine residue that attenuates its cytotoxic activity compared to its ged counterpartMMAE. r, due to its super toxicity, auristatin F cannot be used as a drug itself, but can belinked to a monoclonal antibody (mAb) that directs it to the cancer cells. In one embodiment, thelinker to the anti-B7-H3 antibody is stable in extracellular fluid, but is cleaved by sin once theconjugate has d a tumor cell, thus activating the anti-mitotic mechanism.

MEl 24985843V.1 386117813-12620The ures of MMAF and MMAE are provided below.

Monomethyl Auristatin E (MMAE)Monomethyl Auristatin F (MMAF)An example of huAbl3v l, huAb3v2.5, or huAb3v2.6-chMAE is also ed in Figure3. Notably, Figure 3 describes a situation Where the antibody (e.g., huAbl3vl, huAb3v2.5, orhuAb3v2.6) is d to a single drug and, ore, has a DAR of 1. In certain embodiments, theADC will have a DAR of 2 to 8, or, alternatively, 2 to 4.

Other Drugsfor ConjugationExamples of drugs that may be used in ADCs, i.e., drugs that may be conjugated to the anti-B7-H3 antibodies of the invention, are provided below, and include mitotic inhibitors, antitumorantibiotics, immunomodulating agents, gene therapy vectors, alkylating agents, antiangiogenic agents,antimetabolites, boron-containing , chemoprotective agents, hormone agents, glucocorticoids,photoactive therapeutic agents, ucleotides, radioactive isotopes, radiosensitizers, topoisomeraseinhibitors, kinase inhibitors, and combinations thereof.

MEl 24985843V.1 387117813-12620I. Mitotic InhibitorsIn one aspect, anti-B7-H3 antibodies may be conjugated to one or more mitotic inhibitor(s) toform an ADC for the treatment of cancer. The term “mitotic inhibitor”, as used herein, refers to acytotoxic and/or therapeutic agent that blocks mitosis or cell division, a biological process particularlyimportant to cancer cells. A mitotic inhibitor disrupts microtubules such that cell division isprevented, often by ing microtubule polymerization (e. g., inhibiting microtubulepolymerization) or microtubule depolymerization (e. g., stabilizing the microtubule cytoskeletont depolymerization). Thus, in one embodiment, an anti-B7-H3 antibody of the invention isated to one or more mitotic inhibitor(s) that disrupts microtubule formation by inhibitingtubulin polymerization. In another embodiment, an anti-B7-H3 antibody of the invention isconjugated to one or more c inhibitor(s) that stabilizes the microtubule cytoskeleton fromdepolymerization. In one embodiment, the mitotic inhibitor used in the ADCs of the invention isIxempra pilone). Examples of mitotic inhibitors that may be used in the 7-H3 ADCs ofthe ion are provided below. Included in the genus of mitotic inhibitors are auristatins, describedabove.a. DolastatinsThe anti-B7-H3 antibodies of the ion may be conjugated to at least one dolastatin toform an ADC. Dolastatins are short peptidic nds isolated from the Indian Ocean sea hareDolabella laria (see Pettit et al., J. Am. Chem. Soc., 1976, 98, 4677). Examples of dolastatinsinclude atin 10 and dolastatin 15. Dolastatin 15, a seven-subunit depsipeptide derived fromlla auricularia, and is a potent totic agent structurally related to the antitubulin agentdolastatin 10, a five-subunit peptide obtained from the same organism. Thus, in one embodiment, theanti-B7-H3 ADC of the invention comprises an 7-H3 antibody, as described , and at leastone dolastatin. Auristatins, described above, are synthetic derivatives of dolastatin 10.b. MaytansinoidsThe 7-H3 antibodies of the invention may be conjugated to at least one maytansinoid toform an ADC. Maytansinoids are potent antitumor agents that were originally isolated from sof the higher plant families Celastraceae, Rhamnaceae, and Euphorbiaceae, as well as some speciesof mosses (Kupchan et al, J. Am. Chem. Soc. 94:1354-1356 [1972]; Wani et al, J. Chem. Soc. Chem.

Commun. 390: [1973]; Powell et al, J. Nat. Prod. 46:660-666 [1983]; Sakai et al, J. Nat. Prod. 512845-850 [1988]; and Suwanborirux et al, Experientia 46:117-120 [1990]). Evidence suggests thatmaytansinoids inhibit mitosis by inhibiting polymerization of the microtubule protein tubulin, therebypreventing formation of microtubules (see, e.g., US. Pat. No. 6,441,163 and Remillard et al., Science,189, 1002-1005 (1975)). Maytansinoids have been shown to inhibit tumor cell growth in vitro usingMEI 24985843V.1 388117813-12620cell culture models, and in viva using laboratory animal systems. Moreover, the cytotoxicity ofmaytansinoids is 1,000-fold greater than conventional chemotherapeutic agents, such as, for example,methotrexate, daunorubicin, and vincristine (see, e.g., US. Pat. No. 020).

Maytansinoids to include maytansine, maytansinol, C—3 esters of maytansinol, and othermaytansinol analogues and derivatives (see, e.g., US. Pat. Nos. 5,208,020 and 6,441,163, each ofwhich is orated by reference herein). C—3 esters of maytansinol can be lly occurring orsynthetically derived. Moreover, both naturally occurring and synthetic C—3 maytansinol esters can beclassified as a C—3 ester with simple carboxylic acids, or a C-3 ester with derivatives of N-methyl-L-e, the latter being more cytotoxic than the former. Synthetic maytansinoid analogues aredescribed in, for example, n er al., J. Med. Chem., 21, 31-37 (1978).

Suitable maytansinoids for use in ADCs of the ion can be isolated from natural sources,synthetically produced, or semi-synthetically produced. Moreover, the maytansinoid can be modifiedin any suitable manner, so long as ient cytotoxicity is preserved in the ultimate conjugatemolecule. In this regard, maytansinoids lack suitable functional groups to which antibodies can belinked. A linking moiety desirably is utilized to link the maytansinoid to the antibody to form theate, and is described in more detail in the linker section below. The structure of an arymaytansinoid, mertansine (DMl), is provided below.

Mertansine (DM 1)Representative examples of maytansinoids include, but are not limited, to DMl (N2'-deacetyl-N2'-(3-mercapto-l-oxopropyl)-maytansine; also referred to as mertansine, drug maytansinoid l;MEl 24985843v.1 389117813-12620ImmunoGen, Inc.; see also Chari er al. (1992) Cancer Res ), DM2, DM3 (N2'-deacetyl-N2'-(4-mercapto- l -oxopentyl)-maytansine), DM4 (4-methylmercapto- l -oxopentyl)-maytansine), andmaytansinol (a synthetic maytansinoid analog). Other examples of maytansinoids are described in USPatent No. 784, incorporated by reference .

Ansamitocins are a group of maytansinoid antibiotics that have been isolated from variousbacterial sources. These compounds have potent mor activities. Representative examplesinclude, but are not limited to ansamitocin Pl, ansamitocin P2, ansamitocin P3, and ansamitocin P4.

In one embodiment of the ion, an anti-B7-H3 antibody is conjugated to at least oneDMl. In one embodiment, an anti-B7-H3 dy is conjugated to at least one DM2. In oneembodiment, an anti-B7-H3 antibody is conjugated to at least one DM3. In one ment, an anti-B7-H3 antibody is conjugated to at least one DM4.d. Plant AlkaloidsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one plant alkaloid,e.g., a taxane or vinca alkaloid. Plant alkaloids are chemotherapy treatments derived made fromcertain types of plants. The vinca ids are made from the periwinkle plant ranthus rosea),whereas the taxanes are made from the bark of the Pacific Yew tree (taxus). Both the vinca alkaloidsand taxanes are also known as antimicrotubule agents, and are bed in more detail below.

TaxanesAnti-B7-H3 antibodies described herein may be conjugated to at least one taxane. The term“taxane” as used herein refers to the class of antineoplastic agents having a mechanism of microtubuleaction and having a structure that includes the taxane ring structure and a stereospecific side chain thatis required for cytostatic activity. Also ed within the term “taxane” are a variety of knowntives, ing both hydrophilic derivatives, and hydrophobic derivatives. Taxane derivativesinclude, but not limited to, galactose and mannose derivatives described in International PatentApplication No. WO 99/18113; zino and other derivatives described in W0 99/14209; taxanetives described in WO 21, WO 98/22451, and US. Pat. No. 5,869,680; 6-thio derivativesdescribed in WO 98/28288; sulfenamide derivatives described in US. Pat. No. 5,821,263; and taxolderivative described in US. Pat. No. 5,415,869, each of which is incorporated by reference herein.

Taxane compounds have also previously been described in US. Pat. Nos. 803, 5,665,671,,380,751, 5,728,687, 5,415,869, 5,407,683, 5,399,363, 5,424,073, 5,157,049, 5,773,464, 5,821,263,,840,929, 4,814,470, 5,438,072, 5,403,858, 4,960,790, 5,433,364, 4,942,184, 5,362,831, 5,705,503,and 5,278,324, all of which are expressly orated by reference. Further examples of taxanesinclude, but are not limited to, docetaxel (Taxotere; Sanofi Aventis), paclitaxel (Abraxane or Taxol;Abraxis Oncology), carbazitaxel, xel, opaxio, larotaxel, taxoprexin, BMS-l 84476, hongdoushanA, hongdoushan B, and hongdoushan C, and nanoparticle paclitaxel (ABI-007 / Abraxene; AbraxisMEl 24985843V.l 390117813-12620Bioscience).

In one embodiment, the anti-B7-H3 antibody of the invention is conjugated to at least onedocetaxel molecule. In one ment, the anti-B7-H3 antibody of the ion is ated to atleast one paclitaxel le.

Vinca alkaloidsIn one embodiment, the anti-B7-H3 antibody is conjugated to at least one vinca alkaloid.

Vinca alkaloids are a class of cell-cycle-specific drugs that work by ting the ability of cancercells to divide by acting upon tubulin and preventing the formation of microtubules. Examples ofvinca alkaloids that may be used in the ADCs of the ion include, but are not limited to,vindesine sulfate, vincristine, vinblastine, and vinorelbine.2. Antimmor AntibioticsAnti-B7-H3 antibodies of the invention may be conjugated to one or more antitumorantibiotic(s) for the treatment of . As used herein, the term “antitumor antibiotic” means anantineoplastic drug that blocks cell growth by interfering with DNA and is made from amicroorganism. Often, antitumor antibiotics either break up DNA strands or slow down or stop DNAsynthesis. Examples of antitumor otics that may be included in the anti-B7-H3 ADCs of theinvention include, but are not d to, mycines (e.g., pyrrolo[2,l-c][l,4]benzodiazepines),anthracyclines, calicheamicins, and duocarmycins, described in more detail below.a. ActinomycinsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one actinomycin.

Actinomycins are a subclass of antitumor antibiotics isolated from bacteria of the genus Streptomyces.

Representative es actinomycins include, but are not limited to, actinomycin D (Cosmegen[also known as actinomycin, dactinomycin, actinomycin IV, actinomycin Cl], Lundbeck, Inc.),anthramycin, ycin A, DC-8l, mazethramycin, neothramycin A, neothramycin B,porothramycin, prothracarcin B, SG2285, sibanomicin, sibiromycin, and tomaymycin. In oneembodiment, the anti-B7-H3 antibody of the invention is conjugated to at least onepyrrolobenzodiazepine (PBD). Examples of PBDs include, but are not limited to, anthramycin,chicamycin A, DC-8l, mazethramycin, neothramycin A, neothramycin B, porothramycin,prothracarcin B, SG2000 (SJG-l36), SG2202 (ZC-207), SG2285 (ZC-423), sibanomicin, sibiromycinand tomaymycin. Thus, in one embodiment, anti-B7-H3 antibodies of the invention are ated toat least one actinomycin, e.g., actinomycin D, or at least one PBD, e.g., a pyrrolobenzodiazepine(PBD) dimer.

The structures of PBDs can be found, for example, in US. Patent Application Pub. Nos.2013/0028917 and 2013/0028919, and inMEl 24985843V.1 391117813-12620by reference in their entirety. The c structure of a PBD is provided below.

PBDs differ in the number, type and position of substituents, in both their aromatic A rings andpyrrolo C rings, and in the degree of tion of the C ring. In the B-ring, there is generally animine (N=C), a carbinolamine (NH-CH(OH)), or a carbinolamine methyl ether (NH-CH(OMe)) at the1 position which is the electrophilic center sible for alkylating DNA. All of the knownnatural products have an (S)-configuration at the chiral C110t position which provides them with aright-handed twist when viewed from the C ring s the A ring. The PBD examples providedherein may be conjugated to the anti-B7-H3 antibodies of the invention. Further examples of PBDswhich may be conjugated to the anti-B7-H3 antibodies of the invention can be found, for example, inUS. Patent ation Publication Nos. 2013/0028917 A1 and 2013/0028919 A1, in US. PatentNos. 7,741,319 B2 and inincorporated herein by reference in their entirety.

A representative PBD dimer having the following formula XXX may be conjugated to theanti-B7-H3 antibodies of the invention:R33 R33 R34\ R35YX' YX N\RXXX/ HR32 R32 NO R31' R31 20 0(XXX)wherein:R30 is of formula XXXE:Q Q (XXXI)MEl 24985843V.1 392117813-12620where A is 3 (75,7 aryl group, X is a group conjugated to the Linker unit selected from the groupconsisting of ------O------ , -------S------ ------C(O‘h.)------- ------C(D) ------ ------NiltCEQ)------ and -------NtRN)------- wherein RN is, , , , ,selected from the group consisting of H, CM alkyl and (CZH4O)“,CH3, where s is l to 3, and either:(i) Q1 is a single bond, and Q2 is selected from the group consisting of a single bond and —Z(:C}{g,:)n-—, where Z is selected from the group consisting of a single bond, 0, S and NH and n is froml to 3; or(it) of is ———————(SPEECH...... and oz is a, single bond;R130 is a (15:13 aryl group, optionally substituted by one or more tuents selected from thegroup consisting of halo, nitro, cyano, CH3, alltoxy, (23,20heteroeyclonlkoxy, CH) aryloxy,heteroaryloxy, allrylalkoxy, arylalltoxy, alkylaryloxy, heteronrylalkoxy, alltylheteroaryloxy, CH alkyl,(13,7 heterocyclyl and bis—oxy~(‘,1,3 allrylene;R3 I and R33 are independently selected from the group consisting of H, R", OR, OR“, SH, SEX,Nl-lg, NHR", NRXRH’, nitro, MegSn and halo;where R and R’ are independently selected from the group consisting of optionally substituted.

CH2 alkyl, (13,29. heterocyclyl and (15,29. aryl groups;Rszis selected from the group consisting of ll, Rx, Oil, ORX, Silt SR", NR2, NHR“, NHRXRX",nitro, Me3Sn and halo;either:(a) Rmis H, and R“ is GB, GR”, where R"A is CH alkyl;(b) R34 and R35 form a nitrogei'i—carhon double bond between the nitrogen and carbon atoms towhich they are bound; or(e) R34is H and R35is SOZM, where z is 2 or 3;R” is a C3,]; alkylene group, which chain may be interrupted by one or more atoms,selected from the group consisting of O, S, NH, and an aromatic ring;Y“ and Yx’ are is selected from the group consisting of O, S, and NH;R31, R32], R“3 are selected from the same groups as R31, R32 and R“3 respectively and R34. andR35. are the same as R34 and R35, and each M is a lent pharinaceutically able cation orboth M groups together are a nt pharmaceutically able cation.

C142 alkyl: The term “C142 alkyl” as used herein, pertains to a monovalent moiety obtained byremoving a hydrogen atom from a carbon atom of a hydrocarbon compound having from 1 to 12carbon atoms, which may be tic or alicyclic, and which may be saturated or unsaturated (e. g.partially unsaturated, fully unsaturated). Thus, the term “alkyl” includes the sub-classes l,alkynyl, cycloalkyl, etc., discussed below.es of saturated alkyl groups include, but are not limited to, methyl (C1), ethyl (C2),propyl (C3), butyl (C4), pentyl (C5), hexyl (C6) and heptyl (C7).

Examples of ted linear alkyl groups include, but are not limited to, methyl (C1), ethyl(C2), yl (C3), n-butyl (C4), n-pentyl (amyl) (C5), n-hexyl (C6) and n-heptyl (C7).

MEI 24985843V.1 393117813-12620Examples of ted ed alkyl groups include iso-propyl (C3), iso-butyl (C4), sec-butyl(C4), utyl (C4), iso-pentyl (C5), and neo-pentyl (C5).

C320 heterocyclyl: The term “C320 heterocyclyl” as used herein, pertains to a monovalentmoiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, whichmoiety has from 3 to 20 ring atoms, of which from 1 to 10 are ring heteroatoms. Preferably, each ringhas from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms.

In this context, the prefixes (e. g. C320, C34, C56, etc.) denote the number of ring atoms, orrange of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term “C5,6heterocyclyl”, as used herein, pertains to a cyclyl group having 5 or 6 ring atoms.

Examples of monocyclic heterocyclyl groups include, but are not limited to, those derivedfrom:N1: aziridine (C3), azetidine (C4), pyrrolidine hydropyrrole) (C5), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C5), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C5), dine(C6), dihydropyridine (C6), tetrahydropyridine (C6), azepine (C7); 01: oxirane (C3), e (C4),oxolane (tetrahydrofuran) (C5), oxole (dihydrofuran) (C5), oxane (tetrahydropyran) (C6), dihydropyran(C6), pyran (C6), oxepin (C7); 81: thiirane (C3), thietane (C4), thiolane (tetrahydrothiophene) (C5),thiane (tetrahydrothiopyran) (C6), thiepane (C7); 02: dioxolane (C5), dioxane (C6), and dioxepane (C7);03: trioxane (C6); N2: imidazolidine (C5), pyrazolidine lidine) (C5), imidazoline (C5), pyrazoline(dihydropyrazole) (C5), piperazine (C6); N101: tetrahydrooxazole (C5), dihydrooxazole (C5),tetrahydroisoxazole (C5), oisoxazole (C5), morpholine (C6), tetrahydrooxazine (C6),dihydrooxazine (C6), oxazine (C6); N181: thiazoline (C5), thiazolidine (C5), thiomorpholine (C6); N201:oxadiazine (C6); 0181: oxathiole (C5) and ane (thioxane) (C6); and, N10181: oxathiazine (C6).

Examples of substituted clic heterocyclyl groups include those derived fromsaccharides, in cyclic form, for example, furanoses (C5), such as arabinofuranose, lyxofuranose,ranose, and xylofuranse, and pyranoses (C6), such as allopyranose, altropyranose,glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

C520 aryl: The term “C520 aryl”, as used herein, pertains to a monovalent moiety obtained byremoving a hydrogen atom from an aromatic ring atom of an aromatic compound, which moiety hasfrom 3 to 20 ring atoms. ably, each ring has from 5 to 7 ring atoms.

In this context, the prefixes (e.g. C320, C57, C56, etc.) denote the number of ring atoms, orrange of number of ring atoms, whether carbon atoms or heteroatoms. For e, the term "C56aryl" as used herein, pertains to an aryl group having 5 or 6 ring atoms.

In one embodiment, the anti-B7-H3 antibodies of the invention may be conjugated to a PBDdimer having the following formula XXXIa:MEl 24985843V.1 394117813-12620O\/\/O \ HOCH3 H3CO N(XXXIa)wherein the above structure describes the PBD dimer SG2202 (ZC-207) and is conjugated to the anti-B7-H3 antibody of the invention via a linker L. SG2202 (ZC-207) is disclosed in, for example, U.S.

Patent App. Pub. No. 2007/0173497, which is incorporated herein by reference in its entirety.

In another embodiment, a PBD dimer, SGD-1882, is conjugated to 7-H3 antibody ofthe invention via a drug linker, as depicted in Figure 4. SGD-l882 is disclosed in Sutherland er al.(2013) Blood 122(8):l455 and in U.S Patent App. Pub. No. 2013/0028919, which is incorporatedherein by reference in its entirety. As described in Figure 4, the PBD dimer 82 may beconjugated to an antibody via an mc-val-ala-dipeptide linker (collectively ed to as SGD-l910 inFigure 4). In a n ment, an anti-B7-H3 antibody, as sed herein, is conjugated to thePBD dimer described in Figure 4. Thus, in a further ment, the invention includes an anti-B7-H3 antibody, as disclosed , conjugated to a PBD dimer via a mc-val-ala-dipeptide linker, asdescribed in Figure 4. In certain ments, the invention includes an anti-B7-H3 antibodycomprising a heavy chain variable region comprising a CDR3 domain comprising the amino acidsequence of SEQ ID NO: 35, a CDR2 domain comprising the amino acid ce of SEQ ID NO:34, and a CDRl domain comprising the amino acid sequence of SEQ ID NO: 33, and a light chainvariable region comprising a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 39, aCDR2 domain comprising the amino acid sequence of SEQ ID NO: 38, and a CDRl domainsing the amino acid sequence of SEQ ID NO: 37, conjugated to a PBD, including, but notlimited to, the PBD dimer described in Figure 4. In certain embodiments, the invention includes ananti-B7-H3 antibody comprising a heavy chain variable region comprising a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprising the amino acidsequence of SEQ ID NO: 140, and a CDRl domain comprising the amino acid ce of SEQ IDNO: 10, and a light chain variable region comprising a CDR3 domain comprising the amino acidsequence of SEQ ID NO: 15, a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 7,and a CDRl domain comprising the amino acid sequence of SEQ ID NO: 136, ated to a PBD,including, but not limited to, the PBD dimer described in Figure 4. In certain embodiments, theinvention includes an anti-B7-H3 antibody comprising a heavy chain variable region comprising aCDR3 domain comprising the amino acid sequence of SEQ ID NO: 12, a CDR2 domain comprisingthe amino acid sequence of SEQ ID NO: 140, and a CDRl domain comprising the amino acidMEl 24985843V.1 395117813-12620sequence of SEQ ID NO: 10, and a light chain variable region comprising a CDR3 domaincomprising the amino acid sequence of SEQ ID NO: 15, a CDR2 domain comprising the amino acidsequence of SEQ ID NO: 7, and a CDR1 domain comprising the amino acid sequence of SEQ ID NO:138, conjugated to a PBD, including, but not limited to, the PBD dimer described in Figure 4. Incertain embodiments, the invention includes an anti-B7-H3 dy comprising the heavy chainvariable region of huAb13V1 as defined by the amino acid sequence set forth in SEQ ID NO: 147, orhuAb3V2.5 or huAb3v2.6 as d by the amino acid ce set forth in SEQ ID NO: 139,and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 144, 135, or137 corresponding to huAb13V 1, huAb3v2.5, or huAb3v2.6, respectively, n the antibody isconjugated to a PBD, such as, but not limited to, the exemplary PBD dimer of Figure 4.b. cyclinesAnti-B7-H3 antibodies of the invention may be conjugated to at least one anthracycline.

Anthracyclines are a subclass of antitumor antibiotics isolated from bacteria of the genusStreptomyces. Representative examples include, but are not limited to daunorubicin (Cerubidine,Bedford Laboratories), doxorubicin (Adriamycin, Bedford tories; also referred to asdoxorubicin hydrochloride, hydroxydaunorubicin, and Rubex), epirubicin (Ellence, Pfizer), andidarubicin (Idamycin; Pfizer Inc.). Thus, in one embodiment, the anti-B7-H3 antibody of the inventionis conjugated to at least one anthracycline, e. g., doxorubicin.c. eamicinsThe anti-B7-H3 dies of the invention may be conjugated to at least one calicheamicin.

Calicheamicins are a family of enediyne antibiotics derived from the soil organism Micromonosporaechinospora. Calicheamicins bind the minor groove of DNA and induce double-stranded DNAbreaks, resulting in cell death with a 100 fold increase over other chemotherapeutics (Damle er al.(2003) Curr Opin Pharmacol 3:386). Preparation of calicheamicins that may be used as drugates in the invention have been described, see US. Pat. Nos. 5,712,374; 5,714,586; 5,739,116;,767,285; 5,770,701; 5,770,710; 5,773,001; and 5,877,296. Structural analogues of calicheamicinwhich may be used e, but are not limited to, 3211, (12], (x31, N-acetyl-y11, PSAG and 011 (Hinman etal., Cancer Research 53:3336-3342 , Lode er al., Cancer Research 58:2925-2928 (1998) andthe aforementioned US. Patent Nos. 5,712,374; 586; 5,739,116; 5,767,285; 5,770,701;710; 5,773,001; and 5,877,296). Thus, in one embodiment, the anti-B7-H3 antibody of theinvention is conjugated to at least one calicheamicin.

MEl 24985843V.1 396-12620d. DaocarmycinsAnti-B7-H3 antibodies of the invention may be conjugated to at least one duocarmycin.

Duocarmycins are a subclass of antitumor otics isolated from bacteria of the genusomyces. (see Nagamura and Saito (1998) Chemistry of Heterocyclic Compounds, Vol. 34, No.12). Duocarmycins bind to the minor groove of DNA and alkylate the nucleobase adenine at the N3position (Boger (1993) Pure and Appl Chem 65(6): 1 123; and Boger and Johnson (1995) PNAS USA9223642). Synthetic analogs of duocarmycins include, but are not limited to, adozelesin, bizelesin,and carzelesin. Thus, in one embodiment, the anti-B7-H3 antibody of the invention is conjugated toat least one duocarmycin.e. Other antitumor antibioticsIn on to the foregoing, onal antitumor antibiotics that may be used in the anti-B7-H3 ADCs of the invention include bleomycin (Blenoxane, Bristol-Myers Squibb), mitomycin, andplicamycin (also known as mithramycin).3. Immanomodalating AgentsIn one , anti-B7-H3 antibodies of the invention may be conjugated to at least oneimmunomodulating agent. As used herein, the term “immunomodulating agent” refers to an agentthat can stimulate or modify an immune response. In one embodiment, an immunomodulating agentis an immunostimulator that enhances a subject’s immune response. In another embodiment, animmunomodulating agent is an immunosuppressant that prevents or decreases a subject’s immuneresponse. An immunomodulating agent may modulate myeloid cells ytes, macrophages,dendritic cells, megakaryocytes and granulocytes) or lymphoid cells (T cells, B cells and natural killer(NK) cells) and any further differentiated cell f. Representative examples include, but are notlimited to, us calmette-guerin (BCG) and sole (Ergamisol). Other examples ofimmunomodulating agents that may be used in the ADCs of the invention include, but are not limitedto, cancer vaccines, cytokines, and immunomodulating gene therapy.a. Cancer vaccinesAnti-B7-H3 dies of the invention may be conjugated to a cancer vaccine. As used, the term “cancer vaccine” refers to a composition (e. g., a tumor antigen and a cytokine) thatelicits a tumor-specific immune response. The response is ed from the subject's own immunesystem by administering the cancer vaccine, or, in the case of the instant invention, administering anADC comprising an anti-B7-H3 antibody and a cancer vaccine. In preferred embodiments, theimmune response results in the eradication of tumor cells in the body (e. g., primary or metastatictumor cells). The use of cancer vaccines generally involves the administration of a particular antigenor group of antigens that are, for example, present on the surface a particular cancer cell, or present onMEl 24985843V.1 397117813-12620the surface of a particular ious agent shown to tate cancer ion. In someembodiments, the use of cancer vaccines is for prophylactic purposes, while in other embodiments,the use is for therapeutic purposes. Non-limiting examples of cancer vaccines that may be used in theanti-B7-H3 ADCs of the invention include, recombinant bivalent human papillomavirus (HPV)vaccine types 16 and 18 vaccine (Cervarix, mithKline), recombinant quadrivalent humanpapillomavirus (HPV) types 6, ll, 16, and 18 vaccine (Gardasil, Merck & Company), and sipuleucel-T (Provenge, on). Thus, in one embodiment, the anti-B7-H3 dy of the ion isconjugated to at least one cancer vaccine that is either an immunostimulator or is ansuppressant.b. CytokinesThe anti-B7-H3 antibodies of the invention may be ated to at least one ne. Theterm “cytokine” generally refers to proteins released by one cell population which act on another cellas intercellular mediators. Cytokines directly stimulate immune effector cells and stromal cells at thetumor site and enhance tumor cell recognition by cytotoxic effector cells (Lee and Margolin (2011)s 323856). Numerous animal tumor model studies have demonstrated that cytokines havebroad anti-tumor activity and this has been translated into a number of cytokine-based approaches forcancer y (Lee and Margoli, supra). Recent years have seen a number of cytokines, includingGM-CSF, IL-7, IL-12, IL-15, IL-18 and IL-21, enter clinical trials for patients with advanced cancer(Lee and Margoli, supra).

Examples of cytokines that may be used in the ADCs of the invention include, but are notlimited to, parathyroid hormone; thyroxine; insulin; proinsulin; relaxin; prorelaxin; glycoproteinhormones such as le stimulating hormone (FSH), thyroid ating hormone (TSH), andluteinizing hormone (LH); hepatic growth factor; fibroblast growth factor; prolactin; placentallactogen; tumor necrosis ; mullerian-inhibiting substance; mouse gonadotropin-associatedpeptide; inhibin; activin; vascular endothelial growth factor; integrin; thrombopoietin (TPO); nervegrowth factors such as NGF; platelet-growth factor; transforming growth factors (TGFs); insulin-likegrowth -1 and -II; erythropoietin (EPO); osteoinductive s; interferons such as interferon 0t,B,and y, colony stimulating factors (CSFs); granulocyte-macrophage-C-SF (GM-CSF); andgranulocyte-CSF (G-CSF); interleukins (ILs) such as IL-1, IL-loc, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7,IL-8, IL-9, IL-1 1, IL-12; tumor necrosis factor; and other polypeptide factors including LIF and kitligand (KL). As used herein, the term cytokine includes proteins from natural sources or fromrecombinant cell culture and biologically active equivalents of the native sequence cytokines. Thus,in one embodiment, the invention provides an ADC comprising an anti-B7-H3 antibody describedherein and a cytokine.

MEl 24985843V.1 398117813-12620c. Colony-stimulatingfactors (CSFs)The anti-B7-H3 antibodies of the invention may be conjugated to at least one colonystimulating factor (CSF). Colony stimulating s (CSFs) are growth s that assist the bonemarrow in making white blood cells. Some cancer treatments (e. g., chemotherapy) can affect whiteblood cells (which help fight infection); therefore, colony-stimulating factors may be introduced tohelp t white blood cell levels and then the immune system. Colony-stimulating factorsmay also be used following a bone marrow transplant to help the new marrow start producing whiteblood cells. Representative examples of CSFs that may be used in the anti-B7-H3 ADCs of theinvention e, but are not limited to erythropoietin (Epoetin), filgrastim (Neopogen (also knownas granulocyte colony-stimulating factor (G-CSF); Amgen, Inc.), sargramostim (leukine (granulocyte-macrophage colony-stimulating factor and GM-CSF); Genzyme Corporation), promegapoietin, andOprelvekin (recombinant IL-1 1; Pfizer, Inc.). Thus, in one embodiment, the invention provides anADC comprising an anti-B7-H3 antibody bed herein and a CSF.4. Gene yThe anti-B7-H3 antibody of the invention may be conjugated to at least one c acid(directly or indirectly via a carrier) for gene therapy. Gene therapy generally refers to the introductionof genetic material into a cell whereby the genetic material is designed to treat a disease. As itpertains to immunomodulatory agents, gene therapy is used to stimulate a subject's natural ability toinhibit cancer cell proliferation or kill cancer cells. In one embodiment, the anti-B7-H3 ADC of theinvention comprises a nucleic acid encoding a functional, therapeutic gene that is used to replace amutated or otherwise dysfunctional (e. g. truncated) gene associated with . In otherembodiments, the anti-B7-H3 ADC of the invention comprises a nucleic acid that encodes for orotherwise provides for the production of a therapeutic protein to treat . The nucleic acid thatencodes the therapeutic gene may be directly conjugated to the anti-B7-H3 antibody, or alternatively,may be conjugated to the anti-B7-H3 antibody through a carrier. Examples of carriers that may beused to deliver a nucleic acid for gene therapy include, but are not limited to, viral s or5. Alkylating AgentsThe anti-B7-H3 dies of the invention may be conjugated to one or more alkylatingagent(s). Alkylating agents are a class of antineoplastic nds that attaches an alkyl group toDNA. Examples of alkylating agents that may be used in the ADCs of the invention include, but arenot limited to, alkyl sulfonates, nimimes, methylamine derivatives, epoxides, nitrogen mustards,nitrosoureas, triazines, and ines.

MEl 24985843V.1 399117813-12620a. Alkyl SulfonatesThe anti-B7-H3 antibodies of the invention may be ated to at least one alkyl sulfonate.

Alkyl sulfonates are a subclass of alkylating agents with a general formula: O-Rl, n Rand R1 are typically alkyl or aryl groups. A representative example of an alkyl sulfonate includes, butis not limited to, busulfan (Myleran, mithKline; Busulfex IV, PDL BioPharma, Inc.).19. Nitrogen MustardsThe anti-B7-H3 antibodies of the invention may be ated to at least one nitrogenmustard. Representative es of this subclass of anti-cancer compounds include, but are notlimited to chlorambucil (Leukeran, GlaxoSmithKline), cyclophosphamide (Cytoxan, Bristol-MyersSquibb; Neosar, Pfizer, Inc.), estramustine (estramustine phosphate sodium or Estracyt), Pfizer, Inc.),ifosfamide (Ifex, Bristol-Myers Squibb), mechlorethamine (Mustargen, Lundbeck Inc.), andmelphalan (Alkeran or L-Pam or phenylalanine mustard; GlaxoSmithKline).c. NitrosoureasThe anti-B7-H3 antibody of the invention may be conjugated to at least one nitrosourea.oureas are a subclass of alkylating agents that are lipid soluble. Representative examplese, but are not limited to, carmustine (BCNU [also known as BiCNU, N,N—Bis(2-chloroethyl)-N-nitrosourea, or 1, 3-bis (2-chloroethyl)-l-nitrosourea], Bristol-Myers Squibb), fotemustine (alsoknown as Muphoran), lomustine (CCNU or l-(2-chloro-ethyl)cyclohexyl-l-nitrosourea, Bristol-Myers Squibb), nimustine (also known as ACNU), and streptozocin (Zanosar, Teva Pharmaceuticals).d. Triazines and HydrazinesThe anti-B7-H3 antibody of the invention may be conjugated to at least one triazine orhydrazine. Triazines and hydrazines are a subclass of nitrogen-containing alkylating agents. In someembodiments, these compounds spontaneously decompose or can be lized to produce alkyldiazonium intermediates that facilitate the transfer of an alkyl group to nucleic acids, es, and/orpolypeptides, thereby causing mutagenic, carcinogenic, or xic effects. Representative examplesinclude, but are not limited to dacarbazine (DTIC-Dome, Bayer Healthcare Pharmaceuticals Inc.),procarbazine (Mutalane, Sigma-Tau Pharmaceuticals, Inc.), and temozolomide ar, Scheringe. Other Alkylating AgentsThe anti-B7-H3 dies of the invention may be conjugated to at least one ethylenimine,methylamine derivative, or epoxide. Ethylenimines are a subclass of alkylating agents that typicallycontaining at least one ine ring. Epoxides represent a ss of alkylating agents that arecharacterized as cyclic ethers with only three ring atoms.

MEl 24985843V.1 400117813-12620Representatives examples of nimines include, but are not limited to thiopeta (Thioplex,Amgen), diaziquone (also known as aziridinyl benzoquinone (AZQ)), and mitomycin C. MitomycinC is a natural product that contains an aziridine ring and appears to induce cytoxicity through cross-linking DNA (Dorr RT, et al. Cancer Res. 1985;45:3510; Kennedy KA, et al Cancer Res.1985;45:3541). Representative es of methylamine derivatives and their analogs include, butare not d to, altretamine (Hexalen, MGI , Inc.), which is also known as hexamethylamineand at. Representative examples of epoxides of this class of anti-cancer compound include, butare not limited to dianhydrogalactitol. Dianhydrogalactitol (l,2:5,6-dianhydrodulcitol) is chemicallyrelated to the aziridines and generally facilitate the er of an alkyl group through a similarism as described above. Dibromodulcitol is hydrolyzed to dianhydrogalactitol and thus is apro-drug to an epoxide (Sellei C, et al. Cancer Chemother Rep. 1969;53:377).6. Antiangiogenic AgentsIn one aspect, the 7-H3 antibodies described herein are conjugated to at least oneantiangiogenic agent. giogenic agents inhibit the growth of new blood vessels. Antiangiogenicagents exert their s in a variety of ways. In some embodiments, these agents ere with theability of a growth factor to reach its target. For example, vascular endothelial growth factor (VEGF)is one of the primary proteins involved in initiating angiogenesis by binding to particular receptors ona cell surface. Thus, n antiangiogenic , that prevent the interaction of VEGF with itscognate receptor, prevent VEGF from initiating angiogenesis. In other embodiments, these agentsinterfere with intracellular signaling es. For example, once a particular receptor on a cellsurface has been triggered, a cascade of other chemical signals is initiated to promote the growth ofblood vessels. Thus, certain enzymes, for example, some tyrosine kinases, that are known to facilitateintracellular signaling cascades that contribute to, for example, cell proliferation, are targets for cancerent. In other embodiments, these agents interfere with intercellular signaling cascades. Yet, inother ments, these agents e specific targets that activate and promote cell growth or bydirectly interfering with the growth of blood vessel cells. Angiogenesis inhibitory properties havebeen discovered in more than 300 substances with numerous direct and indirect inhibitory effects.entative examples of antiangiogenic agents that may be used in the ADCs of theinvention include, but are not limited to, angiostatin, ABX EGF, Cl-1033, PKI-l66, EGF vaccine,EKB-569, GW2016, ICR-62, EMD 55900, CP358, PD153035, AGl478, IMC-C225 (Erbitux,ZDl839 (Iressa), OSI-774, Erlotinib (tarceva), angiostatin, arrestin, endostatin, BAY 12-9566 andw/fluorouracil or doxorubicin, canstatin, carboxyamidotriozole and with paclitaxel, EMD121974, S-24, vitaxin, dimethylxanthenone acetic acid, IM862, Interleukin-l2, Interleukin-2, NM-3, HuMV833,PTK787, RhuMab, angiozyme (ribozyme), IMC-lCl l, Neovastat, marimstat, prinomastat, BMS-275291,COL-3, , SUlOl, SU6668, SU11248, SU54l6, with paclitaxel, with gemcitabine andcisplatin, and with irinotecan and tin and with radiation, tecogalan, temozolomide and PEGMEl 24985843V.1 401117813-12620interferon (12b, tetrathiomolybdate, TNP-470, thalidomide, CC-5013 and with taxotere, tumstatin, 2-methoxyestradiol, VEGF trap, mTOR inhibitors (deforolimus, everolimus (Afinitor, NovartisPharmaceutical Corporation), and temsirolimus (Torisel, Pfizer, Inc.)), kinase inhibitors (e.g.,erlotinib va, Genentech, Inc.), imatinib (Gleevec, Novartis Pharmaceutical ation),nib (Iressa, AstraZeneca Pharmaceuticals), dasatinib (Sprycel, Brystol-Myers Squibb), sunitinibt, Pfizer, Inc.), nilotinib (Tasigna, Novartis Pharmaceutical Corporation), lapatinib (Tykerb,GlaxoSmithKline ceuticals), sorafenib (Nexavar, Bayer and Onyx), phosphoinositide 3-kinases (PI3K), Osimertinib, Cobimetinib, Trametinib, Dabrafenib, Dinaciclib).7. AntimetabolitesThe anti-B7-H3 antibodies of the invention may be conjugated to at least one antimetabolite.

Antimetabolites are types of chemotherapy treatments that are very similar to normal substanceswithin the cell. When the cells incorporate an antimetabolite into the cellular metabolism, the result isnegative for the cell, 6. g., the cell is unable to divide. Antimetabolites are classified according to thesubstances with which they interfere. Examples of tabolites that may be used in the ADCs ofthe invention include, but are not d to, a folic acid antagonist (e.g., rexate), a pyrimidineantagonist (e. g., 5-Fluorouracil, Foxuridine, Cytarabine, Capecitabine, and abine), a purineantagonist (e. g., aptopurine and 6-Thioguanine) and an adenosine deaminase inhibitor (6. g.,Cladribine, abine, Nelarabine and Pentostatin), as described in more detail below.a. AntifolatesThe anti-B7-H3 antibodies of the invention may be ated to at least one antifolate.

Antifolates are a ss of antimetabolites that are structurally similar to folate. Representativeexamples include, but are not d to, methotrexate, 4-amino-folic acid (also known as aminopterinand 4-aminopteroic acid), lometrexol (LMTX), pemetrexed (Alimpta, Eli Lilly and Company), andtrimetrexate (Neutrexin, Ben Venue Laboratories, Inc.)19. Purine AntagonistsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one purineantagonist. Purine analogs are a subclass of antimetabolites that are structurally similar to the groupof compounds known as purines. Representative examples of purine antagonists include, but are notlimited to, azathioprine (Azasan, Salix; Imuran, GlaxoSmithKline), cladribine (Leustatin [also knownas 2-CdA], Janssen Biotech, Inc.), mercaptopurine ethol [also known as 6-mercaptoethanol],GlaxoSmithKline), fludarabine (Fludara, Genzyme ation), pentostatin (Nipent, also known asxycoformycin (DCF)), 6-thioguanine (Lanvis [also known as thioguanine], GlaxoSmithKline).

MEl 24985843V.1 402117813-12620c. Pyrimidine AntagonistsThe anti-B7-H3 antibodies of the invention may be ated to at least one pyrimidineantagonist. Pyrimidine antagonists are a subclass of antimetabolites that are structurally similar to thegroup of compounds known as purines. Representative examples of pyrimidine antagonists include,but are not d to azacitidine (Vidaza, Celgene ation), capecitabine (Xeloda, RocheLaboratories), bine (also known as cytosine arabinoside and arabinosylcytosine, Bedfordtories), decitabine (Dacogen, Eisai Pharmaceuticals), 5-fluorouracil (Adrucil, TevaPharmaceuticals; Efudex, Valeant Pharmaceuticals, Inc), 5-fluoro-2’-deoxyuridine 5’-phosphate(FdUMP), 5-fluorouridine triphosphate, and gemcitabine (Gemzar, Eli Lilly and Company).8. Boron-Containing AgentsThe anti-B7-H3 antibody of the invention may be conjugated to at least one boron containingagent. Boron-containing agents comprise a class of cancer therapeutic compounds which interferewith cell proliferation. Representative examples of boron containing agents include, but are notlimited, to borophycin and bortezomib (Velcade, Millenium Pharmaceuticals).9. Chemoprotective AgentsThe 7-H3 antibodies of the invention may be conjugated to at least onechemoprotective agent. Chemoprotective drugs are a class of compounds, which help protect thebody against specific toxic effects of herapy. Chemoprotective agents may be administeredwith various chemotherapies in order to protect healthy cells from the toxic effects of chemotherapydrugs, while simultaneously allowing the cancer cells to be treated with the steredchemotherapeutic. Representative chemoprotective agents e, but are not limited to amifostine(Ethyol, Medimmune, Inc.), which is used to reduce renal toxicity ated with cumulative dosesof cisplatin, dexrazoxane (Totect, Apricus Pharma; Zinecard), for the treatment of extravasationcaused by the administration of anthracycline (Totect), and for the treatment of cardiac-relatedcomplications caused by the administration of the antitumor antibiotic doxorubicin (Zinecard), andmesna (Mesnex, l-Myers Squibb), which is used to prevent hemorrhagic cystitis duringchemotherapy treatment with ifocfamide.

. Hormone agentsThe anti-B7-H3 dy of the invention may be conjugated to at least one hormone agent.

A hormone agent (including synthetic hormones) is a compound that eres with the production oractivity of endogenously produced hormones of the endocrine system. In some embodiments, thesecompounds interfere with cell growth or produce a cytotoxic effect. Non-limiting examples eandrogens, estrogens, medroxyprogesterone acetate ra, Pfizer, Inc.), and progestins.

MEl 24985843V.1 403117813-12620I I. Antihormone AgentsThe anti-B7-H3 dies of the invention may be ated to at least one antihormoneagent. An “antihormone” agent is an agent that suppresses the production of and/or prevents thefunction of n nous hormones. In one embodiment, the antihormone agent interferes withthe activity of a hormone selected from the group comprising androgens, estrogens, progesterone, andgoanadotropin-releasing hormone, thereby interfering with the growth of various cancer cells.

Representative examples of antihormone agents include, but are not limited to, aminoglutethimide,anastrozole (Arimidex, AstraZeneca Pharmaceuticals), bicalutamide (Casodex, AstraZenecaceuticals), cyproterone acetate (Cyprostat, Bayer PLC), degarelix (Firmagon, FerringPharmaceuticals), exemestane (Aromasin, Pfizer Inc.), de (Drogenil, Schering-Plough Ltd),fulvestrant (Faslodex, AstraZeneca Pharmaceuticals), goserelin (Zolodex, AstraZenecaceuticals), letrozole (Femara, Novartis Pharmaceuticals Corporation), leuprolide (Prostap),lupron, medroxyprogesterone acetate (Provera, Pfizer Inc.), Megestrol acetate e, Bristol-MyersSquibb Company), fen (Nolvadex, AstraZeneca Pharmaceuticals), and triptorelin (Decapetyl,Ferring) .12. CorticosteroidsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one corticosteroid.

Corticosteroids may be used in the ADCs of the ion to decrease inflammation. An example of acorticosteroid includes, but is not limited to, a orticoid, for example, prednisone sone,Pharmacia & Upjohn Company, a division of Pfizer, Inc.).13. Photoactive Therapeutic AgentsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one photoactivetherapeutic agent. Photoactive therapeutic agents include compounds that can be deployed to killtreated cells upon exposure to electromagnetic radiation of a particular wavelength. Therapeuticallyrelevant compounds absorb electromagnetic radiation at wavelengths which penetrate . Inpreferred embodiments, the compound is administered in a non-toxic form that is e ofproducing a photochemical effect that is toxic to cells or tissue upon sufficient activation. In otherpreferred embodiments, these compounds are retained by cancerous tissue and are readily clearedfrom normal tissues. miting examples include various chromagens and dyes.

I4. OligonucleotidesThe anti-B7-H3 antibodies of the invention may be conjugated to at least one oligonucleotide.

Oligonucleotides are made of short nucleic acid chains that work by interfering with the processing ofc information. In some embodiments, the ucleotides for use in ADCs are unmodifiedsingle-stranded and/or double-stranded DNA or RNA molecules, while in other embodiments, theseMEl 24985843V.1 404117813-12620therapeutic oligonucleotides are chemically-modified single-stranded and/or double-stranded DNA orRNA molecules. In one embodiment, the oligonulceotides used in the ADCs are relatively short (19—tides) and hybridize to a unique nucleic acid sequence in the total pool of nucleic acidtargets present in cells. Some of the important oligonucleotide technologies include the antisenseoligonucleotides (including RNA interference (RNAi)), aptamers, CpG oligonucleotides, andribozymes.a. Antisense oligonucleotidesThe anti-B7-H3 antibody of the ion may be conjugated to at least one antisenseoligonucleotide. Antisense ucleotides are designed to bind to RNA through Watson—Crickhybridization. In some embodiments the antisense oligonucleotide is mentary to a nucleotideencoding a , domain, portion, or segment of B7-H3. In some embodiments, the antisenseoligonucleotide comprises from about 5 to about 100 nucleotides, from about 10 to about 50nucleotides, from about 12 to about 35, and from about 18 to about 25 nucleotides. In someembodiments, the oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or at least 100% homologousto a region, n, domain, or segment of the B7-H3 gene. In some embodiments there is substantialsequence gy over at least 15, 20, 25, 30, 35, 40, 50, or 100 consecutive nucleotides of the B7-H3 gene. In preferred embodiments, the size of these antisense oligonucleotides ranges from 12 to 25nucleotides in length, with the majority of antisense oligonucleotides being 18 to 21 nucleotides inlength. There are le mechanisms that can be ted to inhibit the function of the RNA oncethe oligonucleotide binds to the target RNA (Crooke ST. (1999). Biochim. Biophys. Acta, 1489, 30—42). The best-characterized antisense mechanism results in cleavage of the targeted RNA byendogenous cellular ses, such as RNase H or the nuclease associated with the RNA interferencemechanism. However, oligonucleotides that inhibit expression of the target gene by non-catalyticmechanisms, such as modulation of splicing or translation arrest, can also be potent and selectivemodulators of gene function.

Another RNase-dependent antisense mechanism that has recently received much attention isRNAi (Fire et al. (1998). Nature, 391, 806—811.; Zamore PD. (2002). Science, 296, 1265—1269.).

RNA interference (RNAi) is a post-transcriptional process Where a double stranded RNA inhibitsgene expression in a sequence specific fashion. In some embodiments, the RNAi effect is achievedthrough the uction of relatively longer double-stranded RNA (dsRNA), while in preferredembodiments, this RNAi effect is achieved by the introduction of shorter double-stranded RNAs, e. g.small interfering RNA ) and/or microRNA (miRNA). In yet another embodiment, RNAi canalso be achieved by introducing of plasmid that generate dsRNA complementary to target gene. Ineach of the ing embodiments, the double-stranded RNA is designed to interfere with the geneexpression of a particular the target sequence within cells. Generally, the mechanism involvesMEl 24985843V.1 405117813-12620conversion of dsRNA into short RNAs that direct ribonucleases to homologous mRNA targets(summarized, Ruvkun, e 22942797 (2001)), which then degrades the ponding endogenousmRNA, thereby resulting in the modulation of gene expression. Notably, dsRNA has been reported tohave anti-proliferative properties, which makes it possible also to envisage therapeutic applications(Aubel et al., Proc. Natl. Acad. Sci., USA 882906 (1991)). For example, synthetic dsRNA has beenshown to inhibit tumor growth in mice (Levy et al. Proc. Nat. Acad. Sci. USA, 62:357-361 (1969)), isactive in the treatment of leukemic mice nick et al., Proc. Soc. Exp. Biol. Med. 130: 126-128(1969)), and inhibits chemically induced tumorigenesis in mouse skin (Gelboin et al., e167:205-207 (1970)). Thus, in a red ment, the ion provides for the use ofantisense oligonucleotides in ADCs for the treatment of breast cancer. In other embodiments, theinvention provides compositions and methods for initiating antisense oligonucleotide treatment,wherein dsRNA interferes with target cell expression of B7-H3 at the mRNA level. dsRNA, as usedabove, refers to lly-occurring RNA, partially purified RNA, recombinantly produced RNA,synthetic RNA, as well as altered RNA that differs from naturally-occurring RNA by the inclusion ofnon-standard nucleotides, non-nucleotide material, nucleotide analogs (e. g. locked nucleic acid(LNA)), ibonucleotides, and any combination thereof. RNA of the invention need only besufficiently similar to natural RNA that it has the ability to mediate the antisense oligonucleotide-based modulation described herein.[9. AptamersThe anti-B7-H3 antibodies of the invention may be conjugated to at least one aptamer. Anaptamer is a nucleic acid molecule that has been selected from random pools based on its ability tobind other les. Like antibodies, aptamers can bind target molecules with extraordinary affinityand specificity. In many embodiments, rs assume complex, sequence-dependent, three-dimensional shapes that allow them to interact with a target protein, resulting in a tightly boundx analogous to an antibody-antigen interaction, thereby interfering with the function of saidprotein. The particular capacity of aptamers to bind tightly and specifically to their target proteinunderlines their potential as targeted molecular therapies.c. CpG ucleotidesThe anti-B7-H3 antibodies of the ion may be conjugated to at least one CpGoligonucleotide. ial and viral DNA are known to be a strong activators of both the innate andspecific immunity in . These immunologic characteristics have been associated withunmethylated CpG dinucleotide motifs found in bacterial DNA. Owing to the fact that these motifsare rare in humans, the human immune system has evolved the ability to recognize these motifs as anearly indication of infection and subsequently initiate immune responses. Therefore, oligonucleotidescontaining this CpG motif can be exploited to initiate an antitumor immune se.

MEl 24985843V.1 406117813-12620d. RibozymesThe anti-B7-H3 antibody of the invention may be conjugated to at least one ribozyme.

Ribozymes are catalytic RNA molecules ranging from about 40 to 155 nucleotides in length. Theability of ribozymes to ize and cut specific RNA molecules makes them ial candidatesfor therapeutics. A representative example includes angiozyme.

I5. uclide Agents (Radioactive Isotopes)The anti-B7-H3 antibodies of the invention may be conjugated to at least one radionuclideagent. Radionuclide agents se agents that are characterized by an unstable nucleus that iscapable of undergoing radioactive decay. The basis for successful radionuclide ent depends onient tration and prolonged retention of the radionuclide by the cancer cell. Other factorsto consider include the radionuclide half-life, the energy of the emitted particles, and the maximumrange that the emitted particle can travel. In preferred embodiments, the therapeutic agent is aradionuclide selected from the group consisting of 111In, 177Lu, 212Bi, 213Bi, 211At, 62Cu, 64Cu, 67Cu, 90Y,125I, 131I, 32F, 33F, 47Sc, 111Ag, 67Ga, 142Pr, 153Sm, 161Tb, 166Dy, 166Ho, 186Re, 188Re, 189Re, me, 223Ra,225Ac, 59Fe, 75Se, 77As, 89Sr, 99Mo, 105Rh, 109Pd, 143Pr, 149Pm, 169Er, 194Ir, 198Au, 199Au, and 211Pb. Alsopreferred are radionuclides that substantially decay with Auger-emitting particles. For example, Co-58, Ga-67, Br-80m, , Rh-103m, Pt-109, In-l ll 1, Sb-l l9, I-125, , Os-l89m and Ir-192. Decay es of useful beta-particle-emitting nuclides are preferably Dy-152, At-2l l, Bi-212,Ra-223, Rn-219, Po-215, Bi-2l l, Ac-225, Fr-221, At-2l7, Bi-213 and Fm-255. Decay energies ofuseful alpha-particle-emitting radionuclides are preferably 2,000-10,000 keV, more preferably 3,000-8,000 keV, and most preferably 4,000-7,000 keV. Additional potential radioisotopes of use include11C, 13N, 150, 75Br, 198Au, 224Ac, 1261, 1331, 77Br, 113%, 95Ru, 97Ru, 103Ru, 105Ru, 107Hg, 203Hg,121mTe,mmTe, 125mTe, 165Tm, I67Tm, 168Tm, 197Pt, 109Pd, 105Rh, 142Pr, 143Pr, 161Tb, “Ho, 199Au, 57Co,58Co, 51Cr, 59Fe, 75Se, 201Tl,225Ac,76Br,169Yb, and the like.16. RadiosensitizersThe anti-B7-H3 antibodies of the invention may be conjugated to at least one ensitizer.

The term “radiosensitizer,” as used herein, is defined as a le, preferably a low molecularweight molecule, administered to animals in therapeutically effective s to increase thesensitivity of the cells to be radiosensitized to electromagnetic radiation and/or to promote thetreatment of diseases that are treatable with omagnetic radiation. Radiosensitizers are agentsthat make cancer cells more sensitive to radiation therapy, while typically having much less of aneffect on normal cells. Thus, the radiosensitizer can be used in combination with a radiolabeledantibody or ADC. The addition of the radiosensitizer can result in enhanced efficacy when comparedto treatment with the radiolabeled antibody or antibody fragment alone. Radiosensitizers areMEl 24985843V.1 407117813-12620described in D. M. rg (ed.), Cancer Therapy with Radiolabeled Antibodies, CRC Press (1995).

Examples of radiosensitizers include gemcitabine, 5-fluorouracil, taxane, and cisplatin.

Radiosensitizers may be activated by the omagnetic radiation of X-rays. Representativeexamples of X-ray activated radiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole, etanidazole, nimorazole,mitomycin C, RSU 1069, SR 4233, E09, RB 6145, nicotinamide, 5-bromodeoxyuridine , 5-iododeoxyuridine (IUdR), bromodeoxycytidine, fluorodeoxyuridine , hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same. Alternatively, radiosensitizers maybe ted using photodynamic therapy (PDT). Representative examples of photodynamicradiosensitizers include, but are not limited to, hematoporphyrin derivatives, Photofrin(r),benzoporphyrin derivatives, NPe6, tin etioporphyrin ), pheoborbide a, iochlorophyll a,naphthalocyanines, phthalocyanines, zinc phthalocyanine, and therapeutically effective analogs andderivatives of the same.16. Topoisomerase torsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one topoisomeraseinhibitor. Topoisomerase inhibitors are chemotherapy agents designed to interfere with the action oftopoisomerase enzymes (topoisomerase I and II), which are enzymes that control the s in DNAstructure by catalyzing then breaking and rejoining of the phosphodiester backbone of DNA strandsduring the normal cell cycle. Representative examples of DNA omerase I inhibitors include,but are not d to, camptothecins and its derivatives irinotecan (CPT-l l, Camptosar, Pfizer, Inc.)and topotecan (Hycamtin, GlaxoSmithKline Pharmaceuticals). Representative examples of DNAomerase II inhibitors include, but are not limited to, amsacrine, daunorubicin, doxotrubicin,epipodophyllotoxins, ellipticines, epirubicin, etoposide, razoxane, and teniposide.

I 7. Kinase InhibitorsThe anti-B7-H3 antibodies of the invention may be conjugated to at least one kinase inhibitor.

By blocking the ability of protein kinases to function, tumor growth may be inhibited. Examples ofkinase inhibitors that may be used in the ADCs of the ion include, but are not d to,Axitinib, Bosutinib, Cediranib, Dasatinib, Erlotinib, Gefitinib, Imatinib, Lapatinib, Lestaurtinib,Nilotinib, nib, Sunitinib, Osimertinib, Cobimetinib, Trametinib, Dabrafenib, Dinaciclib, andVandetanib.18. Other AgentsExamples of other agents that may be used in the ADCs of the invention e, but are notlimited to, abrin (e. g. abrin A , alpha toxin, Aleurites fordii proteins, amatoxin, , curcin,dianthin proteins, diptheria toxin (6. g. diphtheria A chain and nonbinding active fragments ofMEl 24985843V.1 408117813-12620eria toxin), deoxyribonuclease (Dnase), n, mitogellin, modeccin A chain, momordicacharantia inhibitor, neomycin, onconase, phenomycin, Phytolaca americana proteins (PAPI, PAPII,and PAP-S), pokeweed antiviral protein, Pseudomonas endotoxin, Pseudomonas exotoxin (e. g.exotoxin A chain (from Pseudomonas aeruginosa)), restrictocin, ricin A chain, ribonuclease (Rnase),sapaonaria officinalis inhibitor, saporin, alpha-sarcin, Staphylcoccal enterotoxin-A, tetanus toxin,cisplatin, carboplatin, and oxaliplatin (Eloxatin, Sanofi Aventis), proteasome inhibitors (6. g. PS-34l[bortezomib or Velcade]), HDAC inhibitors (vorinostat (Zolinza, Merck & Company, Inc.)),belinostat, stat, mocetinostat, and panobinostat), COX-2 inhibitors, substituted ureas, heat shockprotein inhibitors (6. g. Geldanamycin and its us s), adrenocortical suppressants, and thetricothecenes. (See, for example, WO 93/21232). Other agents also include asparaginase (Espar,Lundbeck Inc.), hydroxyurea, levamisole, mitotane (Lysodren, Bristol-Myers Squibb), and tretinoin(Renova, t Pharmaceuticals Inc.).

III.C. Anti-B7-H3 ADCs: Other Exemplary LinkersIn addition to the linkers mentioned above, other exemplary linkers include, but are not dto, 6-maleimidocaproyl, maleimidopropanoyl (“MP”), valine-citrulline (“val-cit” or “vc”), alanine-phenylalanine (“ala-phe”), p-aminobenzyloxycarbonyl (a , N-Succinimidyl 4-(2-pyridylthio)pentanoate (“SPP”), and 4-(N-maleimidomethyl)cyclohexane-l carboxylate (“MCC”).

In one aspect, an anti-B7-H3 antibody is conjugated to a drug, (such as auristatin, e.g.,MMAE), via a linker comprising maleimidocaproyl (“mc”), valine citrulline (val-cit or “vc”), andPABA (referred to as a “mc-vc-PABA linker”). Maleimidocaproyl acts as a linker to the anti-B7-H3antibody and is not cleavable. Val-cit is a dipeptide that is an amino acid unit of the linker and allowsfor cleavage of the linker by a protease, specifically the protease cathepsin B. Thus, the val-citcomponent of the linker provides a means for releasing the auristatin from the ADC upon exposure tothe intracellular nment. Within the linker, p-aminobenzylalcohol (PABA) acts as a spacer andis self tive, allowing for the e of the MMAE. The ure of the mc-vc-PABA-MMAElinker is provided in Figure 3.

As described above, suitable linkers e, for example, cleavable and non-cleavablelinkers. A linker may be a “cleavable linker,” tating release of a drug. Nonlimiting exemplarycleavable linkers include acid-labile linkers (e.g., comprising hydrazone), protease-sensitive (e. g.,peptidase-sensitive) s, photolabile linkers, or disulfide-containing linkers (Chari et al., Cancerch 52:127-131 (1992); US. Pat. No. 020). A cleavable linker is typically susceptible tocleavage under intracellular conditions. Suitable cleavable s e, for example, a peptidelinker cleavable by an intracellular protease, such as lysosomal protease or an endosomal protease. Inexemplary embodiments, the linker can be a ide , such as a valine-citrulline (val-cit) or aphenylalanine-lysine (phe-lys) linker.

MEl 24985843V.1 409117813-12620Linkers are preferably stable extracellularly in a sufficient manner to be therapeuticallyeffective. Before transport or delivery into a cell, the ADC is preferably stable and s intact, i.e.the antibody remains conjugated to the drug moiety. Linkers that are stable outside the target cell maybe cleaved at some efficacious rate once inside the cell. Thus, an effective linker will: (i) maintain thespecific binding properties of the antibody; (ii) allow ry, e. g., intracellular delivery, of the drugmoiety; and (iii) maintain the therapeutic effect, e. g., cytotoxic , of a drug moiety.

In one embodiment, the linker is cleavable under intracellular conditions, such that cleavageof the linker sufficiently releases the drug from the antibody in the ellular environment to betherapeutically effective. In some embodiments, the cleavable linker is pH-sensitive, i. e., sensitive tohydrolysis at certain pH values. Typically, the pH-sensitive linker is hydrolyzable under acidicconditions. For example, an acid-labile linker that is hydrolyzable in the lysosome (e. g., a hydrazone,rbazone, thiosemicarbazone, cis-aconitic amide, orthoester, acetal, ketal, or the like) can beused. (See, e.g., US. Pat. Nos. 5,122,368; 5,824,805; 5,622,929; hik and Walker, 1999,Pharm. Therapeutics 83:67-123; Neville et al., 1989, Biol. Chem. 264:14653-14661.) Such linkersare relatively stable under neutral pH conditions, such as those in the blood, but are unstable at belowpH 5.5 or 5.0, the approximate pH of the lysosome. In certain embodiments, the hydrolyzable linkeris a thioether linker (such as, e. g., a thioether attached to the therapeutic agent via an acylhydrazonebond (see, e.g., US. Pat. No. 929).

In other embodiments, the linker is cleavable under reducing conditions (e. g., a disulfidelinker). A variety of disulfide linkers are known in the art, including, for example, those that can beformed using SATA (N-succinimidylacetylthioacetate), SPDP (N-succinimidyl(2-ldithio)propionate), SPDB (N-succinimidyl(2-pyridyldithio)butyrate) and SMPT (N-succinimidyloxycarbonyl-alpha-methyl-alpha-(2-pyridyl-dithio)toluene), SPDB and SMPT. (See, e.g.,Thorpe et al., 1987, Cancer Res. 47:5924-5931; Wawrzynczak et al., In Immanoconjagates: AntibodyConjugates in Radioimagery and Therapy of Cancer (C. W. Vogel ed., Oxford U. Press, 1987. Seealso US. Pat. No. 935.).

In some embodiments, the linker is ble by a cleaving agent, e. g., an , that ispresent in the ellular environment (e. g., within a lysosome or endosome or caveolea). The linkercan be, e. g., a peptidyl linker that is d by an intracellular peptidase or protease enzyme,including, but not d to, a lysosomal or endosomal protease. In some embodiments, the peptidyllinker is at least two amino acids long or at least three amino acids long. Cleaving agents can includecathepsins B and D and plasmin, all of which are known to hydrolyze dipeptide drug derivativesresulting in the release of active drug inside target cells (see, e. g., Dubowchik and Walker, 1999,Pharm. Therapeutics 83:67-123). Most typical are peptidyl linkers that are ble by enzymes thatare present in B7-H3-expressing cells. Examples of such s are described, e. g., in US. Pat. No.6,214,345, incorporated herein by reference in its entirety and for all purposes. In a specificembodiment, the peptidyl linker cleavable by an intracellular protease is a Val-Cit linker or a Phe-LysMEl 24985843V.1 410117813-12620linker (see, e.g., US. Pat. No. 6,214,345, which describes the synthesis of doxorubicin with the val-cit). One advantage of using intracellular proteolytic release of the therapeutic agent is that theagent is typically attenuated when conjugated and the serum stabilities of the conjugates are typicallyhigh.

In other embodiments, the linker is a malonate linker (Johnson et al., 1995, Anticancer Res.: 1387-93), a maleimidobenzoyl linker (Lau er al., 1995, Bioorg-Med—Chem. 3(10):1299-1304), or a3'—N-amide analog (Lau et al., 1995, Bioorg-Med-Chem. 3(10): 1305-12).

In yet other embodiments, the linker unit is not cleavable and the drug is released, forexample, by antibody degradation. See US. Publication No. 20050238649 incorporated by referenceherein in its entirety. An ADC comprising a non-cleavable linker may be designed such that the ADCs substantially outside the cell and cts with certain receptors on a target cell surface suchthat the binding of the ADC tes (or prevents) a particular cellular signaling pathway.

In some embodiments, the linker is substantially hydrophilic linker (e.g., PEG4Mal and sulfo-SPDB). A hilic linker may be used to reduce the extent to which the drug may be pumped outof resistant cancer cells through MDR (multiple drug resistance) or functionally similar transporters.

In other embodiments, upon cleavage, the linker functions to directly or indirectly inhibit cellgrowth and/or cell proliferation. For example, in some embodiments, the linker, upon ge, canfunction as an intercalating agent, thereby inhibiting macromolecular biosynthesis (e. g. DNAation, RNA transcription, and/or protein synthesis).

In other embodiments, the linker is designed to facilitate bystander killing (the killing ofneighboring cells) through diffusion of the linker-drug and/or the drug alone to oring cells. Inother, ments, the linker promotes cellular internalization.

The presence of a sterically hindered disulfide can increase the stability of a ulardisulfide bond, enhancing the potency of the ADC. Thus, in one embodiment, the linker es asterically hindered disulfide linkage. A sterically hindered disulfide refers to a disulfide bond presentwithin a particular molecular environment, wherein the nment is characterized by a particularspatial arrangement or orientation of atoms, lly within the same molecule or compound, whichprevents or at least partially inhibits the reduction of the disulfide bond. Thus, the presence of bulky(or sterically hindering) chemical moieties and/or bulky amino acid side chains proximal to theide bond prevents or at least partially ts the disulfide bond from potential interactions thatwould result in the reduction of the disulfide bond.

Notably, the aforementioned linker types are not mutually ive. For example, in oneembodiment, the linker used in the anti-B7-H3 ADCs described herein is a non-cleavable linker thatpromotes cellular internalization.

In some embodiments, a linker component comprises a cher unit” that links an antibodyto another linker component or to a drug moiety. An illustrative her unit described in US.8,309,093, incorporated by reference herein. In certain embodiments, the stretcher unit is linked toMEl 24985843V.1 41 1117813-12620the anti-B7-H3 antibody via a ide bond between a sulfur atom of the anti-B7-H3 antibody unitand a sulfur atom of the stretcher unit. A representative stretcher unit of this embodiment is edin US. 8,309,093, incorporated by reference herein. In yet other embodiments, the stretcher containsa reactive site that can form a bond with a primary or secondary amino group of an antibody.

Examples of these reactive sites include but are not limited to, activated esters such as succinimideesters, 4 nitrophenyl esters, pentafluorophenyl esters, tetrafluorophenyl esters, anhydrides, acidchlorides, sulfonyl chlorides, isocyanates and isothiocyanates. Representative stretcher units of thisembodiment are depicted in US. 8,309,093, incorporated by reference herein.

In some embodiments, the stretcher contains a ve site that is reactive to a modifiedcarbohydrate's (—CHO) group that can be present on an antibody. For example, a carbohydrate canbe mildly oxidized using a reagent such as sodium periodate and the resulting (—CHO) unit of theoxidized carbohydrate can be condensed with a Stretcher that contains a functionality such as ahydrazide, an oxime, a primary or secondary amine, a hydrazine, a thiosemicarbazone, a hydrazinecarboxylate, and an arylhydrazide such as those described by Kaneko et al., 1991, BioconjugateChem. 2: 133-41. Representative Stretcher units of this embodiment are ed in US. 093,incorporated by reference herein.

In some embodiments, a linker component comprises an “amino acid unit”. In some suchembodiments, the amino acid unit allows for ge of the linker by a protease, thereby facilitatingrelease of the drug from the immunoconjugate upon exposure to intracellular proteases, such aslysosomal enzymes (Doronina et al. (2003) Nat. Biotechnol. 212778-784). Exemplary amino acidunits include, but are not limited to, dipeptides, tripeptides, tetrapeptides, and pentapeptides.

Exemplary dipeptides e, but are not limited to, valine-citrulline (vc or val-cit), ephenylalanine(af or ala-phe); phenylalanine-lysine (fl< or phe-lys); phenylalanine-homolysine (phe-homolys); and N-methyl-valine-citrulline (Me-val-cit). Exemplary tripeptides include, but are notlimited to, glycine-valine-citrulline (gly-val-cit) and glycine-glycine-glycine (gly-gly-gly). An aminoacid unit may comprise amino acid residues that occur lly and/or minor amino acids and/or non-lly occurring amino acid analogs, such as citrulline Amino acid units can be designed andoptimized for enzymatic cleavage by a particular enzyme, for example, a tumor-associated se,cathepsin B, C and D, or a plasmin protease.

In one embodiment, the amino acid unit is valine-citrulline (vc or val-cit). In r aspect,the amino acid unit is phenylalanine-lysine (i.e., fl<). In yet another aspect of the amino acid unit, theamino acid unit is N-methylvaline-citrulline. In yet r , the amino acid unit is 5-aminovaleric acid, homo phenylalanine lysine, tetraisoquinolinecarboxylate lysine, cyclohexylalaninelysine, isonepecotic acid , beta-alanine lysine, glycine serine valine glutamine and isonepecoticacid.

Alternatively, in some embodiments, the amino acid unit is ed by a glucuronide unitthat links a her unit to a spacer unit if the stretcher and spacer units are present, links a stretcherMEl 24985843V.1 412117813-12620unit to the drug moiety if the spacer unit is , and links the linker unit to the drug if the stretcherand spacer units are absent. The glucuronide unit includes a site that can be cleaved by a B-glucuronidase enzyme (See also US 2012/0107332, incorporated by reference herein). In somements, the onide unit comprises a sugar moiety (Su) linked via a glycoside bond (—O'—) to a self-immolative group (Z) of the formula as depicted below (See also US 2012/0107332,incorporated by reference herein).

O‘—Z—l—The glycosidic bond (—O'—) is typically a B-glucuronidase-cleavage site, such as a bond cleavableby human, lysosomal B-glucuronidase. In the context of a glucuronide unit, the term “self-immolativegroup” refers to a di- or tri-functional chemical moiety that is capable of ntly linking togethertwo or three spaced chemical moieties (i.e., the sugar moiety (via a idic bond), a drug moiety(directly or indirectly via a spacer unit), and, in some embodiments, a linker (directly or indirectly viaa her unit) into a stable molecule. The self-immolative group will spontaneously separate fromthe first chemical moiety (6. g., the spacer or drug unit) if its bond to the sugar moiety is cleaved.

In some ments, the sugar moiety (Su) is cyclic hexose, such as a pyranose, or a cyclicpentose, such as a furanose. In some embodiments, the pyranose is a glucuronide or hexose. Thesugar moiety is usually in the [5-D conformation. In a specific embodiment, the pyranose is a [5-D-glucuronide moiety (i.e., B-D-glucuronic acid linked to the mmolative group —Z— via aglycosidic bond that is cleavable by B-glucuronidase). In some ments, the sugar moiety isunsubstituted (e. g., a naturally occurring cyclic hexose or cyclic pentose). In other embodiments, thesugar moiety can be a substituted B-D-glucuronide (i.e., glucuronic acid substituted with one or moregroup, such hydrogen, hydroxyl, n, sulfur, nitrogen or lower alkyl. In some embodiments, theglucuronide unit has one of the formulas as described in US 2012/0107332, incorporated by referenceherein.

In some embodiments, the linker comprises a spacer unit (—Y—), which, when present, linksan amino acid unit (or Glucuronide unit, see also US 2012/0107332, incorporated by reference herein)to the drug moiety when an amino acid unit is present. Alternately, the spacer unit links the stretcherunit to the drug moiety when the amino acid unit is absent. The spacer unit may also links the drugunit to the antibody unit when both the amino acid unit and stretcher unit are absent.

Spacer units are of two general types: non self-immolative or self-immolative. A non self-immolative spacer unit is one in which part or all of the spacer unit remains bound to the drug moietyafter cleavage, particularly tic, of an amino acid unit (or glucuronide unit) from the antibody-drug conjugate. Examples of a non self-immolative spacer unit include, but are not d to a(glycine-glycine) spacer unit and a glycine spacer unit (see US. 8,309,093, incorporated by referenceMEl 24985843V.1 413117813-12620herein)).Other examples of self-immolative spacers include, but are not limited to, aromaticcompounds that are onically similar to the PAB group such as 2-aminoimidazolmethanolderivatives (Hay et al., 1999, Bioorg. Med. Chem. Lett. 922237) and ortho or para-aminobenzylacetals. Spacers can be used that undergo cyclization upon amide bond hydrolysis, suchas substituted and unsubstituted 4-aminobutyric acid amides (Rodrigues et al., 1995, tryy , appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems (Storm et al.,1972, J. Amer. Chem. Soc. 9425815) and 2-aminophenylpropionic acid amides (Amsberry et al.,1990, J. Org. Chem. 5525867). Elimination of amine-containing drugs that are substituted at the (1-position of glycine (Kingsbury et al., 1984, J. Med. Chem. 2721447) are also examples of self-immolative spacers. .

Other examples of self-immolative spacers include, but are not d to, aromaticcompounds that are onically similar to the PAB group such as oimidazolmethanolderivatives (see, e. g., Hay et al., 1999, Bioorg. Med. Chem. Lett. 922237) and ortho or para-aminobenzylacetals. s can be used that undergo ation upon amide bond hydrolysis, suchas substituted and unsubstituted 4-aminobutyric acid amides (see, e. g., Rodrigues et al., 1995,Chemistry Biology 22223), appropriately substituted bicyclo[2.2.1] and bicyclo[2.2.2] ring systems(see, e. g., Storm et al., 1972, J. Amer. Chem. Soc. 9425815) and 2-aminophenylpropionic acid amides(see, e. g., Amsberry et al., 1990, J. Org. Chem. 5525867). Elimination of amine-containing drugs thatare substituted at the a-position of glycine (see, e. g., Kingsbury et al., 1984, J. Med. Chem. 2721447)are also examples of self-immolative spacers.

Other suitable spacer units are disclosed in Published US. Patent Application No. 2005-9, the disclosure of which is incorporated by reference herein.

Another approach for the generation of ADCs involves the use of heterobifunctional cross-linkers which link the anti-B7-H3 antibody to the drug moiety. Examples of cross-linkers that may beused include N-succinimidyl 4-(5-nitropyridyldithio)-pentanoate or the highly water-soluble analogN-sulfosuccinimidyl 4-(5-nitropyridyldithio)-pentanoate, N-succinimidyl(2-pyridyldithio)butyrate (SPDB), N-succinimidyl(5-nitropyridyldithio) butyrate , and N-sulfosuccinimidyl(5-nitropyridyldithio) butyrate ), N-succinimidylmethyl(5-nitro-2-pyridyldithio)pentanoate (SMNP), N-succinimidyl(5-N,N-dimethylcarboxamidopyridyldithio)te (SCPB) or N-sulfosuccinimidyl4-(5-N,N-dimethylcarboxamidopyridyldithio) te(SSCPB)). The dies of the invention may be modified with the cross-linkers N-succinimidyl 4-(5-nitropyridyldithio)-pentanoate, N-sulfosuccinimidyl 4-(5 -nitropyridyldithio)-pentanoate,SPDB, SNPB, SSNPB, SMNP, SCPB, or SSCPB can then react with a small excess of a particulardrug that contains a thiol moiety to give excellent yields of an ADC. Preferably, the cross-linkers arecompounds of the formula as depicted in US. Patent No. 6,913,748, incorporated by reference herein.

In one embodiment, charged linkers (also referred to as pro-charged linkers) are used toconjugate anti-B7-H3 antibodies to drugs to form ADCs. Charged linkers include linkers that becomeMEl 24985843V.1 414117813-12620charged after cell processing. The presence of a charged group(s) in the linker of a particular ADC oron the drug after ar processing provides several advantages, such as (i) greater water solubilityof the ADC, (ii) ability to operate at a higher concentration in aqueous solutions, (iii) y to link agreater number of drug molecules per antibody, potentially resulting in higher potency, (iv) potentialfor the charged conjugate species to be retained inside the target cell, resulting in higher potency, and(v) improved sensitivity of multidrug ant cells, which would be unable to export the chargeddrug species from the cell. es of some suitable charged or pro-charged cross-linkers and theirsynthesis are shown in Figures 1 to 10 of US. Patent No. 8,236, 319, and are incorporated byreference herein. ably, the charged or pro-charged cross-linkers are those containing sulfonate,phosphate, carboxyl or nary amine substituents that significantly increase the solubility of theADCs, ally for ADCs with 2 to 20 conjugated drugs. Conjugates prepared from linkerscontaining a pro-charged moiety would produce one or more charged moieties after the conjugate ismetabolized in a cell.onal examples of linkers that can be used with the compositions and methods includevaline-citrulline; maleimidocaproyl; amino benzoic acids; p-aminobenzylcarbamoyl (PAB);lysosomal -cleavable linkers; maleimidocaproyl-polyethylene glycol (MC(PEG)6-OH); N-methyl-valine citrulline; N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-l-carboxylate (SMCC);N-Succinimidyl 4-(2-pyridyldithio)butanoate (SPDB); and N-Succinimidyl 4-(2-pyridylthio)pentanoate (SPP) (See also US 2011/0076232). Another linker for use in the inventionincludes an -biotin linkage to provide an avidin-biotin-containing ADC (See also US. PatentNo. 4,676,980, PCT publication Nos. WOl992/022332A2, WOl994/016729A1, WOl995/015770Al,WOl997/03l655A2, WOl998/035704Al, WOl999/019500Al, WO2001/09785A2,WO2001/090198Al, WO2003/093793A2, WO2004/050016A2, WO2005/08 l 898A2,WO2006/083562A2, WO2006/089668Al, WO2007/150020Al, WO2008/135237A1,WO2010/111198A1, WO2011/057216A1, WO2011/058321A1, WO2012/027494A1, andEP77671B1), wherein some such linkers are ant to biotinidase cleavage. Additional linkers thatmay be used in the invention include a n/dockerin pair to provide a cohesion-dockerin-containing ADC (See PCT publication Nos. WO2008/097866A2, WO2008/097870A2,WO2008/103947A2, and WO2008/103953A2).

Additional linkers for use in the invention may contain ptide polymers lesinclude, but are not limited to, polyethylene glycol, polypropylene glycol, polyoxyethylated polyols,nyl alcohol, ccharides, dextran, polyvinyl ethyl ether, PLA (poly(lactic acid)), PLGA(poly(lactic acid-glycolic , and combinations thereof, wherein a preferred polymer ispolyethylene glycol) (See also PCT publication No. WO2011/000370). Additional linkers are alsodescribed in WO 2004-010957, U.S. Publication No. 20060074008, U.S. Publication No.20050238649, and US. Publication No. 20060024317, each of which is incorporated by referenceherein in its ty).

MEl 24985843V.1 415117813-12620For an ADC sing a maytansinoid, many positions on maytansinoids can serve as theposition to ally link the linking moiety. In one embodiment, maytansinoids comprise a gmoiety that contains a reactive chemical group are C—3 esters of maytansinol and its analogs where thelinking moiety contains a disulfide bond and the chemical reactive group comprises a N-succinimidylor N-sulfosuccinimidyl ester. For example, the C—3 position having a hydroxyl group, the C-14position ed with hydroxymethyl, the C-15 on modified with hydroxy and the C—20position having a hydroxy group are all useful. The linking moiety most preferably is linked to the C-3 position of maytansinol.

The conjugation of the drug to the antibody via a linker can be accomplished by anytechnique known in the art. A number of different reactions are available for covalent attachment ofdrugs and linkers to antibodies. This may be accomplished by reaction of the amino acid residues ofthe antibody, including the amine groups of lysine, the free carboxylic acid groups of glutamic andaspartic acid, the sulfliydryl groups of cysteine and the various es of the aromatic amino acids.

One of the most commonly used non-specific methods of covalent attachment is the carbodiimidereaction to link a carboxy (or amino) group of a compound to amino (or y) groups of theantibody. Additionally, bifunctional agents such as dialdehydes or imidoesters have been used to linkthe amino group of a compound to amino groups of an antibody. Also available for attachment ofdrugs to antibodies is the Schiff base reaction. This method involves the periodate oxidation of a drugthat contains glycol or hydroxy groups, thus forming an aldehyde which is then reacted with thebinding agent. ment occurs via formation of a Schiff base with amino groups of the antibody.

Isothiocyanates can also be used as coupling agents for covalently attaching drugs to antibodies.

Other techniques are known to the skilled artisan and within the scope of the invention.

In certain embodiments, an intermediate, which is the precursor of the linker, is reacted withthe drug under appropriate ions. In certain embodiments, reactive groups are used on the drugor the intermediate. The t of the reaction between the drug and the intermediate, or thederivatized drug, is uently reacted with the anti-B7-H3 antibody under appropriate ions.

The synthesis and structure of ary linkers, stretcher units, amino acid units, self-immolativespacer units are described in US. Patent Application Publication Nos. 20030083263, 20050238649and 20050009751, each if which is incorporated herein by reference.

Stability of the ADC may be measured by rd analytical techniques such as massspectroscopy, HPLC, and the separation/analysis technique LC/MS.

IV. Purification of Anti-B7-H3 ADCsPurification of the ADCs may be ed in such a way that ADCs having certain DARs arecollected. For e, HIC resin may be used to separate high drug loaded ADCs from ADCshaving optimal drug to antibody ratios (DARs), e. g. a DAR of 4 or less. In one embodiment, ahydrophobic resin is added to an ADC mixture such that undesired ADCs, i.e., higher drug loadedMEl 24985843V.1 416117813-12620ADCs, bind the resin and can be selectively removed from the mixture. In n embodiments,separation of the ADCs may be achieved by ting an ADC mixture (6. g., a mixture comprising adrug loaded species of ADC of 4 or less and a drug loaded species of ADC of 6 or more) with ahydrophobic resin, n the amount of resin is sufficient to allow g of the drug loadedspecies which is being removed from the ADC e. The resin and ADC mixture are mixedtogether, such that the ADC species being removed (6. g., a drug loaded species of 6 or more) binds tothe resin and can be ted from the other ADC species in the ADC mixture. The amount of resinused in the method is based on a weight ratio between the species to be removed and the resin, wherethe amount of resin used does not allow for significant binding of the drug loaded species that isdesired. Thus, s may be used to reduce the average DAR to less than 4. Further, thepurification methods described herein may be used to isolate ADCs having any desired range of drugloaded species, e.g., a drug loaded species of 4 or less, a drug loaded species of 3 or less, a drugloaded species of 2 or less, a drug loaded species of l or less.

Certain species of molecule(s) binds to a surface based on hydrophobic interactions betweenthe species and a hydrophobic resin. In one embodiment, method of the invention refers to apurification process that relies upon the intermixing of a hydrophobic resin and a mixture of ADCs,wherein the amount of resin added to the mixture ines which species (6. g., ADCs with a DARof 6 or more) will bind. Following production and purification of an antibody from an expressionsystem (e.g., a mammalian expression system), the antibody is reduced and d to a drug througha conjugation reaction. The resulting ADC mixture often contains ADCs having a range of DARs,e.g., l to 8. In one embodiment, the ADC mixture comprises a drug loaded species of 4 or less and adrug loaded species of 6 or more. According to the methods of the invention, the ADC mixture maybe purified using a process, such as, but not limited to, a batch process, such that ADCs having a drugloaded species of 4 or less are selected and separated from ADCs having a higher drug load (e. g.,ADCs having a drug loaded species of 6 or more). Notably, the cation methods described hereinmay be used to isolate ADCs having any desired range of DAR, e.g., a DAR of 4 or less, a DAR of 3or less, or a DAR of 2 or less.

Thus, in one embodiment, an ADC mixture comprising a drug loaded species of 4 or less anda drug loaded s of 6 or more may be contacted with a hydrophobic resin to form a resin mixture,wherein the amount of hydrophobic resin contacted with the ADC mixture is sufficient to allowbinding of the drug loaded species of 6 or more to the resin but does not allow significant binding ofthe drug load species of 4 or less; and ng the hydrophobic resin from the ADC mixture, suchthat the composition comprising ADCs is obtained, wherein the composition comprises less than 15%of the drug loaded s of 6 or more, and wherein the ADC comprises an antibody conjugated to aBcl-xL inhibitor. In a separate embodiment, the method of the ion comprises contacting anADC mixture comprising a drug loaded species of 4 or less and a drug loaded species of 6 or morewith a hydrophobic resin to form a resin mixture, wherein the amount of hydrophobic resin contactedMEl 24985843V.1 417117813-12620with the ADC mixture is ient to allow binding of the drug loaded species of 6 or more to theresin but does not allow significant binding of the drug load species of 4 or less; and removing thehydrophobic resin from the ADC mixture, such that the composition comprising ADCs is obtained,wherein the composition comprises less than 15% of the drug loaded species of 6 or more, andwherein the ADC comprises an antibody conjugated to a Bcl-xL inhibitor, wherein the hydrophobicresin weight is 3 to 12 times the weight of the drug loaded species of 6 or more in the ADC mixture.

The ADC separation method described herein method may be performed using a batchpurification method. The batch purification process generally es adding the ADC e to thehydrophobic resin in a vessel, mixing, and subsequently separating the resin from the supernatant.

For example, in the context of batch purification, a hydrophobic resin may be prepared in orbrated to the desired equilibration buffer. A slurry of the hydrophobic resin may thus beobtained. The ADC mixture may then be contacted with the slurry to adsorb the specific species ofADC(s) to be separated by the hobic resin. The solution comprising the desired ADCs that donot bind to the hydrophobic resin material may then be separated from the slurry, e.g., by filtration orby allowing the slurry to settle and removing the supernatant. The resulting slurry can be subjected toone or more washing steps. In order to elute bound ADCs, the salt concentration can be decreased. Inone embodiment, the process used in the invention includes no more than 50 g of hobic resin.

Thus, a batch method may be used to contact an ADC mixture comprising a drug loadedspecies of 4 or less and a drug loaded species of 6 or more with a hydrophobic resin to form a resine, wherein the amount of hydrophobic resin contacted with the ADC e is sufficient toallow binding of the drug loaded species of 6 or more to the resin but does not allow significantbinding of the drug load species of 4 or less; and removing the hobic resin from the ADCmixture, such that the composition comprising ADCs is obtained, n the ition comprisesless than 15% of the drug loaded species of 6 or more, and n the ADC comprises an antibodyconjugated to a Bcl-xL tor. In a separate ment, a batch method is used to contact anADC mixture comprising a drug loaded species of 4 or less and a drug loaded species of 6 or morewith a hydrophobic resin to form a resin mixture, wherein the amount of hobic resin contactedwith the ADC mixture is sufficient to allow binding of the drug loaded species of 6 or more to theresin but does not allow significant binding of the drug load species of 4 or less; and removing thehydrophobic resin from the ADC mixture, such that the composition comprising ADCs is obtained,wherein the composition comprises less than 15% of the drug loaded species of 6 or more, andwherein the ADC comprises an dy conjugated to a Bcl-xL inhibitor, wherein the hydrophobicresin weight is 3 to 12 times the weight of the drug loaded species of 6 or more in the ADC mixture.

Alternatively, in a separate embodiment, purification may be performed using a circulationprocess, whereby the resin is packed in a container and the ADC mixture is passed over thehydrophobic resin bed until the specific species of ADC(s) to be separated have been removed. TheMEl 24985843V.1 418117813-12620supernatant (containing the desired ADC species) is then pumped from the container and the resin bedmay be subjected to g steps.

A circulation process may be used to t an ADC mixture comprising a drug loadeds of 4 or less and a drug loaded species of 6 or more with a hydrophobic resin to form a resinmixture, wherein the amount of hydrophobic resin contacted with the ADC mixture is sufficient toallow binding of the drug loaded species of 6 or more to the resin but does not allow significantbinding of the drug load species of 4 or less; and removing the hydrophobic resin from the ADCmixture, such that the composition comprising ADCs is obtained, wherein the ition comprisesless than 15% of the drug loaded species of 6 or more, and wherein the ADC ses an antibodyconjugated to a Bcl-xL inhibitor. In a separate embodiment, a ation process is used to contact anADC mixture comprising a drug loaded species of 4 or less and a drug loaded s of 6 or morewith a hydrophobic resin to form a resin mixture, wherein the amount of hobic resin contactedwith the ADC mixture is ient to allow binding of the drug loaded s of 6 or more to theresin but does not allow significant binding of the drug load species of 4 or less; and removing thehydrophobic resin from the ADC mixture, such that the composition comprising ADCs is obtained,wherein the composition comprises less than 15% of the drug loaded species of 6 or more, andwherein the ADC comprises an antibody conjugated to a Bcl-xL inhibitor, wherein the hydrophobicresin weight is 3 to 12 times the weight of the drug loaded species of 6 or more in the ADC mixture.

Alternatively, a flow through process may be used to purify an ADC mixture to arrive at acomposition sing a majority of ADCs having a n desired DAR. In a flow throughprocess, resin is packed in a container, 6. g., a column, and the ADC mixture is passed over the packedresin such that the desired ADC species does not substantially bind to the resin and flows through theresin, and the undesired ADC species is bound to the resin. A flow through process may beperformed in a single pass mode (where the ADC species of interest are obtained as a result of asingle pass through the resin of the container) or in a pass mode (where the ADC species ofst are obtained as a result of multiple passes through the resin of the container). The flowthrough process is performed such that the weight of resin selected binds to the undesired ADCpopulation, and the desired ADCs (e. g., DAR 2-4) flow over the resin and are collected in the flowthrough after one or multiple passes.

A flow through process may be used to contact an ADC mixture comprising a drug loadedspecies of 4 or less and a drug loaded species of 6 or more with a hydrophobic resin, wherein theamount of hydrophobic resin contacted with the ADC mixture is sufficient to allow binding of thedrug loaded species of 6 or more to the resin but does not allow significant binding of the drug loadspecies of 4 or less, where the drug load species of 4 or less passes over the resin and is subsequentlycollected after one or multiple passes, such that the composition comprising the d ADCs (e.g.

DAR 2-4) is obtained, wherein the composition comprises less than 15% of the drug loaded species of6 or more, and wherein the ADC comprises an antibody conjugated to a Bcl-xL tor. In aMEl 24985843V.1 419117813-12620separate embodiment, a flow h process is used to contact an ADC mixture comprising a drugloaded species of 4 or less and a drug loaded species of 6 or more with a hydrophobic resin by passingthe ADC mixture over the resin, n the amount of hobic resin contacted with the ADCmixture is sufficient to allow binding of the drug loaded species of 6 or more to the resin but does notallow significant binding of the drug load species of 4 or less, where the drug load species of 4 or lesspasses over the resin and is subsequently collected, such that the composition comprising ADCs ised, wherein the composition comprises less than 15% of the drug loaded species of 6 or more,and wherein the ADC comprises an antibody conjugated to an a drug, e.g., a Bcl-xL inhibitor, whereinthe amount of hydrophobic resin weight is 3 to 12 times the weight of the drug loaded species of 6 ormore in the ADC mixture.

Following a flow through process, the resin may be washed with a one or more washesfollowing in order to further recover ADCs having the desired DAR range (found in the washfiltrate). For example, a plurality of washes having decreasing conductivity may be used to furtherrecover ADCs having the DAR of interest. The elution material obtained from the washing of theresin may be subsequently combined with the filtrate resulting from the flow through process forimproved recovery of ADCs having the DAR of interest.

The aforementioned batch, circulation, and flow through process purification methods arebased on the use of a hydrophobic resin to separate high vs. low drug loaded species of ADC.

Hydrophobic resin ses hydrophobic groups which interact with the hydrophobic properties ofthe ADCs. Hydrophobic groups on the ADC interact with hydrophobic groups within thehydrophobic resin. The more hydrophobic a protein is the er it will interact with thehobic resin.

Hydrophobic resin normally comprises a base matrix (e. g., cross-linked agarose or syntheticcopolymer material) to which hydrophobic ligands (e. g., alkyl or aryl groups) are coupled. Manyhydrophobic resins are available commercially. es include, but are not limited to, PhenylSepharoseTM 6 Fast Flow with low or high substitution (Pharmacia LKB Biotechnology, AB,Sweden); Phenyl oseTM High mance (Pharmacia LKB Biotechnology, AB, Sweden);Octyl SepharoseTM High Performance (Pharmacia LKB Biotechnology, AB, Sweden); FractogelTMEMD Propyl or FractogelTM EMD Phenyl columns (E. Merck, Germany); Macro-PrepTM Methyl orPrepTM. l ts ad, California); WP HI-Propyl (C3)TM (J. T. Baker, NewJersey); and ToyopearlTM ether, hexyl, phenyl or butyl (TosoHaas, PA). In one embodiment, thehydrophobic resin is a butyl hydrophobic resin. In another embodiment, the hydrophobic resin is aphenyl hydrophobic resin. In another embodiment, the hydrophobic resin is a hexyl hydrophobicresin, an octyl hydrophobic resin, or a decyl hydrophobic resin. In one embodiment, the hydrophobicresin is a rylic polymer having n-butyl ligands (e. g. TOYOPEARL® Butyl-600M).

MEl 24985843V.1 420117813-12620Further methods for purifying ADC es to obtain a composition having a desired DARare described in US. Application No. 14/210,602 (US. Patent Appln. Publication No. US2014/0286968), incorporated by reference in its entirety.

In certain embodiments of the invention, ADCs described herein having a DAR2 are purifiedfrom ADCs having higher or lower DARs. Such ed DAR2 ADCs are referred to herein as “E2”.cation methods for achieving a composition having E2 anti-B7-H3 ADCs. In one ment,of the ion provides a composition comprising an ADC mixture, wherein at least 75% of theADCs are anti-B7H3 ADCs (like those described herein) having a DAR2. In another embodiment,the invention provides a composition comprising an ADC mixture, wherein at least 80% of the ADCsare anti-B7H3 ADCs (like those described herein) having a DAR2. In another embodiment, theion provides a composition comprising an ADC mixture, wherein at least 85% of the ADCs areanti-B7H3 ADCs (like those described herein) having a DAR2. In another embodiment, the inventiones a ition comprising an ADC mixture, wherein at least 90% of the ADCs are anti-B7H3 ADCs (like those described herein) having a DAR2.

V. Uses of Anti-B7-H3 Antibodies and Anti-B7-H3 ADCsThe dies and ADCs of the invention preferably are capable of neutralizing human B7-H3 activity both in vivo and in vitro. Accordingly, such antibodies and ADCs of the invention can beused to inhibit hB7-H3 activity, e.g., in a cell culture containing , in human subjects or inother ian subjects having B7-H3 with which an antibody of the invention cross-reacts. In oneembodiment, the invention provides a method for inhibiting hB7-H3 activity comprising contactinghB7-H3 with an antibody or ADC of the invention such that hB7-H3 activity is inhibited. Forexample, in a cell culture containing, or suspected of containing , an antibody or dyportion of the ion can be added to the culture medium to inhibit hB7-H3 activity in the culture.

In another embodiment, of the invention a method for reducing hB7-H3 activity in a subject,advantageously from a subject suffering from a disease or disorder in which B7-H3 ty isdetrimental. The invention provides methods for reducing B7-H3 activity in a subject suffering fromsuch a disease or disorder, which method comprises administering to the subject an antibody or ADCof the invention such that B7-H3 activity in the subject is reduced. Preferably, the B7-H3 is humanB7-H3, and the subject is a human t. Alternatively, the subject can be a mammal expressing aB7-H3 to which antibodies of the invention are capable of binding. Still further the subject can be amammal into which B7-H3 has been introduced (e.g., by administration of B7-H3 or by expression ofa B7-H3 transgene). Antibodies or ADCs of the invention can be administered to a human subject fortherapeutic purposes. Moreover, antibodies or ADCS of the invention can be administered to a non-human mammal sing a B7-H3 with which the antibody is capable of binding for veterinarypurposes or as an animal model of human disease. Regarding the latter, such animal models may beMEl 24985843V.1 421117813-12620useful for evaluating the therapeutic efficacy of antibodies of the invention (e.g., testing of dosagesand time courses of administration).

As used herein, the term “a disorder in which B7-H3 expression is detrimental” is intended toinclude diseases and other disorders in which the presence of B7-H3 in a subject ing from theer has been shown to be expressed, or has been shown to be or is suspected of being eitherresponsible for the pathophysiology of the disorder or a factor that contributes to the er. Forexample, the ADCs of the invention may be used to target tumor cells that are expressing B7-H3.

Non-limiting examples of disorders that can be treated with the ADCs of the invention, for example,an ADC comprising huAbl3vl, include, but are not limited to, a variety of cancers including, but notd to, small cell lung , non small cell lunch cancer (NSCLC), breast cancer, ovariancancer, lung , a glioma, prostate cancer, pancreatic cancer, colon cancer, head and neck cancer,leukemia, e.g., acute myeloid leukemia (AML), lymphoma, e.g., non-Hodgkin's lymphoma (NHL),and kidney cancer. Other examples of cancer that may be treated using the compositions and methodssed herein include squamous cell carcinoma (6. g., squamous lung cancer or squamous head andneck cancer), triple negative breast cancer, non-small cell lung , colorectal cancer, andmesothelioma. In one embodiment, the antibodies or ADCs disclosed herein are used to treat a solidtumor, 6. g., inhibit growth of or decrease size of a solid tumor, overexpressing B7-H3 or which is B7-H3 positive. In one embodiment, the invention is ed to the treatment of squamous lung cancerassociated with B7-H3 expression. In another embodiment, the antibodies and ADCs sed hereinare used to treat triple negative breast cancer (TNBC). Diseases and disorders described herein maybe treated by 7-H3 antibodies or ADCs of the invention, as well as pharmaceuticalcompositions comprising such anti-B7-H3 dies or ADCs.

In certain embodiments, the cancer may be characterized as having EGFR overexpression. Inone ment, the ADCs of the invention may be used to treating cancer associated with anactivating EGFR mutation. Examples of such mutations include, but are not limited to, an exon 19deletion mutation, a single-point substitution mutation L858R in exon 21, a T790M point mutation,and combinations thereof.

In certain embodiments, the antibodies or ADCs disclosed herein are administered to asubject in need thereof in order to treat advanced solid tumor types likely to exhibit elevated levels ofB7-H3. Examples of such tumors include, but are not limited to, small cell lung , breast ,n cancer, head and neck squamous cell carcinoma, non-small cell lung cancer, triple negativebreast cancer, colorectal carcinoma, and glioblastoma multiforme.

In certain embodiments, the invention includes a method for inhibiting or decreasing solidtumor growth in a subject having a solid tumor, said method comprising administering an anti-B7-H3antibody or ADC described , to the subject having the solid tumor, such that the solid tumorgrowth is inhibited or decreased. In certain embodiments, the solid tumor is a all cell lungcarcinoma or a glioblastoma. In further embodiments, the solid tumor is a B7-H3 -expressing solidMEl 24985843V.1 422-12620tumors. In further embodiments, the solid tumor is an B7-H3 overexpressing solid tumors. In certainments the anti-B7-H3 antibodies or ADCs described herein are administered to a subjecthaving glioblastoma orme, alone or in combination with an additional agent, 6. g., radiationand/or temozolomide.

In certain embodiments the anti-B7-H3 ADCs described herein are are administered to asubject having small cell lung cancer, alone or in ation with an additional agent, e.g., ABT-l99(venetoclax).

In certain embodiments the anti-B7-H3 ADCs described herein are administered to a subjecthaving non-small cell lung cancer, alone or in combination with an additional agent, e.g., a taxane. Incertain embodiments the 7-H3 antibodies or ADCs described herein are administered to asubject having breast cancer, alone or in combination with an additional agent, e.g., a taxane. Incertain embodiments the 7-H3 antibodies or ADCs described herein are administered to asubject having ovarian cancer, alone or in combination with an additional agent, e.g., a .

Other combination therapies which are included in the invention are the administration of ananti-B7-H3 ADC with an agent selected from the group consisting of an anti-PDl antibody (e. g.pembrolizumab), an anti-PD-Ll antibody (e. g., atezolizumab), an TLA-4 antibody (e.g.ipilimumab), a MEK inhibitor (e. g. inib), an ERK inhibitor, a BRAF inhibitor (e. g. dabrafenib),tinib, erlotinib, gefitinib, sorafenib, a CDK9 inhibitor (e.g. dinaciclib), a MCL-l inhibitor,temozolomide, a Bcl-xL inhibitor, a Bcl-2 inhibitor (e.g. venetoclax), ibrutinib, a mTOR tor(e. g. imus), a PI3K inhibitor (e.g. buparlisib), duvelisib, idelalisib, an AKT inhibitor, a HER2inhibitor (e.g. lapatinib), a taxane (e. g., docetaxel, paclitaxel, nab-paclitaxel), venetoclax, an ADCsing an auristatin, an ADC comprising a PBD (e.g. rovalpituzumab tesirine), an ADCcomprising a maytansinoid (e. g. TDMl), a TRAIL agonist, a proteasome inhibitor (e. g. bortezomib),and a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.

Combination therapies include administration of an ADC of the invention prior to,concurrently with, or following administration of an additional therapeutic agent, including thosedescribed above.

In certain embodiments, the invention es a method for inhibiting or decreasing solidtumor growth in a subject having a solid tumor which was identified as an B7-H3 expressing or B7-H3 overexpressing tumor, said method comprising administering an anti-B7-H3 antibody or ADCdescribed herein, to the subject having the solid tumor, such that the solid tumor growth is inhibited ordecreased. Methods for identifying B7-H3 expressing tumors (e.g., B7-H3 overexpressing )are known in the art, and include FDA-approved tests and validation . For example, the B7-H3assay is a qualitative immunohistochemical (IHC) kit system used to identify B7-H3 sion innormal and neoplastic tissues routinely-fixed for ogical evaluation. In addition, sedassays may also be used for identifying B7-H3 overexpressing tumors. The amplified PCR productsmay be subsequently analyzed, for example, by gel electrophoresis using standard methods known inMEl 24985843V.1 423117813-12620the art to determine the size of the PCR products. Such tests may be used to identify tumors that maybe treated with the s and compositions described herein.

Any of the methods for gene therapy available in the art can be used according to theinvention. For general reviews of the methods of gene therapy, see Goldspiel et al., 1993, ClinicalPharmacy 122488-505; Wu and Wu, 1991, Biotlierapy 3:87-95; Tolstoshev, 1993, Ann. Rev.

Pharmacol. Toxicol. 32:573-596; Mulligan, Science 6- 932 (1993); and Morgan and Anderson,1993, Ann. Rev. Biochem. 622191-217; May, 1993, TIBTECH 11(5):155-215. Methods commonlyknown in the art of recombinant DNA logy which can be used are described in Ausubel et al.(eds.), Current Protocols in Molecular Biology, John Wiley &Sons, NY (1993); and Kriegler, GeneTransfer and Expression, A tory , Stockton Press, NY (1990). Detailed description ofs methods of gene therapy is provided in US20050042664 A1 which is incorporated herein byreference.

In another aspect, this application features a method of treating (e. g., , suppressing,ameliorating, delaying or preventing the onset of, or preventing recurrence or relapse of) orpreventing a B7-H3-associated disorder, in a t. The method includes: administering to thesubject an B7-H3 binding agent, e. g., an anti-B7-H3 dy or fragment f as described herein,in an amount sufficient to treat or t the B7-H3 iated disorder. The B7-H3 antagonist, e. g.,the anti-B7-H3 antibody or fragment f, can be administered to the subject, alone or incombination with other therapeutic modalities as described herein.

Antibodies or ADCs of the invention, or antigen binding portions thereof can be used alone orin combination to treat such diseases. It should be understood that the antibodies of the invention orantigen g portion thereof can be used alone or in combination with an additional agent, e. g., atherapeutic agent, said additional agent being selected by the skilled artisan for its intended purpose.

For example, the additional agent can be a eutic agent art-recognized as being useful to treat thedisease or condition being treated by the antibody of the invention. The additional agent also can bean agent that imparts a beneficial attribute to the therapeutic composition, e. g., an agent which affectsthe viscosity of the composition.

It should further be understood that the combinations which are to be included within thisinvention are those combinations useful for their intended purpose. The agents set forth below areillustrative for purposes and not intended to be limited. The combinations, which are part of thisinvention, can be the antibodies of the invention and at least one additional agent selected from thelists below. The combination can also include more than one additional agent, e. g., two or threeonal agents if the combination is such that the formed composition can perform its intendedfunction.

The combination therapy can include one or more B7-H3 antagonists, e. g., anti-B7-H3antibodies or nts thereof, formulated with, and/or co-administered with, one or more additionaltherapeutic , e. g., one or more cytokine and growth factor inhibitors, suppressants, anti-MEl 24985843V.1 424117813-12620inflammatory agents (e.g., ic anti-inflammatory agents), anti-fibrotic agents, licinhibitors, enzyme inhibitors, and/or cytotoxic or cytostatic agents, mitotic inhibitors, antitumorantibiotics, immunomodulating agents, vectors for gene therapy, alkylating agents, antiangiogenicagents, antimetabolites, boron-containing agents, chemoprotective agents, hormones, antihormoneagents, corticosteroids, ctive therapeutic agents, oligonucleotides, radionuclide agents,topoisomerase inhibitors, kinase inhibitors, or radiosensitizers, as bed in more herein.

In a particular embodiment, the anti-B7-H3 g proteins described herein, for e,7-H3 antibodies, are used in combination with an ancer agent or an antineoplastic agent.

The terms “anti-cancer agent” and “antineoplastic agent” refer to drugs used to treat malignancies,such as cancerous growths. Drug therapy may be used alone, or in combination with other treatmentssuch as surgery or radiation therapy. Several classes of drugs may be used in cancer treatment,depending on the nature of the organ ed. For example, breast cancers are commonly stimulatedby estrogens, and may be treated with drugs which inactive the sex hormones. Similarly, prostatecancer may be treated with drugs that inactivate androgens, the male sex hormone. Anti-canceragents that may be used in conjunction with the anti-B7-H3 antibodies or ADCs of the inventione, among others, an Dl antibody (e.g., pembrolizumab), an anti-PD-Ll antibody (e.g.,atezolizumab), an anti-CTLA-4 antibody (e.g., ipilimumab), a MEK inhibitor (e. g., trametinib), anERK inhibitor, a BRAF inhibitor (e.g., dabrafenib), osimertinib (AZD9291), erlotinib, gefitinib,sorafenib, a CDK9 inhibitor (e.g., dinaciclib), a MCL-l inhibitor, temozolomide, a Bcl-xL inhibitor,a Bcl-2 inhibitor (e.g., venetoclax), ibrutinib, a mTOR tor (e. g., everolimus), a PI3K inhibitor(e. g., buparlisib), duvelisib, idelalisib, an AKT tor, a HER2 inhibitor (e.g., lapatinib), Herceptin,a taxane (e. g., docetaxel, paclitaxel, clitaxel), an ADC comprising an auristatin, an ADCcomprising a PBD (e. g., rovalpituzumab tesirine), an ADC comprising a maytansinoid (e. g., TDMl),a TRAIL agonist, a proteasome inhibitor (e.g., bortezomib), and a nicotinamidephosphoribosyltransferase (NAMPT) tor, as well as the following agents:MEl 24985843V.1 425117813-12620Anti-Cancer Agent Comments Examplesdies Antibodies which bind IGF- A12 (fully humanized mAb)1R (insulin-like growth 19D12 (fully humanized mAb)factor type 1 receptor), Cp751-871 (fully humanized mAb)which is expressed on the H7C10 (humanized mAb)cell surface of most human alphaIR3 (mouse)cancers ScFV/FC (mouse/human chimera)EM/164 (mouse)Antibodies which bindEGFR; Mutations affecting mab (EMD72000)EGFR expression or ty Erbitux® / Cetuximab (Imclone)could result in cancer Vectibix® / Panitumumab (Amgen)mAb 806Antibodies which bind Nimotuxumab (TheraCIM)cMET (Mesechymalepithelial transition factor); AVEO (AV299) (AVEO)a member of the MET AMG102 (Amgen)family of receptor tyrosine 5D5 (OA-5d5) (Genentech)s) H244G11 (Pierre Fabre)Anti-ErbB3 antibodies Ab #14 (MM 121-14)Herceptin® (Trastuzumab; Genentech)1B4C3; 2D1D12 (U3 Pharma AG)Small Molecules Insulin-like growth factor NVP-AEW541-ATargeting IGF1R type 1 receptor which is EMS-536,924 (1H-benzoimidazolyl)-1H-expressed on the cell pyridin0ne)surface of many human EMS-554,417cancers CycloliganTAE226PQ401Small Molecules EGFR; Iressa® / Gefitinib (AstraZeneca)Targeting EGFR Overexpression 0r CI-1033 (PD ) (Pfizer)mutations ing EGFR Lapatinib 2016) (GlaxoSmithKline)expression or actiVity could Tykerb® / Lapatinib Ditosylate (Smith Klineresult in cancer Beecham)Tarceva ® / Erlotinib HCL (OSI-774) (OSIPKI-166 (Novartis)PD-158780Tyrphostin AG 1478 (4-(3-Chlor0anillin0)-6,7-dimeth0xyquinazoline)Small Molecules cMET (Mesenchymal PHA665752ing cMET epithelial transition factor); ARQ 197a member of the METfamily of receptor tyrosinekinases)Antimetabolites Flourouracil (5-FU)MEl 24985843V.1 426117813-12620Capecitabine / XELODA® (HLR Roche)-Trifluoromethyl-2’ -deoxyuridineMethotrexate sodium (Trexall) (Barr)Raltitrexed/ Tomudex® (AstraZeneca)exed / Alimta® (Lilly)TegafurCytosine Arabinoside (Cytarabine, Ara-C) /Thioguanine® (GlaxoSmithKline)-azacytidine6-mercaptopurine (Mercaptopurine, 6-MP)Azathioprine / Azasan® (AAIPHARMA LLC)6-thioguanine (6-TG) / Purinethol® (TEVA)Pentostatin / Nipent® (Hospira Inc.)abine phosphate / Fludara® (BayerHealth Care)Cladribine , 2-chlorodeoxyadenosine) /Leustatin® (Ortho Biotech)Alkylating agents An alkylating antineoplastic Ribonucleotide Reductase Inhibitor (RNR)agent is an alkylating agent Cyclophosphamide / Cytoxan (BMS)that attaches an alkyl group Neosar (TEVA)to DNA. Since cancer cells Ifosfamide / Mitoxana® (ASTA Medica)lly proliferate Thiotepa (Bedford, Abraxis, Teva)unrestrictively more than do BCNU—> l,3-bis(2-chloroethyl)- l -nitosoureahealthy cells they are more CCNU—> l, -(2-chloroethyl)cyclohexyl-l-sensitive to DNA damage, nitrosourea (methyl CCNU)and ting agents are Hexamethylmelamine (Altretamine, HMM) /used clinically to treat a n® (MGI Pharma Inc.)variety of tumors. Busulfan / n (GlaxoSmithKline)Procarbazine HCL/ Matulane (Sigma TauPharmaceuticals, Inc.)Dacarbazine (DTIC)Chlorambucil / Leukara® (SmithKlineBeecham)Melphalan / Alkeran® (GlaxoSmithKline)Cisplatin (Cisplatinum, CDDP) / ol(Bristol Myers)Carboplatin / atin (BMS)Oxaliplatin /Eloxitan® (Sanofi-Aventis US)Topoisomerase Topoisomerase inhibitors Doxorubicin HCL / Doxil® (Alza)inhibitors are chemotherapy agents Daunorubicin citrate / Daunoxome® (Gilead)designed to interfere with Mitoxantrone HCL / rone (EMDthe action of omerase Serono)enzymes (topoisomerase I Actinomycin Dand II), which are enzymes Etoposide / Vepesid® (BMS)/ Etopophos®that control the changes in (Hospira, Bedford, Teva Parenteral, Etc.)DNA structure by Topotecan HCL / Hycamtin®catalyzing the ng and (GlaxoSmithKline)rejoining of the Teniposide (VM-26) / Vumon® (BMS)phosphodiester backbone of Irinotecan T-ll) / Camptosar®DNA strands during the (Pharmacia & Upjohn)normal cell cycle.

Microtubule Microtubules are one of the Vincristine / Oncovin® (Lilly)MEI 24985843V.1 427117813-12620targeting agents components of the Vinblastine sulfate / Velban®(discontinued)cytoskeleton. They have (Lilly)diameter of ~24 nm and Vinorelbine tartrate / Navelbine®length varying from several (PierreFabre)micrometers to possibly Vindesine sulphate / Eldisine® (Lilly)millimeters in axons of axel / Taxol® (BMS)nerve cells. Microtubules Docetaxel / Taxotere® (Sanofi s US)serve as structural Nanoparticle paclitaxel (ABI-007) /components within cells and Abraxane® (Abraxis BioScience, Inc.)are involved in many Ixabepilone / IXEMPRATM (BMS)cellular processes includingmitosis, cytokinesis, andvesicular transport.

Kinase inhibitors Kinases are enzymes that Imatinib mesylate / Gleevec (Novartis)catalyze the transfer of Sunitinib malate / Sutent® r)ate groups from nib tosylate / Nexavar® (Bayer)high-energy, phosphate- Nilotinib hydrochloride monohydrate /donating molecules to Tasigna® (Novartis), Osimertinib,specific substrates, and are tinib, Trametinib, Dabrafenib,utilized to transmit signals Dinacicliband regulate complexprocesses in cells.

Protein sis Induces cell apoptosis L-asparaginase / Elspar® (Merck & Co.)inhibitorsImmunotherapeutic Induces cancer patients to Alpha eronagents exhibit immune Angiogenesis Inhibitor / Avastin®1'6 SpOl’lSlVCl’lCSS (Genentech)IL-2—> Interleukin 2 (Aldesleukin) / Proleukin® (Chiron)IL-12—> Interleukin 12Antibody / small moleculeimmune checkpoint Anti-CTLA-4 and PR-l therapiesmodulators Yervoy® (ipilimumab; Bristol-Myers Squibb)Opdivo® (nivolumab; l-Myers )Keytrada® (pembrolizumab; Merck)Hormones Hormone therapies Toremifene citrate / Fareston® (GTX, Inc.)associated with menopause Fulvestrant / Faslodex® (AstraZeneca)and aging seek to increase Raloxifene HCL / Evista® (Lilly)the amount of certain azole / Arimidex® (AstraZeneca)hormones in your body to Letrozole / Femara® (Novartis)compensate for age- or Fadrozole (CGS l6949A )disease-related hormonal Exemestane / Aromasin® (Pharmacia &declines. Hormone therapy )as a cancer treatment either Leuprolide acetate / Eligard® (QTL USA)reduces the level of specific ® (TAP Pharm)hormones or alters the Goserelin acetate / Zoladex® (AstraZeneca)’s ability to use these Triptorelin pamoate / Trelstar® (Watson Labs)hormones to grow and Buserelin / Suprefact® (Sanofi Aventis)spread. Nafarelin / Synarel® r)Cetrorelix / Cetrotide® (EMD Serono)tamide / Casodex® Zeneca)Nilutamide / Nilandron® (Aventis Pharm.)MEl 24985843V.1 428117813-12620Megestrol acetate / Megace® (BMS)Somatostatin Analogs (Octreotide acetate /Sandostatin® (Novartis)Glucocorticoids Anti-inflammatory drugs soloneused to reduce swelling that Dexamethasone / Decadron® (Wyeth)causes cancer pain.

Aromatose tors Includes imidazoles KetoconazolemTOR inhibitors the mTOR signaling Sirolimus (Rapamycin) / Rapamune® (Wyeth)pathway was originally Temsirolimus (CCI-779) / Torisel® (Wyeth)discovered during studies of Deforolimus 73) / (Ariad Pharm.)the immunosuppressive Everolimus (RADOOI) / Certican® (Novartis)agent rapamycin. Thishighly conserved pathwayregulates cell proliferationand metabolism in responseto nmental factors,linking cell growth factorreceptor signaling viaphosphoinositidekinase(PI-3K) to cellgrowth, proliferation, andangiogenesis.

In addition to the above anti-cancer agents, the anti-B7-H3 antibodies and ADCs describedherein may be administered in combination with the agents described herein. Further, theaforementioned anti-cancer agents may also be used in the ADCs of the invention.

In particular embodiments, the anti-B7-H3 antibodies or ADCs can be administered alone orwith another anti-cancer agent which acts in conjunction with or synergistically with the antibody totreat the disease ated with B7-H3 activity. Such anti-cancer agents include, for example, agentswell known in the art (6. g., xins, chemotherapeutic agents, small molecules and radiation).

Examples of anti-cancer agents include, but are not limited to, Panorex -Welcome), Rituxan(IDEC/Genentech/Hoffman la Roche), Mylotarg (Wyeth), Campath (Millennium), Zevalin (IDEC andng AG), Bexxar (Corixa/GSK), Erbitux (Imclone/BMS), Avastin (Genentech) and tin(Genentech/Hoffman la Roche). Other anti-cancer agents include, but are not limited to, thosedisclosed in US. Patent No. 7,598,028 and International Publication No. W02008/100624, thecontents of which are hereby incorporated by reference. One or more anti-cancer agents may beadministered either simultaneously or before or after stration of an antibody or antigen bindingportion thereof of the invention.

In particular embodiments of the invention, the anti-B7-H3 antibodies or ADCs describedherein can be used in a combination therapy with an apoptotic agent, such as a Bcl-XL tor or aBcl-2 (B -cell lymphoma 2) inhibitor (e.g., ABT-l99 (venetoclaX)) to treat , such as leukemia, ina subject. In one embodiment, the anti-B7-H3 antibodies or ADCs bed herein can be used in aation therapy with a Bcl-XL inhibitor for treating . In one embodiment, the anti-B7-H3MEl 24985843V.1 429-12620antibodies or ADCs described herein can be used in a combination y with venetoclax fortreating .

In particular embodiments of the invention, the anti-B7-H3 antibodies or ADCs describedherein can be used in a combination therapy with an inhibitor of NAMPT (see examples of inhibitorsin US 2013/0303509; Abeie, Inc., incorporated by reference herein) to treat a subject in needthereof. NAMPT (also known as pre-B -cell-colony-enhancing factor (PBEF) and in) is anenzyme that catalyzes the phosphoribosylation of nicotinamide and is the rate-limiting enzyme in oneof two pathways that salvage NAD. In one embodiment of the invention, anti-B7-H3 antibodies andADCs described herein are administered in combination with a NAMPT inhibitor for the treatment ofcancer in a subject.

In ular ments of the invention, the anti-B7-H3 antibodies or ADCs describedherein can be used in a combination therapy with SN-38, which is the active lite of thetopoisomerase inhibitor irinotecan.

In other embodiments of the ion, the anti-B7-H3 antibodies or ADCs described hereincan be used in a combination therapy with a PARP (poly ADP ribose polymerase) inhibitor,e.g.,veliparib, to treat cancer, including breast, ovarian and non-small cell lung cancers.

Further es of additional therapeutic agents that can be co-administered and/orformulated with anti-B7-H3 antibodies or 7-H3 ADCs described , include, but are notlimited to, one or more of: inhaled steroids; beta-agonists, e.g., short-acting or long- acting beta-agonists; antagonists of leukotrienes or leukotriene receptors; ation drugs such as ADVAIR;IgE inhibitors, 6. g., anti-IgE antibodies (6. g., XOLAIR®, omalizumab); phosphodiesterase inhibitors(6. g., PDE4 inhibitors); xanthines; anticholinergic drugs; mast cell-stabilizing agents such ascromolyn; IL-4 inhibitors; IL-5 inhibitors; eotaxin/CCR3 inhibitors; antagonists of histamine or itsreceptors ing H1, H2, H3, and H4, and antagonists of glandin D or its receptors (DPl andCRTH2). Such combinations can be used to treat, for example, asthma and other respiratorydisorders. Other examples of additional therapeutic agents that can be co-administered and/orformulated with anti-B7-H3 antibodies or anti-B7-H3 ADCs described herein, include, but are notlimited to, one or more of, an Dl antibody (e.g., pembrolizumab), an anti-PD-Ll antibody (e.g.,atezolizumab), an TLA-4 antibody (e.g., ipilimumab), a MEK tor (e. g., trametinib), anERK inhibitor, a BRAF inhibitor (e.g., dabrafenib), osimertinib (AZD929l), erlotinib, gefitinib,sorafenib, a CDK9 inhibitor (e.g., dinaciclib), a MCL-l inhibitor, temozolomide, a Bcl-xL inhibitor,a Bcl-2 inhibitor (e.g., venetoclax), ibrutinib, a mTOR inhibitor (e.g., everolimus), a PI3K inhibitor(e. g., buparlisib), duvelisib, idelalisib, an AKT inhibitor, a HER2 inhibitor (e.g., lapatinib), Herceptin,a taxane (e. g., docetaxel, paclitaxel, nab-paclitaxel), an ADC comprising an auristatin, an ADCcomprising a PBD (e. g., rovalpituzumab tesirine), an ADC comprising a maytansinoid (e. g., TDMl),a TRAIL agonist, a proteasome tor (e.g., bortezomib), and a nicotinamidephosphoribosyltransferase (NAMPT) inhibitor. Additional examples of therapeutic agents that can beMEl 24985843V.1 430117813-12620co-administered and/or formulated with one or more anti-B7-H3 antibodies or nts thereofinclude one or more of: TNF antagonists (e.g., a e nt of a TNF receptor, 6. g., p55 or p75human TNF receptor or derivatives thereof, e.g., 75 kD TNFR-IgG (75 kD TNF receptor-IgG fusionprotein, ENBREL)); TNF enzyme antagonists, e.g., TNF converting enzyme (TACE) inhibitors;muscarinic receptor antagonists; ta antagonists; interferon gamma; perfenidone;chemotherapeutic agents, e.g., methotrexate, leflunomide, or a sirolimus (rapamycin) or an analogthereof, e.g., CCI-779; COX2 and cPLA2 inhibitors; NSAIDs; immunomodulators; p38 inhibitors,TPL-2, MK-2 and NFkB inhibitors, among others.

Other preferred combinations are cytokine suppressive anti-inflammatory drug(s) (CSAIDs);antibodies to or antagonists of other human cytokines or growth factors, for example, IL-1, IL-2, IL-3,IL-4, IL-5, IL-6, IL-7, IL-8, IL-15, IL-l6, IL-l8, IL-21, IL-31, interferons, EMAP-II, GM-CSF, FGF,EGF, PDGF, and edothelin-l, as well as the ors of these cytokines and growth s.

Antibodies of the invention, or antigen binding portions f, can be combined with antibodies tocell e molecules such as CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69,CD80 (B7.l), CD86 (B7.2), CD90, CTLA, CTLA-4, PD-l, or their ligands including CD154 (gp39 orPreferred combinations of therapeutic agents may interfere at different points in theinflammatory cascade; preferred es include TNF antagonists like chimeric, humanized orhuman TNF antibodies, adalimumab, (HUMIRA; D2E7; PCT Publication No. WO 97/29131 and US.

Patent No. 6,090,382, incorporated by reference herein), CA2 (RemicadeTM), CDP 571, and solublep55 or p75 TNF receptors, derivatives, f, (p75TNFRlgG (EnbrelTM) or p55TNFRlgG(Lenercept), and also TNF converting enzyme (TACE) inhibitors; similarly IL-l tors(Interleukin-l-converting enzyme inhibitors, IL-lRA etc.) may be effective for the same reason.

Other preferred combinations include Interleukin 4.

The pharmaceutical compositions of the invention may include a “therapeutically effectiveamount” or a “prophylactically effective amount” of an antibody or antibody portion of the invention.

A peutically effective amount” refers to an amount effective, at dosages and for periods of timenecessary, to achieve the desired therapeutic . A therapeutically effective amount of theantibody or antibody portion may be ined by a person skilled in the art and may vary accordingto s such as the disease state, age, sex, and weight of the individual, and the ability of theantibody or antibody portion to elicit a desired response in the individual. A therapeutically effectiveamount is also one in which any toxic or detrimental effects of the antibody, or antibody portion, areoutweighed by the therapeutically beneficial effects. A “prophylactically ive amount” refers toan amount effective, at dosages and for periods of time ary, to achieve the desired prophylacticresult. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease,the prophylactically effective amount will be less than the therapeutically effective amount.

MEl 24985843V.1 431117813-12620Dosage regimens may be adjusted to provide the optimum desired response (e.g., atherapeutic or prophylactic response). For example, a single bolus may be administered, severaldivided doses may be administered over time or the dose may be proportionally reduced or increasedas indicated by the cies of the therapeutic situation. It is especially advantageous to formulateeral itions in dosage unit form for ease of administration and uniformity of dosage.

Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for themammalian subjects to be treated; each unit containing a predetermined quantity of active ndcalculated to produce the desired therapeutic effect in association with the required ceuticalr. The specification for the dosage unit forms of the invention are dictated by and directlydependent on (a) the unique characteristics of the active compound and the particular therapeutic orprophylactic effect to be ed, and (b) the limitations inherent in the art of compounding such anactive compound for the treatment of sensitivity in individuals.

An exemplary, non-limiting range for a therapeutically or prophylactically effective amountof an ADC, an antibody or antibody portion of the invention is 0.1-20 mg/kg, more preferably 1-10mg/kg. In one embodiment, the dose of the antibody or ADC described herein is l to 6 mg/kg,ing the individual doses recited therein, e.g., 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, and6 mg/kg. In another embodiment, the dose of the antibody or ADC described herein is l to 200ug/kg, including the individual doses recited therein, e.g., l ug/kg, 2 ug/kg, 3 ug/kg, 4 ug/kg, 5ug/kg, 10 ug/kg, 20 ug/kg, 30 ug/kg, 40 ug/kg, 50 ug/kg, 60 ug/kg, 80 ug/kg, 100 ug/kg, 120 ug/kg,140 ug/kg, 160 ug/kg, 180 ug/kg and 200 ug/kg. It is to be noted that dosage values may vary withthe type and severity of the condition to be alleviated. It is to be further understood that for anyparticular subject, specific dosage ns should be adjusted over time according to the individualneed and the professional judgment of the person administering or supervising the administration ofthe compositions, and that dosage ranges set forth herein are exemplary only and are not intended tolimit the scope or practice of the claimed composition.

In one embodiment, an anti-B7-H3 ADC, including an ADC comprising antibody huAbl3vl,huAb3v2.5, or 2.6, is administered to a subject in need thereof, e.g., a subject having cancer,at a dose of 0.1 to 30 mg/kg. In another embodiment, the anti-B7-H3 antibody, e.g., huAbl3vl,huAb3v2.5, 2.6, or an antigen g portion thereof, is administered to a subject in needthereof, e.g., a subject having cancer, as an ADC at a dose of l to 15 mg/kg. In another embodiment,the anti-B7-H3 antibody, e.g., huAbl3vl, 2.5, huAb3v2.6, or an antigen binding portionthereof, is administered to a subject in need f, 6. g., a subject having cancer, as an ADC at a doseof l to 10 mg/kg. In another embodiment, the 7-H3 antibody, e.g., huAbl3vl, huAb3v2.5,2.6, or an antigen binding n thereof, is administered to a subject in need thereof, e.g., asubject having cancer, as an ADC at a dose of 2 to 3. In another embodiment, the anti-B7-H3antibody, e.g., huAbl3vl, huAb3v2.5, huAb3v2.6, or an antigen binding portion thereof, isMEl 24985843V.1 432-12620administered to a subject in need thereof, e.g., a subject having cancer, as an ADC at a dose of l to 4mg/kg.

In one embodiment, an anti-B7-H3 antibody or ADC described herein, e.g., huAbl3vl,huAb3v2.5, huAb3v2.6, is administered to a subject in need thereof, e.g., a subject having cancer, asan ADC at a dose of l to 200 ug/kg. In another embodiment, the anti-B7-H3 antibody, e.g.,huAbl3vl, huAb3v2.5, 2.6, or an antigen binding portion thereof, is administered to a subjectin need thereof, e.g., a subject having cancer, as an ADC at a dose of 5 to 150 ug/kg. In anotherembodiment, the anti-B7-H3 antibody, e.g., huAbl3vl, huAb3v2.5, huAb3v2.6, or an n bindingportion thereof, is administered to a subject in need thereof, e.g., a t having cancer, as an ADCat a dose of 5 to 100 ug/kg. In another embodiment, the anti-B7-H3 antibody, e.g., huAbl3vl,huAb3v2.5, huAb3v2.6, or an antigen binding portion thereof, is administered to a subject in needthereof, e.g., a subject having cancer, as an ADC at a dose of 5 to 90 ug/kg. In another embodiment,the anti-B7-H3 antibody, e.g., vl, huAb3v2.5, huAb3v2.6, or an antigen binding portionf, is administered to a subject in need thereof, 6. g., a subject having cancer, as an ADC at a doseof 5 to 80 ug/kg. In r embodiment, the anti-B7-H3 antibody, e.g., huAbl3vl, huAb3v2.5,huAb3v2.6, or an antigen binding portion thereof, is administered to a subject in need thereof, e.g., asubject having cancer, as an ADC at a dose of 5 to 70 ug/kg. In another embodiment, the anti-B7-H3antibody, e.g., huAbl3vl, huAb3v2.5, huAb3v2.6, or an n binding n thereof, isadministered to a subject in need thereof, e.g., a subject having cancer, as an ADC at a dose of 5 to 60ug/kg. In r embodiment, the anti-B7-H3 antibody, e.g., huAbl3vl, huAb3v2.5, huAb3v2.6, oran antigen binding portion thereof, is administered to a subject in need thereof, 6. g., a subject havingcancer, as an ADC at a dose of 10 to 80 ug/kg.

Doses described above may be useful for the administration of either anti-B7-H3 ADCs orantibodies disclosed herein.

In another aspect, this application provides a method for detecting the presence of B7-H3 in asample in vitro (e.g., a biological , such as serum, plasma, tissue, and ). The subjectmethod can be used to diagnose a er, 6. g., a cancer. The method includes: (i) contacting thesample or a control sample with the anti-B7-H3 antibody or nt thereof as described herein; and(ii) detecting ion of a complex between the anti-B7-H3 antibody or fragment thereof, and thesample or the control , wherein a tically significant change in the formation of thecomplex in the sample relative to the control sample is indicative of the presence of B7-H3 in thesample.

Given their ability to bind to human B7-H3, the anti-human B7-H3 antibodies, or portionsthereof, of the invention, (as well as ADCs thereof) can be used to detect human B7-H3 (e. g., in abiological sample, such as serum or plasma), using a conventional immunoassay, such as an enzymelinked sorbent assays (ELISA), an mmunoassay (RIA) or tissue immunohistochemistry.

In one aspect, the invention provides a method for detecting human B7-H3 in a ical sampleMEl 24985843V.1 433117813-12620comprising contacting a biological sample with an antibody, or dy portion, of the invention anddetecting either the antibody (or antibody portion) bound to human B7-H3 or unbound antibody (orantibody portion), to thereby detect human B7-H3 in the biological sample. The antibody is directlyor indirectly labeled with a detectable substance to facilitate detection of the bound or unboundantibody. Suitable detectable substances include various enzymes, prosthetic groups, fluorescentmaterials, luminescent materials and radioactive materials. es of suitable s includehorseradish peroxidase, alkaline phosphatase, B-galactosidase, or acetylcholinesterase; examples ofsuitable prosthetic group complexes include streptavidin/biotin and avidin/biotin; es of suitablecent materials include iferone, cein, fluorescein isothiocyanate, rhodamine,rotriazinylamine fluorescein, dansyl chloride or phycoerythrin; an example of a luminescentmaterial includes luminol; and examples of suitable radioactive material e 3H, 14C, 35S, 90Y, 99Tc,111In, 125I, 131I, 177Lu,166Ho, or 153Sm.

Alternative to labeling the antibody, human B7-H3 can be assayed in biological fluids by aition immunoassay utilizing th7-H3 rds labeled with a detectable substance and anunlabeled anti-human B7-H3 antibody. In this assay, the biological sample, the labeled th7-H3standards and the anti-human B7-H3 antibody are combined and the amount of labeled th7-H3standard bound to the unlabeled antibody is determined. The amount of human B7-H3 in thebiological sample is inversely proportional to the amount of labeled th7-H3 standard bound to theanti-B7-H3 antibody. Similarly, human B7-H3 can also be assayed in ical fluids by acompetition immunoassay ing th7-H3 rds labeled with a detectable substance and anunlabeled anti-human B7-H3 antibody.

In yet another aspect, this ation provides a method for detecting the ce of B7-H3in vivo (e.g., in vivo imaging in a subject). The subject method can be used to diagnose a disorder,e.g., a B7-H3 -associated disorder. The method includes: (i) administering the anti-B7-H3 antibody orfragment thereof as bed herein to a subject or a control subject under conditions that allowbinding of the antibody or fragment to B7-H3; and (ii) detecting formation of a complex between theantibody or fragment and B7-H3, wherein a statistically significant change in the formation of thecomplex in the subject relative to the control subject is indicative of the presence of B7-H3.

VI. Pharmaceutical CompositionsThe invention also provides pharmaceutical compositions sing an antibody, or antigenbinding portion thereof, or ADC of the invention and a pharmaceutically acceptable carrier. Thepharmaceutical compositions comprising antibodies or ADCs of the invention are for use in, but notlimited to, diagnosing, detecting, or monitoring a disorder, in ting, ng, ng, orameliorating of a disorder or one or more symptoms thereof, and/or in research. In a specificembodiment, a composition comprises one or more antibodies of the invention. In anotherMEl 24985843v.1 434117813-12620embodiment, the pharmaceutical composition comprises one or more antibodies or ADCs of theinvention and one or more prophylactic or therapeutic agents other than antibodies or ADCs of theinvention for treating a er in which B7-H3 activity is detrimental. Preferably, the prophylacticor therapeutic agents known to be useful for or having been or currently being used in the prevention,treatment, management, or amelioration of a disorder or one or more symptoms thereof. In accordancewith these ments, the composition may further comprise of a carrier, diluent or excipient.

The antibodies and antibody-portions or ADCs of the invention can be incorporated intopharmaceutical compositions suitable for administration to a subject. Typically, the pharmaceuticalition ses an antibody or antibody portion of the invention and a pharmaceuticallyacceptable carrier. As used herein, “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungal agents, ic and absorptionng agents, and the like that are physiologically ible. es of pharmaceuticallyacceptable carriers include one or more of water, saline, ate buffered saline, dextrose, ol,ethanol and the like, as well as combinations f. In many cases, it will be preferable to eisotonic , for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in thecomposition. Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliarysubstances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelflife or effectiveness of the antibody or antibody portion or ADC.s delivery systems are known and can be used to administer one or more antibodies orADCs of the invention or the combination of one or more antibodies of the invention and aprophylactic agent or eutic agent useful for preventing, managing, treating, or ameliorating adisorder or one or more symptoms thereof, e.g., encapsulation in liposomes, microparticles,microcapsules, recombinant cells capable of expressing the antibody or antibody fragment, or-mediated endocytosis (see, e.g., Wu and Wu, J. Biol. Chem. 262:4429-4432 (1987)), construction of anucleic acid as part of a retroviral or other vector, etc. Methods of administering a prophylactic ortherapeutic agent of the invention include, but are not limited to, parenteral administration (e.g.,intradermal, intramuscular, intraperitoneal, intravenous and subcutaneous), epidural administration,intratumoral administration, and mucosal administration (6. g., intranasal and oral routes). In addition,pulmonary administration can be employed, e.g., by use of an r or nebulizer, and formulationwith an aerosolizing agent. See, e.g., US. Pat. Nos. 6,019,968, 5,985, 320, 5,985,309, 5,934, 272,,874,064, 5,855,913, 5,290, 540, and 4,880,078; and PCT Publication Nos. WO 92/19244, WO97/32572, WO 97/44013, WO 98/31346, and WO 99/66903, each of which is incorporated herein bynce their entireties. In one embodiment, an antibody of the invention, combination y, or aition of the invention is administered using Alkermes AIR® pulmonary drug deliverytechnology (Alkermes, Inc., Cambridge, Mass.). In a specific embodiment, prophylactic or therapeuticagents of the invention are administered intramuscularly, enously, intratumorally, orally,intranasally, pulmonary, or aneously. The prophylactic or therapeutic agents may beMEl 24985843V.1 435117813-12620administered by any convenient route, for example by on or bolus injection, by tionh epithelial or mucocutaneous linings (e. g., oral mucosa, rectal and intestinal mucosa, etc.) andmay be administered together with other biologically active agents. Administration can be systemic orlocal.

In a specific embodiment, it may be desirable to administer the prophylactic or therapeuticagents of the invention locally to the area in need of treatment; this may be achieved by, for example,and not by way of limitation, local infusion, by injection, or by means of an implant, said implantbeing of a porous or non-porous material, including membranes and matrices, such as sialasticmembranes, rs, fibrous matrices (e. g., Tissuel®), or collagen matrices. In one embodiment, aneffective amount of one or more antibodies of the invention antagonists is administered locally to theaffected area to a subject to prevent, treat, manage, and/or ameliorate a disorder or a symptom thereof.

In r embodiment, an effective amount of one or more antibodies of the invention isadministered locally to the affected area in combination with an effective amount of one or moretherapies (e. g., one or more prophylactic or therapeutic agents) other than an antibody of the ionof a subject to prevent, treat, manage, and/or ameliorate a er or one or more symptoms thereof.

In another embodiment, the prophylactic or eutic agent of the invention can bered in a controlled release or sustained release system. In one embodiment, a pump may be usedto achieve controlled or sustained release (see Langer, supra; Sefton, 1987, CRC Crit. Ref. Biomed.

Eng. 14:20; Buchwald et al., 1980, Surgery 88:507; Saudek et al., 1989, N. Engl. J. Med. 321:574). Inr embodiment, polymeric materials can be used to achieve controlled or sustained release of thetherapies of the invention (see e. g., Medical Applications of Controlled Release, Langer and Wise(eds.), CRC Pres., Boca Raton, Fla. (1974); Controlled Drug Bioavailability, Drug Product Designand Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and , 1983, J.,Macromol. Sci. Rev. ol. Chem. 23:61; see also Levy et al., 1985, Science 228:190; During etal., 1989, Ann. Neurol. 25:351; Howard et al., 1989, J. Neurosurg. 7 1:105); US. Pat. No. 377;US. Pat. No. 5, 916,597; U. S. Pat. No. 015; US. Pat. No. 5,989,463; US. Pat. No. 5,128,326;PCT Publication No. W0 99/15154; and PCT Publication No. WO 99/20253. Examples of polymersused in sustained release formulations include, but are not limited to, poly(2-hydroxy ethylmethacrylate), poly(methyl methacrylate), poly(acrylic acid), poly(ethylene-co-vinyl acetate),ethacrylic acid), ycolides (PLG), hydrides, poly(N- vinyl pyrrolidone), poly(vinylalcohol), polyacrylamide, poly(ethylene glycol), polylactides (PLA), poly(lactide-co-glycolides)(PLGA), and polyorthoesters. In a preferred ment, the polymer used in a sustained releaseformulation is inert, free of leachable impurities, stable on storage, sterile, and biodegradable. In yetanother embodiment, a controlled or sustained release system can be placed in proximity of theprophylactic or therapeutic target, thus requiring only a fraction of the systemic dose (see, e. g.,Goodson, in Medical ations of Controlled Release, supra, vol. 2, pp. 115-138 ).

MEl 24985843V.1 436117813-12620Controlled e systems are discussed in the review by Langer (1990, Science 249: 1527-1533). Any technique known to one of skill in the art can be used to produce sustained eformulations comprising one or more therapeutic agents of the invention. See, e. g., U. S. Pat. No.4,526, 938, PCT publication WO 91/05548, PCT publication WO 96/20698, Ning et al., 1996,“Intratumoral Radioimmunotherapy of a Human Colon Cancer Xenograft Using a Sustained-ReleaseGel,” Radiotherapy & Oncology 39:179-189, Song et al., 1995, “Antibody Mediated Lung Targetingof Long- Circulating Emulsions,” PDA Journal ofPharmaceutical Science & Technology 50:372-397,Cleek et al., 1997, “Biodegradable Polymeric Carriers for a bFGF Antibody for CardiovascularApplication,” Pro. Int’l. Symp. Control. Rel. . Mater. 24:853-854, and Lam et al., 1997,“Microencapsulation of Recombinant Humanized onal Antibody for Local Delivery,” Proc.

Int’l. Symp. Control Rel. Bioact. Mater. 24:759- 760, each of which is incorporated herein byreference in their entireties.

In a specific embodiment, where the composition of the invention is a nucleic acid encoding aprophylactic or therapeutic agent, the nucleic acid can be administered in vivo to promote expressionof its encoded prophylactic or therapeutic agent, by ucting it as part of an appropriate nucleicacid expression vector and stering it so that it becomes ellular, e. g., by use of a retroviralvector (see U. S. Pat. No. 4,980,286), or by direct injection, or by use of microparticle bombardment(e. g., a gene gun; Biolistic, Dupont), or coating with lipids or cell-surface ors or transfectingagents, or by administering it in linkage to a homeobox-like peptide which is known to enter thes (see, e. g., Joliot et al., 1991, Proc. Natl. Acad. Sci. USA 4-1868). Alternatively, anucleic acid can be introduced ellularly and incorporated within host cell DNA for expressionby homologous recombination.

A pharmaceutical composition of the invention is ated to be compatible with itsintended route of administration. Examples of routes of administration include, but are not limited to,parenteral, e. g., intravenous, intradermal, subcutaneous, oral, intranasal (e.g., inhalation), ermal(e. g., topical), transmucosal, and rectal administration. In a specific embodiment, the composition isformulated in accordance with routine procedures as a pharmaceutical composition adapted forintravenous, aneous, intramuscular, oral, intranasal, or topical administration to human beings.

Typically, itions for intravenous stration are ons in sterile isotonic aqueous buffer.

Where necessary, the composition may also include a solubilizing agent and a local anesthetic such aslignocaine to ease pain at the site of the injection.

If the method of the invention comprises intranasal administration of a composition, thecomposition can be ated in an aerosol form, spray, mist or in the form of drops. In particular,prophylactic or therapeutic agents for use according to the invention can be conveniently delivered inthe form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of asuitable propellant (e. g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,carbon dioxide or other suitable gas). In the case of a pressurized aerosol the dosage unit may beMEl 24985843V.1 437117813-12620determined by ing a valve to deliver a metered amount. Capsules and cartridges (composed of,e.g., gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of thecompound and a suitable powder base such as lactose or starch.

If the method of the invention comprises oral administration, compositions can be formulatedorally in the form of tablets, capsules, cachets, gel caps, solutions, suspensions, and the like. Tabletsor capsules can be ed by conventional means with pharmaceutically acceptable excipients suchas binding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate);lubricants (e.g., magnesium stearate, talc, or ); disintegrants (e.g., potato starch or sodium starchglycolate) ; or wetting agents (6. g., sodium lauryl sulphate). The tablets may be coated by methodsnown in the art. Liquid preparations for oral administration may take the form of, but notlimited to, ons, syrups or suspensions, or they may be presented as a dry product for constitutionwith water or other suitable e before use. Such liquid preparations may be prepared bytional means with pharmaceutically able additives such as suspending agents (6. g.,sorbitol syrup, cellulose derivatives, or hydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (6. g., almond oil, oily esters, ethyl alcohol, or fractionated vegetableoils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). The preparationsmay also n buffer salts, flavoring, coloring, and sweetening agents as appropriate. Preparationsfor oral administration may be suitably formulated for slow release, controlled release, or sustainedrelease of a lactic or therapeutic agent(s).

The method of the invention may comprise pulmonary stration, 6. g., by use of aninhaler or nebulizer, of a composition formulated with an aerosolizing agent. See, 6. g., US. Pat. Nos.6,019, 968, 5,985, 320, 5, 985,309, 5,934,272, 5,874,064, 5,855,913, 540, and 4,880,078; andPCT Publication Nos. W0 92/ 19244, WO 97/32572, WO 97/44013, WO 98/31346, and WO99/66903, each of which is incorporated herein by nce their entireties. In a specific embodiment,an dy of the ion, combination therapy, and/or composition of the ion isadministered using Alkermes AIR® pulmonary drug delivery technology (Alkermes, Inc., Cambridge,Mass.).

The method of the invention may comprise administration of a composition formulated forparenteral administration by injection (e.g., by bolus injection or continuous infusion). Formulationsfor injection may be presented in unit dosage form (6. g., in ampoules or in dose containers) withan added preservative. The compositions may take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and may contain atory agents such as suspending, stabilizingand/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitutionwith a suitable vehicle (e.g., sterile pyrogen-free water) before use.

The methods of the invention may additionally comprise of administration of compositionsformulated as depot preparations. Such long acting ations may be administered by implantationMEl 24985843v.1 438117813-12620(e. g., subcutaneously or intramuscularly) or by intramuscular injection. Thus, for e, theitions may be formulated with suitable polymeric or hydrophobic materials (e.g., as anemulsion in an acceptable oil) or ion exchange resins, or as sparingly e derivatives (6. g., as asparingly e salt).

The methods of the invention encompass administration of compositions formulated asneutral or salt forms. Pharmaceutically acceptable salts include those formed with anions such asthose derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed withcations such as those derived from , potassium, ammonium, calcium, ferric hydroxides,isopropylamine, triethylamine, 2- ethylamino ethanol, histidine, procaine, etc.

Generally, the ingredients of compositions are supplied either separately or mixed together inunit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermeticallysealed container such as an ampoule or sachette ting the quantity of active agent. Where themode of administration is infusion, composition can be dispensed with an infusion bottle containingsterile pharmaceutical grade water or saline. Where the mode of administration is by injection, anampoule of sterile water for ion or saline can be provided so that the ingredients may be mixedprior to administration.

In particular, the invention also provides that one or more of the prophylactic or therapeuticagents, or pharmaceutical compositions of the ion is ed in a hermetically sealedcontainer such as an ampoule or te indicating the ty of the agent. In one embodiment, oneor more of the prophylactic or therapeutic agents, or pharmaceutical compositions of the invention issupplied as a dry sterilized lyophilized powder or water free concentrate in a hermetically sealedcontainer and can be tituted (e.g., with water or saline) to the appropriate concentration foradministration to a subject. Preferably, one or more of the prophylactic or therapeutic agents orpharmaceutical compositions of the ion is supplied as a dry sterile lyophilized powder in ahermetically sealed container at a unit dosage of at least 5 mg, at least 10 mg, at least 15 mg, at leastmg, at least 35 mg, at least 45 mg, at least 50 mg, at least 75 mg, or at least 100 mg. Thelyophilized lactic or therapeutic agents or pharmaceutical compositions of the invention shouldbe stored at between 2° C. and 8° C. in its original container and the prophylactic or therapeuticagents, or pharmaceutical compositions of the invention should be administered within 1 week, within5 days, within 72 hours, within 48 hours, within 24 hours, within 12 hours, within 6 hours, within 5hours, within 3 hours, or within 1 hour after being reconstituted. In an alternative embodiment, one ormore of the prophylactic or eutic agents or pharmaceutical compositions of the invention issupplied in liquid form in a hermetically sealed container indicating the quantity and concentration ofthe agent. Preferably, the liquid form of the administered composition is ed in a hermeticallysealed container at least 0.25 mg/ml, at least 0.5 mg/ml, at least 1 mg/ml, at least 2.5 mg/ml, at least 5mg/ml, at least 8 mg/ml, at least 10 mg/ml, at least 15 mg/kg, at least 25 mg/ml, at least 50 mg/ml, atMEl 24985843V.1 439117813-12620least 75 mg/ml or at least 100 mg/ml. The liquid form should be stored at between 2° C. and 8° C. inits original container.

The antibodies and antibody-portions of the invention can be incorporated into apharmaceutical composition suitable for parenteral administration. ably, the antibody orantibody-portions will be prepared as an injectable solution containing 0.1-250 mg/ml antibody. Theinjectable solution can be composed of either a liquid or lyophilized dosage form in a flint or ambervial, ampule or pre-filled syringe. The buffer can be L-histidine (l-50 mM), optimally 5-10 leI, atpH 5.0 to 7.0 (optimally pH 6.0). Other suitable buffers include but are not limited to, sodiumsuccinate, sodium citrate, sodium phosphate or potassium phosphate. Sodium chloride can be used tomodify the ty of the solution at a tration of 0-300 mM (optimally 150 mM for a liquiddosage form). Cryoprotectants can be included for a lyophilized dosage form, principally 0-10%sucrose (optimally 05-10%). Other suitable cryoprotectants include ose and lactose. gagents can be included for a lized dosage form, principally l-10% mannitol (optimally 2-4%).

Stabilizers can be used in both liquid and lyophilized dosage forms, principally l-50 lel L-methionine (optimally 5-10 mM). Other suitable bulking agents e glycine, arginine, can beincluded as 0-0.05% polysorbate-80 (optimally 0.005-0.01%). Additional surfactants include but arenot limited to polysorbate 20 and BRIJ surfactants. The ceutical composition comprising theantibodies and dy-portions of the invention prepared as an injectable solution for parenteraladministration, can further comprise an agent useful as an adjuvant, such as those used to increase theabsorption, or dispersion of a therapeutic protein (e.g., antibody). A particularly useful adjuvant ishyaluronidase, such as Hylenex® (recombinant human hyaluronidase). Addition of hyaluronidase inthe able on improves human bioavailability following parenteral administration,particularly subcutaneous stration. It also allows for greater injection site volumes (Le. greaterthan 1 ml) with less pain and discomfort, and minimum incidence of injection site reactions. (seeWO2004078140, US2006104968 incorporated herein by reference).

The compositions of this invention may be in a variety of forms. These include, for example,liquid, semi-solid and solid dosage forms, such as liquid ons (6. g., injectable and infusiblesolutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. Thered form depends on the intended mode of administration and therapeutic application. Typicalpreferred compositions are in the form of injectable or infusible solutions, such as compositionssimilar to those used for passive immunization of humans with other antibodies. The preferred modeof administration is parenteral (e. g., intravenous, aneous, intraperitoneal, intramuscular). In apreferred embodiment, the antibody is administered by intravenous infusion or injection. In anotherpreferred embodiment, the antibody is administered by uscular or aneous injection.

Therapeutic compositions typically must be e and stable under the conditions ofmanufacture and storage. The ition can be formulated as a solution, microemulsion, dispersion,liposome, or other d structure suitable to high drug concentration. Sterile injectable ons canMEl 24985843V.1 440117813-12620be prepared by incorporating the active compound (i.e., antibody or dy portion) in the requiredamount in an appropriate t with one or a combination of ingredients enumerated above, asrequired, followed by filtered sterilization. Generally, dispersions are prepared by incorporating theactive compound into a sterile vehicle that contains a basic dispersion medium and the required otheringredients from those enumerated above. In the case of sterile, lyophilized powders for the preparationof sterile injectable solutions, the preferred methods of preparation are vacuum drying and spray-dryingthat yields a powder of the active ingredient plus any additional desired ingredient from a previouslysterile-filtered solution f. The proper fluidity of a solution can be maintained, for example, by theuse of a coating such as lecithin, by the nance of the required particle size in the case ofdispersion and by the use of tants. Prolonged absorption of injectable compositions can bebrought about by including, in the composition, an agent that delays tion, for e,monostearate salts and gelatin.

The antibodies and antibody-portions or ADCs of the invention can be administered by avariety of methods known in the art, although for many therapeutic applications, the preferredroute/mode of administration is subcutaneous injection, intravenous injection or infusion. As will beappreciated by the skilled artisan, the route and/or mode of administration will vary depending upon thedesired results. In certain embodiments, the active compound may be ed with a carrier that willprotect the nd against rapid release, such as a controlled release formulation, ing implants,transdermal patches, and microencapsulated delivery systems. Biodegradable, biocompatible polymerscan be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen,polyorthoesters, and polylactic acid. Many methods for the ation of such formulations arepatented or generally known to those skilled in the art. See, e. g., ned and Controlled ReleaseDrug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

In certain embodiments, an antibody or antibody portion or ADC of the invention may be orallyadministered, for example, with an inert diluent or an assimilable edible carrier. The compound (andother ingredients, if desired) may also be enclosed in a hard or soft shell gelatin capsule, compressedinto tablets, or incorporated directly into the subject's diet. For oral therapeutic administration, thecompounds may be incorporated with excipients and used in the form of ingestible tablets, buccals, troches, es, elixirs, suspensions, syrups, wafers, and the like. To administer a compoundof the invention by other than parenteral administration, it may be ary to coat the compound with,or co-administer the compound with, a material to t its inactivation.

In other embodiments, an antibody or antibody portion or ADC of the invention may beconjugated to a polymer-based species such that said polymer-based species may confer a sufficient sizeupon said antibody or antibody portion of the invention such that said antibody or antibody portion ofthe invention benefits from the ed permeability and retention effect (EPR effect) (See also PCTation No. WO2006/042l46A2 and US. Publication Nos. 2004/0028687Al, 2009/0285757Al,MEl 24985843V.1 441117813-12620and 2011/0217363Al, and US. Patent No. 7,695,719 (each of which is incorporated by reference hereinin its entirety and for all purposes).

Supplementary active compounds can also be incorporated into the compositions. In certainembodiments, an antibody or antibody portion or ADC of the invention is formulated with and/or co-stered with one or more additional therapeutic agents that are useful for treating disorders inwhich B7-H3 activity is ental. For example, an anti-hB7-H3 antibody or antibody portion orADC of the invention may be formulated and/or co-administered with one or more additionalantibodies that bind other targets (6. g., antibodies that bind cytokines or that bind cell surfacemolecules). Furthermore, one or more antibodies of the invention may be used in combination withtwo or more of the ing therapeutic . Such combination therapies may advantageouslyutilize lower s of the administered therapeutic agents, thus avoiding possible toxicities orcomplications ated with the various monotherapies.

In certain embodiments, an antibody or ADC to B7-H3 or fragment thereof is linked to ahalf-life extending vehicle known in the art. Such vehicles include, but are not limited to, the Fcdomain, polyethylene glycol, and dextran. Such vehicles are described, e.g., in US. ApplicationSerial No. 09/428,082 and published PCT Application No. WO 99/25044, which are herebyincorporated by reference for any purpose.

It will be readily apparent to those skilled in the art that other suitable modifications andadaptations of the s of the invention described herein are obvious and may be made usingsuitable equivalents without departing from the scope of the ion or the embodiments disclosedherein. Having now bed the invention in detail, the same will be more y understood byreference to the following examples, which are included for es of illustration only and are notintended to be limitingEXAMPLESExample 1: Synthesis of Exemplary Bcl-xL InhibitorsThis example provides synthetic methods for ary Bcl-xL inhibitory compounds W2.01-W2.9l.

Bcl-xL inhibitors (W2.01-W2.9l) and synthons (Examples 2.1-2.176) were named using ACD/Name2012 release (Build 56084, 05 April 2012, Advanced Chemistry pment Inc., Toronto, o),ACD/Name 2014 release (Build 66687, 25 October 2013, ed Chemistry Development Inc.,Toronto, Ontario), ChemDraw® Ver. 9.0.7 (CambridgeSoft, Cambridge, MA), ChemDraw® UltraVer. 12.0 (CambridgeSoft, Cambridge, MA), or ChemDraw® Professional Ver. 15.0.0.106. Bcl-xLinhibitor and synthon intermediates were named with ACD/Name 2012 release (Build 56084, 05April 2012, Advanced Chemistry Development Inc., Toronto, Ontario), ACD/Name 2014 release(Build 66687, 25 October 2013, Advanced Chemistry pment Inc., Toronto, Ontario),ChemDraw® Ver. 9.0.7 (CambridgeSoft, Cambridge, MA), ChemDraw® Ultra Ver. 12.0(CambridgeSoft, Cambridge, MA), or ChemDraw® Professional Ver. 15.0.0.106.

MEl 24985843V.1 442117813-126201.1 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2—({2-[2-(carboxymethoxy)ethoxy]ethyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid (Compound W2.01)1.1.1 3-bromo-5,7-dimethyladamantanecarboxylic acidInto a 50 mL round-bottomed flask at 0 CC, was added bromine (16 mL). Iron powder (7g) was added, and the reaction was stirred at 0 CC for 30 minutes. 3,5-Dimethyladamantane-lcarboxylicacid (12 g) was added. The mixture was warmed up to room temperature and stirred for 3days. A mixture of ice and concentrated HCl was poured into the reaction mixture. The resultingsion was treated twice with NaZSO3 (50 g in 200 mL water) and extracted three times withromethane. The combined organics were washed with lN aqueous HCl, dried over sodiumsulfate, filtered, and concentrated to give the title compound.1.1.2 3-bromo-S,7-dimethyladamantanemethanolTo a solution of Example l.l.l (15.4 g) in tetrahydrofuran (200 mL) was added BH3 (lMin ydrofuran, 150 mL), and the e was d at room temperature overnight. The reactionmixture was then carefully quenched by adding methanol dropwise. The mixture was thenconcentrated under vacuum, and the residue was balanced between ethyl acetate (500 mL) and 2Naqueous HCl (100 mL). The aqueous layer was further extracted twice with ethyl acetate, and thecombined c extracts were washed with water and brine, dried over sodium sulfate, and filtered.

Evaporation of the solvent gave the title compound.1.1.3 1-((3-bromo-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl)-1H-pyrazoleTo a solution of Example 1.1.2 (8.0 g) in toluene (60 mL) was added lH-pyrazole (1.55 g)and cyanomethylenetributylphosphorane (2.0 g), and the mixture was stirred at 90 OC overnight. Thereaction mixture was concentrated, and the residue was purified by silica gel column chromatography(10:1 heptane:ethyl acetate) to give the title nd. MS (ESI) m/e 324.2 (M+H)+.1.1.4 2-{[3,5-dimethy1(1H-pyrazolylmethyl)tricyclo[3.3.1.13’7]decyl]oxy}ethanolTo a solution of Example 1.1.3 (4.0 g) in ethane-l,2-diol (12 mL) was added triethylamine(3 mL). The mixture was stirred at 150 0C under ave conditions (Biotage Initiator) for 45minutes. The mixture was poured into water (100 mL) and extracted three times with ethyl acetate.

The combined organic ts were washed with water and brine, dried over sodium sulfate, andfiltered. Evaporation of the solvent gave a residue that was ed by silica gel chromatography,eluting with 20% ethyl acetate in heptane, ed by 5% methanol in dichloromethane, to give thetitle compound. MS (ESI) m/e 305.2 (M+H)+.

MEl 24985843V.1 443117813-126201.1.5 2-({3,5-dimethyl[(S-methyl-lH-pyrazolyl)methyl]tricyclo[3.3.1.13’7]dec-l-yl}0xy)ethanolTo a cooled (-78 OC) solution of Example 1.1.4 (6.05 g) in tetrahydrofuran (100 mL) wasadded n-BuLi (40 mL, 2.5M in ), and the mixture was stirred at-78 0C for 1.5 hours.

Iodomethane (10 mL) was added h a syringe, and the mixture was stirred at-78 0C for 3 hours.

The reaction mixture was then quenched with aqueous NH4Cl and extracted twice with ethyl acetate,and the combined c extracts were washed with water and brine. After drying over sodiumsulfate, the solution was filtered and concentrated, and the residue was purified by silica gel columntography, eluting with 5% ol in dichloromethane, to give the title compound. MS (ESI)m/e 319.5 (M+H)+.1.1.6 5-dimethyl[2-(hydroxy)eth0xy]tricyclo[3.3.1.13’7]decyl}methyl)i0d0methyl-1H-pyrazoleTo a solution of Example 1.1.5 (3.5 g) in N,N-dimethylformamide (30 mL) was added N-iodosuccinimide (3.2 g), and the mixture was stirred at room temperature for 1.5 hours. The reactionmixture was diluted with ethyl acetate (600 mL) and washed with aqueous NaHSO3, water and brine.

The organic layer was dried over sodium sulfate, filtered and trated under reduced pressure.

The residue was purified by silica gel chromatography, eluting with 20% ethyl acetate indichloromethane, to give the title compound. MS (ESI) m/e 445.3 (M+H)+.1.1.7 1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)i0d0methyl-1H-pyrazoleTert-butyldimethylsilyl romethanesulfonate (5.34 mL) was added to a solution ofExample 1.1.6 (8.6 g) and 2,6-lutidine (3.16 mL) in dichloromethane (125 mL) at-40 OC, and thereaction was allowed to warm to room ature overnight. The mixture was concentrated, and theresidue was ed by silica gel chromatography, eluting with 5-20% ethyl acetate in heptanes, togive the title compound. MS (ESI) m/e 523.4 (M+H)+.1.1.8 1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)-1H-pyrazolen-Butyllithium (8.42 mL, 2.5M in hexanes) was added to Example 1.1.7 (9.8 g) in 120 mLtetrahydrofuran at-78 CC, and the reaction was stirred for 1 minute. Trimethyl borate (3.92 mL) wasadded, and the reaction stirred for 5 minutes. Pinacol (6.22 g) was added, and the reaction wasallowed to warm to room temperature and was stirred 2 hours. The reaction was quenched with pH 7buffer, and the mixture was poured into ether. The layers were separated, and the organic layer wasconcentrated under reduced pressure. The e was purified by silica gel chromatography, elutingwith 1-25% ethyl acetate in heptanes, to give the title compound.

MEI 24985843V.1 444117813-126201.1.9 6-flu0r0br0m0picolinic acidA slurry of 6-aminobromopicolinic acid (25 g) in 400 mL 1:1dichloromethane/chloroform was added to nitrosonium tetrafluoroborate (18.2 g) in dichloromethane(100 mL) at 5 0C over 1 hour. The resulting mixture was stirred for another 30 minutes, then warmedto 35 OC and stirred overnight. The reaction was cooled to room temperature, and then ed to pH4 with aqueous NaHZPO4 solution. The resulting solution was extracted three times withdichloromethane, and the combined extracts were washed with brine, dried over sodium sulfate,filtered and concentrated to provide the title nd.1.1.10 Tert-butyl3-br0m0flu0r0picolinatePara-toluenesulfonyl chloride (27.6 g) was added to a solution of Example 1.1.9 (14.5 g)and pyridine (26.7 mL) in dichloromethane (100 mL) and tert-butanol (80 mL) at 0 CC. The reactionwas stirred for 15 minutes, and then warmed to room temperature, and stirred ght. The onwas concentrated and partitioned between ethyl acetate and aqueous NazCO3 solution. The layerswere separated, and the aqueous layer extracted with ethyl acetate. The organic layers werecombined, rinsed with aqueous NazCO3 solution and brine, dried over sodium sulfate, filtered, andconcentrated to provide the title compound.1.1.11 methyl 2-(5-br0m0(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of methyl 1,2,3,4-tetrahydroisoquinolinecarboxylate hydrochloride (12.37g) and Example 1.1.10 (15 g) in dimethyl sulfoxide (100 mL) was added N,N-diisopropylethylamine(12 mL), and the mixture was stirred at 50 0C for 24 hours. The e was then diluted with ethyle (500 mL) and washed with water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated under d pressure. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in hexane, to give the title compound. MS (ESI) m/e448.4 (M+H)+.1.1.12 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butyldimethylsilyl)0xy)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateA mixture of Example 1.1.11 (3.08 g), Example 1.1.8 (5 g),tris(dibenzylideneacetone)dipalladium(0) (126 mg), 1,3,5,7-tetramethyltetradecyl-2,4,6-trioxaphosphaadamantane (170 mg), and K3PO4 (3.65 g) in 1,4-dioxane (25 mL) and water (25 mL) washeated to 90 0C for 2 hours. The mixture was cooled and poured into 1:1 l ether:ethyl acetate.

The layers were separated, and the organic was washed with saturated s NaHZPO4 solution,water (2x), and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated.

The residue was purified by silica gel chromatography, eluting with 1-25% ethyl acetate in es,to give the title compound. MS (ESI) m/e 799.6 .

MEl 24985843v.1 445117813-126201.1.13 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butyldimethylsilyl)0xy)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylic acide 1.1.12 (5 g) and lithium hydroxide monohydrate (0.276 g) were stirred togetherin a solvent mixture of ydrofuran (50 mL), methanol (5 mL) and water (15 mL) at 70 0C for 2days. The reaction was cooled, acidified with 1M aqueous HCl solution, and ted twice withethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate,filtered, and concentrated. The residue was dissolved in dichloromethane (100 mL), cooled at-40 CC,and 2,6-lutidine (1.8 mL) and tert-butyldimethylsilyl trifluoromethanesulfonate (3.28 g) were added.

The reaction was allowed to warm to room temperature and was stirred for 2 hours. The e wasdiluted with ether, and the layers were separated. The organic layer was concentrated. The residuewas dissolved in tetrahydrofuran and treated with saturated aqueous K2C03 solution for 1 hour. Thismixture was acidified with concentrated HCl and extracted twice with ethyl acetate. The combinedorganic layers were dried over sodium sulfate, filtered, and concentrated under d pressure. Theresidue was purified by silica gel chromatography, eluting with 10-100% ethyl acetate in heptanesthen 5% methanol in ethyl acetate, to give the title compound. MS (ESI) m/e 785.6 (M+H)+.1.1.14 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateExample 1.1.13 (970 mg), N,N-diisopropylethylamine (208 mg), and 2-(3H-]triazolo[4,5-b]pyridinyl)-l,1,3,3-tetramethylisouronium hexafluorophosphate (HATU) (970mg) were stirred in 7 mL N,N-dimethylformamide at 0 0C for 10 minutes. d]thiazolamine(278 mg) was added, and the mixture was d for 24 hours at 50 CC. The mixture was cooled anddiluted with ethyl acetate. The organic layer was washed with water and brine, dried over sodiumsulfate, filtered, and concentrated. The e was dissolved in tetrahydrofuran (50 mL), andtetrabutyl ammonium fluoride (10 mL, 1M in tetrahydrofuran) was added. The reaction was dfor 1 hour, poured into ethyl acetate and washed with pH 7 buffer and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue waspurified by silica gel chromatography, eluting with 10-100% ethyl e in heptanes, to give the titlecompound. MS (ESI) m/e 803.7 (M+H)+.1.1.15 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-0x0eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateMEl 24985843V.1 446117813-12620To an ambient on of Example 1.1.14 (100 mg) in dichloromethane (1.3 mL) wasadded Dess-Martin periodinane (58.1 mg) in a single portion. The reaction was stirred for 0.5 hours,and additional Dess-Martin periodinane (8 mg) was added. The reaction was stirred for 1 hour andquenched by the addition of ~10% aqueous NaOH solution and dichloromethane. The layers wereseparated, and the c layer was washed with ~10% aqueous NaOH solution. The organic layerwas dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to a solid,which was used in the subsequent reaction without further purification. MS (ESI) m/e 801.3 (M+H)+.1.1.16 2-(2-(2—((2-((3-((4—(6-(8—(benzo[d]thiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-yl)-2—(tert-butoxycarbonyl)pyridinyl)methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantan-xy)ethyl)amin0)eth0xy)ethoxy)acetic acidTo an ambient solution of 2—(2-(2-aminoethoxy)ethoxy)acetic acid (22 mg) and Example1.1.15 (100 mg) in methanol (1.3 mL) was added MP-CNBH3 (65 mg, 2.49 mmol/g loading). Thereaction was gently shaken ght and filtered h a 0.4 micron filter. The crude al waspurified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired fractions were ed and freeze-dried toprovide the title nd. MS (ESI) m/e 948.3 (M+H)+.1.1.17 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)(1-((3-(2-((2-(2-xymethoxy)ethoxy)ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo an ambient solution of Example 1.1.16 (15 mg) in romethane (1 mL) was addedtrifluoroacetic acid (1 mL). The reaction was stirred for 16 hours and then concentrated underreduced pressure. The residue was purified by reverse phase HPLC using a Gilson system, elutingwith 20-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions werecombined and freeze-dried to provide the title compound. 1H NMR (400MHz, dimethyl sulfoxide-d6)ppm 12.70 (bs, 2H), 8.29 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53—7.42 (m, 3H), 7.40—7.32 (m, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (bs, 2H), 4.03 (s, 2H), 3.90 (t, 2H), 3.84 (s, 2H), 3.68 (t,2H), 3.63—3.54 (m, 6H), 3.17—3.04 (m, 4H), 3.00 (t, 2H), 2.10 (s, 3H), 1.45—1.40 (m, 2H), 1.36—1.20(m, 4H), 1.21—0.96 (m, 7H), 0.91—0.81 (m, 6H). MS (ESI) m/e 892.3 (M+H)+.1.2 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Compound W2.02)MEl 24985843V.1 447117813-126201.2.1 methyl tert-but0xycarb0nyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2—yl)pyridinyl)-1,2,3,4-tetrahydroisoquinoline-8-carb0xylateTo a solution of Example 1.1.11 (2.25 g) and [1,1'—phenylphosphino)ferrocene]dichloropalladium(II) (205 mg) in acetonitrile (30 mL) was addedtriethylamine (3 mL) and pinacolborane (2 mL), and the mixture was stirred at reflux for 3 hours. Themixture was diluted with ethyl acetate (200 mL) and washed with water and brine. The clayer was dried over sodium e, filtered and concentrated under reduced pressure. Purification ofthe residue by silica gel chromatography, eluting with 20% ethyl acetate in hexane, provided the titlecompound.1.2.2 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2-hydr0xyeth0xy)-,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of Example 1.2.1 (2.25 g) in tetrahydrofuran (30 mL) and water (10 mL) wasadded Example 1.1.6 (2.0 g), 1,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (329mg), tris(dibenzylideneacetone)dipalladium(0) (206 mg) and potassium phosphate tribasic (4.78 g).

The mixture was refluxed overnight, cooled and diluted with ethyl acetate (500 mL). The ingmixture was washed with water and brine, and the organic layer was dried over sodium sulfate,filtered and concentrated. The residue was purified by flash chromatography, g with 20% ethylacetate in heptanes followed by 5% methanol in romethane, to provide the title compound.1.2.3 methyl 2-(6-(tert-butoxycarbonyl)(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a cold solution of Example 1.2.2 (3.32 g) in dichloromethane (100 mL) in an ice-bathwas sequentially added triethylamine (3 mL) and methanesulfonyl chloride (1.1 g). The reactionmixture was stirred at room temperature for 1.5 hours and diluted with ethyl acetate, and washed withwater and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated toprovide the title compound.1.2.4 methyl 2-(5-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(tert-carbonyl)pyridinyl)-1,2,3,4-tetrahydr0is0quinolineylateTo a solution of Example 1.2.3 (16.5 g) in N,N-dimethylformamide (120 mL) was addedsodium azide (4.22 g). The mixture was heated at 80 0C for 3 hours, cooled, diluted with ethyl acetateand washed with water and brine. The organic layer was dried over sodium sulfate, ed, andMEI 24985843V.1 448117813-12620concentrated. The residue was purified by flash chromatography, g with 20% ethyl acetate ines, to provide the title nd.1.2.5 2-(5-(1-((3-(2-azidoethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-tetrahydr0is0quinolinecarboxylic acidTo a solution of e 1.2.4 (10 g) in a mixture of tetrahydrofuran (60 mL), methanol(30 mL) and water (30 mL) was added lithium hydroxide monohydrate (1.2g). The mixture wasstirred at room temperature overnight and neutralized with 2% aqueous HCl. The resulting mixturewas concentrated, and the residue was ved in ethyl acetate (800 mL), and washed with brine.

The organic layer was dried over sodium sulfate, ed, and concentrated to provide the titlecompound.1.2.6 tert-butyl 3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydr0isoquinolin-2(1H)-yl)picolinateA mixture of Example 1.2.5 (10 g), benzo[d]thiazolamine (3.24 g), fluoro-N,N,N',N'—tetramethylformamidinium hexafluorophosphate (5.69 g) and N,N-diisopropylethylamine (5.57 g) inN,N-dimethylformamide (20 mL) was heated at 60 CC for 3 hours, cooled and diluted with ethylacetate. The resulting mixture was washed with water and brine. The organic layer was dried oversodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography, elutingwith 20% ethyl acetate in dichloromethane to give the title compound.1.2.7 tert-butyl 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydr0isoquinolin-2(1H)-yl)picolinateTo a solution of Example 1.2.6 (2.0 g) in tetrahydrofuran (30 mL) was added Pd/C (10%,200 mg). The mixture was stirred under a hydrogen atmosphere overnight. The insoluble materialwas filtered off and the filtrate was concentrated to e the title compound.1.2.8 tert-butyl 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[(2,2,7,7-tetramethyl-10,10-di0xid0-3,3-diphenyl-4,9-di0xathiaazasilapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyraz01yl]pyridinecarb0xylateTo a solution of Example 1.2.7 (500 mg) in N,N-dimethylformamide (8 mL) was added 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (334 mg). The reaction was dat room temperature ght and methylamine (0.3 mL) was added to quench the reaction. Theing mixture was stirred for 20 minutes and purified by reverse-phase chromatography using anMEl 24985843V.1 449117813-12620ix system (C18 column), eluting with 50-100% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound.1.2.9 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidExample 1.2.8 (200 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid(2.5 mL) ght. The reaction e was concentrated and purified by reverse phasechromatography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm12.86 (s, 1H), 8.32 (s, 2H), 8.02 (d, 1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.51 (d, 1H), 7.40-7.49 (m, 2H),7.31-7.39 (m, 2H), 7.27 (s, 1H), 6.95 (d, 1H), 4.94 (s, 2H), 3.87 (t, 2H), 3.81 (s, 2H), .25 (m,2H), 3.03-3.13 (m, 2H), 3.00 (t, 2H), 2.79 (t, 2H), 2.09 (s, 3H), 1.39 (s, 2H), 1.22-1.34 (m, 4H), 0.94-1.18 (m, 6H), 0.85 (s, 6H). MS (ESI) m/e 854.1 (M+H)+.1.3 Synthesis of 2-{[(2-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}ethyl)sulf0nyl]amino}de0xy-D-gluc0pyranose(Compound W2.03)1.3.1 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidExample 1.2.7 (200 mg) in dichloromethane (2.5 mL) was treated with trifluoroacetic acid(2.5 mL) overnight. The reaction mixture was concentrated, and the residue was purified by reversephase chromatography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound. MS (ESI) m/e 746.2 (M+H)+.1.3.2 ,5S,6R)(acet0xymethyl)sulfonamid0)tetrahydr0-2H-pyran-2,4,5-triyl triacetateTo a suspension of (3R,4R,5S,6R)(acetoxymethyl)aminotetrahydro-2H-pyran-2,4,5-triyl triacetate (7.7 g) in dichloromethane (100 mL) at 0 0C was added 2-chloroethanesulfonyl chloride(4.34 g). The mixture was stirred at 0 0C for 15 minutes, and triethylamine (12.1 mL) was added.

The mixture was stirred at 0 0C for 1 hour, warmed to room temperature and stirred for 2 days. Thee was d with dichloromethane and washed with water and brine. The organic layer wasdried over sodium sulfate, filtered, and concentrated to provide the title compound.1.3.3 N-((3R,4R,5S,6R)-2,4,5-trihydr0xy(hydr0xymethyl)tetrahydr0-2H-pyranyl)ethenesulf0namideMEl 24985843V.1 450117813-12620To a on of Example 1.3.2 (6.74 g) in methanol (150 mL) was added triethylamine(10 mL). The mixture was d for 4 days and concentrated. The residue was dissolved inmethanol and treated with Dowex HCR-5 until the solution was neutral. The mixture was ed,and the filtrate was concentrated. The residue was purified by chromatography using a column ofSephadex LH-20 (100 g), eluting with methanol to provide the title compound.1.3.4 2-{[(2-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}oxy)ethyl]amino}ethyl)sulfonyl]amino}deoxy-D-glucopyranoseA mixture of Example 1.3.1 (23.5 mg), Example 1.3.3 (42.4 mg), and N,N-diisopropylethylamine (55 uL) in N,N-dimethylformamide (1 mL) and water (0.3 mL) was stirred fordays. The mixture was purified by reverse phase chromatography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/v roacetic acid, to provide the title compound. 1HNMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.42 (s, 1H), 8.42 (s, 1H), 8.03 (d, 1H),7.79 (d, 1H), 7.55-7.66 (m, 1H), 7.46-7.54 (m, 2H), 7.42-7.47 (m, 1H), 7.33-7.40 (m, 2H), 7.29 (s,1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 2.97-3.14 (m, 6H), 2.10 (s, 3H), 1.44 (s,2H), 1.22-1.39 (m, 4H), 0.97-1.20 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 1015.3 (M+H)+.1.4 This paragraph was intentionally left blank.1.5 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(4-{[(3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-ZH-pyran-2—yl]methyl}benzyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid(Compound W2.05)1.5.1 [4-((3S,4R,5R,6R)-3,4,5-Tris—methoxymethoxymethoxymethoxymethyl-tetrahydro-pyranylmethyl)-phenyl]-methanolThe title compound was prepared according to J. R. Walker et al., Bioorg. Med. Chem.2006, 14, 048. MS (ESI) m/e 478 )+.1.5.2 4-((3S,4R,5R,6R)-3,4,5-Tris-methoxymethoxymethoxymethoxymethyl-tetrahydro-pyranylmethyl)-benzaldehydeExample 1.5.1 (1.000 g) was dissolved in dichloromethane (25 mL), and Dess-Martinperiodinane (1.013 g) was added. The solution was stirred 16 hours at room temperature. Thesolution was diluted with l ether (25 mL) and 2 M aqueous sodium carbonate solution (25 mL)was added. The mixture was extracted with l ether three times. The organic extracts wereMEl 24985843V.1 451117813-12620combined, washed with brine, and dried over anhydrous sodium sulfate. After filtration, the solutionwas concentrated under reduced pressure and purified by silica gel tography, eluting with 50-70% ethyl acetate in heptanes. The solvent was evaporated under reduced pressure to e the titlecompound. MS (ESI) m/e 476 )+.1.5.3 Acetic acid (2R,3R,4R,5S)-3,4,5-triacetoxy(4-f0rmyl-benzyl)-tetrahydro-pyranylmethyl esterExample 1.5.2 (660 mg) was dissolved in methanol (145 mL). 6 M Hydrochloric acid (8mL) was added, and the solution was stirred at room temperature for two days. The solvents wereremoved under reduced re, azeotroping with ethyl acetate three times. The material was driedunder vacuum for four days. The material was dissolved in N,N-dimethylformamide (50 mL). Aceticanhydride (12 mL), pyridine (6 mL), and N,N-dimethylpyridinamine (10 mg) were addedsequentially, and the solution was stirred at room temperature for 16 hours. The solution was dwith water (150 mL) and extracted with ethyl acetate (50 mL) three times. The organics werecombined, washed with water, washed with brine, and dried over ous sodium sulfate. Afterfiltration, the solution was concentrated under reduced pressure and purified by chromatography onsilica gel, eluting with 40-50% ethyl acetate in heptanes. The t was evaporated under reducedpressure to provide the title compound.1.5.4 ,4R,5S)(acet0xymethyl)(4-(((2-((3-((4-(6-(8-[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)(tert-butoxycarbonyl)pyridinyl)methyl-1H-pyrazol-1-yl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)amin0)methyl)benzyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 1.5.7 (40 mg) and Example 1.5.3 (22.5 mg) were stirred in dichloromethane (1mL) at room temperature for 10 minutes. Sodium triacetoxyborohydride (14 mg) was added, and thesolution was stirred at room temperature for 16 hours. The material was purified by chromatographyon silica gel, eluting with 10% methanol in dichloromethane. The solvent was evaporated underd pressure to provide the title compound. MS (ESI) m/e 1236 (M+H)+.1.5.5 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(4-{[(3R,4R,5$,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-ZH—pyran-Z-yl]methyl}benzyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarb0xylicExample 1.5.4 (68 mg) was dissolved in methanol (0.5 mL). s lithium hydroxidesolution (2M, 1 mL) was added, and the solution was stirred at room temperature for 4.5 hours.

Acetic acid (0.1 mL) was added, and the solvents were removed under . The material wasMEl 24985843V.1 452117813-12620then dissolved in trifluoroacetic acid (2 mL) and stirred at room temperature for 16 hours. Theon was concentrated under vacuum. The residue was purified by reverse phase HPLC using aGilson PLC 2020 with a 150 x 30 mm C18 column, eluting with 20-70% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried toprovide the title compound. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (bs, 1H), 8.68(bs, 2H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), .43 (m, 3H), 7.39-7.24 (m, 6H), 6.96 (d, 1H),.23 (t, 1H), 4.96 (s, 2H), 4.56 (d, 1H), 4.42 (dd, 1H), 4.11 (m, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.61-3.56 (m, 3H), 3.39 (dd, 1H), 3.22 (t, 1H), 3.15 (t, 1H), 3.09 (d, 1H), 3.01 (m, 6H), 2.89 (t, 1H), 2.60(m, 1H), 2.10 (s, 3H), 1.43 (s, 2H), 1.30 (q, 4H), 1.14 (m, 4H), 1.03 (q, 2H), 0.86 (s, 6H). MS (ESI)m/e 1012 (M+H)+.1.6 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Compound W2.06)1.6.1 3-((2-((3-((4-(6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-oisoquinolin-2(1H)-yl)-2—(tert-butoxycarbonyl)pyridinyl)methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantan-1-yl)0xy)ethyl)amin0)pr0pane-l-sulfonic acidA mixture of Example 1.2.7 (100 mg), 1,2-oxathiolane 2,2-dioxide (13 mg) and N,N-diisopropylethylamine (19.07 uL) in N,N-dimethylformamide (2 mL) was heated to 50 OC ght.

The reaction was cooled and purified by reverse phase HPLC (C18 column), eluting with 20-60%itrile in water containing 0.1% v/v trifluoroacetic acid, to provide the title compound. MS(ESI) m/e 924.1 (M+H)+.1.6.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidExample 1.6.1 (40 mg) in romethane (2.5 mL) was treated with trifluoroacetic acid(2.5 mL) ght. The reaction mixture was concentrated, and the residue was purified by reversephase chromatography (C18 column), g with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to e the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm12.86 (s, 1H), 8.52 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41-7.55 (m, 3H), 7.32-7.39 (m,2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.49-3.58 (m, 2H), 2.94-3.12 (m, 6H), 2.56-2.64 (m, 2H), 1.88-1.99 (m, 2H), 1.41 (s, 2H), 1.22-1.36 (m, 4H), 0.96-1.20 (m, 6H), 0.86 (s, 6H).

MS (ESI) m/e 868.3 (M+H)+.

MEl 24985843V.1 453117813-126201.7 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2,3-dihydroxypropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid(Compound W2.07)To a solution of Example 1.2.7 (30 mg) in dichloromethane (3 mL) was added 2,3-dihydroxypropanal (3.6 mg), and NaCNBH3 on resin (200 mg). The mixture was stirred overnight,filtered, and the solvent was evaporated. The residue was dissolved in dimethyl sulfoxide/methanol(1:1, 3 mL) and purified by reverse phase HPLC using a Gilson system, eluting with 10-85%acetonitrile in 0.1% trifluoroacetic acid in water, to give the title compound. 1H NMR (400 MHz,dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 8.27 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (t, 1H),7.33-7.54 (m, 6H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (s, 3H), 3.72-3.89 (m, 8H), .64 (m, 6H),2.99-3.10 (m, 4H), 2.11 (s, 3H), 1.00-1.52 (m, 8H), 0.86 (s, 6H). MS (ESI) m/e 820.3 (M+H)+.1.8 Synthesis of -({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}oxy)ethyl]amino}methyl)phenyl]sulfonyl}amino)deoxy-beta-D-glucopyranose (Compound W2.08)1.8.1 (2R,3S,4S,5R,6S)(acetoxymethyl)(4-formylphenylsulfonamido)tetrahydro-2H-pyran-2,4,5-triyltriacetate4-Formylbenzene-l-sulfonyl chloride (100 mg) and (2S,3R,4R,5S,6R)(acetoxymethyl)-3-aminotetrahydro-2H-pyran-2,4,5-triyl triacetate hydrochloride (563 mg) were added to 1,2-dichloroethane (4 mL). N,N-Diisopropylethylamine (0.51 mL) was added, and the solution washeated at 55 CC for three days. The solution was concentrated under reduced re and purified byflash column chromatography on silica gel, eluting with 70% ethyl acetate in heptanes. The solventwas evaporated under reduced pressure, and the material was dissolved in acetone (4 mL).

Hydrochloric acid (1M, 4 mL) was added, and the solution was stirred at room temperature for 16hours. The solution was then ted with 70% ethyl e in heptanes (20 mL). The clayer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the solventwas ated under reduced pressure to e the title compound. MS (ESI) m/e 514 (M+H)+.1.8.2 (2R,3S,4S,5R,6S)(acetoxymethyl)(4-(((2-((3-((4—(6-(8—(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(tert-butoxycarbonyl)pyridinyl)methyl-1H-pyrazol-ethyl)-5,7-dimethyladamantanyl)oxy)ethyl)amino)methyl)phenylsulfonamido)tetrahydro-2H-pyran-2,4,5-triyl triacetateMEl 24985843V.1 454-12620The title compound was prepared by substituting Example 1.8.1 for Example 1.5.3 inExample 1.5.4. MS (ESI) m/e 1301 (M+H)+.1.8.3 2-({[4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}methyl)phenyl]sulfonyl}amin0)de0xy-beta-D-glucopyranoseThe title nd was prepared by substituting Example 1.8.2 for Example 1.5.4 inExample 1.5.5. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (bs, 1H), 8.87 (bs, 2H), 8.04(d, 1H), 7.91 (d, 2H), 7.79 (d, 1H), 7.70-7.55 (m, 3H), 7.52-7.42 (m, 3H), 7.39-7.33 (m, 2H), 7.29 (m,1H), 6.96 (d, 1H), 4.96 (bs, 2H), 4.85 (dd, 1H), 4.62-4.52 (m, 2H), 4.32 (m, 2H), 3.89 (t, 2H), 3.83 (s,2H), 3.70-3.35 (m, 10H), 3.02 (m, 4H), 2.91 (m, 1H), 2.10 (s, 3H), 1.44 (bs, 2H), 1.37-1.22 (m, 4H),1.18-0.98 (m, 6H), .82 (m, 6H). MS (ESI) m/e 1075 (M+H)+.1.9 Synthesis of 8-(1,3-benzothiazolylcarbam0yl){6-carb0xy[1-({3-[2-({2-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl]ethyl}amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}methyl)methyl-1H-pyrazol-4—yl]pyridinyl}-1,2,3,4-tetrahydr0is0quinolineund W2.09)1.9.1 (2R,3R,4S,5S,6S)(4-(2-hydr0xyethyl)-1H-1,2,3-triazolyl)-hoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a on of (2R,3R,4S,5S,6S)azido(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (720 mg) in nol (8 mL) and water (4 mL) was added butynol (140mg), copper(II) sulfate pentahydrate (5.0 mg) and sodium ascorbate (40 mg). The mixture was stirredminutes at 100 CC under microwave conditions (Biotage Initiator). The reaction mixture wasdiluted with ethyl acetate (300 mL), washed with water and brine, and dried over sodium sulfate.

Filtration and ation of the solvent provided the title compound. MS (ESI) m/e 430.2 (M+H)+.1.9.2 (2S,3S,4S,5R,6R)-2—(methoxycarbonyl)(4-(2—0x0ethyl)-1H-1,2,3-triazolyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a solution of dimethyl sulfoxide (0.5 mL) in romethane (10 mL) at-78 0C wasadded oxalyl chloride (0.2 mL). The mixture was stirred 20 minutes at-78 OC, and a solution of(2R,3R,4S,5S,6S)(4-(2-hydroxyethyl)-1H-1,2,3 -triazolyl)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (233 mg) in dichloromethane (10 mL) was added through a syringe. Afterminutes, ylamine (1 mL) was added to the mixture, and the mixture was stirred for 30minutes while the temperature was allowed to rise to room temperature. The reaction mixture wasdiluted with ethyl acetate (300 mL), washed with water and brine, and dried over sodium sulfate.

Filtration and evaporation of the solvent gave the crude product, which was used in the next reactiont further purification. MS (ESI) m/e 429.2 (M+H)+.

MEl 24985843V.1 455117813-126201.9.3 8-(1,3-benzothiazolylcarbam0yl){6-carb0xy[1-({3-[2-({2-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl}amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazol-4—yl]pyridin—2—yl}-1,2,3,4-tetrahydroisoquinolineTo a solution of Example 1.3.1 (150 mg) in dichloromethane (10 mL) was added Example1.9.2 (86 mg) and NaBH3CN on resin (2.49 mmol/g, 200 mg), and the mixture was stirred overnight.

The reaction mixture was then filtered and concentrated. The residue was ved intetrahydrofuran/methanol/HZO (2: 1 :1, 12 mL) and lithium hydroxide monohydrate (50 mg) wasadded. The mixture was stirred overnight. The mixture was concentrated, and the e waspurified by e phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in 0.1%trifluoroacetic acid in water, to provide the title nd. 1H NMR (400 MHz, yl sulfoxide-d6) 5 ppm 12.84 (s, 1H), 8.48 (s, 2H), 8.20 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.32-7.53(m, 5H), 7.29 (s, 1H), 6.96 (d, 1H), 5.66 (d, 1H), 4.96 (s, 2H), 4.00 (d, 1H), 3.76-3.92 (m, 6H), 3.22-3.26 (m, 2H), 2.96-3.15 (m, 8H), 2.10 (s, 3H), 0.99-1.52 (m, 14H), 0.87 (s, 6H). MS (ESI) m/e1028.3 (M+H)+.1.10 Synthesis of 3-[1-({3-[2-(2-{[4-(beta-D-allopyranosyloxy)benzyl]amin0}eth0xy)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl][8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinecarb0xylic acid (Compound W2.10)1.10.1 2-(2-((3-((1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)eth0xy)ethanolThe title compound was prepared as in Example 1.1.4 by substituting -1,2-diol with2,2'-oxydiethanol. MS (ESI) m/e 349.2 .1.10.2 2-(2-((3,5-dimethyl((5-methyl-1H-pyrazolyl)methyl)adamantanyl)0xy)eth0xy)ethanolThe title compound was prepared as in Example 1.1.5 by substituting Example 1.1.4 withExample 1.10.1. MS (ESI) m/e 363.3 (M+H)+.1.10.3 2-(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)eth0xy)ethanolThe title compound was prepared as in Example 1.1.6 by substituting Example 1.1.5 withExample 1.10.2. MS (ESI) m/e 489.2 .1.10.4 2-(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)eth0xy)ethyl methanesulfonateTo a cooled solution of Example 1.10.3 (6.16 g) in dichloromethane (100 mL) was addedtriethylamine (4.21 g) followed by methanesulfonyl chloride (1.6 g), and the mixture was stirred atMEl 24985843V.1 456117813-12620room temperature for 1.5 hours. The reaction mixture was then diluted with ethyl e (600 mL)and washed with water and brine. After drying over sodium sulfate, the solution was filtered andconcentrated, and the residue was used in the next reaction without further purification. MS (ESI)m/e 567.2 (M+H)+.1.10.5 2-(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)eth0xy)ethanamineA solution of e 1.10.4 (2.5 g) in 7N ammonia in methanol (15 mL) was stirred at100 0C for 20 minutes under microwave conditions (Biotage Initiator). The reaction mixture wasconcentrated under vacuum, and the residue was diluted with ethyl acetate (400 mL) and washed withaqueous NaHCO3, water and brine. After drying over sodium e, the solution was filtered andconcentrated, and the residue was used in the next reaction without further purification. MS (ESI)m/e 488.2 (M+H)+.1.10.6 tert-butyl(2-(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-,7-dimethyladamantanyl)0xy)ethoxy)ethyl)carbamateTo a solution of Example 1.10.5 (2.2 g) in tetrahydrofuran (30 mL) was added di-tert—butyl onate (1.26 g) and 4-dimethylaminopyridine (100 mg). The mixture was stirred at roomtemperature for 1.5 hours and was diluted with ethyl acetate (300 mL). The solution was washed withsaturated aqueous NaHCO3, water (60 mL) and brine (60 mL). The organic layer was dried withsodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography,g with 20% ethyl acetate in dichloromethane, to give the title nd. MS (ESI) m/e 588.2(M+H)+ .1.10.7 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2-(2-((tert-butoxycarbonyl)amin0)ethoxy)eth0xy)-5,7-yladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateThe title compound was prepared as in Example 1.2.2 by substituting Example 1.1.6 withe 1.10.6. MS (ESI) m/e 828.5 (M+H)+.1.10.8 2-(6-(tert-butoxycarbonyl)(1-((3-(2-(2-((tertbutoxycarbonyl)amin0)ethoxy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylicThe title compound was prepared as in Example 1.2.5 by substituting Example 1.2.4 withExample 1.10.7. MS (ESI) m/e 814.5 .

MEl 24985843V.1 457117813-126201.10.10 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-(2—((tertbutoxycarbonyl)amin0)ethoxy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateThe title compound was prepared as in e 1.2.6 by substituting Example 1.2.5 withExample 1.10.8. MS (ESI) m/e 946.2 (M+H)+ .1.10.11 3-(1-((3-(2-(2—aminoethoxy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidThe title compound was ed as in Example 1.1.17 by substituting Example 1.1.16with Example 1.10.9.1.10.12 {3-[2-(2—{[4-(beta-D-allopyranosyloxy)benzyl]amin0}eth0xy)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl][8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]pyridinecarb0xylic acidTo a on of Example 1.10.10 (88 mg) and triethylamine (0.04 mL) in dichloromethane(1.5 mL) was added 4-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyran-2-yl)oxy)benzaldehyde (27.7 mg), methanol (1 mL), MP-CNBH3 (2.49 mmol/g, 117 mg) and aceticacid (18 uL). The reaction mixture was stirred overnight. The reaction was ed, and the tewas concentrated. The residue was purified by purified by e phase chromatography (C18column), eluting with 20-60% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, toprovide the title compound. 1H NMR (400 MHz, yl sulfoxide-d6) 5 ppm 7.99 (d, 1H), 7.77 (d,1H), 7.60 (d, 1H), 7.40-7.50 (m, 2H), 7.29-7.39 (m, 6H), 6.96 (d, 2H), 6.76 (d, 1H), 5.11 (d, 2H), 4.92(s, 2H), 3.83-3.96 (m, 4H), 3.77 (s, 2H), 3.60-3.72 (m, 4H), 3.01 (d, 2H), 2.80 (t, 2H), 2.09 (s, 3H),0.98-1.32 (m, 14H), 0.82 (s, 6H). MS (ESI) m/e 1058.3 (M+H)+.1.11 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(2-sulfoethyl)amin0]ethoxy}eth0xy)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid (Compound W2.11)1.11.1 tert-butyl3-(1-((3-(2-(2—aminoethoxy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinateExample 1.10.9 (6.8 g) was dissolved in 50% trifluoroacetic acid in dichloromethane (10mL) and stirred for 20 minutes, and the solvents were removed under vacuum. The residue wasMEl 24985843V.1 458117813-12620purified by reverse phase tography, eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to provide the title compound. MS (ESI) m/e 790.2(M+H)+.1.11.2 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-oisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(2-((2-(phenoxysulfonyl)ethyl)amino)ethoxy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateTo a solution of Example 1.11.1 (200 mg) and N,N-diisopropylethylamine (146 uL) intetrahydrofuran (3 mL) at 0 0C was added phenyl ethenesulfonate (46 mg). The reaction e wasstirred at 0 0C for 30 minutes, lly warmed to room temperature, stirred overnight andconcentrated to provide the title compound.1.11.3 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(2-((2—(phenoxysulfonyl)ethyl)amino)ethoxy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidA solution of e 1.11.2 (100 mg) in dichloromethane (5 mL) was treated withtrifluoroacetic acid (2.5 mL) overnight and concentrated to provide the title compound. MS (APCI)m/e 974.9 (M+H)+.1.11.4 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(2-sulfoethyl)amin0]ethoxy}eth0xy)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylicTo a solution of Example 1.11.3 (195 mg) in tetrahydrofuran (3 mL) and methanol (2 mL)was slowly added 1M sodium hydroxide aqueous solution (2 mL). The e was stirred overnight,and NaOH pellets (0.5 g) were added. The resulting mixture was heated at 40 0C for 3 hours, cooledand concentrated. The concentrate was purified by reverse phase chromatography (C18 column),eluting with 10-70% itrile in 10 mM aqueous NH4OAc solution, to provide the title compound.1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.41-7.51(m, 3H), 7.32-7.39 (m, 2H), 7.29 (s, 1H), 6.88 (d, 1H), 4.93 (s, 2H), 3.89 (t, 2H), 3.81 (s, 2H), 3.60-3.66 (m, 4H), 3.13-3.19 (m, 2H), 3.05-3.10 (m, 2H), 3.01 (t, 2H), 2.79 (t, 2H), 2.11 (s, 3H), 1.34 (s,2H), 1.26 (s, 4H), 0.96-1.22 (m, 6H), 0.85 (s, 6H). MS (ESI) m/e 898.2 (M+H)+.1.12 Synthesis of 1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-phosphonoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.12)MEl 24985843V.1 459117813-126201.12.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((2-(diethoxyphosphoryl)ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a on of Example 1.2.7 (307 mg) in tetrahydrofuran (5 mL) was added diethylvinylphosphonate (176 mg) in water (2 mL). The on mixture was stirred at 70 0C for 3 days, anda few drops of acetic acid were added. The mixture was purified by reverse phase chromatography(C18 column), g with 10-70% acetonitrile in water containing 0.1% v/v roacetic acid, toprovide the title compound. MS (APCI) m/e 966.8 (M+H)+.1.12.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-phosphonoethyl)amin0]eth0xy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicacidTo a solution of Example 1.12.1 (170 mg) in dichloromethane (2.5 mL) was addedbromotrimethylsilane (82 uL) and allyltrimethylsilane (50.4 uL). The reaction mixture was dovernight and water (0.02 mL) was added. The resulting mixture was stirred overnight andconcentrated. The residue was purified by reverse phase chromatography (C18 column), eluting with20-60% acetonitrile in water containing 0.1% trifluoroacetic acid, to provide the title compound. 1HNMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 8.35 (s, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H),7.41-7.53 (m, 3H), 7.33-7.40 (m, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s,2H), 3.09 (s, 4H), 3.01 (t, 2H), 2.10 (s, 3H), 1.85-2.00 (m, 2H), 1.43 (s, 2H), 1.19-1.37 (m, 4H), 1.14(s, 6H), 0.87 (s, 6H). MS (APCI) m/e 854.4 (M+H)+.1.13 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(3-sulf0-L-alanyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid und W2.13)1.13.1 2-({3-[(4-i0d0methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl methanesulfonateTo a cooled solution of Example 1.1.6 (6.16 g) in dichloromethane (100 mL) was addedtriethylamine (4.21 g) followed by methanesulfonyl chloride (1.6 g), and the e was stirred atroom ature for 1.5 hours. The reaction mixture was diluted with ethyl acetate (600 mL) andwashed with water and brine. After drying over sodium sulfate, the on was filtered andconcentrated, and the residue was used in the next reaction without further purification. MS (ESI)m/e 523.4 (M+H)+ .

MEl 24985843V.1 460117813-126201.13.2 1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)iodo-S-methyl-1H-pyrazoleA solution of Example 1.13.1 (2.5 g) in 2M methylamine in methanol (15 mL) was stirredat 100 0C for 20 minutes under microwave conditions (Biotage Initiator). The reaction mixture wasconcentrated under , and the residue was diluted with ethyl acetate (400 mL) and washed withaqueous NaHCO3, water and brine. After drying over sodium sulfate, the solution was filtered andconcentrated, and the residue was used in the next reaction without further purification. MS (ESI)m/e 458.4 (M+H)+.1.13.3 tert-butyl[2-({3-[(4-i0d0methyl-1H—pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]methylcarbamateTo a solution of Example 1.13.2 (2.2 g) in tetrahydrofuran (30 mL) was added di-tert—butyl dicarbonate (1.26 g) and a catalytic amount of 4-dimethylaminopyridine. The mixture wasstirred at room temperature for 1.5 hours and diluted with ethyl e (300 mL). The solution waswashed with saturated aqueous NaHCO3, water (60 mL) and brine (60 mL). The organic layer wasdried with sodium sulfate, filtered and concentrated. The residue was ed by silica gelchromatography, eluting with 20% ethyl acetate in dichloromethane, to give the title compound. MS(ESI) m/e 558.5 (M+H)+.1.13.4 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolineylateTo a solution of Example 1.2.1 (4.94 g) in tetrahydrofuran (60 mL) and water (20 mL) wasadded Example 1.13.3 (5.57 g), 1,3,5,7-tetramethyltetradecyl-2,4,6-trioxaphosphaadamantane(412 mg), tris(dibenzylideneacetone)dipalladium(0) (457 mg), and K3PO4 (11 g), and the mixture wasstirred at reflux for 24 hours. The reaction mixture was cooled and d with ethyl acetate (500mL), washed with water and brine. The organic layer was dried over sodium sulfate, filtered andtrated under reduced pressure. Purification of the residue by silica gel chromatography, elutingwith 20% ethyl acetate in heptane, provided the title nd. MS (ESI) m/e 799.1 (M+H)+.1.13.5 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarboxylic acidTo a solution of Example 1.13.4 (10 g) in tetrahydrofuran (60 mL), methanol (30 mL) andwater (30 mL) was added m ide drate (1.2 g), and the mixture was stirred at roomMEl 24985843V.1 461117813-12620temperature for 24 hours. The reaction mixture was neutralized with 2% aqueous HCl andconcentrated under vacuum. The residue was diluted with ethyl acetate (800 mL) and washed withwater and brine, and dried over sodium sulfate. Filtration and evaporation of the solvent provided thetitle compound. MS (ESI) m/e 785.1 (M+H)+.1.13.6 tert-butyl6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(tert-butoxycarbonyl)(methyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylateTo a solution of Example 1.13.5 (10 g) in N,N-dimethylformamide (20 mL) was addedd]thiazolamine (3.24 g), fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate(5.69 g) and N,N-diisopropylethylamine (5.57 g), and the mixture was stirred at 60 CC for 3 hours.

The reaction mixture was diluted with ethyl acetate (800 mL) and washed with water and brine, anddried over sodium sulfate. Filtration and evaporation of the solvent and silica gel purification of theresidue, eluting with 20% ethyl acetate in dichloromethane, provided the title compound. MS (ESI)m/e 915.5 (M+H)+.1.13.7 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl][1-({3,5-dimethyl[2-lamin0)eth0xy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acidTo a solution of e 1.13.6 (5 g) in dichloromethane (20 mL) was addedtrifluoroacetic acid (10 mL), and the mixture was stirred overnight. The solvent was evaporated under, and the residue was dissolved in dimethyl sulfoxide/methanol (1:1, 10 mL). The mixturewas purified by reverse phase chromatography using an Analogix system and a C18 column (300 g),and eluting with 10-85% acetonitrile and 0.1% trifluoroacetic acid in water, to give the titlecompound.1.13.8 1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(3-sulf0-L-alanyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidA on of (R)((((9H-fluorenyl)methoxy)carbonyl)amino)sulfopropanoic acid(0.020 g), N,N-diisopropylethylamine (0.045 mL) and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU, 0.020 g) were stirred together in N,N-dimethylformamide (0.75 mL) at room temperature. After stirring for 30 minutes, Example 1.13.7(0.039 g) was added, and the reaction d for an onal 1 hour. Diethylamine (0.027 mL) wasadded to the reaction and stirring was continued for 3 hours. The reaction was diluted with water(0.75 mL) and N,N-dimethylformamide (1 mL), neutralized with trifluoroacetic acid (0.039 mL) andMEl 24985843V.1 462117813-12620purified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired fractions were ed and freeze-dried toprovide the title compound. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 12.89 (s, 1H), 8.11-8.02 (m, 4H), 7.84 (d, 1H), 7.66 (d, 1H), 7.60-7.45 (m, 3H), 7.45-7.36 (m, 2H), 7.34 (d, 1H), 7.00 (dd,1H), 5.00 (s, 2H), 4.57-4.40 (m, 1H), 3.93 (t, 2H), 3.90-3.84 (m, 2H), 3.58-3.43 (m, 2H), 3.41-3.21(m, 2H), 3.18-3.02 (m, 3H), 2.95-2.85 (m, 2H), 2.76 (td, 2H), 2.14 (d, 3H), 1.51-0.85 (m, 18H). MS(ESI) m/e 911.2 (M+H)+.1.14 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.14)1.14.1 di-tert-butyl(3-hydroxypropyl)phosphonateNaH (60% in mineral oil, 400 mg) was added to di-tert-butylphosphonate (1.93 g) in N,N-dimethylformamide (30 mL), and the reaction was stirred at room temperature for 30 s. (3-Bromopropoxy)(tert-butyl)dimethylsilane (2.1 g) was added, and the reaction was stirred overnight.

The mixture was diluted with diethyl ether (300 mL), and the solution was washed three times withwater, and brine, then dried over sodium sulfate, filtered, and concentrated. The residue wasdissolved in 20 mL tetrahydrofuran, and tetrabutyl ammonium fluoride (TBAF, 1M intetrahydrofuran, 9 mL) was added. The solution was stirred for 20 s, and then pH 7 buffer (50mL) was added. The mixture was taken up in diethyl ether, and separated, and the organic layer waswashed with brine, and then concentrated. The crude product was tographed on silica gelusing 10-100% ethyl acetate in heptanes, followed by 5% methanol in ethyl e to provide the title1.14.2 di-tert-butyl(3-0x0pr0pyl)phosph0nateExample 1.14.1 (200 mg) and artin periodinane (370 mg) were stirred inromethane (5 mL) for 2 hours. The mixture was taken up in ethyl acetate, and washed twicewith 1M aqueous NaOH solution, and brine, and then concentrated. The crude product waschromatographed on silica gel, using 50-100% ethyl acetate in heptanes followed by 10% methanol inethyl acetate, to provide the title compound.1.14.3 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((3-oxyphosph0ryl)pr0pyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateThe title compound was prepared as described in Example 1, replacing Example1.10.10 and 4-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyranMEI 24985843V.1 463117813-12620yl)oxy)benzaldehyde with Example 1.2.7 and Example 1.14.2, tively. MS (APCI) m/e 980.9(M+H)+.1.14.5 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylicThe title compound was ed as described in Example 1.12.2, replacing Example1.12.1 with Example 1.14.3. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 8.37 (s, 2H), 8.03 (d,1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.53 (m, 3H), 7.33-7.40 (m, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96(s, 2H), 3.86-3.93 (m, 2H), 3.52-3.59 (m, 2H), 2.93-3.06 (m, 6H), 2.10 (s, 3H), 1.71-1.89 (m, 2H),1.53-1.65 (m, 2H), 1.43 (s, 2H), 1.23-1.37 (m, 4H), 0.96-1.19 (m, 6H), 0.87 (s, 6H). MS (APCI) m/e868.3 (M+H)+.1.15 sis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid (CompoundW2.15)A on of (R)((((9H-fluorenyl)methoxy)carbonyl)amino)sulfopropanoic acid(0.050 g) and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (0.049g) were dissolved in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (0.102 mL) wasadded. After stirring for 15 minutes, Example 1.3.1 (0.100 g) was added, and the on stirred foran additional 3 hours. Diethylamine (0.061 mL) was added to the reaction and stirring was uedovernight. The reaction was neutralized with 2,2,2-trifluoroacetic acid (0.090 mL) and diluted withN,N-dimethylformamide (1 mL) and water (1 mL). The mixture was purified by e phase HPLCusing a Gilson system, eluting with 20-80% itrile in water containing 0.1% v/v trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR(500 MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 8.63 (t, 1H), 8.15-8.01 (m, 4H), 7.79 (d, 1H),7.62 (d, 1H), 7.56-7.41 (m, 3H), 7.40-7.33 (m, 2H), 7.30 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.08-3.97(m, 1H), 3.89 (t, 2H), 3.82 (s, 2H), 3.42-3.31 (m, 2H), 3.28-3.17 (m, 1H), 3.16-3.06 (m, 1H), 3.01 (t,2H), 2.97 (dd, 1H), 2.76 (dd, 1H), 2.10 (s, 3H), 1.39 (s, 2H), 1.32-1.20 (m, 4H), .07 (m, 4H),1.07-0.95 (m, 2H), 0.85 (s, 6H). MS (ESI) m/e 897.2 (M+H)+.1.16 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(3-phosphonopropyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid(Compound W2.16)MEl 24985843V.1 464117813-126201.16.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-(2—((3-(di-tertbutoxyphosphoryll)amin0)eth0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateExample 1.10.10 (338 mg) and Example 1.14.2 (120 mg) were dissolved in ethanol (20mL), and the solution was concentrated. The residue was again taken up in ethanol (20 mL) andconcentrated. The residue was then dissolved in dichloromethane (10 mL) and to this was addedsodium triacetoxyborohydride (119 mg), and the reaction was stirred overnight. The crude mixturewas chromatographed on silica gel, using 1% triethylamine in 95:5 ethyl acetate/methanol, to providethe title compound. MS (ESI) 1080.3 (M+H)+.1.16.2 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(3-phosphonopropyl)amino]ethoxy}eth0xy)tricyclo[3.3.1.13’7]dec-1-yl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylicExample 1.16.1 (22 mg) was d in dichloromethane (3 mL) and trifluoroacetic acid (3mL) for 2 days. The mixture was concentrated and chromatographed via reverse phase on a BiotageIsolera One system using a 40 g C18 column and eluting with 10-90% itrile in 0.1%trifluoroacetic acid/water, to provide the title compound as a trifluoroacetic acid salt. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 8.62 (bs, 1H), 8.10 (d, 1H), 7.86 (d, 1H), 7.68 (d, 1H), 7.57 (d,1H), 7.54 (dd, 1H), 7.50 (d, 1H), 7.42 (m, 2H), 7.35 (s, 1H), 7.02 (d, 1H), 5.02 (s, 2H), 3.94 (m, 2H),3.97 (m, 2H), 3.68 (m, 2H), 3.55 (m, 2H), 3.15 (m, 1H), 3.09 (m, 4H), 2.55 (m, 4H), 2.15 (s, 3H), 1.86(m, 1H), 1.66 (m, 2H), 1.45 (m, 2H), 1.31 (m, 4H), 1.19 (m, 4H), 1.08 (m, 2H), 0.90 (s, 6H). MS(ESI) 912.2 (M+H)+.1.17 sis of 3-{1-[(3-{2-[L-alpha-aspartyl(methyl)amin0]eth0xy}-5,7-yltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}-6—[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinecarb0xylic acid (Compound W2.17)1.17.1 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[{(ZS)tert-but0xy[(tert-butoxycarbonyl)amin0]oxobutanoyl}(methyl)amin0]eth0xy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidA solution of Example 1.13.7 (0.060 g), (S)tert-butyl 1-(2,5-dioxopyrrolidinyl) 2-((tert-butoxycarbonyl)amino)succinate (0.034 g) and N,N-diisopropylethylamine were stirred erMEl 24985843v.1 465117813-12620in dichloromethane (1 mL). After stirring overnight, the reaction was loaded onto silica gel andeluted using a gradient of 0.5-5% methanol/dichloromethane to give the title compound.1.17.2 3-{1-[(3-{2-[L-alpha-aspartyl(methyl)amin0]eth0xy}-5,7-dimethyltricyc10[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]pyridinecarb0xylic acidA solution of Example 1.17.1 (0.049 g) in dichloromethane (1 mL) was treated withroacetic acid (0.5 mL), and the reaction was stirred overnight. The reaction was concentrated,dissolved in N,N-dimethylformamide (2 mL) and water (0.5 mL) then purified by e phaseHPLC using a Gilson system, eluting with 20-80% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The desired fractions were combined and freeze-dried to e the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.15 (d, 3H), 8.03 (d,1H), 7.79 (d, 1H), 7.62 (d, 1H), .41 (m, 3H), 7.36 (td, 2H), 7.29 (d, 1H), 6.95 (d, 1H), 4.96 (s,2H), 4.55 (s, 1H), 3.92-3.86 (m, 2H), 3.60-3.47 (m, 2H), 3.47-3.37 (m, 2H), 3.32-3.21 (m, 1H), 3.09-2.97 (m, 4H), 2.92-2.72 (m, 3H), 2.67-2.53 (m, 1H), 2.10 (s, 3H), 1.46-0.94 (m, 12H), 0.85 (s, 6H).

MS (ESI) m/e 875.2 (M+H)+.1.18 Synthesis of 6-{4-[({2—[2-(2-aminoethoxy)eth0xy]ethyl}[2—({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0)methyl]benzyl}-2,6-anhydro-L-gulonic acid (Compound W2.18)1.18.1 (2S,3S,4R,5S)-3,4,5-Triacetoxy(4-br0m0methyl-benzyl)-tetrahydro-pyrancarb0xylic acid methyl esterThe title nd was prepared as described in J. R. Walker et al., Bioorg. Med.

Chem. 2006, 14, 3038-3048. MS (ESI) m/e 518, 520 (M+NH4)+.1.18.2 ,4R,5S)-3,4,5-Triacet0xy(4-f0rmyl-benzyl)-tetrahydr0-pyrancarb0xylic acid methyl esterExample 1.18.1 (75 mg) and ne N-oxide (14 mg) were added to acetonitrile (0.75mL). Silver (1) oxide (24 mg) was added to the solution, and the solution was stirred at roomature for 16 hours. Anhydrous sodium sulfate (5 mg) was added, and the solution was stirredfor five minutes. The solution was filtered and concentrated. The crude material was purified byflash column chromatography on silica gel, eluting with 50-70% ethyl acetate in heptanes. Thesolvent was evaporated under reduced pressure to provide the title compound.1.18.3 (3R,4S,5R,6R)(4-(((2-((3-((4-(6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)(tertbutoxycarbonyl)pyridinyl)methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanMEl 24985843V.1 466-12620)ethyl)amin0)methyl)benzyl)xycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateThe title compound was prepared by tuting Example 1.18.2 for Example 1.5.3 inExample 1.5.4. MS (ESI) m/e 1222 (M+H)+.1.18.4 {2-[2-(2-Oxo-ethoxy)-eth0xy]-ethyl}-carbamic acid tert-butylesterThe title compound was prepared by substituting {2-[2-(2-hydroxy-ethoxy)-ethoxy]--carbamic acid tert-butyl ester for Example 1.5.1 in Example 1.5.2.1.18.5 (3R,4S,5R,6R)(4-(2-(2—((3-((4-(6-(8-(benzo[d]thiazol-2—ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)(tertbutoxycarbonyl)pyridinyl)methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)-14,14-dimethyl0x0-5,8,13-tri0xa-2,11-diazapentadecyl)benzyl)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateThe title compound was prepared by substituting Example 1.18.3 for Example 1.2.7 andExample 1.18.4 for Example 1.5.3 in Example 1.5.4. MS (ESI) m/e 1453 (M+H)+.1.18.6 6-{4-[({2—[2-(2-aminoethoxy)ethoxy]ethyl}[2-({3-[(4-{6-[8-(1,3-hiazol-Z-ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0)methyl]benzyl}-2,6-anhydr0-L-gulonic acidThe title compound was prepared by substituting Example 1.18.5 for Example 1.5.4 inExample 1.5.5. 1H NMR z, dimethyl sulfoxide-dé) 5 ppm 9.38 (bs, 1H), 8.05 (dd, 1H), 7.90-7.68 (m, 6H), 7.62 (m, 2H), 7.53-7.27 (m, 8H), 6.94 (d, 1H), 4.96 (bs, 1H), 4.38 (bs, 4H), 3.91-3.57(m, 11H), 3.37-3.11 (m, 14H), 2.98 (m, 6H), 2.61 (m, 1H), 2.10 (s, 3H), 1.44 (bs, 2H), 1.26 (m, 4H),1.18-0.90 (m, 6H), 0.87 (bs, 6H). MS (ESI) m/e 1157 (M+H)+.1.19 Synthesis of 4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}methyl)phenyl hexopyranosiduronic acid(Compound W2.19)1.19.1 (2R,3S,4R,5R,6R)(4-f0rmylphen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a solution of (2R,3R,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.42 g) in acetonitrile (30 mL) was added silver(I) oxide (1.4 g) and 4-hydroxybenzaldehyde (620 mg). The reaction mixture was stirred for 4 hours and filtered. TheMEl 24985843V.1 467117813-12620te was concentrated, and the residue was purified by silica gel chromatography, g with 5-50% ethyl acetate in heptanes, to provide the title compound. MS (ESI) m/e 439.2 (M+H)+.1.19.2 4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}oxy)ethyl]amin0}methyl)phenyl hexopyranosiduronic acidTo a solution of Example 1.2.7 (36 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2 mL)was added Example 1.19.1 ( 21 mg) ed by MgSO4 (60 mg). The mixture was stirred for 1 hourbefore the addition of NaBH3CN on resin (153 mg). The mixture was then stirred for 3 hours. Themixture was filtered and lithium hydroxide monohydrate (20 mg) was added to the filtrate. Themixture was stirred for 2 hours and was acidified with trifluoroacetic acid and purified by reversephase HPLC (Gilson ), eluting with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water,to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 8.57-8.72 (m, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.34-7.53 (m, 6H), 7.08 (t, 2H), 6.95 (d, 1H),5.10 (d, , 1H), 4.96 (s, 2H), 4.06-4.15 (m, 4H), 3.83-3.97 (m, 6H), 3.26-3.42 (m, 8H), 2.93-3.10 (m,6H), 2.10 (s, 3H), 1.43 (s, 2H), 1.24-1.38 (m, 6H), 0.97-1.16 (m, 4H), 0.86 (s, 6H). MS (ESI) m/e1028.3 (M+H)+.1.20 Synthesis of 6-[1-(1,3-benz0thiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[(2-phosphonoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.20)1.20.1 2-((3,5-dimethyl((5-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2—yl)-1H-pyrazolyl)methyl)adamantanyl)0xy)ethanolTo a solution of Example 1.1.6 (9 g) and [1,1'—bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (827 mg) in acetonitrile (60mL) was added triethylamine (10 mL) and lborane (6 mL). The mixture was stirred at refluxovernight, cooled and used directly in the next step. MS (ESI) m/e 445.4 (M+H)+.1.20.2 tert-butyl6-ch10r0(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a solution of tert-butyl 3-bromochloropicolinate (5.92 g) in tetrahydrofuran (60mL)and water (30 mL) was added the crude Example 1.20.1 (4.44 g), 1,3,5,7-tetramethylphenyl-trioxaphosphaadamante (1.5 g), tris(dibenzylideneacetone)dipalladium(0) (927 mg) andK3PO4(22 g). The e was stirred at reflux ght, cooled, diluted with ethyl acetate (800 mL)and washed with water and brine. The organic layer was dried over sodium e, filtered, andconcentrated. The residue was purified by flash chromatography, eluting with 20% ethyl acetate inMEl 24985843V.1 468117813-12620heptane followed by 5% methanol in dichloromethane, to give the title compound. MS (ESI) m/e531.1 (M+H)+.1.20.3 tert-butyl3-(1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)chloropicolinateTo a solution of e 1.20.2 (3.2 g) in N,N-dimethylformamide (20 mL) was addedimidazole (0.62 g) and chloro t-buytldimethylsilane (1.37 g). The mixture was stirred ght,diluted with ethyl acetate (300 mL), and washed with water and brine. The organic layer was driedover sodium sulfate, ed, and concentrated. The residue was purified by flash chromatography,eluting with 20% ethyl acetate in heptanes, to provide the title compound. MS (ESI) m/e 645.4(M+H)+.1.20.4 tert-butyl3-(1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(1,2,3,4-tetrahydr0quinolinyl)pic01inateTo a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-tetrahydroquinoline (507 mg) in 1,4-dioxane (10 mL) and water (5 mL) was added e 1.20.3(1.25 g), bis(triphenylphosphine)palladium(II)dichloride (136 mg), and cesium fluoride (884 mg).

The mixture was heated at 120 0C in a microwave synthesizer ge, Initiator) for 20 minutes. Themixture was diluted with ethyl acetate (500 mL), and washed with water and brine. The organic layerwas dried over sodium sulfate, filtered, concentrated and purified by flash chromatography, elutingwith 20% ethyl acetate in heptanes and then with 5% methanol in dichloromethane, to provide the titlecompound. MS (ESI) m/e 741.5 (M+H)+.1.20.5 tert-butyl6-(1-(benz0[d]thiazol-2—ylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-(3-(2-((tert-butyldimethylsilyl)0xy)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateTo a suspension of bis(2,5-dioxopyrrolidinyl) carbonate (295 mg) in itrile (10mL) was added benzo[d]thiazolamine (173 mg), and the mixture was stirred for 1 hour. A solutionof Example 1.20.4 (710 mg) in acetonitrile (10 mL) was added, and the suspension was stirredovernight. The mixture was diluted with ethyl acetate (300 mL), washed with water and brine anddried over sodium sulfate. After filtration, the organic layer was concentrated and ed by silicagel chromatography, eluting with 20% ethyl e in heptanes, to provide the title nd. MS(ESI) m/e 917.2 (M+H)+.1.20.6 tert-butyl6-(1-(benz0[d]thiazol-2—ylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateMEl 24985843V.1 469117813-12620To a solution of Example 1.20.5 (1.4 g) in tetrahydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0 M in tetrahydrofuran, 6 mL). The mixture was stirred for 3 hours, dilutedwith ethyl acetate (300 mL) and washed with water and brine. The c layer was dried oversodium sulfate, filtered, and concentrated to provide the title compound. MS (ESI) m/e 803.41.20.7 tert-butyl6-(1-(benz0[d]thiazol-2—ylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a cooled (0 OC) solution of Example 1.20.6 (1.2 g) in dichloromethane (20 mL) andtriethylamine (2 mL) was added esulfonyl de (300 mg). The mixture was stirred for 4hours, diluted with ethyl acetate (200 mL) and washed with water and brine. The c layer wasdried over sodium sulfate, filtered, and concentrated to provide the title compound. MS (ESI) m/e881.3 (M+H)+.1.20.8 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(1-(benzo[d]thiazol-2—ylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl)picolinateTo a solution of Example 1.20.7 (1.5 g) in N,N-dimethylformamide (20 mL)was addedsodium azide (331 mg). The mixture was stirred for 48 hours, diluted with ethyl acetate (20.0 mL)and washed with water and brine. The organic layer was dried over sodium sulfate, filtered,concentrated and purified by silica gel chromatography, eluting with 20% ethyl acetate indichloromethane, to provide the title compound. MS (ESI) m/e 828.4 (M+H)+.1.20.9 tert-butyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(1-(benzo[d]thiazol-2—ylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl)picolinateTo a solution of Example 1.20.8 (1.5 g) in tetrahydrofuran (30 mL) was added Pd/C (10%,200 mg). The mixture was stirred under a hydrogen atmosphere ght. The reaction was filtered,and the filtrate was concentrated to provide the title compound. MS (ESI) m/e 802.4 (M+H)+.1.20.10 tert-butyl6-(1-(benz0[d]thiazol-2—ylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3-(2-((2-(diethoxyphosphoryl)ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazololinateThe title compound was prepared as bed in Example 1.12.1, replacing Example 1.2.7with Example 1.20.9.

MEl 24985843V.1 470117813-126201.20.11 1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[(2-phosphonoethyl)amin0]eth0xy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicThe title compound was prepared as described in Example 1.12.2, replacing Example1.12.1 with e 1.20.10. 1H NMR (500 MHZ, dimethyl sulfoxide-dé) 5 ppm 8.40 (s, 2H), 8.02(d, 1H), 7.74-7.89 (m, 3H), 7.47 (s, 2H), 7.38 (t, 1H), 7.30 (d, 1H), 7.23 (t, 1H), 3.96 (s, 2H), 3.90 (s,2H), 3.53-3.64 (m, 2H), 3.03-3.18 (m, 2H), 2.84 (t, 2H), 2.23 (s, 3H), 1.87-2.02 (m, 4H), 1.46 (s, 2H),1.26-1.38 (m, 4H), 1.12-1.23 (m, 4H), 0.99-1.11 (m, 2H), 0.89 (s, 6H). MS (ESI) m/e 854.1 (M+H)+.1.21 Synthesis of 1,3-benzothiazolylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[methyl(3-sulf0-L-)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Compound W2.21)1.21.1 tert-butyl(2-((3,5-dimethyl((5-methyl(4,4,5,5-tetramethyl-di0xab0rolanyl)-1H-pyrazolyl)methyl)adamantanyl)0xy)ethyl)(methyl)carbamateTo a solution of Example 1.13.3 (1.2 g) in oxane was addedbis(benzonitrile)palladium(II) chloride (0.04 g), 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.937 mL)and triethylamine (0.9 mL). The mixture was heated at reflux overnight, diluted with ethyl acetateand washed with water (60 mL) and brine (60 mL). The organic layer was dried over sodium sulfate,filtered and concentrated to provide the title compound.1.21.2 tert-butyl3-(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)chloropicolinateThe title compound was prepared as described in Example 1.1.12, replacing Example1.1.11 and e 1.1.8 with utyl 3-bromochloropicolinate and Example 1.21.1,respectively. MS (APCI) m/e 643.9 (M+H)+.1.21.3 tert-butyl3-(1-((3-(2-((tertbutoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(1,2,3,4-tetrahydr0quinolinyl)pic01inateA mixture of Example 1.21.2 (480 mg), 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-tetrahydroquinoline (387 mg), dichlorobis(triphenylphosphine)-palladium(II) (78 mg) andcesium fluoride (340 mg) in 1,4-dioxane (12 mL) and water (5 mL) was heated at 100 0C for 5 hours.

The reaction was cooled and diluted with ethyl acetate. The resulting mixture was washed with waterMEl 24985843v.1 471-12620and brine, and the organic layer was dried over sodium sulfate, filtered, and concentrated. Theresidue was purified by flash chromatography, eluting with 50% ethyl acetate in heptanes, to providethe title compound. MS (APCI) m/e 740.4 (M+H)+.1.21.4 tert-butyl6-(1-(benzo[d]thiazol-2—ylcarbam0yl)-1,2,3,4-ydroquinolinyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a solution of benzo[d]thiazolamine (114 mg) in acetonitrile (5 mL) was addedbis(2,5-dioxopyrrolidinyl) carbonate (194 mg). The e was stirred for 1 hour, and Example1.21.3 (432 mg) in acetonitrile (5 mL) was added. The mixture was stirred overnight, diluted withethyl acetate, washed with water and brine. The organic layer was dried over sodium e, filtered,and concentrated. The residue was purified by silica gel chromatography, eluting with 50% ethylacetate in heptanes, to provide the title compound.1.21.5 6-(1-(benzo[d]thiazolylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3,5-dimethyl(2-(methylamino)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidExample 1.2.4 (200 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid(2.5 mL) overnight. The mixture was concentrated to provide the title compound. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 8.40 (s, 1H), 8.30 (s, 2H), 8.02 (d, 1H), 7.85 (d, 1H), .83(m, 2H), 7.42-7.53 (m, 2H), 7.38 (t, 1H), 7.30 (d, 1H), 7.23 (t, 1H), 3.93-4.05 (m, 2H), 3.52-3.62 (m,2H), 2.97-3.10 (m, 2H), 2.84 (t, 2H), 2.56 (t, 2H), 2.23 (s, 3H), 1.88-2.00 (m, 2H), 1.45 (s, 2H), 1.25-1.39 (m, 4H), 1.12-1.22 (m, 4H), 1.00-1.09 (m, 2H), 0.89 (s, 6H). MS (ESI) m/e 760.1 .1.21.6 6-(1-(benzo[d]thiazolylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3-(2-((R)((tertbutoxycarbonyl)amin0)-N-methylsulfopropanamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acid(R)((tert-butoxycarbonyl)amino)sulfopropanoic acid (70.9 mg) and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU, 65 mg) in N,N-dimethylformamide (1.5 ml) was cooled in ice-bath, and N,N-diisopropylethylamine (68.9 uL) wasadded. The mixture was stirred at 0 0C for 15 minutes and at room ature for 8 hours. Example1.21.5 (100 mg) in N,N-dimethylformamide (1 mL) and N,N-diisopropylethylamine (60 uL) wereadded. The resulting mixture was stirred overnight, concentrated and ed by reverse phasetography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1%roacetic acid, to provide the title compound.

MEl 24985843V.1 472117813-126201.21.7 6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[methyl(3-sulfo-L-alanyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicExample 1.21.6 (80 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid(1.5 mL) for 20 minutes. The reaction mixture was concentrated and purified by e phasechromatography (C18 column), eluting with 0-50% acetonitrile in 4 mM aqueous ammonium acetatesolution, to provide the title compound. 1H NMR (500 MHz, yl sulfoxide-dé) 5 ppm 8.57 (s,1H), 7.59-7.67 (m, 3H), 7.54 (d, 1H), 7.46-7.51 (m, 1H), 7.30 (d, 1H), 7.08-7.17 (m, 2H), 6.90 (t, 1H),3.91-4.10 (m, 3H), 3.84 (s, 2H), 3.04 (s, 2H), 2.75-2.83 (m, 4H), 2.59-2.70 (m, 2H), 2.27-2.39 (m,2H), 2.26 (s, 3H), 1.81-1.93 (m, 2H), 1.74 (s, 9H), 1.42 (s, 2H), 0.96-1.33 (m, 10H), 0.86 (s, 3H). MS(ESI) m/e 909.2 (M-H)’.1.22 Synthesis of 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarb0xylic acid (CompoundW2.22)1.22.1 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinateExample 1.2.5 (560 mg) and thiazolo[5,4-b]pyridinamine (135 mg) were dissolved inromethane (12 mL). N,N-Dimethylpyridinamine (165 mg) and l-N’-(3-dimethylaminopropyl)carbodiimide hloride (260 mg) were added, and the reaction stirred atroom temperature overnight. The reaction mixture was concentrated, and the crude residue waspurified by silica gel chromatography, eluting with 65/35 dichloromethane/ethyl acetate, to providethe title compound. MS (ESI) m/e 829.1 (M+H)+.1.22.2 utyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinateThe title compound was ed by substituting Example 1.22.1 for Example 1.2.6 ine 1.2.7. MS (ESI) m/e 803.2 (M+H)+.1.22.3 tert-butyl3-[1-({3,5-dimethyl[(2,2,7,7-tetramethyl-10,10-dioxid0-3,3-diphenyl-4,9-di0xathiaazaMEl 24985843V.1 473117813-12620silapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl][8-([1,3]thiazolo[5,4-b]pyridin-2—ylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]pyridinecarboxylateTo a on of Example 1.22.2 (70 mg) and 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (48 mg) in dichloromethane (1 mL) was added N,N-ropylethylamine (0.06 mL), and the reaction stirred at room temperature overnight. Theon was concentrated, and the crude residue was purified by silica gel chromatography, gwith a gradient of 1-4% ol in dichloromethane, to provide the title compound. MS (ESI) m/e1249.2 (M+H)+.1.22.4 2-((2-((3-((4-(2-(tert-butoxycarbonyl)(8-(thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)pyridinyl)methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)amin0)ethanesulf0nic acidTo a solution of Example 1.22.3 (70 mg) in tetrahydrofuran (0.25 mL) was addedtetrabutylammonium fluoride (60 uL, 1.0M solution in tetrahydrofuran), and the reaction was stirredat room temperature for two days. The reaction was concentrated, and the residue was purified byreverse phase chromatography (C18 column), eluting with 10-90% itrile in water containing0.1% trifluoroacetic acid, to provide the title nd as a trifluoroacetic acid salt. MS (ESI) m/e911.1 (M+H)+.1.22.5 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]pyridinecarboxylic acidThe title compound was prepared by substituting Example 1.22.4 for Example 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.00 (s, 1H), 8.52 (dd, 2H), 8.33(br s, 2H), 8.16 (dd, 1H), 7.62 (m, 1H), 7.53 (m, 2H), 7.45 (d, 1H), 7.38 (m, 1H), 7.29 (s, 1H), 6.98 (d,1H), 4.96 (s, 2H), 3.88 (m, 2H), 3.83 (s, 2H), 3.54 (m, 2H), 3.22 (m, 2H), 3.10 (m, 2H), 3.02 (t, 2H),2.80 (t, 2H), 2.11 (s, 3H), 1.41 (s, 2H), 1.28 (m, 4H), 1.14 (m, 4H), 1.02 (m, 2H), 0.86 (s, 6H). MS(ESI) m/e 855.2 (M+H)+.1.23 Synthesis of 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarb0xylic acid (CompoundW2.23)MEl 24985843V.1 474117813-126201.23.1 utyl 3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinateThe title compound was ed by substituting thiazolo[4,5-b]pyridinamine forthiazolo[5,4-b]pyridinamine in Example 1.22.1. MS (ESI) m/e 855.2 (M+H)+.1.23.2 tert-butyl 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinateThe title nd was prepared by substituting e 1.23.1 for Example 1.2.6 inExample 1.2.7. MS (ESI) m/e 803.2 (M+H)+.1.23.3 tert-butyl 3-[1-({3,5-dimethyl[(2,2,7,7-tetramethyl-10,10-dioxid0-3,3-diphenyl-4,9-di0xathiaazasilapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl][8-([1,3]thiazolo[4,5-b]pyridin-2—ylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]pyridinecarboxylateThe title compound was prepared by substituting Example 1.23.2 for Example 1.22.2 inExample 1.22.3. MS (ESI) m/e 1249.2 (M+H)+.1.23.4 3-{1-[(3,5-dimethyl{2-[(2-thyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]pyridinecarboxylic acidThe title compound was prepared by substituting Example 1.23.3 for Example 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.20 (br s, 1H), 8.61 (dd, 1H),8.56 (dd, 1H), 8.33 (br s, 2H), 7.56 (d, 1H) 7.52 (d, 1H), 7.46 (d, 1H), 7.39 (m, 2H), 7.29 (s, 1H), 6.98(d, 1H), 4.98 (s, 2H), 3.88 (m, 2H), 3.83 (s, 2H), 3.54 (m, 2H), 3.22 (m, 2H), 3.10 (m, 2H), 3.02 (t,2H), 2.80 (t, 2H), 2.10 (s, 3H), 1.41 (s, 2H), 1.30 (m, 4H), 1.12 (m, 4H), 1.02 (m, 2H), 0.86 (s, 6H).

MS (ESI) m/e 855.1 (M+H)+.1.24 Synthesis of 6-[1-(1,3-benz0thiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid und W2.24)MEl 24985843V.1 475117813-126201.24.1 tert-butyl6-[1-(1,3-benzothiazolylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl][1-({3,5-dimethyl[(2,2,7,7-tetramethyl-10,10—di0xid0-3,3-diphenyl-4,9-di0xa-low-thiaazasilapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)—5-methyl-1H-pyraz01yl]pyridinecarb0xylateThe title nd was ed as described in Example 1.2.8, replacing Example 1.2.7with Example 1.20.9.1.24.2 6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.l.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared as described in Example 1.2.9, replacing Example 1.2.8with Example 1.24.1. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 8.26-8.46 (m, 3H), 8.02 (d,1H), 7.89 (d, 1H), 7.82 (d, 1H), 7.75-7.79 (m, 1H), 7.47 (s, 2H), 7.37 (t, 1H), 7.30 (d, 1H), 7.22 (t,1H), 3.96 (s, 2H), 3.90 (s, 2H), 3.54-3.61 (m, 2H), 3.18-3.29 (m, 2H), 3.07-3.15 (m, 2H), 2.78-2.92(m, 4H), 2.23 (s, 3H), 1.87-2.02 (m, 2H), 1.44 (s, 2H), 1.32 (q, 4H), .25 (m, 4H), 1.00-1.11 (m,2H), 0.88 (s, 6H). MS (ESI) m/e 854.0 (M+H)+.1.25 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.25)1.25.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-oisoquinolin-2(1H)-yl)(1-((3-(2-((3-(tert-but0xy)oxopropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateThe title compound was prepared as described in Example , replacing diethylVinylphosphonate with tert-butyl acrylate. MS (APCI) m/e 930.6 (M+H)+.1.25.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl)amin0]ethoxy}-5,7-yltricyclo[3.3.l.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared as described in Example 1.6.2, replacing Example 1.6.1with Example 1.25.1. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 8.03 (d, 1H), 7.78 (d, 1H),7.61 (d, 1H), 7.39-7.50 (m, 2H), 7.32-7.38 (m, 3H), 7.23 (s, 1H), 6.73 (d, 1H), 4.88 (s, 2H), 3.88 (t,2H), 3.79 (s, 2H), 2.99 (t, 2H), 2.86-2.93 (m, 2H), 2.50-2.58 (m, 2H), 2.08 (s, 3H), 1.35 (d, 2H), 1.01-1.30 (m, 10H), 0.86 (s, 6H). MS (APCI) m/e 819.0 (M+H)+.

MEl 24985843V.1 476-126201.26 Synthesis of 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)(piperidinyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid(Compound W2.26)1.26.1 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(((1r,3r)(2-((1-(tertbutoxycarbonyl)piperidinyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateA solution of Example 1.2.7 (0.020 g), tert—butyl 4-0x0piperidinecarb0xylate (4.79 mg)and sodium triacetoxyborohydride (7 mg) was stirred in dichloromethane (0.5 mL) at roomtemperature. The reaction was stirred overnight and purified t workup by silica gelchromatography, eluting with 0 to 10% ol in dichloromethane, to give the title compound. MS(ELSD) m/e 985.4 (M+H)+.1.26.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-onopropyl)(piperidinyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acidA solution of Example 1.26.1 (0.108 g), Example 1.14.2 (0.030 g) and sodiumtriacetoxyborohydride (0.035 g) in dichloromethane (1 mL) was stirred at room temperature for 1hour. Trifluoroacetic acid (1 mL) was added to the reaction, and stirring was continued ght.

The reaction was concentrated, dissolved in methylf0rmamide (2 mL) and water (0.5 mL) andpurified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired ons were combined and freeze-dried toprovide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 8.83 (s, 1H), 8.50 (s,1H), 8.04 (d, 2H), 7.80 (d, 2H), 7.63 (d, 2H), 7.56-7.42 (m, 5H), 7.37 (tt, 3H), 7.30 (s, 1H), 6.96 (d,1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.44 (d, 6H), 3.31-3.16 (m, 6H), 3.09-2.98 (m, 2H), 2.98-2.85 (m, 1H),2.18 (d, 2H), 2.10 (s, 3H), 2.00-1.74 (m, 4H), 1.71-1.57 (m, 2H), 1.51-0.97 (m, 12H), 0.87 (s, 6H).

MS (ESI) m/e 951.2 (M+H)+.1.27 Synthesis of 3-{1-[(3-{2-[D-alpha-aspartyl(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid (Compound W2.27)MEl 24985843V.1 477117813-126201.27.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(methylamino)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateThe title compound was prepared as described in Example 1.11.1 by substituting Example1.10.9 with Example 1.13.6.1.27.2 3-{1-[(3-{2-[D-alpha-aspartyl(methyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-lyl}[8—(1,3-benz0thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]pyridinecarb0xylic acidA solution of Example 1.27.1 (0.074 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.038 g), isopropylethylamine (0.048 mL)and (R)(tert-butoxy)((tert-butoxycarbonyl)amino)oxobutanoic acid (0.029 g) indichloromethane (1 mL) was stirred for 2 hours. Trifluoroacetic acid (0.5 mL) was added, and stirringwas continued overnight. The reaction was concentrated, dissolved in N,N-dimethylformamide (1.5mL) and water (0.5 mL), and purified by e phase HPLC using a Gilson , eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions werecombined and freeze-dried to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6)ppm 12.88 (s, 1H), 8.16 (s, 3H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.55-7.42 (m, 3H), 7.41-7.33 (m, 2H), 7.33-7.27 (m, 1H), 6.96 (d, 1H), 4.96 (s, 2H), .49 (m, 1H), 3.89 (t, 2H), 3.82 (s,2H), 3.61-3.37 (m, 4H), 3.10-2.97 (m, 4H), 2.89-2.73 (m, 2H), .52 (m, 1H), 2.10 (s, 3H), 1.45-0.95 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 875.3 (M+H)+.1.28 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[1-(carb0xymethyl)piperidinyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid und W2.28)A solution of Example 1.2.7 (0.055 g,), tert—butyl 2-(4-oxopiperidinyl)acetate (0.014 g)and sodium triacetoxyborohydride (0.019 g) was stirred in dichloromethane (0.5 mL) at roomtemperature. After stirring for 2 hours, trifluoroacetic acid (0.5 mL) was added to the reaction, andstirring was continued overnight. The reaction was concentrated, dissolved in N,N-dimethylformamide (1.5 mL) and water (0.5 mL) and purified by reverse phase HPLC using a Gilsonsystem, eluting with 10-80% acetonitrile in water containing 0.1% v/v roacetic acid. Thed fractions were combined and freeze-dried to provide the title compound. 1H NMR (501 MHz,dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.80 (s, 2H), 8.03 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H),7.55-7.41 (m, 3H), 7.36 (q, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 4.07 (s, 2H), 3.89 (t, 2H),3.83 (s, 2H), 3.66-3.55 (m, 4H), 3.30 (s, 1H), 3.08 (s, 4H), 3.02 (t, 2H), 2.22 (d, 2H), 2.10 (s, 3H),MEl 24985843v.1 478117813-126201.97-1.78 (m, 2H), 1.44 (s, 2H), 1.31 (q, 4H), 1.20-0.96 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 887.3(M+H)+.1.29 Synthesis of N-[(5S)amino{[2—({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}oxy)ethyl](methyl)amino}oxohexyl]-N,N-dimethylmethanaminium(Compound W2.29)A solution of Fmoc-N-a-(trimethyl)-L-lysine hydrochloride (0.032 g), 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.028 g)and N,N-diisopropylethylamine (0.034 mL) in N,N-dimethylformamide (0.5 mL) was stirred for 5minutes. The reaction was added to Example 1.13.7 (0.050 g), and stirring was continued at roomtemperature overnight. Diethylamine (0.069 mL) was added to the reaction, and stirring wascontinued for an additional 2 hours. The reaction was diluted with N,N-dimethylformamide (1 mL),water (0.5 mL), and roacetic acid (0.101 mL). The mixture was purified by reverse phaseHPLC using a Gilson system, eluting with 10-90% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The desired fractions were ed and freeze-dried to provide the titlecompound. 1H NMR (500 MHz, dimethyl ide-dé) 5 ppm 12.87 (s, 1H), 8.13 (s, 3H), 8.04 (d,1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.54-7.42 (m, 3H), 7.42-7.34 (m, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96(s, 2H), .24 (m, 1H), 3.89 (t, 2H), 3.82 (s, 2H), 3.29-3.16 (m, 2H), 3.08-3.00 (m, 15H), 2.87 (s,2H), 2.10 (s, 3H), 1.84-1.60 (m, 4H), 1.42-0.97 (m, 15H), 0.85 (s, 6H). MS (ESI) m/e 930.3 (M+H)+.1.30 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[piperidinyl(2-thyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-lyl}pyridinecarboxylic acid (Compound W2.30)1.30.1 tert-butyl6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl](1-{[3-({13-[1-(tertbutoxycarbonyl)piperidinyl]-2,2,7,7-tetramethyl-10,10-dioxido-3,3-diphenyl-4,9-dioxathiaazasilapentadecanyl}oxy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazol-4—yl)pyridinecarboxylateA solution of Example 1.2.8 (0.111 g), tert-butyl 4-oxopiperidinecarboxylate (0.021 g)and sodium triacetoxyborohydride (0.028 g) in romethane (1 mL) was stirred at roomtemperature for 1 hour. Acetic acid (7.63 ML) was added, and stirring was continued overnight.

Additional utyl 4-oxopiperidinecarboxylate (0.021 g), sodium triacetoxyborohydride (0.028g) and acetic acid (8 ML) were added to the reaction, and stirring was continued for an additional 4MEl 24985843V.1 479117813-12620hours. The reaction was loaded directly onto silica gel and eluted with a gradient of 0.5-4% methanolin dichloromethane to give the title compound.1.30.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[piperidinyl(2-thyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.30.1 (0.078 g) in romethane (1 mL) was addedtrifluoroacetic acid (0.5 mL), and the reaction was stirred at room temperature overnight. Theon was concentrated and dissolved in N,N-dimethylformamide (1.5 mL) and water (0.5 mL).

The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-75%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combinedand freeze-dried to provide the title compound. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm12.89 (s, 1H), 9.31 (s, 1H), 8.75 (d, 1H), 8.36-8.19 (m, 1H), 8.08 (d, 1H), 7.84 (d, 1H), 7.66 (d, 1H),7.58 (d, 1H), 7.55-7.45 (m, 2H), 7.40 (td, 2H), 7.34 (s, 1H), 6.99 (d, 1H), 5.00 (s, 2H), 3.93 (t, 2H),3.87 (s, 2H), 3.49 (d, 6H), 3.39-3.31 (m, 2H), 3.01 (m, 6H), 2.15 (s, 6H), 1.94 (s, 2H), .99 (m,12H), 0.91 (s, 6H). MS (ESI) m/e 937.3 .1.31 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)(3-phosphonopropoxy)-3,4-dihydr0is0quinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)methyl-1H-pyrazol-4—yl]pyridinecarb0xylic acid (Compound W2.31)1.31.1 tert-butyl8—br0m0hydr0xy-3,4-dihydr0isoquinoline-2(1H)-carboxylateTo a solution of utyl 5-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (9 g) inN,N-dimethylformamide (150 mL) was added N-bromosuccinimide (6.43 g). The mixture was stirredovernight and quenched with water (200 mL). The mixture was diluted with ethyl acetate (500 mL),washed with water and brine, and dried over sodium e. Evaporation of the solvent gave the titlecompound, which was used in the next on without further purification. MS(ESI) m/e 329.2(M+H)+.1.31.2 tert-butyl 5-(benzyloxy)-8—br0m0-3,4-dihydr0is0quinoline-2(1H)-carb0xylateTo a solution of Example 1.31.1 (11.8 g) in acetone (200 mL) was added benzyl bromide(7.42 g) and K2C03 (5 g), and the mixture was stirred at reflux overnight. The mixture wasconcentrated, and the residue was partitioned between ethyl acetate (600 mL) and water (200 mL).

The organic layer was washed with water and brine, dried over sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography, eluting with 10% ethyl acetatein heptane, to provide the title nd. MS (ESI) m/e 418.1 (M+H)+.

MEl 24985843V.1 480117813-126201.31.3 -butyl 8-methyl 5-(benzyloxy)-3,4-dihydr0is0quinoline-)-dicarb0xylateol (100 mL) and triethylamine (9.15 mL) were added to Example 1.31.2 (10.8 g)and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.48 g) in a 500 mL stainless steelpressure reactor. The vessel was sparged with argon several times. The reactor was pressurized withcarbon monoxide and stirred for 2 hours at 100 CC under 60 psi of carbon monoxide. After cooling,the crude reaction mixture was concentrated under vacuum. The residue was added to ethyl acetate(500 mL) and water (200 mL). The c layer was further washed with water and brine, dried oversodium sulfate, ed and concentrated. The residue was purified by silica gel chromatography,eluting with 10-20% ethyl acetate in heptane, to provide the title compound. MS (ESI) m/e 398.1(M+H)+.1.31.4 methyl 5-(benzyloxy)-1,2,3,4-tetrahydroisoquinolinecarboxylate hydrochlorideTo a on of Example 1.31.3 (3.78 g) in tetrahydrofuran (20 mL) was added 4N HCl in1,4-dioxane (20 mL), and the mixture was stirred overnight. The mixture was concentrated undervacuum to give the title compound, which was used in the next reaction without further purification.

MS(ESI) m/e 298.1 (M+H)+.1.31.5 methyl5-(benzyloxy)(5-br0m0(tertbutoxycarbonyl)pyridinyl)-1,2,3,4-tetrahydr0is0quinolinecarboxylateTo a on of Example 1.31.4 (3.03 g) in dimethyl sulfoxide (50 mL) was addedExample 1.1.10 (2.52 g) and triethylamine (3.8 mL), and the mixture was d at 60 CC overnightunder nitrogen. The reaction mixture was diluted with ethyl acetate (500 mL), washed with water andbrine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane, to give the title compound. MS (ESI) m/e553.1 (M+H)+.1.31.6 tert-butyl(2-((3,5-dimethyl((5-methyl(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)-1H-pyrazolyl)methyl)adamantanyl)0xy)ethyl)(methyl)carbamateTo a solution of Example 1.13.3 (2.6 g) and [1,1'—bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane (190 mg) in itrile (30mL) was added triethylamine (2.0 mL) and pinacolborane (1.4 mL), and the mixture was stirred atreflux overnight. The e was used directly in the next reaction without work up. MS (ESI) m/e558.4 (M+H)+.

MEl 24985843V.1 481117813-126201.31.7 methyl 5-(benzyloxy)(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of Example 1.31.5 (2.58 g) in tetrahydrofuran (40 mL) and water (20 mL)was added Example 1.31.6 (2.66 g), 7-tetramethylphenyl-2,4,8-trioxaphosphaadamante(341 mg), tris(dibenzylideneacetone)dipalladium(0) (214 mg), and K3PO4 (4.95 g), and the mixturewas stirred at reflux for 4 hours. The e was diluted with ethyl e (500 mL), washed withwater and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography, eluting with 20% ethyl acetate in dichloromethane, to provide the titlecompound. MS (ESI) m/e 904.5 (M+H)+.1.31.8 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)hydr0xy-1,2,3,4-tetrahydroisoquinolinecarboxylateExample 1.31.7 (3.0 g) in tetrahydrofuran (60 mL) was added to Pd(OH)2 (0.6 g, Degussa#E101NE/W, 20% on carbon, 49% water content) in a 250 mL stainless steel pressure bottle. Themixture was shaken for 16 hours under 30 psi of hydrogen gas at 50 CC. The mixture was filteredthrough a nylon membrane, and the solvent was evaporated under vacuum to provide the titlend. MS (ESI) m/e 815.1(M+H)+.1.31.9 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)(3-(di-tert-butoxyphosphoryl)pr0p0xy)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of Example 1.31.8 (163 mg) in tetrahydrofuran (10 mL) was added Example1.14.1 (50.5 mg), triphenylphosphine (52.5 mg) and t-butylazodicarboxylate (46.2 mg), and thee was stirred for 3 hours. The mixture was diluted with ethyl acetate (200 mL), washed withwater and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography, eluting with 20% ethyl acetate in es followed by 5% methanol indichloromethane, to provide the title compound. MS (ESI) m/e 1049.2 (M+H)+.0 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)(3-(di-tert-butoxyphosphoryl)pr0p0xy)-1,2,3,4-tetrahydr0is0quinolinecarb0xylic acidMEl 24985843V.1 482117813-12620To a on of Example 1.31.9 (3 g) in tetrahydrofuran (20 mL), methanol (10 mL) andwater (10 mL) was added lithium hydroxide monohydrate (30 mg), and the mixture was stirred atroom temperature for 24 hours. The on e was neutralized with 2% aqueous HCl andconcentrated under vacuum. The residue was diluted with ethyl acetate (800 mL), washed with waterand brine, and dried over sodium sulfate. Filtration and evaporation of solvent provided the titlecompound. MS (ESI) m/e 1034.5 (M+H)+.1.31.11 6-[8-(1,3-benzothiazolylcarbamoyl)(3-phosphonopropoxy)-3,4-dihydr0is0quinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]dec-ethyl)methyl-1H-pyrazolyl]pyridinecarb0xylicTo a on of Example 1.31.10 (207 mg) in N,N-dimethylformamide (4 mL) was addedbenzo[d]thiazolamine(45.1mg, 0.3 mmol), fluoro-N,N,N',N'— tetramethylformamidiniumhexafluorophosphate (79 mg) and N,N-diisopropylethylamine(150 mg), and the mixture was stirred at60 CC for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL,) washed with waterand brine, dried over sodium e, filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane followed by 5% methanol inromethane. After concentration, the material was ved in a mixture of dichloromethaneand trifluoroacetic acid (1:1, 6 mL) and was allowed to sit at room temperature overnight. Thesolvent was evaporated, and the residue was dissolved in dimethyl sulfoxide/methanol (1:1, 9 mL).

The mixture was purified by e phase HPLC using a Gilson system, eluting with 10-85%acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title compound. 1H NMR(501 MHz, yl sulfoxide-d6) 5 ppm 8.27 (s, 2H), 8.02 (d, 1H), 7.76 (dd, 2H), 7.43-7.56 (m, 2H),7.32-7.37 (m, 1H), 7.29 (s, 1H), 7.00 (dd, 2H), 5.02 (s, 2H), 4.15 (t, 2H), 3.88-3.93 (m, 2H), 3.83 (s,3H), 3.50-3.59 (m, 4H), 2.95-3.08 (m, 2H), 2.78-2.87 (m, 2H), 2.51-2.55 (m, 3H), 2.11 (s, 3H), 1.90-2.01 (m, 2H), 1.65-1.75 (m, 2H), 1.41 (s, 2H), 1.22-1.36 (m, 6H), 0.98-1.18 (m, 6H), 0.87 (s, 6H).

MS (ESI) m/e 898.2 (M+H)+.1.32 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[N-(2—carb0xyethyl)-L-alpha-aspartyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}--methyl-lH-pyrazolyl)pyridinecarb0xylic acid (Compound W2.32)1.32.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((S)(tert-but0xy)((tert-butoxycarbonyl)amin0)0x0butanamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateMEl 24985843V.1 483117813-12620To a cold (0 CC) solution of (S)(tert-butoxy)((tert-butoxycarbonyl)amino)oxobutanoic acid (136 mg) and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluroniumhexafluorophosphate (HATU, 179 mg) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (165 uL). The reaction mixture was stirred for 10 minutes, and Example 1.2.7(252 mg) in N,N-dimethylformamide (1 mL) was added. The mixture was stirred at roomtemperature for 1.5 hours and was purified by reverse phase chromatography (C18 column), elutingwith % itrile in water containing 0.1% v/v roacetic acid, to provide the titlecompound.1.32.2 3-(1-((3-(2-((S)amin0carboxypropanamid0)eth0xy)-5,7-yladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidExample 1.32.1 (100 mg) in dichloromethane (3 mL) was treated with trifluoroacetic acid(2.5 mL) ght. The reaction mixture was concentrated to provide the title compound.1.32.3 6-(8-(benz0[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((S)((3-(tert-butoxy)0x0pr0pyl)amin0)carb0xypr0panamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)-1H-pyrazol-4—yl)picolinic acidTo a mixture of Example 1.32.2 (102 mg) and N,N-diisopropylethylamine (0.21 mL) inN,N-dimethylformamide (1.5 mL) was added tert-butyl acrylate (80 mg) and water (1.5 mL). Themixture was heated at 50 0C for 24 hours and purified by reverse phase chromatography (C18column), eluting with 20-60% acetonitrile in water ning 0.1% v/v trifluoroacetic acid, toprovide the title compound. MS (APCI) m/e 989.1 (M+H)+.1.32.4 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl](1-{[3-(2-{[N-(2-carb0xyethyl)-L-alpha-aspartyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]dechyl}methyl-1H-pyrazolyl)pyridinecarb0xylicThe title compound was prepared as described in Example 1.6.2, replacing Example 1.6.1with Example 1.32.3. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.86 (s, 3H), 8.62-9.21 (m,2H), 8.52 (t, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.42-7.53 (m, 3H), 7.33-7.41 (m, 2H), 7.29(s, 1H), 6.95 (d, 1H), 4.96 (s, 2H), 4.04-4.19 (m, 1H), 3.89 (t, 2H), 3.81 (s, 2H), 3.32-3.41 (m, 2H),3.16-3.27 (m, 2H), 3.10 (t, 2H), 3.01 (t, 2H), 2.83 (d, 2H), 2.66 (t, 2H), 2.10 (s, 3H), 1.39 (s, 2H),1.20-1.32 (m, 4H), 0.94-1.16 (m, 6H), 0.85 (s, 6H). MS (ESI) m/e 933.2 (M+H)+.

MEl 24985843V.1 484117813-126201.33 Synthesis of (3-{2-[(2-aminoethyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid (Compound W2.33)1.33.1 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-yl)(1-((3-(2-((2-((tert-butoxycarbonyl)amino)ethyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)picolinic acidTo a solution of Example 1.2.9 (188 mg), tert-butyl (2-oxoethyl)carbamate (70.1 mg) andisopropylethylamine (384 11L) was added sodium triacetoxyborohydride (140 mg), and themixture was stirred overnight. 3 (13.83 mg) was added. The resulting mixture was stirredfor 1 hour, and methanol (1 mL) was added. The mixture was stirred for 10 minutes, diluted withethyl acetate, and washed with brine. The organic layer was dried over sodium sulfate, filtered andconcentrated. The residue was purified by reverse phase chromatography (C18 column), eluting with20-80% itrile in water containing 0.1% v/v trifluoroacetic acid, to provide the title nd.1.33.2 3-{1-[(3-{2-[(2—aminoethyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8—(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acidThe title compound was prepared as described in Example 1.6.2, replacing e 1.6.1with Example 1.33.1. 1H NMR (400 MHZ, dimethyl ide-dé) 5 ppm 12.85 (s, 1H), 8.03 (d, 1H),7.87 (s, 2H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41-7.56 (m, 3H), 7.33-7.40 (m, 2H), 7.29 (s, 1H), 6.96 (d,1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.50 (s, 2H), 3.29-3.40 (m, 4H), 3.19 (s, 2H), 3.01 (t, 2H), 2.94 (t, 2H),2.11 (s, 3H), 1.43 (s, 2H), 1.25-1.37 (m, 4H), 0.98-1.19 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 897.2(M+H)+.1.34 Synthesis of 6-[5-(2—aminoethoxy)(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-lamino)ethoxy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazol-4—yl]pyridine-2—carboxylic acid (Compound W2.34)1.34.1 methyl 5-(2—(((benzyloxy)carbonyl)amino)ethoxy)(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarboxylateTo a mixture of Example 1.31.8 (500 mg), benzyl (2-hydroxyethyl)carbamate (180 mg)and triphenyl phosphine (242 mg) in tetrahydrofuran (9 mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (212 mg). The mixture was stirred for 2 hours, diluted with ethyl acetate and washedMEl 24985843V.1 485117813-12620with water and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated.

The e was purified by silica gel chromatography, eluting with 50-100% ethyl e ines, to provide the title compound. MS (APCI) m/e 991.1 .1.34.2 ((benzyloxy)carb0nyl)amin0)eth0xy)(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylicTo a solution of Example 1.34.1 (480 mg) in tetrahydrofuran (10 mL) and methanol (5mL) was added 1 M lithium hydroxide (1.94 mL). The mixture was heated at 50 OC overnight,cooled, acidified with 10% aqueous HCl to pH 3 and concentrated. The residue was purified byreverse phase chromatography (C18 column), eluting with 40-99% acetonitrile in water ning0.1% v/v roacetic acid, to provide the title compound. MS (ESI) m/e 977.4 (M+H)+.1.34.3 tert-butyl6-(8-(benzo[d]thiazol-Z-ylcarbamoyl)(2-zyloxy)carbonyl)amin0)eth0xy)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a mixture of Example 1.34.2 (245 mg), benzo[d]thiazolamine (151 mg) and fluoro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TFFH) (132 mg) in N,N-ylformamide (3 mL) was added N,N-diisopropylethylamine (876 uL). The reaction mixturewas heated at 65 0C for 24 hours, cooled, diluted with ethyl acetate and washed with water and brine.

The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purifiedby silica gel chromatography, eluting with 0-80% ethyl e in heptanes, to provide the titlecompound. MS (APCI) m/e 1109.5 (M+H)+.1.34.4 6-[5-(2-amin0eth0xy)(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acidExample 1.34.3 (100 mg) in dichloromethane (0.5 mL) was treated with trifluoroacetic acid (10 mL)overnight. The reaction mixture was concentrated and purified by reverse phase chromatography(C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, toprovide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.75 (s, 2H), 8.27 (s,2H), 7.89-8.09 (m, 4H), 7.77 (s, 2H), 7.44-7.53 (m, 2H), 7.35 (t, 1H), 7.29 (s, 1H), 7.02 (dd, 2H), 5.02(s, 2H), 4.27 (t, 2H), 3.87-3.97 (m, 2H), 3.83 (s, 2H), 3.50-3.58 (m, 2H), 3.00 (s, 2H), 2.88-2.96 (m,MEl 24985843V.1 486117813-126202H), 2.52-2.60 (m, 2H), 2.10 (s, 3H), 1.42 (s, 2H), 1.23-1.36 (m, 4H), .19 (m, 6H), 0.87 (s, 6H).

MS (ESI) m/e 819.3 .1.35 Synthesis of 1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]dec-1-yl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid(Compound W2.35)1.35.1 tert-butyl6-chloro(1-((3,5-dimethyl(2-oxoethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a on of oxalyl chloride (8 mL, 2.0 M in dichloromethane) in dichloromethane (20mL) at-78 0C, was added dropwise dimethyl sulfoxide (1 mL) in dichloromethane (10 mL) over 20s. The solution was stirred for 30 minutes under argon, and Example 1.20.2 (3.8 g) as asolution in dichloromethane (30 mL) was added over 10 s. The reaction mixture was stirred at-78 0C for an additional 60 minutes. Triethylamine (2 mL) was added at-78 OC, and the reactionmixture was stirred for 60 minutes. The cooling bath was removed, and the on allowed to warmto room temperature overnight. Water (60 mL) was added. The aqueous layer was acidified with 1%aqueous HCl solution and extracted with romethane. The combined organic layers werewashed with 1% aqueous HCl solution, aqueous NaHCO3 solution, and brine. The organic layer wasdried over sodium sulfate and concentrated to provide the title compound. MS (ESI) m/e 527.9(M+H)+.1.35.2 2,2,2-trifluoro(p-tolyl)ethyl3-iodopropanesulfonateThe title compound was prepared ing to a procedure reported in J. Org. Chem,2013, 78, 711-716.1.35.3 2,2,2-trifluoro(p-tolyl)ethyl3-aminopropanesulfonateA solution of Example 1.35.2 (2.0 g) in 7 N ammonia in methanol (20 mL) was heated to80 0C under microwave conditions (Biotage Initiator) for 45 minutes. The mixture was concentrated,and the residue was dissolved in ethyl acetate (300 mL). The organic layer was washed with waterand brine, dried over sodium sulfate, filtered, and concentrated to provide the title nd. MS(ESI) m/e 312.23 (M+H)+.1.35.4 tert-butyl6-chloro(1-(((3,5-dimethyl(2-((3-((2,2,2-trifluoro-l-(p-tolyl)ethoxy)sulfonyl)propyl)amino)ethoxy)adamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateTo a solution of Example 1.35.3 (1.96 g) in dichloroethane (30 mL) was added Example1.35.1 (3.33 g). The reaction mixture was stirred at room temperature for 1 hour, and a suspension ofNaBH4 (1.2 g) in methanol (8 mL) was added. The mixture was stirred at room temperature for 3hours and diluted with ethyl e (300 mL). The organic layer was washed with 2N aqueousMEl 24985843V.1 487117813-12620NaOH, water, and brine, dried over sodium sulfate, filtered and concentrated. The residue wasdissolved in tetrahydrofuran (30 mL), and di-tert-butyl dicarbonate (2 g) was added ed by theaddition of catalytic amount of 4-dimethylaminopyridine. The mixture was stirred at roomtemperature overnight. The mixture was diluted with ethyl acetate (300 mL) and washed with waterand brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to provide thetitle compound. MS (ESI) m/e 924,42 (M+H)+.1.35.5 7-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(3-((2,2,2-triflu0r0(pt01yl)eth0xy)sulfonyl)pr0pyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)naphth0ic acidTo a on of methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)naphthoate (203mg) in a e of 1,4-dioxane (10 mL) and water (5 mL) was added e 1.35.4 (600 mg),bis(triphenylphosphine)palladium(II)dichloride (45.6 mg), and cesium e (296 mg). Themixture was heated at 120 0C under microwave conditions (Biotage Initiator) for 30 minutes, dilutedwith ethyl acetate (200 mL), and washed with water and brine. The organic layer was dried oversodium sulfate, ed, and concentrated. The residue was purified by silica gel chromatography,eluting with 20% ethyl acetate in heptane, to provide an ester intermediate. The residue was dissolvedin a mixture of tetrahydrofuran (8 mL), methanol (4 mL) and water (4 mL), and was treated withlithium hydroxide monohydrate (200 mg) for 3 hours. The on was ied with 1N aqueousHCl to pH 4 and was diluted with ethyl acetate (400 mL). The resulting mixture was washed withwater and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated toprovide the title compound. MS (ESI) m/e 4 (M+H)+.1.35.6 6-[8-(1,3-benz0thiazolylcarbamoyl)naphthalen-Z-yl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.35.5 (405 mg) in dichloromethane (10 mL) was addedbenzo[d]thiazolamine (57.4 mg), 1-ethyl[3 -(dimethylamino)propyl]-carbodiimide hydrochloride(146 mg) and 4-(dimethylamino)pyridine (93 mg). The mixture was stirred at room temperatureovernight, diluted with ethyl e (200 mL), and washed with water and brine. The organic layerwas dried over sodium sulfate, filtered, and concentrated. The residue was dissolved indichloromethane (3 mL) and treated with trifluoroacetic acid (3 mL) overnight. The on mixturewas concentrated, and the residue was purified by reverse phase HPLC (Gilson system), eluting with ant of 10-85% acetonitrile in water ning 0.1% v/v trifluoroacetic acid, to provide the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 13.08 (s, 1H), 9.00 (s, 1H), 8.53 (s,2H), 8.36 (dd, 1H), 8.26-8.13 (m, 3H), 8.06 (dd, 1H), 8.04-7.97 (m, 1H), 7.94 (d, 1H), 7.80 (d, 1H),MEl 24985843V.1 488117813-126207.69 (dd, 1H), 7.51-7.43 (m, 2H), 7.40-7.31 (m, 1H), 7.19 (d, 0H), 3.88 (s, 2H), 3.54 (t, 2H), 3.16-2.91 (m, 4H), 2.68-2.55 (m, 2H), 2.29 (s, 0H), 2.22 (s, 3H), 1.93 (p, 2H), 1.43 (s, 2H), 1.38-1.23 (m,4H), 1.10 (dq, 6H), 0.87 (s, 6H). MS (ESI) m/e 863.2 (M+H)+.1.36 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)(piperidinyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.36)1.36.1 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(((1r,3r)(2-((3-(tert-butoxy)oxopropyl)(1-(tert-butoxycarbonyl)piperidinyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateA solution of Example 1.25.1 (0.086 g), tert-butyl 4-oxopiperidinecarboxylate (0.037g), sodium triacetoxyborohydride (0.039 g) and acetic acid (11 pL) in dichloromethane (1 mL) wasstirred at room temperature. After ng overnight, the reaction was loaded onto silica gel andeluted using a gradient of 0.5 to 5% methanol in dichloromethane to give the title compound. MS(ELSD) m/e 1113.5 (M+H)+.1.36.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)(piperidinyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylicA on of Example 1.36.1 (0.050) in dichloromethane (0.5 mL) was treated withtrifluoroacetic acid (0.5 mL), and the reaction was stirred overnight. The reaction was concentratedand dissolved in dimethyl sulfoxide and methanol (1:1). The mixture was purified by reverse phaseHPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The d fractions were combined and freeze-dried to provide the titlend. 1H NMR (400 MHz, dimethyl ide-dé) 5 ppm 12.84 (s, 1H), 9.38 (s, 1H), 8.78 (s,1H), 8.42 (s, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.55-7.42 (m, 3H), 7.41-7.33 (m, 2H), 7.30(s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.73-3.54 (m, 3H), 3.53-3.34 (m, 4H),3.34-3.25 (m, 2H), 3.02 (t, 2H), 2.99-2.85 (m, 2H), 2.78 (t, 2H), .04 (m, 5H), 1.92-1.76 (m,2H), 1.43 (s, 2H), 1.39-1.23 (m, 4H), 1.23-0.96 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 901.3 (M+H)+.1.37 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfo-L-alanyl)(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]-1H-pyrazol-4—yl}pyridinecarboxylic acid und W2.37)MEl 24985843v.1 489117813-12620A solution of (R)((((9H-fluorenyl)methoxy)carbonyl)amino)sulfopropanoic acid(0.011 g) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouroniumhexafluorophosphate(V) (10.80 mg) in N,N-dimethylformamide (0.5 mL) was stirred for 5 minutes.

This solution was added to Example 1.2.9 (0.025 g) and N,N-diisopropylethylamine (0.014 mL).

After stirring for 2 hours, diethylamine (0.013 mL) was added to the reaction, and stirring wascontinued for an additional 1 hour. The reaction was diluted with N,N-dimethylformamide and waterand quenched with trifluoroacetic acid. The mixture was purified by reverse phase HPLC using aGilson system, eluting with 10-75% acetonitrile in water containing 0.1% V/V trifluoroacetic acid.

The desired fractions were combined and freeze-dried to provide the title nd. 1H NMR (400MHz, dimethyl ide-d6) 5 ppm 12.84 (s, 1H), 8.03 (dd, 4H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54 (dd,1H), 7.51-7.41 (m, 2H), 7.36 (td, 2H), 7.33 (s, 1H), 6.98 (dd, 1H), 4.96 (s, 2H), 4.42 (dd, 2H), 3.89 (t,2H), 3.83 (s, 2H), 3.73 (ddd, 2H), 3.57-3.38 (m, 2H), 3.31 (dt, 1H), 3.08 (dd, 1H), 3.02 (t, 2H), 2.87(tt, 1H), 2.81-2.54 (m, 2H), 2.10 (d, 3H), 1.51-0.91 (m, 12H), 0.85 (s, 6H). MS (ESI) m/e 1005.21.38 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[{2-[(2—carboxyethyl)amino]ethyl}(2-sulfoethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridine-2—carb0xylic acid (Compound W2.38)1.38.1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((2-((3-(tert-but0xy)oxopropyl)amin0)ethyl)(2-sulf0ethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared as described in e 1.32.3, replacing Example1.32.2 with Example 1.33.2.1.38.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[{2-[(2-carboxyethyl)amin0]ethyl}(2-sulfoethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicThe title compound was prepared as described in Example 1.6.2, replacing Example 1.6.1with e 1.38.1. 1H NMR (501 MHz, dimethyl ide-d6) 5 ppm 12.87 (s, 1H), 8.68 (s, 2H),8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.42-7.50 (m, 2H), 7.33-7.40 (m, 2H), 7.29 (s,1H), 6.96 (d, 1H), 4.96 (s, 3H), 3.89 (t, 2H), 3.83 (s, 2H), 3.66 (t, 2H), 3.31-3.53 (m, 8H), 3.18 (t, 2H),3.02 (t, 2H), 2.95 (t, 2H), 2.67 (t, 2H), 2.11 (s, 3H), 1.43 (s, 2H), 1.22-1.37 (m, 6H), 0.98-1.19 (m,6H), 0.87 (s, 6H). MS (APCI) m/e 971.0 (M+H)+.

MEl 24985843V.1 490117813-126201.39 Synthesis of 3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid(Compound W2.39)1.39.1 tert-butyl 3-(1-((3-(2-((3-(di-tert-butoxyphosphoryl)propyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinateExample 1.23.2 (520 mg) and Example 1.14.2 (175 mg) were dissolved indichloromethane (6 mL) and d at room temperature for two hours. A suspension of sodiumborohydride (32 mg) in methanol (1 mL) was added, and the mixture was stirred for 30 minutes. Thereaction was added to ted aqueous NaHCO3 solution and extracted with ethyl acetate. Theorganic layer was washed with brine and dried over sodium sulfate. After filtration and concentration,purification by silica gel chromatography, eluting with a gradient of 0.5-5.0% methanol indichloromethane, gave the title compound. MS (ESI) m/e 1037.3 (M+H)+.1.39.2 (3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[4,5-dinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acidThe title compound was prepared by substituting Example 1.39.1 for e 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 8.60 (dd, 1H), 8.52 (dd, 1H), 8.41(br s, 2H), 7.65 (d, 1H) 7.48 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.29 (s, 1H), 6.97 (d, 1H), 4.97 (s,2H), 3.89 (m, 2H), 3.83 (s, 2H), 3.56 (m, 2H), 3.02 (m, 6H), 2.11 (s, 3H), 1.81 (m, 2H), 1.61 (m, 2H),2.11 (s, 3H), 1.43 (s, 2H), 1.30 (m, 4H), 1.14 (m, 4H), 1.04 (m, 2H), 0.87 (s, 6H). MS (ESI) m/e869.2 (M+H)+.1.40 Synthesis of 3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid(Compound W2.40)MEl 24985843V.1 491117813-126201.40.1 tert-butyl3-(1-((3-(2-((3-(di-tert-butoxyphosphoryl)propyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)pic01inateThe title compound was prepared by substituting Example 1.22.2 for Example 1.23.2 inExample 1.39.1. MS (ESI) m/e 1037.3 .1.40.2 (3,5-dimethyl{2-[(3-phosphonopropyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8—([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-idinecarb0xylic acidThe title compound was ed by substituting Example 1.40.1 for Example 1.2.8 inExample 1.2.9. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 8.52 (dd, 2H), 8.41 (br s, 2H), 8.17(dd, 1H), 7.63 (m, 1H), 7.53 (m, 2H), 7.46 (d, 1H), 7.38 (t, 1H), 7.30 (s, 1H), 6.98 (d, 1H), 4.96 (s,2H), 3.88 (m, 2H), 3.83 (s, 2H), 3.56 (t, 2H), 3.00 (m, 6H), 2.11 (s, 3H), 1.81 (m, 2H), 1.60 (m, 2H),1.43 (s, 2H), 1.31 (m, 4H), 1.14 (m, 4H), 1.04 (m, 2H), 0.87 (s, 6H). MS (ESI) m/e 869.2 .1.41 sis of 6-[8-(1,3-benzothiazolylcarbam0yl)(carboxymethoxy)-3,4-dihydr0isoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.l.l3’7]decyl}methyl)methyl-1H-pyrazol-4—yl]pyridine-Z-carboxylic acid (Compound W2.41)1.41.1 methyl 5-(2-(tert-but0xy)0x0eth0xy)(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of Example 1.31.8 (163 mg) in N,N-dimethylformamide (10 mL) was addedtert-butyl 2-bromoacetate (58.6 mg), and KZCO3 (83 mg), and the reaction was stirred overnight. Themixture was diluted with ethyl acetate (200 mL), washed with water and brine, and dried over sodiumsulfate. Filtration and evaporation of the solvent gave a residue that was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane, to provide the title compound. MS (ESI)m/e 929.2 (M+H)+.1.41.2 5-(2-(tert-but0xy)oxoethoxy)(6-(tert-but0xycarb0nyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylicMEl 24985843v.1 492117813-12620To a solution of Example 1.41.1 (3 g) in tetrahydrofuran (20 mL), ol (10 mL) andwater (10 mL) was added lithium ide monohydrate (300 mg). The mixture was stirred at roomtemperature for 24 hours. The reaction mixture was neutralized with 2% aqueous HCl solution andtrated under vacuum. The residue was diluted with ethyl acetate (800 mL), washed with waterand brine, and dried over sodium sulfate. tion and evaporation of the solvent provided the titlecompound. MS (ESI) m/e 914.5 (M+H)+.1.41.3 6-[8-(1,3-benzothiazolylcarbamoyl)(carboxymethoxy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]dec-l-yl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acidTo a solution of Example 1.41.2 (183 mg) in N,N-dimethylformamide (4 mL) was addedd]thiazolamine (45.1 mg), fluoro-N,N,N',N'— tetramethylformamidiniumhexafluorophosphate (79 mg) and N,N-diisopropylethylamine (0.203 mL). The mixture was stirred at60 CC overnight. The mixture was diluted with ethyl acetate (300 mL), washed with water and brine,and dried over sodium sulfate. Filtration and evaporation of the solvent gave a residue that wasdissolved in dichloromethane/trifluoroacetic acid (1:1, 10 mL) and stirred ght. The mixture wasconcentrated, and the residue was purified by reverse phase HPLC using a Gilson system, eluting with-85% acetonitrile in in water containing 0.1% v/v trifluoroacetic acid, to provide the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.73 (s, 1H), 8.30 (s, 2H), 7.99-8.07(m, 1H), 7.75-7.79 (m, 1H) , 7.70 (d, 1H), 7.44-7.56 (m, 2H), 7.30-7.39 (m, 2H) , 7.30 (s, 1H) ,7.03(t, 1H), 6.87-6.93 (m, 1H), 4.98-5.18 (m, 4H), 4.84 (s, 3H), .01 (m, 4H), 3.55 (t, 2H). 2.77-3.07(m, 4H), 2.53-2.61 (m, 3H), 2.04-2.16 (m, 3H), 1.41 (s, 2H), 1.02-1.34 (m, 6H), 0.83-0.91 (m, 6H).

MS (ESI) m/e 834.2 (M+H)+.1.42 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-carb0xypr0pyl)(piperidin-4—yl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.42)1.42.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(((1r,3r)(2-((1-(tert-butoxycarbonyl)piperidinyl)(4-meth0xyoxobutyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)picolinateA on of Example 1.26.1 (0.169 g), methyl 4-oxobutanoate (0.024 g) and sodiumtriacetoxyborohydride (0.055 g) was stirred in romethane (2 mL) at room ature. After 2hours, the reaction was diluted with dichloromethane (50 mL) and washed with saturated ssodium bicarbonate (10 mL). The organic layer was separated, dried over magnesium sulfate, filteredand concentrated. Silica gel chromatography, eluting with a gradient of 0.5-5%MEl 24985843V.1 493117813-12620ol/dichloromethane containing ammonia, provided the title compound. MS (ELSD) m/e1085.5 (M+H)+.1.42.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[(3-carb0xypr0pyl)(piperidinyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicA solution of Example 1.42.1 (0.161 g) in dichloromethane (0.5 mL) was treated withtrifluoroacetic acid (0.5 mL), and the reaction was stirred overnight. The reaction was concentrated,dissolved in methanol (0.6 mL) and d with lithium hydroxide monohydrate (0.124 g) as asolution in water (0.5 mL). After stirring for 1.5 hours, the reaction was ed with trifluoroaceticacid (0.229 mL) and diluted with N,N-dimethylformamide (0.5 mL). The e was purified byreverse phase HPLC using a Gilson system, g with 10-60% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired fractions were ed and freeze-dried to provide thetitle compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.84 (s, 1H), 9.40 (s, 1H), 8.89-8.79 (m, 1H), 8.57-8.41 (m, 1H), 8.03 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.55-7.41 (m, 3H), 7.41-7.32 (m, 2H), 7.30 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.44 (d, 2H), 3.26 (s,2H), 3.22-3.11 (m, 2H), 3.09-2.85 (m, 6H), 2.34 (t, 2H), 2.19 (d, 2H), 2.10 (s, 3H), 1.95-1.71 (m, 5H),1.44 (s, 2H), 1.39-1.27 (m, 4H), 1.22-0.96 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 915.3 (M+H)+.1.43 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]dechyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid(Compound W2.43)1.43.1 utyl3-(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantan-1-yl)methyl)methyl-1H-pyrazolyl)(8—(methoxycarbonyl)naphthalenyl)pic01inateTo a solution of methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)naphthoate(2.47 g) in 1,4-dioxane (40 mL) and water (20 mL) was added Example 1.20.2 (4.2 g),iphenylphosphine)palladium(II)dichloride (556 mg), and cesium fluoride (3.61 g), and thereaction was stirred at reflux overnight. The mixture was diluted with ethyl acetate (400 mL) andwashed with water and brine, and dried over sodium sulfate. Filtration and evaporation of the solventgave a residue that was purified by silica gel chromatography, eluting with 20% ethyl acetate inheptane followed by 5% methanol in dichloromethane, to provide the title compound. MS (ESI) m/e680.7 (M+H)+.

MEl 24985843V.1 494117813-126201.43.2 tert-butyl3-(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)(8-(methoxycarbonyl)naphthalenyl)picolinateTo a cooled (0 CC) solution of Example 1.43.1 (725 mg) in dichloromethane (10 mL) andylamine (0.5 mL) was added methanesulfonyl chloride (0.249 mL), and the mixture was stirredfor 4 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with water andbrine, and dried over sodium sulfate. Filtration and evaporation of the solvent gave the title product,which was used in the next reaction without r purification. MS (ESI) m/e 759.9 (M+H)+.1.43.3 tert-butyl3-(1-(((3-(2-azidoethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(methoxycarbonyl)naphthalenyl)pic01inateTo a solution of Example 1.43.2 (4.2 g) in N,N-dimethylformamide (30 mL) was addedsodium azide (1.22 g), and the mixture was stirred for 96 hours. The reaction mixture was dilutedwith ethyl acetate (600 mL) washed with water and brine, and dried over sodium sulfate. Filtrationand ation of the solvent provided the title compound. MS (ESI) m/e 705.8 (M+H)+.1.43.4 7-(5-(1-((3-(2-azidoethoxy)-5,7-dimethyladamantanhyl)methyl-1H-pyrazol-4—yl)(tertbutoxycarbonyl)pyridinyl)naphth0ic acidTo a solution of Example 1.43.3 (3.5 g) in ydrofuran/methanol/water (2: 1 :1, 30 mL)was added m hydroxide monohydrate (1.2 g), and the mixture was stirred overnight. Thereaction mixture was acidified with 1N aqueous HCl and was d with ethyl acetate (600 mL),washed with water and brine, and dried over sodium sulfate. Filtration and evaporation of the solventprovided the title compound. MS (ESI) m/e 691.8 (M+H)+.1.43.5 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)naphthalenyl)picolinateTo a solution of Example 1.43.4 (870 mg) in N,N-dimethylformamide (10 mL) was addedbenzo[d]thiazolamine (284 mg), fluoro-N,N,N',N'— tetramethylformamidiniumhexafluorophosphate (499 mg) and N,N-diisopropylethylamine (488 mg). The e was stirred at60 CC for 3 hours. The reaction mixture was diluted with ethyl acetate (200 mL) and washed withwater and brine, and dried over sodium sulfate. Filtration and evaporation of the solvent provided thetitle compound. MS (ESI) m/e 824.1 (M+H)+.1.43.6 tert-butyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)naphthalenyl)picolinateMEl 24985843V.1 495117813-12620To a solution of e 1.43.5 (890 mg) in tetrahydrofuran (30 mL) was added Pd/C (90mg). The mixture was stirred under 1 atmosphere of hydrogen overnight. The reaction e wasfiltered, and the catalyst was washed with ethyl acetate. The solvent was evaporated to provide thetitle compound. MS (ESI) m/e 798.1 (M+H)+.1.43.7 6-[8-(1,3-benz0thiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.43.6 (189 mg) in N,N-dimethylformamide (6 mL) was addedrt-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (106 mg). The mixture was stirredfor 4 days. The mixture was diluted with ethyl acetate (300 mL) and washed with water and brine anddried over sodium e. After filtration and evaporation of the t, the e was dissolved intrifluoroacetic acid (10 mL) and sat overnight. The roacetic acid was evaporated undervacuum, and the residue was dissolved in dimethyl sulfoxide/methanol (1:1, 6 mL). The mixture waspurified by reverse phase HPLC (Gilson system), eluting with 10-85%acetonitrile in water containing0.1% v/v trifluoroacetic acid, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6)ppm 13.09 (s, 1H), 9.02 (s, 1H), 8.31-8.43 (m, 3H), 8.16-8.26 (m, 3H), 7.93-8.08 (m, 3H), 7.82 (d,1H), 7.66-7.75 (m, 1H), 7.46-7.55 (m, 2H), 7.37 (t, 1H), 3.90 (s, 3H), 3.17-3.28 (m, 2H), 3.07-3.16(m, 2H), 2.82 (t, 2H), 2.24 (s, 3H), 1.44 (s, 2H), 0.99-1.37 (m, 12H), 0.87 (s, 6H). MS (ESI) m/e849.1 (M+H)+.1.44 Synthesis of 3-{1-[(3-{2-[L-alpha-aspartyl(2-sulfoethyl)amin0]ethoxy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8—(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinecarb0xylic acid (Compound W2.44)1.44.1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-yl)(1-((3-(2-((S)(tert-butoxy)((tertbutoxycarbonyl)amin0)0x0-N-(2-sulfoethyl)butanamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo a cold (0 CC) solution of (S)(tert-butoxy)((tert-butoxycarbonyl)amino)oxobutanoic acid (40.7 mg) and O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluroniumhexafluorophosphate (HATU, 40.1 mg,) in N,N-dimethylformamide (3 mL) was added N,N-diisopropylethylamine (98 11L). The reaction mixture was d at room temperature for 1 hour, andExample 1.2.9 (60 mg) in N,N-dimethylformamide (1 mL) was added. The mixture was stirred for1.5 hours and was purified by reverse phase chromatography (C18 column), eluting with 20-90%acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to provide the title compound. MS(ESI) m/e 1123.4 (M-H)’.

MEl 24985843V.1 496117813-126201.44.2 3-{1-[(3-{2-[L-alpha-aspartyl(2—sulfoethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8—(1,3-benzothiazol-2—ylcarbamoyl)-3,4-oisoquinolin-2(1H)-yl]pyridinecarb0xylic acidExample 1.44.1 (100 mg) in dichloromethane (5 mL) was d with roacetic acid(1.5 mL) overnight. The reaction mixture was concentrated and purified by reverse phasechromatography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm12.85 (s, 2H), 8.11-8.22 (m, 3H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.41-7.54 (m, 3H), 7.32-7.39 (m, 2H), 7.29 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 4.80 (s, 1H), 3.89 (t, 2H), 3.81 (s, 2H), 3.55-3.71 (m, 2H), 3.01 (t, 4H), 2.74-2.86 (m, 1H), 2.57-2.73 (m, 2H), 2.09 (s, 3H), 0.91-1.46 (m, 13H),0.84 (s, 6H). MS (ESI) m/e 969.2 (M+H)+.1.45 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(1,3-dihydr0xypr0pan-2—yl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (Compound W2.45)1.45.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(0xetan-3-ylamin0)ethoxy)adamantanyl)methyl)methyl-1H-lyl)pic01inateA on of Example 1.2.7 (0.095 g), oxetanone (10 mg) and sodiumtriacetoxyborohydride (0.038 g) was stirred in dichloromethane (1 mL) at room temperature. Afterstirring overnight, the reaction mixture was loaded ly onto silica gel and eluted using a gradientof 0.5- 5% methanol in dichloromethane containing ammonia to give the title compound. MS (ELSD)m/e 858.4 (M+H)+.1.45.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-yl]{1-[(3-{2-[(1,3-dihydr0xypr0pan-2—yl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicacidExample 1.45.1 was dissolved in dichloromethane (0.5 mL) and was treated withtrifluoroacetic acid (0.5 mL) and stirred overnight. The reaction was purified by reverse phase HPLCusing a Gilson system, eluting with 10-60% acetonitrile in water containing 0.1% v/v trifluoroaceticacid. The d fractions were combined and freeze-dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.84 (s, 1H), 8.19 (s, 2H), 8.02 (d, 1H), 7.78 (d, 1H), 7.61(d, 1H), 7.53-7.40 (m, 3H), .31 (m, 2H), 7.28 (s, 1H), 6.94 (d, 1H), 4.95 (s, 2H), 3.87 (t, 2H),MEl 24985843V.1 497117813-126203.82 (s, 2H), 3.67-3.62 (m, 4H), 3.22-3.14 (m, 1H), 3.14-3.06 (m, 2H), 3.00 (t, 4H), 2.09 (s, 3H), 1.41(s, 2H), 1.37-1.20 (m, 4H), 1.20-0.95 (m, 6H), 0.85 (s, 6H). MS (ESI) m/e 820.2 (M+H)+.1.46 Synthesis of 6-[5-(2—aminoethoxy)(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl-7—{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid (Compound W2.46)1.46.1 1,3-benzothiazolylcarbamoyl)(2-{[(benzyloxy)carbonyl]amino}ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[(2,2,7,7,13-pentamethyl-10,10-dioxido-3,3-diphenyl-4,9-dioxathiaazasilapentadecanyl)oxy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acidThe title compound was prepared as described in Example 1.2.8, replacing Example 1.2.7with e 1.35.1.46.2 6-[5-(2—aminoethoxy)(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acidThe title compound was prepared as described in Example 1.34.4, replacing e1.34.3 with Example 1.46.1. 1H NMR (500 MHZ, dimethyl ide-dé) 5 ppm 12.74 (s, 2H), 8.96(s, 1H), 8.03 (d, 1H), 7.94 (s, 3H), 7.72-7.81 (m, 2H), 7.53 (d, 1H), 7.47 (t, 1H), 7.35 (t, 1H), 7.28 (s,1H), 7.02 (t, 2H), 5.03 (s, 2H), 4.26 (t, 2H), 3.92 (t, 2H), 3.83 (s, 2H), 3.23-3.38 (m, 4H), 3.13-3.25(m, 1H), .00 (m, 4H), 2.78 (d, 3H), 2.11 (s, 3H), 1.23-1.50 (m, 6H), 0.95-1.21 (m, 6H), 0.86 (s,6H). MS (ESI) m/e 927.2 (M+H)+.1.47 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl){2-[(2-sulfoethyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.l.13’7]dec-ethyl]—5-methyl-1H-pyrazolyl}pyridine-2—carboxylic acid(Compound W2.47)1.47.1 6-[8-(1,3-benzothiazolylcarbamoyl)[(2,2,7,7-tetramethyl-,10-dioxido-3,3-diphenyl-4,9—dioxathiaazasilapentadecanyl)oxy]-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2—[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H—pyrazolyl}pyridinecarboxylic acidMEl 24985843V.1 498117813-12620The title compound was prepared as described in Example 1.2.8, replacing Example 1.2.7with e 1.46.2.1.47.2 6-[8-(1,3-benzothiazolylcarbamoyl){2-[(2—sulfoethyl)amin0]ethoxy}-3,4-dihydr0is0quinolin-2(1H)-yl],5-dimethyl{2—[methyl(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.l.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acide 1.47.1 (100 mg) in dichloromethane (5 mL) was treated with trifluoroacetic acid(5 mL) overnight. The reaction mixture was concentrated and purified by reverse phasechromatography (C18 column), eluting with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title nd. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppmm 12.74 (s, 1H), 8.96 (d, 1H), 8.64 (s, 2H), 8.02 (d, 1H), 7.76 (dd, 2H), 7.41-7.57 (m, 2H), .40(m, 2H), 7.02 (t, 2H), 5.03 (s, 2H), 4.23-4.42 (m, 2H), 3.90 (t, 2H), 3.83 (s, 2H), 3.25-3.40 (m, 6H),3.12-3.24 (m, 2H), 2.81-3.01 (m, 6H), 2.78 (d, 3H), 2.10 (s, 3H), 1.22-1.47 (m, 6H), 0.97-1.21 (m,6H), 0.86 (s, 6H). MS (ESI) m/e 1035.3 (M+H)+.1.48 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-oisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl){2-[(2-sulf0ethyl)amin0]ethyl}amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid(Compound W2.48)1.48.1 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{[2,2,7,7—tetramethyl-10,10-dioxid0-3,3-diphenyl(2-sulf0ethyl)-4,9-di0xa-low-thia-13,16-diazasila0ctadecanyl]0xy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicThe title compound was prepared as described in Example 1.2.8, replacing e 1.2.7with Example 1.33.2.1.48.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl){2-[(2-sulfoethyl)amin0]ethyl}amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicThe title compound was prepared as described in Example 1.47.2, replacing Example1.47.1 with Example 1.48.1. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.87 (s, 3H), 8.55(s, 4H), 8.04 (d, 2H), 7.79 (d, 2H), 7.62 (d, 1H), 7.40-7.56 (m, 3H), 7.32-7.40 (m, 2H), 7.29 (s, 1H),MEl 24985843v.1 499117813-126206.96 (d, 2H), 4.96 (s, 3H), 3.89 (t, 2H), 3.83 (s, 2H), 3.47 (d, 2H), 3.36 (s, 2H), 3.18-3.30 (m, 2H),3.01 (t, 2H), 2.94 (t, 2H), 2.82 (t, 2H), 2.11 (s, 3H), 1.26-1.49 (m, 6H), 0.96-1.20 (m, 6H), 0.87 (s,6H). MS (ESI) m/e 1005.2 (M+H)+.1.49 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl){2-[(2-carboxyethyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.l.13’7]dec-1-yl)methyl]—5-methyl-1H-pyrazolyl}pyridine-2—carboxylic acid(Compound W2.49)1.49.1 6-(8-(benzo[d]thiazolylcarbamoyl)(2-((3-(tert-butoxy)oxopropyl)amino)ethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(methyl(2-sulfoethyl)amino)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared as bed in Example 1.32.3, replacing Example1.32.2 with Example 1.46.2.1.49.2 1,3-benzothiazolylcarbamoyl){2-[(2—carboxyethyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acidThe title compound was ed as described in Example 1.6.2, replacing Example 1.6.1with Example 1.49.1. 1H NMR (400 MHz, yl sulfoxide-dé) 5 ppm 12.75 (s, 1H), 8.96 (s, 1H),8.59 (s, 2H), 8.03 (d, 1H), 7.72-7.82 (m, 2H), 7.54 (d, 1H), 7.43-7.51 (m, 2H), 7.35 (t, 1H), 7.28 (s,1H), 7.02 (dd, 2H), 5.02 (s, 2H), 4.34 (s, 2H), 3.93 (s, 2H), 3.83 (s, 2H), 3.62 (s, 2H), 2.84-3.01 (m,4H), 2.78 (d, 3H), 2.65-2.75 (m, 2H), 2.11 (s, 3H), 1.20-1.45 (m, 7H), 0.95-1.21 (m, 6H), 0.86 (s, 6H).

MS (ESI) m/e 999.2 (M+H)+.1.50 Synthesis of 3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)(piperidin-4—yl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-l-4—yl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid (CompoundW250)1.50.1 tert-butyl3-(1-((3-(2-((1-(tert-butoxycarbonyl)piperidinyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(thiazolo[4,5-b]pyridinylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinateExample 1.23.2 (205 mg) was dissolved in dichloromethane (2.4 mL), and tert-butyl 4-oxopiperidinecarb0xylate (51 mg) and sodium triacetoxyborohydride (75 mg) were added. TheMEl 24985843V.1 500117813-12620reaction was stirred at room temperature for two hours. More dichloromethane was added, and thereaction was poured into to saturated aqueous NaHCO3 on. The organic layer was washed withbrine and dried over sodium sulfate. After filtration and tration, the reside was purified bysilica gel tography on a Grace Reveleris® Amino cartridge, eluting with a nt of 0.5 to.0% methanol in dichloromethane, to give the title compound. MS (ESI) m/e 986.3(M+H)+.1.50.2 3-{1-[(3,5-dimethyl{2-[(3-phosph0n0pr0pyl)(piperidinyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]pyridinecarboxylic acidExample 1.50.1 (94 mg) was dissolved in dichloromethane (1 mL), then Example 1.14.2(25 mg) and sodium triacetoxyborohydride (30 mg) were added. The reaction was stirred at roomtemperature for four hours. Trifluoroacetic acid (1.5 mL) was added, and the reaction stirred at roomtemperature overnight. The reaction mixture was concentrated and purified by reverse phasechromatography (C18 column), eluting with 10-90% itrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound as a trifluoroacetic acid salt. 1H NMR (400 MHz,dimethyl sulfoxide-d6) 5 ppm 8.82 (br s, 1H) 8.60 (dd, 1H), 8.52 (dd, 1H), 8.50 (br s, 1H), 7.66 (d,1H), 7.50 (d, 1H), 7.46 (d, 1H), 7.38 (m, 2H), 7.30 (s, 1H), 6.97 (d, 1H), 4.98 (s, 2H), 3.89 (t, 2H),3.83 (s, 2H) 3.69 (m, 2H), 3.61 (m, 1H), 3.44 (m, 2H) 3.23 (m, 4H), 3.02 (t, 2H), 2.93 (m, 2H), 2.18(m, 2H), 2.10 (s, 3H), 1.92 (m, 2H), 1.83 (m, 2H), 1.64 (m, 2H), 1.44 (s, 2H), 1.31 (m, 4H), 1.14 (m,4H), 1.04 (m, 2H), 0.87 (s, 6H). MS (ESI) m/e 952.3 (M+H)+.1.51 Synthesis of 6-[4-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydr0-2H-1,4-benzoxazinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Compound W2.51)1.51.1 tert-butyl3-(1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)chloropicolinateTo a solution of Example 1.20.2 (3.2 g) in N,N-dimethylformamide (20 mL) was addedimidazole (0.616 g) and chloro t-butyldimethylsilane (1.37 g). The mixture was stirred overnight.

The on mixture was diluted with ethyl acetate (300 mL), washed with water and brine, and driedover sodium sulfate. Filtration and evaporation of the solvent gave the crude product that waspurified by silica gel chromatography, eluting with 20% ethyl acetate in heptane, to provide the titlecompound. MS (ESI) m/e 645.4 (M+H)+.1.51.2 tert-butyl3-(1-((3-(2-((tert-butyldimethylsilyl)0xy)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(3,4-dihydr0-2H-benzo[b][1,4]0xazinyl)picolinateMEl 24985843V.1 501117813-12620To a solution of 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (507 mg) in 1,4-dioxane (10 mL) and water (5 mL) was added Example 1.51.1(1.25 g), bis(triphenylphosphine)palladium(II)dichloride (136 mg), and cesium fluoride (884 mg).

The mixture was stirred at 120 0C under microwave conditions (Biotage, Initiator) for 20 minutes.

The mixture was diluted with ethyl acetate (500 mL), washed with water and brine, and dried oversodium sulfate. Filtration and evaporation of the solvent gave a residue that was purified by silica gelchromatography, g with 20% ethyl e in heptane ed by 5% methanol indichloromethane, to provide the title compound. MS (ESI) m/e 744.1 (M+H)+.1.51.3 tert-butyl6-(4-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0-2H-benzo[b][1,4]0xazinyl)(1-((3-(2—((tertbutyldimethylsilyl)0xy)ethoxy)-5,7-dimethyladamantanhyl)methyl-1H-pyrazol-4—yl)picolinateTo an ambient suspension of bis(2,5-dioxopyrrolidinyl) carbonate (295 mg) inacetonitrile (10 mL) was added benzo[d]thiazolamine (173 mg), and the mixture was stirred for 1hour. A on of Example 1.51.2 (710 mg) in acetonitrile (10 mL) was added, and the suspensionwas vigorously d overnight. The mixture was diluted with ethyl acetate (300 mL), washed withwater and brine, and dried over sodium sulfate. Filtration and evaporation of the solvent gave aresidue that was purified by silica gel chromatography, eluting with 20% ethyl e in heptane, togive the title compound. MS (ESI) m/e 920.2 (M+H)+.1.51.4 tert-butyl6-(4-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0-2H-benzo[b][1,4]0xazinyl)(1-((3-(2—hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a solution of e 1.51.3 (1.4 g) in ydrofuran (10 mL) was added tetrabutylammonium fluoride (1.0M in tetrahydrofuran, 6 mL). The mixture was stirred for 3 hours. Themixture was d with ethyl acetate (300 mL), washed with water and brine, and dried over sodiumsulfate. Filtration and evaporation of the solvent gave title product, which was used in the nexton without further purification. MS (ESI) m/e 806.0 (M+H)+.1.51.5 utyl6-(4-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0-2H-benzo[b][1,4]0xazinyl)(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a cooled (0 OC) solution of Example 1.51.4 (1.2 g) in dichloromethane (20 mL) andtriethylamine (2 mL) was added methanesulfonyl chloride (300 mg). The mixture was stirred for 4hours. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water and brine,and dried over sodium sulfate. Filtration and evaporation of the solvent gave title product, which wasused in the next reaction without further purification. MS (ESI) m/e 884.1 (M+H)+.

MEl 24985843V.1 502117813-126201.51.6 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(4-(benzo[d]thiazolylcarbamoyl)-3,4—dihydr0-2H-benzo[b][1,4]0xazinyl)picolinateTo a solution of Example 1.51.5 (1.5 g) in N,N-dimethylformamide (20 mL) was addedsodium azide (331mg). The mixture was stirred for 48 hours. The reaction mixture was diluted withethyl acetate (200 mL), washed with water and brine, and dried over sodium sulfate. Filtration andevaporation of the solvent gave a residue that was purified by silica gel chromatography, eluting with% ethyl acetate in dichloromethane, to e the title compound. MS (ESI) m/e 831.1 (M+H)+.1.51.7 tert-butyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(4-(benzo[d]thiazolylcarbamoyl)-3,4—dihydr0-2H-benzo[b][1,4]0xazinyl)picolinateTo a solution of Example 1.51.6 (1.5 g) in tetrahydrofuran (30 mL) was added Pd/C (10%,200 mg). The mixture was stirred under 1 atmosphere of hydrogen overnight. The reaction mixturewas filtered, and the filtrate was concentrated under vacuum to give crude product. MS (ESI) m/e805.1 .1.51.8 6-[4-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0-2H-1,4-benzoxazinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.51.7 (164 mg) in methylformamide (10 mL) and N,N-diisopropylethylamine (0.5 mL) was added rt-butyldiphenylsilyl)oxy)-2,2-dimethylbutylethenesulfonate (91 mg). The e was stirred overnight. The reaction mixture was diluted withethyl e (200 mL), washed with water and brine, and dried over sodium sulfate. Filtration andevaporation of the solvent gave a residue that was dissolved in tetrahydrofuran (2 mL). utylammonium fluoride (1 mL, 1M in tetrahydrofuran) was added, and the mixture was d overnight.

The mixture was concentrated under vacuum, and the residue was dissolved indichloromethane/trifluoroacetic acid (1:1, 6 mL), which was allowed to sit ght. Afterevaporation of the solvent, the residue was purified by reverse phase HPLC (Gilson system), elutingwith 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to provide the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 8.74 (s, 1H), 8.35 (s, 2H), 7.94-8.00(m, 1H), 7.86 (s, 1H) 7.24 (t, 1H), 7.02 (d, 1H),, 7.71-7.82 (m, 2H), 7.46 (s, 1H), 7.34-7.44 (m, 2H),4.28-4.39 (m, 2H), 4.10-4.19 (m, 2H), 3.90 (s, 3H), 3.55-3.61 (m, 4H), 3.21-3.30 (m, 3H) , 3.07-3.16(m, 3H), 2.23 (s, 3H), 1.44 (s, 2H), .37 (m, 9H), 0.89 (s, 6H). MS (ESI) m/e 856.1 (M+H)+.

MEl 24985843V.1 503117813-126201.52 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)(3-sulfopropoxy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.l.l3’7]decyl}methyl)methyl-1H-pyrazol-4—yl]pyridine-2—carboxylic acid (Compound W2.52)1.52.1 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)(3-((2,2,2-trifluoro(p-tolyl)ethoxy)sulfonyl)propoxy)-1,2,3,4-tetrahydroisoquinolinecarboxylateTo a solution of Example 1.31.8 (460 mg) in N,N-dimethylformamide (10 mL) was addedtrifluoro-l-(p-tolyl)ethyl 3-iodopropane-l-sulfonate (239 mg, prepared according to J. Org.

Chem., 2013, 78, 711-716) and KZCO3 (234 mg), and the mixture was stirred overnight. The mixturewas diluted with ethyl acetate (200 mL), washed with water and brine, and dried over sodium sulfate.tion and evaporation of the t gave a residue that was purified by silica gelchromatography, eluting with 20% ethyl acetate in e, to provide the title compound. MS (ESI)m/e 1018.5 (M+H)+.1.52.2 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-carbonyl)(methyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)(3-((2,2,2-trifluoro(p-tolyl)ethoxy)sulfonyl)propoxy)-1,2,3,4-tetrahydroisoquinolinecarboxylic acid.

To a on of Example 1.52.1 (176 mg) in tetrahydrofuran (4 mL), methanol (3 mL) andwater (3 mL) was added lithium ide monohydrate (60 mg), and the mixture was stirredovernight. The mixture was then diluted with ethyl acetate (200 mL), washed with 1N aqueous HCl,water and brine, and dried over sodium sulfate. Filtration and evaporation of the solvent gave the titleproduct, which was used in the next reaction without r purification. MS (ESI) m/e 1095.2(M+H)+.1.52.3 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)(3-((2,2,2—trifluoro(p-tolyl)ethoxy)sulfonyl)propoxy)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a solution of Example 1.52.2 (117 mg) in dichloromethane (6 mL) was addedbenzo[d]thiazolamine (19.27 mg), l[3-(dimethylamino)propyl]-carbodiimidehydrochloride (37 mg) and 4-(dimethylamino)pyridine (23.5 mg), and the mixture was stirredovernight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water andbrine, and dried over sodium sulfate. Filtration and evaporation of the solvent gave the title product.

MS (ESI) m/e 1226.1 (M+H)+.

MEl 24985843V.1 504117813-126201.52.4 6-[8—(1,3-benz0thiazolylcarbamoyl)(3-sulf0pr0p0xy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-lyl]pyridinecarb0xylic acidExample 1.52.3 (130 mg) was dissolved in dichloromethane/trifluoroacetic acid (1 :1, 6mL) and stirred overnight. After evaporation of the solvent, the residue was dissolved in N,N-dimethylformamide/water (1 :1, 12 mL) and purified by e phase HPLC (Gilson), eluting with 10to 85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title compound. 1HNMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.68 (s, 1H), 8.13-8.32 (m, 2H), 8.01 (d, 1H), 7.75(dd, 2H), 7.42-7.56 (m, 2H), 7.29 (s, 1H), 7.28-7.34 (m, 1H), 7.00 (dd, 2H), 5.03 (s, 2H), 4.19 (t, 2H),3.83 (s, 3H) , 3.50-3.57 (m, 4H), .05 (m, 2H), 2.81 (t, 2H), 2.52-2.65 (m, 4H), 1.39 (s, 2H),0.96-1.32 (m, 12H), 0.87 (s, 6H). MS (ESI) m/e 898.3 (M+H)+.1.53 Synthesis of 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[1-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl]pyridinecarb0xylic acid (Compound W2.53)1.53.1 tert-butyl 6-ch10r0(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pic01inateThe title compound was ed as described in Example 1.51.4, replacing Example1.51.3 with Example .1.53.2 tert-butyl6-ch10r0(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)pic01inateTo a cooled (0 CC) solution of Example 1.53.1 (1.89 g) in dichloromethane (30 mL) andtriethylamine (3 mL) was added methanesulfonyl de (1.03 g), and the mixture was stirred for 4hours. The on e was diluted with ethyl acetate (200 mL), washed with water and brine,and dried over sodium sulfate. Filtration and evaporation of the solvent gave the title product, whichwas used in the next reaction without further purification.1.53.4 tert-butyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)chlor0picolinateExample 1.53.2 (2.2 g) was dissolved in 7N ammonia in methanol (40 mL), and themixture was stirred at 80 CC under microwave conditions (Biotage Initiator) for 2 hours. The mixturewas concentrated under vacuum and, and the residue was dissolved in ethyl acetate, washed withwater and brine, and dried over sodium sulfate. Filtration and evaporation of the t provided thetitle compound.

MEl 24985843V.1 505117813-126201.53.5 utyl 6-ch10r0[1-({3,5-dimethyl[(2,2,7,7—tetramethyl-10,10-dioxid0-3,3-diphenyl-4,9-di0xa-low-thiaazasilapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridine-Z-carboxylateTo a solution of Example 1.53.3 (1.59 g) in N,N-dimethylformamide (30 mL) was added 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (1.6 g) and N,N-diisopropylethylamine (1 mL), and the mixture was stirred for 4 days. The reaction mixture wasdissolved in ethyl e (400 mL), washed with water and brine, and dried over sodium sulfate.

Filtration and evaporation of the solvent gave the title product, which was used in the next ont further cation. MS (ESI) m/e 976.8 (M+H)+.1.53.6 tert-butyl3-{1-[(3-{[13-(tert-butoxycarbonyl)-2,2,7,7-tetramethyl-,10-dioxido-3,3-diphenyl-4,9-di0xathiaazasilapentadecanyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}chlor0pyridinecarboxylateTo a solution of Example 1.53.4 (2.93 g) in tetrahydrofuran (50 mL) was added di-t-icarbonate (0.786 g) and 4-(dimethylamino)pyridine (100 mg), and the mixture was stirredovernight. The mixture was concentrated under vacuum, and the residue was dissolved in ethylacetate (300 mL), washed with 1N s HCl solution, water and brine, and dried over sodiumsulfate. Filtration and evaporation of the solvent gave a residue that was purified by silica gelchromatography, eluting with 20% ethyl e in heptane, to provide the title compound. MS (ESI)m/e 1076.9 (M+H)+.1.53.7 tert-butyl3-{1-[(3-{[13-(tert-butoxycarbonyl)-2,2,7,7-tetramethyl-,10-dioxido-3,3-diphenyl-4,9-di0xathiaazasilapentadecanyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}(1,2,3,4-tetrahydr0quinolinyl)pyridinecarb0xylateTo a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-tetrahydroquinoline (65 mg) in 1,4-dioxane (10 mL) and water (5 mL) was added Example 1.53.5(220 mg), bis(triphenylphosphine)palladium(II)dichloride (7 mg), and cesium fluoride (45.6 mg). Themixture was stirred at 120 0C for 30 s under microwave conditions (Biotage Initiator). Themixture was diluted with ethyl acetate (200 mL), washed with water and brine, and dried over sodiumsulfate. Filtration and evaporation of the solvent gave a residue that was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane, to give the title compound. MS (ESI) m/e1173.9 (M+H)+.

MEl 24985843V.1 506117813-126201.53.8 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-azolyl}[1-([1,3]thiazolo[4,5-b]pyridin-Z-ylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl]pyridine-Z-carboxylic acidTo an t suspension of bis(2,5-dioxopyrrolidinyl) carbonate (48.2 mg) inacetonitrile (10 mL) was added thiazolo[4,5-b]pyridinamine (34 mg), and the mixture was stirredfor 1 hour. A solution of Example 1.53.6 (220 mg) in acetonitrile (5 mL) was added, and thesuspension was usly stirred ght. The mixture was d with ethyl acetate (200 mL),washed with water and brine, and dried over sodium sulfate. Filtration and evaporation of the solventgave a residue, which was dissolved in roacetic acid (10 mL) and stirred overnight. Afterevaporation of the solvent, the residue was purified by reverse phase HPLC (Gilson system), elutingwith 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to provide the titlecompound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 8.42-8.48 (m, 1H), 8.31-8.40 (m, 4H),8.03 (d, 1H), 7.89 (d, 1H), 7.80 (d, 1H) 7.47 (s, 1H), 7.26-7.37 (m, 2H), 3.93-4.02 (m, 3H), 3.90 (s,3H), 3.52-3.60 (m, 3H), 3.17-3.26 (m, 2H), 3.05-3.14 (m, 2H), 2.76-2.89 (m, 5H), 2.23 (s, 3H), 1.90-2.01 (m, 2H), 1.44 (s, 2H), .37 (m, 4H), 0.99-1.22 (m, 5H), 0.88 (s, 6H). MS (ESI) m/e 855.1(M+H)+.1.54 Synthesis of 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)naphthalenyl]pyridine-Z-carboxylic acid (CompoundW2.54)1.54.1 tert-butyl3-{1-[(3-{[13-(tert-butoxycarbonyl)-2,2,7,7-tetramethyl-,10-dioxido-3,3-diphenyl-4,9-di0xathiaazasilapentadecanyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}[8-(methoxycarbonyl)naphthalenyl]pyridine-Z-carboxylateThe title nd was prepared by substituting methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)naphthoate for 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-tetrahydroquinoline in Example 1.53.6. MS (ESI) m/e 1226.6 (M+H)+.1.54.2 7-[6-(tert-but0xycarb0nyl){1-[(3-{[13-(tert-but0xycarb0nyl)-2,2,7,7-tetramethyl-10,10-dioxido—3,3-diphenyl-4,9-di0xa-low-thiaazasilapentadecanyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinyl]naphthalenecarboxylic acidMEl 24985843V.1 507-12620To a solution of Example 1.54.1 (79 mg) in tetrahydrofuran (4 mL), methanol (3 mL) andwater (3 mL) was added m ide monohydrate(60 mg), and the mixture was stirredovernight. The reaction was diluted with ethyl acetate (200 mL), washed with 1N aqueous HCl, waterand brine, and dried over sodium sulfate. tion and evaporation of the solvent gave the titleproduct, which was used in the next step without further purification. MS (ESI) m/e 1211.6 (M+H)+.1.54.3 3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)naphthalen-Z-yl]pyridinecarb0xylic acidTo a solution of Example 1.54.2 (60 mg) in dichloromethane (4 mL) was addedthiazolo[4,5-b]pyridinamine (7.56 mg), 1-ethyl[3-(dimethylamino)propyl]-carbodiimidehydrochloride ( 19 mg) and 4-(dimethylamino)pyridine (12.2 mg), and the mixture was stirredovernight. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water andbrine, and dried over sodium e. Filtration and evaporation of the solvent gave the title product,which was dissolved in dichloromethane/trifluoroacetic acid (1:1, 6 mL) and d overnight. Afterevaporation of solvent, the residue was dissolved in N,N-dimethylformamide/water (1 :1, 12 mL) andpurified by reverse phase HPLC (Gilson system), g with 10-85% itrile in water containing0.1% trifluoroacetic acid, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5ppm 13.42 (s, 1H), 9.05 (s, 1H), 8.51-8.69 (m, 2H), 8.31-8.41 (m, 2H), 8.18-8.26 (m, 4H), 8.06 (d,1H), 7.97 (d, 1H), 7.68-7.79 (m, 1H), 7.49 (s, 1H), 7.40 (dd, 1H), 3.90 (s, 3H), 3.18-3.29 (m, 3H),3.07-3.15 (m, 2H), 2.82 (t, 3H), 2.24 (s, 3H), 1.44 (s, 2H), 0.97-1.37 (m, 10H), 0.88 (s, 6H). MS(ESI) m/e 850.1 (M+H)+.1.55 Synthesis of (1g)({2-[5-(1-{[3-(2-amin0eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)carboxypyridin-Z-yl](1,3-benzothiazolylcarbam0yl)-1,2,3,4—tetrahydroisoquinolin-S-yl}methyl)-1,S-anhydro-D-glucitol (CompoundW2.55)1.55.1 (2R,3R,4S,5R)-3,4,5-tris(meth0xymeth0xy)oxymethoxy)methyl)methylenetetrahydr0-2H-pyranThe title nd was prepared according to J. R. Walker et al., Bioorg. Med. Chem.2006, 14, 3038-3048. MS (ESI) m/e 370 (M+NH4)+.1.55.2 4-Bromocyan0methyl-benzoic acid methyl esterTo a solution of trimethylsilanecarbonitrile (3.59 mL) in tetrahydrofuran (6 mL) wasadded 1M tetrabutylammonium fluoride (26.8 mL, 1 M in tetrahydrofuran) dropwise over 30 minutes.

The solution was stirred at room temperature for 30 minutes. Methyl 4-bromo(bromomethyl)benzoate (7.50 g) was dissolved in acetonitrile (30 mL) and was added to the firstMEl 24985843V.1 508117813-12620solution dropwise over 30 minutes. The solution was heated to 80 CC for 30 minutes and cooled. Thesolution was concentrated under d pressure, and the residue was ed by silica geltography, eluting with 20-30% ethyl acetate in es, to provide the title compound.1.55.3 3-(2-Amin0ethyl)br0m0benzoic acid methyl esterExample 1.55.2 (5.69 g) was dissolved in tetrahydrofuran (135 mL), and 1 M borane (intetrahydrofuran, 24.6 mL) was added. The solution was stirred at room ature for 16 hours andwas slowly quenched with methanol and 1 M aqueous hydrochloric acid. 4 M Aqueous hydrochloricacid (150 mL) was added, and the solution was stirred at room temperature for 16 hours. The mixturewas trated under reduced pressure, and the pH was adjusted to between 11 and 12 using solidpotassium carbonate. The solution was then extracted with dichloromethane (3 x 100 mL). Theorganic extracts were combined and dried over anhydrous sodium sulfate. The solution was filteredand concentrated under reduced re, and the residue was purified by silica gel chromatography,eluting with 10- 20% methanol in dichloromethane, to provide the title compound. MS (ESI) m/e258, 260 (M+H)+.1.55.4 4-Br0m0[2-(2,2,2—trifluoroacetylamino)-ethyl]-benzoic acid methylesterExample 1.55.2 (3.21 g) was dissolved in dichloromethane (60 mL). The solution wascooled to 0 CC, and triethylamine (2.1 mL) was added. Trifluoroacetic anhydride (2.6 mL) was addeddropwise. The solution was stirred at 0 CC for ten minutes, and the g bath was removed. After1 hour, water (50 mL) was added, and the solution was diluted with ethyl acetate (100 mL). 1 MAqueous hydrochloric acid was added (50 mL), and the organic layer was separated, washed with 1 Maqueous hydrochloric acid, and washed with brine. The on was dried with anhydrous sodiumsulfate, filtered and concentrated under reduced pressure to provide the title compound. MS (ESI)m/e 371, 373 (M+H)+.1.55.5 5-Bromo(2,2,2-triflu0r0acetyl)-1,2,3,4-tetrahydr0is0quinoline-S-carboxylic acid methyl esterExample 1.55.4 (4.40 g) and paraformaldehyde (1.865 g) were placed in a flask andconcentrated sulfuric acid (32 mL) was added. The solution was stirred at room temperature for onehour. Cold water (120 mL) was added, and the solution was extracted with ethyl acetate (3x 100 mL).

The extracts were ed, washed with ted aqueous sodium bicarbonate (100 mL) and water(100 mL), and dried over ous sodium sulfate. The mixture was filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography, eluting with 20-30% ethylacetate in heptanes, to provide the title compound. MS (ESI) m/e 366, 368 (M+H)+.1.55.6 Methyl 2-(2,2,2-triflu0r0acetyl)(((3S,4R,5R,6R)-3,4,5-tris(meth0xymeth0xy)-6—((methoxymethoxy)methyl)tetrahydr0-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylateMEl 24985843V.1 509117813-12620Example 1.55.1 (242 mg) was dissolved in tetrahydrofuran (7 mL) and 9-borabicyclo[3.3.1]nonane (3.0 mL) was added dropwise. The solution was refluxed for 4.5 hours andallowed to cool to room temperature. Potassium phosphate (3M, 0.6 mL) was added, and the solutionwas stirred for 10 minutes. The solution was then degassed and flushed with nitrogen three times.

Separately, Example 1.55.5 (239 mg) and dichloro[1,1’-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (39 mg) were dissolved in N,N-dimethylformamide (7 mL), and thesolution was degassed and flushed with en three times. The N,N-dimethylformamide solutionwas added se to the tetrahydrofuran solution, and the mixture was d for 18 hours. HClsolution (0.1 M aqueous, 25 mL) was added, and the solution was extracted with ethyl acetate (30mL) three times. The organic extracts were combined, washed with brine, dried over oussodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography,eluting with 30-50% ethyl acetate in heptanes, to yield the title compound. MS (ESI) m/e 710(M+NH4)+.1.55.7 Methyl 5-(((3S,4R,5R,6R)-3,4,5-tris(meth0xymeth0xy)((methoxymethoxy)methyl)tetrahydro-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateExample 1.55.6 (247 mg) was dissolved in methanol (1 mL), tetrahydrofuran (1 mL), andwater (0.5 mL). ium carbonate (59 mg) was added, and the solution was stirred at roomtemperature for 16 hours. The solution was diluted with ethyl acetate (10 mL) and washed withted aqueous sodium bicarbonate (1 mL). The organic layer was dried over anhydrous sodiume, filtered and concentrated under reduced pressure to yield the title compound. MS (ESI) m/e600 (M+H)+.1.55.8 Methyl 2-(5-br0m0(tert-butoxycarb0nyl)pyridinyl)(((3S,4R,5R,6R)-3,4,5-tris(meth0xymeth0xy)((methoxymethoxy)methyl)tetrahydro-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateThe title compound was ed by tuting Example 1.55.7 for methyl 4-tetrahydroisoquinolinecarboylate in Example 1.1.11. MS (ESI) m/e 799, 801 (M-tert-butyl)+.1.55.9 Methyl 2-(6-(tert-but0xycarb0nyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—Z-yl)pyridinyl)(((3S,4R,5R,6R)-3,4,5-tris(meth0xymeth0xy)-6—((methoxymethoxy)methyl)tetrahydr0-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylateThe title compound was prepared by substituting Example 1.55.8 for Example 1.1.11 inExample 1.2.1. MS (ESI) m/e 903 (M+H)+, 933 H-H)’.1.55.10 2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)ethanamineMEI 24985843V.1 510117813-12620The title compound was ed by substituting Example 1.13.1 for Example 1.10.4 inExample 1.10.5. MS (ESI) m/e 444 (M+H)+.1.55.11 tert-butyl(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)carbamateThe title compound was prepared by substituting Example 1.55.10 for Example 1.10.5 inExample 1.10.6. MS (ESI) m/e 544 (M+H)+, 488 (M-tert-butyl)+, 542 (M-H)’.1.55.12 Methyl 2-(6-(tert-but0xycarb0nyl)(1-((3-(2—((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pyridinyl)(((3R,4S,5S,6S)-3,4,5-tris(meth0xymeth0xy)-6—((methoxymethoxy)methyl)tetrahydr0-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylateThe title compound was prepared by substituting Example 1.55.9 for Example 1.2.1 andExample 1.55.11 for Example 1.13.3 in Example 1.13.4. MS (ESI) m/e 1192 (M+H)+.3 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pyridinyl)(((3R,4S,5S,6S)-3,4,5-tris(meth0xymeth0xy)-6—((methoxymethoxy)methyl)tetrahydr0-2H-pyranyl)methyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylic acidThe title compound was prepared by substituting Example 1.55.12 for Example 1.2.4 inExample 1.2.5. MS (ESI) m/e 1178 (M+H)+, 1176 (M-H)’.1.55.14 Tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)(((3R,4S,5S,6S)-3,4,5-tris(meth0xymeth0xy)-6—((methoxymethoxy)methyl)tetrahydro-2H-pyranyl)methyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanhyl)methyl-1H-pyrazol-4—yl)picolinateThe title compound was prepared by tuting Example 1.55.13 for Example 1.52.2 inExample 1.52.3. MS (ESI) m/e 1310 (M+H)+, 1308 (M-H)’.1.55.15 (1§)({2-[5-(1-{[3-(2-amin0eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]dec-1-yl]methyl}methyl-1H-pyrazolyl)carb0xypyridinyl](1,3-benzothiazol-Z-ylcarbamoyl)-1,2,3,4-tetrahydroisoquinolin-S-yl}methyl)-1,5-anhydr0-D-glucitolThe title compound was ed by substituting e 1.55.14 for e 1.52.3 and4M aqueous hydrochloric acid for trifluoroacetic acid in e 1.52.4. 1H NMR (400 MHZ,dimethyl sulfoxide-dé) 5 ppm 7.96 (d, 1H), 7.73 (d, 1H), 7.58 (bs, 3H), 7.46 (d, 1H), 7.43-7.39 (m,2H), 7.30 (d, 1H), .25 (m, 2H), 6.88 (d, 1H), 4.90 (q, 2H), 3.76 (m, 4H), 3.51 (m, 1H), 3.21 (d,2H), 3.18 (d, 1H), 3.12 (m, 2H), 3.02 (m, 4H), 2.93 (m, 4H), 2.83 (m, 2H), 2.59 (m ,2H), 2.03 (s, 3H),MEl 24985843V.1 51 1117813-126201.44 (s, 1H), 1.34 (s, 2H), 1.23 (q, 4H), 1.07 (m, 4H), 0.97 (q, 2 H), 0.80 (s, 6H). MS (ESI) m/e 922(M+H)+, 920 (M-H)’.1.56 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-carboxypropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dechyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid(Compound W2.56)1.56.1 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((4-(tert-butoxy)yl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a on of Example 1.2.7 (0.103 g) and tert-butyl 4-bromobutanoate (0.032 g) indichloromethane (0.5 mL) was added N,N-diisopropylethylamine (0.034 mL) at 50 CC in a sealedamber vial overnight. The reaction was concentrated, dissolved in dimethyl sulfoxide/methanol (1:1,2 mL) and purified by e phase HPLC using a Gilson system, eluting with 5-75% acetonitrile inwater containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-driedto provide the title compound. MS (ESI) m/e 944.6 (M+1).1.56.1 1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-carboxypropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acidA solution of Example 1.56.1 (0.049 g) was dissolved in dichloromethane (1 mL) andtreated with trifluoroacetic acid (0.5 mL) and the mixture was stirred overnight. The reaction wasconcentrated, dissolved in a (1:1) N,N-dimethylformamide /water mixture (2 mL), and purified byreverse phase HPLC using a Gilson system, eluting with 5-75% acetonitrile in water containing 0.1%v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 1309- 12.32 (m, 2H), 8.31 (s, 2H),8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54- 7.40 (m, 3H), 7.40- 7.32 (m, 2H), 7.29 (s, 1H), 6.96 (d,1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.55 (d, 2H), 3.02 (q, 4H), 2.92 (q, 2H), 2.33 (t, 2H), 2.10(s, 3H), 1.80 (p, 2H), 1.43 (s, 2H), 1.30 (q, 4H), 1.21- 0.95 (m, 6H), 0.87 (s, 6H). MS (ESI) m/e 832.3(M+H)+.1.57 Synthesis of 1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid und W2.57)MEl 24985843V.1 512117813-126201.57.1 tert-butyl 3-(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(methoxycarbonyl)naphthalenyl)pic01inateTo a solution of methyl ,5,5-tetramethyl-1,3,2-dioxaborolanyl)naphthoate(2.47 g) in 1,4-dioxane (40 mL) and water (20 mL) was added Example 1.20.2 (4.2 g),bis(triphenylphosphine)palladium(II)dichloride (556 mg), and cesium fluoride (3.61 g). The mixturewas refluxed overnight, diluted with ethyl acetate (400 mL) and washed with water and brine. Theorganic layer was dried over sodium sulfate, ed, and trated. The residue was purified bysilica gel chromatography, eluting with 20% ethyl acetate in dichloromethane and then with 5%methanol in dichloromethane, to provide the title compound. MS (ESI) m/e 680.84 (M+H)+.1.57.2 tert-butyl3-(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)(8-(methoxycarbonyl)naphthalen-Z-yl)picolinateTo a cooled (0 OC) solution of Example 1.57.1 (725 mg) in dichloromethane (10 mL) andylamine (0.5 mL) was added methanesulfonyl chloride (0.249 mL). The mixture was stirred atroom temperature for 4 hours, diluted with ethyl acetate, and washed with water and brine. Theorganic layer was dried over sodium sulfate, filtered, and concentrated to provide the title nd.

MS (ESI) m/e 758.93 .1.57.3 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(methoxycarbonyl)naphthalenyl)pic01inateTo a solution of Example 1.57.2 (4.2 g) in N,N-dimethylformamide (30 mL) was addedsodium azide (1.22 g). The mixture was stirred at room temperature for 96 hours, diluted with ethylacetate (600 mL) and washed with water and brine. The organic layer was dried over sodium sulfate,filtered, and concentrated to provide the title compound. MS (ESI) m/e 704.86 (M+H)+.1.57.4 7-(5-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(tert-butoxycarbonyl)pyridinyl)naphthoic acidTo a solution of Example 1.57.3 (3.5 g) in tetrahydrofuran/methanol/HZO (2: 1 : 1, 30 mL)was added lithium hydroxide monohydrate (1.2 g), and the mixture was stirred at room atureovernight. The reaction mixture was ied with 1N aqueous HCl solution, diluted with ethylacetate (600 mL) and washed with water and brine. The organic layer was dried over sodium e,filtered, and concentrated to provide the title compound. MS (ESI) m/e 691.82 (M+H)+.1.57.5 tert-butyl3-(1-((3-(2-azid0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)naphthalenyl)picolinateMEl 24985843V.1 513117813-12620To a solution of Example 1.57.4 (870 mg) in N,N-dimethylformamide (10 mL) was addedbenzo[d]thiazolamine (284 mg), fluoro-N,N,N’N’-tetramethylformamidium hexafluorophosphate(499 mg) and isopropylethylamine (488 mg). The mixture was stirred at 60 0C for 3 hours,diluted with ethyl acetate (200 mL), and washed with water and brine. The organic layer was driedover sodium sulfate, filtered, and concentrated to provide the title compound. MS (ESI) m/e 824.021.57.6 tert-butyl3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)naphthalenyl)picolinateTo a solution of Example 1.57.5 (890 mg) in tetrahydrofuran (30 mL) was added Pd/C (90mg, 5%). The mixture was stirred under a hydrogen atmosphere at room temperature ght, andfiltered. The filtrate was concentrated to provide the title compound. MS (ESI) m/e 798.2 (M+H)+.1.57.7 6-[8-(1,3-benzothiazolylcarbam0yl)naphthalenyl]{1-[(3,5-yl{2-[(3-phosphonopropyl)amin0]eth0xy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.57.6 (137 mg) in dichloromethane (6 mL) was added Example1.14.2 (43 mg). The mixture was d at room ature for 1.5 hours, and a solution of NaBH4(26 mg) in methanol (2 mL) was added. The mixture was stirred at room temperature for 2 hours,diluted with ethyl acetate (200 mL) and washed with 2N aqueous NaOH solution, water and brine.

The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue wasdissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (5 mL) overnight. Thereaction mixture was concentrated. The residue was purified by e phase HPLC (Gilson system),eluting with a gradient of 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acidsolution, to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 9.03 (s, 1H),8.48-8.35 (m, 3H), 8.29-8.16 (m, 3H), 8.08 (dd, 1H), 8.03 (dd, 1H), 7.94 (d, 1H), 7.82 (d, 1H), 7.71(dd, 1H), 7.53-7.47 (m, 2H), 7.38 (td, 1H), 4.81-0.53 (m, 89H). MS (ESI) m/e 863.2 (M+H)+.1.58 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[4-(beta-D-gluc0pyran0syloxy)benzyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid (Compound W2.58)To a solution of Example 1.3.1 (44.5 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2mL) was added 4-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyranyl)oxy)benzaldehyde (17 mg) and MgSO4 (300 mg). The e was d at room temperature for1 hour before the on of sodium cyanoborohydride on resin (300 mg). The mixture was stirred atroom temperature ght and filtered. The filtrate was concentrated, and the residue was purifiedMEl 24985843V.1 514117813-12620by reverse phase HPLC (Gilson system), eluting with a gradient of 10-85% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid solution, to provide the title compound. MS (ESI) m/e1015.20 (M+H)+.1.59 Synthesis of 3-(1-{[3-(2-{[4-(beta-D-allopyranosyloxy)benzyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid (Compound W259)To a solution of Example 1.3.1 (44.5 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2mL) was added 4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyran)benzaldehyde (17 mg) and MgSO4 (300 mg), and the mixture was stirred at room aturefor 1 hour before the addition of sodium cyanoborohydride on resin (300 mg). The mixture wasstirred at room temperature overnight and filtered. The filtrate was concentrated, and the residue waspurified by reverse phase HPLC (Gilson system), eluting with a gradient of 10-85% acetonitrile inwater containing 0.1% v/v trifluoroacetic acid, to e the title compound. MS (ESI) m/e 1015.20(M+H)+.1.60 Synthesis of (3-{2-[azetidinyl(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-idinecarboxylic acid (Compound W2.60)1.60.1 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((1-(tertbutoxycarbonyl)azetidinyl)(2-((4-(tert-butyldiphenylsilyl)hydroxy-2,2-dimethylbutoxy)sulfonyl)ethyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)picolinateA solution of Example 1.2.8 (0.075 g), tert-butyl 3-oxoazetidinecarboxylate (0.021 g)and sodium triacetoxyborohydride (0.025 g) in dichloromethane (0.5 mL) was stirred at roomtemperature ght. The reaction was loaded onto silica gel and eluted with 0-10% methanol indichloromethane to give the title compound. MS (ESI) m/e 1403.9 (M+1).1.60.2 3-{1-[(3-{2-[azetidinyl(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-idinecarboxylic acidA solution of e 1.60.1 (0.029 g) in dichloromethane (1 mL) was treated withtrifluoroacetic acid (1 mL) and stirred overnight. The reaction was concentrated, dissolved in1:1dimethyl sulfoxide/methanol (2 mL), and the mixture was purified by reverse phase HPLC using aGilson system, eluting with 10-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

MEl 24985843V.1 515117813-12620The desired fractions were combined and -dried to provide the title compound. 1H NMR (400MHz, dimethyl ide-dé) 5 ppm 12.86 (s, 1H), 8.81 (s, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d,1H), 7.52 (d, 1H), 7.50- 7.46 (m, 1H), 7.44 (d, 1H), 7.40- 7.33 (m, 2H), 7.30 (s, 1H), 6.96 (d, 1H),4.96 (s, 2H), 4.37 (q, 1H), 4.27 (s, 2H), 4.11 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.58- 3.54 (m, 2H),3.32 (t, 2H), 3.24 (s, 2H), 3.01 (t, 2H), 2.85 (t, 2H), 2.10 (s, 3H), 1.48- 0.97 (m, 12H), 0.87 (s, 6H).

MS (ESI) m/e 909.2 (M+H)+.1.61 Synthesis of 3-{1-[(3-{2-[(3-aminopropyl)(2-sulfoethyl)amino]ethoxy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid (Compound W2.61)1.61.1 6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3-(2-((3-((tert-butoxycarbonyl)amino)propyl)(2-sulfoethyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared using the procedure for e 1.33.1, replacing tert-butyl ethyl)carbamate with tert-butyl (3-oxopropyl)carbamate. MS (ESI) m/e 1011.5 (M+H).1.61.2 3-{1-[(3-{2-[(3-aminopropyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acidThe title compound was prepared as described in Example 1.6.2, replacing Example 1.6.1with Example 1.61.1. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.87 (s, 1H), 9.10 (s, 1H),8.04 (d, 1H), 7.88-7.67 (m, 4H), 7.62 (d, 1H), 7.57-7.40 (m, 3H), 7.36 (td, 2H), 6.96 (d, 1H), 4.96 (s,2H), 4.05-3.78 (m, 4H), 3.41-3.08 (m, 3H), 2.94 (tt, 6H), 2.11 (s, 3H), 1.92 (t, 2H), 1.53-0.95 (m,11H), 0.87 (s, 6H). MS (ESI) m/e 911.3 (M+H).1.62 Synthesis of 1,3-benzothiazol-2—ylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridine-2—carboxylic acid (Compound W2.62)1.62.1 utyl3-(1-((3-(2-((3-(tert-butoxy)oxopropyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)chloropicolinateTo an ambient solution of Example 1.53.3 (521 mg) in ethanol (10 mL) was addedtriethylamine (3 mL) followed by tert-butyl acrylate (2 mL). The mixture was stirred at roomtemperature for 3 hours and then concentrated to dryness. The residue was dissolved in ethyl acetate(200 mL), and the solution was washed with water and brine. The organic layer was dried overMEl 24985843V.1 516117813-12620sodium sulfate, filtered and concentrated under reduced pressure to give the title compound, whichwas used in the next reaction without further purification. MS (ESI) m/e 657.21 (M+H)+.1.62.2 tert-butyl3-(1-((3-(2-((3-(tert-but0xy)0x0pr0pyl)(tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)chlor0picolinateTo a solution of Example 1.62.1 (780 mg) in tetrahydrofuran (10 mL) was added di-tert—butyl dicarbonate (259 mg) followed by a catalytic amount of 4-dimethylaminopyridine. The reactionwas stirred at room temperature for 3 hours and then concentrated to dryness. The residue wasdissolved in ethyl acetate (200 mL), and the on was washed with saturated aqueous NaHCO3solution, water and brine. The organic layer was dried over sodium e, filtered and concentratedunder reduced pressure. The residue was purified by chromatography on silica gel, eluting with 20%ethyl acetate in heptane, to give the title compound. MS (ESI) m/e 757.13 (M+H)+.1.62.3 utyl3-(1-((3-(2-((3-(tert-but0xy)0x0pr0pyl)(tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-yl-1H-pyrazolyl)(1,2,3,4-tetrahydr0quinolinyl)picolinateTo a solution of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1,2,3,4-ydroquinoline (234 mg) in 1,4-dioxane (10 mL) and water (5 mL) was added Example 1.62.2(685 mg), bis(triphenylphosphine)palladium(II)dichloride (63.2 mg), and cesium e (410 mg).

The mixture was heated to 120 0C for 30 minutes by microwave irradiation ge Initiator). Thereaction was quenched by the addition of ethyl acetate and water. The layers were separated, and theorganic layer was washed with brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The e was purified by chromatography on silica gel, eluting with 20% ethylacetate in heptane, to give the title compound. MS (ESI) m/e 854.82 (M+H)+.1.62.4 tert-butyl6-(1-(benzo[d]thiazol-2—ylcarbam0yl)-1,2,3,4-tetrahydroquinolinyl)(1-((3-(2-((3-(tert-but0xy)oxopropyl)(tert-butoxycarbonyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)picolinateTo an ambient suspension of 5-dioxopyrrolidinyl) carbonate (150 mg) inacetonitrile (10 mL) was added d]thiazolamine (88 mg), and the mixture was stirred for 1hour. A solution of Example 1.62.3 (500 mg) in itrile (2 mL) was added, and the suspensionwas vigorously stirred overnight. The reaction was quenched by the addition of ethyl acetate andwater. The layers were separated, and the organic layer was washed with brine, dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residue was purified bychromatography on silica gel, g with 20% ethyl acetate in dichloromethane, to give the titlecompound. MS (ESI) m/e 1030.5 (M+H)+.

MEl 24985843V.1 517117813-126201.62.5 6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl]-(3-{2-[(2-carboxyethyl)amin0]ethoxy}-5,7—dimethyltricyclo[3.3.l.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo an ambient on of Example 1.62.4 (110 mg) in dichloromethane (0.53 mL) wasadded trifluoroacetic acid (0.53 mL). The reaction was stirred overnight and was concentrated to aviscous oil. The residue was dissolved in dimethyl sulfoxide/methanol (1 :1, 2 mL) and purified byreverse phase HPLC (Gilson system), eluting with 10-55% acetonitrile in 0.1% trifluoroacetic acid inwater, to give the title compound. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 13.10 (s, 3H),8.37 (s, 1H), 8.26 (s, 2H), 7.98 (d, 1H), 7.86-7.71 (m, 3H), 7.44 (s, 1H), 7.39-7.31 (m, 1H), 7.26 (d,1H), 7.19 (t, 1H), 3.92 (d, 2H), 3.87 (s, 2H), 3.55 (t, 2H), 3.17-3.00 (m, 4H), 2.80 (t, 2H), 2.62 (t, 2H),2.19 (s, 3H), 1.95-1.88 (m, 2H), 1.43 (s, 2H), 1.33-1.25 (m, 4H), 1.18-1.11 (m, 4H), 1.09-0.97 (m,2H), 0.85 (s, 6H). MS (ESI) m/e 818.0 (M+H)+.1.63 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(N6,N6-dimethyl-L-lysyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.63)A solution of (S)((((9H-fluorenyl)methoxy)carbonyl)amino)hylamino)hexanoic acid (0.029 g) and l-[bis-(dimethylaminohnethylene]—1H—l,2,3-triazolo{4,5—b]pyridinium 3-—oxid hexafluorophosphate (0.028 g) was stirred together in N,N-dimethylformamide(0.5 mL) with N,N-diisopropylamine (0.035 mL). After stirring for 5 minutes, the on was addedto Example 1.13.7 (0.051 g) and ng was continued at room temperature overnight. To theon was added diethylamine (0.070 mL), and the reaction was stirred for 2 hours. The reactionwas diluted with N,N-dimethylformamide (1 mL), water (0.5 ml), and 2,2,2-trifluoroacetic acid (0.103ml) then purified via reverse-phase HPLC using a gradient of 10% to 90% acetonitrile/water. Theproduct containing ons were collected and lyophilized to give the title compound. 1H NMR (500MHz, dimethyl sulfoxide-dé) 5 9.59 (s, 1H), 8.41 (s, 1H), 8.12 (t, 3H), 8.01 (d, 1H), 7.85 (dd, 1H),7.81 (d, 1H), 7.77 (dd, 1H), 7.47 (s, 1H), 7.38 (t, 1H), 7.30 (d, 1H), 7.22 (t, 1H), 3.97 (t, 2H), 3.89 (s,2H), 3.49 (dt, 4H), 3.06 (s, 2H), 2.99 (q, 2H), 2.88 (s, 2H), 2.84 (t, 2H), 2.75 (d, 6H), 2.22 (s, 3H),2.00 — 1.90 (m, 2H), 1.84 — 1.52 (m, 4H), 1.48 — 0.95 (m, 14H), 0.87 (d, 6H). MS (ESI) m/e 916.2(M+H)+.1.64 Synthesis of 3-{1-[(3-{2-[(3-aminopropyl)(methyl)amino]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[1-(1,3-benzothiazol-2—ylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl]pyridinecarb0xylic acid (W2.64)MEl 24985843v.1 518117813-126201.64.1 6-(1-(benzo[d]thiazolylcarbam0yl)-1,2,3,4-tetrahydr0quinolinyl)-3-(1-((3-(2-((3-((tert-butoxycarbonyl)amin0)propyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinicA solution of Example 1.21.5 (100 mg), N,N-diisopropylethylamine (68.9 uL) and tert-butyl (3-oxopropyl)carbamate (68.4 mg) in dichloromethane (3 mL) was stirred at ambienttemperature for 2 hours, and NaCNBH4 (8.27 mg) was added. The reaction was stirred at ambienttemperature overnight. Methanol (1 mL) and water (0.2 mL) were added. The ing mixture wasstirred for 10 minutes and concentrated. The residue was dissolved in dimethyl sulfoxide and purifiedby e-phase HPLC on a Gilson system (C18 column), eluting with 30-80% acetonitrile in 0.1%trifluoroacetic acid water solution, to provide the title compound as a trifluoroacetic acid salt. MS(ESI) m/e 459.4 (M+2H)2+.1.64.2 (3-{2-[(3-aminopropyl)(methyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-[1-(1,3-benz0thiazolylcarbamoyl)-1,2,3,4-tetrahydr0quinolinidinecarb0xylic acidExample 1.64.1 (100 mg) in dichloromethane (4 mL) at 0 0C was treated withtrifluoroacetic acid (1 mL) for 1 hour, and the mixture was trated. The residue was purified byreverse phase HPLC (C18 column), eluting with a gradient of 10-60% acetonitrile in 0.1%trifluoroacetic acid water solution, to e the title compound as a trifluoroacetic acid salt. 1HNMR (400 MHz, dimethyl ide-dé) 5 9.38 (s, 1H), 8.37 (s, 1H), 7.98 (d, 1H), 7.90 — 7.69 (m,6H), 7.44 (s, 2H), 7.35 (td, 1H), 7.27 (d, 1H), 7.22 — 7.16 (m, 1H), 3.94 (d, 2H), 3.87 (s, 2H), 3.64 (t,2H), 3.28 — 2.98 (m, 4H), 2.87 — 2.70 (m, 8H), 2.19 (s, 3H), 1.90 (dp, 4H), 1.43 (s, 2H), 1.36 — 1.22(m, 4H), 1.15 (s, 4H), 1.08 — 0.95 (m, 2H), 0.86 (s, 6H). MS (ESI) m/e 817.6 (M+H)+.1.65 Synthesis of 3-{1-[(3-{2-[azetidinyl(methyl)amin0]ethoxy}-5,7-yltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}[1-(1,3-benzothiazol-2—ylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl]pyridinecarb0xylic acid (W2.65)1.65.1 6-(1-(benzo[d]thiazolylcarbam0yl)-1,2,3,4-tetrahydr0quinolinyl)-3-(1-((3-(2-((1-(tert-butoxycarbonyl)azetidinyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared using the procedure described in Example 1.64.1,substituting tert-butyl (3-oxopropyl)carbamate with tert-butyl 3-oxoazetidine-l-carboxylate. MS(ESI) m/e 915.3 (M+H)+.

MEl 24985843V.1 519117813-126201.65.2 3-{1-[(3-{2-[azetidinyl(methyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-[1-(1,3-benz0thiazolylcarbamoyl)-1,2,3,4-tetrahydr0quinolinyl]pyridinecarb0xylic acidThe title compound was prepared using the procedure in Example 1.64.2, substitutingExample 1.64.1 with Example 1.65.1. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 9.01 (s, 2H),8.37 (s, 1H), 7.98 (d, 1H), 7.86 — 7.70 (m, 3H), 7.44 (s, 2H), 7.34 (td, 1H), 7.27 (d, 1H), 7.23 — 7.15(m, 1H), 4.22 (s, 4H), 4.07 (s, 2H), 3.93 (t, 2H), 3.58 (t, 2H), 3.11 (s, 2H), 2.80 (t, 2H), 2.68 (s, 3H),2.19 (s, 3H), 1.92 (p, 2H), 1.42 (s, 2H), 1.30 (s, 4H), 1.15 (s, 4H), 1.09 — 0.96 (m, 2H), 0.85 (s, 6H).

MS (ESI) m/e 815.5 (M+H)+.1.66 sis of N6-(37-0x0-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-L-lysyl-N-[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]-L-alaninamide (W2.66)1.66.1 (S)((((9H-flu0renyl)meth0xy)carb0nyl)amin0)((tertbutoxycarbonyl)hexanoic acidTo a solution of (S)amino((tert-butoxycarbonyl)amino)hexanoic acid (8.5 g) in amixture of 5% aqueous NaHCO3 solution (300 mL) and dioxane (40 mL), chilled in an ice bath, wasadded dropwise a solution of (9H-fluorenyl)methyl pyrrolidinyl carbonate (11.7 g) in dioxane(40 mL). The reaction mixture was allowed to warm to room temperature and was stirred for 24hours. Three additional vials were set up as described above. After the reaction was completed, allfour reaction mixtures were combined, and the organic solvent was removed under vacuum. Thes residue was acidified to pH 3 with aqueous hydrochloric acid on (1N) and thenextracted with ethyl acetate (3 X 500 mL). The combined c layers were washed with brine,dried over magnesium sulfate, filtered, and concentrated under vacuum to give a crude compoundwhich was recrystallized from methyl tert-butyl ether to afford the title nd. 1H NMRz, chloroform-d) 5 11.05 (br. s., 1H), 7.76 (d, 2H), 7.59 (d, 2H), 7.45 - 7.27 (m, 4H), 6.52 -6.17 (m, 1H), 5.16 - 4.87 (m, 1H), 4.54 - 4.17 (m, 4H), 3.26 - 2.98 (m, 2H), 1.76 - 1.64 (m, 1H), 1.62 -1.31 (m, 14H).1.66.2 tert-butyl17-hydr0xy-3,6,9,12,15-penta0xaheptadecan-l-oateTo a solution of 3,6,9,12-tetraoxatetradecane-1,14-diol (40 g) in e (800 mL) wasadded portion-wise potassium tert-butoxide (20.7 g). The e was stirred at room temperature forminutes. Tert-butyl 2-bromoacetate (36 g) was added dropwise to the mixture. The reaction wasstirred at room temperature for 16 hours. Two additional vials were set up as described above. Afterthe reactions were ted, all three reaction mixtures were combined. Water (500 mL) was addedto the combined mixture, and the mixture was concentrated to 1 L. The mixture was extracted withMEl 24985843v.1 520117813-12620dichloromethane and was washed with s 1N ium tert-butoxide solution (1 L). Thec layer was dried over NaZSO4, filtered and concentrated to obtain crude product, which waspurified by silica gel column chromatography, eluting with dichloromethane:methanol 50:1, to obtainthe title compound. 1H NMR (400MHz, chloroform-d) 5 4.01 (s, 2H), 3.75 - 3.58 (m, 21H), 1.46(s,9H).1.66.3 tert-butyl17-(t0syloxy)-3,6,9,12,15-pentaoxaheptadecan-l-oateTo a on of Example 1.66.2 (30 g) in romethane (500 mL) was added dropwisea solution of 4-methylbenzenesulfonyl de (19.5 g) and triethylamine (10.3 g) indichloromethane (500 mL) at 0 CC under a nitrogen here. The mixture was stirred at roomtemperature for 18 hours and was poured into water (100 mL). The solution was extracted withdichloromethane (3 X 150 mL), and the organic layer was washed with hydrochloric acid (6N, 15 mL)then NaHCO3 (5% aqueous solution, 15 mL) followed by water (20 mL). The organic layer was driedover NaZSO4, filtered and concentrated to obtain a residue, which was purified by silica gel columnchromatography, eluting with eum ether:ethyl acetate 10:1 to dichloromethane:methanol 5:1, toobtain the title compound. 1H NMR (400MHz, chloroform-d) 5 7.79 (d, 2H), 7.34 (d, 2H), 4.18 - 4.13(m, 2H), 4.01 (s, 2H), 3.72 - 3.56 (m, 18H), 2.44 (s, 3H), 1.47 (s, 9H).1.66.4 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontan0ic acidTo a on of 2,5,8,11,14,17-hexaoxanonadecanol (32.8 g) in tetrahydrofuran (300mL) was added sodium hydride (1.6 g) at 0 CC. The mixture was stirred at room temperature for 4hours. A solution of Example 1.66.3 (16 g) in tetrahydrofuran (300 mL) was added dropwise at roomtemperature to the reaction mixture. The resulting on mixture was stirred at room temperaturefor 16 hours and then water (20 mL) was added. The mixture was stirred at room temperature foranother 3 hours to complete the tert-butyl ester hydrolysis. The final reaction mixture wasconcentrated under vacuum to remove the organic solvent. The aqueous residue was extracted withdichloromethane (2 X 150 mL). The aqueous layer was acidified to pH 3 and then ted withethyl acetate (2 X 150 mL). The aqueous layer was concentrated to obtain crude product, which waspurified by silica gel column chromatography, eluting with a gradient of petroleum ether:ethyl acetate1:1 to dichloromethane:methanol 5:1, to obtain the title compound. 1H NMR z, chloroform-d) 5 4.19 (s, 2H), 3.80 - 3.75 (m, 2H), 3.73 - 3.62 (m, 40H), 3.57 (dd, 2H), 3.40 (s, 3H).1.66.5 (43S,46S)((tert-butoxycarbonyl)amin0)methyl-37,44-di0x0-2,5,8,11,14,17,20,23,26,29,32,35-d0decaoxa-38,45-diazaheptatetracontan0ic acidExample 1.66.5 was synthesized using standard Fmoc solid phase peptide synthesisprocedures and a 2-chlorotrytil resin. 2-Chlorotrytil resin (12 g, 100 mmol), (S)((((9H-fluorenyl)methoxy)carbonyl)amino)propanoic acid (10 g, 32.1 mmol) and N,N-diisopropylethylamine (44.9mL, 257 mmol) in anhydrous, sieve-dried romethane (100 mL) was shaken at 14 CC for 24hours. The mixture was filtered and the cake was washed with dichloromethane (3 X 500 mL),MEl 24985843V.1 521117813-12620ylformamide (2 X 250 mL) and methanol (2 X 250 mL) (for 5 minutes for each step). To theabove resin was added 20% piperidine/dimethylformamide (100 mL) to remove the Fmoc group. Themixture was bubbled with en for 15 minutes and then filtered. The resin was washed with 20%piperidine/dimethylformamide (100 mL) another five times (5 minutes each step), and washed withdimethylformamide (5 X 100 mL) to give the deprotected, L-Ala loaded resin.

To a solution of Example 1.66.1 (9.0 g) in N,N-dimethylformamide (50 mL) was addedhydroxybenzotriazole (3.5 g), 2-(6-chloro-1H-benzotriazoleyl)-1,1,3,3-tetramethylaminiumhexafluorophosphate (9.3 g) and isopropylethylamine (8.4 mL). The mixture was stirred at 20CC for 30 minutes. The above e was added to the D-Ala loaded resin and mixed by bubblingwith en at room temperature for 90 minutes. The mixture was filtered and the resin was washedwith dimethylformamide (5 minutes each step). To the above resin was added approximately 20%piperidine/ N,N-dimethylformamide (100 mL) to remove the Fmoc group. The mixture was dwith nitrogen for 15 minutes and filtered. The resin was washed with 20%piperidine/dimethylformamide (100 mL) for another five times (5 minutes for each step), and finallywashed with dimethylformamide (5 X 100 mL).

To a solution of Example 1.66.4 (11.0 g) in N,N-dimethylformamide (50 mL) was addedhydroxybenzotriazole (3.5 g), 2-(6-chloro-1H-benzotriazoleyl)-1,1,3,3-tetramethylaminiumhexafluorophosphate (9.3g) and N,N-diisopropylethylamine (8.4 mL), and the mixture was added tothe resin and mixed by bubbling with nitrogen at room temperature for 3 hours. The mixture wasfiltered and the residue was washed with dimethylformamide (5 X 100 mL), dichloromethane (8 X 100mL) (5 minutes for each step).

To the final resin was added 1% trifluoroacetic acid/dichloromethane (100 mL) andnitrogen was bubbled h for 5 minutes. The mixture was ted and the filtrate was collected.

The cleavage operation was repeated for four times. The combined filtrate was brought to pH 7 byNaHCO3 and washed with water. The organic layer was dried over NaZSO4, filtered and concentratedto obtain the title compound. 1H NMR z, methanol-d4) 5 4.44 - 4.33 (m, 1H), 4.08 - 4.00 (m,1H), 3.98 (s, 2H), 3.77 - 3.57 (m, 42H), 3.57 - 3.51 (m, 2H), 3.36 (s, 3H), 3.25 (t, 2H), 1.77 (br. s.,1H), 1.70 - 1.51 (m, 4H), 1.44 (s, 9H), 1.42 - 1.39 (m, 3H).1.66.6 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(((43S,46S)((tertbutoxycarbonyl)methyl-37,44,47-tri0x0-2,5,8,11,14,17,20,23,26,29,32,35-d0decaoxa-38,45,48-triazapentac0ntan-50-yl)0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4-yl)picolinateExample 1.66.5 (123 mg, 0.141 mmol), was mixed with 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (58.9mg) and N,N-diisopropylethylamine (0.049 mL) in N-methylpyrrolidone (1 mL) for 10 minutesMEl 24985843V.1 522-12620and then added to a solution of Example 1.2.7 (142 mg) and N,N-diisopropylethylamine (0.049 mL)in N-methylpyrrolidone (1.5 mL). The reaction mixture was stirred at room temperature for twohours. The crude on mixture was purified by reverse phase HPLC using a Gilson system and aC18 25 x 100 mm column, eluting with 5-85% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The t fractions were lyophilized to give the title compound. MS (LC/MS)m/e 1695.5 (M+H)+.1.66.7 3-(1-((3-(((43S,46S)amin0methyl-37,44,47-tri0x0-2,5,8,11,14,17,20,23,26,29,32,35-d0decaoxa-38,45,48-triazapentac0ntan-50-yl)0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4-yl)(8-(benz0[d]thiazolylcarbam0yl)-3,4—dihydr0is0quinolin-2(1H)-yl)picolinic acidExample 1.66.6 (82 mg) was treated with 1 mL of trifluoroacetic acid at room temperaturefor 30 minutes. The solvent was evaporated under a gentle stream of nitrogen, and the e waspurified by reverse phase HPLC using a Gilson system and a C18 25 x 100 mm , g with5-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The product fractions werelyophilized to give the title compound as the trifluoroacetic acid salt. 1H NMR (400 MHz, ylsulfoxide-d6) 5 ppm 12.86 (s, 1H), 8.04 (dd, 4H), 7.64 (dt, 2H), 7.55 — 7.41 (m, 3H), 7.36 (q, 2H),6.95 (d, 1H), 4.96 (s, 2H), 4.40 — 4.27 (m, 1H), 3.93 — 3.72 (m, 7H), 3.59 — 3.47 (m, 42H), 3.33 — 3.27(m, 3H), 3.23 (s, 5H), 3.05 (dt, 5H), 2.10 (s, 3H), 1.72 — 1.64 (m, 2H), 1.48 — 1.36 (m, 4H), 1.35 —1.16 (m, 10H), 1.16 — 0.94 (m, 6H), 0.84 (d, 6H). MS (ESI) m/e 751.8 (2M+H)2+.1.67 Synthesis of methyl 6-[4-(3-{[2—({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}pr0pyl)-1H-1,2,3-triazolyl]de0xy-beta-L-glucopyranoside (W2.67)1.67.1 6-(8-(benz0[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,S-dimethyl(2-(pent-4—ynylamin0)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo a solution of tert-butyl 3-(1-((3 -(2-aminoethoxy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate (85 mg) in tetrahydrofuran (2 mL) was added pentynal (8.7 mg), acetic acid (20 mg,0.318) and anhydrous sodium sulfate (300 mg). The mixture was stirred at room temperature for 1hour. Sodium triacetoxyborohydride (45 mg) was added to the reaction mixture. The mixture wasstirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (200 mL),washed with water and brine, and dried over ous sodium sulfate. Filtration and evaporation ofthe t gave crude product, which was dissolved in dichloromethane (5 mL) and trifluoroaceticacid (3 mL). The mixture was stirred at room temperature overnight. After evaporation of theMEl 24985843V.1 523117813-12620t, the residue was dissolved in dimethyl sulfoxide/methanol (1 :1, 3 mL) and purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in watercontaining 0.1% roacetic acid, to give the title nd. MS (APCI) m/e 812.2 .1.67.2 methyl 6-[4-(3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec)ethyl]amin0}pr0pyl)-1H-1,2,3-triazolyl]de0xy-beta-L-glucopyranosideTo a solution of (2R,3R,4S,5S,6S)azido(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8.63 mg) in t-BuOH (2 mL) and water (1 mL) was added Example 1.67.1 (20mg), copper (II) sulfate pentahydrate (2.0 mg) and sodium ascorbate (5 mg). The mixture was heatedfor 20 minutes at 100 C)C under ave conditions (Biotage Initiator). LiOH H20 (50 mg) wasadded to the mixture, which was stirred at room temperature overnight. The mixture was neutralizedwith trifluoroacetic acid and purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlecompound. MS (APCI) m/e 1032.2 (M+H)+.1.68 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3-{2-[(2-carboxyethyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-lH-pyrazolyl}pyridine-2—carb0xylic acid1.68.1 2-((3,5-dimethyl((5-methyl(4,4,5,5-tetramethyl-1,3,2-orolan—Z-yl)-1H-pyrazolyl)methyl)adamantanyl)0xy)ethanol (W2.68)To a on of 2-((3-((4-iodomethyl-1H-pyrazolyl)methyl)-5,7-yladamantanyl)oxy)ethanol (8.9 g) and PdClz(dppf)-CH2C12 adduct (([1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1), 818 mg) in acetonitrile (120 mL) wasadded trimethylamine (10 mL) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (12.8 mL). The mixturewas stirred at reflux overnight. The mixture was cooled to room temperature and used in the nextreaction without further work up. MS (ESI) m/e 467.3 (M+Na)+.1.68.2 tert-butyl6-ch10r0(1-((3-(2-hydr0xyeth0xy)-5,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)pic01inateTo a solution of tert-butyl 3-bromochloropicolinate (6.52 g) in tetrahydrofuran (100mL) and water (20 mL) was added Example 1.68.1 (9.90 g), (1S,3R,5R,7S)-1,3,5,7-tetramethyltetradecyl-2,4,6-trioxaphosphaadamantane (0.732 g), tris(dibenzylideneacetone)dipalladium(0)(Pd2(dba)35 1.02 g), and K3PO4 (23.64 g). The mixture was stirred at reflux overnight. The mixturewas concentrated under reduced pressure, the residue was dissolved in ethyl acetate (500 mL), washedMEl 24985843V.1 524117813-12620with water and brine, and dried over anhydrous sodium sulfate. Filtration and evaporation of thesolvent gave crude product, which was purified by silica gel chromatography eluting with 20 to 40%ethyl acetate in dichloromethane to give the title nd. MS (ESI) m/e 530.3 (M+H)+.1.68.3 tert-butyl6-ch10r0(1-((3,5-dimethyl(2-((methylsulfonyl)0xy)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a cooled (0 C)C) solution of Example 1.68.2 (3.88 g) in dichloromethane (30 mL) andtriethylamine (6 mL) was added methanesulfonyl chloride (2.52 g). The mixture was stirred at roomtemperature for 4 hours. The reaction mixture was diluted with ethyl acetate (400 mL), washed withwater and brine, and dried over ous sodium sulfate. Filtration and evaporation of the solventgave the crude product (4.6 g), which was used in the next reaction without further purification. MS(ESI) m/e 608.1 (M+H)+.1.68.4 utyl 3-{1-[(3-{2—[bis(tert-butoxycarbonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-chlor0pyridinecarb0xylateTo a solution of Example 1.68.3 (151 mg) in N,N-dimethylformamide (3 mL) was addeddi-tert-butyl iminodicarboxylate (54 mg). The mixture was stirred at room temperature overnight.

The reaction mixture was diluted with ethyl acetate (200 mL), washed with water and brine, and driedover anhydrous sodium sulfate. Filtration and evaporation of the solvent gave the title compound,which was used in the next step without further cation. MS (ESI) m/e 729.4 (M+H)+.1.68.5 7-(6-(tert-butoxycarbonyl)(1-((3-(2-((tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-lH-pyrazolyl)pyridinyl)naphth0ic acidTo a solution of methyl 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)naphthoate (257 mg) in 1,4-e (10 mL) and water (5 mL) was added Example 1.68.4 (600 mg),bis(triphenylphosphine)palladium(II) dichloride (57.8 mg), and CsF (375 mg). The mixture wasd at 120 CC for 30 minutes under microwave conditions (Biotage Initiator). The mixture wasdiluted with ethyl e (200 mL), washed with water and brine, and dried over anhydrous sodiume. tion and ation of the solvent gave crude product, which was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane to give a di-ester intermediate. Theresidue was dissolved in tetrahydrofuran (10 mL), methanol (5 mL) and water (5 mL) and LiOH H20(500 mg) was added, and the mixture was stirred at room temperature overnight. The mixture wasied with 2N s HCl, dissolved in 400 mL of ethyl acetate, washed with water and brine,and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent gave the titlecompound. MS (APCI) m/e 765.3 (M+H)+.

MEl 24985843V.1 525117813-126201.68.6 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)naphthalenyl)picolinic acidTo a solution of Example 1.68.5 (500 mg) in dichloromethane (10 mL) was addedbenzo[d]thiazolamine (98 mg), l~ethyl—3—(3dimethylaminopropyl)carbodiinude (251 mg) and 4—dimethylaminopyridine (160 mg). The e was stirred at room temperature overnight. Thereaction e was diluted with ethyl acetate (400 mL), washed with water and brine, and driedover anhydrous sodium sulfate. Filtration and evaporation of the solvent gave a residue that wasdissolved in dichloromethane and trifluoroacetic acid (10 mL, 1:1). After stirring overnight, thesolution was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (12 mL) and purified by reverse-phase HPLC (using a Gilson system and a C18column, eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid) to give thetitle compound. MS (ESI) m/e 741.2 (M+H)+.1.68.7 6-[8-(1,3-benz0thiazolylcarbam0yl)naphthalenyl]{1-[(3-{2-[(2—carboxyethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dechyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.68.6 (35 mg) in methylformamide (4 mL) was addedtert-butyl te (120 mg) and H20 (138 mg). The mixture was stirred at room temperatureght. The reaction mixture was diluted with ethyl acetate (400 mL), washed with water andbrine, and dried over anhydrous sodium sulfate. Filtration and evaporation of the solvent gave aresidue that was dissolved in dichloromethane and trifluoroacetic acid (10 mL, 1:1). After 16 hours,the e was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (2 mL) and purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 13.08 (s, 1H), 8.99 (d, 1H), 8.43 —8.24 (m, 4H), 8.24 — 8.11 (m, 3H), 8.04 (d, 1H), 7.99 (d, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.74 — 7.62(m, 1H), 7.53 — 7.43 (m, 2H), 7.35 (q, 1H), 3.87 (s, 2H), 3.08 (dp, 4H), 2.62 (t, 2H), 2.20 (s, 3H), 1.43(s, 2H), 1.29 (q, 4H), 1.14 (s, 4H), 1.03 (q, 2H), 0.85 (s, 6H).1.69 Synthesis of 6-[5-(1,3-benzothiazolylcarbam0yl)quinolinyl]{1-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid1.69.1 methyl 3-br0m0quinolinecarb0xylate )To a solution of 3-bromoquinoline-5 -carboxylic acid (2 g) in methanol (30 mL) was addedconcentrated H2SO4 (5 mL). The solution was stirred at reflux overnight. The mixture wasconcentrated under reduced pressure. The residue was dissolved in ethyl acetate (300 mL) andwashed with aqueous NazCO3 solution, water and brine. After drying over ous sodium sulfate,filtration and evaporation of the solvent gave the title compound. MS (ESI) m/e 266 (M+H)+.

MEl 24985843V.1 526117813-126201.69.2 methyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)quinoline-S-carboxylateTo a solution of e 1.69.1 (356 mg) in N,N-dimethylformamide (5 mL) was addedPdClz(dppf)-CH2C12 adduct ([1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1 : 1), 55mg) potassium acetate (197 mg) and bis(pinacolato)diboron (510 mg). The mixture was stirred at 60CC overnight. The e was cooled to room temperature and used in the next reaction withoutfurther work up. MS (ESI) m/e 339.2 (M+Na)+.1.69.3 methyl 3-[5-{1-[(3-{2—[bis(tert-butoxycarbonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-(tert-but0xycarb0nyl)pyridinyl]quinoline-S-carboxylateTo a solution of Example 1.69.2 (626 mg) in 1,4-dioxane (10 mL) and water (5 mL) wasadded Example 1.68.4 (1.46 g), bis(triphenylphosphine)palladium(II) dichloride (140 mg), and CsF(911 mg). The mixture was stirred at 120 0C for 30 minutes under microwave conditions (BiotageInitiator). The mixture was diluted with ethyl acetate (200 mL), washed with water and brine, driedover anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gelchromatography, g with 20% ethyl acetate in e (1 L) to give the title compound. MS(ESI) m/e 880.3 (M+H)+.1.69.4 3-(6-(tert-butoxycarbonyl)(1-((3-(2-((tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)pyridinyl)quinoline-S-carboxylic acidTo a on of e 1.69.3 (1.34 g) in tetrahydrofuran (10 mL), methanol (5 mL) andwater (5 mL) was added LiOH H20 (120 mg), and the mixture was stirred at room temperatureovernight. The mixture was acidified with 2N aqueous HCl, diluted with ethyl acetate (400 mL),washed with water and brine, and dried over anhydrous sodium sulfate. tion and evaporation ofthe solvent gave the title compound. MS (APCI) m/e 766.3 (M+H)+.1.69.5 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(5-(benzo[d]thiazolylcarbam0yl)quinolin-3-yl)picolinic acidTo a on of Example 1.69.4 (200 mg) in dichloromethane (10 mL) was addedbenzo[d]thiazolamine (39.2 mg), 1-ethyl(3-dimethylaminopropyl)carbodiimide (50 mg) and 4-dimethylaminopyridine (32 mg). The mixture was d at room temperature overnight. Thereaction mixture was diluted with ethyl acetate (200 mL), washed with water and brine, dried overanhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dichloromethaneand trifluoroacetic acid (10 mL, 1:1), and the reaction was stirred overnight. The e wasconcentrated, and the residue was dissolved in N,N-dimethylformamide (12 mL) and purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e 742.1 (M+H)+.

MEl 24985843V.1 527-126201.69.6 6-[5-(1,3-benz0thiazolylcarbamoyl)quinolinyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.69.5 (36 mg) in N,N-dimethylformamide (2 mL) was added 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (22 mg) and H20 (0.3 mL)). Themixture was stirred at room temperature for 3 hours. The reaction mixture was diluted withdichloromethane and trifluoroacetic acid (10 mL, 1:1) and d overnight. The mixture wastrated, and the residue was dissolved in N,N-dimethylformamide (4 mL) and purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. 1H NMR (400 MHz, dimethylsulfoxide-dé) 5 ppm 13.19 (s, 2H), 9.70 (d, 1H), 9.40 (s, 1H), 8.31 (d, 2H), 8.16 (d, 1H), 8.06 (d, 1H),8.01 (d, 1H), 7.98 — 7.88 (m, 1H), 7.80 (d, 1H), 7.52 — 7.43 (m, 2H), 7.37 (q, 1H), 3.89 (s, 2H), 3.22(p, 2H), 3.10 (q, 2H), 2.80 (t, 2H), 2.23 (s, 3H), 1.43 (s, 2H), 1.30 (q, 4H), 1.23 — 1.10 (m, 4H), 1.04(q, 2H), 0.87 (s, 6H). MS (ESI) m/e 850.2 (M+H)+.1.70 Synthesis of 6-[4-(1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.70)1.70.1 ethyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-Z-yl)quinolinecarboxylateTo a solution of ethyl 6-bromoquinolinecarboxylate (140 mg) in N,N-dimethylformamide (2 mL) was added PdClz(dppf)-CH2C12 adduct (([l,l’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1), 20.42 mg), potassium acetate (147 mg)and bis(pinacolato)diboron (190 mg). The e was stirred at 60 OC overnight. The mixture wascooled to room temperature and used in the next reaction without further work up. MS (ESI) m/e328.1(M+H)+.1.70.2 ethyl 6-[5-{1-[(3-{2—[bis(tert-butoxycarbonyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-(tert-but0xycarb0nyl)pyridinyl]quinolinecarb0xylateTo a solution of Example 1.70.1 (164 mg) in 1,4-dioxane (10 mL) and water (5 mL) wasadded Example 1.68.4 (365 mg), bis(triphenylphosphine)palladium(II) dichloride (35 mg), and CsF(228 mg). The mixture was stirred at 120 0C for 30 minutes under ave conditions geInitiator). The e was diluted with ethyl acetate (200 mL), washed with water and brine, driedover anhydrous sodium e, filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in heptane (l L) to give the title compound. MS(ESI) m/e 894.3 (M+H)+.

MEl 24985843V.1 528117813-126201.70.3 6-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pyridinyl)quinolinecarb0xylic acidTo a solution of Example 1.70.2 (3.1 g) in tetrahydrofuran (20 mL), methanol (10 mL) andwater (10 mL) was added LiOH H20(240 mg). The e was stirred at room temperatureght. The mixture was acidified with 2N aqueous HCl and diluted with ethyl acetate (400 mL).

The organic layer was washed with water and brine and dried over anhydrous sodium sulfate.

Filtration and ation of the t gave the title compound. MS (ESI) m/e 766.3 (M+H)+.1.70.4 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)-1H-pyrazolyl)(4-(benzo[d]thiazolylcarbam0yl)quinolin-6-yl)picolinic acidTo a solution of Example 1.70.3 (4.2 g) in dichloromethane (30 mL) was addedbenzo[d]thiazolamine (728 mg), 1-ethyl(3-dimethylaminopropyl)carbodiimide (1.40 g) and 4-dimethylaminopyridine (890 mg), and the mixture was stirred at room temperature overnight. Thereaction mixture was diluted with ethyl acetate (500 mL), washed with water and brine, and driedover anhydrous sodium sulfate. Filtration and evaporation of the solvent gave a residue that wasdissolved in dichloromethane and trifluoroacetic acid (10 mL, 1:1) and stirred overnight. The mixturewas trated, and the residue was dissolved in N,N-dimethylformamide (4 mL) and purified byreverse-phase HPLC on a Gilson system (C18 ), eluting with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e 742.2 (M+H)+.1.70.5 1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.70.4 (111 mg) in N,N-dimethylformamide (4 mL) was added4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutylethenesulfonate (67 mg), N,N-diisopropylethylamine (0.2 mL) and H20 (0.3 mL). The mixture was stirred at room temperature for3 hours. The reaction mixture was diluted with dichloromethane and trifluoroacetic acid (10 mL, 1:1)and stirred overnight. The mixture was trated, and the residue was dissolved in N,N-ylformamide (4 mL) and purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 13.31 (s, 1H), 9.10 (d, 1H), 8.91 (s,1H), 8.58 (dd, 1H), 8.47 — 8.16 (m, 4H), 8.06 (dd, 1H), 7.99 — 7.89 (m, 2H), 7.79 (d, 1H), 7.53 — 7.43(m, 2H), 7.42 — 7.31 (m, 1H), 3.87 (s, 2H), 3.53 (d, 1H), 3.20 (p, 2H), 3.07 (p, 2H), 2.78 (t, 2H), 2.20(s, 3H), 1.40 (s, 2H), 1.28 (q, 4H), 1.21 — 1.07 (m, 4H), 1.02 (q, 2H), 0.84 (s, 6H). MS (ESI) m/e850.1 (M+H)+.

MEl 24985843V.1 529117813-126201.71 Synthesis of 6-[5-(1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3--carb0xyethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dechyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.71)To a solution of e 1.69.5 (140 mg) in N,N-dimethylformamide (10 mL) was addedtert-butyl acrylate (242 mg), and H20 (0.3 mL), and the e was stirred at room temperature overthe weekend. The reaction mixture was d with dichloromethane and trifluoroacetic acid (10 mL,1:1) and stirred overnight. The mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (4 mL) and purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlend. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.17 (s, 2H), 9.69 (d, 1H), 9.37 (d,1H), 8.30 (dd, 3H), 8.15 (dd, 1H), 8.04 (dd, 1H), 7.99 — 7.88 (m, 2H), 7.79 (d, 1H), 7.53 — 7.40 (m,2H), 7.34 (td, 1H), 3.88 (s, 2H), 3.55 (t, 2H), 3.08 (dt, 4H), 2.62 (t, 2H), 2.21 (s, 3H), 1.43 (s, 2H),1.29 (q, 4H), 1.14 (s, 4H), 1.03 (q, 2H), 0.85 (s, 6H). MS (ESI) m/e 814.2 (M+H)+.1.72 Synthesis of 6-[1-(1,3-benzothiazolylcarbam0yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.72)1.72.1 ethyl 7-(5-br0m0(tert-butoxycarbonyl)pyridinyl)-5,6,7,8-tetrahydroimidazofl,5-a]pyrazine-l-carboxylateThe title compound was prepared by substituting ethyl 5,6,7,8-tetrahydroimidazo[1,5-a]pyrazinecarboxylate hydrochloride for 1,2,3,4-tetrahydroisoquinolinecarboxylatehydrochloride in Example 1.1.11. MS (ESI) m/e 451, 453 (M+H)+, 395, 397 (M-tert-butyl)+.1.72.2 ethyl 7-(6-(tert-butoxycarbonyl)(4,4,5,5-tetramethyl-1,3,2-orolan—2-yl)pyridinyl)-5,6,7,8-tetrahydr0imidazo[1,5-a]pyrazine-l-carboxylateThe title compound was prepared by substituting Example 1.72.1 for Example 1.1.11 inExample 1.2.1. MS (ESI) m/e 499 , 443 (M- tert-butyl)+, 529 (M+CH3OH-H)'.1.72.3 ethyl7-(6-(tert-butoxycarbonyl)(1-((3-(2-((tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)pyridinyl)-5,6,7,8-tetrahydr0imidazo[1,5-a]pyrazine-l-carboxylateThe title compound was prepared by substituting Example 1.72.2 for Example 1.2.1 andExample 1.55.11 for Example 1.13.3 in Example 1.13.4. MS (ESI) m/e 760 (M+H)+, 758 .1.72.4 7-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pyridinyl)-5,6,7,8-tetrahydr0imidazo[1,5-a]pyrazinecarb0xylic acidMEl 24985843v.1 530117813-12620The title compound was ed by substituting Example 1.72.3 for Example 1.1.12 inExample . MS (ESI) m/e 760 (M+H)+, 758 (M-H)’.1.72.5 tert-butyl6-(1-(benzo[d]thiazolylcarbam0yl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)picolinateThe title compound was prepared by substituting Example 1.72.4 for Example 1.52.2 inExample 1.52.3. MS (ESI) m/e 892 (M+H)+, 890 (M-H)’.1.72.6 3-(1-{[3-(2-amin0eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazol-4—yl)[1-(1,3-benzothiazolamoyl)-5,6-dihydr0imidazo[1,5-a]pyrazin-7(8H)-yl]pyridinecarboxylic acidThe title compound was prepared by substituting e 1.72.5 for Example 1.1.16 inExample 1.1.17. MS (ESI) m/e 736 (M+H)+, 734 (M-H)’.1.72.7 6-(1-(benzo[d]thiazolylcarbam0yl)-5,6-dihydr0imidazo[1,5-a]pyrazin-7(8H)-yl)(1-((3-(2-((2-(((4-((tert-butyldiphenylsilyl)0xy)methylbutanyl)oxy)sulfonyl)ethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinicThe title compound was prepared by substituting Example 1.72.6 for Example 1.2.7 inExample 1.2.8.1.72.8 1,3-benzothiazolylcarbamoyl)-5,6—dihydr0imidazo[1,5-a]pyrazin-7(8H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared by substituting Example 1.72.7 for Example 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-dg) 5 ppm 8.36 (bs, 2H), 8.03 (bs, 1H), 7.99(d, 1H), 7.76 (d, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.34 (s, 1H), 7.33 (t, 1H), 7.17 (d, 1H), 5.12 (s, 2H),4.28 (t, 2H), 4.11 (t, 2H), 3.86 (s, 2H), 3.56 (t, 2H), 3.24 (m, 2H), 3.11 (m, 2H), 2.82 (t, 2H), 2.15 (s,3H), 1.42 (s, 2H), 1.32 (q, 4H), 1.17 (q, 4, H), 1.03 (m, 2H), 0.88 (s, 6H). MS (ESI) m/e 844 (M+H)+,842 (M-H)’.1.73 Synthesis of 8-(1,3-benzothiazolylcarbam0yl){6-carb0xy[1-({3-[2-({3-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl]pr0pyl}amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)-5-methyl-1H-pyrazolyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline(W2.73)MEl 24985843V.1 5 31117813-12620To a on of (2R,3R,4S,5S,6S)azido(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8.63 mg) in t-CH3OH (2 mL) and water (1 mL) was added Example 1.67.1 (20mg), copper(II) sulfate pentahydrate (2.0 mg) and sodium ascorbate (5 mg). The mixture was stirredfor 20 minutes at 100 C)C under microwave conditions (Biotage Initiator). LiOH H20 (50 mg) wasadded to the e, and stirring was continued ght. The mixture was neutralized withtrifluoroacetic acid and purified by reverse-phase HPLC on a Gilson system (C18 column), elutingwith 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound.

MS (APCI) m/e 987.3 (M+H)+.1.74 Synthesis of 6- [7-(1,3-benzothiazolylcarbam0yl)-1H-ind01yl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.74)1.74.1 methyl2-[5-{1-[(3-{2-[bis(tert-butoxycarbonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-t-but0xycarb0nyl)pyridinyl]-1H-indolecarb0xylateExample 1.74.1 was prepared by substituting methyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)-1H-indolecarboxylate for Example 1.2.1 and substituting e 1.68.4 forExample 1.1.6 in Example 1.1.12. MS (ESI) m/e 866.3 (M-H)’.1.74.2 2-(6-(tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)pyridinyl)-1H-indolecarb0xylic acidExample 1.74.2 was prepared by substituting Example 1.74.1 for Example 1.1.12 inExample 1.1.13. MS (ESI) m/e 754.4 (M+H)+.1.74.3 tert-butyl6-(7-(benzo[d]thiazol-2—ylcarbam0yl)-1H-ind01yl)(1-((3-(2-((tert-butoxycarbonyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateExample 1.74.3 was prepared by substituting Example 1.74.2 for Example 1.1.13 inExample 1.1.14. MS (ESI) m/e 886.5 .1.74.4 (3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)-1H-pyrazolyl)(7-(benzo[d]thiazolylcarbam0yl)-1H-indolyl)picolinic acidExample 1.74.4 was prepared by substituting Example 1.74.3 for Example 1.1.16 ine 1.1.17. MS (ESI) m/e 730.2 (M+H)+.1.74.5 6-[7-(1,3-benzothiazolylcarbamoyl)-1H-indolyl][1-({3,5-dimethyl[(2,2,7,7-tetramethyl-10,10-dioxid0-3,3-diphenyl-4,9-di0xa-1016-thiaazasilapentadecanyl)0xy]tricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazol-4—yl]pyridinecarb0xylic acidMEl 24985843V.1 532117813-12620Example 1.74.5 was prepared by substituting Example 1.74.4 for e 1.2.7 inExample 1.2.8. MS (ESI) m/e 1176.7 (M+H)+.1.74.6 6-[7-(1,3-benzothiazolylcarbamoyl)-1H-indolyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidExample 1.74.6 was prepared by substituting Example 1.74.5 for e 1.2.8 inExample 1.2.9. 1H NMR (400 MHZ, dimethyl ide-d6) 5 ppm 11.32 (d, 1H), 8.23 (dd, 1H), 8.18(d, 1H), 7.93 — 7.82 (m, 3H), 7.71 (d, 1H), 7.62 (s, 3H), 7.57 — 7.51 (m, 1H), 7.47 (s, 1H), 7.40 (d,1H), 7.35 (t, 1H), 7.22 (t, 1H), 4.86 (t, 2H), 3.85 (s, 2H), 3.47 (t, 2H), 3.08 (t, 2H), 2.88 (p, 2H), 2.21(s, 3H), 1.37 (s, 2H), 1.32 — 1.20 (m, 4H), 1.14 (q, 4H), 1.07 — 0.94 (m, 2H), 0.84 (s, 6H). MS (ESI)m/e 838.2 (M+H)+.1.75 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)[3-(methylamin0)pr0pyl]-3,4-dihydr0isoquinolin-2(1H)-yl]{1-[(3,5-yl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.75)1.75.1 3-br0m0(br0m0methyl)benzoateAzobisisobutyronitrile (1.79 g) was added to methyl 3-bromomethylbenzoate (50 g)and N-bromosuccinimide (44.7 g) in 350 mL acetonitrile, and the mixture was refluxed ght. Anadditional 11 g of osuccinimide and 0.5 g of azobisisobutyronitrile was added, and therefluxing was continued for 3 hours. The mixture was concentrated, taken up in 500 mL diethyl ether,and stirred for 30 minutes. The mixture was filtered, and the resulting solution was concentrated.

The crude product was chromatographed on silica gel using 10% ethyl acetate in heptanes to give thetitle compound.1.75.2 methyl 3-br0m0(cyan0methyl)benzoateTetrabutylammonium cyanide (50 g) was added to Example 1.75.1 (67.1 g) in 300 mLacetonitrile, and the mixture was heated to 70°C overnight. The mixture was cooled, poured intodiethyl ether, and rinsed with water and brine. The mixture was then trated andchromatographed on silica gel using 2-20% ethyl acetate in heptanes to give the title compound.1.75.3 methyl 3-(2-amin0ethyl)br0m0benzoateBorane-THF complex (126 mL, 1M solution) was added to a solution of Example 1.75.2(16 g) in 200 mL tetrahydrofuran, and the mixture was stirred overnight. The reaction was carefullyed with methanol (50 mL), and then concentrated to 50 mL volume. The mixture was taken upin 120 mL ol / 120 mL 4M HCl/ 120 mL dioxane, and stirred overnight. The organics wereremoved under reduced pressure, and the residue was extracted twice with diethyl ether. The extractswere discarded. The organic layer was basified with solid K2C03, and then extracted with ethylacetate, and dichloromethane (2x). The extracts were combined, dried over , filtered andconcentrated to give the title compound.

MEl 24985843V.1 533-126201.75.4 methyl 3-br0m0(2-(2,2,2-trifluoroacetamid0)ethyl)benzoateTrifluoroacetic anhydride (9.52 mL) was added dropwise to a mixture of Example 1.75.3(14.5 g) and trimethylamine (11.74 mL) in 200 mL dichloromethane at 0 CC. Upon addition themixture was allowed to warm to room temperature and was stirred for three days. The mixture waspoured into diethyl ether, and washed with NaHCO3 solution and brine. The mixture wasconcentrated and tographed on silica gel using 5-30% ethyl acetate in heptanes to give the titlecompound.1.75.5 methyl 6-br0m0(2,2,2—triflu0roacetyl)-1,2,3,4-ydroisoquinolinecarb0xylateSulfuric acid was added to Example 1.75.4 (10 g) until it went into solution (40 mL), atwhich time paraformaldehyde (4.24 g) was added and the mixture was d for 2 hours. Thesolution was then poured onto 400 mL ice, and stirred 10 minutes. The mixture was extracted withethyl acetate (3x), and the combined extracts were washed with NaHCO3 solution and brine, and thenconcentrated The crude product was chromatographed on silica gel using 2-15% ethyl acetate inheptanes to give the title compound.1.75.6 methyl 6-(3-((tert-butoxycarbonyl)(methyl)amin0)pr0pynyl)(2,2,2—triflu0r0acetyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateA solution of Example 1.75.5 (5.1 g), tert-butyl methy1(propyny1)carbamate (2.71 g),bis(triphenylphosphine)palladiumm) dichloride (PdC12(PPh3)2, 0.49 g), CuI (0.106 g), andtriethylamine (5.82 mL) was d in 50 mL dioxane at 50 CC overnight. The mixture wasconcentrated and chromatographed on silica gel using 10-50% ethyl e in heptanes to give thetitle compound.1.75.7 methyl 6-(3-((tert-butoxycarbonyl)(methyl)amin0)pr0pyl)(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydroisoquinoline-S-carboxylateExample 1.75.6 (4.2 g), tetrahydrofuran (20 mL) and methanol (20.00 mL) were added towet 20% Pd(OH)2/C (3 g) in a 250 mL pressure bottle and shaken under a pressure of 50 psi and 50CC for 12 hours. The solution was filtered and concentrated to give the title compound.1.75.8 methyl2-(5-bromo—6-(tert-butoxycarbonyl)pyridinyl)(3-((tertbutoxycarbonyl)(methyl)amin0)pr0pyl)-1,2,3,4-tetrahydr0is0quinoline-0xylateExample 1.75.7 (4.22 g), and potassium carbonate (1.53 g) were stirred in 60 mLtetrahydrofuran, 25 mL methanol, and 10 mL water overnight. The mixture was concentrated and 60mL N,N-dimethy1formamide was added. To this was then added Example 1.1.9 (3.05 g) andtriethylamine (5 mL), and the reaction was stirred at 60 CC ght. The mixture was cooled toroom temperature, poured into ethyl acetate (600 mL), washed with water (3x) and brine, dried over, filtered, and trated. The residue was chromatographed on silica gel using 5-50% ethylacetate in heptanes to give the title compound. MS (ESI) m/e 618.2 (M+H)+.

MEI 24985843V.1 534117813-126201.75.9 methyl 6-(3-((tert-butoxycarbonyl)(methyl)amin0)pr0pyl)(6-(tert-carbonyl)(4,4,5,5-tetramethyl-1,3,2-di0xab0rolanyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of Example 1.75.8 (3.7 g), triethylamine (2.50 mL) and PdC12(dppf) (([1,1’-phenylphosphino)ferrocene]dichloropalladium(II) (1:1), 0.29 g) in 25 mL acetonitrile was added4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.74 mL), and the reaction mixture was heated to 75 CC for 5hours, then stirred at 60 CC overnight. The e was concentrated and chromatographed on silicagel using 5-50% ethyl acetate in heptanes to give the title compound. MS (ESI) m/e 666.4 (M+H)+.1.75.10 4-((tert-butyldiphenylsilyl)oxy)-2,2—dimethylbutyl2-((2-((3-((4-i0d0methyl-lH-pyrazolyl)methyl)-5,7-dimethyladamantanyl)0xy)ethyl)amin0)ethanesulf0nateExample 1.55.10 (2.39 g), 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutylsulfonate (2.41 g), and triethylamine (1.51 mL) were stirred in 30 mL N,N-dimethylformamideat 45 0C for 3 hours. The mixture was cooled and poured into diethyl ether (400 mL), and the diethylether solution was washed with water (3x) and brine, and concentrated. The crude product waschromatographed on silica gel using 2-50% ethyl acetate in heptanes, with 1% added triethylamine togive the title nd. MS (ESI) m/e 890.6 .1.75.11 6-(6-(3-((tert—butoxycarbonyl)(methyl)amin0)pr0pyl)(methoxycarbonyl)-3,4-dihydr0isoquinolin-2(1H)-yl)(1-((3-(2—((2-((4-((tert-butyldiphenylsilyl)0xy)-2,2-ylbutoxy)sulf0nyl)ethyl)amin0)eth0xy)-5,7-dimethyladamantan-1-yl)methyl)methyl-1H-pyrazolyl)picolinic acidExample 1.75.9 (1.777 g), Example 1.75.10 (1.98 g),tris(dibanzylidcncacetone)dipalladiu131(0) (0.102 g), 1,3,5,7-tetramethyltetradecyl-2,4,6-trioxaphosphaadamantane (0.918 g), and potassium phosphate (1.889 g) were added to 25 mL dioxane / 10mL water, and the solution was evacuated/filled with nitrogen several times. The reaction was clear,and was stirred at 70 CC overnight. The mixture was cooled and poured into ethyl acetate (200 mL),and washed with water and brine. The mixture was concentrated and chromatographed on silica gelusing 5-50% ethyl acetate in heptanes, followed by 10% methanol in ethyl acetate with 1%triethylamine to give the title compound. MS (ESI) m/e 1301.4 .1.75.12 6-(3-((tert-but0xycarb0nyl)(methyl)amin0)pr0pyl)(5-(1-((3-(2-((2-tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulf0nyl)ethyl)amin0)eth0xy)-5,7-dimethyladamantan-1-yl)methyl)methyl-1H-pyrazolyl)carb0xypyridin-2—yl)-1,2,3,4—tetrahydroisoquinolinecarb0xylic acidExample 1.75.11 (1.5 g) and LiOH-HZO (0.096 g) were stirred in 15 mL tetrahydrofuranand 3 mL water at 45 CC for 10 days. The mixture was poured into 200 mL ethyl acetate / 20 mLMEI 24985843V.1 535117813-12620NaHzPO4 on, and concentrated HCl solution was added until the pH reached 3. The layers wereseparated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layerswere washed with brine and concentrated. The residue was chromatographed on silica gel using 0-5%methanol in ethyl acetate to give the title compound. MS (ESI) m/e 1287.3 (M+H)+.1.75.13 6-(8-(benzo[d]thiazolylcarbam0yl)(3-((tert-butoxycarbonyl)(methyl)amin0)pr0pyl)-3,4-dihydr0is0quinolin-2(1H)-(1-((3-(2-((2-((4-((tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulf0nyl)ethyl)amin0)eth0xy)-5,7-dimethyladamantan-1-yl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared as bed in Example 1.2.6, substituting Example1.2.5 with Example 1.75.12. MS (ESI) m/e 1419.5 (M+H)+.1.75.14 6-[8-(1,3-benzothiazolylcarbamoyl)[3-(methylamin0)pr0pyl]-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared as described in Example 1.2.9, tuting Example1.2.8 with Example 1.75.13. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 12.90 (bs, 1H), 8.33(m, 2H), 8.02 (d, 1H), 7.78 (d, 1H), 7.66 (m, 1H), 7.47 (m, 3H), 7.35 (m, 3H), 7.25 (s, 2H), 6.95 (d,1H), 4.95 (s, 2H), 4.28 (t, 2H), 4.11 (t, 2H), 3.95 (m, 2H), 3.20 (m, 2H), 3.08 (m, 2H), 2.96 (m, 2H),2.89 (m, 2H), 2.78 (m, 2H), 2.65 (m, 2H), 2.55 (t, 2H), 2.12 (s, 3H), 1.95 (m, 2H), 1.39 (s, 2H), 1.25(m, 6H), 1.12 (m, 6H), 0.93 (s, 3H), 0.85 (s, 6H). MS (ESI) m/e 926.8 (M+H)+.1.76 Synthesis of 5-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}de0xy-D-arabinitol (W2.76)1.76.1 utyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-((((4R,4'R,5R)-,2'-tetramethyl-[4,4'-bi(1,3-di0xolan)]yl)methyl)amin0)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinateExample 1.2.7 (75 mg) and (4R,4'R,5S)-2,2,2',2'—tetramethyl-[4,4'-bi(1,3-dioxolane)]—5-carbaldehyde (22 mg) were dissolved in dichloromethane (1 mL). Sodium triacetoxyborohydride (40mg) was added, and the solution was stirred for 16 hours at room temperature. The solution wasconcentrated under reduced pressure, and the material was purified by flash column chromatographyon silica gel, eluting with 5-10% methanol in dichloromethane. The solvent was evaporated underreduced pressure to e the title compound. MS (ESI) m/e 1016 (M+H)+, 1014 (M-H)’.

MEl 24985843V.1 536117813-126201.76.2 5-{[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec)ethyl]amin0}de0xy-D-arabinitolExample 1.76.1 (45 mg) was dissolved in trifluoroacetic acid (1 mL) and water (0.2 mL).

The solution was mixed at room temperature for five days. The solvents were removed under reducedre, and the material was taken up in methanol (2 mL). The material was purified by reverse-phase HPLC using 25-75% acetonitrile in water (w/0.l% TFA) over 30 minutes on a Grace Revelerisequipped with a Luna column: Cl8(2), 100 A, 250 x 30 mm. Product fractions were pooled, frozen,and lized to yield the title compound as the bis trifluoroacetic acid salt. 1H NMR (400 MHz,dimethyl sulfoxide-dg) 5 ppm 12.85 (bs, 2H), 8.31 (m, 1H), 8.16 (m, 1H), 8.04 (d, 1H), 7.80 (d, 1H),7.62 (d, 1H), 7.51-7.43 (m, 3H), 7.37 (q, 2H), 7.29 (s, 1H), 6.69 (d, 1H), 4.96 (s, 2H), 4.04 (t, 2H),3.89 (m, 2H), 3.59 (m, 3H), 3.49 (m, 4H), 3.42 (dd, 2H), 3.22 (dd, 2H), 3.06 (m, 2H), 3.02 (m, 4H),2.10 (s, 3H), 1.43 (s, 2H), 1.30 (q, 4H), 1.14 (t, 4H), 1.04 (q, 2H), 0.87 (s, 6H). MS (ESI) m/e 880(M+H)+, 878 (M-H)’.1.77 Synthesis of 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}-1,2-dide0xy-D-arabino—hexitol (W2.77)1.77.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(((3R,4S,5R)-3,4,5,6-tetrahydr0xyhexyl)amin0)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinate(4R,5S,6R)(Hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol (15 mg) was dissolved inyl sulfoxide (0.5 mL). Example 1.2.7 (88 mg) was added, followed by sodiumcyanoborohydride (27 mg). Acetic acid (82 mg) was added dropwise, and the solution was heated at60 CC for 16 hours. The on was cooled, diluted with 1 mL of methanol, and purified by reverse-phase HPLC using 20-75% itrile in water (w/0.l% TFA) over 60 minutes on a Grace Revelerisequipped with a Luna column: Cl8(2), 100 A, 150 x 30 mm. Product ons were pooled, frozen,and lyophilized to yield the title compound as the bis trifluoroacetic acid salt. MS (ESI) m/e 950(M+H)+, 948 (M-H)’.1.77.2 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}-1,2-dideoxy-D-arabino-hexitolExample 1.77.1 (39 mg) was dissolved in dichloromethane (0.5 mL). Trifluoroacetic acid(740 mg) was added, and the solution was stirred at room temperature for 16 hours. The tsMEl 24985843V.1 537-12620were d under reduced pressure. The e was dissolved in N,N-dimethylformamide (0.5mL) and 1 M aqueous sodium hydroxide (0.5 mL) was added. The solution was stirred at roomtemperature for one hour. Trifluoroacetic acid (0.25 mL) was added, and the material was purified byreverse-phase HPLC using 20-75% acetonitrile in water (w/0.1% TFA) over 60 minutes on a Graceris equipped with a Luna column: C18(2), 100 A, 150 x 30 mm. Product fractions werepooled, frozen, and lyophilized to yield the title compound as the bis trifluoroacetic acid salt. 1HNMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 12.74 (bs, 1H), 8.28 (bs, 1H), 8.20 (bs,1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.51-7.43 (m, 3H), 7.37 (q, 2H), 7.29 (s, 1H), 6.96 (d,1H), 4.96 (s, 2H), 4.53 (bs, 3H), 3.89 (t, 2H), 3.83 (s, 2H), 3.77 (d, 1H), 3.60 (dd, 2H), 3.56 (t, 2H),3.48 (m, 2H), 3.15 (d, 1H), 3.02 (m, 6H), 2.10 (s, 3H), 1.84 (m, 1H), 1.69 (m, 1H), 1.43 (s, 2H), 1.31(q, 4H), 1.14 (t, 4H), 1.05 (q, 2H), 0.87 (s, 6H). MS (ESI) m/e 894 (M+H)+, 892 (M-H)’.1.78 Synthesis of 6-[4-(1,3-benzothiazolylcarbamoyl)is0quinolinyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.78)1.78.1 methyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)is0quin01inecarboxylateTo a solution of methyl 6-bromoisoquinolinecarboxylate (1.33 g) in N,N-ylformamide (30 mL) was added PdClz(dppf)-CH2C12 adduct (([1,1’-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1:1), 204 mg), potassium acetate (1.48 g) andbis(pinacolato)diboron (1.92 g). The mixture was stirred at 60 C)C overnight. The mixture was cooledto room ature and used in the next reaction without further work up. MS (APCI) m/e 313.3(M+H)+.1.78.2 methyl 6-[5-{1-[(3-{2-[bis(tert-butoxycarbonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl)methyl]methyl-1H-pyrazolyl}-6-(tert-but0xycarb0nyl)pyridinyl]isoquinolinecarb0xylateTo a solution of the Example 1.68.4 (1.2 g) in 1,4-dioxane (20 mL) and water (10 mL) wasadded Example 1.78.1 (517 mg), iphenylphosphine)palladium(II) dichloride (58 mg), and CsF(752 mg). The mixture was stirred at reflux overnight. LC/MS showed the expected product as amajor peak. The mixture was diluted with ethyl acetate (200 mL), washed with water and brine, driedover anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in dichloromethane to give the title compound. MS(ESI) m/e 880.8 (M+H)+.1.78.3 tert-butoxycarbonyl)(1-((3-(2-((tertbutoxycarbonyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)pyridinyl)is0quinolinecarb0xylic acidMEl 24985843V.1 538117813-12620To a solution of Example 1.78.2 (3.1 g) in tetrahydrofuran (20 mL), methanol (10 mL) andwater(10 mL) was added LiOH H20 (240 mg). The mixture was d at room temperatureovernight. The mixture was ied with s 2N HCl and diluted with ethyl acetate (400 mL).

The organic layer was washed with water and brine and dried over anhydrous sodium sulfate.

Filtration and evaporation of the solvent gave the title compound. MS (ESI) m/e 766.4 (M+H)+.1.78.4 3-(1-((3-(2-amin0eth0xy)-5,7-dimethyladamantanyl)methyl)-1H-pyrazolyl)(4-(benzo[d]thiazolylcarbamoyl)isoquinolinyl)picolinic acidTo a solution of Example 1.78.3 (1.2 g) in dichloromethane (20 mL) was addedbenzo[d]thiazolamine (0.236 g), 1-ethyl(3-dimethylaminopropyl)carbodiimide (451 mg), and 4-dimethylaminopyridine (288 mg), and the mixture was d at room temperature overnight. Thereaction mixture was diluted with ethyl acetate (500 mL), washed with water and brine, and driedover anhydrous sodium sulfate. Filtration and evaporation of the solvent gave a residue that wasdissolved in dichloromethane and trifluoroacetic acid (10 mL, 1:1) and stirred overnight. The mixturewas concentrated, and the residue was dissolved in N,N-dimethylformamide (4 mL) and purified byreverse-phase HPLC on a Gilson system (C18 column), g with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title nd. MS (ESI) m/e 742.1 (M+H)+.1.78.5 6-[4-(1,3-benz0thiazolylcarbamoyl)isoquinolinyl]{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amino]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.78.4 (55 mg) in N,N-dimethylformamide (6 mL) was added 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (34 mg), N,N—diigopropylethylamine(0.6 mL) and H20 (0.6 mL). The mixture was stirred at room ature overnight. The reactionmixture was diluted with dichloromethane and roacetic acid (10 mL, 1:1) and stirred overnight.

The mixture was concentrated, and the residue was dissolved in N,N-dimethylformamide (4 mL) andpurified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrilein water containing 0.1% trifluoroacetic acid, to give the title compound. 1H NMR (400 MHz,yl sulfoxide-d6) 5 ppm 13.25 (s, 2H), 9.58 (s, 1H), 9.06 (s, 1H), 9.00 (s, 1H), 8.52 (dd, 1H),8.42 (d, 1H), 8.35 (d, 2H), 8.26 (d, 1H), 8.11 — 8.03 (m, 1H), 8.01 (d, 1H), 7.80 (d, 1H), 7.52 — 7.44(m, 2H), 7.41 — 7.28 (m, 1H), 3.89 (s, 2H), 3.55 (t, 2H), 3.22 (t, 2H), 3.09 (s, 2H), 2.80 (t, 2H), 2.23(s, 3H), 1.43 (s, 2H), 1.30 (q, 4H), 1.23 — 1.11 (m, 4H), 1.04 (q, 2H), 0.86 (s, 6H). MS (ESI+) m/e850.1 (M+H)+.1.79 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl](1-{[3-(2-{[3-hydroxy(hydr0xymethyl)pr0pyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridine-2-carb0xylic acid (W2.79)1.79.1 2,2-dimethyl-1,3-di0xanecarbaldehydeMEl 24985843V.1 539117813-12620To a stirred suspension of pyridinium chromate (1.1 g) and diatomaceous earth (10g) in dichloromethane (10 mL) was added (2,2-dimethyl-1,3-dioxanyl)methanol (0.5 g) as asolution in dichloromethane (3 mL) dropwise. The e was stirred at room temperature for 2hours. The sion was filtered through diatomaceous earth and washed with ethyl acetate. Thecrude product was filtered through silica gel and concentrated to give the title compound. 1H NMR(501 MHz, chloroform-d) 5 9.89 (s, 1H), 4.28 — 4.17 (m, 4H), 2.42 — 2.32 (m, 1H), 1.49 (s, 3H), 1.39(s, 3H). MS (ESI) m/e 305.9 (2M+NH4)+.1.79.2 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-(((2,2—dimethyl-1,3-di0xanyl)methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateTo a solution of Example 1.2.7 (100 mg) and Example 1.79.1 (20 mg) in dichloromethane(1 mL) was added sodium triacetoxyborohydride (40 mg), and the mixture was stirred at roomtemperature for 2 hours. The reaction was diluted with romethane and washed with tedsodium bicarbonate solution. The aqueous layer was back extracted with dichloromethane. Thecombined organic layers were dried over sodium sulfate, filtered and concentrated. Purification of theresidue by silica gel chromatography, eluting with 0% ethyl acetate/ethanol (3: 1) in heptane,provided the title compound. MS (ESI) m/e 930.3 .1.79.3 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl](1-{[3-(2-{[3-hydr0xy(hydroxymethyl)pr0pyl]amin0}eth0xy)-,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acidExample 1.79.3 was prepared by substituting Example 1.79.2 for Example 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.82 (s, 1H), 8.13 (s, 2H), 8.00(dd, 1H), 7.76 (d, 1H), 7.59 (d, 1H), 7.49 — 7.38 (m, 3H), 7.37 — 7.29 (m, 2H), 7.25 (s, 1H), 6.92 (d,1H), 4.92 (s, 4H), 3.85 (t, 2H), 3.79 (s, 2H), 3.53 (t, 2H), 3.47 (dd, 2H), 3.00 (dt, 7H), 2.07 (s, 3H),1.93 (p, 1H), 1.38 (s, 2H), 1.32 — 1.19 (m, 4H), 1.16 — 0.91 (m, 6H), 0.83 (s, 7H). MS (ESI) m/e834.3 (M+H)+.1.80 Synthesis of 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec)ethyl]amin0}-1,2-dide0xy-D-erythro-pentitol (W2.80)The title compound was prepared by substituting (4S,5R)-tetrahydro-2H-pyran-2,4,5-triolfor ,6R)(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol and Example 1.3.1 for Example1.2.7 in Example 1.77.1. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (bs, 1H), 12.72(bs, 1H), 8.21 (bs, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.52-7.42 (m, 3H), 7.37 (q, 2H), 7.29MEl 24985843V.1 540117813-12620(s, 1H), 6.95 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.65 (m, 2H), 3.56 (m, 2H), 3.38 (m,2H), 3.32 (m, 2H), 3.24 (m, 2H), 3.03 (m, 5H), 2.10 (s, 3H), 1.89 (m, 1H), 1.67 (m, 1H), 1.44 (s, 2H),1.31 (q, 4H), 1.14 (t, 4H), 1.05 (q, 2H), 0.86 (s, 6H). MS (ESI) m/e 864 (M+H)+, 862 (M-H)’.1.81 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-oisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{[(2S,3S)-2,3,4-trihydroxybutyl]amino}ethoxy)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid (W2.81)1.81.1 carbonic acid utyl ester (4S,5S)hydroxymethyl-2,2-dimethyl-[1,3]dioxolanylmethyl ester((4S,5S)-2,2-Dimethyl-1,3-dioxolane-4,5-diyl)dimethanol (1000 mg) was dissolved inN,N-dimethylformamide (50 mL). Sodium hydride (60% in mineral oil, 259 mg) was added. Thesolution was mixed at room temperature for 15 minutes. Di-tert-butyl dicarbonate (1413 mg) wasadded slowly. The solution was mixed for 30 minutes, and the reaction was quenched with saturatedaqueous ammonium de solution. The solution was diluted with water (150 mL) and extractedtwice using 70% ethyl acetate in heptanes. The organic portions were combined and extracted withwater (100 mL), extracted with brine (50 mL), and dried on anhydrous sodium sulfate. The solutionwas concentrated under reduced pressure, and the material was purified by flash columnchromatography on silica gel, eluting with 30% ethyl acetate in es. The solvent was evaporatedunder reduced pressure to e the title compound. MS (ESI) m/e 284 (M+Na)+.1.81.2 carbonic acid tert-butyl ester (4S,5R)formyl-2,2-dimethyl-[1,3]dioxolanylmethyl esterExample 1.81.1 (528 mg) was dissolved in dichloromethane (20 mL). Dess-Martininane (896 mg) was added, and the solution was stirred at room temperature for four hours.

The solution was concentrated under reduced pressure, and the material was purified by flash columnchromatography on silica gel, eluting with 20%-50% ethyl acetate in heptanes. The solvent wasevaporated under reduced re to e the title nd.1.81.3 tert-butyl6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-(((1S,3s,5R,7S)(2-((((4S,5S)(((tert-butoxycarbonyl)oxy)methyl)-2,2-dimethyl-1,3-dioxolanyl)methyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateThe title nd was prepared by substituting Example 1.81.2 for (4R,4'R,5S)-2,2,2',2'—tetramethyl-[4,4'—bi(1,3-dioxolane)]carbaldehyde in Example 1.76.1.1.81.4 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{[(2S,3S)-2,3,4—trihydroxybutyl]amino}ethoxy)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acidMEl 24985843V.1 541117813-12620The title compound was prepared by substituting Example 1.81.3 for Example 1.76.1 inExample 1.76.2. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.86 (bs, 2H), 8.28 (bs, 1H),8.18 (bs, 1H), 8.04 (d, 1H), 7.80 (d, 1H), 7.63 (d, 1H), 7.51-7.43 (m, 3H), 7.36 (q, 2H), 7.29 (s, 1H),6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (m, 3H), 3.46 (m, 4H), 3.40 (m, 4H), .96 (m, 6H),2.10 (s, 3H), 1.43 (s, 2H), 1.30 (q, 4H), 1.14 (t, 4H), 1.04 (q, 2H), 0.87 (s, 6H). MS (ESI) m/e 850(M+H)+, 848 (M-H)’.1.82 Synthesis of 6- [8 -(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[(2S,3S,4R,5R,6R)-2,3,4,5,6,7-hexahydroxyheptyl]amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid (W2.82)The title compound was prepared by substituting (2R,3R,4S,5R,6R)-2,3,4,5,6,7-hexahydroxyheptanal for (4R,5S,6R)(hydroxymethyl)tetrahydro-2H-pyran-2,4,5-triol and Example1.3.1 for Example 1.2.7 in Example 1.77.1. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.86(bs, 1H), 8.34-8.08 (m, 2H), 8.05 (d, 1H), 7.79 (d, 1H), 7.54-7.43 (m, 3H), 7.37 (m, 2H), 7.30 (s, 1H),6.95 (d, 1H), 4.96 (s, 2H), 3.93 (m, 2H), 3.90 (m, 4H), 3.83 (s, 2H), 3.47 (m, 4H), 3.41 (m, 4H), 3.18-3.08 (m, 7H), 3.03 (t, 2H), 2.12 (s, 3H), 1.46 (s, 2H), 1.28 (q, 4H), 1.15 (t, 4H), 1.05 (q, 2H), 0.89 (s,6H). MS (ESI) m/e 940 (M+H)+.1.83 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[({3-[(1,3-dihydr0xypr0panyl)amino]propyl}sulf0nyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-lH-pyrazolyl}pyridine-2—carb0xylic acid (W2.83)1.83.1 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-(3-((1,3-dihydr0xypr0panyl)amin0)propylsulfonamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateTo a cooled (ice bath) solution of e 1.2.7 (31 mg) and N,N-diisopropylethylamine(60 uL) in dichloromethane (1 mL) was added 3-chloropropanesulfonyl chloride (5 uL). Themixture was stirred at room temperature for 2 hours. The reaction was concentrated, dissolved inN,N-dimethylformamide (1 mL), transferred to a 2 mL ave tube and 2-aminopropane-1,3-diol(70 mg) was added. The mixture was heated at 130 CC under microwave conditions (Biotagetor) for 90 minutes. The reaction e was concentrated, and the residue was ed byreverse-phase HPLC using a Gilson system, g with 20-100% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to e thetitle compound. MS (ESI) m/e 997.2 (M+H)+.

MEl 24985843V.1 542117813-126201.83.2 6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[({3-[(1,3-dihydr0xypr0panyl)amin0]propyl}sulf0nyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidExample 1.83.2 was prepared by substituting Example 1.83.1 for Example 1.2.8 inExample 1.2.9. 1H NMR (400 MHz, dimethyl sulfoxide-dg) 5 ppm 12.84 (s, 1H), 8.40 (s, 2H), 8.05 —7.98 (m, 1H), 7.77 (d, 1H), 7.60 (d, 1H), 7.51 — 7.39 (m, 3H), 7.38 — 7.30 (m, 2H), 7.27 (s, 1H), 7.13(t, 1H), 6.93 (d, 1H), 4.94 (s, 2H), 3.61 (qd, 4H), 3.36 (t, 2H), 3.16 — 2.93 (m, 10H), 2.08 (s, 3H), 2.00(p, 2H), 1.38 (s, 2H), 1.25 (q, 4H), 1.15 — 0.92 (m, 6H), 0.84 (s, 6H). MS (ESI) m/e 941.2 (M+H)+.1.84 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-{[1,3-dihydr0xy(hydroxymethyl)pr0panyl]amino}oxopropyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-lH-pyrazolyl}pyridine-2—carb0xylic acid (W284)To a on of tert-butyl 3-(1-((3 -(2-aminoethoxy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinate (55 mg) in N,N-dimethylformamide (6 mL) was added N-(1,3-dihydroxy(hydroxymethyl)propanyl)acrylamide (73.4 mg), .7‘v’,[\7~diisopropylethylamine (0.2 mL) and H20(0.2 mL). The mixture was stirred at room temperature 4 days. LC/MS showed the expected productas a major peak. The reaction mixture was diluted with ethyl acetate (500 mL), washed with waterand brine, and dried over anhydrous sodium sulfate. Filtration and evaporation of the t gave aresidue that was dissolved in dichloromethane and trifluoroacetic acid (10 mL, 1:1) and stirredovernight. The e was concentrated, and the residue was dissolved in methylformamide(8 mL) and purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80%itrile in water containing 0.1% roacetic acid, to give the title compound. 1H NMR (400MHz, dimethylsulfonxide-dé) 5 ppm 12.84 (s, 1H), 8.45 (s, 2H), 8.01 (d, 4H), 7.78 (d, 1H), 7.60 (d,1H), 7.53 — 7.39 (m, 3H), 7.39 — 7.30 (m, 2H), 7.27 (s, 1H), 6.94 (d, 1H), 4.94 (s, 2H), 4.14 (s, 2H),3.87 (t, 2H), 3.81 (s, 2H), 3.52 (d, 4H), 3.19 (s, 3H), 3.13 — 2.97 (m, 5H), 2.75 (t, 2H), 2.08 (s, 3H),1.42 (s, 2H), 1.29 (q, 4H), 1.12 (s, 4H), 1.09 — 0.99 (m, 2H), 0.85 (s, 7H). MS (ESI) m/e 921.21.85 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[(3S)-3,4—dihydroxybutyl]amin0}eth0xy)-5,7-dimethyltricyc10[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid (W285)To a solution of Example 1.2.7 (213 mg) in dichloromethane (2 mL) was added (S)(2,2-dimethyl-l,3-dioxolanyl)acetaldehyde (42 mg). After stirring at room temperature for 30 minutes,MEl 24985843V.1 543117813-12620sodium toxyborohydride (144 mg) was added. The reaction mixture was stirred at roomtemperature ght. Trifluoroacetic acid (2 mL) was added and stirring was ued overnight.

The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC using aGilson system, eluting with 5-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. Thedesired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz,dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 8.22 (d, 2H), 8.05 — 8.01 (m, 1H), 7.79 (d, 1H), 7.61 (d,1H), 7.53 — 7.41 (m, 3H), 7.36 (td, 2H), 7.28 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.88 (t, 2H), 3.82 (s,2H), 3.26 — 2.94 (m, 7H), 2.10 (s, 3H), 1.84 — 1.75 (m, 1H), 1.52-1.63 (m, 1H), 1.45 — 1.23 (m, 6H),1.19 — 0.96 (m, 7H), 0.86 (s, 6H). MS (ESI) m/e 834.3 (M+H)+.1.86 Synthesis of 4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}methyl)phenyl beta-D-glucopyranosiduronic acid(W2.86)To a solution of 3-(l-((3-(2-aminoethoxy)-5,7-dimethyladamantan-l-yl)methyl)methyl-lH-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(lH)-yl)picolinicacid (36 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2 mL) was added (2S,3R,4S,5S,6S)(4-formylphenoxy)(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (21 mg) followed byMgSO4 (60 mg). The mixture was stirred at room temperature for 1 hour before the addition of MP-cyanoborohydride (Biotage, 153 mg, 2.49 mmol/g). The mixture was then stirred at roomtemperature for 3 hours. The mixture was filtered, and LiOH H20 (20 mg) was added to the filtrate.

The mixture was stirred at room temperature for 2 hours and then acidified with trifluoroacetic acid.

The solution was purified by reverse-phase HPLC on a Gilson system (C18 ), eluting with 20-80% acetonitrile in water containing 0.1% roacetic acid, to give the title compound. MS (ESI)m/e 1028.3 (M+H)+.1.87 Synthesis of ({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}pr0pyl beta-D-glucopyranosiduronic acid (W2.87)1.87.1 ,5S,6S)(3-hydr0xypr0p0xy)(methoxycarbonyl)tetrahydro-an-3,4,5-triyl triacetateTo a stirred solution of (2R,3R,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (3.98 g) in toluene (60 mL) was added propane-1,3-diol (15.22 g). Themixture was stirred at 75 C)C, and AngO3 (5.52 g) was added in three portions over a period of 3hours. The mixture was stirred at room temperature ght, after which the suspension wasMEl 24985843V.1 544-12620filtered. The filtrate was concentrated, and the residue was purified by silica gel chromatographyeluting with 50% ethyl acetate in heptane to give the title compound. MS (ESI) m/e 409.9 (M+NH4)+.1.87.2 ,5R,6R)(methoxycarbonyl)(3-0x0pr0p0xy)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of dimethyl sulfoxide (0.5 mL) in dichloromethane (10 mL) at -78 C)C wasadded oxalyl chloride (0.2 mL). The mixture was stirred 20 minutes at -78 C)C, and a solution ofExample 1.87.1 (393 mg ) in dichloromethane (10 mL) was added through a syringe. After 20s, triethylamine (1 mL) was added. The mixture was stirred for 30 minutes, and thetemperature was allowed to rise to room ature. The reaction mixture was diluted with ethylacetate (300 mL), washed with water and brine, and dried over anhydrous sodium sulfate. Filtrationand evaporation of the solvent gave the title compound, which was used t further purification.

MS (DCI) m/e 408.1 (M+NH4)+.1.87.3 3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}pr0pyl beta-D-yranosiduronic acidTo a solution of Example 1.68.6 (171 mg) in dichloromethane (10 mL) was addedExample 1.87.2 (90 mg), and NaBH(OAc)3 (147 mg). The mixture was stirred at room temperatureovernight. The reaction mixture was d with ethyl acetate (200 mL), washed with 2% aqueousHCl solution, water, and brine, dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was dissolved in tetrahydrofuran (6 mL), methanol (3 mL) and water (3 mL) and LiOH H20(100 mg) was added. The mixture was stirred at room temperature for 2 hours, acidified withtrifluoroacetic acid and concentrated under reduced pressure. The residue was dissolved in dimethylsulfoxide/methanol (1 :1 12 mL) and purified by reverse-phase HPLC on a Gilson system (C18), eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid) to give thetitle nd. 1H NMR (400 MHz, dimethylsulfonxide-d6) 5 ppm 13.07 (s, 2H), 8.99 (s, 1H), 8.34(dd, 1H), 8.29 — 8.11 (m, 5H), 8.06 — 8.02 (m, 1H), 7.99 (d, 1H), 7.90 (d, 1H), 7.78 (d, 1H), 7.68 (dd,1H), 7.55 — 7.40 (m, 2H), 7.34 (td, 1H), 4.23 (d, 1H), 3.87 (s, 2H), 3.76 (dt, 1H), 3.60 (d, 1H), 3.53(dt, 3H), 3.29 (t, 1H), 3.15 (t, 1H), 3.06 — 2.91 (m, 6H), 2.20 (s, 3H), 1.83 (p, 2H), 1.44 (s, 2H), 1.30(q, 4H), 1.14 (s, 4H), 1.03 (q, 2H), 0.85 (s, 7H). MS (ESI) m/e 975.2(M+H)+.1.88 Synthesis of 6-[4-(1,3-benzothiazolylcarbam0yl)0xid0is0quinolinyl][1-({3,5-dimethyl[2-(methylamin0)eth0xy]tricyclo[3.3.l.13’7]dec-1-yl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid(W2.88)MEl 24985843V.1 545117813-126201.88.1 methyl 6-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)isoquinolinecarboxylateTo a solution of Example 1.78.1 (0.73 g) in 1,4-dioxane (20 mL) and water (10 mL) wasadded tert-butyl 3-(1-((3-(2-((tert-butoxycarbonyl)(methyl)amino)ethoxy)-5,7-dimethyladamantan-l-yl)methyl)methyl-lH-pyrazolyl)chloropicolinate (1.5 g),bis(triphenylphosphine)palladium(II) dichloride (82 mg), and CsF (1.06 g), and the reaction wasstirred at reflux overnight. The mixture was diluted with ethyl acetate (200 mL), washed with waterand brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purifiedby silica gel chromatography, g with 20% ethyl acetate in heptane (l L) to give the titlend. MS (ESI) m/e 794.8 (M+H)+.1.88.2 6-(6-(tert-butoxycarbonyl)(1-((3-(2-((tertbutoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)isoquinolinecarboxylic acidTo a solution of Example 1.88.1 (300 mg) in tetrahydrofuran (6 mL), methanol (3 mL) andwater (3 mL) was added LiOH H20 (100 mg). The mixture was stirred at room temperature for 2hours. The mixture was acidified with aqueous 2N HCl solution, diluted with ethyl e (300 mL),washed with water and brine, dried over anhydrous sodium e, filtered and concentrated to givethe title nd, which was used without r purification. MS (ESI) m/e 781.2 (M+H)+.1.88.3 tert-butyl 6-(4-(benzo[d]thiazolylcarbamoyl)is0quinolinyl)(1-((3-(2-((tert-butoxycarbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)pic01inateTo a on of Example 1.88.2 (350 mg) in dichloromethane (10 mL) was addedd]thiazolamine (67.5 mg), l-ethyl(3-dimethylaminopropyl)carbodiimide (129 mg), and 4-dimethylaminopyridine (82 mg). The mixture was d at room temperature overnight. Themixture was diluted with ethyl acetate (300 mL), washed with water and brine, and dried overanhydrous sodium sulfate. Filtration and evaporation of the t gave a residue, which waspurified by silica gel chromatography, eluting with 5% methanol in dichloromethane, to give the titlecompound. MS (APCI) m/e 912.3 (M+H)+.1.88.4 4-(benzo[d]thiazolylcarbamoyl)(6-carb0xy(1-((3,5-dimethyl(2-(methylamino)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)is0quinoline 2-0xideTo a solution of Example 1.88.3 (100 mg) in dichloromethane (6 mL) was added In»-chloroperoxybenzoic acid (19 mg). The mixture was stirred at room temperature for 4 hours. Themixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous NaHCO3 solution,MEl 24985843v.1 546117813-12620water, and brine, and dried over anhydrous sodium sulfate. Filtration and evaporation of the solventgave a residue that was dissolved in dichloromethane/trifluoroacetic acid (10 mL, 1:1) and stirred atroom temperature overnight. The ts were evaporated, and the residue was purified by e-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in water containing0.1% trifluoroacetic acid, to give the title compound. 1H NMR (501 MHz, dimethyl ide-d6) 5ppm 13.32 (s, 2H), 9.21 (d, 1H), 8.71 (d, 1H), 8.49 (dd, 1H), 8.36 — 8.19 (m, 4H), 8.12 (dd, 1H), 8.07(d, 1H), 7.96 (dd, 1H), 7.82 (d, 1H), 7.56 — 7.46 (m, 3H), 7.42 — 7.35 (m, 1H), 3.90 (d, 3H), 3.56 (td,3H), 3.02 (p, 3H), 2.55 (t, 4H), 2.29 — 2.19 (m, 4H), 1.45 (d, 3H), 1.37 — 1.26 (m, 5H), 1.16 (d, 6H),1.10 — 1.01 (m, 3H), 0.88 (d, 8H). MS (ESI) m/e 772.1 (M+H)+.1.89 Synthesis of 6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]acetamid0}tricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazol-4—yl}pyridinecarboxylic acid (W2.89)1.89.1 1-((3-br0m0-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazoleTo a cooled (-30 CC) solution of Example 1.1.3 (500 mg) in tetrahydrofuran (30 mL) wasadded n-butyllithium (9.67 mL), and the e was stirred at -30 CC for 2 hours. Methyl iodide(1.934 mL) was added dropwise at -30 CC. After tion of the addition, the mixture was stirredat -30 CC for additional 2 hours. 1N aqueous HCl in ice water was added slowly, such that thetemperature was ined below 0 CC, until the pH reached 6. The mixture was stirred at roomtemperature for 10 minutes, and diluted with ter (10 mL) and ethyl acetate (20 mL). The layerswere separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organicphases were washed with brine, dried over MgSO4, filtered and concentrated. The residue waspurified by flash silica gel chromatography, eluting with 15/1 to 10/1petroleumeum/ethyl acetate, togive the title compound. MS ) m/e 337, 339 (M+H)+.1.89.2 1-(3,5-dimethyl((5-methyl-1H-pyrazolyl)methyl)adamantanyl)ureaExample 1.89.1 (2.7 g) and urea (4.81 g) was mixed and d at 140 CC for 16 hours.

The mixture was cooled to room temperature and suspended in methanol (200 mL x 2). The insolublematerial was removed by filtration. The filtrate was concentrated to give the title compound. MS(LC-MS) m/e 317.3 (M+H) +.1.89.3 methyl((S-methyl-1H-pyrazolyl)methyl)adamantan-l-amineTo a solution of Example 1.40.2 (2.53 g) in 20% ethanol in water (20 mL) was added sodiumhydroxide (12.79 g). The mixture was stirred at 120 0C for 16 hours and at 140 CC for another 16hours. 6N Aqueous HCl was added until pH 6. The mixture was concentrated, and the residue wassuspended in methanol (200 mL). The insoluble material was filtered off. The filtrate wasconcentrated to give the title compound as an HCl salt. MS (LC-MS) m/e 273.9 (M+H)+.

MEl 24985843V.1 547117813-126201.89.4 tert-butyl(2-((3,5-dimethyl((S-methyl-1H-pyrazolyl)methyl)adamantanyl)amino)0x0ethyl)carbamateTo a solution of Example 1.89.3 (2.16g) in N,N-dimethylformamide (100 mL) was addedtriethylamine (3.30 mL), 2-((tert-butoxycarbonyl)amino)acetic acid (1.799 g) and l-imethylaminohnethylene]~1H-l .2,3—[riazoloitl,5-b]pyridinium 3~oxid hexafluorophosphate (3.90g). The mixture was stirred at room temperature for 2 hours. Water (40 mL) was added, and themixture was extracted with ethyl acetate (70 mL x 2). The combined organic phases were washedwith brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gelchromatography, eluting with 3/1 to 2/1 petroleum/ethyl acetate, to give the title nd. MS (LC-MS) m/e 430.8 (M+H)+.1.89.5 tert-butyl(2-((3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)amin0)0x0ethyl)carbamateTo an ambient solution of Example 1.89.4 (1.7 g) in N,N-dimethylformamide (20 mL) wasadded NIS (N-iodosuccinimide, 1.066 g) in portions, and the e was stirred at room temperaturefor 16 hours. Ice-water (10 mL) and saturated aqueous 3 solution (10 mL) were added. Themixture was extracted with ethyl acetate (30 mL x 2). The combined organic phases were washedwith brine, dried over sodium sulfate, filtered and trated. The residue was purified by silica gelchromatography, eluting with 3/1 to 2/1 petroleum/ethyl acetate, to give the title compound. MS (LC-MS) m/e 556.6 (M+H)+.1.89.6 methyl 2-(5-bromo(tert-butoxycarbonyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateTo a solution of methyl 1,2,3,4-tetrahydroisoquinolinecarboxylate hydrochloride (12.37g) and Example 1.1.10 (15 g) in dimethyl ide (100 mL) was added N,N-diisopropylethylamine(12 mL), and the mixture was stirred at 50 0C for 24 hours. The e was then diluted with ethylacetate (500 mL) and washed with water and brine. The organic layer was dried over sodium sulfate,filtered and concentrated under reduced pressure. The residue was purified by silica gelchromatography, eluting with 20% ethyl acetate in hexane, to give the title compound. MS (ESI) m/e448.4 (M+H)+.1.89.7 methyl 2-(6-(tert-butoxycarbonyl)(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—Z-yl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarboxylateTo a on of Example 1.89.6 (2.25 g) and [1,1'—bis(diphenylphosphino)ferrocene]dichloropalladium(II) (205 mg) in itrile (30 mL) was addedtriethylamine (3 mL) and pinacolborane (2 mL), and the mixture was stirred at reflux for 3 hours. Themixture was diluted with ethyl e (200 mL) and washed with water and brine. The c layerwas dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification of theMEl 24985843V.1 548117813-12620residue by flash chromatography, g with 20% ethyl acetate in hexane, provided the title1.89.8 methyl 2-(6-(tert-butoxycarbonyl)(1-((3-(2—((tert-butoxycarbonyl)amin0)acetamido)-5,7-dimethyladamantanhyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylateThe title compound was prepared using the procedure in Example 1.2.2, substitutingExample 1.1.6 with Example 1.89.5. MS (ESI) m/e 797.4 (M+H)+.1.89.9 tert-butoxycarbonyl)(1-((3-(2-((tert-butoxycarbonyl)amin0)acetamido)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylic acidThe title compound was prepared using the procedure in Example 1.2.5, substitutingExample 1.2.4 with Example . MS (ESI) m/e 783.4 (M+H)+.1.89.10 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((tertbutoxycarbonyl)amin0)acetamido)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinateThe title compound was prepared using the procedure in Example 1.2.6, substitutingExample 1.2.5 with Example 1.89.9. MS (ESI) m/e 915.3 (M+H)+.1.89.11 3-(1-{[3-(2-amin0acetamid0)-5,7-dimethyltricyclo[3.3.1.13’7]decanyl]methyl}methyl-1H-pyrazol-4—yl){8—[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}pyridinecarb0xylicThe title compound was prepared using the procedure in e 1.2.9, substitutingExample 1.2.8 with Example 1.89.10. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 12.82 (s, 1H),8.00 (dd, 1H), 7.90 — 7.79 (m, 4H), 7.76 (d, 1H), 7.59 (dd, 1H), 7.49 — 7.38 (m, 3H), 7.37 — 7.29 (m,2H), 7.25 (s, 1H), 6.92 (d, 1H), 4.92 (s, 2H), 3.85 (t, 2H), 3.77 (s, 2H), 3.40 (q, 2H), 2.98 (t, 2H), 2.07(s, 3H), 1.63 (s, 2H), 1.57 — 1.38 (m, 4H), 1.15 — 0.93 (m, 6H), 0.80 (s, 6H). MS (ESI) m/e 759.2(M+H)+.1.89.12 6-{8-[(1,3-benz0thiazolyl)carbamoyl]-3,4-dihydr0isoquinolin-2(1H)-yl}{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amin0]acetamid0}tricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 1.89.11 (102 mg) in N,N-dimethylformamide (6 mL) was added4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (60 mg),and the mixture wasstirred at room temperature over a weekend. The mixture was diluted with ethyl acetate (300 mL),MEl 24985843V.1 549117813-12620washed with water and brine, and dried over anhydrous sodium sulfate. Filtration and evaporation ofthe solvent gave a residue that was dissolved in dichloromethane/trifluoroacetic acid (10 mL, 1:1) andstirred at room temperature overnight. The solvents were evaporated, and the residue was purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. 1H NMR (501 MHz, dimethylsulfoxide-d6) 5 12.83 (s, 1H), 8.57 (s, 2H), 8.02 (d, 1H), 7.95 (s, 1H), 7.77 (d, 1H), 7.60 (d, 1H), 7.52— 7.37 (m, 3H), 7.39 — 7.29 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.94 (s, 2H), 3.87 (t, 2H), 3.79 (s, 2H),3.16 (q, 2H), 2.99 (t, 2H), 2.77 (t, 2H), 2.08 (s, 3H), 1.64 (s, 2H), 1.55 (d, 2H), 1.45 (d, 2H), 1.21 —0.95 (m, 6H), 0.82 (s, 6H). MS (ESI) m/e 867.2 (M+H)+.1.90 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl({2-[(2-sulfoethyl)amin0]ethyl}sulfanyl)tricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid (W2.90)1.90.1 3-((1H-pyrazolyl)methyl)-5,7—dimethyladamantanethi01A mixture of Example 1.1.3 (2.8g) and thiourea (15.82 g) in 33% (w/w) HBr in acetic acid(50 mL) was stirred at 110 CC for 16 hours and was concentrated under d pressure to give aresidue. The residue was ved in 20% ethanol in water (v/v: 200 mL), and sodium hydroxide(19.06 g) was added. The resulting solution was stirred at room temperature for 16 hours and wasconcentrated. The residue was dissolved in water (60 mL), and acidified with 6 N aqueous HCl to pH5 — pH 6. The mixture was extracted with ethyl acetate (200 mL x 2). The combined organic layerswere washed with brine, dried over MgSO4, filtered and concentrated to give the title compound. MS(ESI) m/e 319.1 .1.90.2 2-((((1H-pyrazolyl)methyl)-5,7—dimethyladamantanyl)thi0)ethan01To a solution of Example 1.90.1 (3.3g) in ethanol (120 mL) was added sodium de(2.437 g). The e was d for 10 minutes, and 2-chloroethanol (1.80 mL) was addeddropwise. The mixture was stirred at room temperature for 6 hours and was lized with 1 Naqueous HCl to pH 7. The mixture was concentrated, and the e was extracted with ethyl acetate(200 mL x 2). The combined c layers were washed with brine, dried over MgSO4, filtered andconcentrated. The residue was purified by column chromatography on silica gel, g withpetroleum ether /ethyl acetate from 6/1 to 2/ 1, to give the title compound. MS (ESI) m/e 321.2(M+H)+.1.90.3 2-((-3,5-dimethyl((5-methyl-lH-pyrazolyl)methyl)adamantanyl)thi0)ethan01To a solution of e 1.90.2 (2.3 g) in tetrahydrofuran (60 mL) was added n-butyllithium (14.35 mL, 2M in hexane) at -20 CC dropwise under nitrogen. The mixture was stirred atthis temperature for 2 hours. Methyl iodide (4.49 mL) was added to the resulting mixture at -20 CC,MEl 24985843V.1 550117813-12620and the mixture was stirred at -20 CC for 2 hours. The reaction was quenched by the dropwiseaddition of saturated aqueous NH4Cl solution at -20 CC. The resulting mixture was stirred for 10minutes and acidified with 1 N aqueous HCl to pH 5. The mixture was extracted with ethyl acetatetwice. The combined organic layers were washed with brine, dried over MgSO4, ed andconcentrated to give the title nd. MS (ESI) m/e 335.3 (M+H)+.1.90.4 -((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)thi0)ethanolTo a solution of Example 1.90.3 (3.65 g) in N,N-dimethylformamide (90 mL) was addedN-iodosuccinimide (3.68 g). The mixture was d at room temperature for 16 hours. The reactionwas quenched by the on of ice-water (8 mL) and ted aqueous NaSZO3solution (8 mL). Themixture was stirred for an additional 10 minutes and was ted with ethyl acetate (30 mL x 2).

The combined organic layers were washed with brine, dried over MgSO4, filtered and concentratedunder reduced pressure. The residue was ed by silica gel chromatography, eluting withpetroleum ether/ethyl acetate (6/1 to 3/1), to give the title compound. MS (ESI) m/e 461.2 (M+H)+.1.90.5 di-tert-butyl[2-({3-[(4-i0d0methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decanyl}sulfanyl)ethyl]imidodicarbonateTo a cold solution (0 OC bath) of e 1.90.4 (3 g) in dichloromethane (100 mL) wasadded triethylamine (1.181 mL) and mesyl chloride (0.559 mL). The mixture was stirred at roomtemperature for 4 hours, and the reaction was quenched by the addition of ice-water (30 mL). Themixture was stirred for an additional 10 minutes and was extracted with dichloromethane (50 mL x 2).

The combined organic layers were washed with brine, dried over MgSO4, filtered and concentratedunder reduced pressure. The residue was dissolved in acetonitrile (100 mL) and NH(Boc)2 (1.695 g)and CsZCO3 (4.24 g) were added. The e was stirred at 85 CC for 16 hours, and the reaction wasquenched by the addition of water (20 mL). The mixture was stirred for 10 minutes and was tedwith ethyl acetate (40 mL x 2). The combined organic layers were washed with brine, dried overMgSO4, filtered and concentrated. The residue was purified by silica gel chromatography, elutingwith petroleum ether/ethyl acetate from 10/1 to 6/1, to give the title compound. MS (ESI) m/e 660.1(M+H)+.1.90.6 methyl 2-[5-(1-{[3-({2-[bis(tert-but0xycarb0nyl)amin0]ethyl}sulfanyl)-,7-dimethyltricyclo[3.3.1.13’7]decanyl]methyl}methyl-1H-pyrazolyl)(tert-but0xycarb0nyl)pyridin-Z-yl]-1,2,3,4-tetrahydroisoquinolinecarb0xylateThe title compound was prepared using the procedure in Example 1.2.2, replacingExample 1.1.6 with Example 1.90.5. MS (ESI) m/e 900.2 (M+H)+.

MEl 24985843V.1 5 51117813-12620190.7A 2-(6-(tert-butoxycarbonyl)(1-((3-((2—((tert-butoxycarbonyl)amin0)ethyl)thi0)-5,7-dimethyladamantanhyl)methyl-1H-pyrazolyl)pyridinyl)-1,2,3,4-tetrahydroisoquinolinecarb0xylic acidThe title compound was prepared as bed in Example 1.2.5, replacing Example 1.2.4with Example 1.90.6. MS (ESI) m/e 786.2 (M+H)+.190.7B tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-((2-((tertbutoxycarbonyl)amin0)ethyl)thi0)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinateThe title compound was prepared as described in Example 1.2.6, replacing Example 1.2.5with e 1.90.7A. MS (ESI) m/e 918.8 (M+H)+.1.90.8 tert-butyl3-(1-((3-((2-aminoethyl)thi0)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinateTo a solution of Example 1.90.7B (510 mg) in dichloromethane (5 mL) was addedroacetic acid (5 mL,) and the reaction was stirred at room temperature for 30 minutes. Thereaction was quenched by the addition of saturated s sodium bicarbonate solution and extractedwith romethane thrice. The ed organics were dried with anhydrous sodium sulfate,filtered and concentrated under reduced pressure. The residue was purified by reverse-phase HPLCon a Gilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title product. MS (ESI) m/e 818.1 (M+H)+.1.90.9 3-(1-((3-((2-aminoethyl)thi0)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidExample 1.90.9 was isolated during the preparation of Example 1.90.8. MS (ESI) 762.2(M+H)+.1.90.10 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-((2-((2-((4-((tert-butyldiphenylsilyl)0xy)-2,2-ylbutoxy)sulf0nyl)ethyl)amin0)ethyl)thi0)-5,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)pic01inateExample 1.90.8 (235 mg) and 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutylethenesulfonate (150 mg) were dissolved in dichloromethane (1 mL), N,N-diisopropylethylamine(140 uL) was added, and the mixture was stirred at room temperature for six days. The reaction wasdirectly purified by silica gel tography, eluting with a gradient of 0.5-3.0% ol indichloromethane, to give the title compound.

MEl 24985843V.1 552117813-126201.90.11 6-(8—(benz0[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3,5-dimethyl((2-((2-sulfoethyl)amino)ethyl)thi0)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidThe title compound was prepared by substituting Example 1.90.10 for Example 1.2.8 inExample 1.2.9. 1H NMR (500 MHZ, yl sulfoxide-dg) 5 ppm 8.39 (br s, 2H), 8.03 (d, 1H), 7.79(d, 1H), 7.62 (d, 1H), 7.51 (d, 1H),7.47 (ddd, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 7.35 (ddd, 1H), 7.30 (s,1H), 6.96 (d, 1H), 4.96 (s, 2H), 3.89 (t, 2H), 3.81 (s, 2H), 3.22 (m, 2H), 3.06 (br m, 2H), 3.01 (t, 2H),2.79 (t, 2H), 2.74 (m, 2H), 2.10 (s, 3H), 1.51 (s, 2H), 1.37 (m, 4H), 1.15 (m, 4H), 1.05 (m, 2H), 0.83(s, 6H). MS (ESI) m/e 870.1 (M+H)+.1.91 Synthesis of 6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3,5-dimethyl{3-[(2-sulfoethyl)amin0]propyl}tricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid (W2.91)1.91.1 1-((3-allyl-S,7-dimethyladamantanyl)methyl)-1H-pyrazoleTo a solution of Example 1.1.3 (0.825 g, 2.55 mmol) in toluene (5 mL) was added N, N'-azoisobutyronitrile (AIBN, 0.419 g, 2.55 mmol) and allyltributylstannane (2.039 n11, 6.38 mmol). Themixture was purged with N2 stream for 15 minutes, heated at 80°C for 8 hours and concentrated. Theresidue was purified by flash chromatography, eluting with 5% ethyl acetate in eum ether toprovide the title compound. MS (ESI) m/e 285.2 (M+H) +.1.91.2 1-((3-allyl-S,7-dimethyladamantanyl)methyl)methyl-1H-pyrazoleTo a solution of Example 1.91.1 (200 mg, 0.703 mmol) in tetrahydrofuran (5 ml) at -78°Cunder N2 was added n-butyllithium (2.81 mL, 7.03 mmol). The mixture was stirred for 2 hours whilethe temperature increased to -20°C and then it was stirred at -20°C for 1 hour. Iodomethane (0.659ml, 10.55 mmol) was added and the resulting mixture was d for 0.5 hours at -20°C. The reactionwas quenched with saturated NH4Cl and extracted with ethyl e twice. The combined organiclayer was washed with brine and concentrated to give the title compound. MS (ESI) m/e 299.2(M+H) +.1.91.3 3-(3,5-dimethyl((5-methyl-1H-pyrazolyl)methyl)adamantanyl)pr0panolUnder en atmosphere, a solution of Example 1.91.2 (2.175 g, 7.29 mmol) inanhydrous tetrahydrofuran (42.5 mL) was cooled to 0°C. BH3-THF (15.30 mL, 15.30 mmol) wasadded se. The reaction mixture was stirred at room temperature for 2 hours and cooled to 0°C.

To the reaction mixture was added 10 N aqueous NaOH (5.03 mL, 50.3 mmol) dropwise, followed bypercent H202 (16.52 mL, 146 mmol) water on. The resulting mixture was warmed to roomtemperature and stirred for 90 s. The reaction was quenched with 10 percent hydrochloric acid(35 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x60 mL). The combined organic layers were washed with brine (3 x 60 mL) and cooled in an ice bath.

MEl 24985843V.1 553117813-12620A saturated aqueous solution of sodium sulfite (15 mL) was carefully added and the mixture wasstirred for a few minutes. The organic layer was dried over sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by flash tography, eluting with petroleum ether/ethylacetate (3:1 to 1:1) to provide the title compound. MS (ESI) m/e 317.3 (M+H) +.1.91.4 3-(3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)pr0panolA mixture of Example 1.91.3 (1.19 g, 3.76 mmol) and 1-iodopyrrolidine-2, 5-dione (1.015g, 4.51 mmol) in methylformamide (7.5 mL) was d for 16 hours at room temperature.

The reaction was quenched with saturated NazSO3, The mixture was diluted with ethyl acetate andwashed with saturated NaZSO3, saturated NazCO3, water and brine. The organic layer was dried overanhydrous NaZSO4, ed, and concentrated. The residue was purified by flash chromatography,eluting with petroleum ether/ ethyl acetate (3:1 tol : 1) to provide the title compound. MS (ESI) m/e443.1 (M+H) +.1.91.5 3-(3-((4-i0d0methyl-1H-pyrazolyl)methyl)-5,7-dimethyladamantanyl)pr0pyl methanesulfonateTo a on of Example 1.91.4 (1.55 g, 3.50 mmol) in CHzClz (20 mL) at 0°C wereadded (CH3CH2)3N (0.693 mL, 4.98 mmol) and mesyl chloride (0.374 mL, 4.80 mmol) slowly. Themixture was stirred for 3.5 hours at 20°C and diluted with , washed with saturated NH4Cl,NaHCO3 and brine. The organic layer was dried over , filtered, and concentrated to providethe title compound. MS (ESI) m/e 521.1 (M+H) +.1.91.6 di-tert-butyl(3-{3-[(4-i0d0methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decanyl}pr0pyl)-2—imidodicarbonateTo a solution of e 1.91.5 (1.92 g, 3.69 mmol) in CH3CN (40 ml) at 20°C wasadded di-tert-butyl iminodicarbonate (0.962 g, 4.43 mmol) and CsZCO3 (2.404 g, 7.38 mmol). Themixture was stirred for 16 hours at 80°C and was diluted with ethyl acetate, and was washed withwater and brine. The organic layer was dried over NaZSO4, filtered, and concentrated. The residuewas purified by flash chromatography, eluting with eum ether/ ethyl acetate (10: 1) to providethe title compound. MS (ESI) m/e 642.3 (M+H) +.1.91.7 methyl 2-[5-{1-[(3-{3-[bis(tert-butoxycarbonyl)amino]propyl}-5,7-dimethyltricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazolyl}-6—(tert-but0xycarb0nyl)pyridinyl]-1,2,3,4-ydroisoquinolinecarb0xylateThe title compound was prepared using the procedure in Example 1.2.2, replacingExample 1.1.6 with Example 1.91.6. MS (ESI) m/e 882.2 (M+H)+.

MEl 24985843V.1 554117813-126201.91.8 2-[6-(tert-butoxycarbonyl){1-[(3-{3-[(tert-butoxycarbonyl)amin0]propyl}-5,7-dimethyltricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinyl]-1,2,3,4-tetrahydroisoquinolinecarb0xylic acidThe title nd was prepared using the procedure in e 1.2.5, replacingExample 1.2.4 with Example 1.91.7. MS (ESI) m/e 768.4 (M+H)+.1.91.9 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(3-((tertbutoxycarbonyl)propyl)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)picolinateThe title compound was prepared using the procedure in Example 1.2.6, replacingExample 1.2.5 with Example 1.91.8. MS (ESI) m/e 901.1 (M+H)+.1.91.10 tert-butyl3-(1-((3-(3-amin0pr0pyl)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydr0isoquinolin-2(1H)-yl)picolinateTo a solution of Example 1.91.9 (500 mg) in dichloromethane (5 mL) was addedtrifluoroacetic acid (5 mL) and the reaction was stirred at room ature for 30 minutes. Thereaction was quenched by the addition of saturated aqueous sodium bicarbonate solution and extractedwith dichloromethane . The combined organics were dried with ous sodium sulfate,filtered and concentrated under reduced pressure. The e was ed by reverse-phase HPLCon a Gilson system (C18 ), eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title product.1.91.11 3-(1-((3-(3-amin0pr0pyl)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidTo a solution of Example 1.91.9 (350 mg) in dichloromethane (5 mL) was addedtrifluoroacetic acid (5 mL). The mixture was stirred overnight. The mixture was concentrated and theresidue was purified by reverse phase HPLC using a Gilson system, eluting with 20-80% acetonitrilein water containing 0.1% v/v trifluoroacetic acid, to provide the title compound. 1H NMR (500 MHz,DMSO-dé) 5 ppm 12.86 (s, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.62 (d, 4H), 7.47 (dt, 3H), 7.36 (q, 2H),7.27 (s, 1H), 6.95 (d, 1H), 4.95 (s, 2H), 3.77 (s, 2H), 3.01 (t, 2H), 2.72 (q, 2H), 2.09 (s, 3H), 1.45 (t,2H), 1.18 — 1.05 (m, 9H), 1.00 (d, 6H), 0.80 (s, 6H). MS (ESI) m/e 744.2 ( M+H)+.1.91.12 tert-butyl6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(3-((2-((4—((tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulf0nyl)ethyl)amin0)pr0pyl)-5,7-dimethyladamantan-1-yl)methyl)methyl-1H-pyrazolyl)picolinateMEl 24985843V.1 555117813-12620The title compound was prepared using the procedure in Example 1.2.8, replacingExample 1.2.7 with Example 1.91.10.1.91.13 6-{8-[(1,3-benz0thiazolyl)carbamoyl]-3,4-dihydr0is0quinolin-2(1H)-yl}{1-[(3,5-dimethyl{3-[(2-thyl)amin0]propyl}tricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H—pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared using the ure in Example 1.2.9, replacingExample 1.2.8 with e 1.91.12. 1H NMR (501 MHz, é) 5 12.85 (s, 1H), 8.02 (dd, 1H),7.77 (d, 1H), 7.60 (d, 1H), 7.54 — 7.39 (m, 3H), 7.38 — 7.31 (m, 2H), 7.26 (s, 1H), 6.94 (d, 1H), 4.94(s, 2H), 3.87 (t, 2H), 3.15 (p, 2H), 3.00 (t, 2H), 2.86 (dq, 2H), 2.76 (t, 2H), 2.08 (s, 3H), 1.47 (td, 2H),1.08 (d, 9H), 0.99 (d, 7H), 0.79 (s, 7H). MS (ESI) m/e 852.2 .e 2: Synthesis of Exemplary SynthonsThis example provides tic methods for exemplary synthons useful to make ADCs.2.1 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon CZ)Example 1.2.9 (100 mg) and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)-3 -methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate(purchased from Synchem, 114 mg) in N,N-dimethylformamide (7 mL) was cooled in an water-icebath, and N,N-diisopropylethylamine (0.15 mL) was added. The mixture was stirred at 0 0C for 30minutes and then at room temperature overnight. The reaction was purified by a reverse phase HPLCusing a Gilson system, eluting with 20-60% acetonitrile in water containing 0.1% v/v trifluoroaceticacid, to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H),9.99 (s, 1H), 8.04 (t, 2H), 7.75-7.82 (m, 2H), .63 (m, 6H), 7.32-7.39 (m, 2H), 7.24-7.29 (m,3H), 6.99 (s, 2H), 6.95 (d, 1H), 6.01 (s, 1H), 4.83-5.08 (m, 4H), 4.29-4.48 (m, 1H), 4.19 (t, 1H), 3.84-3.94 (m, 2H), 3.80 (d, 2H), 3.14-3.29 (m, 2H), 2.87-3.06 (m, 4H), 2.57-2.69 (m, 2H), 2.03-2.24 (m,5H), 1.89-2.02 (m, 1H), 1.53-1.78 (m, 2H), 1.26-1.53 (m, 8H), 0.89-1.27 (m, 12H), 0.75-0.88 (m,12H). MS (ESI) m/e 1452.2 (M+H)+.2.2 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-MEl 24985843v.1 556117813-12620sulfopropyl)carbam0y1}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon DH)The title compound was prepared as described in Example 2.1, replacing e 1.2.9with Example 1.6.2. 1H NMR (400 MHZ, yl ide-dé) 5 ppm 12.83 (s, 1H), 9.98 (s, 1H),8.04 (t, 2H), 7.75-7.81 (m, 2H), 7.54-7.64 (m, 3H), .54 (m, 3H), .39 (m, 2H), 7.24-7.31(m, 3H), 6.93-7.01 (m, 3H), 4.86-5.03 (m, 4H), 4.32-4.48 (m, 2H), 4.13-4.26 (m, 2H), 3.31-3.45 (m,4H), 3.24 (d, 4H), 2.88-3.07 (m, 4H), 2.30-2.39 (m, 2H), 2.04-2.24 (m, 5H), 1.86-2.03 (m, 1H), 0.89-1.82 (m, 27H), 0.74-0.88 (m, 13H). MS (ESI) m/e 1466.3 .2.3 This paragraph was intentionally left blank.2.4 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[{2-[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)eth0xy]ethyl}(2-sulf0ethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon EP)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.11.4. 1H NMR (500 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 10.00 (s, 1H),8.01-8.10 (m, 2H), 7.79 (dd, 2H), 7.55-7.65 (m, 3H), 7.41-7.53 (m, 3H), 7.32-7.38 (m, 2H), 7.25-7.30(m, 3H), 6.97-7.02 (m, 2H), 6.96 (d, 1H), 6.03 (s, 1H), 4.90-5.03 (m, 4H), 4.31-4.46 (m, 1H), 4.20 (s,1H), 3.88 (t, 2H), 3.82 (s, 2H), .06 (m, 2H), 2.88-2.98 (m, 1H), 2.58-2.68 (m, 2H), 2.05-2.22(m, 5H), 1.92-2.02 (m, 1H), 0.89-1.75 (m, 23H), 0.77-0.87 (m, 12H). MS (ESI) m/e 1496.3 (M+H)+.2.5 Synthesis of methyl 6-[4—(3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]({[4-({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N5-carbam0yl-L-ornithyl}amin0)benzyl]0xy}carb0nyl)amin0}pr0pyl)-1H-1,2,3-triazolyl]de0xy-beta-L-glucopyranoside (Synthon EF)2.5.1 pent-4—ynalTo a on of oxalyl chloride (9.12 mL) dissolved in dichloromethane (200 mL) at-780C was added yl sulfoxide (14.8 mL) dissolved in dichloromethane (40 mL) over 20 minutes.

After the solution was stirred for an additional 30 minutes, 4-pentynol (8.0 g) dissolved inromethane (80 mL) was added over 10 minutes. The reaction mixture was stirred at-78 0C foran additional 60 minutes. Triethylamine (66.2 mL) was added at-78 OC, and the reaction mixture wasstirred for 60 minutes and then allowed to warm to 10 0C over an additional hour. Water (200 mL)was added, and the two layers were separated. The s layer was acidified with 1% aqueous HCland then back-extracted with dichloromethane (3x 100 mL). The combined organic layers wereMEl 24985843V.1 557117813-12620washed with 1% aqueous HCl, and s NaHCO3. The aqueous extracts were back-extracted withdichloromethane (2x 100 mL), and the combined organic extracts were washed with brine and driedover sodium e. After filtration, the solvent was removed by rotary evaporation (30 OC waterbath) to provide the title nd.2.5.2 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3,5-dimethyl(2-(pentynylamin0)eth0xy)adamantanyl)methyl)methyl-1H-pyrazol-4-yl)picolinic acidTo a solution of Example 1.2.7 (85 mg) in tetrahydrofuran (2 mL) was added pentyanl(8.7 mg), acetic acid (20 mg) and sodium e (300 mg). The e was stirred for 1 hour, andsodium triacetoxyborohydride (45 mg) was added to the reaction mixture. The mixture was stirredovernight, then diluted with ethyl e (200 mL), washed with water and brine, and dried oversodium sulfate. Filtration and evaporation of the solvent gave a residue, which was dissolved indimethyl ide/methanol (1:1, 3 mL). The mixture was purified by e phase HPLC on aGilson system, g with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water, to give the titlecompound. MS (ESI) m/e 812.1 (M+H)+.2.5.3 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3,5-dimethyl(2-((3-(1-(((2S,3R,4R,5S,6S)-3,4,5-trihydr0xymeth0xytetrahydr0-2H-pyranyl)methyl)-1H-1,2,3-triazolyl)propyl)amin0)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo a solution of (2S,3S,4R,SS,6S)(azidomethyl)methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (8.63 mg) in t-butanol (2 mL) and water (1 mL) was added Example 2.5.2 (20 mg),copper(II) sulfate pentahydrate (2.0 mg) and sodium ascorbate (5 mg). The mixture was stirred 20minutes at 100 CC under microwave conditions (Biotage Initiator). Lithium hydroxide monohydrate(50 mg) was added to the mixture, and it was stirred overnight. The mixture was neutralized withroacetic acid and purified by reverse phase HPLC (Gilson system), eluting with 10-85%acetonitrile in 0.1% trifluoroacetic acid in water, to provide the title compound. MS (ESI) m/e 1032.2(M+H)+.2.5.4 methyl 6-[4-(3-{[2-({3-[(4—{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl]({[4-({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N5-carbamoyl-L-0rnithyl}amin0)benzyl]0xy}carb0nyl)amin0}propyl)-1H-1,2,3-triazolyl]de0xy-beta-L-glucopyranosideMEl 24985843V.1 558117813-12620To a solution of 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanamido)methylbutanamido)ureidopentanamido)benzyl 4-nitrophenyl carbonate (7.16 mg) and Example2.5.3 (10 mg) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.1 mL).

The mixture was stirred overnight, then ied with trifluoroacetic acid and purified by reversephase HPLC (Gilson system), eluting with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water,to provide the title compound. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 9.65 (s, 1H), 7.97(d, 1H) , 7.76 (d, 1H), .72 (m, 2H), 7.53-7.63 (m, 3H), 7.38-7.51 (m, 4H), 7.30-7.37 (m, 2H),.27 (m, 3H), 6.84-6.98 (m, 3H), 4.97 (d, 4H), 4.65 (dd, 1H), 4.50 (d, 1H), 4.36-4.46 (m, 1H),4.25-4.32 (m, 1H), 4.10-4.20 (m, 1H), 3.85-3.95 (m, 2H), 3.79 (s, 2H) , 3.66-3.73 (m, 2H), 2.99-3.03(m, 7H), 2.57 (t, 3H), 2.12-2.22 (m, 3H), 2.08 (s, 3H), 1.99-2.05 (m, 2H), 1.70-1.88 (m, 4H) , 1.39-1.67 (m, 8H), 1.35 (s, 3H), 0.92-1.28 (m, 14H), 0.80-0.88 (m, 16H). MS (ESI) m/e 1629.5 (M+H)+.2.6 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-Valyl-N-(4-{[([2-({3-[(4-{6-[8-(1,3-benz0thiazol-2-ylcarbam0yl)-3,4—dihydr0is0quinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl]{3-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl]propyl}carbam0yl)oxy]methyl}phenyl)-N5-carbam0yl-L-ornithinamide on2.6.1 benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((3-(1-((2R,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydro-2H-pyranyl)-1H-1,2,3-triazol-4—yl)pr0pyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-lH-pyrazolyl)pic01inic acidTo a solution of (2R,3R,4S,5S,6S)azido(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (8.63 mg) in t-butanol (2 mL) and water (1 mL) was added Example 2.5.2 (20mg), copper(II) sulfate pentahydrate ( 2.0 mg) and sodium ascorbate (5 mg). The mixture was dminutes at 100 CC under microwave conditions (Biotage Initiator). Lithium hydroxidemonohydrate (50 mg) was added to the mixture, and it was stirred overnight. The mixture wasneutralized with trifluoroacetic acid and purified by reverse phase HPLC (Gilson system) eluting with-85% acetonitrile in 0.1% trifluoroacetic acid in water, to provide the title compound. MS (ESI)m/e 1032.1 (M+H)+.2.6.2 N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-valyl-N-(4-{[([2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]{3-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-MEl 24985843V.1 559117813-12620l-4—yl]propyl}carbam0yl)0xy]methyl}phenyl)-N5-carbamoyl-L-0rnithinamideThe title compound was prepared by substituting Example 2.6.1 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.64 (s, 1H), 7.98 (d, 1H), 7.90 (s,1H), 7.76 (d, 1H) , 7.68 (s, 1H), 7.52-7.62 (m, 3H), 7.20-7.50 (m, 9H), .98 (m, 3H), 5.56 (d,1H), 4.98 (d, 4H), .49 (m, 2H), 4.11-4.23 (m, 2H), 3.96 (d, 2H), 3.74-3.91 (m, 7H), 3.51-3.58(m, 5H), 3.35-3.49 (m, 10H), 2.97-3.02 (m, 6H), 2.57-2.66 (m, 3H), 2.12-2.24 (m, 2H) , 2.08 (s, 3H),.01 (m, 3H), 1.35-1.65 (m, 9H), 0.93-1.28 (m, 10H), 0.81-0.89 (m, 10H). MS (ESI) m/e 1629.4(M+H)+ .2.7 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[(2R){[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)amin0}0x0sulf0pr0panyl]carbam0yl}0xy)methyl]phenyl}-L-alaninamide (Synthon EH)To a solution of Example 1.13.8 (0.018 g) and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate(0.015 g, 0.023 mmol) in N,N-dimethylformamide (0.75 mL) was added N,N-diisopropylethylamine(0.015 mL). After stirring overnight, the reaction was diluted with N,N-dimethylformamide (0.75mL) and water (0.5 mL). The mixture was purified by reverse phase HPLC using a Gilson system,eluting with 10-70% itrile in water ning 0.1% v/v trifluoroacetic acid. The desiredfractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHz,yl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 9.93 (s, 1H), 8.14 (d, 1H), 8.04 (d, 1H), 7.84-7.76 (m,2H), 7.61 (d, 1H), 7.57 (d, 2H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.39-7.30 (m, 4H), 7.26 (d,2H), 6.99 (s, 2H), 6.97 (dd, 1H), 4.96 (s, 2H), 4.90 (t, 2H), 4.75-4.65 (m, 1H), 4.46-4.33 (m, 2H), 4.17(dd, 2H), 3.66-3.47 (m, 4H), 3.36 (t, 4H), 3.12 (s, 2H), 3.01 (t, 2H), 2.85-2.60 (m, 4H), 2.25-2.05 (m,5H), 2.05-1.90 (m, 1H), 1.58-0.76 (m, 32H). MS (ESI) m/e 1423.2 (M+H)+.2.8 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][4-(beta-D-glucopyranosyloxy)benzyl]carbamoyl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide(Synthon ER)2.8.1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3,5-dimethyl(2-((4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydr0-2H-pyranMEl 24985843V.1 560117813-12620yl)0xy)benzyl)amin0)ethoxy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo a solution of Example 1.2.7 (44.5 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2mL) was added 4-(((2S,3R,4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyran)benzaldehyde (17 mg) and MgSO4 (300 mg). The mixture was stirred for 1 hour before theaddition of sodium cyanoborohydride on resin (300 mg). The mixture was stirred ght. Themixture was filtered, and the solvent was evaporated. The residue was dissolved in dimethylsulfoxide/methanol (1 :1, 4 mL) and purified by e phase HPLC (Gilson system), eluting with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water, to give the title nd. MS (ESI) m/e1015.2 (M+H)+.2.8.2 N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][4-(beta-D-yranosyloxy)benzyl]carbamoyl}0xy)methyl]phenyl}-N5-carbamoyl-L-0rnithinamideThe title compound was prepared by substituting Example 2.8.1 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.87 (s, 1H), 10.00 (s, 1H), 7.96-8.14 (m, 2H) , 7.79 (d, 2H), 7.55-7.68 (m, 3H), 7.09-7.52 (m, 11H), 6.91-7.01 (m, 5H), 5.09 (d, 1H),4.95 (dd, 4H) , 4.35-4.47 (m, 4H), 4.14-4.23 (m, 3H), 3.86-3.94 (m, 6H), 3.31-3.46 (m, 8H), 3.16-3.25(m, 3H), 2.90-3.04 (m, 4H), 2.59 (s, 1H), 1.88-2.24 (m, 6H), 0.88-1.75 (m, 24H), 0.76-0.90 (m, 12H).

MS (ESI) m/e 1613.7 .2.9 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[4-(beta-D-allopyranosyloxy)benzyl][2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec)ethyl]carbamoyl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon ES)2.9.1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3,5-dimethyl(2-((4-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydr0-2H-pyranyl)0xy)benzyl)amin0)eth0xy)adamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidTo a solution of Example 1.2.7 (44.5 mg) in tetrahydrofuran (2 mL) and acetic acid (0.2mL) was added 4-(((2S,3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyranMEl 24985843V.1 561117813-12620yl)oxy)benzaldehyde (17 mg) and MgSO4 (300 mg). The mixture was stirred for 1 hour before theon of sodium cyanoborohydride on resin (300 mg). The mixture was stirred overnight. Themixture was filtered, and the solvent was evaporated. The residue was ved in dimethylsulfoxide/methanol (1 :1, 4 mL) and purified by reverse phase HPLC (Gilson system), eluting with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water, to give the title compound. MS (ESI) m/e1015.2 (M+H)+.2.9.2 N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-valyl-N-{4-[({[4-(beta-D-allopyranosyloxy)benzyl][2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideThe title compound was prepared by substituting Example 2.9.1 for e 2.5.3 inExample 2.5.4. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 12.86 (s, 1H), 10.00 (s, 1H), 7.96-8.11 (m, 2H), 7.79 (d, 2H), 7.53-7.65 (m, 3H), 7.08-7.52 (m, 10H) , 6.91-7.00 (m, 5H), 5.09 (d, 1H),4.99 (d, 4H), 4.35-4.48 (m, 3H), 4.13-4.23 (m, 2H), 3.82-3.96 (m, 8H), 3.32-3.50 (m, 10H), 3.12-3.25(m, 3H), 2.90-3.06 (m, 5H), 1.89-2.19 (m, 6H), 0.88-1.75 (m, 22H), 0.76-0.88 (m, 11H). MS (ESI)m/e 1612.5 (M+H)+.2.10 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-0n0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon EQ)The title compound was prepared as described in e 2.1, replacing Example 1.2.9with Example 1.12.2. 1H NMR (500 MHz, yl sulfoxide-dé) 5 ppm 9.99 (s, 1H), 8.01-8.09 (m,2H), .81 (m, 2H), 7.56-7.64 (m, 3H), 7.41-7.53 (m, 3H), 7.36 (q, 2H), 7.25-7.30 (m, 3H), 6.99(s, 2H), 6.94 (d, 1H), 5.98 (s, 1H), 4.89-5.07 (m, 4H), 4.38 (s, 1H), 4.19 (t, 1H), 3.88 (t, 2H), 3.80 (d,2H), 2.89-3.08 (m, 5H), 2.04-2.24 (m, 5H), 1.89-2.02 (m, 1H), 1.76-1.87 (m, 2H), 0.89-1.72 (m,23H), 0.78-0.88 (m, 12H). MS (ESI) m/e 1452.2 (M+H)+.2.11 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-phosph0n0ethyl)carbam0yl}0xy)methyl]phenyl}-L-alaninamide (SynthonMEl 24985843V.1 562117813-12620The title compound was prepared as described in Example 2.1, replacing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.12.2 and 4-((S)((S)(6-ioxo-2,5 -dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-henyl) carbonate, respectively. 1H NMR (400 MHz, yl sulfoxide-dé) 5 ppm 9.93 (s, 1H),8.12 (d, 1H), 8.03 (d, 1H), 7.72-7.83 (m, 2H), .65 (m, 3H), 7.41-7.54 (m, 3H), .40 (m,2H), 7.24-7.30 (m, 3H), 6.99 (s, 2H), 6.94 (d, 1H), 4.87-5.11 (m, 3H), 4.11-4.45 (m, 1H), 3.88 (t, 2H),3.79 (d, 2H), 2.97-3.05 (m, 2H), 2.63-2.70 (m, 1H), 2.29-2.37 (m, 1H), 2.03-2.20 (m, 5H), 1.73-2.00(m, 5H), 1.39-1.55 (m, 4H), 0.88-1.38 (m, 19H), 0.72-0.89 (m, 12H). MS (ESI) m/e 1364.5 (M-H)’.2.12 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-oisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-phosphonopropyl)carbamoyl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon EV)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.14.4. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.98 (s, 1H), 8.04 (t, 2H),7.78 (t, 2H), 7.61 (t, 3H), 7.39-7.54 (m, 3H), 7.32-7.39 (m, 2H), 7.25-7.30 (m, 3H), 6.99 (s, 2H), 6.95(d, 1H), 6.01 (s, 1H), 4.97 (d, 4H), 4.29-4.47 (m, 2H), 4.14-4.23 (m, 2H), 3.85-3.93 (m, 2H), 3.32-3.42 (m, 2H), 3.24 (s, 2H), 2.88-3.09 (m, 3H), 1.87-2.23 (m, 6H), 0.91-1.74 (m, 27H), 0.72-0.89 (m,12H). MS (ESI) m/e 1466.3 (M+H)+.2.13 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[(2R){[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0y1)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]amin0}0x0sulf0pr0panyl]carbam0yl}0xy)methyl]phenyl}-L-alaninamide (Synthon EW)To a solution of Example 1.15 (0.020 g) and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate(0.017 g) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.017 mL).

The reaction was d overnight and was diluted with N,N-dimethylformamide (1 mL), water (0.5mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70%acetonitrile in water containing 0.1% v/v roacetic acid. The desired fractions were combinedand freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm12.85 (s, 1H), 9.93 (s, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.86-7.76 (m, 3H), 7.63-7.41 (m, 7H), 7.39-7.32 (m, 2H), 7.30 (s, 1H), 7.30-7.21 (m, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.96 (s, 2H), 4.93 (s, 2H),4.49-4.33 (m, 2H), 4.18 (dd, 2H), 4.15-4.08 (m, 2H), 3.90-3.86 (m, 2H), 3.36 (t, 2H), 3.34-3.27 (m,MEl 24985843V.1 563117813-126201H), 3.18-3.04 (m, 2H), 3.04-2.96 (m, 2H), 2.89-2.61 (m, 2H), 2.27-2.05 (m, 5H), 2.03-1.87 (m, 1H),1.59-1.42 (m, 4H), 1.42-0.91 (m, 18H), 0.91-0.76 (m, 11H). MS (-ESI) m/e 1407.5 (M-H)’.2.14 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-[4-({[{2-[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)eth0xy]ethyl}(3-phosphonopropyl)carbamoyl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide on EX)A mixture of Example 1.16.2 (59 mg), ((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)carbonate (48 mg), and N,N-diisopropylethylamine (0.056 mL) in 2 mL N,N-dimethylformamide wasstirred for 24 hours. The mixture was purified via reverse phase chromatography on a Biotage aOne system using a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% roaceticacid/water. The desired fractions were concentrated and the product was lyophilized from water and1,4-dioxane to give the title compound as a trifluoroacetic acid salt. 1H NMR (400MHz, dimethylide-dé) 5 ppm 9.97 (bs, 1H), 8.04 (m, 2H), 7.79 (d, 2H), 7.59 (m, 3H), 7.46 (m, 3H), 7.36 (m,2H), 7.27 (m, 2H), 6.99 (s, 2H), 6.94 (d, 1H), 4.97 (m, 4H), 4.40 (m, 2H), 4.17 (dd, 2H), .10(m, 6H), 3.45 (m, 2H), 3.40 (m, 2H), 3.26 (m, 2H), 3.01 (m, 2H), 2.95 (s, 2H), 2.79 (s, 2H), 2.15 (m,2H), 2.09 (s, 2H), 1.68 (m, 2H), 1.60 (m, 1-2H), 1.35-1.50 (m, 6H), 1.25 (m, 4H), 1.17 (m, 2H), 1.10(m, 2H), 0.97 (m, 1-2H), 0.84 (m, 12H). MS (ESI) m/e 1510.4 (M+H)+.2.15 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[{2-[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethoxy]ethyl}(3-phosphonopropyl)carbam0yl]0xy}methyl)phenyl]-L-alaninamide (Synthon EY)A mixture of Example 1.16.2 (59 mg), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl rophenyl) carbonate (42mg), and N,N-diisopropylethylamine (0.042 mg) in 2 mL N,N-dimethylformamide was stirred for 24hours. The mixture was purified via reverse phase chromatography on a e Isolera One systemusing a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water.

Fractions were concentrated and the product was lyophilized from water and 1,4-dioxane to give thetitle compound as a trifluoroacetic acid salt. MS (ESI) m/e 1422.6 (M-H)+.2.16 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-MEl 24985843v.1 564117813-12620lyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-phosphonopr0pyl)carbam0yl}0xy)methyl]phenyl}-L-alaninamide(Synthon EZ)A mixture of Example 1.14.4 (50 mg), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (38mg), and N,N-diisopropylethylamine (0.050 mL) in 2 mL N,N-dimethylformamide was stirred for 24hours. The mixture was ed via reverse phase chromatography on a e Isolera One systemusing a 40 g C18 column, eluting with 10-90% acetonitrile in 0.1% trifluoroacetic acid/water. Thedesired fractions were concentrated and the product was lyophilized from water and 1,4-dioxane togive the title compound as a roacetic acid salt. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5ppm 9.94 (bs, 1H), 8.12 (d, 1H), 8.04 (d, 1H), 7.80 (d, 2H), 7.61 (m, 3H), 7.47 (m, 3H), 7.36 (m, 2H),7.29 (m, 2H), 6.99 (s, 2H), 6.95 (d, 1H), 4.97 (m, 4H), 4.40 (m, 2H), 4.16 (dd, 2H), 3.50-4.10 (m,6H), 3.68 (m, 2H), 3.55 (m, 2H), 3.25 (m, 4H), 3.02 (m, 2H), 2.94 (s, 2H), 2.79 (s, 2H), 2.15 (m, 1H),2.08 (s, 2H), 1.65 (m, 2H), 1.40-1.50 (m, 6H), 1.20-1.30 (m, 6H), 1.08-1.19 (m, 4H), 0.97 (m, 1-2H),0.76-0.89 (m, 12H). MS (ESI) m/e 1380.3 .2.17 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[(2S)carb0xy({[(4-{[(2S)-2-{[(2S){[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}methylbutanoyl]amin0}pr0pan0yl]amin0}benzyl)0xy]carbonyl}amin0)propanoyl](methyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid(Synthon FD)To a solution of Example 1.17 (0.040 g) and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate(0.034 g) in N,N-dimethylformamide (1 mL) was added isopropylethylamine (0.035 mL). Thereaction was stirred overnight and diluted with methylformamide (1 mL) and water (0.5 mL).

The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-70%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were edand freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm12.84 (s, 1H), 9.92 (s, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.79 (d, 2H), 7.62 (d, 1H), 7.57 (d, 2H), 7.54-7.41 (m, 3H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 4H), 6.99 (s, 2H), 6.95 (dd, 1H), 5.01-4.89 (m, 4H),4.78 (dq, 1H), 4.45-4.30 (m, 1H), 4.23-4.11 (m, 1H), 3.88 (t, 2H), 3.80 (s, 2H), 3.42-3.26 (m, 6H),3.06 (s, 1H), 3.01 (t, 2H), 2.80 (s, 2H), 2.76-2.62 (m, 1H), 2.46-2.36 (m, 1H), 2.25-2.05 (m, 5H),2.05-1.92 (m, 1H), 1.58-1.42 (m, 4H), 1.42-0.91 (m, 20H), 0.91-0.78 (m, 9H). MS (ESI) m/e 1387.4(M+H)+.

MEl 24985843V.1 565117813-126202.18 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][4-D-glueopyranuronosyloxy)benzyl]carbamoyl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide 0n FS)The title compound was prepared by substituting Example 1.19.2 for Example 2.5.3 inExample 2.5.4. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 12.86 (s, 1H), 10.00 (s, 1H), 7.97-8.14 (m, 2H), 7.79 (d, 2H), 7.07-7.65 (m, 13H), 6.87-7.01 (m, 4H), .08 (m, 1H), 4.87-5.07 (m,4H), 4.33-4.48 (m, 3H), 4.13-4.26 (m, 1H), 3.74-3.94 (m, 6H), 3.14-3.34 (m, 8H), 2.84-3.05 (m, 6H),1.87-2.25 (m, 6H), 0.89-1.73 (m, 21H), 0.76-0.87 (m, 12H). MS (ESI) m/e 1626.4 (M+H)+.2.19 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-0n0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon F1)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.20.11. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 10.00 (s, 1H), 8.40 (s, 1H),8.07 (d, 1H), 8.00 (d, 1H), 7.84-7.90 (m, 1H), 7.79 (dd, 3H), 7.55-7.66 (m, 2H), 7.46 (s, 2H), 7.37 (t,1H), 7.29 (t, 3H), 7.18-7.25 (m, 1H), 6.99 (s, 2H), 5.99 (s, 1H), 5.00 (d, 1H), 4.38 (s, 1H), 4.13-4.24(m, 1H), 3.96 (s, 2H), 3.87 (d, 2H), 2.88-3.08 (m, 4H), 2.84 (q, 2H), 2.04-2.26 (m, 5H), 1.89-2.01 (m,3H), 1.75-1.88 (m, 2H), 1.63-1.74 (m, 1H), 0.91-1.63 (m, 21H), 0.76-0.89 (m, 12H). MS (ESI) m/e1450.5 (M-H)’.2.20 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-NS-carbamoyl-N-{4-[({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}-S-methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-L-ornithinamide (Synth0n FV)The title compound was prepared by substituting Example 1.22.5 for Example 1.2.9 inExample 2.1. 1H NMR (500 MHz, dimethyl ide-dé) 5 ppm 13.00 (V br s, 1H), 10.00 (s, 1H),8.52 (dd, 1H), 8.16 (dd, 1H), 8.06 (d, 1H), 7.78 (d, 1H), 7.62 (d, 1H), 7.59 (br m, 2H), 7.53 (m, 2H),7.45 (d, 1H), 7.37 (t, 1H), 7.30 (s, 1H) 7.27 (d, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.98 (m, 4H), 4.39 (m,1H), 4.19 (br m, 1H), 3.88 (t, 2H), 3.80 (br d, 2H), 3.44, 3.36 (br m, m, total 6H), 3.24 (m, 2H), 2.94-3.01 (m, 4H), 2.63 (br m, 2H), 2.14 (m, 2H), 2.10 (s, 3H), 1.97 (br m, 1H), 1.68 (br m, 1H), 1.58 (brMEl 24985843V.1 566117813-12620m, 1H), 1.34-1.47 (m, 8H), 1.08-1.23 (m 10H), 0.95 (br m, 2H), 0.85-0.80 (m, 12H). MS (ESI) m/e1451.4 (M-H)’.2.21 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[(2R){[2-({3-[(4-{6—[1-(1,3-benzothiazolylcarbam0y1)-1,2,3,4-tetrahydr0quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)amin0}0x0sulf0pr0panyl]carbam0y1}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide(Synthon GC)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.21.7. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 9.98 (s, 1H), 8.40 (s, 1H),8.07 (d, 1H), 8.01 (dd, 1H), 7.89 (t, 1H), 7.74-7.84 (m, 3H), 7.58 (d, 2H), 7.47 (s, 2H), 7.37 (t, 1H),7.19-7.33 (m, 5H), 7.00 (s, 2H), 4.91 (q, 2H), 4.64-4.76 (m, 2H), .43 (m, 2H), 4.15-4.24 (m,2H), 3.92-4.03 (m, 2H), 3.88 (s, 2H), 3.32-3.50 (m, 6H), 3.10-3.22 (m, 2H), 2.89-3.07 (m, 2H), 2.70-2.89 (m, 4H), .70 (m, 1H), 2.05-2.28 (m, 5H), 1.90-2.03 (m, 3H), 1.64-1.77 (m, 1H), 1.53-1.65(m, 1H), 0.92-1.53 (m, 21H), 0.77-0.92 (m, 12H). MS (ESI) m/e 1507.3 (M-H)’.2.22 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[(2R){[2-({3-[(4-{6—[1-(1,3-benzothiazolylcarbam0y1)-1,2,3,4-tetrahydr0quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)amin0}0x0sulf0pr0panyl]carbam0yl}0xy)methyl]phenyl}-L-alaninamide (Synthon GB)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.21.7 and 4-((S)((S)(6-(2,5-dioxo-2,5 -dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate, respectively. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 9.93 (s, 1H),8.39 (s, 1H), 8.13 (d, 1H), 8.01 (dd, 1H), 7.88 (t, 1H), 7.74-7.84 (m, 3H), 7.57 (d, 2H), 7.46 (s, 2H),7.37 (t, 1H), 7.17-7.33 (m, 5H), 6.99 (s, 2H), 4.91 (d, 2H), 4.65-4.76 (m, 1H), 4.30-4.51 (m, 1H),.21 (m, 1H), 3.92-4.00 (m, 2H), 3.88 (s, 2H), 3.29-3.46 (m, 4H), 2.93-3.21 (m, 3H), 2.68-2.88(m, 4H), 2.58-2.68 (m, 1H), 2.04-2.26 (m, 5H), 1.89-2.02 (m, 3H), 1.37-1.54 (m, 6H), 0.92-1.34 (m,15H), 0.75-0.91 (m, 12H). MS (ESI) m/e (M+H)+.2.23 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-NS-carbamoyl-N-{4-[({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}-yl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decMEl 24985843V.1 567117813-12620yl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-L-ornithinamide (Synthon FW)The title compound was prepared by substituting Example 1.23.4 for e 1.2.9 inExample 2.1. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 13.38 (V br s, 1H), 10.00 (s, 1H),8.66 (m, 2H), 8.06 (d, 1H), 7.78 (d, 1H), 7.65 (d, 1H), 7.59 (br m, 2H), 7.53 (m, 1H), 7.47 (m 2H),7.37 (t, 1H), 7.30 (s, 1H) 7.27 (d, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.98 (m, 4H), 4.39 (m, 1H), 4.19 (brm, 1H), 3.88 (t, 2H), 3.80 (br d, 2H), 3.40 (br m, 6H), 3.24 (m, 2H), 2.98 (m, 4H), 2.63 (m, 2H), 2.16(m, 2H), 2.10 (s, 3H), 1.97 (br m, 1H), 1.68 (br m, 1H), 1.58 (br m, 1H), 1.34-1.47(m, 8H), 1.08-1.23(m, 10H), 0.95 (br m, 2H), .80 (m, 12H). MS (ESI) m/e 1451.5 (M-H)’.2.24 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon GD)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.24.2. 1H NMR (500 MHz, dimethyl ide-dé) 5 ppm 10.00 (s, 1H), 8.38 (s, 1H),8.07 (d, 1H), 8.00 (d, 1H), 7.85-7.92 (m, 1H), 7.73-7.85 (m, 3H), 7.55-7.65 (m, 2H), 7.46 (s, 2H),7.37 (t, 1H), 7.28 (t, 3H), 7.22 (t, 1H), 6.99 (s, 2H), 6.00 (s, 1H), 4.99 (d, 1H), 4.28-4.50 (m, 1H), 4.19(s, 1H), 3.77-4.03 (m, 4H), 3.31-3.41 (m, 2H), 3.20-3.29 (m, 2H), 2.87-3.08 (m, 3H), 2.83 (t, 2H),2.63 (d, 2H), 2.05-2.25 (m, 5H), 1.88-2.01 (m, 3H), 1.69 (t, 1H), 1.53-1.63 (m, 1H), 1.31-1.53 (m,8H), 1.04-1.29 (m, 11H), 0.89-1.02 (m, 2H), .88 (m, 12H). MS (ESI) m/e 1450.4 .2.25 Synthesis of 2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon GK)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.25.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 9.98 (s, 1H),8.04 (t, 2H), 7.75-7.82 (m, 2H), 7.60 (t, 3H), 7.41-7.53 (m, 3H), 7.32-7.39 (m, 2H), 7.24-7.29 (m,3H), 6.99 (s, 2H), 6.94 (d, 3H), 5.97 (s, 1H), 4.88-5.04 (m, 4H), 4.38 (d, 1H), 4.12-4.24 (m, 1H), 3.88(t, 2H), .84 (m, 2H), 3.32-3.40 (m, 2H), 3.28 (d, 2H), 2.90-3.05 (m, 4H), 2.42-2.49 (m, 2H),2.05-2.22 (m, 5H), 1.87-2.01 (m, 1H), 0.90-1.76 (m, 22H), 0.74-0.88 (m, 12H). MS (ESI) m/e 1414.5(M-H)’.

MEl 24985843V.1 568117813-126202.26 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbamoyl}0xy)methyl]phenyl}-L-alaninamide onThe title compound was prepared as described in Example 2.1, replacing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.25.2 and 4-((S)((S)(6-(2,5-dioxo-2,5 -dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate, respectively. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.78 (s,1H), 9.93 (s, 1H), 8.12 (d, 1H), 8.03 (d, 1H), 7.75-7.83 (m, 2H), 7.54-7.65 (m, 3H), 7.41-7.52 (m,3H), 7.32-7.40 (m, 2H), 7.24-7.29 (m, 3H), 6.98 (s, 2H), 6.94 (d, 1H), 4.90-5.04 (m, 4H), 4.32-4.45(m, 2H), 4.12-4.21 (m, 2H), 3.88 (t, 2H), 3.79 (d, 2H), .46 (m, 4H), 3.23-3.31 (m, 2H), 3.01 (t,2H), 2.46 (t, 2H), 2.04-2.22 (m, 5H), 1.87-2.02 (m, 1H), .60 (m, 4H), 0.91-1.37 (m, 17H), 0.76-0.88 (m, 12H). MS (ESI) m/e 1328.4 (M-H)’.2.27 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[(2R)carb0xy({[(4-{[(2S)-2-{[(2S){[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}methylbutanoyl]amin0}pr0pan0yl]amin0}benzyl)0xy]carbonyl}amin0)propanoyl](methyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acidon GW)A on of Example 1.27 (0.043 g) in N,N-dimethylformamide (0.5 mL) was added 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate (0.042 g) followed by N,N-diisopropylethylamine (0.038 mL), and the reaction was stirred at room temperature. After stirringfor 16 hours, the reaction was d with water (0.5 mL) and N,N-dimethylformamide (1 mL). Themixture was purified by reverse phase HPLC using a Gilson system, g with 10-70% acetonitrilein water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.05 (s, 1H),.15 (s, 1H), 8.36 (d, 1H), 8.26 (d, 1H), 8.02 (d, 2H), .77 (m, 4H), 7.77-7.63 (m, 3H), 7.63-7.54 (m, 2H), 7.54-7.46 (m, 3H), 7.22 (s, 2H), 7.18 (dd, 1H), 5.17 (d, 4H), 5.01 (dq, 1H), 4.61 (p, 1H),4.39 (t, 1H), 4.11 (t, 2H), 4.03 (s, 2H), .49 (m, 2H), 3.29 (s, 1H), 3.24 (t, 2H), 3.03 (s, 2H), 2.92(dt, 1H), 2.73-2.61 (m, 4H), 2.35 (d, 4H), 2.18 (dt, 1H), 1.71 (h, 4H), 1.65-1.13 (m, 18H), 1.13-1.01(m, 13H). MS (ESI) m/e 1387.3 (M+H)+.

MEl 24985843v.1 569117813-126202.28 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][1-(carboxymethyl)piperidinyl]carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide (Synthon HF)A solution of Example 1.28 (0.0449 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)ate (0.049 g) and N,N-diisopropylethylamine (0.044 mL) were stirred er in N,N-dimethylformamide (0.5 mL) at room temperature. The reaction mixture was stirred overnight anddiluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture was purified byreverse phase HPLC using a Gilson system, eluting with 10-90% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired fractions were combined and -dried to provide thetitle compound. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 9.99 (s, 1H), 8.04(t, 2H), 7.78 (t, 2H), 7.65-7.58 (m, 3H), 7.54-7.41 (m, 3H), 7.38 (d, 1H), 7.34 (d, 1H), 7.32-7.24 (m,3H), 6.99 (s, 2H), 6.95 (d, 1H), 5.97 (s, 1H), 5.01 (s, 2H), 4.96 (s, 2H), 4.38 (q, 1H), 4.23-4.14 (m,1H), 4.05 (s, 2H), 3.88 (t, 2H), 3.80 (s, 2H), 3.36 (t, 2H), 3.26-2.86 (m, 8H), 2.27-2.02 (m, 6H), 2.02-1.86 (m, 2H), 1.86-1.75 (m, 2H), 1.75-1.54 (m, 2H), 1.54-0.90 (m, 24H), 0.89-0.72 (m, 14H). MS(ESI) m/e 1485.2 (M+H)+.2.29 sis of (S)((2-((3-((4-(6-(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)carb0xypyridinyl)methyl-1H-pyrazolyl)methyl)-5,7—dimethyladamantanyl)0xy)ethyl)(methyl)amin0)((((4-((S)((S)(6-(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)hexanamid0)methylbutanamid0)ureidopentanamid0)benzyl)0xy)carb0nyl)amin0)-N,N,N-trimethyl0x0hexanaminium salt (Synthon HG)A solution of Example 1.29 (8 mg), ((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate (8.24mg) and N,N-diisopropylethylamine (7.50 ul, 0.043 mmol) in N,N-dimethylformamide (0.250 mL)was stirred at room temperature. After 3 hours, the reaction was diluted with N,N-dimethylformamide (1.25 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-90% acetonitrile in water containing 0.1% v/v trifluoroaceticacid. The desired ons were combined and -dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 9.96 (s, 1H), 8.04 (t, 2H), 7.83-7.76 (m, 2H),7.66-7.56 (m, 3H), 7.53-7.42 (m, 4H), 7.41-7.32 (m, 2H), 7.31-7.23 (m, 3H), 6.99 (s, 2H), 6.95 (d,1H), 5.99 (s, 1H), 5.04-4.87 (m, 4H), 4.44-4.33 (m, 2H), .12 (m, 2H), 3.88 (t, 2H), 3.81 (s, 2H),MEl 24985843v.1 570117813-126203.50-3.13 (m, 9H), 3.11-2.92 (m, 14H), 2.80 (s, 1H), 2.25-2.04 (m, 5H), 2.03-1.89 (m, 1H), 1.75-0.91(m, 28H), .77 (m, 12H). MS (ESI) m/e 1528.5 .2.30 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-L-alaninamide (Synthon HP)The title compound was prepared as bed in Example 2.1, replacing 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)-3 -methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)propanamido)benzyl (4-nitrophenyl) carbonate.1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.83 (s, 1H), 9.94 (s, 1H), 8.12 (d, 1H), 8.04 (d,1H), 7.79 (d, 2H), 7.40-7.63 (m, 6H), 7.32-7.39 (m, 2H), 7.24-7.30 (m, 3H), 6.99 (s, 2H), 6.95 (d,1H), 4.90-5.03 (m, 4H), 4.31-4.47 (m, 1H), 4.09-4.24 (m, 1H), 3.84-3.93 (m, 2H), 3.81 (s, 2H), 3.30-3.39 (m, 2H), 3.20-3.28 (m, 2H), 3.01 (t, 2H), 2.57-2.65 (m, 2H), 2.05-2.22 (m, 5H), 1.87-2.02 (m,2H), 1.41-1.58 (m, 4H), 1.22 (d, 18H), 0.74-0.89 (m, 12H). MS (ESI) m/e 1364.5 (M-H)’.2.31 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-thyl)amin0}piperidinyl)carb0nyl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon HR)A solution of e 1.30.2 (0.038 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H--1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)carbonate (0.035 g) and N,N-diisopropylethylamine (0.032 mL) in N,N-dimethylformamide (0.5 mL)was d at room temperature. After ng for 3 hours, the reaction was diluted with N,N-dimethylformamide (1.25 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-90% itrile in water containing 0.1% V/V trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.98 (s, 1H), 9.02 (s, 1H), .00 (m, 2H), 7.79 (d, 2H),7.64-7.56 (m, 3H), 7.53 (d, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.39-7.32 (m, 2H), 7.29 (d, 3H), 6.99 (s,2H), 6.95 (d, 1H), 6.00 (s, 1H), 4.99 (s, 2H), 4.96 (s, 2H), 4.48-4.32 (m, 2H), 4.27-4.15 (m, 2H), 4.11(d, 2H), 3.88 (t, 2H), 3.82 (s, 2H), 3.40-3.33 (m, 4H), 3.24-3.11 (m, 2H), 3.11-2.72 (m, 8H), 2.26-2.04(m, 4H), 2.04-1.80 (m, 3H), 1.80-0.92 (m, 26H), 0.92-0.77 (m, 12H). MS (ESI) m/e 1535.4 (M+H)+.2.32 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)(3-phosphonopropoxy)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridin-MEl 24985843V.1 571117813-126203-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon HU)The title compound was prepared by substituting Example 1.31.11 for Example 2.5.3 ine 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.98 (s, 1H), 8.03 (dd, 2H), 7.70-7.84 (m, 3H), 7.59 (d, 2H), 7.48 (dd, 2H), 7.23-7.37 (m, 4H) 4.12-, 6.93-7.02 (m, 4H), 4.99 (d, 4H),4.21 (m, 8H), 3.88-3.96 (m, 4H), .84 (m, 4H), 3.23-3.49 (m, 7H), 2.73-3.07 (m, 8H), 1.89-2.21(m, 9H), 0.91-1.77 (m, 25H), 0.77-0.91 (m, 12H). MS (ESI) m/e 1496.3 (M+H)+.2.33 Synthesis of 2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-phosphonopr0pyl)amin0}piperidinyl)carb0nyl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide on HT)A solution of Example 1.26.2 (0.040 g), ((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1 xanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)carbonate (0.030 g) and N,N-diisopropylethylamine (0.020 mL) in N,N-dimethylformamide (0.5 mL)was d at room temperature. After stirring for 3 hours, the reaction was diluted with N,N-dimethylformamide (1.25 mL) and water (0.5 mL). The mixture was ed by reverse phase HPLCusing a Gilson system, eluting with 10-90% acetonitrile in water containing 0.1% V/V trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR(500 MHz, dimethyl sulfoxide-d6) 5 ppm 9.98 (s, 1H), 9.26 (s, 1H), 8.06 (d, 1H), 8.05-8.01 (m, 1H),7.79 (d, 2H), 7.62 (d, 1H), 7.61-7.57 (m, 2H), 7.52-7.42 (m, 3H), 7.38 (d, 1H), 7.35 (d, 1H), 7.32-7.26(m, 3H), 6.99 (s, 2H), 6.95 (d, 1H), 6.01 (s, 1H), 4.99 (s, 2H), 4.96 (s, 3H), 4.44-4.33 (m, 2H), 4.18(dd, 2H), 3.88 (t, 2H), 3.83 (s, 2H), 3.71-3.61 (m, 2H), 3.53 (t, 2H), 3.36 (t, 2H), 3.07-2.66 (m, 8H),2.28-2.06 (m, 6H), 2.05-1.92 (m, 2H), 1.92-1.80 (m, 2H), 1.78-0.95 (m, 32H), 0.92-0.77 (m, 14H).

MS (ESI) m/e 1549.5 (M+H)+.2.34 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-onopropyl)carbamoyl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon HV)The title compound was prepared by substituting Example 1.14.4 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.98 (s, 1H), 9.02 (s, 1H), 8.32-8.45 (m, 1H), 8.12-8.27 (m, 3H), 7.98-8.09 (m, 3H), 7.93 (d, 1H), 7.66-7.83 (m, 4H), 7.54-7.64 (m,MEl 24985843V.1 572117813-126202H), 7.46-7.50 (m, 2H), 7.24-7.40 (m, 3H), 6.99 (s, 2H), 5.93-6.09 (m, 1H), 4.99 (s, 3H), 4.33-4.49(m, 3H), 4.15-4.20 (m, 3H), 3.19-3.50 (m, 10H), 2.86-3.07 (m, 3H), 1.87-2.27 (m, 7H), 0.91-1.77 (m,26H), .89 (m, 10H). MS (ESI) m/e 1461.1 (M+H)+ .2.35 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)amin0}piperidinyl)carb0nyl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon HZ)A solution of Example 1.36.2 (0.031 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H--1 -yl)hexanamido)methylbutanamido)-5 opentanamido)benzyl (4-nitrophenyl)carbonate (0.025 g) and N,N-diisopropylethylamine (0.016 mL) in N,N-dimethylformamide (0.5 mL)was stirred at room temperature. After stirring for 3 hours, the reaction was diluted with N,N-dimethylformamide (1.25 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLCusing a Gilson , eluting with 10-90% acetonitrile in water ning 0.1% V/V trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-dé) 8 ppm 12.84 (s, 1H), 9.98 (s, 1H), 8.82 (s, 1H), 8.05 (dd, 2H), 7.79(d, 2H), 7.70-7.53 (m, 2H), 7.53-7.24 (m, 6H), 6.99 (s, 2H), 6.95 (d, 1H), 6.00 (s, 1H), 4.99 (s, 2H),4.96 (s, 2H), 4.37 (q, 2H), 4.25-4.15 (m, 2H), 3.88 (t, 2H), 3.83 (s, 2H), 3.69-3.61 (m, 2H), 3.44-3.30(m, 4H), 3.08-2.90 (m, 4H), 2.90-2.72 (m, 4H), 2.27-2.04 (m, 5H), 2.04-1.89 (m, 2H), 1.77-0.94 (m,28H), 0.91-0.78 (m, 14H). MS (ESI) m/e 1499.5 (M+H)+.2.36 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-NS-carbamoyl-N-{4-[({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}-S-methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)carbamoyl}0xy)methyl]phenyl}-L-ornithinamide (Synthon IA)The title compound was prepared by substituting Example 1.39.2 for Example 1.2.9 inExample 2.1. 1H NMR (400 MHz, yl ide-dé) 5 ppm 9.98 (s, 1H), 8.60 (dd, 1H), 8.52 (dd,1H), 8.06 (d, 1H), 7.78 (d, 1H), 7.65 (d, 1H), 7.59 (br m, 2H), 7.50 (m, 1H), 7.45 (d, 1H), 7.38 (m,2H), 7.28 (s, 1H), 7.27 (d, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 5.98 (br s, 1H), 4.98 (s, 4H), 4.39 (m, 1H),4.19 (br m, 1H), 3.88 (t, 2H), 3.80 (br d, 2H), 3.36 (br m, 3H), 3.24 br (m, 4H), 2.98 (m, 4H), 2.16 (m,2H), 2.12 (s, 3H), 1.95 (br m, 1H), 1.67 (br m, 3H), 1.34-1.47 (m, 9H), 1.08-1.23 (m, 11H), 0.95 (brm, 2H), 0.85-0.80 (m, 12H). MS (ESI) m/e 1465.5 (M-H)’.2.37 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-NS-carbamoyl-N-{4-[({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}-MEl 24985843V.1 573117813-12620S-methyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-phosph0n0pr0pyl)carbamoyl}0xy)methyl]phenyl}-L-ornithinamide (Synthon IF)The title compound was prepared by substituting Example 1.40.2 for e 1.2.9 inExample 2.1. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.98 (s, 1H), 8.52 (dd, 1H), 8.16 (dd,1H), 8.05 (br d, 1H), 7.78 (br d, 1H), 7.62 (m, 1H), 7.58 (br m, 2H), 7.52 (m, 2H), 7.44 (d, 1H), 7.38(t, 1H), 7.29 (s, 1H) 7.27 (d, 2H), 6.99 (s, 2H), 6.97 (d, 1H), 4.98 (s, 2H), 4.96 (s, 2H), 4.39 (m, 1H),4.19 (br m, 1H), 3.88 (t, 2H), 3.80 (br d, 2H), 3.36 (br m, 3H), 3.24 br (m, 4H), 2.98 (m, 4H), 2.16 (m,2H), 2.12 (s, 3H), 1.95 (br m, 1H), 1.67 (br m, 3H), 1.47-1.34 (m, 9H), .23 (m, 11H), 0.95 (brm, 2H), 0.85-0.80 (m, 12H). MS (ESI) m/e 1451.5 (M-H)’.2.38 Synthesis of N-{6-[(chloroacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3--[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridin—3-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-L-alaninamide (Synthon IG)2.38.1 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamid0)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-yl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidA solution of Example 1.2.9 (0.050 g), (9H-fluorenyl)methyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)oxopropanyl)amino)-1 -oxobutanyl)carbamate (0.039 g) and N,N-diisopropylethylamine (0.027 mL) in N,N-dimethylformamide (1mL) was stirred at room temperature. After stirring overnight, diethylamine (0.027 mL) was added tothe reaction, and stirring was continued for 2 hours. The reaction was quenched with trifluoroaceticacid, and the mixture was purified by reverse phase HPLC using a Gilson system, eluting with 5-75%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combinedand -dried to e the title compound. MS (ESI) m/e 1499.5 (M+H)+.2.38.2 N-{6-[(chloroacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-L-alaninamideTo a solution of 6-(2-chloroacetamido)hexanoic acid (6 mg) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.011 g) in N,N-ylformamide (1 mL) was added N,N-diisopropylethylamine (0.015 mL), and the reactionstirred for 5 minutes. This on was added to Example 2.38.1 (0.022 g) and was stirred for 1 hour.

MEl 24985843V.1 574117813-12620The on was diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture waspurified by reverse phase HPLC using a Gilson system, eluting with 10-90% acetonitrile in watercontaining 0.1% V/V trifluoroacetic acid. The desired fractions were combined and freeze-dried toprovide the title nd. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.83 (s, 1H), 9.93 (s,1H), 8.20-8.10 (m, 2H), 8.04 (d, 1H), 7.83-7.76 (m, 2H), 7.64-7.55 (m, 3H), 7.55-7.50 (m, 1H), 7.50-7.41 (m, 2H), 7.40-7.32 (m, 2H), 7.32-7.24 (m, 3H), 6.96 (d, 1H), 5.07-4.92 (m, 3H), 4.39 (p, 1H),4.18 (dd, 2H), 4.01 (s, 2H), 3.92-3.76 (m, 6H), .32 (m, 4H), 3.25 (t, 2H), 3.13-2.93 (m, 4H),2.72-2.58 (m, 2H), 2.29-2.12 (m, 2H), 2.09 (s, 3H), 2.05-1.92 (m, 1H), 1.58-0.89 (m, 18H), 0.89-0.77(m, 12H). MS (ESI) m/e 1362.2 (M+H)+.2.39 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)(carboxymethoxy)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinmethyl-lH-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-1-yl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon IJ)The title compound was prepared by substituting Example 1.41.3 for Example 2.5.3 ine 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 10.03 (s, 1H), 9.96 (s, 1H), 8.26-8.34 (m, 1H), 7.95-8.11 (m, 2H), 7.73-7.82 (m, 2H), 7.22-7.70 (m, 11H) , 6.95-7.05 (m, 3H), 6.89 (d,1H), 5.23 (s, 1H), 4.98 (d, 3H), 4.83 (s, 1H), 4.33-4.43 (m, 1H), 4.11-4.23 (m, 1H), 3.74-3.95 (m, 3H),.39 (m, 10H), 2.78-3.06 (m, 12H), 1.91-2.22 (m, 8H) , 0.93-1.68 (m, 20H), 0.77-0.88 (m, 10H).

MS (ESI) m/e 1432.2 (M+H)+.2.40 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(2-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-thyl)amin0}ethyl)(2-carb0xyethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide (Synthon IJ)The title compound was prepared as described in Example 2.1, ing Example 1.2.9with Example 1.38.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.86 (s, 1H), 9.99 (s, 1H),9.10 (s, 1H), 8.04 (t, 2H), 7.73-7.85 (m, 2H), 7.61 (t, 3H), 7.41-7.55 (m, 3H), 7.26-7.39 (m, 5H), 6.99(s, 2H), 6.95 (d, 1H), 6.00 (s, 1H), 4.99 (d, 4H), 4.34-4.45 (m, 2H), 4.19 (dd, 2H), 3.88 (t, 2H), 3.82(s, 2H), 3.36 (t, 4H), 2.85-3.09 (m, 5H), 2.06-2.22 (m, 4H), 1.89-2.02 (m, 1H), 0.94-1.77 (m, 20H),0.77-0.90 (m, 11H). MS (ESI) m/e 1567.4 (M+H)+.2.41 sis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-({(2S)[{[(4-{[(2S)(carbamoylamin0){[(2S){[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}MEl 24985843V.1 575117813-12620methylbutanoyl]amin0}pentan0yl]amin0}benzyl)0xy]carb0nyl}(2-carboxyethyl)amin0]carboxypr0pan0yl}amin0)eth0xy]-5,7-yltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon IK)The title nd was ed as described in Example 2.1, replacing Example 1.2.9with Example 1.32.4. MS (ESI) m/e 1592.4 .2.42 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[(2S)({[(4-{[(2S)moylamin0){[(2S){[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}methylbutanoyl]amin0}pentan0yl]amin0}benzyl)0xy]carb0nyl}amin0)carboxypropanoyl](2-sulfoethyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid (Synthon IL)The title compound was prepared as described in Example 2.1, ing Example 1.2.9with Example 1.44.2. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.82 (s, 1H), 9.96 (s, 1H),8.03 (t, 2H), 7.77 (d, 2H), 7.39-7.62 (m, 7H), 7.30-7.39 (m, 2H), .29 (m, 3H), 6.98 (s, 2H),6.92-6.96 (m, 1H), 5.97 (s, 1H), 4.83-5.05 (m, 3H), 3.83-3.92 (m, 1H), 3.79 (s, 1H), 3.00 (s, 2H),2.03-2.22 (m, 8H), 1.94 (s, 2H), 1.34 (d, 30H), 0.69-0.90 (m, 13H). MS (ESI) m/e 1565.5 (M-H)’.2.43 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-carb0xypr0pyl)amin0}piperidinyl)carbonyl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon IM)A solution of Example 1.42.2 (0.045 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)ate (0.035 g) and N,N-diisopropylethylamine (0.038 mL) in N,N-dimethylformamide (0.5 mL)was stirred at room temperature. After stirring for 3 hours, the reaction was diluted with N,N-dimethylformamide (1.25 mL) and water (0.5 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-90% acetonitrile in water containing 0.1% V/V trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.76 (s, 1H), 9.91 (s, 1H), 8.79 (s, 1H), 7.98 (dd, 2H), 7.72(d, 2H), 7.68-7.47 (m, 3H), 7.47-7.00 (m, 7H), 6.96-6.83 (m, 3H), 5.93 (s, 1H), 4.91 (d, 3H), 4.30 (q,1H), 4.17-3.97 (m, 4H), 3.96-3.53 (m, 4H), 3.34-2.65 (m, 12H), 2.25 (t, 2H), 2.16-1.67 (m, 12H),1.67-0.88 (m, 26H), 0.84-0.70 (m, 12H). MS (ESI) m/e 1513.6 (M+H)+.

MEl 24985843V.1 576117813-126202.44 Synthesis of 4-[(1E)({[2-({3-[(4-{6-[8-(1,3-benzothiazolamoyl)(carboxymethoxy)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)pr0penyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid (Synthon 10)2.44.1 (E)-tert-butyldimethyl((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan—2-yl)allyl)0xy)silaneTo a flask charged with tert-butyldimethyl(propyn-l-yloxy)silane (5 g) anddichloromethane (14.7 mL) under nitrogen atmosphere was added se 4,4,5,5-tetramethyl-l,3,2-orolane (3.94 g). The mixture was stirred at room temperature for one minute then transferredvia cannula to a nitrogen-sparged flask containing CpZZrClH (chloridobis(n5-cyclopentadienyl)hydridozirconium, Schwartz’s Reagent) (379 mg). The ing reaction mixturewas stirred at room temperature for 16 hours. The mixture was carefully ed with water (15mL), and then extracted with diethyl ether (3x 30 mL). The combined organic phases were washedwith water (15 mL), dried over MgSO4, filtered, and purified by silica gel chromatography, elutingwith a gradient from 0-8% ethyl acetate/heptanes to give the title compound. MS (ESI) m/z 316.0(M+NH4)+.2.44.2 (2S,3R,4S,5S,6S)(4-br0m0nitr0phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl tate(2R,3R,4S,SS,6S)Bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyltriacetate (5 g) was dissolved in itrile (100 mL). AgZO (2.92 g) was added to the solution, andthe on was stirred for 5 minutes at room temperature. 4-Bromonitrophenol (2.74 g) wasadded, and the reaction mixture was stirred at room temperature for 4 hours. The silver salt residuewas filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure.

The residue was purified by silica gel tography, eluting with a nt of 10-70% ethylacetate in heptanes, to give the title compound. MS (ESI+) m/z 550.9 )+.2.44.3 (2S,3R,4S,5S,6S)(4-((E)((tert-butyldimethylsilyl)0xy)pr0p-1-enyl)nitr0phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateExample 2.44.2 (l g), sodium carbonate (0.595 g), tris(dibenzylideneacetone)dipalladium(Pd2(dba)3) (0.086 g), and l,3,5,7-tetramethylphenyl-2,4,8-trioxaphosphaadamantane (0.055 g)were combined in a 3-neck 50-mL round bottom flask equipped with a reflux condenser and thesystem was degassed with nitrogen. Separately, a solution of Example 2.44.1 (0.726 g) intetrahydrofuran (15 mL) was degassed with nitrogen for 30 minutes. The latter solution wastransferred via cannula into the flask containing the solid reagents, followed by addition of degassedMEl 24985843v.1 577117813-12620water (3 mL) via e. The reaction was heated to 60 CC for two hours. The reaction mixture waspartitioned between ethyl acetate (3x 30 mL) and water (30 mL). The ed organic phases weredried (NaZSO4), filtered, and concentrated. The residue was purified by silica gel chromatography,eluting with a gradient from 0-35% ethyl e in heptanes, to provide the title compound. MS(ESI+) m/z 643.1 (M+NH4)+.2.44.4 (2S,3R,4S,5S,6S)(2-amin0((E)hydr0xypr0penyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateA 500-mL three-neck, en-flushed flask equipped with a pressure-equalizing additionfunnel was charged with zinc dust (8.77 g). A degassed solution of Example 2.44.3 (8.39 g) inydrofuran (67 mL) was added via cannula. The ing suspension was chilled in an ice bath,and 6N HCl (22.3 mL) was added dropwise via the addition funnel at such a rate that the internaltemperature of the reaction did not exceed 35 CC. After the addition was complete, the reaction wasstirred for two hours at room temperature, and ed through a pad of diatomaceous earth, rinsingwith water and ethyl acetate. The filtrate was treated with saturated aqueous NaHCO3 solution untilthe water layer was no longer acidic, and the mixture was filtered to remove the resulting solids. Thefiltrate was transferred to a separatory funnel, and the layers were ted. The aqueous layer wasextracted with ethyl acetate (3x 75 mL), and the combined organic layers were washed with water(100 mL), dried over NaZSO4, filtered, and trated. The residue was ated with diethyl etherand the solid collected by filtration to provide the title compound. MS (ESI+) m/z 482.0 (M+H)+.2.44.5 (9H-flu0renyl)methyl (3-chlor00x0pr0pyl)carbamateTo a solution of 3-((((9H-fluorenyl)methoxy)carbonyl)amino)propanoic acid (5.0 g) indichloromethane (53.5 mL) was added sulfurous dichloride (0.703 mL). The mixture was stirred at60 CC for one hour. The mixture was cooled and trated to give the title compound, which wasused in the next step without further purification.2.44.6 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0renyl)meth0xy)carbonyl)amin0)propanamid0)((E)hydroxypropenyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 2.44.4 (6.78 g) was dissolved in dichloromethane (50 mL), and the solution wasd to 0 CC in an ice bath. N,N-Diisopropylethylamine (3.64 g) was added, followed by dropwiseaddition of a solution of Example 2.44.5 (4.88 g) in romethane (50 mL). The reaction wasstirred for 16 hours allowing the ice bath to come to room temperature. Saturated aqueous NaHCO3solution (100 mL) was added, and the layers were separated. The aqueous layer was further extractedwith dichloromethane (2 x 50 mL). The extracts were dried over NaZSO4, filtered, concentrated andpurified by silica gel chromatography, eluting with a gradient of 5-95% ethyl acetate/heptane, to givean inseparable mixture of starting aniline and desired product. The mixture was partitioned betweenMEl 24985843V.1 578117813-126201N aqueous HCl (40 mL) and a 1:1 mixture of l ether and ethyl acetate (40 mL), and then theaqueous phase was further ted with ethyl acetate (2x 25 mL). The organic phases werecombined, washed with water (2x 25 mL), dried over NaZSO4, ed, and concentrated to give thetitle compound. MS (ESI+) m/z 774.9 (M+H)+.2.44.7 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0ren-9—yl)meth0xy)carbonyl)amin0)propanamid0)((E)(((4-nitrophenoxy)carb0nyl)0xy)pr0p-l-enyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 2.44.6 (3.57 g) was dissolved in dichloromethane (45 mL) and bis(4-nitrophenyl)carbonate (2.80 g) was added, followed by dropwise addition of N,N-diisopropylethylamine (0.896 g). The reaction mixture was stirred at room temperature for two hours.

Silica gel (20 g) was added to the reaction solution, and the mixture was concentrated to drynessunder reduced pressure, keeping the bath temperature at or below 25 CC. The silica e wasloaded atop a column, and the t was purified by silica gel chromatography, eluting with agradient from 0-100% ethyl acetate-heptane, providing partially purified product which wascontaminated with nitrophenol. The material was triturated with methyl tert-butyl ether (250 mL),and the resulting slurry was allowed to sit for 1 hour. The product was collected by filtration. Threesuccessive crops were collected in a r fashion to give the title compound. MS (ESI+) m/z 939.8(M+H)+.2.44.8 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)phenyl)allyl)0xy)carb0nyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benz0[d]thiaz01ylcarbamoyl)(carboxymethoxy)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidTo a cold (0 CC) solution of Example 2.44.7 (19.7 mg) and Example 1.41.3 (18.5 mg) inmethylformamide (2 mL) was added N,N-diisopropylethylamine (0.054 mL). The reactionwas slowly warmed to room temperature and stirred overnight. To the reaction mixture was addedwater (2 mL) and lithium hydroxide monohydrate (50 mg), and the mixture was stirred overnight.

The mixture was acidified with trifluoroacetic acid and filtered. The mixture was purified by ephase HPLC (Gilson system), g with 10-85% acetonitrile in 0.1% trifluoroacetic acid in water,to provide the title nd. MS (ESI) m/e 1273.2 (M+H)+.2.44.9 4-[(1E)({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)(carboxymethoxy)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decMEl 24985843V.1 579117813-12620yl}0xy)ethyl](methyl)carbamoyl}0xy)pr0p-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-betaalanyl}amin0)phenyl beta-D-glucopyranosiduronic acidTo a solution of Example 2.44.8 (10 mg) and 2,5-dioxopyrrolidinyl 6-(2,5-dioxo-2,5-o-1H-pyrrolyl)hexanoate (2.3 mg) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (0.054 mL). The reaction was stirred overnight. The reaction e wasd with methanol (2 mL) and acidified with trifluoroacetic acid. The mixture was purified byreverse phase HPLC (Gilson system), eluting with 10-85% acetonitrile in 0.1% trifluoroacetic acid inwater, to give the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.70 (s, 1H)9.03 (s, 1H) , 8.25 (s, 1H) , 8.01 (d, 1H), 7.87 (t, 1H), 7.77 (d, 1H), 7.69 (d, 1H), .55 (m, 2H),7.23-7.38 (m, 2H), 6.79-7.16 (m, 7H) , 6.56 (d, 1H), 6.09-6.25 (m, 1H), 4.96-5.07 (m, 3H), 4.84 (s,3H), 4.64 (d, 3H), 3.87-3.97 (m, 5H), 3.24-3.47 (m, 12H), 2.77-2.95 (m, 6H), 1.94-2.08 (m, 6H), 0.92-1.56 (m, 20H), 0.74-0.86 (m, 6H). MS (ESI) m/e 1487.3 (M+Na)+.2.45 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-inamide on IP)The title compound was prepared by substituting Example 1.43.7 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.09 (s, 1H), 9.99 (s, 1H), 9.02(s, 1H), 8.30-8.40 (m, 3H), 7.93-8.25 (m, 6H), 7.23-7.86 (m, 10H), 6.92-7.05 (m, 2H) , 4.99 (d, 2H),4.36-4.44 (m, 2H), .23 (m, 2H), 2.87-3.35 (m, 12H) , 2.81 (t, 2H), 2.59-2.70 (m, 2H), 1.84-2.28(m, 8H), 0.97-1.77 (m, 20H), 0.77-0.88 (m,10H). MS (ESI) m/e 1448.3 (M+Na)+.2.46 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(2-{[8-(1,3-benzothiazolylcarbam0yl)(6-carb0xy{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinyl)-1,2,3,4-tetrahydroisoquinolin-S-yl]0xy}ethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide on IS)The title compound was prepared as bed in Example 2.1, replacing Example 1.2.9with Example 1.46.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.69 (s, 1H), 9.97 (s, 1H),8.97 (s, 1H), 8.04 (dd, 2H), 7.78 (d, 2H), 7.71 (d, 1H), 7.59 (d, 2H), 7.44-7.54 (m, 3H), 7.26-7.37 (m,4H), 6.96-7.03 (m, 4H), 5.97 (s, 1H), 4.99 (d, 4H), 4.31-4.45 (m, 1H), 4.18 (dd, 1H), 4.09 (s, 2H),3.85-3.93 (m, 2H), 3.83 (s, 2H), 3.39-3.47 (m, 2H), 3.24-3.39 (m, 4H), 3.12-3.24 (m, 2H), 2.75-3.07MEl 24985843v.1 580117813-12620(m, 9H), 2.06-2.23 (m, 5H), 1.90-2.01 (m, 1H), 1.54-1.75 (m, 2H), 1.24-1.52 (m, 12H), 0.91-1.24 (m,8H), 0.77-0.88 (m, 12H). MS (ESI) m/e 1525.4 (M+H)+.2.47 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(2-{[8-(1,3-benzothiazolylcarbam0yl)(6-carb0xy{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinyl)-1,2,3,4-tetrahydroisoquinolin-S-yl]0xy}ethyl)(2-sulf0ethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide (Synthon IU)The title compound was prepared as bed in Example 2.1, replacing Example 1.2.9with Example 1.47.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.70 (s, 1H), 9.99 (s, 1H),8.97 (s, 1H), 8.04 (dd, 2H), 7.78 (d, 2H), 7.71 (d, 1H), 7.59 (d, 2H), 7.43-7.55 (m, 2H), 7.28-7.37 (m,4H), 6.94-7.07 (m, 4H), 6.05 (s, 1H), 4.93-5.11 (m, 4H), 4.31-4.46 (m, 2H), 4.12-4.26 (m, 4H), 3.80-3.95 (m, 4H), 3.40-3.50 (m, 2H), 3.24-3.40 (m, 6H), .24 (m, 2H), 2.74-3.08 (m, 9H), 2.63-2.73(m, 2H), 2.05-2.23 (m, 5H), 1.96 (s, 1H), 1.52-1.77 (m, 2H), 1.23-1.53 (m, 12H), 0.97-1.22 (m, 8H),0.77-0.89 (m, 12H). MS (ESI) m/e 1631.5 (M-H)’.2.48 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(2-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)amin0}ethyl)(2-sulf0ethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide on IV)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.48.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.82 (s, 1H), 10.00 (s, 1H),9.29-9.57 (m, 1H), 8.05 (t, 2H), 7.79 (d, 2H), 7.51-7.63 (m, 4H), 7.40-7.50 (m, 2H), 7.27-7.39 (m,5H), 6.93-7.02 (m, 3H), 4.99 (d, 3H), 4.30-4.47 (m, 1H), 4.19 (t, 1H), 3.79-3.92 (m, 3H), 3.60-3.74(m, 2H), 3.01 (s, 9H), 2.70 (d, 4H), .23 (m, 6H), 1.96 (d, 2H), 1.53-1.78 (m, 3H), .54 (m,13H), 0.89-1.22 (m, 9H), 0.75-0.89 (m, 13H). MS (ESI) m/e 1603.3 (M+H)+.2.49 Synthesis of N-{6-[(chloroacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quin01in-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-inamide (Synthon IZ)2.49.1 3-(1-(((1r,3r)(2-((((4-((S)((S)amin0methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-MEI 24985843V.1 5 81117813-12620sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidA solution of Example 1.2.9 (0.045 g) (9H-fluorenyl)methyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)oxoureidopentanyl)amino)oxobutanyl)carbamate (0.043 g) and N,N-diisopropylethylamine (0.041 mL) were stirred togetherin methylformamide (1 mL) at room temperature. After ng overnight, diethylamine(0.024 mL) was added to the reaction, and ng was ued for 2 hours. The reaction wasquenched with trifluoroacetic acid then purified by reverse phase HPLC using a Gilson ,eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desiredfractions were combined and freeze-dried to provide the title compound.2.49.2 N-{6-[(chloroacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideA solution of 6-(2-chloroacetamido)hexanoic acid (6.43 mg) and 2-(3H-[1,2,3]triazolo[4,5-b]pyridinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.012 g)in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.019 mL), and thereaction stirred for 5 minutes. This solution was added to Example 2.49.1 (0.026 g) and was stirredfor 1 hour. The reaction was diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). Themixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-60% acetonitrilein water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the title compound. 1H NMR (500 MHZ, dimethyl ide-d6) 5 ppm 12.85 (s, 1H),9.99 (s, 1H), 8.18 (q, 1H), 8.08 (d, 1H), 8.04 (d, 1H), 7.84-7.76 (m, 2H), 7.64-7.56 (m, 3H), 7.56-7.50(m, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.37 (d, 1H), 7.35 (d, 1H), 7.29 (s, 1H), 7.27 (d, 2H), 6.95 (d, 1H),6.05 (s, 1H), 5.05-4.91 (m, 4H), 4.48-4.33 (m, 1H), 4.26-4.14 (m, 1H), 4.02 (s, 2H), 3.88 (t, 2H), 3.81(d, 2H), 3.25 (t, 2H), 3.14-2.98 (m, 6H), .87 (m, 2H), 2.74-2.59 (m, 2H), 2.27-2.05 (m, 6H),2.04-1.92 (m, 1H), 1.78-1.65 (m, 1H), 1.65-1.53 (m, 1H), 1.53-0.90 (m, 22H), 0.90-0.73 (m, 12H).

MS (ESI) m/e 1448.2 (M+H)+.2.50 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[4-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0-2H-1,4-benzoxazinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon JD)MEl 24985843V.1 582117813-12620The title compound was prepared by substituting e 1.51.8 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, yl sulfoxide-dé) 5 ppm 9.56 (s, 1H), 8.51-8.59 (m, 1H),7.89 (d, 1H), 7.82 (d, 1H), 7.69-7.77 (m, 2H), 7.34-7.62 (m, 7H) , 7.16-7.34 (m, 4H), 6.95 (dd, 1H),.95-6.05 (m, 1H), 4.95 (s, 2H) , 4.06-4.44 (m, 6H), 3.85 (s, 3H), 3.39-3.59 (m, 7H), 2.61-2.74 (m,3H), 2.19 (s, 3H), 1.88-2.16 (m, 3H), 0.96-1.75 (m, 22H), 0.71-0.89 (m, 13H). MS (ESI) m/e 1454.2(M+Na)+.2.51 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(2-{[8-(1,3-benzothiazolylcarbam0yl)(6-carb0xy{1-dimethyl{2-[methyl(2-sulfoethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinyl)-1,2,3,4-tetrahydroisoquinolin-S-yl]0xy}ethyl)(2-carb0xyethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon JF)The title compound was ed as described in Example 2.1, replacing Example 1.2.9with Example 1.49.2. 1H NMR (500 MHz, yl sulfoxide-dé) 5 ppm 12.71 (s, 1H), 10.00 (s, 1H),8.97 (s, 1H), 8.08 (d, 1H), 8.02 (d, 1H), 7.78 (d, 2H), 7.72 (d, 1H), 7.60 (d, 2H), 7.52 (d, 1H), 7.44-7.50 (m, 1H), 7.27-7.39 (m, 4H), 6.96-7.06 (m, 3H), 5.98 (s, 1H), 5.01 (d, 4H), 4.31-4.46 (m, 1H),4.18 (s, 3H), 3.79-3.95 (m, 4H), 3.67-3.76 (m, 2H), 3.12-3.39 (m, 6H), 2.73-3.07 (m, 8H), 2.04-2.24(m, 4H), 1.87-2.02 (m, 1H), 1.22-1.75 (m, 12H), 0.96-1.20 (m, 7H), 0.76-0.90 (m, 10H). MS (ESI)m/e 1597.4 (M+H)+.2.52 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)(3-sulfopropoxy)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}--methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon JK)The title compound was prepared by substituting Example 1.52.4 for Example 2.5.3 inExample 2.5.4. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.97 (s, 1H), 7.96-8.11 (m, 2H),7.67-7.82 (m, 3H), 7.59 (d, 2H), 7.42-7.52 (m, 2H), 7.23-7.36 (m, 4H), 6.91-7.08 (m, 4H), 4.99 (d,4H), 4.33-4.47 (m, 1H), 4.14-4.23 (m, 4H), 3.86-3.95 (m, 6H), 3.21-3.45 (m, 15H), 2.75-3.07 (m,9H), 2.56-2.69 (m, 2H), 1.93-2.20 (m, 8H), .72 (m, 20H), 0.74-0.89 (m, 11H). MS (ESI) m/e1496.3 (M+Na)+.2.53 sis of N-[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-MEl 24985843V.1 583117813-12620sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon JJ)A solution of Example 2.49.1 (0.030 g), 2,5-dioxopyrrolidin-l-yl 3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoate (6.34 mg) and N,N-diisopropylethylamine (0.012 mL) in N,N-dimethylformamide (0.5 mL) was d at room temperature. After 1 hour the reaction wasquenched with a 3:1 mixture of N,N-dimethylformamide:water (1.5 mL). The mixture was purifiedby reverse phase HPLC using a Gilson , eluting with 10-85% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired ons were combined and freeze-dried to provide thetitle compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 9.99 (s, 1H), 8.18(q, 1H), 8.12-8.00 (m, 2H), .75 (m, 2H), 7.65-7.55 (m, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d,1H), 7.36 (q, 2H), 7.33-7.23 (m, 3H), 6.95 (d, 1H), 6.05 (s, 1H), 5.03-4.92 (m, 4H), 4.39 (q, 1H),.14 (m, 1H), 4.02 (s, 2H), 3.88 (t, 2H), 3.81 (d, 2H), 3.39-3.16 (m, 2H), 3.14-2.86 (m, 10H),2.68-2.60 (m, 2H), 2.25-2.04 (m, 6H), 2.03-1.90 (m, 1H), 1.78-1.65 (m, 1H), 1.64-1.54 (m, 1H), 1.54-0.90 (m, 20H), 0.89-0.75 (m, 12H). MS (ESI) m/e 1410.1 (M+H)+.2.54 Synthesis of N-[(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetyl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-inamide (Synthon JL)A solution of Example 2.49.1 (0.039 g), 2,5-dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (7.81 mg) and N,N-diisopropylethylamine (0.016 mL) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature. After 1 hour, the reaction wasquenched with a 3:1 e of N,N-dimethylformamide:water (1.5 mL). The mixture was purifiedby reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried to e thetitle compound. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 12.85 (s, 1H), 10.00 (d, 1H), 8.24(d, 2H), 8.04 (d, 1H), 7.79 (d, 1H), 7.59 (q, 3H), 7.53 (dd, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.36 (td,2H), 7.30 (s, 1H), 7.27 (d, 2H), 7.07 (s, 2H), 6.96 (d, 1H), 5.04-4.85 (m, 4H), 4.39 (q, 2H), 4.26 (dd,2H), 4.13 (s, 2H), 3.86-3.17 (m, 8H), 3.07-2.81 (m, 4H), 2.63 (t, 2H), 2.09 (s, 3H), 2.03-1.79 (m, 1H),.51 (m, 2H), 1.51-1.03 (m, 12H), 1.01-0.76 (m, 16H). MS (ESI) m/e 1394.4 (M-H)’.2.55 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[(2S)({[(4-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]0xy}[(3-{[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexanoyl]amin0}pr0pan0yl)amin0]benzyl)0xy]carbonyl}amin0)sulfopropanoyl](methyl)amin0}eth0xy)-5,7-MEI 24985843V.1 5 84117813-12620dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolidinecarb0xylic acid (Synthon FE)2.55.1 (2S,3R,4S,5S,6S)(4-f0rmylnitr0phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of (2R,3R,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H- pyran-3,4,5-triyl triacetate (4 g) in acetonitrile (100 mL)) was added silver(I) oxide (10.04 g) and 4-hydroxy-3-nitrobenzaldehyde (1.683 g). The reaction mixture was stirred for 4 hours at room ature andfiltered. The filtrate was concentrated, and the residue was purified by silica gel chromatography,eluting with 5-50% ethyl e in heptanes, to provide the title compound. MS (ESI) m/e (M+l8)+.2.55.2 (2S,3R,4S,5S,6S)(4-(hydroxymethyl)nitr0phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of Example 2.55.1 (6 g) in a mixture of chloroform (75 mL) and isopropanol(18.75 mL) was added 0.87 g of silica gel. The ing mixture was cooled to 0 CC, NaBH4 (0.470g) was added, and the resulting suspension was stirred at 0 CC for 45 minutes. The reaction mixturewas diluted with dichloromethane (100 mL) and filtered through diatomaceous earth. The filtrate waswashed with water and brine and trated to give the crude t, which was used withoutfurther purification. MS (ESI) m/e (M+NH4)+:2.55.3 (2S,3R,4S,5S,6S)(2-amino(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateA stirred solution of Example 2.55.2 (7 g) in ethyl e (81 mL) was hydrogenated at 20CC under 1 atmosphere H2, using 10% Pd/C (1.535 g) as a catalyst for 12 hours. The reaction mixturewas filtered through diatomaceous earth, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel tography, eluting with 95/5 dichloromethane/methanol, togive the title compound.2.55.4 9H-flu0renyl)meth0xy)carbonyl)amin0)pr0pan0ic acidopropanoic acid (4.99 g) was dissolved in 10% aqueous NazCO3 solution (120 mL)in a 500 mL flask and cooled with an ice bath. To the resulting solution, (9H-fluorenyl)methylcarbonochloridate (14.5 g) in 1,4-dioxane (100 mL) was gradually added. The reaction mixture wasstirred at room temperature for 4 hours, and water (800 mL) was then added. The aqueous phaselayer was separated from the reaction mixture and washed with diethyl ether (3 x 750 mL). Theaqueous layer was acidified with 2N HCl aqueous solution to a pH value of 2 and extracted with ethylacetate (3 x 750 mL). The organic layers were combined and concentrated to obtain crude product.

The crude product was recrystallized in a mixed solvent of ethyl acetate: hexane 1:2 (300 mL) to givethe title compound.

MEl 24985843V.1 585117813-126202.55.5 (9H-flu0renyl)methyl (3-chloro0x0pr0pyl)carbamateTo a solution of Example 2.55.4 in dichloromethane (160 mL) was added sulfurousdichloride (50 mL). The mixture was stirred at 60 CC for 1 hour. The mixture was cooled andtrated to give the title compound.2.55.6 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0renh0xy)carbonyl)amin0)propanamid0)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl tateTo a solution of Example 2.55.3 (6 g) in dichloromethane (480 mL) was added N,N-diisopropylethylamine (4.60 mL). Example 2.55.5 (5.34 g) was added, and the mixture was stirred atroom temperature for 30 minutes. The mixture was poured into saturated aqueous sodium bicarbonateand was extracted with ethyl acetate. The combined extracts were washed with water and brine andwere dried over sodium sulfate. Filtration and concentration gave a residue that was purified viaradial chromatography, using 0-100% ethyl e in petroleum ether as mobile phase, to give thetitle compound.2.55.7 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0renyl)meth0xy)carbonyl)amin0)propanamid0)((((4—henoxy)carb0nyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a mixture of Example 2.55.6 (5.1 g) in N,N-dimethylformamide (200 mL) was addedbis(4-nitrophenyl) carbonate (4.14 g) and N,N-diisopropylethylamine (1.784 mL). The mixture wasstirred for 16 hours at room temperature and concentrated under reduced pressure. The crude materialwas dissolved in dichloromethane and aspirated directly onto a 1 mm radial Chromatotron plate andeluted with % ethyl acetate in hexanes to give the title compound. MS (ESI) m/e (M+H)+.2.55.8 (3-(2-((R)((((3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)amin0)-N-methylsulfopropanamid0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidA solution of Example 1.13.7 (0.055 g) and Example 2.55.7 (0.055 g) were stirred togetherin N,N-dimethylformamide (1.5 mL) and N,N-diisopropylethylamine (0.053 mL) was added. Afterstirring for 3 hours, the reaction was diluted with ethyl acetate (75 mL) and washed with water (20mL) and brine (25 mL), dried over magnesium sulfate, filtered, and trated. The residue wasved in methanol (1 mL) and treated with lithium hydroxide hydrate (0.025 g) in water (0.6 mL).

After stirring for 2 hours, the reaction was quenched with roacetic acid (0.047 ml) and dilutedwith N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using aMEl 24985843V.1 586117813-12620Gilson system, eluting with 10-80% acetonitrile in water ning 0.1% v/v trifluoroacetic acid.

The desired fractions were ed and -dried to provide the title compound as atrifluoroacetic acid salt.2.55.9 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl](1-{[3-(2—{[(2S)({[(4-{[(2S,3R,4S,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-2H-pyranyl]0xy}[(3-{[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}pr0pan0yl)amin0]benzyl)0xy]carbonyl}amin0)sulf0pr0pan0yl](methyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.l.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acidA solution of Example 2.55.8 (0.013 g) and 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoate (3.07 mg) were stirred in N,N-dimethylformamide (1 mL) andN,N-diisopropylethylamine (7.90 uL) was added. The reaction was stirred for 1 hour and diluted withN,N-dimethylformamide and water. The mixture was purified by reverse phase HPLC using a Gilsonsystem, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. Thedesired fractions were combined and freeze-dried to provide the title compound. 1H NMR (400 MHZ,dimethyl sulfoxide-d6) 8 ppm 12.84 (s, 1H), 9.07 (s, 1H), 8.15 (s, 1H), 8.04 (d, 1H), 7.89 (t, 1H), 7.79(d, 1H), 7.61 (d, 1H), 7.56-7.50 (m, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.39-7.32 (m, 2H), 7.31 (s, 1H),7.28 (d, 1H), 7.06 (d, 1H), 7.04-6.92 (m, 4H), 5.00-4.79 (m, 5H), 4.73-4.64 (m, 1H), 3.94-3.78 (m,4H), 3.57-2.84 (m, 12H), 2.84-2.56 (m, 6H), 2.14-1.73 (m, 5H), 1.57-0.89 (m, 22H), 0.84 (s, 6H). MS(ESI) m/e 1516.2 .2.56 sis of 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl}-5-methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenylbeta-D-glucopyranosiduronic acid (Synthon GG)2.56.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)oxy)phenyl)allyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(thiazolo[5,4-b]pyridinylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidExample 1.22.5 (48 mg) was dissolved in dimethylformamide (0.5 mL), and Example2.44.7 (55 mg) and N,N-diisopropylethylamine (90 uL) were added. The on mixture was stirredat room ature overnight. The on was concentrated, and the residue was dissolved inMEl 24985843v.1 587117813-12620methanol (1 mL) and 1.94N aqueous LiOH (0.27 mL) was added. The mixture was stirred at roomtemperature for one hour. Purification of the mixture by e phase tography (C18column), eluting with 10-90% acetonitrile in water containing 0.1% V/V trifluoroacetic acid, providedthe title compound as a trifluoroacetic acid salt. MS (ESI-) m/e 1291.4 .2.56.2 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)prop-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-betaalanyl}amin0)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by tuting Example 1.56.1 for Example 1.2.9 inExample 2.1. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.00 (V br s, 1H), 9.03 (s, 1H), 8.53(dd, 1H), 8.24 (s, 1H), 8.16 (dd, 1H), 7.90 (br s, 1H), 7.61 (d, 1H), 7.54 (d, 1H) 7.52 (d, 1H), 7.44 (d,1H), 7.37 (t, 1H), 7.30 (s, 1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.58 (m, 1H),6.15 (m,1H), 4.96 (s, 2H), 4.88 (br m, 1 H), 4.64 (br m, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.48(m, 14H), 3.01 (m, 2H), 2.67 (br m, 2H), 2.54 (m, 2H), 2.09 (s, 3H), 2.03 (t, 2H), 1.45 (m, 6H), 1.37(br m, 2H), 1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1484.4 (M-H)’.2.57 Synthesis of 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl}--methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenylbeta-D-glucopyranosiduronic acid (Synthon GM)2.57.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)phenyl)allyl)0xy)carbonyl)(2-sulf0ethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8—(thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting Example 1.23.4 for Example 1.22.5 inExample . MS (ESI) m/e 1291.4 (M-H)’.2.57.2 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]pyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)prop-l-enyl]({N-[6-(2,5-di0x0-MEl 24985843V.1 588117813-126202,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl -glucopyranosiduronic acidThe title compound was prepared by substituting Example 1.57.1 for Example 1.2.9 inExample 2.1. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 9.03 (s, 1H), 8.72 (d, 1H), 8.66 (d,1H), 8.25 (s, 1H), 7.89 (br m, 1H), 7.65 (d, 1H), 7.52 (br m, 2H), 7.46 (d, 1H), 7.39 (t, 1H), 7.30 (s,1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.58 (m, 1H), 6.15 (m,1H), 4.96 (s, 2H),4.88 (br m, 1 H), 4.64 (br m, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.48 (m, 14H), 3.01 (m, 2H),2.67 (br m, 2H), 2.54 (m, 2H), 2.09 (s, 3H), 2.03 (t, 2H), 1.45 (m, 6H), 1.37 (br m, 2H), 1.28-0.90 (m,10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1484.4 (M-H)’.2.58 Synthesis of 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenylbeta-D-glucopyranosiduronic acid (Synthon HD)2.58.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)phenyl)allyl)0xy)carbonyl)(2-sulf0ethyl)amin0)eth0xy)-5,7—dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8—(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl)picolinic acidThe title compound was ed by substituting Example 1.2.9 for Example 1.22.5 inExample 2.56.1. MS (ESI-) m/e 1290.2 (M-H)’.2.58.2 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benz0thiazolylcarbamoyl)-hydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)prop-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl -glucopyranosiduronic acidThe title compound was ed by substituting Example 1.58.1 for Example 1.56.1 inExample 2.56.2. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.03 (s, 1H), 8.25 (s, 1H), 8.03(d, 1H), 7.89 (br m, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53 (br m, 1H), 7.46 (m, 2H), 7.37 (m, 2H), 7.32(s, 1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.58 (m, 1H), 6.15 , 4.96 (s,2H), 4.88 (br m, 1 H), 4.64 (br m, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.48 (m, 14H), 3.01 (m,2H), 2.67 (br m, 2H), 2.54 (m, 2H), 2.09 (s, 3H), 2.03 (t, 2H), 1.45 (m, 6H), 1.37 (br m, 2H), 1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI-) m/e 1483.3 (M-H)’.

MEl 24985843V.1 589117813-126202.59 Synthesis of 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}--methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid on HS)2.59.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-2-yl)oxy)phenyl)allyl)0xy)carb0nyl)(3-phosphonopropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting Example 1.40.2 for e 1.22.5 inExample 2.56.1. MS (ESI-) m/e 1305.4 (M-H)’.2.59.2 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[5,4-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by substituting Example 1.59.1 for Example 1.56.1 inExample 2.56.2. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 9.03 (s, 1H), 8.53 (dd, 1H), 8.24(s, 1H), 8.16 (dd, 1H), 7.90 (br s, 1H), 7.61 (d, 1H), 7.54 (d, 1H) 7.52 (d, 1H), 7.44 (d, 1H), 7.37 (t,1H), 7.28 (s, 1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.56 (m, 1H), 6.16 (m,1H),4.96 (s, 2H), 4.86 (br m, 1 H), 4.64 (br d, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.44 (m, 14H),3.01 (m, 2H), 2.54 (m, 2H), 2.08 (s, 3H), 2.03 (t, 2H), 1.46 (m, 6H), 1.37 (br m, 2H), 1.28-0.90 (m,10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1498.4 (M-H)’.2.60 Synthesis of 4-[(1E)({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)(3-ph0sph0n0pr0p0xy)-3,4-dihydr0is0quinolin-2(1H)-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)pr0penyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl -yranosiduronic acid (Synthon HW)MEl 24985843V.1 590117813-126202.60.1 3-(1-(((3-(2-(((((E)(3-(3-amin0pr0panamid0)3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyran)phenyl)allyl)0xy)carb0nyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8—(benz0[d]thiazolylcarbamoyl)(3-ph0sph0n0pr0p0xy)-3,4-dihydroisoquinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting Example 1.31.11 for Example 1.22.5 inExample 2.56.1. MS (ESI) m/e 1336.2 (M+Na)+.2.60.2 4-[(1E)({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)sphonopropoxy)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-yltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbamoyl}0xy)pr0p-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl -glucopyranosiduronic acidThe title compound was prepared by substituting Example 1.60.1 for Example 1.56.1 inExample 2.56.2. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 9.03 (s, 1H) 8.25 (s, 1H), 8.01 (d,1H), 7.83-7.91 (m, 1H), 7.75 (dd, 2H), 7.42-7.58 (m, 2H), 7.34 (t, 1H), 7.28 (s, 1H), 6.93-7.15 (m,6H), 6.56 (d, 1H), 6.09-6.24 (m, 1H), 5.01 (s, 3H), 4.80-4.92 (m, 2H), 4.57-4.69 (m, 3H), 4.12-4.21(m, 6H), 3.86-3.94 (m, 7H), 3.28-3.47 (m, 12H), 2.77-2.96 (m, 6H), 2.52-2.58 (m, 2H), 2.09 (s, 3H),1.90-2.05 (m, 4H) , 1.65-1.78 (m, 2H), 0.90-1.53 (m, 16H), 0.80 (m, 6H). MS (ESI) m/e 1529.5(M+H)+.2.61 Synthesis of 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)hexan0yl]-betaalanyl}amin0)phenyl beta-D-glucopyranosiduronic acid (Synthon HX)2.61.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)oxy)phenyl)allyl)0xy)carb0nyl)(3-phosphonopropyl)amin0)eth0xy)-5,7-dimethyladamantanhyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting Example 1.14.4 for Example 1.22.5 inExample 2.56.1. MS (ESI) m/e 1304.3 .

MEl 24985843V.1 591117813-126202.61.2 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbam0y1)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)carbamoyl}0xy)prop-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by substituting Example 1.61.1 for Example 1.56.1 ine 2.56.2. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 9.03 (s, 1H), 8.25 (br s, 1H), 8.03(d, 1H), 7.89 (br m, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53 (br m, 1H), 7.46 (m, 2H), 7.37 (m, 2H), 7.28(s, 1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.56 (m, 1H), 6.17 (m,1H), 4.96 (s,2H), 4.86 (br m, 1 H), 4.64 (br d, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.44 (m, 14H), 3.01 (m,2H), 2.54 (m, 2H), 2.08 (s, 3H), 2.03 (t, 2H), 1.46 (m, 6H), 1.37 (br m, 2H), 1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI-) m/e 1497.4 (M-H)’.2.62 Synthesis of 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}eth0xy)ethoxy]phenyl beta-D-glucopyranosiduronic acid (Synthon HY)2.62.1 ,4S,5S,6S)(4-f0rmylhydr0xyphen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl tate2,4-Dihydroxybenzaldehyde (15 g) and (2S,3R,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (10 g) were dissolved in acetonitrilefollowed by the addition of silver carbonate (10 g) and the reaction was heated to 49°C. After ngfor 4 hours, the reaction was , filtered and concentrated. The crude title compound wassuspended in dichloromethane and was filtered through aceous earth and concentrated. Theresidue was purified by silica gel chromatography eluting with 1-100% ethyl acetate/heptane toprovide the title compound.2.62.2 (2S,3R,4S,5S,6S)(3-hydroxy(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateA solution of e 2.62.1 (16.12 g) in tetrahydrofuran (200 mL) and methanol (200mL) was cooled to 0°C and sodium borohydride (1.476 g) was added portionwise. The reaction wasstirred for 20 minutes and was quenched with a 1:1 mixture of water:aqueous saturated sodiumbicarbonate solution (400 mL). The ing solids were filtered off and rinsed with ethyl acetate.

The phases were separated and the aqueous layer was extracted four times with ethyl acetate. Thecombined organic layers were dried over magnesium sulfate, filtered, and concentrated. The crudeMEl 24985843V.1 592117813-12620title compound was purified via silica gel chromatography eluting with 1-100% ethyl acetate/heptanesto provide the title compound. MS (ESI) m/e 473.9 )+.2.62.3 (2S,3R,4S,5S,6S)(4-(((tert-butyldimethylsilyl)0xy)methyl)hydroxyphenoxy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 2.62.2 (7.66 g) and tert—butyldimethylsilyl de (2.78 g) in dichloromethane(168 mL) at-5 C’C was added imidazole (2.63 g) and the reaction was d overnight allowing theinternal temperature of the reaction to warm to 12°C. The reaction mixture was poured into saturatedaqueous um chloride and extracted four times with dichloromethane. The combined organicswere washed with brine, dried over magnesium sulfate, filtered and concentrated. The crude titlecompound was purified via silica gel chromatography eluting with 1-50% ethyl acetate/heptanes toprovide the title compound. MS (ESI) m/e 593.0 (M+Na)+.2.62.4 (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-flu0renyl)methoxy)carbonyl)amin0)ethoxy)ethoxy)(((tert-imethylsilyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl tateTo Example 2.62.3 (5.03 g) and triphenylphosphine (4.62 g) in toluene (88 mL) was addeddi-tert—butyl-azodicarboxylate (4.06 g) and the reaction was stirred for 30 minutes. (9H-Fluorenyl)methyl (2-(2-hydroxyethoxy)ethyl)carbamate was added and the reaction was stirred for anaddition 1.5 hours. The reaction was loaded ly onto silica gel and was eluted with 1-50% ethylacetate/heptanes to provide the title compound.2.62.5 (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-flu0renyl)methoxy)carbonyl)amin0)ethoxy)eth0xy)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateExample 2.62.4 (4.29 g) was stirred in a 3:121 on of acetic acid:water:tetrahydrofuran(100 mL) overnight. The reaction was poured into saturated aqueous sodium bicarbonate andextracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered andconcentrated. The crude title compound was purified via silica gel chromatography, eluting with 1-50% ethyl acetate/heptanes to provide the title compound.2.62.6 (2S,3R,4S,5S,6S)(3-(2-(2-((((9H-flu0renyl)methoxy)carbonyl)amin0)ethoxy)eth0xy)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl tateTo a solution of Example 2.62.5 (0.595 g) and bis(4-nitrophenyl) carbonate (0.492 g) inN,N-dimethylformamide (4 mL) was added l-N-isopropylpropanamine (0.212 mL). After1.5 hours, the reaction was concentrated under high . The reaction was loaded directly ontoMEl 24985843V.1 593117813-12620silica gel and eluted using 1-50% ethyl acetate/heptanes to provide the title nd. MS (ESI) m/e922.9 (M+Na)+.2.62.7 3-(1-((3-(2-((((2—(2-(2-aminoethoxy)eth0xy)-4—(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidTo a solution of Example 1.2.9 (0.073 g) and Example 2.62.6 (0.077 g) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.066 mL), and the reaction wasstirred overnight. The reaction was concentrated, and the residue was ved in tetrahydrofuran(0.5 mL) and methanol (0.5 mL) and treated with lithium hydroxide monohydrate (0.047 g) as asolution in water (0.5 mL). After 1 hour, the reaction was diluted with N,N-dimethylformamide andwater and was quenched by the addition of trifluoroacetic acid (0.116 mL). The mixture was purifiedby reverse phase HPLC using a Gilson , eluting with 10-75% acetonitrile in water ning0.1% v/v trifluoroacetic acid. The d fractions were combined and freeze-dried to provide thetitle compound.2.62.8 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl][2—(2-{[3-i0x0-2,5-dihydr0-lH-pyrrolyl)pr0pan0yl]amin0}eth0xy)ethoxy]phenyl beta-D-glucopyranosiduronic acidA solution of Example 2.62.7 (0.053 g), 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (0.012 g) and N,N-diisopropylethylamine (0.033 mL) in N,N-dimethylformamide (0.75 mL) was stirred at room temperature. After stirring for 1 hour, the reactionwas diluted with N,N-dimethylformamide and water. The mixture was purified by reverse phaseHPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The d fractions were combined and freeze-dried to provide the titlecompound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 8.04 (d, 2H), 7.79 (d,1H), 7.61 (d, 1H), 7.54 (d, 1H), 7.51-7.40 (m, 2H), 7.40-7.31 (m, 3H), 7.20 (d, 1H), 7.00-6.94 (m,3H), 6.73-6.57 (m, 2H), 5.06 (t, 1H), 5.01-4.91 (m, 4H), 3.96-3.85 (m, 2H), 3.85-3.78 (m, 2H), 3.78-3.69 (m, 2H), 3.59 (t, 2H), 3.53-3.34 (m, 6H), 3.34-3.21 (m, 4H), 3.17 (q, 2H), 3.02 (t, 2H), 2.66 (t,2H), 2.33 (t, 2H), 2.10 (s, 3H), 1.44-0.90 (m, 16H), 0.83 (d, 6H). MS (-ESI) m/e 1432.4 (M-H)’.

MEl 24985843V.1 594117813-126202.63 Synthesis of 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}--methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid (Synthon IB)2.63.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)oxy)phenyl)allyl)0xy)carb0nyl)(3-phosphonopropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting e 1.39.2 for Example 1.22.5 inExample 2.56.1.2.63.2 4-[(1E)({[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)carbamoyl}0xy)propenyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by substituting Example 2.63.1 for e 1.56.1 inExample 2.56.2. 1H NMR (400 MHZ, yl ide-dé) 5 ppm 9.03 (s, 1H), 8.61 (d, 1H), 8.55(d, 1H), 8.25 (br s, 1H), 7.89 (br m, 1H), 7.65 (d, 1H), 7.50 (br d, 1H), 7.46 (d, 1H), 7.39 (m, 2H),7.28 (s, 1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.56 (m, 1H), 6.17 (m,1H), 4.97(s, 2H), 4.86 (br m, 1 H), 4.64 (br d, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.27-3.44 (m, 14H), 3.01 (m,2H), 2.54 (m, 2H), 2.08 (s, 3H), 2.03 (t, 2H), 1.46 (m, 6H), 1.37 (br m, 2H), 1.28-0.90 (m, 10H), 0.77-0.82 (m, 6H). MS (ESI) m/e 1498.3 (M-H)’.2.64 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl)({[(2E)(4-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]0xy}[(3-{[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}pr0pan0yl)amin0]phenyl)pr0penyl]0xy}carb0nyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid(Synthon IE)MEl 24985843V.1 595117813-126202.64.1 3-(1-((3-(2-(((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)oxy)phenyl)allyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acid,oroacetic acid saltTo a solution of Example 1.25.2 (0.050 g) and Example 2.44.7 (0.061 g) in N,N-ylformamide (1 mL) was added N,N-diisopropylethylamine (0.047 mL), and the reaction wasstirred at room temperature overnight. The reaction was concentrated, and the residue was dissolvedin methanol (0.5 mL) and tetrahydrofuran (0.5 mL) and treated with a on of lithium hydroxidehydrate (0.034 g) in water (0.5 mL). The reaction was stirred at room temperature for 1 hour. Thereaction was quenched with trifluoroacetic acid (0.083 mL) and d with N,N-dimethylformamide(1 mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions werecombined and -dried to provide the title compound2.64.2 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl)({[(2E)(4-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl]0xy}[(3-{[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01an0yl]amin0}pr0pan0yl)amin0]phenyl)pr0penyl]0xy}carb0nyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidTo a solution of Example 2.64.1 (0.042 g) and 2,5-dioxopyrrolidinyl 6-(2,5-dioxo-2,5-dihydro-lH-pyrrolyl)hexanoate (10 mg) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.027 mL), and the reaction was stirred at room temperature for 2 hours. Thereaction was diluted with N,N-dimethylformamide (1 mL) and water (0.5 mL). The mixture waspurified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-dried toprovide the title nd. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 9.04 (s,1H), 8.25 (s, 1H), 8.03 (d, 1H), 7.87 (t, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.54-7.40 (m, 3H), 7.40-7.31(m, 2H), 7.28 (s, 1H), 7.10 (d, 1H), 7.04 (d, 1H), 6.98 (s, 2H), 6.95 (d, 1H), 6.57 (d, 1H), 6.24-6.11(m, 1H), 4.96 (s, 2H), 4.86 (t, 1H), 4.65 (d, 2H), 3.95-3.84 (m, 2H), 3.84-3.75 (m, 4H), 3.44-3.24 (m,10H), 3.01 (t, 2H), 2.62-2.52 (m, 4H), 2.09 (s, 3H), 2.03 (t, 2H), 1.46 (h, 4H), 1.40-1.31 (m, 2H),1.30-0.88 (m, 14H), .75 (m, 6H). MS (ESI) m/e 1447.5 (M-H)’.

MEl 24985843V.1 596-126202.65 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl){[(4-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]0xy}[2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}eth0xy)eth0xy]benzyl)0xy]carbonyl}amin0]eth0xy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolidine-2—carb0xylic acid (Synthon 11)2.65.1 (3-(2-((((2—(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidA solution of Example 1.25.2 (0.055 g,), Example 2.62.6 (0.060 g) and N,N-diisopropylethylamine (0.052 mL) in N,N-dimethylformamide (0.4 mL) as d ght. Thereaction was concentrated, and the residue was dissolved in tetrahydrofuan (0.5 mL), methanol (0.5mL) then treated with lithium hydroxide hydrate (0.037 g) as a solution in water (0.5 mL). Afterstirring for 1 hour, the reaction was ed with trifluoroacetic acid (0.091 mL) and d withN,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using a Gilsonsystem, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. Thedesired fractions were combined and freeze-dried to provide the title compound as the trifluoroaceticacid salt.2.65.2 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl){[(4-{[(2S,3R,4S,5S,6S)-6-carb0xy-3,4,5-trihydroxytetrahydro-2H-pyranyl]0xy}[2-(2-{[3-(2,5-di0x0-2,5-dihydr0-lH-pyrrol-lyl)pr0pan0yl]amin0}eth0xy)eth0xy]benzyl)0xy]carbonyl}amin0y}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidA on of the trifluoroacetic acid salt of Example 2.65.1 (0.043), 2,5-dioxopyrrolidin-l-yl 3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoate (10 mg) and N,N-diisopropylethylamine(0.028 mL) were stirred together in N,N-dimethylformamide (1 mL) at room temperature. Afterstirring for 1 hour, the reaction was diluted with N,N-dimethylformamide (0.5 mL) and water (0.5mL). The mixture was purified by reverse phase HPLC using a Gilson system, eluting with 5-75%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combinedand freeze-dried to provide the title compound. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm12.84 (s, 1H), 8.03 (d, 1H), 8.00 (t, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.54-7.41 (m, 3H), 7.36 (td, 2H),MEl 24985843V.1 597117813-126207.29 (s, 1H), 7.19 (d, 1H), 6.97 (s, 2H), 6.95 (d, 1H), 6.67 (d, 1H), 6.60 (dd, 1H), 5.14-5.03 (m, 1H),4.96 (d, 4H), 4.08 (tt, 4H), 3.89 (q, 4H), 3.84-3.77 (m, 2H), 3.71 (t, 2H), 3.59 (t, 2H), 3.52-3.35 (m,6H), 3.28 (dq, 4H), 3.17 (q, 2H), 3.01 (t, 2H), 2.46 (d, 1H), 2.33 (t, 2H), 2.09 (s, 3H), 1.45-0.90 (m,12H), 0.82 (d, 6H). MS (ESI) m/e 1396.4 (M-H)’.2.66 Synthesis of N-[6-(ethenylsulfonyl)hexanoyl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide on KY)2.66.1 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidTo a mixture of Example 1.2.9 (57 mg) and (9H-fluorenyl)methyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)oxoureidopentanno)oxobutanyl)carbamate (54 mg) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (103 uL). The e was stirred overnight, and diethylamine (61.5 uL) wasadded. The resulting mixture was stirred for 4 hours and purified by reverse phase HPLC using aGilson system and C18 column, eluting with 10-70% acetonitrile in water ning 0.1% v/vtrifluoroacetic acid, to provide the title compound. MS (ESI) m/e 1257.4 (M-H).2.66.2 N-[6-(ethenylsulfonyl)hexan0yl]-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideThe title compound was prepared using the procedure in Example 2.83, replacing Example1.2.9 and 2,5-dioxopyrrolidinyl 6-(2-chloroacetamido)hexanoate with Example 2.66.1 ande 2.82.5, respectively. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.88 (s, 0H), 9.99(s, 1H), 8.05 (t, 2H), 7.80 (t, 2H), 7.60 (q, 3H), 7.36 (td, 2H), 7.28 (d, 3H), 7.01-6.89 (m, 2H), 6.29-6.15 (m, 2H), 6.02 (s, 1H), 4.97 (d, 4H), 4.40 (td, 1H), 4.20 (t, 1H), 4.00-3.77 (m, 4H), 3.55-3.33 (m,4H), 3.25 (d, 2H), 3.14-2.88 (m, 6H), 2.62 (t, 2H), 2.09 (s, 4H), 1.82-0.90 (m, 10H), 0.84 (dd, 13H).

MS (ESI) m/e 1447.2 (M+H).2.67 Synthesis of 4-[(1E){[(4-{[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}MEl 24985843V.1 598117813-12620methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)amin0}piperidinyl)carb0nyl]0xy}pr0p-l-enyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid on IW)2.67.1 3-(1-((3-(2-((1-((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)phenyl)allyl)0xy)carb0nyl)piperidinyl)(3-phosphonopropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidTo a solution of Example 1.26.2 (0.045 g) and Example 2.44.7 (0.053 g) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine(0.04l mL), and the reaction wasstirred at room temperature overnight. The reaction was concentrated, and the residue was dissolvedin methanol (0.5 mL) and tetrahydrofuran (0.5 mL) and treated with a solution of lithium hydroxidemonohydrate (0.030 g) in water (0.5 mL) at room temperature. After stirring for 1 hour, the reactionwas quenched with trifluoroacetic acid (0.073 mL) and diluted with N,N-dimethylformamide (1 mL).

The mixture was ed by e phase HPLC using a Gilson system, g with 10-60%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions were combinedand freeze-dried to provide the title compound.2.67.2 4-[(1E){[(4-{[2—({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)amin0}piperidinyl)carb0nyl]0xy}pr0penyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acidTo a solution of Example 2.67.1 (0.040 g) and 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)hexanoate (9.84 mg) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (0.023 mL), and the reaction was stirred at room temperature for 2 hours. Theon was diluted with methylformamide (1 mL) and water (1 mL). The mixture waspurified by reverse phase HPLC using a Gilson system, eluting with 10-60% acetonitrile in waterning 0.1% v/v trifluoroacetic acid. The desired ons were combined and freeze-dried toprovide the title compound. 1H NMR (400 MHZ, dimethyl ide-d6) 5 ppm 9.28 (s, 1H), 9.04 (s,1H), 8.25 (s, 1H), 8.03 (d, 1H), 7.87 (t, 1H), 7.79 (d, 1H), 7.62 (dd, 1H), 7.55-7.40 (m, 3H), 7.36 (td,2H), 7.29 (s, 1H), 7.11 (dd, 1H), 7.05 (d, 1H), 6.98 (s, 2H), 6.95 (d, 1H), 6.59 (d, 1H), 6.20 (t, 1H),MEl 24985843V.1 599117813-126206.16 (t, 0H), 4.96 (s, 2H), 4.88 (d, 1H), 4.66 (d, 2H), 4.14 (d, 2H), 3.96-3.86 (m, 2H), 3.83 (s, 2H),3.54 (t, 7H), 3.48-3.28 (m, 12H), 3.01 (t, 2H), 2.84 (s, 2H), 2.55 (t, 2H), 2.10 (s, 3H), 2.07-1.95 (m,4H), 1.88 (s, 2H), 1.73-1.54 (m, 4H), 1.54-1.38 (m, 6H), 1.39-1.26 (m, 4H), .93 (m, 8H), 0.86(s, 6H). MS (ESI) m/e 1582.4 (M+H)+.2.68 sis of 4-[(1E){[(4-{[2-({3-[(4-{2-carb0xy[8-([1,3]thiaz010[4,5-b]pyridinylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}--methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ph0sph0n0pr0pyl)amin0}piperidinyl)carb0nyl]0xy}pr0penyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid (Synthon IY)2.68.1 (3-(2-((1-((((E)(3-(3-amin0pr0panamid0)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)phenyl)allyl)0xy)carb0nyl)piperidinyl)(3-phosphonopropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting e 1.50.2 for Example 1.44.7 ine 2.56.1. MS (ESI) m/e 1388.5 (M-H)’.2.68.2 4-[(1E){[(4-{[2-({3-[(4-{2-carb0xy[8-([1,3]thiazolo[4,5-b]pyridinylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]pyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.l.13’7]dec-l-yl}0xy)ethyl](3-phosphonopropyl)amin0}piperidinyl)carb0nyl]0xy}pr0penyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by substituting Example 1.68.1 for Example 1.56.1 inExample 2.56.2. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 9.03 (s, 1H), 8.61 (d, 1H), 8.50(d, 1H), 8.25 (br s, 1H), 7.89 (t, 1H), 7.65 (d, 1H), 7.49 (d, 1H), 7.46 (d, 1H), 7.36 (m, 2H), 7.29 (s,1H), 7.11 (br d, 1H), 7.03 (d, 1H), 6.98 (s, 2H), 6.97 (d, 1H), 6.58 (m, 1H), 6.17 (m,1H), 4.97 (s, 2H),4.88 (d, 1 H), 4.65 (br d, 2H), 3.88 (m, 3H), 3.79 (br m, 2H), 3.66 (br m, 2H), 3.27-3.44, (m, 14H),3.01 (m, 2H), 2.85 (br m, 2H), 2.54 (m, 2H), 2.10 (s, 3H), 2.03 (t, 2H), 1.98 (br m, 2H), 1.89 (m, 1H),1.62 (m, 4H), 1.46 (m, 6H), 1.31 (m, 4H), 1.15 (m, 6H), 1.04 (m, 2H), 0.86 (s, 6H). MS (ESI) m/e1581.4 (M-H)’.

MEl 24985843V.1 600117813-126202.69 Synthesis of 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benzothiazol-2—ylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}oxy)ethyl](2-sulfoethyl)carbamoyl}oxy)propenyl]({N-[6—(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoyl]-beta-alanyl}amino)phenyl beta-D-glucopyranosiduronic acid (Synthon JA)2.69.1 3-(1-((3-(2-(((((E)(3-(3-aminopropanamido)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-2H-pyranyl)oxy)phenyl)allyl)oxy)carbonyl)(2-sulfoethyl)amino)ethoxy)-5,7—dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8—(benzo[d]thiazolylcarbamoyl)naphthalenyl)picolinic acidThe title compound was prepared by substituting Example 1.43.7 for Example 2.44.7 inExample . MS (ESI) m/e 1309.1 (M+Na)+.2.69.2 4-[(1E)({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl}-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec-l-yl}oxy)ethyl](2-sulfoethyl)carbamoyl}oxy)propenyl]({N-[6-(2,5-dioxo-hydro-1H-pyrrolyl)hexanoyl]-beta-alanyl}amino)phenyl beta-D-glucopyranosiduronic acidThe title compound was prepared by tuting Example 2.69.1 for Example 2.56.1 inExample 2.56.2. 1H NMR (400 MHZ, dimethyl sulfoxide-dé) 5 ppm 13.09 (s, 1H), 9.02 (s, 2H), 8.35(d, 1H), 8.13-8.29 (m, 4H), 7.86-8.09 (m, 5H), 7.81 (d, 1H) , 7.66-7.75 (m, 1H), 7.44-7.55 (m, 1H),7.37 (t, 1H), 7.09-7.18 (m, 1H), 7.03 (d, 1H), 6.98 (s, 1H), 6.48-6.62 (m, 1H), 6.07-6.22 (m, 1H),4.81-4.92 (m, 1H), 4.58-4.74 (m, 2H), 3.80-3.93 (m, 3H), 3.27-3.37 (m, 5H), 2.53-2.68 (m, 4H), 2.15-2.23 (m, 3H), 2.03 (t, 2H), 1.36-1.53 (m, 6H) , 0.97-1.33 (m, 24H), 0.81 (d, 6H). MS (ESI) m/e1478.3(M-H)’.2.70 This paragraph was intentionally left blank.2.71 This paragraph was ionally left blank.2.72 This paragraph was intentionally left blank.2.73 This paragraph was intentionally left blank.2.74 This aph was intentionally left blank.2.75 This paragraph was intentionally left blank.2.76 This paragraph was intentionally left blank.2.77 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-({N-[6-(2,5-dioxo-2,5-dihydro-rolyl)hexanoyl]sulfo-L-alanyl}amino)ethoxy]-5,7-MEl 24985843V.1 601-12620dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon FA)To a solution of Example 1.15 (0.023 g) and 2,5-dioxopyrrolidinyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate (9.12 mg) in methylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.012 mL), and the reaction was stirred overnight. The reaction was dwith methylformamide (1 mL) and water (0.5 mL). The mixture was purified by reverse phaseHPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid. The desired fractions were combined and freeze-dried to provide the titlend. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.90 (d,1H), 7.79 (d, 1H), 7.65-7.57 (m, 2H), 7.54 (d, 1H), 7.51-7.41 (m, 2H), 7.40-7.31 (m, 3H), .96(m, 3H), 4.96 (s, 2H), 4.34-4.28 (m, 3H), 3.89 (t, 2H), 3.83 (s, 2H), 3.37 (t, 2H), 3.29 (t, 2H), 3.16-2.95 (m, 4H), 2.80 (dd, 1H), 2.70 (dd, 1H), 2.11 (s, 3H), 2.06 (t, 2H), 1.47 (tt, 4H), 1.40-0.92 (m,12H), 0.84 (s, 6H). MS (ESI) m/e 1090.3 (M+H)+.2.78 sis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2—(2-{[6-(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)hexan0yl](2-sulfoethyl)amin0}eth0xy)ethoxy]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon FJ)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.11.4 and perfluorophenyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate, respectively. 1H NMR (400 MHz, dimethylsulfoxide-dé) 5 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.42-7.49(m, 2H), 7.33-7.39 (m, 2H), 7.30 (s, 1H), 6.98 (s, 2H), 6.96 (d, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.82 (s,2H), 3.46-3.56 (m, 4H), .46 (m, 10H), 3.01 (t, 2H), 2.61-2.68 (m, 1H), 2.55-2.60 (m, 1H), 2.21-2.32 (m, 2H), 2.10 (s, 3H), 1.40-1.51 (m, 4H), 1.37 (d, 2H), 0.91-1.30 (m, 12H), 0.83 (s, 6H). MS(ESI) m/e 1091.2 (M+H)+.2.79 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrol-l-yl)hexan0yl](2-sulf0ethyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridine-Z-carboxylic acid (Synthon FK)The title compound was prepared as described in Example 2.1, replacing 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)-3 -methylbutanamido)pentanamido)benzyl (4-nitrophenyl) carbonate with perfluorophenyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.85 (s, 1H), 8.04 (d,1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.41-7.49 (m, 2H), 7.32-7.39 (m, 2H), 7.28 (s, 1H),MEl 24985843V.1 602117813-12620.98 (m, 3H), 4.95 (s, 2H), 3.89 (t, 2H), 3.81 (s, 2H), 3.32-3.38 (m, 2H), 3.21-3.27 (m, 2H), 3.01(t, 2H), 2.61-2.67 (m, 2H), 2.53-2.58 (m, 2H), 2.33-2.39 (m, 1H), 2.20-2.29 (m, 2H), 2.09 (s, 3H),1.40-1.51 (m, 4H), 1.34 (s, 2H), 0.93-1.27 (m, 13H), 0.83 (s, 6H). MS (ESI) m/e 1047.2 (M+H)+.2.80 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{[1-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0(2—sulf0ethyl)-3,6,9,12,15,18-hexa0xaracosanyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]--methyl-1H-pyrazolyl}pyridinecarb0xylic acid on FQ)The title compound was prepared as described in Example 2.1, replacing 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)-3 -methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with perfluorophenyl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)-3,9,12,15,18-pentaoxahenicosanoate. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 8 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.42-7.54 (m, 3H), 7.33-7.38 (m,2H), 7.28 (s, 1H), 6.95 (dd, 1H), 4.95 (s, 2H), 3.89 (t, 2H), 3.81 (s, 2H), 3.07-3.53 (m, 24H), 3.01 (t,2H), 2.61-2.69 (m, 1H), 2.54-2.60 (m, 1H), 2.09 (s, 3H), 1.96 (d, 2H), 0.92-1.39 (m, 13H), 0.84 (s,6H). MS (ESI) m/e 1269.4 (M+H)+.2.81 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{[1-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0(2-sulf0ethyl)-3,6,9,12,15,18,25-hepta0xaazaheptacosanyl]oxy}-5,7-dimethyltricyclo[3.3.1.13’7]dechyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid(Synthon FR)The title compound was prepared as described in Example 2.1, ing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)ureidopentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.11.4 and perfluorophenyl 1-ioxo-2,5-dihydro-1H-pyrrolyl)-3,6,9,12,15,18-hexaoxahenicosanoate, respectively. 1HNMR (500 MHz, dimethyl sulfoxide-dé) 8 ppm 12.84 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H),7.52 (d, 1H), 7.41-7.50 (m, 2H), 7.33-7.39 (m, 2H), 7.31 (s, 1H), 7.01 (d, 2H), 6.97 (d, 1H), 4.96 (s,2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.31-3.60 (m, 30H), 3.01 (t, 2H), 2.64-2.71 (m, 1H), 2.53-2.61 (m,3H), 2.10 (s, 3H), 1.38 (s, 2H), 1.20-1.31 (m, 4H), 1.12-1.18 (m, 2H), 0.91-1.12 (m, 4H), 0.84 (s, 6H).2.82 Synthesis of 1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2—{[6-(ethenylsulfonyl)hexanoyl](2-sulf0ethyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylic acid (Synthon JE)2.82.1 ethyl 6-((2-hydr0xyethyl)thi0)hexan0ateMEl 24985843V.1 603117813-12620A mixture of ethyl 6-bromohexanoate (3 g), 2-mercaptoethanol (0.947 mL) and KZCO3 (12g) in ethanol (100 mL) was stirred overnight and filtered. The filtrate was concentrated. The residuewas dissolved in dichloromethane (100 mL) and washed with water and brine. The organic layer wasdried over sodium e, filtered, and concentrated to provide the title compound.2.82.2 hydroxyethyl)thi0)hexan0ic acidA e of e 2.82.1 (12 g) and 3 M aqueous NaOH solution (30 mL) in ethanol(30 mL) was stirred overnight. The organics were removed under reduced pressure. The residualaqueous phase was washed with ethyl acetate, acidified with HCl to pH 5 and extracted withdichloromethane. The extracts were combined, dried over sodium sulfate, filtered and concentrated toprovide the title compound.2.82.3 hydroxyethyl)sulfonyl)hexan0ic acidTo a stirred solution of Example 2.82.2 (4 g) in a mixture of water (40 mL) and 1,4-dioxane (160 mL) was added Oxone® (38.4 g), and the mixture was stirred overnight. The mixturewas filtered, and the te was concentrated. The residual aqueous layer was extracted withdichloromethane. The extracts were combined and dried over sodium sulfate, filtered, andconcentrated to provide the title compound.2.82.4 6-(vinylsulfonyl)hexan0ic acidTo a cold (0 CC) solution of Example 2.82.3 (l g) in dichloromethane (10 mL) was addedtriethylamine (2.8 mL), followed by the addition of methanesulfonyl chloride (1.1 mL) under argon.

The mixture was d overnight and washed with water and brine. The c layer was dried oversodium sulfate, filtered, and concentrated to provide the title compound.2.82.5 2,5-di0x0pyrrolidinyl6-(vinylsulfonyl)hexan0ateTo a stirred on of Example 2.82.4 (0.88 g) in dichloromethane (10 ml) was added 1-hydroxypyrrolidine-2,5-dione (0.54 g) and N,N'-methanediylidenedicyclohexanamine (0.92 g). Themixture was stirred overnight and filtered. The filtrate was concentrated and purified by flashchromatography, eluting with 10-25% ethyl e in petroleum, to e the title compound. MS(ESI) m/e 304.1 (M+1).2.82.6 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl](1-{[3-(2—{[6-(ethenylsulfonyl)hexanoyl](2-sulfoethyl)amin0}eth0xy)-5,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarb0xylicThe title compound was ed as described in Example 2.83, replacing 2,5-dioxopyrrolidin-l-yl 6-(2-chloroacetamido)hexanoate with Example 2.82.5. 1H NMR (400 MHz,dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.53 (dd, 1H),7.42-7.49 (m, 2H), 7.33-7.40 (m, 2H), 7.28 (s, 1H), 6.88-7.00 (m, 2H), 6.17-6.25 (m, 2H), 4.95 (s,2H), 3.89 (t, 2H), 3.81 (s, 2H), 3.38 (dd, 2H), 3.25 (t, 2H), 3.04-3.12 (m, 2H), 3.01 (t, 2H), 2.62-2.69MEl 24985843V.1 604117813-12620(m, 1H), 2.56 (dd, 1H), 2.27 (q, 2H), 2.09 (s, 3H), 1.53-1.62 (m, 2H), 1.43-1.51 (m, 2H), 1.28-1.38(m, 4H), .27 (m, 4H), 0.92-1.19 (m, 6H), 0.84 (s, 6H). MS (ESI) m/e 1042.2 (M+H)+.2.83 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[{6-[(chloroacetyl)amin0]hexan0yl}(2-sulf0ethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-lH-pyrazolyl}pyridine-2—carb0xylic acid (Synthon JM)To a mixture of Example 1.2.9 (12.5 mg) and 2,5-dioxopyrrolidinyl 6-(2-chloroacetamido)hexanoate (6.7 mg) in N,N-dimethylformamide (1.5 mL) was added N,N-diisopropylethylamine (26 uL). The e was stirred for 10 days and purified by e phaseHPLC using a Gilson system and C18 column, eluting with 20-60% acetonitrile in water containing0.1% v/v trifluoroacetic acid, to provide the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 12.83 (s, 1H), 8.15-8.21 (m, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H),7.41-7.49 (m, 2H), .39 (m, 2H), 7.28 (s, 1H), 6.96 (dd, 1H), 4.95 (s, 2H), 4.01 (d, 2H), 3.89 (t,2H), 3.81 (s, 2H), 3.39 (d, 2H), 3.25 (t, 2H), 2.98-3.10 (m, 5H), 2.62-2.70 (m, 1H), 2.56-2.61 (m, 1H),2.23-2.30 (m, 2H), 2.09 (s, 3H), 1.33-1.52 (m, 5H), 1.19-1.30 (m, 6H), 0.91-1.18 (m, 6H), 0.84 (s,6H). MS (ESI) m/e 1043.2 (M+H)+.2.84 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-carb0xypr0pyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon LE)A mixture of Example 1.56 (0.020 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)carbonate (0.022 g) and N,N-diisopropylethylamine (0.018 mL) were stirred together in N,N-dimethylformamide (0.4 mL) at room temperature. After stirring for 5 hours, the reaction was dilutedwith a 1:1 mixture of N,N-dimethylformamide and water (2 mL). The mixture was purified bye phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in water containing0.1% v/v trifluoroacetic acid. The d ons were combined and freeze-dried to provide thetitle compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.82 (s, 1H), 9.97 (s, 1H), 8.10-7.98 (m, 2H), 7.84-7.72 (m, 2H), 7.67-7.54 (m, 3H), .41 (m, 3H), 7.40-7.32 (m, 2H), 7.30-7.23(m, 3H), 6.99 (s, 2H), 6.94 (d, 1H), 5.99 (s, 1H), 4.98 (s, 2H), 4.95 (s, 2H), 4.45-4.35 (m, 2H), 4.19(dd, 2H), 3.88 (t, 2H), 3.82-3.76 (m, 2H), 3.47-3.31 (m, 4H), 3.28-3.19 (m, 4H), 3.07-2.89 (m, 4H),.11 (m, 4H), 2.09 (s, 2H), 2.02-1.89 (m, 1H), 1.77-1.63 (m, 2H), 1.62-1.27 (m, 10H), 1.27-0.90(m, 13H), 0.88-0.78 (m, 12H); MS (ESI) m/e 1430.3 (M+1)+.

MEl 24985843V.1 605117813-126202.85 Synthesis of N-{6-[(bromoacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridin—3-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon LH)2.85.1 1H-benz0[d][1,2,3]triazolyl6-(2-br0moacetamid0)hexanoateTo a solution of 6-(2-bromoacetamido)hexanoic acid (105 mg) and benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP, 325 mg) in N,N-dimethylformamide(3 mL) was added triethylamine (87 uL). The mixture was stirred for 1 hour and purified by a GilsonHPLC system (C18 column), eluting with 20-60% acetonitrile in 0.1% TFA water to e the titlecompound. MS (ESI) m/e 368.7 (M+H).2.85.2 N-{6-[(bromoacetyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-0rnithinamideTo a mixture of e 2.66.1 (6.6 mg) and Example 2.85.2 (3.6 mg) in N,N-dimethylformamide (0.3 mL) was added N,N-diisopropylethylamine (2.52 uL). The mixture wasstirred for 5 minutes, diluted with dimethyl sulfoxide and purified by reverse phase HPLC using aGilson system and C18 column, eluting with 20-60% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to provide the title compound. 1H NMR (500 MHz, dimethyl ide-dé) 5 9.99(s, 1H), 8.24 (s, 1H), 8.08 (d, 1H), 8.04 (d, 1H), 7.80 (dd, 2H), 7.60 (q, 3H), 7.56-7.50 (m, 1H), 7.50-7.41 (m, 2H), 7.36 (q, 2H), 7.32-7.25 (m, 3H), 6.96 (d, 1H), 4.98 (d, 4H), 4.39 (q, 1H), 4.20 (dd, 1H),.68 (m, 6H), 3.42 (dd, 1H), 3.25 (t, 2H), 3.09-2.87 (m, 6H), 2.64 (s, 2H), 2.25-1.87 (m, 5H),1.79-0.89 (m, 17H), .67 (m, 12H). MS (ESI) m/e 1492.5 (M-H).2.86 Synthesis of 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-carboxypropyl)carbamoyl}0xy)methyl][2-(2-{[3-(2,5-di0x0-2,5-dihydro-1H-pyrr01yl)propanoyl]amin0}eth0xy)eth0xy]phenyl -glucopyranosiduronic acid (Synthon LJ)2.86.1 3-(1-((3-(2-((((2—(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-2-yl)0xy)benzyl)0xy)carb0nyl)(3-carboxypropyl)amin0)eth0xy)-5,7-dimethyladamantanMEl 24985843V.1 606117813-12620yl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidTo a solution of Example 1.56 (0.024 g) and e 2.62.6 (0.030 g) in N,N-dimethylformamide (0.4 mL) was added N,N-diisopropylethylamine (0.025 mL), and the reaction wasstirred overnight. The on was concentrated, and the residue dissolved in tetrahydrofuran (0.5mL) and methanol (0.5 mL) and treated with lithium hydroxide e (0.018 g) as a solution inwater (0.5 mL). After stirring for 1 hour, the reaction was diluted with N,N-dimethylformamide (1mL) and purified by reverse phase HPLC using a Gilson system, eluting with 10-75% acetonitrile inwater containing 0.1% v/v trifluoroacetic acid. The desired fractions were combined and freeze-driedto provide the title compound. MS (ESI) m/e 1262.7 (M+H)+.2.86.2 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-carboxypr0pyl)carbam0yl}0xy)methyl][2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}eth0xy)ethoxy]phenyl beta-D-glucopyranosiduronic acidTo a solution of Example 2.86.1 (0.0173 g) and 2,5-dioxopyrrolidinyl -dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (4.38 mg) in N,N-dimethylformamide (0.8 mL) was added 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (4.38 mg), and the reactionwas stirred for 2 hours. The reaction was diluted with a 1:1 mixture of N,N-dimethylformamide:water(1 mL), and the mixture was purified by reverse phase HPLC using a Gilson system, eluting with 10-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired fractions werecombined and freeze-dried to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6)5 ppm 12.77 (s, 1H), 8.03 (d, 1H), 7.99 (t, 1H), 7.77 (d,1H), 7.62 (d, 1H), 7.55-7.41 (m, 3H), 7.40-7.32 (m, 2H), 8.28 (s, 1H), .17 (m, 1H), 6.97 (s, 2H), 6.94 (d, 1H), 6.66 (s, 1H), 6.60 (dd, 1H),.07 (m, 1H), 5.00-4.91 (m, 4H), 4.17-4.02 (m, 2H), 3.96-3.85 (m, 2H), .76 (m, 2H), 3.71 (t,2H), 3.64-3.56 (m, 4H), 3.34-3.12 (m, 10H), 3.01 (, 2H), 2.33 (t, 2H), .12 (m, 2H), 2.09 (s, 3H),1.70 (p, 2H), 1.45-0.88 (m, 12H), 0.88-0.77 (m, 6H); MS (ESI) m/e 1434.2 +.2.87 Synthesis of 4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-ypropyl)amin0}piperidinyl)carbonyl]0xy}methyl)[2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}eth0xy)eth0xy]phenyl beta-D-gluc0pyran0sidur0nicacid (Synthon MA)MEl 24985843V.1 607117813-126202.87.1 3-(1-((3-(2-((1-(((2-(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)oxy)carbonyl)piperidinyl)(3-carboxypropyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidA solution of Example 1.42 (0.050 g) and Example 2.62.6 (0.050 g) in N,N-dimethylformamide (0.5 mL) was treated with N,N-diisopropylethylamine (0.042 mL), and thereaction was stirred at room temperature for 2 hours. The reaction was concentrated, and the residuewas dissolved in methanol (0.5 mL) and tetrahydrofuan (0.5 mL) and treated with lithium hydroxidehydrate (0.031 g) as a on in water (0.5 mL). The reaction was stirred for 1.5 hours and dilutedwith N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using aGilson system, eluting with 10-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

The desired fractions were ed and freeze-dried to e the title nd. MS (ESI) m/e1345.7 .2.87.2 4-({[(4-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-carboxypr0pyl)amin0}piperidinyl)carb0nyl]0xy}methyl)[2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}eth0xy)eth0xy]phenyl beta-D-glucopyranosiduronic acidA solution of Example 2.87.1 (0.047 g) and 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (0.011 g) in N,N-dimethylformamide (0.5 mL) was treated withN,N-diisopropylethylamine (0.031 mL), and the reaction was stirred at room temperature for 2 hours.

The reaction was diluted with a 1:1 mixture of N,N-dimethylformamide:water (2 mL). The mixturewas purified by reverse phase HPLC using a Gilson system, eluting with 10-85% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired fractions were combined and -dried toe the title nd. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 12.87 (s, 1H), 8.96 (s,1H), 8.15-8.07 (m, 2H), 7.88 (d, J: 8.1 Hz, 1H), 7.71 (d, J: 7.5 Hz, 1H), 7.62-7.50 (m, 3H), 7.50-7.45 (m, 1H), 7.45-7.42 (m, 1H), 7.37 (s, 1H), 7.33-7.27 (m, 1H), 7.07 (s, 2H), 7.07-7.02 (m, 1H),6.80-6.74 (m, 1H), 6.72-6.66 (m, 1H), 5.23-5.14 (m, 1H), 5.13-5.00 (m, 4H), 4.27-4.12 (m, 4H), 4.06-3.95 (m, 4H), 3.92 (s, 2H), 3.83-3.78 (m, 2H), 3.57-3.32 (m, 10H), 3.32-3.14 (m, 4H), 3.14-3.06 (m,2H), 2.90 (s, 2H), 2.49-2.37 (m, 4H), 2.19 (s, 3H), 2.12-2.01 (m, 2H), 2.02-1.88 (m, 2H), 1.74-1.57(m, 2H), 1.52 (s, 2H), 1.45-1.30 (m, 4H), 1.30-1.05 (m, 6H), 0.95 (s, 6H); MS (ESI) m/e 1495.4(M+H)+.

MEl 24985843V.1 608117813-126202.88 Synthesis of 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-sulfopropyl)carbamoyl}0xy)methyl][2-(2-{[3-(2,5-di0x0-2,5-dihydr0-rolyl)propanoyl]amin0}eth0xy)eth0xy]phenyl beta-D-glucopyranosiduronic acid (Synthon MD)2.88.1 3-(1-((3-(2-((((2—(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(3-sulfopropyl)amin0)ethoxy)-5,7—dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidA solution of e 1.6 (0.039 g) and Example 2.62.6 (0.041 g) in N,N-dimethylformamide (0.5 mL) was treated with N,N-diisopropylethylamine (0.035 mL), and thereaction was d at room temperature for 2 hours. The reaction was concentrated, and the residuewas dissolved in methanol (0.5 mL) and tetrahydrofuan (0.5 mL) and treated with lithium hydroxidehydrate (0.025 g) as a solution in water (0.5 mL). The reaction was stirred for 1.5 hours and dilutedwith N,N-dimethylformamide (1 mL). The mixture was purified by reverse phase HPLC using aGilson system, eluting with 10-80% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

The desired fractions were combined and freeze-dried to e the title compound. MS (ESI) m/e1297.8 (M+H)+.2.88.2 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](3-sulfopr0pyl)carbam0yl}0xy)methyl][2-(2-{[3-(2,5-di0x0-2,5-dihydr0-lH-pyrrolpan0yl]amin0}eth0xy)ethoxy]phenyl beta-D-yranosiduronic acidTo a solution of Example 2.88.1 (0.024 g) and 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (6.40 mg) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (0.016 mL), and the reaction was stirred at room temperature for 1 hour. Theon was diluted with a 1:1 mixture of N,N-dimethylformamide:water (2 mL). The mixture waspurified by reverse phase HPLC using a Gilson system, eluting with 10-80% acetonitrile in watercontaining 0.1% v/v trifluoroacetic acid. The desired ons were combined and freeze-dried toprovide the title compound. 1H NMR (500 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.87 (s, 1H), 8.09-8.02 (m, 2H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52 (dd, 1H), 7.50-7.42 (m, 2H), 7.40-7.33 (m, 2H), 7.31 (s,1H), 7.20 (t, 1H), 6.98 (s, 3H), 6.66 (s, 1H), 6.60 (dd, 1H), 5.06 (t, 1H), 4.96 (s, 4H), 4.10 (dq, 4H),MEl 24985843V.1 609117813-126203.81 (d, 4H), 3.71 (t, 2H), 3.59 (t, 2H), 3.51-3.35 (m, 4H), 3.26 (td, 6H), 3.17 (q, 2H), 3.01 (t, 2H),2.35 (dt, 4H), 2.10 (d, 3H), 1.75 (d, 2H), 1.44-0.88 (m, 12H), 0.82 (d, 6H); MS (ESI) m/e 1446.4 (M-2.89 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-[4-({[(3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)amin0}azetidinyl)carb0nyl]0xy}methyl)phenyl]-N5-carbamoyl-L-ornithinamide (Synthon MG)A solution of Example 1.60 (0.026 g), 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1 -yl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl rophenyl)ate (0.024 g) and N,N-diisopropylethylamine (0.022 mL) were stirred together in N,N-dimethylformamide (0.8 mL) at room temperature for 3 hours. The reaction was diluted with a 1:1mixture of N,N-dimethylformamide:water (2 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-80% acetonitrile in water containing 0.1% v/v trifluoroaceticacid. The desired ons were combined and freeze-dried to provide the title compound. 1H NMR(400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 9.99 (s, 1H), 8.06 (d, 1H), 8.03 (d, 1H), 7.79(dd, 2H), 7.60 (dd, 3H), 7.55-7.41 (m, 3H), 7.36 (td, 2H), 7.29 (t, 3H), 6.99 (s, 2H), 6.95 (d, 1H), 5.99(s, 1H), 5.04-4.92 (m, 4H), 4.37 (q, 1H), 4.34-4.24 (m, 1H), 4.24-4.10 (m, 4H), 3.88 (t, 2H), 3.82 (s,2H), 3.40-3.29 (m, 4H), 3.01 (t, 2H), 2.99-2.91 (m, 1H), 2.87 (t, 2H), 2.25-2.06 (m, 5H), 1.95 (dt,1H), 1.68 (s, 1H), 1.60 (s, 1H), .24 (m, 12H), 1.24-0.94 (m, 9H), 0.90-0.78 (m, 12H); MS (ESI)m/e 1507.4 (M+H)+.2.90 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{[26-(2,5-di0x0-2,5-dihydr0-1H-pyrrol-l-yl)-8,24-di0x0(2-sulfoethyl)-11,14,17,20-tetraoxa-3,7,23-triazahexacosyl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]-S-methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Synthon MS)To a e of Example 1.61.2 (15 mg) and 2,5-dioxopyrrolidinyl 1-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)oxo-7,10,13,16-tetraoxaazanonadecanoate (16.91 mg) in N,N-dimethylformamide (0.8 mL) was added N,N-diisopropylethylamine (28.8 uL) at 0 OC. The mixturewas stirred for 3 hours and purified by reverse phase HPLC, using a Gilson system and C18 column,eluting with 20-60% acetonitrile in water containing 0.1% trifluoroacetic acid, to provide the titlend. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.87 (s, 1H), 8.98 (s, 1H), .92(m, 3H), 7.79 (d, 1H), 7.62 (d, 1H), .41 (m, 3H), 7.36 (td, 2H), 7.29 (s, 1H), 7.04-6.92 (m, 3H),4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H), 3.48 (d, 4H), 3.44-3.17 (m, 3H), 3.18-2.83 (m, 10H), 2.38-2.24(m, 4H), 2.11 (s, 3H), 1.78 (m, 2H), 1.50-0.94 (m, 12H), 0.86 (s, 6H). MS (ESI) m/e 1309.3 (M-H).

MEl 24985843v.1 610117813-126202.91 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)amin0}pr0pyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide (Synthon MR)To a mixture of Example 1.61.2 (12.8 mg) and ((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)-5 -ureidopentanamido)benzyl (4-nitrophenyl)carbonate (10.4 mg) in N,N-dimethylformamide (0.5 mL) at 0 0C was added N,N-diisopropylethylamine (24.54 uL). The mixture was stirred for 3 hours and purified by reverse phaseHPLC using a Gilson system and a C18 column, eluting with 20-60% acetonitrile in water ning0.1% trifluoroacetic acid, to provide the title compound. 1H NMR (400 MHz, dimethyl sulfoxide-dé)ppm 12.85 (s, 1H), 9.97 (s, 1H), 8.97 (s, 1H), 8.04 (t, 2H), 7.79 (dd, 2H), 7.65-7.40 (m, 7H), 7.36(td, 3H), 7.28 (d, 3H), 6.99 (s, 2H), 6.95 (d, 1H), 5.98 (s, 1H), 4.95 (d, 4H), 4.49-4.30 (m, 1H), 4.24-4.11 (m, 1H), 3.88 (t, 2H), 3.82 (s, 2H), 3.36 (t, 3H), 3.18-2.84 (m, 9H), 2.25-1.88 (m, 5H), 1.85-0.90(m, 14H), .75 (m, 13H). MS (ESI) m/e (M+H).2.92 Synthesis of N-{6-[(iodoacetyl)amin0]hexan0yl}-L-valyl-N-{4-[({[2-({3--[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quin01in-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon MQ)To a mixture of Example 1.2.9 (8.2 mg) and 2,5-dioxopyrrolidinyl 6-(2-iodoacetamido)hexanoate (4.7 mg) in N,N-dimethylformamide (0.3 mL) in an ice-bath was addedN,N-diisopropylethylamine (3 uL). The e was stirred at 0 0C for 1.5 hours. The reaction wasdiluted with dimethyl sulfoxide, and the mixture purified by reverse phase HPLC using a Gilsonsystem and a C18 column, eluting with 20-60% acetonitrile in water containing 0.1% trifluoroaceticacid, to e the title compound. 1H NMR (400 MHz, dimethyl ide-dé) 5 ppm 12.87 (s, 1H),.00 (s, 1H), 8.21 (d, 1H), 8.06 (dd, 2H), 7.81 (dd, 2H), 7.60 (t, 3H), 7.48 (ddd, 3H), 7.36 (td, 2H),7.28 (d, 3H), 6.95 (d, 1H), 4.97 (d, 4H), 4.39 (q, 1H), 4.19 (t, 1H), 3.88 (t, 2H), 3.80 (d, 2H), 3.25 (d,2H), 2.97 (dq, 6H), 2.63 (s, 2H), 2.25-1.88 (m, 5H), 1.78-0.70 (m, 29H). MS (ESI) m/e 1538.4 (M-2.93 Synthesis of N-{6-[(ethenylsulfonyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-MEl 24985843v.1 61 1117813-12620sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon MZ)2.93.1 methyl 6-(vinylsulfonamid0)hexanoateTo a solution of 6-methoxyoxohexanaminium chloride (0.3 g) and triethylamine(1.15 mL) in dichloromethane at 0 CC was added ethenesulfonyl chloride (0.209 g) dropwise. Thereaction mixture was warmed to room ature and stirred for 1 hour. The mixture was dilutedwith dichloromethane and washed with brine. The organic layer was dried over sodium sulfate,filtered, and concentrated to provide the title compound. MS (ESI) m/e 471.0 +.2.93.2 6-(Vinylsulfonamid0)hexan0ic acidA on of Example 2.93.1 (80 mg) and lithium hydroxide monohydrate (81 mg) in amixture of tetrahydrofuran (1 mL) and water (1 mL) was stirred for 2 hours, then diluted with water(20 mL), and washed with diethyl ether (10 mL). The aqueous layer was acidified to pH 4 with 1Naqueous HCl and extracted with dichloromethane (3 x 10 mL). The organic layer was washed withbrine (5 mL), dried over sodium sulfate, ed and concentrated to provide the title compound.2.93.3 2,5-di0x0pyrrolidinyl6-(Vinylsulfonamid0)hexanoateA mixture of Example 2.93.2 (25 mg), 1-ethyl[3 thylamino)propyl]-carbodiimidehydrochloride (43.3 mg) and 1-hydroxypyrrolidine-2,5-dione (15.6 mg) in dichloromethane (8 mL)was stirred overnight, washed with saturated aqueous ammonium chloride solution and brine, andconcentrated to provide the title compound.2.93.4 N-{6-[(ethenylsulfonyl)amin0]hexanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]phenyl}-N5-carbamoyl-L-0rnithinamideThe title compound was prepared as described in Example 2.83, replacing e 1.2.9and 2,5-dioxopyrrolidinyl 6-(2-chloroacetamido)hexanoate with Example 2.66.1 and e2.93.3, respectively. 1H NMR (400 MHz, dimethyl ide-dé) 5 ppm 12.85 (s, 1H), 9.98 (s, 1H),8.05 (dd, 2H), 7.79 (d, 2H), 7.60 (t, 3H), 7.55-7.40 (m, 3H), 7.36 (td, 2H), 7.27 (d, 3H), 7.19 (t, 1H),6.95 (d, 1H), 6.66 (dd, 1H), .90 (m, 2H), 4.97 (d, 4H), 4.39 (q, 1H), 4.20 (t, 1H), 3.88 (t, 2H),3.80 (d, 2H), 3.25 (d, 2H), 2.97 (dt, 4H), 2.78 (q, 2H), 2.64 (q, 2H), 2.22-1.86 (m, 6H), 1.77-0.89 (m,16H), 0.89-0.72 (m, 12H). MS (ESI) m/e 1460.6 (M-H).2.94 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[3-({6-[(iodoacetyl)amin0]hexanoyl}amin0)pr0pyl](2-sulfoethyl)amin0}eth0xy)-,7-dimethyltricyclo[3.3.1.13’7]decyl]methyl}methyl-1H-pyrazol-4—yl)pyridinecarb0xylic acid (Synthon NA)MEI 24985843V.1 612117813-12620The title compound was prepared using the procedure in Example 2.83, replacing e1.2.9 and 2,5-dioxopyrrolidinyl 6-(2-chloroacetamido)hexanoate with Example 2.61.2 and 2,5-dioxopyrrolidinyl 6-(2-iodoacetamido)hexanoate, respectively. 1H NMR (400 MHz, dimethylsulfoxide-dé) 5 ppm 12.87 (s, 1H), 8.98 (s, 1H), 8.20 (t, 1H), 8.04 (d, 1H), 7.91 (t, 1H), 7.79 (d, 1H),7.62 (d, 1H), 7.53 (d, 1H), 7.50-7.41 (m, 2H), 7.36 (td, 2H), 7.29 (s, 1H), 6.96 (d, 1H), 4.96 (s, 2H),3.89 (t, 2H), 3.83 (s, 2H), 3.06 (dt, 8H), 2.89 (t, 2H), 2.17-1.99 (m, 5H), 1.76 (s, 2H), 1.56-0.93 (m,14H), 0.86 (s, 6H). MS (ESI) m/e 1190.3 (M-H).2.95 sis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-oisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-{[6-(ethenylsulfonyl)hexanoyl]amin0}pr0pyl)(2-sulf0ethyl)amin0]ethoxy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridine-2—carb0xylic acid (Synthon NB)The title compound was prepared using the procedure in Example 2.83, replacing Example1.2.9 and 2,5-dioxopyrrolidinyl 6-(2-chloroacetamido)hexanoate with Example 1.61.2 andExample 2.82.5, respectively. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.87 (s, 1H), 8.98(s, 1H), 8.04 (d, 1H), 7.92 (t, 1H), 7.79 (d, 1H), 7.62 (d, 1H), 7.53 (d, 1H), 7.51-7.41 (m, 2H), 7.36(td, 2H), 7.29 (s, 1H), 7.01-6.90 (m, 2H), 6.29-6.16 (m, 2H), 4.96 (s, 2H), 3.89 (t, 2H), 3.83 (s, 2H),3.45-3.19 (m, 2H), 3.19-2.95 (m, 8H), 2.89 (t, 2H), 2.16-1.98 (m, 5H), 1.84-1.66 (m, 2H), 1.64-1.21(m, 13H), 1.08 (dq, 6H), 0.86 (s, 6H). MS (ESI) m/e 1199.3 (M+H).2.96 Synthesis of N-[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]carb0xypyridinyl}methyl-1H-pyrazolhyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon NP)2.96.1 (S)-(9H-flu0renyl)methyl (1-((4-(hydroxymethyl)phenyl)amino)0x0ureid0pentanyl)carbamate(S)((((9H-Fluorenyl)methoxy)carbonyl)amino)ureidopentanoic acid (40 g) wasdissolved in dichloromethane (1.3L). (4-Aminophenyl)methanol (13.01 g), 2-(3H-[1,2,3]triazolo[4,5-dinyl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (42.1 g) and N,N-diisopropylethylamine (0.035 L) were added to the solution, and the resulting e was d atroom temperature for 16 hours. The product was ted by filtration and rinsed withdichloromethane. The combined solids were dried under vacuum to yield the title compound, whichwas used in the next step without further purification. MS (ESI) m/e 503.3 (M+H)+.2.96.2 (S)amin0-N-(4-(hydr0xymethyl)phenyl)ureidopentanamideMEl 24985843V.1 613117813-12620Example 2.96.1 (44 g) was dissolved in N,N-dimethylformamide (300 mL). The solutionwas treated with diethylamine (37.2 mL) and stirred for one hour at room ature. The reactionmixture was filtered, and the t was concentrated under reduced pressure. The crude productwas purified by basic alumina chromatography eluting with a nt of 0-30% methanol in ethyle to give the title compound. MS (ESI) m/e 281.2 (M+H)+.2.96.3 tert-butyl((S)(((S)((4-(hydroxymethyl)phenyl)amino)0x0ureidopentanyl)amin0)methyl0x0butan-2—yl)carbamate(S)(Tert-butoxycarbonylamino)methylbutanoic acid (9.69 g) was dissolved in N,N-dimethylformamide (200 mL). To the solution was added 2-(3H-[l,2,3]triazolo[4,5-b]pyridin-3 -yl)-l,l,3,3-tetramethylisouronium hexafluorophosphate(V) (18.65 g), and the reaction was d for onehour at room temperature. Example 2.96.2 (12.5 g) and N,N-diisopropylethylamine (15.58 mL) wereadded and the reaction e was stirred for 16 hours at room temperature. The solvent wasconcentrated under reduced pressure and the residue was purified by silica gel chromatography,eluting with 10% ol in dichloromethane, to give the title compound. MS (ESI) m/e 480.2(M+H)+.2.96.4 (S)((S)aminomethylbutanamid0)-N-(4-(hydroxymethyl)phenyl)ureid0pentanamideExample 2.96.3 (31.8 g) was dissolved in dichloromethane (650 mL) and trifluoroaceticacid (4.85 mL) was added to the solution. The reaction mixture was stirred for three hours at roomtemperature. The solvent was concentrated under reduced pressure to yield a mixture of the crudetitle compound and 4-((S)((S)amino-3 -methylbutanamido)-5 -ureidopentanamido)benzyl 2,2,2-trifluoroacetate. The crude material was ved in a 1:1 dioxane/water solution (300 mL) and tothe solution was added sodium hydroxide (5.55 g). The mixture was stirred for three hours at roomtemperature. The solvent was concentrated under vacuum, and the crude product was purified byreverse phase HPLC using a CombiFlash system, g with a gradient of 5-60% acetonitrile inwater containing 0.05% v/v ammonium hydroxide, to give the title compound. MS (ESI) m/e 380.2(M+H)+.2.96.5 (S)((S)-2—(3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0panamid0)methylbutanamid0)-N-(4-(hydroxymethyl)phenyl)ureid0pentanamideTo a solution of Example 2.96.4 (38 mg) in methylformamide (l mL)was added2,5-dioxopyrrolidin-l-yl 3-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)propanoate (26.7 mg). Thereaction mixture was stirred at room temperature ght and purified by reverse phase HPLC usinga Gilson system, eluting with a gradient of 10-85% acetonitrile in water containing 0.1% v/vtrifluoroacetic acid, to give the title compound. MS (ESI) m/e 531.06 (M+H)+.

MEl 24985843V.1 614117813-126202.96.6 4-((S)((S)(3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0panamid0)methylbutanamid0)ureidopentanamid0)benzyl r0phenyl) carbonateTo a solution of Example 2.96.5 (53.1 mg) in N,N-dimethylformamide (3 mL) was addedbis(4-nitrophenyl) carbonate (60.8 mg). The reaction mixture was stirred at room temperatureght and purified by reverse phase HPLC using a Gilson system, eluting with a gradient of 10-85% acetonitrile in water containing 0.1% v/v trifluoroacetic acid, to give the title compound. MS(ESI) m/e 696.2 (M+H)+.2.96.7 N-[3-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)pr0pan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbam0yl)-1,2,3,4-tetrahydr0quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-yltricyclo[3.3.1.13,7]dec-l-yl}oxy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamideThe title compound was prepared as described in Example 2.1, ing Example 1.2.9and 4-((S)((S)(6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanamido)methylbutanamido)pentanamido)benzyl (4-nitrophenyl) carbonate with Example 1.24.2 and Example 2.96.6,respectively. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.91 (s, 1H), 9.80 (s, 2H), 8.33 (s,2H), 7.96 (s, 2H), 7.81 (d, 4H), 7.61 (s, 2H), 7.43 (d, 10H), .02 (m, 14H), 5.92 (s, 8H), 4.94-4.70 (m, 6H), 4.18 (d, 11H), 3.85 (s, 8H), 3.05-2.66 (m, 8H), 2.30-2.13 (m, 14H), 2.03-1.49 (m, 2H),0.92-0.63 (m, 40H). MS (ESI) m/e 1408.3 (M-H)+.2.97 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carb0xyethyl){[(2-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydr0-2H-pyran}[2-(2-{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)propanoyl]amino}ethoxy)ethoxy]benzyl)0xy]carbonyl}amin0]eth0xy}-,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridine-Z-carboxylic acid (Synthon NN)2.97.1 4-(2-(2-bromoethoxy)eth0xy)hydr0xybenzaldehydeA solution of 2,4-dihydroxybenzaldehyde (1.0 g), 1-bromo(2-bromoethoxy)ethane (3.4g) and potassium carbonate (1.0 g) in acetonitrile (30 mL) was heated to 75 CC for 2 days. Thereaction was cooled, diluted with ethyl acetate (100 mL), washed with water (50 mL) and brine (50mL), dried over magnesium sulfate, ed and concentrated. Purification of the residue by silica gelchromatography, eluting with a gradient of 5-30% ethyl e in heptane, provided the titlecompound. MS (ELSD) m/e 290.4 (M+H)+.

MEl 24985843V.1 615117813-126202.97.2 4-(2-(2-azidoethoxy)eth0xy)hydr0xybenzaldehydeTo a solution of e 2.97.1 (1.26 g) in N,N-dimethylformamide (10 mL) was addedsodium azide (0.43 g), and the reaction was stirred at room ature overnight. The reaction wasd with l ether (100 mL), washed with water (50 mL) and brine (50 mL), dried overmagnesium sulfate, filtered, and concentrated. Purification of the residue by silica gelchromatography, eluting with a gradient of 5-30% ethyl acetate in heptane, gave the title compound.

MS (ELSD) m/e 251.4 (M+H)+.2.97.3 (2S,3R,4S,5S,6S)(5-(2-(2-azid0eth0xy)eth0xy)formylphenoxy)(meth0xycarb0nyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateA solution of Example 2.97.2 (0.84 g), (3R,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (1.99 g) and silver (I) oxide (1.16 g)were stirred together in acetonitrile (15 mL). After stirring overnight, the on was diluted withdichloromethane (20 mL). Diatomaceous earth was added, and the reaction filtered and concentrated.

Purification of the e by silica gel chromatography, eluting with a gradient of 5-75% ethylacetate in heptane, gave the title compound.2.97.4 (2S,3R,4S,5S,6S)(5-(2-(2-azid0eth0xy)eth0xy)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateA solution of Example 2.97.3 (0.695 g) in methanol (5 mL) and tetrahydrofuran (2 mL)was cooled to 0 CC. Sodium borohydride (0.023 g) was added, and the reaction was warmed to roomtemperature. After stirring for a total of 1 hour, the reaction was poured into a mixture of ethylacetate (75 mL) and water (25 mL), and saturated aqueous sodium onate (10 mL) was added.

The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate, filtered,and concentrated. Purification of the residue by silica gel tography, eluting with a gradient of-85% ethyl acetate in heptane, gave the title compound. MS (ELSD) m/e 551.8 (M-HZO).2.97.5 (2S,3R,4S,5S,6S)(5-(2-(2-amin0eth0xy)eth0xy)xymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo Example 2.97.4 (0.465 g) in tetrahydrofuran (20 mL) was added 5% Pd/C (0.1 g) in a50 mL pressure bottle, and the e was shaken for 16 hours under 30 psi hydrogen. The reactionwas filtered and concentrated to give the title compound, which was used without further purification.

MS (ELSD) m/e 544.1 (M+H)+.2.97.6 (2S,3R,4S,SS,6S)(5-(2-(2-((((9H-flu0renh0xy)carbonyl)amin0)ethoxy)eth0xy)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateMEl 24985843V.1 616117813-12620A solution of Example 2.97.5 (0.443 g) in dichloromethane (8 mL) was cooled to 0 CC,then isopropylethylamine (0.214 mL) and (9H-fluorenyl)methyl carbonochloridate (0.190 g)were added. After 1 hour, the reaction was concentrated. Purification of the residue by silica gelchromatography, eluting with a gradient of 5-95% ethyl acetate in heptane, gave the title compound.

MS (ELSD) m/e 748.15 (M-OH)’.2.97.7 (2S,3R,4S,5S,6S)(5-(2-(2-((((9H-flu0renyl)meth0xy)carbonyl)amin0)ethoxy)eth0xy)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of Example 2.97.6 (0.444 g) in N,N-dimethylformamide (5 mL) was addedN,N-diisopropylethylamine (0.152 mL) and nitrophenyl) carbonate (0.353 g), and the reactionwas stirred at room temperature. After 5 hours, the reaction was concentrated. cation of thee by silica gel chromatography, eluting with a gradient of 5-90% ethyl acetate in heptane, gavethe title compound.2.97.8 3-(1-((3-(2-((((4—(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-2-yl)0xy)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acid,trifluoroacetic acid saltTo a solution of Example 1.25 (0.070 g) and Example 2.97.7 (0.070 g) in N,N-dimethylformamide (0.4 mL) was added isopropylethylamine (0.066 mL). After ngovernight, the reaction was trated. The residue was dissolved in tetrahydrofuran (0.75 mL) andmethanol (0.75 mL), and lithium hydroxide monohydrate (0.047 g) was added as a solution in water(0.75 mL). After 3 hours, the reaction was diluted with N,N-dimethylformamide (1 mL) andquenched with trifluoroacetic acid (0.116 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroaceticacid. The desired fractions were combined and freeze-dried to provide the title compound.2.97.9 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-yl)(1-((3-(2-((((2-(((2S,3R,4S,SS,6S)carb0xy-3,4,5-trihydroxytetrahydro-2H-pyranyl)0xy)(2-(2-(3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0panamid0)ethoxy)ethoxy)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidMEl 24985843V.1 617117813-12620A solution of Example 2.97.8 (0.027 g), 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (7.92 mg) and N,N-diisopropylethylamine (0.017 mL) werestirred together in N,N-dimethylformamide (0.4 mL) for 1 hour. The reaction was quenched with a1:1 mixture of water and N,N-dimethylformamide (2 mL). The mixture was purified by reverse phaseHPLC using a Gilson system, eluting with 10-75% itrile in water containing 0.1% v/vtrifluoroacetic acid. The d fractions were combined and freeze-dried to provide the titlecompound. 1H NMR (400 MHZ, yl sulfoxide-d6) 5 ppm 12.81 (s, 1H), 8.03 (d, 2H), 7.79 (d,1H), 7.62 (d, 1H), 7.54-7.40 (m, 3H), 7.36 (td, 2H), 7.28 (s, 1H), 7.18 (d, 1H), 6.98 (s, 2H), 6.95 (d,1H), 6.69 (d, 1H), 6.60 (d, 1H), 5.03 (d, 3H), 4.96 (s, 2H), 4.05 (s, 2H), 3.93 (d, 2H), 3.88 (t, 2H),3.80 (d, 2H), 3.75-3.67 (m, 2H), 3.59 (t, 6H), 3.29 (q, 6H), 3.17 (q, 2H), 3.01 (t, 2H), 2.47 (d, 2H),2.33 (t, 2H), 2.09 (s, 3H), 1.44-0.88 (m, 12H), 0.82 (d, 6H); MS (ESI) m/e 1396.5 (M-H)’.2.98 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]sulfo-L-alanyl-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide (Synthon NO)2.98.1 3-(1-((3-(2-((((4-((S)((S)amin0methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidA solution of Example 1.25.2 (0.059 g), (9H-fluorenyl)methyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)oxoureidopentanyl)amino)anyl)carbamate (0.053 g) and N,N-diisopropylethylamine (0.055 mL) in N,N-ylformamide (0.5 mL) was stirred at room temperature overnight. Diethylamine (0.066 mL)was added to the reaction, and stirring was ued for 30 minutes. The reaction was diluted with a1:1 mixture of N,N-dimethylformamide and water (2 mL) and quenched by the addition oftrifluoroacetic acid (0.073 mL). The mixture was purified by reverse phase HPLC using a Gilson, eluting with 10-75% itrile in water containing 0.1% v/v trifluoroacetic acid. Thedesired fractions were combined and freeze-dried to provide the title compound. MS (ESI) m/e1223.8 (M+H)+.2.98.2 3-(1-((3-(2-((((4-((S)((S)((R)amin0sulf0pr0panamid0)methylbutanamido)ureid0pentanamid0)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benz0[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)pic01inic acid, trifluoroacetic acid saltMEl 24985843V.1 618117813-12620A solution of (R)((((9H-fluorenyl)methoxy)carbonyl)amino)sulfopropanoic acid(0.021 g), O-(7-azabenzotriazolyl)-N,N,N’,N’ -tetramethyluronium hexafluorophosphate (0.020 g)and N,N-diisopropylethylamine (0.031 mL) in methylformamide (0.4 mL) was stirred for 3minutes. The on was added to Example 2.98.1 (0.043 g) as a solution in N,N-dimethylformamide (0.4 mL). After stirring for 30 minutes, a solution of lithium hydroxidemonohydrate (0.022 g) in water (0.5 mL) was added, and the reaction was d for 1 hour. Thereaction was diluted with a 1:1 mixture of N,N-dimethylformamide and water (2 mL) and quenchedby the addition of trifluoroacetic acid (0.054 mL). The mixture was purified by reverse phase HPLCusing a Gilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroaceticacid. The desired fractions were ed and freeze-dried to provide the title compound. MS (ESI)m/e 1376.5 (M+l).2.98.3 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((2-carb0xyethyl)(((4-((S)((S)((R)(6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexanamid0)sulfopropanamid0)methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acidA solution of e 2.98.2 (0.025 g), 2,5-dioxopyrrolidinyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate (7.77 mg) and N,N-diisopropylethylamine (0.015 mL) in N,N-ylformamide (0.4 mL) was stirred for 1 hour. The reaction was diluted with a 1:1 mixture ofwater and N,N-dimethylformamide (2 mL). The e was purified by reverse phase HPLC using aGilson system, eluting with 10-75% acetonitrile in water containing 0.1% v/v trifluoroacetic acid.

The d fractions were combined and freeze-dried to provide the title compound. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 1H), 9.46 (s, 1H), 8.20 (d, 1H), 8.07 (d, 1H), 8.03 (d,1H), 8.00 (d, 1H), 7.79 (d, 1H), 7.69 (d, 2H), 7.61 (d, 1H), 7.51 (d, 1H), 7.49-7.45 (m, 1H), 7.43 (d,1H), 7.36 (td, 2H), 7.29 (s, 1H), 7.25 (d, 2H), 6.97 (s, 2H), 6.95 (d, 1H), 4.98 (s, 2H), 4.96 (s, 2H),4.73 (s, 2H), 4.16 (s, 2H), 4.03 (dd, 2H), 3.88 (t, 2H), 3.81 (s, 2H), 3.51-3.32 (m, 6H), 3.28 (t, 2H),3.09 (dd, 1H), 3.06-2.94 (m, 4H), 2.89 (dd, 1H), 2.46 (d, 2H), 2.16 (dd, 1H), 2.09 (d, 4H), 1.74 (s,2H), 1.62-1.29 (m, 8H), 1.29-0.92 (m, 12H), 0.92-0.78 (m, 12H). MS (ESI) m/e 1566.6 (M-H)’.2.99 Synthesis of Control n 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]({N-[6-(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)hexan0yl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid (Synthon H)MEI 24985843V.1 619117813-126202.99.1 (2S,3R,4S,5S,6S)(4-f0rmylnitrophenoxy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of ,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H- pyran-triyl tate (4 g) in acetonitrile (100 mL)) was added silver(I) oxide (10.04 g) and 4-hydroxy-3-nitrobenzaldehyde (1.683 g). The on mixture was stirred for 4 hours at room ature andfiltered. The filtrate was concentrated, and the residue was purified by silica gel tography,eluting with 5-50% ethyl acetate in heptanes, to provide the title compound. MS (ESI) m/e (M+l8)+.2.99.2 (2S,3R,4S,5S,6S)(4-(hydroxymethyl)nitr0phen0xy)xycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a solution of Example 2.99.1 (6 g) in a mixture of chloroform (75 mL) and isopropanol(18.75 mL) was added 0.87 g of silica gel. The resulting mixture was cooled to 0 CC, NaBH4 (0.470g) was added, and the resulting suspension was stirred at 0 CC for 45 minutes. The reaction mixturewas diluted with dichloromethane (100 mL) and filtered through diatomaceous earth. The filtrate waswashed with water and brine and concentrated to give the crude product, which was used withoutfurther purification. MS (ESI) m/e (M+NH4)+:2.99.3 (2S,3R,4S,5S,6S)(2-amino(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateA stirred solution of Example 2.99.2 (7 g) in ethyl acetate (81 mL) was hydrogenated at 20CC under 1 here H2, using 10% Pd/C (1.535 g) as a st for 12 hours. The reaction mixturewas filtered through diatomaceous earth, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel chromatography, eluting with 95/5 romethane/methanol, togive the title compound.2.99.4 3-((((9H-flu0renyl)meth0xy)carbonyl)amin0)pr0pan0ic acid3-Aminopropanoic acid (4.99 g) was dissolved in 10% aqueous NazCO3 solution (120 mL)in a 500 mL flask and cooled with an ice bath. To the resulting solution, (9H-fluorenyl)methylcarbonochloridate (14.5 g) in 1,4-dioxane (100 mL) was gradually added. The reaction mixture wasstirred at room temperature for 4 hours, and water (800 mL) was then added. The aqueous phaselayer was separated from the reaction mixture and washed with diethyl ether (3 x 750 mL). Theaqueous layer was acidified with 2N HCl aqueous solution to a pH value of 2 and extracted with ethyle (3 x 750 mL). The organic layers were combined and trated to obtain crude product.

The crude product was recrystallized in a mixed solvent of ethyl acetate: hexane 1:2 (300 mL) to givethe title compound.2.99.5 (9H-flu0ren-9—yl)methyl (3-chlor00x0pr0pyl)carbamateTo a solution of Example 2.99.4 in dichloromethane (160 mL) was added sulfurousdichloride (50 mL). The mixture was stirred at 60 CC for 1 hour. The mixture was cooled andconcentrated to give the title compound.

MEl 24985843V.1 620117813-126202.99.6 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0ren-9—yl)meth0xy)carbonyl)amin0)propanamid0)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a solution of Example 2.99.3 (6 g) in dichloromethane (480 mL) was added N,N-diisopropylethylamine (4.60 mL). Example 2.99.5 (5.34 g) was added, and the mixture was stirred atroom temperature for 30 minutes. The mixture was poured into saturated aqueous sodium bicarbonateand was extracted with ethyl acetate. The combined extracts were washed with water and brine andwere dried over sodium sulfate. Filtration and concentration gave a residue that was ed viaradial chromatography, using 0-100% ethyl acetate in petroleum ether as mobile phase, to give thetitle nd.2.99.7 (2S,3R,4S,5S,6S)(2-(3-((((9H-flu0ren-9—yl)meth0xy)carbonyl)amin0)propanamid0)((((4—nitrophenoxy)carb0nyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a e of e 2.99.6 (5.1 g) in N,N-dimethylformamide (200 mL) was addedbis(4-nitrophenyl) carbonate (4.14 g) and N,N-diisopropylethylamine (1.784 mL). The mixture wasstirred for 16 hours at room temperature and trated under reduced pressure. The crude materialwas dissolved in dichloromethane and aspirated directly onto a 1 mm radial Chromatotron plate andeluted with % ethyl acetate in hexanes to give the title compound. MS (ESI) m/e (M+H)+.2.99.8 3-(1-((3-(2-((((3-(3-amin0pr0panamid0)-4—(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carbonyl)(methyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidTo a solution of Example 1.13.7 (325 mg) and e 2.99.7 (382 mg) in N,N-ylformamide (9 mL) at 0 0C was added N,N-diisopropylamine (49.1 mg). The reaction mixturewas stirred at 0 0C for 5 hours, and acetic acid (22.8 mg) was added. The resulting mixture wasdiluted with ethyl acetate and washed with water and brine. The organic layer was dried overNaZSO4, filtered and concentrated. The residue was dissolved in a e of tetrahydrofuran (10 mL)and methanol (5 mL). To this solution at 0 0C was added 1 M aqueous lithium ide solution(3.8 mL). The resulting mixture was stirred at 0 0C for 1 hour, ied with acetic acid andconcentrated. The concentrate was lyophilized to provide a powder. The powder was dissolved inN,N-dimethylformamide (10 mL), cooled in an ice-bath, and piperidine (1 mL) at 0 0C was added.

The mixture was stirred at 0 0C for 15 minutes and 1.5 mL of acetic acid was added. The solution waspurified by reverse-phase HPLC using a Gilson system, eluting with 30-80% acetonitrile in waterMEl 24985843V.1 621117813-12620containing 0.1% V/V roacetic acid, to provide the title compound. MS (ESI) m/e 1172.2(M+H)+.2.99.9 4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-azolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]({N-[6-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)hexan0yl]-betaalanyl}amin0)phenyl beta-D-glucopyranosiduronic acidTo Example 2.99.8 (200 mg) in N,N-dimethylformamide (5 mL) at 0 CC was added 2,5-dioxopyrrolidin-l-yl -dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate (105 mg) and N,N-diisopropylethylamine (0.12 mL). The e was stirred at 0 CC for 15 minutes, warmed to roomtemperature and purified by reverse-phase HPLC on a Gilson system using a 100g C18 column,eluting with 30-80% acetonitrile in water containing 0.1% V/V trifluoroacetic acid, to e the titlecompound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (s, 2H) 9.07 (s, 1H) 8.18 (s, 1H)8.03 (d, 1H) 7.87 (t, 1H) 7.79 (d, 1H) 7.61 (d, 1H) 7.41-7.53 (m, 3H) 7.36 (q, 2H) 7.28 (s, 1H) 7.03-7.09 (m, 1H) 6.96-7.03 (m, 3H) 6.94 (d, 1H) 4.95 (s, 4H) 4.82 (t, 1H) 3.88 (t, 3H) 3.80 (d, 2H) 3.01 (t,2H) 2.86 (d, 3H) 2.54 (t, 2H) 2.08 (s, 3H) 2.03 (t, 2H) 1.40-1.53 (m, 4H) 1.34 (d, 2H) 0.90-1.28 (m,12H) 0.82 (d, 6H). MS (ESI) m/e 1365.3 (M+H)+.2.100 Synthesis of Control Synthon 4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]({N-[19-(2,5-di0x0-2,5-dihydro—1H-pyrrol-l-yl)0x0-4,7,10,13-tetraoxaazan0nadecanoyl]-beta-alanyl}amin0)phenyl beta-D-glucopyranosiduronic acid(Synthon I)The title compound was prepared using the procedure in Example 2.99.9, replacing 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate with 2,5-dioxopyrrolidinyl -dioxo-2,5-dihydro-1H-pyrrol-l-yl)oxo-7,10,13,16-tetraoxaazanonadecanoate. 1HNMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 8.95 (s, 1H) 8.16 (s, 1H) 7.99 (d, 1H) 7.57-7.81 (m,4H) 7.38-7.50 (m, 3H) 7.34 (q, 2H) 7.27 (s, 1H) 7.10 (d, 1H) 7.00 (d, 1H) 6.88-6.95 (m, 2H) 4.97 (d,4H) 4.76 (d, 2H) 3.89 (t, 2H) 3.84 (d, 2H) 3.80 (s, 2H) 3.57-3.63 (m, 4H) 3.44-3.50 (m, 4H) 3.32-3.43(m, 6H) 3.29 (t, 2H) 3.16 (q, 2H) 3.02 (t, 2H) 2.87 (s, 3H) 2.52-2.60 (m, 2H) 2.29-2.39 (m, 3H) 2.09(s, 3H) 1.37 (s, 2H) 1.20-1.29 (m, 4H) 1.06-1.18 (m, 4H) 0.92-1.05 (m, 2H) 0.83 (s, 6H). MS (ESI)m/e 1568.6 (M-H)’.2.101 Synthesis of 1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{[(43S,46S)({[(4-{[(2S){[(2S)-2—{[6-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)hexan0yl]amin0}MEl 24985843V.1 622117813-12620methylbutanoyl]amin0}pr0pan0yl]amin0}benzyl)0xy] carbonyl}amin0)-46-methyl-37,44,47-tri0x0-2,5,8,11,14,17,20,23,26,29,32,35-d0deca0xa-38,45,48-triazapentacontan-SO-yl]0xy}-5,7-dimethyltricyclo[3.3.1.13’7]dec-1-yl)methyl]—5-methyl-lH-pyrazolyl}pyridine-2—carboxylic acid(Synthon OK)The title compound was prepared as described in e 2.7, replacing Example 1.13.8with Example 1.66.7. 1H NMR (400 MHz, dimethyl sulfoxide-dg) 5 ppm 12.85 (s, 1H), 8.21 — 7.97(m, 4H), 7.79 (d, 4H), 7.71 — 7.32 (m, 15H), 7.28 (t, 4H), 7.02 — 6.91 (m, 3H), 4.95 (d, 5H), 4.33 —4.12 (m, 3H), 3.98 — 3.76 (m, 11H), 3.41 — 3.21 (m, 22H), 3.21 — 2.90 (m, 12H), 2.24 — 2.05 (m, 7H),1.81 — 0.90 (m, 46H), 0.90 — 0.78 (m, 17H). MS (ESI) m/e 2014.0 (M+H)+, 1007.5 (M+2H)2+, 672.0(M+3H)3+.2.102 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon OW)The title compound was ed as described in Example 2.1, replacing Example 1.2.9with Example 1.62.5 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.95 (s, 1H), 8.36 (s, 1H),8.02 (d, 1H), 7.96 (d, 1H), 7.88 — 7.68 (m, 4H), 7.57 (d, 2H), 7.42 (s, 2H), 7.34 (t, 1H), 7.25 (dd, 3H),7.19 (t, 1H), 6.95 (s, 2H), 5.96 (s, 1H), 4.96 (s, 2H), 4.35 (q, 1H), 4.15 (dd, 1H), 3.93 (t, 2H), 3.83 (d,2H), 3.32 (t, 2H), 3.27 (d, 1H), 2.93 (dtd, 1H), 2.80 (t, 2H), 2.47 (p, 19H), 2.24 — 2.02 (m, 5H), 1.91(p, 3H), 1.74 — 1.25 (m, 8H), 1.27 — 0.89 (m, 10H), 0.79 (dd, 13H). MS (ESI) m/e 1414.4 .2.103 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon PC)The title compound was prepared as bed in Example 2.1, replacing Example 1.2.9with Example 1.68.7. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.07 (s, 1H), 9.95 (s, 1H),8.99 (s, 1H), 8.33 (dd, 1H), 8.25 — 8.09 (m, 3H), 8.12 — 7.95 (m, 3H), 7.90 (d, 1H), 7.76 (dd, 2H), 7.73— 7.63 (m, 1H), 7.56 (s, 3H), 7.41 — 7.29 (m, 1H), 6.95 (s, 2H), 5.97 (s, 1H), 4.96 (s, 2H), 4.35 (d,2H), 4.15 (dd, 1H), 3.50 — 3.22 (m, 10H), 2.92 (dtd, 3H), 2.29 — 2.00 (m, 6H), 1.92 (q, 1H), 1.75 —0.88 (m, 24H), 0.79 (dd, 15H). MS (ESI) m/e 1409.5 (M+H)+.

MEl 24985843V.1 623117813-126202.104 Synthesis of 6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3-{2-[(2—carb0xyethyl){[(2-{[(2R,3S,4R,5R,6R)carb0xy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]0xy}[2-(2-{[6-(2,5-di0x0-2,5-dihydro-1H-pyrr01yl)hexan0yl]amin0}eth0xy)eth0xy]benzyl)0xy]carbonyl}amin0] ethoxy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]--methyl-1H-pyrazolyl}pyridinecarb0xylic acid (Synthon PI)1 3-(1-((3-(2-((((4—(2-(2-aminoethoxy)eth0xy)-2—(((2R,3S,4R,5R,6R)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(2-carboxyethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01amoyl)naphthalenyl)picolinic acidTo a cold (0 CC) mixture of e 2.97.7 (26.9 mg) and Example 1.68.7 (23.5 mg) inN,N-dimethylformamide (2 mL) was added N-ethyl-N-isopropylpropanamine (0.043 mL). Thereaction was slowly warmed to room temperature and stirred overnight. LC/MS showed the expectedproduct as the major peak. To the reaction e was added water (1 mL) and LiOH H20 (20 mg).

The mixture was stirred at room ature for 3 hours. The mixture was diluted with N,N-dimethylformamide (2 mL), filtered and purified by reverse-phase HPLC on a Gilson system (C18column), eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give thetitle compound. MS (ESI) m/e 1242.2 (M-H)’.2.104.2 1,3-benz0thiazolylcarbamoyl)naphthalenyl]{1-[(3-{2-[(2-carb0xyethyl){[(2-{[(2R,3S,4R,5R,6R)carb0xy-3,4,5-trihydr0xytetrahydro-ZH-pyranyl]0xy}[2-(2—{[6-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)hexan0yl]amin0}eth0xy)eth0xy]benzyl)0xy]carbonyl}amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acidThe title compound was prepared as described in Example 2.97.9 by replacing Example2.97.8 with Example 2104.1 and replacing 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate with 2,5-dioxopyrrolidinyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolanoate. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.06 (s, 2H), 8.99 (s, 1H), 8.34 (dd,1H), 8.25 — 8.10 (m, 3H), 8.04 (d, 1H), 7.98 (d, 1H), 7.90 (d, 1H), 7.78 (d, 2H), 7.72 — 7.63 (m, 1H),7.50 — 7.42 (m, 2H), 7.34 (t, 1H), 7.16 (d, 1H), 6.94 (s, 2H), 6.65 (d, 1H), 6.56 (dd, 1H), 4.02 (t, 2H),3.90 (d, 1H), 3.83 (s, 2H), 3.66 (t, 3H), 3.28 (q, 4H), 3.15 (q, 2H), 2.19 (s, 3H), 1.99 (t, 2H), 1.51 —1.30 (m, 6H), 1.28 — 0.88 (m, 11H), 0.81 (d, 6H). MS (ESI) m/e 1433.4 (M+H)+.

MEl 24985843V.1 624117813-126202.105 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6—[5-(1,3-benzothiazolylcarbamoyl)quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon PJ)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.69.6. 1H NMR (500 MHz, dimethyl sulfoxide-dé) 5 ppm 13.23 (s, 1H), 9.99 (s, 1H),9.73 (d, 1H), 9.45 (s, 1H), 8.33 (t, 2H), 8.18 (d, 1H), 8.07 (dd, 2H), 8.02 (dd, 1H), 7.97 (dd, 1H), 7.80(t, 2H), 7.65 — 7.55 (m, 2H), 7.53 — 7.44 (m, 2H), 7.37 (t, 1H), 7.27 (d, 2H), 6.98 (s, 2H), 4.98 (d, 2H),4.38 (d, 1H), 4.18 (d, 1H), 3.56 — 3.31 (m, 3H), 3.26 (d, 2H), 3.08 — 2.89 (m, 2H), 2.64 (t, 2H), 2.23(d, 3H), 2.12 (dp, 2H), 1.95 (s, 1H), 1.68 (s, 1H), 1.62 — 1.29 (m, 7H), 1.29 — 0.90 (m, 9H), 0.90 —0.74 (m, 12H). MS (ESI) m/e 1446.3 .2.106 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[4-(1,3-benzothiazolylcarbamoyl)quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-carboxyethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synth0n PU)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.70. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.97 (s, 1H), 9.12 (d, 1H),8.93 (s, 1H), 8.60 (dd, 1H), 8.24 (dd, 2H), 8.05 (dd, 2H), 7.99 — 7.87 (m, 2H), 7.78 (dd, 2H), 7.67 —7.51 (m, 3H), 7.43 — 7.31 (m, 1H), 7.26 (d, 2H), 6.97 (s, 2H), 5.98 (s, 1H), 4.97 (s, 2H), 4.37 (d, 2H),4.17 (dd, 1H), 3.49 — 3.22 (m, 11H), 2.95 (ddd, 3H), 2.20 (s, 4H), 2.19 — 1.86 (m, 3H), 1.74 — 0.89 (m,22H), 0.81 (dd, 15H). MS (ESI) m/e 1410.4 (M-H)’.2.107 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[4-(1,3-benzothiazolylcarbamoyl)quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-yltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synth0n PV)The title compound was ed as described in e 2.1, replacing Example 1.2.9with Example 1.70.5. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.96 (s, 1H), 9.11 (d, 1H),8.92 (s, 1H), 8.60 (dd, 1H), 8.23 (dd, 2H), 8.12 — 7.97 (m, 2H), 7.98 — 7.92 (m, 2H), 7.77 (dd, 2H),7.56 (t, 2H), 7.51 — 7.42 (m, 2H), 7.42 — 7.31 (m, 1H), 7.24 (d, 2H), 6.95 (s, 2H), 4.95 (d, 2H), 4.36(q, 1H), 3.90 — 3.80 (m, 3H), 3.52 — 3.27 (m, 3H), 3.23 (t, 2H), 3.06 — 2.83 (m, 2H), 2.67 — 2.58 (m,MEl 24985843V.1 625117813-126202H), 2.19 (s, 3H), 2.09 (dp, 2H), 1.93 (d, 1H), 1.72 — 1.25 (m, 7H), 1.27 — 0.88 (m, 10H), 0.88 — 0.70(m, 13H). MS (ESI) m/e 1446.3 (M-H)’.2.108 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[5-(1,3-benzothiazolylcarbamoyl)quinolincarb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-yethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon PW)The title compound was ed as described in Example 2.1, replacing Example 1.2.9with Example 1.71. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.97 (s, 1H), 9.70 (d, 1H),9.40 (d, 1H), 8.31 (dd, 2H), 8.16 (d, 1H), 8.05 (t, 2H), 8.01 — 7.91 (m, 2H), 7.78 (dd, 2H), 7.59 (d,3H), 7.52 — 7.44 (m, 2H), 7.36 (t, 1H), 7.26 (d, 2H), 6.96 (s, 2H), 5.99 (s, 1H), 4.97 (s, 2H), 4.37 (d,2H), 4.16 (dd, 1H), 3.53 — 3.20 (m, 9H), 2.94 (dtd, 2H), 2.21 (s, 3H), 2.17 — 1.85 (m, 3H), 1.71 — 0.89(m, 22H), 0.81 (dd, 14H). MS (ESI) m/e 1410.4 (M-H)’.2.109 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-N-{4-[({[2-({3-[(4-{6-[1-(1,3-benzothiazolylcarbamoyl)-5,6-dihydroimidazo[1,S-a]pyrazin-7(8H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon QW)The title compound was prepared by substituting Example 1.72.8 for Example 1.2.9 inExample 2.1. 1H NMR (400 MHz, dimethyl sulfoxide d6) 5 ppm 11.07 (bs, 1H), 10.00 (bs, 1H), 8.27(bs, 1H), 8.12 (m, 2H), 8.07 (d, 1H), 7.99 (d, 1H), 7.84-7.74 (m, 2H), 7.65 (d, 1H), 7.59 (m, 2H),7.54-7.44 (m, 1H), .31 (m, 2H), 7.28 (m, 2H), 7.21 (q, 1H), 7.00 (m, 1H) 6.94-6.92 (m, 2H),6.04 (bs, 1H), 5.14 (s, 2H), 4.99 (m, 3H), 4.39 (m, 2H), 4.30 (bs, 2H), 4.20 (m, 2H), 4.12 (bs, 2H),3.70-3.64 (m, 2H), 3.50 (m, 2H), 3.44-3.35 (m, 2H), 3.27 (m, 2H), 3.02 (m, 2H), 2.95 (m, 2H), 2.68 (t,2H), 2.14 (m, 4H), 1.96 (m, 1H), 1.69 (m, 1H), 1.58 (m, 1H), 1.47 (m, 4H), 1.36 (m, 2H), 1.30-1.02(m, 8H), 0.98 (m, 2H), 0.85-0.80 (m, 16 H).2.110 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[7-(1,3-benzothiazolylcarbamoyl)-1H-indol-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon RM)Example 2.110 was prepared by substituting Example 1.74.6 for Example 1.2.9 inExample 2.1. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 11.30 (s, 1H), 9.93 (s, 1H), 8.26 (d,1H), 8.17 (d, 1H), 8.02 (d, 1H), 7.92 — 7.84 (m, 3H), 7.76 (d, 1H), 7.69 (d, 1H), 7.54 (d, 3H), 7.47 (s,MEl 24985843V.1 626-126201H), 7.35 (dd, 2H), 7.22 (t, 3H), 7.08 (t, 1H), 6.93 (s, 2H), 4.90 (s, 2H), 4.84 (t, 2H), 4.33 (q, 1H),4.16 — 4.09 (m, 1H), 3.32 (t, 4H), 2.99 (m, 6H), 2.21 (s, 3H), 2.09 (m, 2H), 1.91 (m, 1H), 1.71 — 0.71(m, 25H). MS (ESI) m/e 1434.4 (M-H)’.2.111 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[{3-[8-(1,3-benzothiazolylcarbam0yl)(6-carb0xy{1-[(3,5-dimethyl{2-[(2-sulf0ethyl)amin0]ethoxy}tricyclo[3.3.1.13’7]decyl)methyl]methyl-1H-pyrazolyl}pyridinyl)-1,2,3,4-tetrahydroisoquinolinyl]propyl}(methyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide (Synthon RR)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.75.14. 1H NMR (400 MHz, dimethyl sulfoxide-dg) 5 ppm 12.60 (bs, 1H), 9.98 (s,1H), 8.33 (m, 2H), 8.02 (d, 2H), 7.75 (d, 2H), 7.55 (d, 2H), 7.49 (m, 3H), 7.29 (m, 1H), 7.25 (s, 4H),6.99 (d, 2H), 6.95 (d, 1H), 5.90 (m, 1H), 5.42 (m, 2H), 4.95 (s, 2H), 4.90 (m, 2H), 4.35 (t, 1H), 4.18(t, 1H), 3.85 (m, 2H), 3.80 (s, 3H), 3.55 (s, 3H), 3.52 (m, 2H), 3.35 (m, 4H), 3.22 (m, 4H), 3.08 (m,2H), 2.99 (m, 2H), 2.92 (m, 2H), 2.85 (m, 2H), 2.79 (t, 2H), 2.52 (m, 1H), 2.15 (m, 1H), 2.09 (s, 3H),1.94 (m, 1H), 1.88 (m, 1H), 1.68 (m, 1H), 1.54 (m, 1H), 1.42 (m, 4H), 1.38 (m, 4H), 1.27 (m, 4H),1.13 (m, 4H), 1.02 (m, 2H), 0.85 (s, 6H), 0.78 (m, 6H). MS (ESI) m/e 1523.3 (M+H)+, 1521.6 (M-H)’2.112 sis of N-(6-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}hexan0yl)-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SJ)1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((((4-((S)((S)((tertbutoxycarbonyl)amin0)methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pic01inic acidExample 1.2.9, trifluoroacetic acid salt (390 mg), tert-butyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)oxoureidopentanyl)amino)oxobutanyl)carbamate (286 mg) and 1-hydroxybenzotriazole hydrate (185 mg) in N,N-dimethylformamide (5 mL) was cooled in an ice-bath and N,N-diisopropylethylamine (0.35 mL) wasadded. The mixture was stirred at 0 CC for 30 minutes and at room temperature overnight. TheMEl 24985843V.1 627117813-12620reaction mixture was diluted with dimethyl sulfoxide to 10 mL and purified by e-phase HPLCon a Gilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title compound. MS (ESI) m/e 680.1 (M+2H)2+.2.112.2 3-(1-((3-(2-((((4-((S)((S)amin0methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidExample 2112.1 (300 mg) in 10 mL of dichloromethane at 0 CC was treated withtrifluoroacetic acid (4 mL) for 30 minutes and the mixture was concentrated. The e wasdissolved in a mixture of acetonitrile and water and lyophilized to provide the d product as aTFA salt. MS (ESI) m/e 1257.4 .3 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)(1-((3-(2-((((4-((13S,16S)is0pr0pyl-2,2-dimethyl-4,11,14-tri0x0(3-ureid0pr0pyl)0xa-5,12,15-triazaheptadecanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-lH-pyrazolyl)pic01inic acidExample 2.112.2 (trifluoroacetic acid salt, 385 mg,) and 1-hydroxybenzotriazole hydrate(140 mg) in N,N-dimethylformamide (3 mL) was cooled in an ice-water bath. N,N-Diisopropylethylamine (226 uL) was added dropwise, ed by the on of 2,5-dioxopyrrolidinyl 6-((tert-butoxycarbonyl)amino)hexanoate (127 mg), and the mixture was stirredovernight. The e was purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-75% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlecompound. MS (ESI) m/e 1470.2 (M-H)’.2.112.4 3-(1-((3-(2-((((4—((S)((S)(6-amin0hexanamid0)methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidThe title compound was prepared using the procedure in Example 2.112.2, replacingExample 2.1121 with e 2.112.3. MS (ESI) m/e 1370.5 (M-H)’.2.1125 N-(6-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}hexan0yl)-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-MEl 24985843V.1 628-12620yltricyclo[3.3.l.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideExample 2112.4 (25 mg) and 2,5-dioxopyrrolidinyl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetate (9.19 mg) in N,N-dimethylformamide (0.3 mL) was treated with N,N-ropylethylamine (25.4 pL) for 30 minutes at 0 CC. The reaction mixture was purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 35-65% acetonitrile in 4 mMammonium acetate water mixture, to provide the title compound as an ammonium salt. 1H NMR (400MHz, dimethyl sulfoxide-dé) 5 12.81 (s, 1H), 9.94 (s, 1H), 8.01 (dd, 2H), 7.75 (d, 2H), 7.56 (s, 3H),7.51 — 7.45 (m, 1H), 7.45 — 7.37 (m, 2H), 7.36 — 7.28 (m, 2H), 7.24 (t, 3H), 7.17 (s, 2H), 7.05 (s, 3H),7.04 (s, 2H), 6.92 (s, 3H), 5.93 (s, 1H), 5.36 (s, 2H), 5.05 — 4.85 (m, 4H), 4.36 (q, 1H), 4.16 (dd, 1H),3.95 (s, 2H), 3.85 (t, 2H), 3.76 (d, 2H), 3.22 (d, 1H), 3.05 — 2.81 (m, 6H), 2.68 — 2.53 (m, 2H), 2.09(d, 4H), 1.76 — 0.86 (m, 14H), 0.86 — 0.71 (m, 12H). MS (ESI) m/e 1507.5 (M-H)’.2.113 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][3-(beta-L-glucopyranuronosyloxy)propyl]carbamoyl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SM)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example . 1H NMR (501 MHz, dimethyl ide-dé) 5 ppm 13.08 (s, 1H), 9.96 (s, 1H),9.00 (s, 1H), 8.35 (dd, 1H), 8.24 — 8.13 (m, 3H), 8.09 — 8.02 (m, 2H), 8.00 (d, 1H), 7.91 (d, 1H), 7.77(dd, 2H), 7.71 — 7.64 (m, 1H), 7.58 (t, 2H), 7.49 — 7.44 (m, 2H), 7.39 — 7.32 (m, 1H), 7.26 (d, 2H),6.96 (s, 2H), 5.97 (s, 1H), 4.96 (s, 2H), 4.37 (d, 1H), 4.22 — 4.12 (m, 2H), 3.84 (s, 1H), 3.37 — 3.20 (m,6H), 3.15 (t, 1H), 3.04 — 2.81 (m, 2H), 2.20 (s, 3H), 2.11 (dp, 2H), 1.99 — 1.88 (m, 1H), 1.71 (q, 2H),1.62 — 1.26 (m, 8H), 1.29 — 0.88 (m, 11H), 0.80 (dd, 14H). MS (ESI) m/e 1571.4 (M-H)’.2.114 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[4-(1,3-benzothiazolylcarbamoyl)is0quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SN)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.78.5. 1H NMR (400 MHz, dimethyl ide-dé) 5 ppm 9.95 (s, 1H), 9.61 (s, 1H),9.08 (s, 1H), 9.00 (s, 1H), 8.54 (dd, 1H), 8.43 (d, 1H), 8.24 (d, 1H), 8.08 — 7.95 (m, 3H), 7.77 (dd,2H), 7.63 — 7.51 (m, 2H), 7.50 — 7.42 (m, 2H), 7.40 — 7.31 (m, 1H), 7.24 (d, 2H), 6.95 (s, 2H), 6.00 (s,1H), 4.95 (d, 2H), 4.36 (q, 1H), 4.15 (t, 1H), 3.27 (dt, 4H), 3.10 — 2.79 (m, 2H), 2.68 — 2.56 (m, 2H),MEl 24985843V.1 629117813-126202.20 (s, 3H), 1.98 — 1.84 (m, 1H), 1.72 — 0.87 (m, 19H), 0.79 (dd, 13H). MS (ESI) m/e 1446.4 (M-H)’2.115 Synthesis of 2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-alpha-glutamyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SS)2.115.1 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)(1-((3-(2-((((4-((6S,9S,12S)(3-(tert-but0xy)0x0pr0pyl)is0pr0pyl-2,2-dimethyl-4,7,10-tri0x0(3-ureidopropyl)0xa-5,8,11-triazatridecanamid0)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-5-methyl-1H-pyrazolyl)pic01inic acidTo a mixture of Example 2.1122 (85 mg), oxybenzotriazole hydrate (41.3 mg), and(S)tert-butyl l-(2,5-dioxopyrrolidin-l -yl) 2-((tert-butoxycarbonyl)amino)pentanedioate (54.0 mg)in N,N-dimethylformamide (3 mL) at 0 CC was added N,N-diisopropylethylamine (118 uL) se,and the e was stirred at 0 CC for 1 hour. The mixture was purified by reverse-phase HPLC on aGilson system (C18 ), eluting with 35-100% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title compound. MS (ESI) m/e 773.4 (M+2H)2+.2,115.2 3-(1-((3-(2-((((4—((S)((S)((S)-2—amin0carboxybutanamido)methylbutanamid0)pentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidExample 2.1 15.1 (100 mg) in dichloromethane (11 mL) at 0 CC was treated withtrifluoroacetic acid (4 mL). The mixture was stirred at 0 CC for 3.5 hours and concentrated. Theresidue was purified by reverse phase HPLC, eluting with 5-60% acetonitrile in 0.1% trifluoroaceticacid water mixture to provide the title compound.3 N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)hexan0yl]-L-alpha-glutamyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-MEl 24985843v.l 630117813-12620sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideTo a mixture of 1-hydroxybenzotriazole hydrate (2.87 mg), oxopyrrolidinyl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate (5.77 mg) and e 2.1152 (13 mg) at 0 CCwas added N,N-diisopropylethylamine (13.08 uL), and the mixture was stirred at 0 CC for 1 hour.

The reaction was purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-75% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. 1H NMR(501 MHz, dimethyl sulfoxide-dé) 5 12.83 (s, 1H), 9.99 (s, 1H), 8.13 (d, 1H), 8.02 (dd, 1H), 7.97 (d,1H), 7.80 — 7.74 (m, 1H), 7.64 (t, 1H), 7.61 — 7.48 (m, 4H), 7.47 — 7.38 (m, 2H), 7.38 — 7.30 (m, 2H),7.29 — 7.23 (m, 3H), 6.96 (s, 2H), 6.93 (d, 1H), 5.99 (s, 1H), 5.06 — 4.88 (m, 5H), 4.37 (q, 1H), 4.28(q, 1H), 4.18 (dd, 1H), 3.86 (t, 2H), 3.78 (d, 2H), 3.34 (t, 3H), 3.23 (d, 2H), 2.99 (t, 3H), 2.97 — 2.85(m, 1H), 2.62 (dt, 1H), 2.26 — 2.15 (m, 2H), 2.16 — 2.00 (m, 5H), 2.01 — 1.79 (m, 1H), 1.75 — 1.50 (m,3H), 1.50 — 0.87 (m, 17H), 0.81 (dd, 14H). MS (ESI) m/e 1579.6 (M-H)’.2.116 Synthesis of N-[(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)acetyl]-L-alpha-glutamyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon TA)The title compound was prepared using the procedure in e 2.115.3, replacing 2,5-dioxopyrrolidin-l-yl 6-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)hexanoate with 2,5-dioxopyrrolidinyl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetate. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5.02 (s, 1H), 8.38 (d, 1H), 8.14 (d, 1H), 8.03 (d, 1H), 7.82 (dd, 2H), 7.60 (t, 3H), 7.55 — 7.40 (m,3H), 7.35 (td, 2H), 7.31 — 7.24 (m, 3H), 7.07 (s, 2H), 6.95 (d, 1H), 4.97 (d, 4H), 4.37 (ddd, 2H), 4.23— 4.05 (m, 3H), 3.88 (t, 6H), 3.80 (d, 2H), 3.25 (d, 2H), 3.09 — 2.88 (m, 4H), 2.64 (s, 2H), 2.22 (dd,2H), 2.09 (s, 3H), 2.02 — 1.49 (m, 5H), 1.47 — 0.89 (m, 12H), 0.83 (dd, 12H). MS (ESI) m/e 1523.5(M-H)’.2.117 Synthesis of 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]({[4-({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-D-valyl-N5-carbam0yl-D-yl}amin0)benzyl]0xy}carb0nyl)amin0}-1,2—dide0xy-D-arabin0-hexitol (Synthon TW)The title compound was prepared by substituting Example 1.77.2 for Example 1.2.9 ine 2.1. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 12.85 (bs, 1H), 9.98 (s, 1H), 8.06 (d,1H), 8.03 (d, 1H), 7.78 (t, 2H), 7.60 (m, 3H), 7.52-7.42 (m, 4H), 7.36 (q, 2H), 7.28 (s, 1H), 7.27 (d,MEl 24985843V.1 631117813-126202H), 6.99 (s, 1H), 6.95 (d, 1H), 5.97 (bs, 1H), 5.00 (m, 2H), 4.95 (s, 2H), 4.39 (m, 1H), 4.19 (m, 2H),3.88 (t, 2H), 3.79 (m, 4H), 3.58 (m, 4H), 3.46-3.33 (m, 10H), 3.26 (m, 4H), 3.01 (m, 2H), 2.94 (m,1H), 2.14 (m, 2H), 2.09 (s, 3H), 1.96 (m, 1H), 1.69 (m, 2H), 1.59 (m, 1H), 1.47 (m, 4H), 1.35 (m,4H), 1.28-1.03 (m, 10H), 0.95 (m, 2H), 0.82 (m, 12H). MS (ESI) m/e 1493 (M+H)+, 1491 .2.118 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[4-(1,3-benzothiazolylcarbamoyl)0xid0is0quinolinyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](methyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon ST)The title compound was prepared as described in Example 2.1, replacing Example 1.2.9with Example 1.88.4. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 13.29 (s, 2H), 9.95 (s, 1H),9.18 (s, 1H), 8.67 (s, 1H), 8.57 — 8.36 (m, 1H), 8.29 — 7.87 (m, 4H), 7.77 (dd, 2H), 7.56 (d, 2H), 7.53— 7.41 (m, 2H), 7.24 (d, 2H), 6.95 (s, 2H), 5.95 (s, 1H), 4.94 (s, 2H), 4.35 (q, 1H), 4.15 (dd, 1H), 3.84(s, 3H), 3.28 (dt, 4H), 3.06 — 2.77 (m, 3H), 2.19 (d, 3H), 2.17 — 1.80 (m, 3H), 1.74 — 0.88 (m, 22H),0.79 (dd, 13H). MS (ESI) m/e 1368.4 (M-H)’.2.119 Synthesis of N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)0x0--[(2-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiaz01ylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon ZL)2.119.1 (3R,7aS)phenyltetrahydropyrrolo[1,2-c]0xazol-5(3H)-0neA mixture of (S)(hydroxymethyl)pyrrolidinone (25g), benzaldehyde ) andpara-toluenesulfonic acid monohydrate (0.50 g) in e (300 mL) was heated to reflux using aDean-Stark trap under a drying tube for 16 hours. The reaction was cooled to room temperature, andthe solvent was decanted from the insoluble materials. The organic layer was washed with saturatedaqueous sodium bicarbonate mixture (2x) and brine (1x). The organic layer was dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residue was ed by flashchromatography on silica gel, g with 35/65 e/ethyl acetate, to give the title compound.

MS (DCI) m/e 204.0 .2.119.2 (3R,6R,7aS)br0m0phenyltetrahydr0pyrr010[1,2-c]0xazol-(3H)-0neTo a cold (-77 CC) mixture of Example 2.1191 (44.6 g) in ydrofuran (670 mL) wasadded lithium bis(trimethylsilyl)amide (1.0M in hexanes, 250 mL) dropwise over 40 minutes, keepingMEl 24985843V.1 632117813-12620Trxn < -73 CC. The reaction was stirred at -77 CC for 2 hours, and bromine (12.5 mL) was addeddropwise over 20 minutes, keeping Trxn < -64 CC. The reaction was stirred at -77 CC for 75 minutesand was quenched by the addition of 150 mL cold 10% aqueous sodium thiosulfate mixture to the -77CC reaction. The reaction was warmed to room temperature and partitioned n half-saturatedaqueous ammonium chloride mixture and ethyl acetate. The layers were separated, and the organiclayer was washed with water and brine, dried over sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by silica gel chromatography, eluting with a gradient of80/20, 75/25, and 70/30 heptane/ethyl acetate to give the title compound. MS (DCI) m/e 299.0 and301.0 (M+NH3+H)+.2.119.3 (3R,6S,7aS)br0m0phenyltetrahydropyrrolo[1,2-c]0xazol-The title compound was ed as a by-product from Example 2.119.2. MS (DCI) m/e299.0 and 301.0 (M+NH3+H)+.4 (3R,6S,7aS)azid0phenyltetrahydropyrr010[1,2-c]0xazol-5(3H)-0neTo a e of Example 2.1192 (19.3 g) in N,N-dimethylformamide (100 mL) wasadded sodium azide (13.5 g). The reaction was heated to 60 CC for 2.5 hours. The reaction wascooled to room temperature and ed by the addition of water (500 mL) and ethyl acetate (200mL). The layers were separated, and the organic layer was washed brine. The combined aqueouslayers were back-extracted with ethyl acetate (50 mL). The combined organic layers were dried withsodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silicagel chromatography, eluting with 78/22 e/ethyl acetate, to give the title compound. MS (DCI)m/e 262.0 (M+NH3+H)+.2.1195 (3R,6S,7aS)amin0phenyltetrahydropyrrolo[1,2-c]0xazol-5(3H)-0neTo a mixture of e 2.119.4 (13.5 g) in tetrahydrofuran (500 mL) and water (50 mL)was added polymer-supported triphenylphosphine (55 g). The on was mechanically stirredght at room temperature. The reaction was filtered through diatomaceous earth, eluting withethyl acetate and toluene. The e was concentrated under reduced pressure, dissolved indichloromethane (100 mL), dried with sodium sulfate, then filtered and concentrated to give the titlecompound, which was used in the subsequent step t further purification. MS (DCI) m/e 219.0(M+H)+.2.119.6 (3R,6S,7aS)(dibenzylamin0)phenyltetrahydr0pyrrolo[1,2-c]0xazol-5(3H)-0neTo a mixture of Example 2.1195 (11.3 g) in N,N-dimethylformamide (100 mL) wasadded potassium carbonate (7.0 g), potassium iodide (4.2 g), and benzyl bromide (14.5 mL). TheMEl 24985843V.1 633117813-12620reaction was stirred at room temperature overnight and quenched by the addition of water and ethylacetate. The layers were separated, and the organic layer was washed brine. The combined aqueouslayers were back-extracted with ethyl acetate. The ed organic layers were dried with sodiumsulfate, filtered and concentrated under reduced pressure. The e was purified by silica gelchromatography, eluting with a gradient of 10 to 15% ethyl acetate in heptane to give a solid that wastriturated with e to give the title compound. MS (DCI) m/e 399.1 (M+H)+.2.119.7 (3S,5S)(dibenzylamin0)(hydr0xymethyl)pyrrolidinoneTo a mixture of Example 2.1196 (13 g) in ydrofuran (130 mL) was added para-toluene sulfonic acid monohydrate (12.4 g) and water (50 mL), and the reaction was heated to 65 CCfor 6 days. The reaction was cooled to room temperature and quenched by the on of saturateds sodium bicarbonate and ethyl acetate. The layers were ted, and the organic layer waswashed with brine. The combined aqueous layers were back-extracted with ethyl acetate. Thecombined c layers were dried with sodium sulfate, filtered and concentrated under reducedpressure. The waxy solids were triturated with heptane (150 mL) to give the title compound. MS(DCI) m/e 311.1 (M+H)+.2.119.8 (3S,5S)(((tert-butyldimethylsilyl)0xy)methyl)(dibenzylamin0)pyrrolidinoneTo a mixture of Example 2.119.7 (9.3 g) and 1H-imidazole (2.2 g) in N,N-dimethylformamide was added tert-butylchlorodimethylsilane (11.2 mL, 50 weight % in toluene), andthe reaction mixture was stirred overnight. The reaction mixture was ed by the addition ofwater and ethyl ether. The layers were separated, and the organic layer was washed with brine. Thecombined aqueous layers were back-extracted with diethyl ether. The combined organic layers weredried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purifiedby silica gel chromatography, g with 35% ethyl acetate in heptane, to give the title compound.

MS (DCI) m/e 425.1 (M+H)+.2.119.9 tert-butyl2-((3S,5S)(((tert-butyldimethylsilyl)0xy)methyl)zylamino)0x0pyrrolidinyl)acetateTo a cold (0 CC) mixture of e 2.1198 (4.5 g) in tetrahydrofuran (45 mL) was added95% sodium hydride (320 mg) in two portions. The cold mixture was stirred for 40 minutes, and tert-butyl 2-bromoacetate (3.2 mL) was added. The reaction was warmed to room temperature and stirredovernight. The reaction was quenched by the addition of water and ethyl acetate. The layers wereseparated, and the organic layer was washed with brine. The combined aqueous layers were back-extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filteredand concentrated under reduced pressure. The residue was purified by silica gel chromatography,eluting with a gradient of 5-12% ethyl acetate in e, to give the title compound. MS (DCI) m/e539.2 (M+H)+.

MEl 24985843V.1 634117813-126202.119.10 tert-butyl ,5S)(dibenzylamino)(hydr0xymethyl)oxopyrrolidinyl)acetateTo a mixture of Example 2.1199 (5.3 g) in ydrofuran (25 mL) was addedtetrabutylammonium fluoride (11 mL, 1.0M in 95/5 tetrahydrofuran /water). The reaction was stirredat room temperature for one hour and then quenched by the addition of ted aqueous ammoniumchloride mixture, water and ethyl acetate. The layers were separated, and the organic layer waswashed with brine. The ed s layers were back-extracted with ethyl acetate. Thecombined organic layers were dried with sodium sulfate, filtered and concentrated under reducedpressure. The residue was ed by silica gel tography, eluting with 35% ethyl acetate inheptane, to give the title compound. MS (DCI) m/e 425.1 (M+H)+.2.119.11 tert-butyl 2-((3S,5S)((2—((4-((tert-butyldimethylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)(dibenzylamin0)oxopyrrolidinyl)acetateTo a mixture of e 2.119.10 (4.7 g) in dimethyl sulfoxide (14 mL) was added amixture of 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (14.5 g) in dimethylsulfoxide (14 mL). Potassium ate (2.6 g) and water (28 uL) were added, and the reaction washeated at 60 CC under nitrogen for one day. The reaction was cooled to room temperature, and thenquenched by the addition of brine mixture, water and diethyl ether. The layers were separated, andthe organic layer was washed with brine. The combined aqueous layers were back-extracted withdiethyl ether. The combined c layers were dried with sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gel chromatography, eluting with agradient of 15-25% ethyl acetate in heptane, to give the title compound. MS (ESI+) m/e 871.2(M+H)+.2.119.12 tert-butyl 2-((3S,5S)amin0((2-((4-((tert-butyldimethylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)0x0pyrrolidinyl)acetateExample 2.119.11 (873 mg) was dissolved in ethyl acetate (5 mL) and methanol (15 mL),and palladium hydroxide on carbon, 20% by wt (180 mg) was added. The reaction mixture wasstirred under a hydrogen atmosphere (30 psi) at room temperature for 30 hours, then at 50 CC for onehour. The reaction was cooled to room temperature, filtered, and concentrated to give the desiredproduct. MS (ESI+) m/e 691.0 .2.119.13 S,5S)(2-(tert-but0xy)0x0ethyl)((2-((4-((tert-butyldimethylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)0x0pyrrolidinyl)amin0)0x0buten0ic acidMEl 24985843V.1 635117813-12620Maleic anhydride (100 mg) was dissolved in dichloromethane (0.90 mL), and a mixture ofExample 12 (650 mg) in dichloromethane (0.90 mL) was added dropwise, then heated at 40 CCfor 2 hours. The reaction mixture was directly purified by silica gel chromatography, eluting with ant of 1.0-2.5% methanol in dichloromethane containing 0.2% acetic acid. After concentratingthe product-bearing fractions, toluene (10 mL) was added, and the e was trated again togive the title nd. MS (ESI-) m/e 787.3 (M-H)’.2.119.14 tert-butyl 2-((3S,5S)((2—((4-((tert-butyldimethylsilyl)0xy)-2,2-dimethylbutoxy)sulf0nyl)ethoxy)methyl)(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)0x0pyrrolidinyl)acetateExample 2.1 19. 13 (560 mg) was slurried in toluene (7 mL), and triethylamine (220 uL)and sodium sulfate (525 mg) were added. The reaction was heated at reflux under a nitrogenatmosphere for 6 hours, and the reaction mixture was stirred at room temperature overnight. Theon was filtered, and the solids were rinsed with ethyl acetate. The eluent was concentratedunder reduced pressure, and the residue was purified by silica gel chromatography, eluting with 45/55heptane/ethyl acetate to give the title compound.2.119.15 2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2-sulf0eth0xy)methyl)pyrrolidinyl)acetic acidExample 2.1 19. 14 (1.2 g) was dissolved in trifluoroacetic acid (15 mL) and heated to 65-70 CC under nitrogen overnight. The trifluoroacetic acid was removed under reduced re. Theresidue was dissolved in acetonitrile (2.5 mL) and purified by ative reverse-phase liquidchromatography on a Luna C18(2) AXIA column (250 x 50 mm, 10um particle size) using a gradientof 5-75% acetonitrile containing 0.1% trifluoroacetic acid in water over 30 minutes, to give the titlend. MS (ESI-) m/e 375.2 (M-H)’.2,119.16 3-(1-((3-(2-((((4-((S)((S)amin0methylbutanamid0)ureidopentanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)naphthalenyl)picolinic acidThe title compound was prepared by substituting Example 1.43.7 for e 1.2.9 inExample 2.49.1. MS (ESI-) m/e 1252.4 (M-H)’.2.119.17 N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2—sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-valyl-N-{4-[({[2—({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalen-2-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decMEl 24985843V.1 636117813-12620)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]phenyl}-N5-oyl-L-0rnithinamideExample 2.119.15 (7 mg) was dissolved in N,N-dimethylformamide (0.15 mL), and O-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (9 mg) and N,N-diisopropylethylamine (7 uL) were added. The mixture was stirred for 3 minutes at room temperatureand added to a mixture of e 2.119.16 (28 mg) and N,N-diisopropylethylamine (15 uL) in N,N-dimethylformamide (0.15 mL). After 1 hour, the reaction was diluted with N,N-dimethylformamide/water 1/ l (1.0 mL) and purified by reverse-phase tography (C18 column),eluting with 5-75% acetonitrile in 0.1% TFA water, to provide the title compound. 1H NMR (500MHz, dimethyl ide-d6) 5 ppm 9.95 (s, 1H), 9.02 (s, 1H), 8.37 (d, 1H), 8.22 (m, 2H), 8.18 (m,2H), 8.08 (m, 2H), 8.03 (m, 1H), 7.96 (br d, 1H), 7.81 (d, 1H), 7.70 (t, 1H), 7.61 (br m, 3H), 7.48 (m,2H), 7.37 (t, 1H), 7.27 (br m, 2H), 7.08 (s, 2H), 4.99 (br d, 3H), 4.68 (t, 1H), 4.39 (m, 1H), 4.20 (m,2H), 4.04 (m, 1H), 3.87 (br d, 2H), 3.74 (br m, 1H) 3.65 (br t, 2H), 3.48 (br m, 4H), 3.43 (br m, 2H),3.26 (br m, 2H), 3.00 (br m, 2H), 2.80 (m, 1H), 2.76 (m, 1H), 2.66 (br m, 2H), 2.36 (br m, 1H), 2.22(s, 3H), 2.00 (m, 1H), 1.87 (m, 1H), 1.69 (br m, 1H), 1.62 (br m, 1H), 1.40 (br m, 4H), 1.31-1.02 (m,H), 0.96 (m, 2H), 0.85 (m, 12H). MS (ESI-) m/e 1610.3 (M-H)’.2.120 Synthesis of N-{(2S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[4-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyloxy)phenyl]propanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)naphthalen-Z-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulf0ethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-thinamide (Synthon SX)2.120.1 (S)-methyl3-(4-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriac0ntanyloxy)phenyl)((tertbutoxycarbonyl)amin0)propanoateTo a mixture of 2,5,8,l1,14,l7,20,23,26,29,32-undecaoxatetratriacontanyl 4-methylbenzenesulfonate (82.48 g) and potassium ate (84.97 g) in acetonitrile (1.5 L) was added(S)-methyl 2-((tert-butoxycarbonyl)amino)-3 -(4-hydroxyphenyl)propanoate (72.63 g), and theon mixture was stirred at 30 CC for 12 hours. After LC/MS indicated the starting material wasconsumed and the major product was the desired product, the reaction was filtered, and the filtratewas concentrated to afford the crude product which was purified by prep-HPLC to provide the titlecompound. MS (ESI): m/e 811 (M+HZO)+.2.120.2 3-(4-(2,5,8,11,14,17,20,23,26,29,32—undecaoxatetratriacontan-34-yloxy)phenyl)((tert-butoxycarbonyl)amin0)propanoicMEl 24985843V.1 637117813-12620To a mixture of Example 2.1201 (90.00 g) in tetrahydrofuran (1.5 L) and water (500 mL)was added m hydroxide monohydrate (14.27 g). The on mixture was stirred at 30 CC for 12hours, and LC/MS indicated the starting material was ed and the major t was thedesired product. The reaction mixture was adjusted using aqueous HCl to pH=6, and the mixture wasconcentrated to provide the crude title compound. MS (ESI): m/e 778.3 (M-H)’.2,120.3 3-(4-(2,5,8,11,14,17,20,23,26,29,32—undecaoxatetratriacontan-34-yloxy)phenyl)amin0pr0pan0ic acidTo a mixture of Example 2.1202 (88.41 g) in dichloromethane (1.5 L) was addedtrifluoroacetic acid (100 mL) at 25 CC under N2, and the reaction mixture was stirred at 40 CC for 12hours. LC/MS indicated the starting al was consumed, and the major product was the desiredproduct. The mixture was concentrated to afford the crude product which was purified by prep-HPLCprovide the title compound as a trifluoroacetic acid salt. 1H NMR (400 MHz, CDCl3) 5 ppm 7.20 (d,J=8.6 Hz, 2H), 6.93 (d, J=8.2 Hz, 2H), 4.22 (dd, J=5.5, 7.4 Hz, 1H), 4.14-4.06 (m, 2H), 3.84 - 3.79(m, 2H), 3.68-3.50 (m, 40H), 3.33 (s,3H), 3.21 (d, J=5.5 Hz, 1H), 3.12-3.05 (m,1H). MS (ESI) m/e680.1 (M+H)+.2.120.4 4-((2-(4-(2,5,8,11,14,17,20,23,26,29,32-undeca0xatetratriac0ntanyloxy)phenyl)carboxyethyl)amin0)0x0but-2—en0ic acidTo a mixture of Example 2.1203 (80.00 g) in dioxane (l L) was added 2, 5-dione(35 g), and the reaction mixture was stirred at 120 CC for 4 hours. LC/MS indicated the ngmaterial was consumed, and the major t was the desired product. The mixture wasconcentrated to afford crude title compound which was used without cation in the next step. MS(ESI) m/e 795.4 (M+H)+.2.1205 (S)(4-(2,5,8,11,14,17,20,23,26,29,32-undeca0xatetratriac0ntanyloxy)phenyl)(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)pr0pan0ic acidTo a mixture of Example 2.120.4 (96 g, crude) in toluene (1.5 L) and was addedtriethylamine (35.13 g), and the reaction mixture was stirred at 120 CC for 4 hours. LC/MS indicatedthe starting material was consumed, and the major product was the desired product. The reaction wasfiltered to isolate the organic phase, and the organics were trated to afford the crude productwhich was purified by prep-HPLC (Instrument: zu LC-20AP preparative HPLC, Column:enex® Luna® (2) C18 250*50mm i.d. 10u, Mobile phase: A for H20 (0.09% roaceticacid) and B for CH3CN, Gradient: B from 15% to 43 % in 20 minutes, Flow rate: 80 ml/minute,Wavelength: 220 & 254 nm, Injection amount: 1 gram per injection), followed by SFC-HPLC toprovide the title compound. 1H NMR (400 MHz, CDCl3) 5 ppm 6.98 (d, 2H), 6.74 (d, 2H), 6.56 (s,2H), 4.85 (dd, 1H), 4.03 (t, 2H), 3.84 - 3.76 (m, 2H), 3.71 - 3.66 (m, 2H), 3.65 - 3.58 (m, 39H), 3.55 -3.50 (m, 2H), 3.41 - 3.30 (m, 4H). MS (ESI) m/e 760.3 (M+H)+.

MEl 24985843V.1 638117813-126202.120.6 N-{(2S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[4-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyloxy)phenyl]propanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.l.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamideThe title compound was prepared by tuting Example 2.1205 for Example 2.119.15in Example 2.119.17. 1H NMR (400 MHZ, dimethyl sulfoxide-dg) 5 ppm 10.03 (s, 1H), 9.02 (s, 1H),8.37 (d, 1H), 8.22 (m, 3H), 8.16 (d, 1H), 8.12 (br m, 1H), 8.07 (d, 1H), 8.01 (d, 1H), 7.96 (br d, 1H),7.81 (d, 1H), 7.70 (t, 1H), 7.59 (br m, 2H), 7.48 (m, 2H), 7.37 (t, 1H), 7.28 (d, 2H), 7.02 (d, 2H), 6.89(s, 2H), 6.77 (d, 2H), 4.98 (br d, 2H), 4.79 (dd, 1H), 4.39 (br m, 1H), 4.23 (br m, 2H), 3.99 (br m, 2H),3.88 (br m, 2H), 3.69 (br m, 4H), 3.55 (m, 4H), 3.50 (s, 32H), 3.42 (m, 4H), 3.27 (m, 4H), 3.23 (s,3H), 3.20 (m, 1H), 3.03 (br m, 1H), 2.98 (m, 1H), 2.65 (br t, 2H), 2.22 (s, 3H), 1.97 (br m, 1H), 1.69(br m, 1H), 1.61 (br m, 1H), 1.39 (m, 4H), 1.31-0.91 (m, 12H), 0.85 (m, 9H), 0.77 (d, 3H). MS (ESI)m/e 1993.7 .2.121 Synthesis of N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)0x0--[(2-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-carb0xypyridin—3-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SW)The title compound was prepared by substituting Example 2.49.1 for Example 16 inExample 2.119.17. 1H NMR (400 MHZ, dimethyl sulfoxide-dg) 5 ppm 9.96 (s, 1H), 8.17 (br d, 1H),8.03 (d, 2H), 7.79 (d, 1H), 7.61 (m, 3H), 7.55 (d, 1H), 7.45 (m, 2H), 7.37 (m, 3H), 7.27 (d, 2H), 7.08(s, 2H), 6.98 (d, 1H), 4.97 (m, 4H), 4.68 (t, 1H), 4.37 (br m, 1H), 4.22 (br s, 1H), 4.17 (d, 1H), 4.03(d, 1H), 3.89 (br t, 2H), 3.83 (br d, 2H), 3.74 (br m, 1H), 3.65 (t, 2H), 3.49 (m, 3H), 3.40 (br m, 4H),3.25 (br m, 2H), 3.02 (br m, 4H), 2.80 (m, 2H), 2.67 (br m, 2H), 2.37 (br m, 1H), 2.10 (s, 3H), 1.99(m, 1H), 1.86 (m, 1H), 1.69 (br m, 1H), 1.61(br m, 1H), 1.52-0.91 (m, 16H), 0.85 (m, 12H). MS(ESI) m/e 1615.4 (M-H)’.2.122 Synthesis of N-{(2S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[4-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyloxy)phenyl]propanoyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-MEl 24985843V.1 639117813-12620dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon TV)To a mixture of Example 2.1205 (19.61 mg), and O-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium orophosphate (9.81 mg) in N,N-dimethylformamide (0.8 mL) was addedN,N-diisopropylethylamine (27.7 uL). The mixture was stirred for 5 minutes and added to a coldmixture of e 2.1122 in N,N-dimethylformamide (0.5 mL) at 0 CC. The reaction mixture wasstirred at 0 CC for 40 minutes, and purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlecompound. 1H NMR (400 MHz, yl sulfoxide-d6) 5 9.99 (s, 1H), 8.19 (d, 1H), 8.14 — 8.04 (m,1H), 8.00 (dd, 1H), 7.75 (d, 1H), 7.62 — 7.52 (m, 3H), 7.49 (d, 1H), 7.46 — 7.37 (m, 2H), 7.36 — 7.29(m, 2H), 7.28 — 7.21 (m, 3H), 6.99 (d, 2H), 6.92 (d, 1H), 6.85 (s, 2H), 6.79 — 6.71 (m, 2H), 4.94 (d,3H), 4.76 (dd, 1H), 4.35 (d, 1H), 4.20 (t, 1H), 3.96 (dd, 2H), 3.85 (t, 2H), 3.77 (d, 2H), 3.66 (dd, 2H),3.52 (dd, 2H), 3.50 — 3.47 (m, 2H), 3.39 (dd, 2H), 3.20 (s, 4H), 2.97 (t, 3H), 2.60 (t, 2H), 2.13 — 2.01(m, 3H), 1.93 (s, 1H), 1.61 (d, 2H), 1.49 — 0.88 (m, 10H), 0.87 — 0.59 (m, 12H). MS (ESI) m/e 1998.72.123 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gu10nic acid(Synthon SZ)2,123.1 (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)(benzyloxymethyl)-tetrahydropyran-Z-oneTo a mixture of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)((benzyloxy)methyl)tetrahydro-2H-pyranol (75 g) in dimethyl sulfoxide (400 mL) at 0 CC was added acetic anhydride (225 mL).

The mixture was stirred for 16 hours at room temperature before it was cooled to 0 CC. A largevolume of water was added, and stirring was stopped so that the on mixture was allowed tosettle for 3 hours (the crude lactone migrated to the bottom of the flask). The supernatant wasremoved, and the crude mixture was diluted with ethyl acetate and was washed 3 times with water,neutralized with saturated s mixture of NaHCO3, and washed again twice with water. Theorganic layer was then dried over magnesium sulfate, filtered and concentrated to give the titlecompound. MS (ESI) m/e 561 (M+Na)+.

MEl 24985843V.1 640117813-126202,123.2 ,5R,6R)-3,4,5-tris(benzyloxy)(benzyloxymethyl)ethynyl- tetrahydro-ZH-pyran-Z-olTo a mixture of ethynyltrimethylsilane (18.23 g) in tetrahydrofuran (400 mL) underen and chilled in a dry ice/acetone bath (internal temp -65 0C) was added 2.5M BuLi in hexane(55.7 mL) dropwise, keeping the temperature below -60 CC. The mixture was stirred in a cold bathfor 40 minutes, followed by an ice-water bath (internal temp rose to 04°C) for 40 s, and finallycooled to -75°C again. A mixture of Example 2123.1 (50 g) in tetrahydrofuran (50 mL) was addeddropwise, g the internal temperature below -70 CC. The mixture was stirred in a dryice/acetone bath for additional 3 hours. The reaction was quenched with saturated aqueous NaHCO3e (250 mL). The mixture was allowed to warm to room temperature, extracted with ethylacetate (3x 300 mL), dried over MgSO4, filtered, and trated in vacuo to give the titlecompound. MS (ESI) m/e 659 (M+Na)+.2,123.3 trimethyl(((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)(benzyloxymethyl)-tetrahydr0-2H-pyranyl)ethynyl)silaneTo a mixed mixture of Example 2.1232 (60 g) in acetonitrile (450 mL) anddichloromethane (150 mL) at -15 0C in an ice-salt bath was added triethylsilane (81 mL) dropwise,followed by addition of boron trifluoride diethyl ether complex (40.6 mL) at such a rate that theinternal temperature did not exceed -10 CC. The mixture was then stirred at -15 0C to -10 0C for 2hours. The reaction was quenched with saturated s NaHCO3 mixture (275 mL) and stirred for1 hour at room temperature. The mixture was then extracted with ethyl acetate (3 x 550 mL). Theextracts were dried over MgSO4, filtered, and concentrated. The e was purified by flashchromatography eluting with a gradient of 0% to 7% ethyl acetate/petroleum ether to give the titlecompound. MS (ESI) m/e 643 (M+Na)+.2,123.4 (2R,3R,4R,5S)-3,4,5-tris(benzyloxy)(benzyloxymethyl)ethynyl-tetrahydro-2H-pyranTo a mixed mixture of Example 2.1233 (80 g) in dichloromethane (200 mL) and methanol(1000 mL) was added 1N aqueous NaOH mixture (258 mL). The mixture was d at roomtemperature for 2 hours. The solvent was d. The residue was then partitioned n waterand dichloromethane. The ts were washed with brine, dried over NazSO4, filtered, andtrated to give the title compound. MS (ESI) m/e 571 (M+Na)+.2,123.5 (2R,3R,4R,5S)(acet0xymethyl)ethynyl-tetrahydr0-2H-pyran-3,4,5-triyl triacetateTo a mixture of Example 2123.4 (66 g) in acetic anhydride (500 mL) cooled by anice/water bath was added boron trifluoride diethyl ether complex (152 mL) dropwise. The mixturewas d at room temperature for 16 hours, cooled with an ice/water bath and neutralized withsaturated aqueous NaHCO3 mixture. The mixture was extracted with ethyl acetate (3x500 mL), driedover NaZSO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatographyMEl 24985843V.1 641117813-12620eluting with a gradient of 0% to 30% ethyl acetate/petroleum ether to give the title compound. MS(ESI) m/e 357 (M+H)+.2,123.6 (3R,4R,5S,6R)ethynyl(hydroxymethyl)-tetrahydr0-2H-pyran-3,4,5-triolTo a mixture of Example 2123.5 (25 g) in methanol (440 mL) was added sodiummethanolate (2.1 g). The mixture was d at room temperature for 2 hours, and then neutralizedwith 4 M HCl in dioxane. The solvent was removed, and the residue was adsorbed onto silica gel andloaded onto a silica gel column. The column was eluted with a gradient of 0 to 100% ethylacetate/petroleum ether then 0% to 12% methanol/ethyl acetate to give the title compound. MS (ESI)m/e 211 (M+Na)+.2,123.7 (2S,3S,4R,5R)ethynyl-3,4,5-trihydr0xy-tetrahydro-ZH-2-carb0xylic acidA three-necked round bottom flask was charged with e 2.1236 (6.00 g), KBr (0.30g), utylammonium bromide (0.41 g) and 60 mL of saturated aqueous NaHCO3 e.

TEMPO ((2,2,6,6—tetramethylpiperidin—l—yl)oxyl, 0.15 g) in 60 mL dichloromethane was added. Themixture was stirred vigorously and cooled in an ice-salt bath to -2 CC internal temperature. A mixtureof brine (12 mL), aqueous NaHCO3 mixture (24 mL) and NaOCl (154 mL) was added dropwise suchthat the internal temperature was maintained below 2 CC. The pH of the reaction mixture wasmaintained in the 8.2-8.4 range with the addition of solid NaZCO3. After a total of 6 hours, thereaction mixture was cooled to 3 CC internal temperature and ethanol (~20 mL) was added dropwise.

The mixture was stirred for ~ 30 minutes. The mixture was transferred to a tory funnel, and thedichloromethane layer was discarded. The pH of the aqueous layer was ed to 2-3 using 1 Ms HCl. The aqueous layer was then concentrated to s to afford a solid. Methanol (100mL was) added to the dry solid, and the slurry was stirred for ~30 minutes. The mixture was filteredover a pad of diatomaceous earth, and the residue in the funnel was washed with ~100 mL ofmethanol. The te was concentrated under reduced pressure to obtain the title compound.2,123.8 (2S,3S,4R,5R)-methyl6-ethynyl-3,4,5-trihydr0xytetrahydr0-2H-pyrancarb0xylateA 500 mL three-necked round bottom flask was charged with a suspension of Example2123.7 (6.45 g) in methanol (96 mL) and was cooled in an ice-salt-bath with internal ature of -1 CC. Neat thionyl chloride (2.79 mL) was carefully added. The internal temperature kept risingthroughout the addition but did not exceed 10 CC. The reaction was allowed to slowly warm up to 15-CC over 2.5 hours. After 2.5 hours, the reaction was concentrated to give the title compound.2.123.9 (3S,4R,5S,6S)ethynyl(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl tateTo Example 2123.8 (6.9 g) as a mixture in N,N-dimethylformamide (75 mL) was added4-(dimethylamino)pyridine (0.17 g) and acetic anhydride (36.1 mL). The suspension was cooled in anMEl 24985843V.1 642117813-12620th and pyridine (18.04 mL) was added via syringe over 15 minutes. The reaction was allowedto warm to room temperature overnight. Additional acetic anhydride (12 mL) and pyridine (6 mL)were added and stirring was continued for an additional 6 hours. The on was cooled in an ice-bath and 250 mL of saturated aqueous NaHCO3 mixture was added and stirred for 1 hour. Water(100 mL) was added, and the mixture was extracted with ethyl e. The organic extract waswashed twice with ted CuSO4 mixture, dried, filtered, and concentrated. The residue waspurified by flash tography, eluting with 50% ethyl acetate/petroleum ether to give the titlecompound. 1H NMR (500 MHz, methanol-d4) 5 ppm 5.29 (t, 1H), 5.08 (td, 2H), 4.48 (dd, 1H), 4.23(d, 1H), 3.71 (s, 3H), 3.04 (d, 1H), 2.03 (s, 3H), 1.99 (s, 3H), 1.98 (s, 4H).2,123.10 2-i0d0nitr0benzoic acidA 3L fully jacketed flask equipped with a mechanical stirrer, temperature probe and anaddition funnel under a nitrogen atmosphere, was charged with 2-aminonitrobenzoic acid (69.1 g,Combi-Blocks) and sulfuric acid, 1.5 M aqueous (696 mL). The resulting suspension was cooled to 0CC internal temperature, and a mixture of sodium nitrite (28.8 g) in water (250 mL) was addedse over 43 minutes with the temperature kept below 1 CC. The reaction was stirred at ca. 0 CCfor 1 hour. A mixture of potassium iodide (107 g) in water (250 mL) was added dropwise over 44minutes with the internal temperature kept below 1 CC. (Initially addition was rmic and therewas gas evolution). The reaction was stirred 1 hour at 0 CC. The temperature was raised to 20 CC andthen stirred at ambient temperature overnight. The on mixture became a suspension. Thereaction mixture was filtered, and the collected solid was washed with water. The wet solid (~ 108 g)was stirred in 10 % sodium sulfite (350 ml, with ~ 200 mL water used to wash in the solid) for 30minutes. The suspension was acidified with concentrated hydrochloric acid (35 mL), and the solidwas collected by filtration and washed with water. The solid was slurried in water (1L) and re-filtered, and the solid was left to dry in the funnel ght. The solid was then dried in a vacuumoven for 2 hours at 60 CC. The ing solid was triturated with dichloromethane (500 mL), and thesuspension was filtered and washed with additional dichloromethane. The solid was air-dried to givethe title compound2,123.11 (2-i0d0nitrophenyl)methanolA flame-dried 3 L 3-necked flask was charged with Example 2.123.10 (51.9 g) andtetrahydrofuran (700 mL). The mixture was cooled in an ice bath to 0.5 CC, and boranetetrahydrofurancomplex (443 mL, 1M in THF) was added dropwise (gas evolution) over 50 minutes,reaching a final al temperature of 1.3 C’C. The reaction mixture was stirred for 15 s, andthe ice bath was removed. The reaction was left to come to ambient temperature over 30 minutes. Aheating mantle was installed, and the reaction was heated to an internal temperature of 65.5 CC for 3hours, and then allowed to cool to room temperature while stirring overnight. The reaction mixturewas cooled in an ice bath to 0 CC and quenched by dropwise on of methanol (400 mL). After abrief incubation , the temperature rose quickly to 2.5 C’C with gas evolution. After the first 100MEl 24985843V.1 643117813-12620mL are added over ~ 30 minutes, the addition was no longer exothermic, and the gas evolution ceased.

The ice bath was removed, and the mixture was stirred at ambient temperature under nitrogenovernight. The mixture was trated to a solid, dissolved in dichloromethane/methanol andadsorbed on to silica gel (~ 150 g). The residue was loaded on a plug of silica gel (3000 mL) andeluted with dichloromethane to give the title compound.2,123.12 (4-amin0i0d0phenyl)methanolA 5 L flask equipped with a mechanical stirrer, heating mantle controlled by a JKEMtemperature probe and a condenser was charged with Example 2.123.11 (98.83 g) and ethanol (2 L).

The reaction was stirred rapidly, and iron (99 g) was added, followed by a mixture of ammoniumchloride (20.84 g) in water (500 mL). The reaction was heated over the course of 20 minutes to anal temperature of 80.3 C’C, where it began to reflux vigorously. The mantle was dropped untilthe reflux calmed. Thereafter, the mixture was heated to 80 CC for 1.5 hour. The reaction was filteredhot h a membrane , and the iron residue was washed with hot 50% ethyl acetate/methanol(800 mL). The eluent was passed through a diatomaceous earth pad, and the filtrate was concentrated.

The residue was partitioned between 50% brine (1500 mL) and ethyl acetate (1500 mL). The layerswere separated, and the aqueous layer was extracted with ethyl acetate (400 mL x 3). The edorganic layers were dried over sodium e, filtered and concentrated to give the title compound,which was used without further purification.2.123.13 4-(((tert-butyldimethylsilyl)0xy)methyl)i0doanilineA 5 L flask with a mechanical stirrer was charged with Example 2.123.12 (88 g) anddichloromethane (2 L). The suspension was cooled in an ice bath to an al temperature of 2.5 CC,and tert-butylchlorodimethylsilane (53.3 g) was added portion-wise over 8 minutes. After 10 minutes,1H-imidazole (33.7 g) was added portionwise to the cold reaction. The reaction was stirred 90minutes while the al ature rose to 15 CC. The reaction mixture was diluted with water (3L) and dichloromethane (1 L). The layers were separated, and the organic layer was dried oversodium sulfate, filtered, and concentrated to an oil. The residue was purified by silica gelchromatography (1600 g silica gel), eluting a gradient of 0 - 25% ethyl e in heptane, to give thetitle compound as an oil.14 ((S)((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanoic acidTo a mixture of (S)((((9H-fluorenyl)methoxy)carbonyl)amino)methylbutanoicacid (6.5 g) in dimethoxyethane (40 mL) was added (S)aminopropanoic acid (1.393 g) and sodiumbicarbonate (1.314 g) in water (40 mL). Tetrahydrofuran (20 mL) was added to aid lity. Theresulting mixture was stirred at room temperature for 16 hours. Aqueous citric acid (15%, 75 mL)was added, and the mixture was extracted with 10% 2-propanol in ethyl acetate (2 x 100 mL). Aprecipitate formed in the organic layer. The combined organic layers were washed with water (2 x150 mL). The organic layer was concentrated under reduced re and then triturated with diethylMEl 24985843V.1 644117813-12620ether (80 mL). After brief sonication, the title compound was collected by filtration. MS (ESI) m/e411 (M+H)+.2,123.15 (9H-flu0ren-9—yl)methyl ((S)(((S)((4-(((tertbutyldimethylsilylethyl)i0d0phenyl)amin0)oxopropan-Z-yl)amin0)methyl0x0butanyl)carbamateA e of e 2.123.13 (5.44 g) and Example 14 (6.15 g) in a mixture ofdichloromethane (70 mL) and ol (35.0 mL) was added ethyl 2-ethoxyquinoline-l(2H)-carboxylate (4.08 g), and the reaction was stirred overnight. The reaction mixture was concentratedand loaded onto silica gel, eluting with a gradient of 10% to 95% heptane in ethyl acetate followed by5% methanol in dichloromethane. The product-containing fractions were concentrated, dissolved in0.2% methanol in dichloromethane (50 mL), loaded onto silica gel and eluted with a gradient of 0.2%to 2% methanol in dichloromethane. The product containing fractions were collected to give the titlecompound. MS (ESI) m/e 756.0 (M+H)+.2,123.16 (2S,3S,4R,5S,6S)((5-((S)((S)((((9H-flu0ren-9—yl)meth0xy)carbonyl)amin0)methylbutanamido)propanamid0)(((tertbutyldimethylsilyl)0xy)methyl)phenyl)ethynyl)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl tateA mixture of Example 2.1239 (4.500 g), e 2.123.15 (6.62 g), (I) iodide(0.083 g) and bis(triphenylphosphine)palladium(II) dichloride (0.308 g) were combined in vial anddegassed. N,N-dimethylformamide (45 mL) and N-ethyl-N-isopropylpropanamine (4.55 mL) wereadded, and the reaction vessel was flushed with nitrogen and stirred at room temperature overnight.

The reaction was partitioned between water (100 mL) and ethyl acetate (250 mL). The layers wereseparated, and the organic layer was dried over magnesium e, filtered, and concentrated. Thee was purified by silica gel chromatography, eluting with a gradient of 5% to 95% ethyl acetatein heptane. The product containing fractions were collected, concentrated and purified by silica gelchromatography, eluting with a nt of 0.25% to 2.5% methanol in dichloromethane to give thetitle compound. MS (ESI) m/e 970.4 (M+H)+.2,123.17 (2S,3S,4R,5S,6S)(5-((S)((S)-2—((((9H-flu0ren-9—yl)meth0xy)carbonyl)amin0)methylbutanamido)propanamid0)(((tert-butyldimethylsilyl)0xy)methyl)phenethyl)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 2.123.16 (4.7 g) and tetrahydrofuran (95 mL) were added to 5% Pt/C (2.42 g,wet) in a 50 mL re bottle and shaken for 90 minutes at room temperature under 50 psi ofhydrogen. The reaction was filtered and concentrated to give the title compound. MS (ESI) m/e974.6 (M+H)+.

MEl 24985843V.1 645117813-126202,123.18 (2S,3S,4R,5S,6S)(5-((S)((S)-2—((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanamido)xymethyl)phenethyl)(methoxycarbonyl)tetrahydro—2H-pyran-3,4,5-triyl triacetateA mixture of e 2.123.17 (5.4 g) in tetrahydrofuran (7 mL), water (7 mL) andglacial acetic acid (21 mL) was stirred overnight at room temperature. The reaction was d withethyl acetate (200 mL) and washed with water (100 mL), saturated s NaHCO3 mixture (100mL), brine (100 mL), dried over magnesium sulfate, filtered, and concentrated. The residue waspurified by silica gel chromatography, eluting with a gradient of 0.5% to 5% methanol indichloromethane, to give the title compound. MS (ESI) m/e 860.4 (M+H)+.2,123.19 (2S,3S,4R,5S,6S)(5-((S)((S)-2—((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanamid0)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phenethyl)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a mixture of Example 2.123.18 (4.00 g) and bis(4-nitrophenyl) carbonate (2.83 g) inacetonitrile (80 mL) was added N-ethyl-N-isopropylpropanamine (1.22 mL) at room temperature.

After stirring overnight, the reaction was concentrated, dissolved in dichloromethane (250 mL) andwashed with saturated aqueous NaHCO3 mixture (4 x 150 mL). The c layer was dried overmagnesium sulfate, filtered, and trated. The resulting foam was purified by silica gelchromatography, eluting with a gradient of 5% to 75% ethyl e in hexanes to give the titlecompound. MS (ESI) m/e 1025.5 (M+H)+.3-(1-((3-(2-((((4—((R)((R)amin0methylbutanamido)propanamid0)(2-((2S,3R,4R,5S,6S)y-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)benzyl)0xy)carbonyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidTo a cold (0 CC) mixture of Example 2.123.19 (70 mg) and Example 1.2.9 (58.1 mg) inN,N-dimethylformamide (4 mL) was added N-ethyl-N-isopropylpropanamine (0.026 mL). Thereaction was slowly warmed to room temperature and stirred overnight. To the on mixture wasadded water (1 mL) and LiOH H20 (20 mg). The mixture was stirred at room temperature for 3hours. The e was acidified with trifluoroacetic acid, filtered and purified by reverse-phaseHPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title compound. MS (ESI) m/e 1564.4 (M-H)’.

MEl 24985843V.1 646117813-126202,123.21 (6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)acetyl]-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonic acidThe title compound was prepared as described in Example 2.54, replacing Example 2.49.1with Example 2.123.20. 1H NMR (500 MHZ, dimethyl sulfoxide-d6) 5 ppm 12.86 (s, 1H), 9.92 (d,1H), 8.35 — 8.19 (m, 2H), 8.04 (d, 1H), 7.80 (d, 1H), 7.61 (d, 1H), 7.57 — 7.32 (m, 8H), 7.28 (s, 1H),7.22 (d, 1H), 7.08 (s, 2H), 6.95 (d, 1H), 5.12 — 4.91 (m, 5H), 4.39 (t, 1H), 4.32 — 4.19 (m, 1H), 4.12 (s,2H), 3.89 (t, 2H), 3.80 (d, 2H), 3.14 (t, 1H), 3.06 — 2.87 (m, 4H), 2.69 — 2.58 (m, 4H), 2.37 (p, 1H),2.09 (d, 4H), 2.04 — 1.91 (m, 4H), 1.54 (d, 1H), 1.40 — 0.99 (m, 20H), 0.99 — 0.74 (m, 16H). MS(ESI) m/e 1513.5 (M-H)’.2.124 Synthesis of 3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl]({[4-(4-{[6-(2,5-di0x0-2,5-dihydr0-lH-pyrrol-lyl)hexanoyl]amin0}butyl)(beta-D-glucopyranuronosyloxy)benzyl]oxy}carbonyl)amin0}pr0pyl beta-D-glucopyranosiduronic acid (Synthon ZM)2.124.1A (9H-flu0renyl)methyl butynylcarbamateA mixture of butynamine hydrochloride (9 g) and isopropylethylamine (44.7mL) was stirred in romethane (70 mL) and cooled to 0 CC. A mixture of (9H-fluorenyl)methyl carbonochloridate (22.06 g) in dichloromethane (35 mL) was added, and the on stirredfor 2 hours. The reaction was concentrated, and the residue purified by silica gel chromatography,eluting with petroleum ether in ethyl acetate (10%-25%) to give the title compound. MS (ESI) m/e314 +.2.124.1B (3R,4S,5S,6S)(2-f0rmyli0d0phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateTo a stirred solution of 2-hydroxyiodobenzaldehyde (0.95 g) in acetonitrile (10 ml) wasadded (3R,4S,5S,6S)bromo(methoxycarbonyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (2.5 g)and silver oxide (2 g). The mixture was covered with um foil and was stirred at roomtemperature overnight. After filtration through diatomaceous earth, the filtrate was washed with ethylacetate, the on was trated. The reaction mixture was purified by flash chromatographyusing an ISCO CombiFlash system, SF40-80g column, eluted with 15-30% ethyl acetate/heptane(flow rate : 60ml/min), to provide the title compound. MS (ESI) m/e 586.9 (M+Na)+.

MEl 24985843v.1 647117813-126202.1242 (2S,3S,4S,5R,6S)-methyl6-(5-(4-(((9H-flu0renyl)meth0xy)carbonylamin0)butynyl)f0rmylphen0xy)-3,4,5-triacet0xy-tetrahydr0-2H-pyrancarb0xylateExample 2.124.1B (2.7 g), Example 2.124.1A (2.091 g),iphenylphosphine)palladium(II) chloride (0.336 g) and copper(I) iodide (0.091 g) were weighedinto a vial and flushed with a stream of nitrogen. Triethylamine (2.001 mL) and tetrahydrofuran (45mL) were added, and the reaction stirred at room temperature. After stirring for 16 hours, the onwas diluted with ethyl acetate (200 mL) and washed with water (100 mL) and brine (100 mL). Theorganic layer was dried over magnesium sulfate, filtered, and concentrated. The residue was purifiedby silica gel chromatography, eluting with petroleum ether in ethyl acetate (10%-50%), to give thetitle compound. MS (ESI) m/e 750 (M+Na)+.2,124.3 (2S,3S,4S,5R,6S)-methyl6-(5-(4-(((9H-flu0renyl)meth0xy)carbonylamin0)butyl)f0rmylphen0xy)-3,4,5-triacetoxy-tetrahydro-ZH-pyrancarb0xylateExample 2.1242 (1.5 g) and tetrahydrofuran (45 mL) were added to 10% Pd-C (0.483 g)in a 100 mL pressure bottle and d for 16 hours under 1 atm H2 at room temperature. Thereaction was filtered and concentrated to give the title compound. MS (ESI) m/e 754 (M+Na)+.2.124.4 (2S,3S,4S,5R,6S)-methyl6-(5-(4-(((9H-flu0renyl)meth0xy)carbonylamin0)butyl)(hydr0xymethyl)phenoxy)-3,4,5-triacet0xy-tetrahydr0-2H-pyrancarb0xylateA mixture of Example 2.1243 (2.0 g) in tetrahydrofuran (7.00 mL) and ol (7 mL)was cooled to 0 CC and NaBH4 (0.052 g) was added in one portion. After 30 minutes, the reactionwas diluted with ethyl acetate (150 mL) and water (100 mL). The organic layer was separated,washed with brine (100 mL), dried over magnesium sulfate, filtered, and trated. The residuewas purified by silica gel chromatography, eluting with petroleum ether in ethyl e (10% -40%),to give the title compound. MS (ESI) m/e 756 (M+Na)+.2.1245 ,4S,5R,6S)-methyl6-(5-(4-(((9H-flu0renyl)meth0xy)carbonylamin0)butyl)(((4-nitrophenoxy)carb0nyloxy)methyl)phenoxy)-3,4,5-triacet0xy-tetrahydro-ZH-pyran-2—carb0xylateTo a e of Example 2.124.4 (3.0 g) and bis(4-nitrophenyl) carbonate (2.488 g) in dryitrile (70 mL) at 0 CC was added N,N-diisopropylethylamine (1.07 mL). After stirring at roomtemperature for 16 hours, the reaction was concentrated to give the residue, which was purified bysilica gel chromatography, eluting with petroleum ether in ethyl acetate (10%-50%), to give the titlecompound. MS (ESI) m/e 921 (M+Na)+.

MEl 24985843V.1 648117813-126202.124.6 3-(1-((3-(2-((((4—(4-amin0butyl)(((2R,3S,4R,5R,6R)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(3-(((2S,3S,4R,5R,6R)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)pr0pyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)naphthalenyl)picolinic acidTo a cold (0 CC) mixture of Example 2.1245 (44 mg) and Example 1.87.3 (47.4 mg) inN,N-dimethylformamide (4 mL) was added N-ethyl-N-isopropylpropanamine (0.026 mL). Theon was slowly warmed to room temperature and stirred overnight. To the reaction mixture wasadded water (1 mL) and LiOH H20(20 mg). The mixture was stirred at room temperature for 3 hours.

The mixture was acidified with trifluoroacetic acid, filtered and purified by reverse-phase HPLC on aGilson system (C18 column), eluting with 20-80% acetonitrile in water ning 0.1%trifluoroacetic acid, to give the title compound. MS (ESI) m/e 1564.4 (M-H)’.2.124.7 3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalen-Z-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyc10[3.3.1.13,7]decyl}0xy)ethyl]({[4-(4-{[6-(2,5-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amin0}butyl)(beta-D-glucopyranuronosyloxy)benzyl]0xy}carb0nyl)amin0}pr0pyl-glucopyranosiduronic acidThe title compound was prepared as described in Example 2.5.4, replacing Example 2.5.3with Example 2.124.6. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 13.06 (s, 2H), 8.99 (s, 1H),8.34 (dd, 1H), 8.25 — 8.09 (m, 3H), 8.08 — 8.02 (m, 1H), 7.98 (d, 1H), 7.89 (d, 1H), 7.78 (d, 1H), 7.66(q, 2H), 7.50 — 7.41 (m, 2H), 7.37 — 7.31 (m, 1H), 7.14 (t, 1H), 6.94 (s, 2H), 6.90 (s, 1H), 6.82 (d,1H), 5.14 — 5.02 (m, 2H), 4.97 (d, 1H), 4.19 (d, 1H), 3.85 (dd, 3H), 3.37 — 3.23 (m, 9H), 3.14 (t, 1H),3.04 — 2.92 (m, 4H), 2.19 (s, 3H), 1.96 (t, 2H), 1.73 (s, 2H), 1.55 — 0.87 (m, 21H), 0.81 (d, 6H). MS(ESI) m/e 1564.4 (M-H)’.2.125 sis of N-{[(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)(methoxymethyl)0x0pyrrolidinyl]acetyl}-L-valyl-N-{4-[({[2-({3-[(4-(1,3-benzothiazolylcarbam0yl)-3,4—dihydroisoquinolin-2(1H)-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon SV)MEl 24985843V.1 649117813-126202.125.1 tert-butyl2-((3S,5S)(dibenzylamino)(meth0xymethyl)-2—rolidinyl)acetateTo a mixture of Example 2.119.10 (1.4 g) in N,N-dimethylformamide (5 mL) was addediodomethane (0.8 mL). The reaction was cooled to 0 CC, and 95% sodium hydride (80 mg) wasadded. After five minutes the cooling bath was removed, and the reaction stirred at room temperaturefor 2.5 hours. The reaction was quenched by the addition of water (20 mL) and ethyl acetate (40 mL).

The layers were separated, and the c layer was washed with brine. The combined aqueouslayers were back-extracted with ethyl acetate (10 mL). The combined organic layers were dried withsodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silicagel tography, eluting with 80/20 heptane/ethyl acetate, to give the title compound. MS (DCI)m/e 439.2 (M+H)+.2.125.2 tert-butyl2-((3S,5S)amin0(methoxymethyl)-2—oxopyrrolidinyl)acetateTo a mixture of Example 2.1251 (726 mg) in 2,2,2-trifluoroethanol (10 mL) was addedpalladium hydroxide on carbon (20% by wt, 150 mg). The reaction was stirred under a hydrogenatmosphere (50 psi) at room temperature for two hours. The reaction was filtered and concentrated togive the title compound. MS (DCI) m/e 259.0 (M+H)+.2.125.3 S,5S)(2-(tert-but0xy)oxoethyl)(meth0xymethyl)-2—rolidinyl)amin0)0x0buten0ic acidThe title compound was prepared by substituting Example 2.1252 for Example 2.119.12in Example 2.119.13. MS (DCI) m/e 374.0 (M+NH3+H)+.4 tert-butyl2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)--(methoxymethyl)0x0pyrr01idinyl)acetateThe title compound was prepared by substituting e 2.1253 for Example 2.119.13in Example 2.119.14. MS (DCI) m/e 356.0 +H)+.2.1255 2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)(methoxymethyl)0x0pyrrolidinyl)acetic acidTo a mixture of e 2.125.4 (120 mg) in dichloromethane (8 mL) was addedtrifluoroacetic acid (4 mL). The reaction was stirred at room temperature for 90 minutes and thenconcentrated under d pressure. The residue was dissolved in acetonitrile (4 mL) and purifiedby preparative reverse-phase HPLC with a Luna C18(2) AXIA column, 250 x 50 mm, 10u particlesize, using a gradient of 5-75% acetonitrile in 0.1% trifluoroacetic acid in water over 30 minutes, togive the title compound. MS (DCI) m/e 300.0 (M+NH3+H)+.2.125.6 N-{[(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)(methoxymethyl)oxopyrrolidin-l-yl]acetyl}-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-MEl 24985843V.1 650117813-126201H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]phenyl}-N5-carbamoyl-L-0rnithinamideThe title compound was ed by tuting Example 2.1255 for Example 2.119.15and Example 2.49.1 for Example 2.119.16 in Example 2.119.17. 1H NMR (400 MHZ, dimethylsulfoxide-dg) 5 ppm 9.98 (s, 1H), 8.19 (br d, 1H), 8.03 (d, 1H), 7.96 (d, 1H), 7.79 (d, 1H), 7.61 (m,3H), 7.55 (d, 1H), 7.45 (m, 2H), 7.37 (m, 2H), 7.32 (s, 1H), 7.27 (d, 2H), 7.08 (s, 2H), 6.96 (d, 1H),.00 (m, 2H), 4.96 (s, 2H), 4.69 (t, 1H), 4.39 (br m, 1H), 4.28 (m, 1H), 4.20 (d, 1H), 3.88 (t, 3H), 3.81(br m, 3H), 3.46 (m, 3H), 3.40 (m, 2H), 3.26 (br m, 2H), 3.25 (s, 3H), 3.01 (m, 3H), 2.96 (m,1H), 2.65(t, 2H), 2.36 (br m, 1H), 2.10 (s, 3H), 2.00 (m, 1H), 1.94 (m, 1H), 1.69 (br m, 1H), 1.59 (br m, 1H),1.49-0.92 (m, 16H), 0.88 (d, 3H), 0.83 (m, 9H). MS (ESI) m/e 1521.5 (M-H)’.2.126 Synthesis of (6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]({N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-Valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonicacid (Synthon SY)The title compound was prepared as described in e 21, replacing 2,5-dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetate with 2,5-dioxopyrrolidinyl6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-l-yl)hexanoate. 1H NMR (501 MHZ, dimethyl sulfoxide-dé) 5ppm 12.83 (s, 1H), 9.87 (s, 1H), 8.09 (d, 1H), 8.05 — 7.95 (m, 1H), 7.77 (d, 2H), 7.59 (d, 1H), 7.55 —7.31 (m, 7H), 7.28 (s, 1H), 7.20 (d, 1H), 6.97 (s, 2H), 6.94 (d, 1H), 5.08 — 4.84 (m, 5H), 4.36 (p, 1H),3.78 (d, 2H), 3.54 (t, 1H), 3.48 — 3.28 (m, 9H), 3.21 (s, 2H), 3.12 (t, 2H), 3.02 — 2.84 (m, 4H), 2.81 —2.54 (m, 6H), 2.19 — 1.84 (m, 9H), 1.63 — 1.39 (m, 6H), 1.35 (s, 1H), 1.29 — 0.86 (m, 18H), 0.80 (td,15H). MS (ESI) m/e 1568.4 (M-H)’.2.127 Synthesis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](4-{[3-(2,5-di0x0-2,5-dihydr0-1H-yl)pr0pan0yl]amin0}butyl)phenyl beta-D-glucopyranosiduronicacid (Synthon TK)2,127.1 3-(1-((3-(2-((((4—(4-amin0butyl)-2—(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)oxy)carbonyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)-6—MEl 24985843V.1 651117813-12620(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidTo a mixture of Example 1.2.9 (0.030 g), Example 2.1245 (0.031 g) and 1H-d][1,2,3]triazolol e (5 mg) in N,N-dimethylformamide (0.5 mL) was added N-ethyl-N-isopropylpropanamine (0.017 mL), and the reaction mixture was stirred for 3 hours. Thereaction mixture was concentrated, dissolved in tetrahydrofuran (0.4 mL) and methanol (0.4 mL) andtreated with lithium ide e (0.020 g) as a mixture in water (0.5 mL). After 1 hour, thereaction was quenched with 2,2,2-trifluoroacetic acid (0.072 mL), diluted with N,N-ylformamide:water (1:1) (1 mL) and purified by preparatory reverse-phase HPLC using aGilson PLC 2020 , eluting with a gradient of 5% to 75% acetonitrile/water. Product-containingons were combined and lyophilized to give to title compound. MS (ESI) m/e 1251.7 (M+H)+.2,127.2 2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl](4—{[3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]amin0}butyl)phenyl beta-D-glucopyranosiduronic acidTo a mixture of Example 2.127.1 (0.027 g) and 2,5-dioxopyrrolidinyl 3-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)propanoate (6.32 mg) in N,N-dimethylformamide (0.4 mL) was added N-ethyl-N-isopropylpropanamine (0.017 mL), and the reaction was stirred for 1 hour at roomtemperature. The reaction was quenched with a mixture of 2,2,2-trifluoroacetic acid (0.038 mL),water (1.5 mL) and N,N-dimethylformamide (0.5 mL) and purified by preparatory reverse-phaseHPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1H NMR (501 MHz, dimethylsulfoxide-dé) 5 12.84 (s, 1H), 8.03 (dd, 1H), 7.91 — 7.85 (m, 1H), 7.78 (d, 1H), 7.61 (dd, 1H), 7.52(dd, 1H), 7.50 — 7.40 (m, 2H), 7.39 — 7.31 (m, 2H), 7.31 (s, 1H), 7.17 (dd, 1H), 6.99 — 6.90 (m, 4H),6.83 (d, 1H), 5.15 — 5.04 (m, 2H), 5.05 — 4.96 (m, 1H), 4.95 (s, 2H), 3.91 — 3.83 (m, 4H), 3.81 (d,3H), 3.58 (t, 2H), 3.42 (td, 3H), 3.33 — 3.24 (m, 5H), 3.00 (q, 4H), 2.68 (dt, 2H), 2.29 (t, 2H), 2.09 (d,3H), 1.49 (d, 3H), 1.34 (td, 5H), 1.21 (dd, 5H), 1.15 — 1.07 (m, 2H), 1.07 (s, 4H), 0.95 (q, 1H), 0.82(d, 6H). MS (ESI) m/e 1402.1 (M+H)+.2.128 sis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0y1}0xy)methyl][4-({(2S)(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)[4-(2,5,8,11,14,17,20,23,26,29,32—undecaoxatetratriacontan—34-MEl 24985843V.1 652-12620yloxy)phenyl]propanoyl}amin0)butyl]phenyl beta-D-glucopyranosiduronic acid (Synthon TR)A mixture of Example 2.1205 (0.035 g), O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (0.015 g) and N-ethyl-N-isopropylpropanamine (0.015mL) was stirred in methylformamide (0.4 mL) for 5 minutes. The mixture was added to amixture of Example 2.127.1 (0.030 g) and N-ethyl-N-isopropylpropanamine (0.015 mL) in N,N-dimethylformamide (0.4 mL) and stirred at room temperature for 3 hours. The reaction was dilutedwith a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and trifluoroacetic acid(0.034 mL) and purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using agradient of 5% to 85% acetonitrile/water. The product-containing fractions were lyophilized to givethe title compound. 1H NMR (400 MHz, yl sulfoxide-d6) 5 12.83 (s, 1H), 8.04 — 7.93 (m, 2H),7.76 (d, 1H), 7.58 (dd, 1H), 7.53 — 7.36 (m, 3H), 7.37 — 7.25 (m, 3H), 7.15 (d, 1H), 6.97 — 6.88 (m,4H), 6.87 (d, 2H), 6.85 — 6.77 (m, 1H), 6.76 — 6.69 (m, 2H), 5.13 — 4.96 (m, 3H), 4.92 (s, 2H), 3.95(dd, 2H), 3.84 (d, 2H), 3.78 (s, 8H), 3.69 — 3.60 (m, 2H), 3.47 (d, 38H), 3.48 — 3.35 (m, 6H), 3.20 (s,8H), 3.10 (dd, 2H), 2.98 (t, 2H), 2.69 — 2.60 (m, 2H), 2.50 (d, 1H), 2.06 (s, 3H), 1.49 (t, 2H), 1.35 (s,4H), 1.21 (d, 4H), 1.05 (s, 6H), 0.79 (d, 6H). MS (ESI) m/e 1991.6 (M-H)’.2.129 Synthesis of ,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][(N-{(2S)(2,5-di0x0-2,5-dihydr0-rolyl)[4-(2,5,8,11,14,17,20,23,26,29,32—undecaoxatetratriacontan—34-yloxy)phenyl]propanoyl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid (Synthon TY)A mixture of Example 2.1205 (0.033 g), O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (0.014 g) and N-ethyl-N-isopropylpropanamine (0.015mL) was stirred in N,N-dimethylformamide (0.4 mL) for 5 minutes. This mixture was added to amixture of Example 2.123.20 (0.032 g) and N-ethyl-N-isopropylpropanamine (0.015 mL) in N,N-dimethylformamide (0.4 mL) and d at room temperature for 3 hours. The reaction was dilutedwith a mixture of water (1.5 mL), methylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid(0.033 mL) and purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using agradient of 5% to 85% acetonitrile/water. The product-containing fractions were lyophilized to givethe title compound. 1H NMR (501 MHz, dimethyl sulfoxide-d6) 5 9.90 (d, 1H), 8.25 (d, 1H), 8.12 (m,1), 8.01 (m, 1H), 1.78 (m, 1H), 7.59 (d, 1H), 7.53 — 7.40 (m, 4H), 7.43 — 7.30 (m, 4H), 7.27 (s, 1H),7.18 (d, 2H), 7.06 (s, 1H), 7.00 (d, 2H), 6.97 — 6.91 (m, 2H), 6.87 (s, 2H), 6.76 (d, 2H), 5.02 — 4.92(m, 4H), 4.77 (dd, 1H), 4.20 (t, 1H), 3.98 (dd, 2H), 3.86 (t, 2H), 3.78 (d, 2H), 3.70 — 3.65 (m, 2H),3.54 (s, 2H), 3.55 — 3.45 (m, 38H), 3.45 — 3.37 (m, 2H), 3.35 — 3.25 (m, 2H), 3.21 (s, 4H), 3.17 — 3.06MEl 24985843V.1 653-12620(m, 2H), 2.99 (t, 2H), 2.73 (s, 2H), 2.61 (s, 4H), 2.07 (d, 4H), 2.01 (s, 2H), 1.94 (s, 2H), 1.54 (s, 2H),1.27 (d, 4H), 1.22 (s, 2H), 1.11 (s, 6H), 1.08 — 0.99 (m, 2H), 0.90 — 0.79 (m, 6H), 0.76 (d, 6H). MS(ESI) m/e 705.6 3'.2.130 Synthesis of 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2-((((2-(2-((2S,3R,4R,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-ZH-pyranyl)ethyl)((S)((S)(2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)-2—0x0((2—sulfoethoxy)methyl)pyrrolidinyl)acetamid0)methylbutanamid0)propanamido)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinic acid (Synthon TX)The title compound was prepared by substituting Example 2.123.20 for Example 2.119.16in Example 17. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 ppm 9.85 (s, 1H), 8.17 (br d,1H), 8.01 (d, 2H), 7.77 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.43 (m, 4H), 7.34 (m, 3H), 7.19 (d, 1H),7.06 (s, 2H), 6.96 (d, 1H), 4.99 (m, 2H), 4.95 (s, 2H), 4.63 (t, 1H), 4.36 (t, 1H), 4.19 (br m, 1H), 4.16(d, 1H), 3.98 (d, 1H), 3.87 (br t, 2H), 3.81 (br d, 2H), 3.73 (brm, 1H), 3.63 (t, 2H), 3.53 (m, 2H), 3.44(m, 4H), 3.31 (t, 2H), 3.21 (br m, 2H), 3.17 (m, 2H), 3.00 (m, 2H), 2.92 (br m, 1H), 2.75 (m, 3H),2.65 (br m, 3H), 2.35 (br m, 1H), 2.07 (s, 3H), 1.98 (br m, 2H), 1.85 (m, 1H), 1.55 (br m, 1H), 1.34(br m, 1H), 1.26 (br m, 6H), 1.09 (br m, 7H), 0.93 (br m, 1H), 0.87, 0.83, 0.79 (all d, total 12H). MS(ESI) m/e 1733.4 (M-H)’.2.131 Synthesis of 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2—((((2-(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-ZH-pyranyl)0xy)(4-(2-((3S,5S)-3-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)0x0((2-sulfoethoxy)methyl)pyrrolidinyl)acetamid0)butyl)benzyl)0xy)carb0nyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-yladamantanyl)methyl)methyl-1H-pyrazolyl)picolinicacid (Synthon TZ)The title compound was prepared by substituting Example 2127.1 for Example 2.119.16in Example 2.119.17. 1H NMR (500 MHz, dimethyl sulfoxide-dg) 5 ppm 8.02 (d, 1H), 7.82 (br t,1H), 7.77 (d, 1H), 7.60 (d, 1H), 7.53 (br d, 1H), 7.45 (ddd, 1H), 7.42 (d, 1H), 7.36 (d, 1H), 7.35 (s,1H), 7.33 (m, 1H), 7.15 (d, 1H), 7.05 (s, 2H), 6.97 (d, 1H), 6.94 (s, 1H), 6.83 (d, 1H), 5.07 (br m, 2H),.00 (d, 1H), 4.95 (s, 2H), 4.69 (t, 1H), 4.04 (d, 2H), 3.87 (m, 3H), 3.82 (m, 3H), 3.73 (br m, 1H),3.61 (m, 2H), 3.47 (br m, 3H), 3.40 (m, 4H), 3.29 (m, 4H), 3.06 (br m, 2H), 3.00 (t, 2H), 2.73 (br m,2H) 2.69 (br m, 2H), 2.52 (br t, 2H), 2.35 (br m, 1H), 2.08 (s, 3H), 1.81 (m, 1H), 1.53 (br m, 2H), 1.40(m, 2H), 1.35 (br m, 2H), 1.29-0.88 (br m, 10H), 0.82, 0.80 (both s, total 6H). MS (ESI-) m/e 1607.5(M-H)’.

MEl 24985843V.1 654117813-126202.132 Synthesis of 2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)phenyl beta-D-glucopyranosiduronic acid(Synthon UA)To a mixture of Example 2.127.l (0.032 g) in N,N-dimethylformamide (0.4 mL) wasadded N-ethyl-N-isopropylpropanamine (0.025 mL), and the mixture cooled to 0 CC. 2,5-Dioxopyrrolidin-l-yl -dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (8.86 mg) was added in oneportion and stirred at 0 CC for 45 minutes. The reaction was diluted with a mixture of water (1.5 mL),N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.036 mL) and was purified bypreparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75%itrile/water. The product-containing fractions were lyophilized to give the title compound. 1HNMR (501 MHz, dimethyl sulfoxide-dé) 5 12.86 (s, 1H), 8.06 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H),7.60 (dd, 1H), 7.51 (dd, 1H), 7.49 — 7.39 (m, 2H), 7.38 — 7.28 (m, 3H), 7.17 (dd, 1H), 7.06 (d, 2H),6.98 — 6.89 (m, 2H), 6.83 (d, 1H), 5.13 — 5.03 (m, 2H), 5.04 — 4.96 (m, 1H), 4.94 (s, 2H), 3.97 (s, 2H),3.90 — 3.77 (m, 6H), 3.50 (s, 1H), 3.50 — 3.41 (m, 2H), 3.41 (dt, 3H), 3.28 (dt, 4H), 3.06 — 2.96 (m,4H), 2.66 (dt, 2H), 2.51 (s, 2H), 2.08 (d, 3H), 1.52 (s, 2H), 1.42 — 1.32 (m, 4H), 1.23 (d, 4H), 1.11 (q,2H), 1.06 (s, 4H), 0.81 (d, 6H). MS (ESI) m/e 1388.0 (M+H)+.2.133 Synthesis of 2-[({[2—({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)phenyl beta-D-glucopyranosiduronic acidon UZ)2,133.1 3-(1-((3-(2-((((4—(4-amin0butyl)(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)oxy)carbonyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-yladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)naphthalenyl)pic01inicTo a mixture of Example 2.1245 (0.060 g), e 1.43.7 (0.056 g) and 1H-benzo[d][l,2,3]triazol-l-ol (8 mg) in dimethyl ide (0.5 mL) was added N-ethyl-N-isopropylpropanamine (0.056 mL), and the reaction was stirred at room temperature for 3 hours.

The reaction was treated with a mixture of lithium hydroxide hydrate (0.026 g) in water (1 mL) andstirred for 30 minutes. Methanol (0.5 mL) was added to the reaction and stirring was continued for 30minutes. Diethylamine (0.033 mL) was added to the reaction and stirring was ued overnight.

MEl 24985843V.1 655-12620The reaction was quenched with 2,2,2-trifluoroacetic acid (0.120 mL) and purified by preparatoryreverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75% acetonitrile/water. Theproduct-containing fractions were lyophilized to give the title nd. MS (ESI) m/e 1247.7(M+H)+.2.133.2 2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)naphthalen-Z-yl]carb0xypyridinyl}-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl](4-{[(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)acetyl]amin0}butyl)phenyl beta-D-yranosiduronic acidTo a mixture of Example 2.1331 (0.030 g) in N,N-dimethylformamide (0.400 mL) wasadded N-ethyl-N-isopropylpropanamine (0.023 mL) and the mixture was cooled to 0 CC. 2,5-Dioxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetate (8.34 mg) was added in oneportion and he mixture was stirred at 0 CC for 30 minutes. The reaction was diluted with a mixture ofwater (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroacetic acid (0.034 mL) and waspurified by preparatory reverse-phase HPLC on a Gilson 2020 system, using a gradient of 5% to 75%acetonitrile/water. The product-containing fractions were lyophilized to give the title compound. 1HNMR (400 MHz, dimethyl sulfoxide-d6) 5 13.08 (s, 1H), 9.01 (s, 1H), 8.39 — 8.31 (m, 1H), 8.25 —8.11 (m, 3H), 8.06 (d, 2H), 7.99 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.68 (t, 1H), 7.51 — 7.42 (m, 1H),7.46 (s, 1H), 7.35 (t, 1H), 7.22 — 7.13 (m, 1H), 7.06 (d, 2H), 6.93 (d, 1H), 6.83 (d, 1H), 5.15 — 5.00(m, 2H), 4.99 (d, 1H), 3.97 (s, 2H), 3.86 (d, 3H), 3.42 (d, 4H), 3.29 (d, 5H), 3.03 (p, 2H), 2.72 — 2.62(m, 2H), 2.51 (d, 3H), 2.21 (s, 3H), 1.51 (q, 2H), 1.37 (q, 4H), 1.24 (d, 4H), 1.10 (s, 5H), 0.83 (d, 6H),0.61 (s, 2H). MS (ESI) m/e 1383.0 (M+H)+.2.134 Synthesis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)naphthalenyl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7—dimethyltricyc10[3.3.1.13’7]decyl}0xy)ethyl](2-thyl)carbam0y1}0xy)methyl][4-({(2S)(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)[4-(2,5,8,11,14,17,20,23,26,29,32—undecaoxatetratriacontan—34-yloxy)phenyl]propanoyl}amin0)butyl]phenyl beta-D-glucopyranosiduronic acid (Synthon UK)A mixture of Example 2.1205 (0.028 g), O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (0.013 g) and l-N-isopropylpropanamine (0.015mL) were stirred in N,N-dimethylformamide (0.4 mL) for 5 minutes. The mixture was added to amixture of Example 2.1331 (0.030 g) and N-ethyl-N-isopropylpropanamine (0.015 mL) in N,N-dimethylformamide (0.4 mL) and was stirred at room ature for 1 hour. The reaction wasMEl 24985843V.1 656117813-12620d with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroaceticacid (0.042 mL) and was purified by preparatory reverse-phase HPLC on a Gilson 2020 system, usinga gradient of 5% to 75% acetonitrile/water. The product-containing fractions were lyophilized to givethe title compound. 1H NMR (400 MHz, dimethyl sulfoxide-d6) 5 9.01 (s, 1H), 8.35 (dd, 1H), 8.27 —8.13 (m, 3H), 8.06 (d, 1H), 8.00 (d, 1H), 7.94 (d, 1H), 7.79 (d, 1H), 7.73 — 7.64 (m, 1H), 7.53 — 7.43(m, 2H), 7.42 — 7.32 (m, 1H), 7.17 (d, 1H), 7.06 (s, 1H), 7.04 — 6.91 (m, 3H), 6.89 (d, 2H), 6.83 (d,1H), 6.74 (d, 1H), 5.16 — 4.93 (m, 4H), 4.63 (dd, 2H), 3.96 (t, 2H), 3.86 (d, 4H), 3.66 (s, 4H), 3.55 —3.46 (m, 36H), 3.45 — 3.35 (m, 8H), 3.35 — 3.24 (m, 6H), 3.21 (s, 2H), 3.11 (s, 2H), 2.99 (d, 2H), 2.83— 2.59 (m, 3H), 2.52 (d, 2H), 2.21 (s, 3H), 1.57 — 0.86 (m, 14H), 0.83 (d, 4H). MS (ESI) m/e 1986.6.2.135 Synthesis of N-[(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetyl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](4-carb0xybutyl)phenyl}-L-alaninamide (Synthon UU)2,135.1 methyl rt-butoxycarbonyl)amin0)i0d0benzoate3-Iodo(methoxycarbonyl)benzoic acid (9 g) was dissolved in tert-butanol (100 mL),and yl phosphorazidate (7.6 mL) and triethylamine (4.9 mL) were added. The mixture washeated to 83 CC (internal temperature) ght. The mixture was concentrated to s andpurified by flash chromatography, eluting with a gradient of 0% to 20% ethyl acetate in heptane togive the title nd. MS (ESI) m/e 377.9 (M+H)+.2,135.2 methyl 4-amin0i0d0benzoateExample 2.1351 (3 g) was stirred in dichloromethane (30 mL) and trifluoroacetic acid (10mL) at room temperature for 1.5 hours. The reaction was concentrated to dryness and partitionedbetween water (adjusted to pH 1 with hydrochloric acid) and diethyl ether. The layers were separated,and the aqueous layer was washed with aqueous sodium bicarbonate mixture, dried over sodiumsulfate, filtered and concentrated to dryness. The resulting solid was triturated with toluene to givethe title compound. MS (ESI) m/e 278.0 .2,135.3 methyl 4-((S)((S)((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanamido)i0d0benzoateA flask was charged with Example 2.1352 (337 mg) and Example 2.123.14 (500 mg).

Ethyl acetate (18 mL) was added followed by pyridine (0.296 mL). The resulting suspension waschilled in an ice bath, and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50% ein ethyl acetate, 1.4 mL) was added dropwise. Stirring was continued at 0 CC for 45 minutes, and thereaction was placed in a -20°C freezer overnight. The reaction was allowed to warm to roomMEl 24985843V.1 657117813-12620temperature and was quenched with water. The layers were separated, and the aqueous layer wasextracted twice more with ethyl acetate. The combined extracts were dried with anhydrous sodiumsulfate, filtered and concentrated. The residue was dissolved in dichloromethane and diluted withdiethyl ether to precipitate the title compound, which was ted by filtration. MS (ESI) m/e 669.7(M+H)+.2,135.4 (9H-flu0renyl)methyl((S)(((S)((4-(hydr0xymethyl)i0d0phenyl)amin0)0x0pr0panyl)amin0)methyl0x0butanyl)carbamateExample 2.54.3 (1 g) was dissolved in tetrahydrofuran (15 mL), and the mixture waschilled to -15 CC in an ice-acetone bath. Lithium aluminum e (1N in tetrahydrofuran, 3 mL)was then added dropwise, keeping the temperature below -10 CC. The reaction was stirred for 1 hourand carefully quenched with 10% citric acid (25 mL). The layers were separated, and the aqueouslayer was extracted thrice with ethyl acetate. The combined organic layers were washed with waterand brine, dried over anhydrous sodium sulfate, ed and concentrated. The residue was adsorbedonto silica gel and purified by flash chromatography, eluting with a gradient of 5% to 6% methanol indichloromethane, to give the title nd. MS (ESI) m/e 664.1 .2,135.5 methyl 5-(5-((S)((S)((((9H-flu0renyl)meth0xy)carbonyl)amin0)butanamido)propanamido)(hydroxymethyl)phenyl)pent-4—ynoateTo a stirred mixture of methyl pentynoate (50 mg), Example 2.1354 (180 mg) andN,N-diisopropylethylamine (0.15 mL) in N,N-dimethylformamide (2 mL) was addedbis(triphenylphosphine)palladiumfil) ride (20 mg) and copper iodide (5 mg). The mixture waspurged with en three times and stirred at room temperature overnight. The reaction was dilutedwith ethyl e and washed with water and brine. The aqueous layers were back extracted withethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated.

The residue was purified by reverse-phase HPLC on a Gilson system, eluting with 20-90%acetonitrile in water containing 0.1% v/v trifluoroacetic acid. The desired ons were combinedand freeze-dried to provide the title compound. MS (ESI) m/e 608.0 (M-HZO)+.2,135.6 methyl 5-(5-((S)((S)((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanamido)(hydroxymethyl)phenyl)pentanoateA mixture of Example 2.1355 (0.084 g) and 10% Pd/C (0.02 g) in tetrahydrofuran (5 mL)was stirred at 20 CC under an atmosphere of 50 psi Hz for 1 hour. The reaction mixture was filteredthrough diatomaceous earth, and the solvent was evaporated under reduced pressure to provide thetitle nd. MS (ESI) m/e 612.0 (M-HZO)+.

MEl 24985843V.1 658117813-126202,135.7 methyl 5-(5-((S)((S)((((9H-flu0renyl)meth0xy)carbonyl)amin0)methylbutanamido)propanamid0)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phenyl)pentanoateExample 2.1357 was ed by tuting e 2.1357 for Example 2.55.6 inExample 2.55.7. MS (ESI) m/e 795.4 (M+H)+.2,135.8 3-(1-((3-(2-((((4-((S)((S)amin0methylbutanamido)propanamid0)(4-carboxybutyl)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidExample 2.1358 was prepared by substituting 2.1357 for (9H-flu0renyl)methy1 ((S)methyl(((S)((4-((((4-nitr0phen0xy)carbony1)0xy)methy1)phenyl)amin0)0x0-5 -ureid0pentan-2-y1)amin0)0x0butany1)carbamate in Example 2.49.1. MS (ESI) m/e 1271.4 (M-H)’.2,135.9 N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](4—carboxybutyl)phenyl}-L-alaninamideExample 2.1359 was prepared by substituting 2.1358 for Example 2.49.1 in Example2.54. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 9.88 (d, 1H), 8.3 - 8.2 (m, 2H), 8.01 (dd,1H), 7.77 (d, 1H), 7.59 (dd, 1H), 7.52 (dd, 1H), 7.47 — 7.29 (m, 8H), 7.23 — 7.18 (m, 1H), 7.05 (s,2H), 6.95 (d, 1H), 5.00 (d, 2H), 4.94 (s, 2H), 4.37 (p, 1H), 3.51 — 3.28 (m, 5H), 3.26 — 3.14 (m, 2H),2.99 (t, 2H), 2.65 (t, 2H), 2.57 (s, 2H), 2.26 — 2.17 (m, 3H), 2.07 (d, 3H), 1.94 (dd, 1H), 1.61 — 0.69(m, 35H). MS (ESI) m/e 1408.5 (M-H)+.2.136 sis of 2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](3-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}pr0pyl)phenyl beta-D-glucopyranosiduronicacid (Synthon UV)2,136.1 (3R,4S,5S,6S)(5-(3-((((9H-flu0renyl)meth0xy)carbonyl)amin0)pr0pynyl)-2—f0rmylphen0xy)-6-(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateMEl 24985843V.1 659117813-12620Example 2.1361 was prepared by substituting (9H-flu0renyl)methyl propynamate for 2.124.1A in Example 2.1242. MS (ESI) m/e 714.1 (M+H)+.2.136.2 (2S,3R,4S,5S,6S)(5-(3-((((9H-flu0ren-9—yl)methoxy)carbonyl)amin0)pr0pyl)f0rmylphen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl tateExample 2.1362 was prepared by tuting 2.1361 for 2.1242 in e 2.124.3.

MS (ESI) m/e 718.5 (M+H)+.2.136.3 (2S,3R,4S,5S,6S)(5-(3-((((9H-flu0ren-9—yl)methoxy)carbonyl)amin0)propyl)(hydroxymethyl)phen0xy)(methoxycarbonyl)tetrahydr0-2H-pyran-3,4,5-triyl triacetateExample 2.1363 was prepared by substituting 2.1362 for 21243 in Example 4.

MS (ESI) m/e 742.2 (M+Na)+.2.136.4 (2S,3R,4S,5S,6S)(5-(3-((((9H-flu0ren-9—yl)methoxy)carbonyl)amin0)propyl)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phen0xy)(methoxycarbonyl)tetrahydro-ZH-pyran-3,4,5-triyl triacetateExample 2.136.4 was prepared by substituting 2.1363 for 21244 in Example 2.124.5.

MS (ESI) m/e 885.2 (M+Na)+.2.1365 3-(1-((3-(2-((((4—(3-amin0pr0pyl)-2—(((3R,4S,5S,6S)carb0xy-trihydr0xytetrahydr0-2H-pyran)benzyl)oxy)carbonyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidExample 2.1365 was prepared by substituting Example 2.136.4 for (9H-flu0renyl)methyl ((S)-3 -methyl(((S)((4-((((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amino)0x0--ureid0pentanyl)amin0)0x0butanyl)carbamate in Example 2.49.1. MS (ESI) m/e 1237.7(M+H)+.6 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](3-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}propyl)phenylbeta-D-glucopyranosiduronic acidExample 2.1366 was prepared by substituting Example 2.1365 for Example 2.49.1 inExample 2.54. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 8.14 (d, 1H), 8.01 (d, 1H), 7.59 (d,MEl 24985843V.1 660117813-126201H), 7.53 — 7.39 (m, 4H), 7.38 — 7.28 (m, 3H), 7.22 — 7.15 (m, 2H), 7.13 — 6.91 (m, 5H), 6.84 (d, 1H),.17 — 4.91 (m, 5H), 3.35-3.2 (m, 4H), 3.10-2.90 (m, 4H), 2.75-2.65 (m, 2H), 2.08 (s, 3H), 1.65 (s,2H), 1.39 — 0.71 (m, 21H). MS (ESI) m/e 1372.3 (M-H)’.2.137 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[({[2-{[(2S,3R,4S,5S,6S)carboxy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]0xy}(4-{[(2,5-di0x0-2,5-dihydr0-lH-pyrrol-lyl)acetyl]amin0}butyl)benzyl]0xy}carb0nyl)(3-{[1,3-dihydr0xy(hydroxymethyl)pr0panyl]amino}oxopropyl)amin0]eth0xy}-5,7-dimethyltricyclo[3.3.1.13’7]decyl)methyl]methyl-lH-pyrazolyl}pyridine-2—carb0xylic acid (Synthon UZ)2.137.1 3-(1-((3-(2-((((4—(4-amin0butyl)(((2R,3S,4R,5R,6R)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)(3-((1,3-dihydr0xy-2—(hydroxymethyl)propanyl)amin0)pyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidThe title compound was prepared as described in Example 2.124.6, replacing Example1.87.3 with Example 1.84. MS (ESI) m/e 1319.4 (M-H)’.2.137.2 6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4—dihydr0is0quinolin-yl]{1-[(3-{2-[({[2-{[(2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydroxytetrahydro-2H-pyranyl]0xy}(4-{[(2,5-di0x0-2,5-dihydro-lH-pyrrol-l-yl)acetyl]amin0}butyl)benzyl]0xy}carb0nyl)(3-{[1,3-dihydr0xy-2-(hydroxymethyl)pr0panyl]amin0}0x0pr0pyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylicThe title nd was ed as described in Example 2.54, replacing Example 2.49.1with e 21371 1H NMR (501 MHZ, dimethyl sulfoxide-dé) 5 ppm 12.83 (s, 2H), 8.12 (s, 0H),8.06 (s, 1H), 8.03 — 7.99 (m, 1H), 7.77 (d, 1H), 7.72 (s, 0H), 7.60 (d, 1H), 7.52 — 7.39 (m, 3H), 7.34(td, 2H), 7.26 (s, 1H), 7.21 — 7.11 (m, 2H), 7.05 (s, 2H), 6.93 (d, 2H), 6.83 (d, 1H), 5.09 (d, 2H), 5.00(d, 1H), 4.94 (s, 2H), 4.12 (t, 1H), 3.97 (s, 2H), 3.87 (q, 4H), 3.79 (d, 2H), 3.29 (q, 2H), 3.12 — 2.93(m, 5H), 2.47 — 2.23 (m, 1H), 2.07 (d, 3H), 1.50 (d, 3H), 1.36 (d, 5H), 1.31 — 0.85 (m, 9H), 0.81 (d,7H). MS (ESI) m/e 1568.4 (M-H)’.

MEl 24985843V.1 661117813-126202.138 Synthesis of 6-(8-(benzo[d]thiazolylcarbamoyl)naphthalenyl)(1-((3-(2-((((2-(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-ZH-pyran-2—yl)0xy)(4-(2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2-sulf0eth0xy)methyl)pyrrolidinyl)acetamid0)butyl)benzyl)0xy)carb0nyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)picolinicacid on VB)The title compound was prepared by substituting Example 2.1331 for Example 2.119.16in Example 2.119.17. 1H NMR (400 MHz, dimethyl sulfoxide-dg) 5 ppm 8.99 (s, 1H), 8.34 (dd, 1H),8.19 (d, 1H), 8.17 (d, 1H), 8.13 (d, 1H), 8.04 (d, 1H), 7.97 (d, 1H), 7.93 (d, 1H), 7.80 (br t, 1H), 7.77(d, 1H), 7.67 (dd, 1H), 7.45 (s, 1H), 7.45 (dd, 1H), 7.34 (dd, 1H), 7.14 (d, 1H), 7.03 (s, 2H), 6.93 (s,1H), 6.82 (br d, 1H), 5.06 (br m, 2H), 4.98 (d, 1H), 4.67 (t, 1H), 4.02 (d, 2H), 3.85 (m, 3H), 3.71 (brm, 1H), 3.59 (t, 2H), 3.45 (br m, 3H), 3.41 (m, 4H), 3.27 (m, 4H), 3.03 (m, 2H), 2.70 (m, 2H) 2.65 (brm, 2H), 2.50 (br t, 2H), 2.31 (br m, 1H), 2.19 (s, 3H), 1.80 (m, 1H), 1.52 (br m, 2H), 1.38 (m, 2H),1.35 (br m, 2H), 1.29-0.88 (br m, 10H), 0.82 (s, 3H), 0.80 (s, 3H). MS (ESI) m/e 1602.4 (M-H)’.2.139 sis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl][3-hydroxy(hydroxymethyl)pr0pyl]carbamoyl}0xy)methyl](3-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}pr0pyl)phenyl beta-D-glucopyranosiduronic acid (Synthon VC)2,139.1 3-(1-((3-(2-((((4—(3-amin0pr0pyl)(((2S,3R,4S,5S,6S)y-3,4,5-trihydroxytetrahydro-2H-pyran)benzyl)oxy)carbonyl)(3-hydr0xy(hydroxymethyl)propyl)amin0)ethoxy)-5,7—dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)-6—(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidExample 21391 was prepared by substituting Example 2.1364 for (9H-flu0renyl)methyl ((S)-3 -methyl(((S)((4-((((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amino)0x0--ureid0pentanyl)amin0)0x0butanyl)carbamate and substituting Example 1.79.3 for Example1.2.9 in Example 2.49.1. MS (ESI) m/e 1217.7 (M+H)+.2.139.2 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl][3-hydr0xy(hydroxymethyl)pr0pyl]carbamoyl}0xy)methyl](3-{[(2,5-MEl 24985843V.1 662117813-12620di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}pr0pyl)phenylbeta-D-glucopyranosiduronic acidExample 21391 was prepared by substituting Example 2.1391 for Example 2.49.1 inExample 2.54. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 12.84 (s, 2H), 8.11 (t, 1H), 8.00(dd, 1H), 7.76 (d, 1H), 7.62 — 7.56 (m, 1H), 7.50 — 7.37 (m, 3H), 7.37 — 7.29 (m, 2H), 7.25 (s, 1H),7.16 (d, 1H), 7.04 (s, 2H), 6.96 — 6.88 (m, 2H), 6.82 (d, 1H), 5.06 (s, 2H), 4.98 (d, 1H), 4.92 (s, 2H),3.97 (s, 2H), 3.44 — 3.18 (m, 11H), 3.07 — 2.90 (m, 4H), 2.05 (s, 3H), 1.80 (s, 1H), 1.64 (p, 2H), 1.38— 0.67 (m, 19H). (m, 21H). MS (ESI) m/e 1352.5 (M-H)’.2.140 Synthesis of N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)0x0-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0y1}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadeca0xatripentac0ntynyl)phenyl}-L-alaninamide(Synth0n2.140.1 2-i0d0nitr0benzoic acid2-Aminonitrobenzoic acid (50 g) was added to a mixture of concentrated H2SO4 (75mL) and water (750 mL) at 0 CC, and the e was stirred for 1 hour. To the mixture was added amixture of sodium nitrite (24.62 g) in water (300 mL) dropwise at 0 CC. The resulting mixture wasstirred at 0 CC for 3 hours. A e of sodium iodide (65.8 g) in water (300 mL) was added toabove mixture slowly. After the completion of the addition, the resulting mixture was stirred at 0 CCfor 2 hours, then at room temperature for 16 hours and at 60 0C for 2 hours. The resulting mixturewas cooled to room ature and diluted with ice-water (300 mL). The solid was collected byfiltration, washed by water (100 mL x 5), and dried in air for 16 hours to give the title compound. MS(LC-MS) m/e 291.9 (M-H)’.2.140.2 methyl 2-i0d0nitr0benzoateA mixture of Example 2.1401 (130 g) in a e of methanol (1000 mL) and sulfuricacid (23.65 mL) was stirred at 85 CC for 16 hours and concentrated to dryness. The residue wastriturated with methanol (100 mL) and the suspension was stirred for 10 minutes. The solid wascollected by filtration, washed with water (200 mL x 3) and methanol (20 mL), and ied for 16hours to give the title compound. MS (LC-MS) m/e 308.0 (M+H)+.2,140.3 methyl 4-amin0i0d0benzoateTo a mixture of ammonium chloride (122 g) and iron (38.2 g) in ethanol (1000 mL) andwater (100 mL) was added Example 2.1402 (70 g,) at room temperature. The mixture was stirred at80 CC for 4 hours and filtered to remove insoluble material. The filtrate was concentrated underMEI 24985843V.1 663117813-12620reduced re. The residue was dissolved in ethyl acetate (1000 mL) and washed with water (500mL). The aqueous phase was extracted with ethyl acetate (1000 mL x 2). The combined organicphase was washed with brine, dried over MgSO4, filtered and trated to give the title compound.

MS ) m/e 278.0 .2.140.4 (4-amin0i0d0phenyl)methanolTo a mixture of Example 2.1403 (40 g) in tetrahydrofuran (800 mL) was added 1Mdiisobutylaluminum hydride (505 mL) dropwise at -50 CC. The mixture was stirred at -50 CC for 3hours and cooled to -20 CC. Ice-water (180 mL) was added dropwise (keeping temperature below 0CC) to the mixture. After the addition of ter, the mixture was stirred for 10 minutes and filtered.

The filtrate was concentrated, and the residue was dissolved in ethyl acetate (800 mL) and water (200mL). The aqueous phase was extracted with ethyl acetate (300 mL x 2). The ed organicphases were washed with brine, dried over MgSO4, filtered and concentrated to give the titlecompound. MS (LC-MS) m/e 250.0 (M+H)+.2.1405 4-(((tert-butyldimethylsilyl)0xy)methyl)i0doanilineTo a e of Example 2.140.4 (40 g) and imidazole (21.87 g) in romethane (600mL) and tetrahydrofuran (150 mL) was added tert-butyldimethylchlorosilane (29.0 g). The mixturewas stirred at room temperature for 16 hours and filtered to remove the solid. To the filtrate wasadded ice-water (50 mL). The mixture was stirred for 10 s and water (100 mL) was added.

The mixture was extracted with dichloromethane (500 mL x 2). The combined organic phases werewashed with brine, dried over MgSO4, filtered and trated. The residue was purified by silicagel chromatography, eluting with 15/1 to 10/1 petroleum ether/ethyl acetate, to give the titlecompound. MS (LC-MS) m/e 364.0 .2.140.6 (S)-tert-butyl (1-((4-(((tert-butyldimethylsilyl)0xy)methyl)i0d0phenyl)amin0)0x0pr0panyl)carbamateTo a mixed mixture of (S)((tert-butoxycarbonyl)amino)propanoic acid (15.62 g) andExample 2.1405 (30 g) in dichloromethane (600 mL) at 0 CC was added POCl3 (15.39 mL) dropwise.

The mixture was stirred at 0 CC for 2 hours. Ice-water (60 mL) was carefully added to the mixturedropwise (keeping temperature below 5 CC). The mixture was stirred for 30 minutes and concentratedto remove dichloromethane. The residue was suspended in ethyl e (500 mL) and water (100mL). The suspension was filtered. The c phase was washed by water (200 mL x 2) and brine,dried over MgSO4, filtered and concentrated to give the title compound. MS (LC-MS) m/e 533.0 (M-H) J“.2.140.7 (S)-tert-butyl (1-((4-(hydroxymethyl)i0d0phenyl)amin0)0x0pr0panyl)carbamateTo a mixture of Example 2.140.6 (60 g) in tetrahydrofuran (600 mL) was added tetrabutylammonium fluoride (28.2 g) in tetrahydrofuran (120 mL) at 0 CC. The mixture was stirred at roomtemperature for 16 hours and filtered. To the filtrate was added water (100 mL). The mixture wasMEl 24985843V.1 664117813-12620stirred for 10 minutes and then concentrated. The e was diluted with ethyl acetate (800 mL) andwater (300 mL). The s phase was ted with ethyl acetate (200 mL x 3). The combinedc phases were washed with brine, dried over MgSO4, filtered and trated. The residuewas purified by silica gel chromatography, eluting with 3/1 to 1/1 petroleum ether/ethyl acetate, togive the title compound. MS (LC-MS) m/e 443.0 (M+Na)+.2,140.8 (S)amin0-N-(4-(hydr0xymethyl)i0d0phenyl)pr0panamideA mixture of Example 2.1407 (20 g) in a mixture of dichloromethane (80 mL) andtrifluoroacetic acid (40 mL) was stirred at room temperature for 2 hours and concentrated. Theresidue was dissolved in dichloromethane (80 mL) and triethylamine (16.95 mL) was added to adjustthe pH to 8. The title compound was obtained as free base in dichloromethane, which was used innext step without further cation. MS (LC-MS) m/e 321.1 (M+H)+.2.140.9 tert-butyl((S)(((S)((4-(hydr0xymethyl)i0d0phenyl)amin0)0x0pr0panyl)amin0)methyl0x0butanyl)carbamateA mixture of (S)((tert-butoxycarbonyl)amino)methylbutanoic acid (6.79 g),triethylamine (9.58 mL) and 1-hydroxybenzotriazole hydrate (5.26 g) in dichloromethane (250 mL)was stirred for 20 minutes. The resulting mixture was added to a mixture of Example 2.1408 (10 g)and 1-ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (6.59 g) in dichloromethane(100 mL) at 0 CC, dropwise. After the completion of addition, the mixture was stirred at 0 CC for 2hours. ter (200 mL) was added, and the resulting e was stirred for 20 minutes. Theorganic phase was washed with saturated aqueous sodium bicarbonate mixture (100 mL x 2), water(100 mL x 2) and brine (100 mL), dried over MgSO4, filtered and concentrated. The e waspurified by silica gel chromatography, eluting with 3/1 to 1/1 petroleum ether/ethyl acetate, to give thetitle compound. LC-MS m/e 542.1 +.2.140.10 tert-butyl ((S)(((S)((4-(hydr0xymethyl)(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontynyl)phenyl)amin0)oxopropan-Z-yl)amin0)methyl0x0butanyl)carbamateTo a mixture of Example 2.1409 (50 mg),2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontyne (149 mg),iphenylphosphine)palladium(II) dichloride (27.0 mg) and N,N-diisopropylethylamine (0.05 mL)in N,N-dimethylformamide (1 mL) was added copper(I) iodide (3.67 mg). The reaction was purgedwith a stream of nitrogen gas for 10 minutes and stirred overnight. The reaction was diluted withdimethyl sulfoxide purified by reverse-phase HPLC on a Gilson system (C18 column), g with20-70% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS(LC-MS) m/e 1164.2 (M-H)’.

MEl 24985843V.1 665117813-126202.140.11 tert-butyl ((S)methyl(((S)((4-((((4-nitrophenoxy)carb0nyl)0xy)methyl)(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontynyl)phenyl)amin0)0x0pr0panyl)amin0)0x0butanyl)carbamateTo a mixture of Example 10 (80 mg) and bis(4-nitrophenyl) carbonate (31.3 mg) inN,N-dimethylformamide (0.2 mL) was added N,N-diisopropylethylamine (0.06 mL). The mixturewas stirred 3 hours and was purified by reverse-phase HPLC on a Gilson system (C18 column),eluting with 35-75% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the titlend.12 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)(1-((3-(2-((((4-((S)((S)((tert-butoxycarbonyl)amin0)methylbutanamid0)pr0panamid0),11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontynyl)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)pic01inic acidTo a mixture of Example 1.2.9 (95 mg), Example 2.140.11 (148 mg) and 1-hydroxybenzotriazole hydrate (68.1 mg) in N,N-dimethylformamide (2.5 mL) was added N,N-diisopropylethylamine (97 uL). The mixture was stirred for 3.5 hours and purified by reverse-phaseHPLC on a Gilson system (C18 column), eluting with 35-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title compound.13 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamido)(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontynyl)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidA cold (0 CC) mixture of Example 2.140.12 (135 mg) in dichloromethane (4 mL) wastreated with trifluoroacetic acid (1 mL) for 5 hours. The mixture was concentrated and purified byreverse-phase HPLC on a Gilson system (C18 column), eluting with 20-60% acetonitrile in waterning 0.1% roacetic acid, to give the title compound. MS (ESI) m/e 973.4 (M+2H)2+.2.140.14 N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-MEl 24985843V.1 666117813-126201H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontynyl)phenyl}-L-alaninamideA mixture of Example 2.119.15 (20.88 mg) and O-(7-azabenzotriazol-l-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (21.1 mg) in N,N-dimethylformamide (0.4 mL) was treatedwith N,N-diisopropylethylamine (16.2 uL) for 7 minutes, and a mixture of Example 2.140.13 (60 mg)and isopropylethylamine (32.3 uL) in N,N-dimethylformamide (0.6 mL) was slowly added.

The reaction mixture was stirred for 10 minutes and was purified by reverse-phase HPLC on a Gilsonsystem (C18 column), eluting with 20-70% acetonitrile in water containing 0.1% roacetic acid,to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 10.01 (d, 1H), 8.22 (d,1H), 8.02 (t, 2H), 7.90 — 7.75 (m, 2H), 7.66 — 7.50 (m, 3H), 7.50 — 7.39 (m, 3H), 7.35 (q, 3H), 7.05 (s,2H), 7.00 (d, 1H), 5.08 (d, 2H), 4.97 (s, 2H), 4.65 (t, 1H), 4.47 — 4.31 (m, 4H), 4.23 — 4.14 (m, 2H),3.90 — 3.69 (m, 5H), 3.68 — 3.58 (m, 4H), 3.57 — 3.53 (m, 2H), 3.52 — 3.43 (m, 57H), 3.42 — 3.33 (m,4H), 3.22 (s, 5H), 3.01 (t, 2H), 2.49 (p, 3H), 2.09 (d, 3H), 2.04 — 1.77 (m, 1H), 1.40 — 1.17 (m, 6H),1.06 (dd, 6H), 0.97 — 0.63 (m, 11H). MS (ESI) m/e 1153.3 (M+2H)2+.2.141 Synthesis of N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)0x0--[(2-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridin—3-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)phenyl}-L-alaninamide (Synthon VT)2.141.1 tert-butyl((S)(((S)((3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontanyl)(hydroxymethyl)phenyl)amino)0x0pr0panyl)amin0)methyl0x0butan-2—yl)carbamateA mixture of Example 2.140.10 (304 mg) and 10% Pd/C (90 mg, dry) in tetrahydrofuran(20 mL) was shaken in a re bottle for 2 hours under 50 psi of en gas. The insolubleal was filtered off, and the filtrate was trated to provide the title compound. MS (ESI)m/e 1168.3 (M-H)’.

MEl 24985843V.1 667117813-126202.141.2 tert-butyl((S)(((S)((3-(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxadopentacontanyl)((((4-nitrophenoxy)carb0nyl)0xy)methyl)phenyl)amino)oxopropan-Z-yl)amino)methyl0x0butanyl)carbamateThe title compound was prepared using the procedure in Example 2.140.11, ingExample 2.140.10 with Example 2.141.1.2.141.3 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl)(1-((3-(2-((((4-((S)((S)((tert-carbonyl)amin0)methylbutanamid0)pr0panamid0)(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)--methyl-lH-pyrazolyl)pic01inic acidThe title compound was ed using the procedure in Example 2.140.12, replacing Example2.140.11 with Example 2.141.2.2.141.4 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamido)(2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)-6—(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidThe title compound was prepared using the procedure in Example 2.140.13, replacinge 2.140.12 with Example 2.141.3. MS (ESI) m/e 1948.8 (M-H)’.2.1415 N-({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulf0eth0xy)methyl]pyrrolidinyl}acetyl)-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-azolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)phenyl}-L-alaninamideThe title compound was prepared using the procedure in Example 2.140.14, replacingExample 2.140.13 with Example 4. 1H NMR (501 MHZ, dimethyl sulfoxide-dé) 5 12.87 (s,1H), 9.84 (s, 1H), 8.18 (d, 1H), 8.03 (dd, 2H), 7.78 (d, 1H), 7.61 (d, 1H), 7.52 (d, 1H), 7.45 (ddd, 4H),7.40 — 7.32 (m, 2H), 7.30 (s, 1H), 7.22 (d, 1H), 7.07 (s, 2H), 6.96 (d, 1H), 5.01 (d, 2H), 4.95 (s, 2H),MEl 24985843V.1 668117813-126204.64 (t, 1H), 4.38 (t, 1H), 4.24 — 4.12 (m, 2H), 4.00 (d, 1H), 3.88 (t, 2H), 3.78 (t, 3H), 3.64 (ddt, 2H),3.49 (dd, 62H), 3.43 — 3.37 (m, 6H), 3.23 (s, 3H), 3.01 (t, 2H), 2.84 — 2.68 (m, 1.5H), 2.63 (dd, 4H),2.36 (d, 0.5H), 2.08 (d, 3H), 1.74 (t, 2H), 1.25 (dt, 6H), 1.17 — 1.00 (m, 6H), 0.99 — 0.72 (m, 11H).

MS (ESI) m/e 1153.0 (M-2H)2’.2.142 Synthesis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyc10[3.3.1.13’7]decyl}0xy)ethyl][(3S)-3,4-dihydr0xybutyl]carbamoyl}0xy)methyl](3-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}pr0pyl)phenylbeta-D-glucopyranosiduronic acid on VY)2.142.1 3-(1-((3-(2-((((4—(3-amin0pr0pyl)-2—(((2S,3R,4S,5S,6S)-6—carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)((S)-3,4—dihydroxybutyl)amin0)ethoxy)-5,7-dimethyladamantanhyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidExample 21421 was prepared by substituting Example 2136.4 for (9H-flu0renyl)methyl ((S)-3 -methyl(((S)- l (((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amin0)-l -0x0--ureid0pentanyl)amin0)-l-0x0butanyl)carbamate and substituting Example 1.85 for Example1.2.9 in Example . MS (ESI) m/e 1217.3 (M+H)+.2.142.2 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl][(3S)-3,4-dihydr0xybutyl]carbamoyl}0xy)methyl]-5-(3-{[(2,5-di0x0-2,5-dihydr0-lH-pyrrol-l-yl)acetyl]amin0}pr0pyl)phenyl beta-D-glucopyranosiduronicExample 21422 was prepared by substituting Example 2142.1 for Example 2.49.1 inExample 2.54. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 8.14 (d, 1H), 8.03 (dt, 1H), 7.81 —7.76 (m, 1H), 7.61 (dd, 1H), 7.53 — 7.41 (m, 3H), 7.38 — 7.32 (m, 2H), 7.28 (s, 1H), 7.18 (d, 1H), 7.06(d, 2H), 6.97 — 6.92 (m, 2H), 6.85 (dd, 1H), 5.10 (q, 2H), 5.01 (d, 1H), 4.96 (s, 2H), 3.48 — 3.18 (m,12H), 3.06 (q, 2H), 3.00 (t, 2H), 2.08 (s, 3H), 1.77 — 0.66 (m, 16H). MS (ESI) m/e 1352.5 (M-H)’.2.143 Synthesis of 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyc10[3.3.1.13’7]decyl}0xy)ethyl]({[4-(4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)(beta-D-MEl 24985843V.1 669117813-12620glucopyranuronosyloxy)benzyl]0xy}carb0nyl)amin0}-1,2-dide0xy-D-o-hexitol (Synthon WI)2,143.1 3-(1-((3-(2-((((4—(4-amin0butyl)-2—(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)((3R,4S,5R)-3,4,5,6-tetrahydroxyhexyl)amin0)ethoxy)-5,7—dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidThe title compound was prepared by substituting Example 1.77.2 for Example 1.25 andExample 2.1245 for Example 2.97.7 in Example 2.97.8. MS (ESI) m/e 1291 (M+H)+, 1289 (M-H)’.2,143.2 1-{[2-({3-[(4-{6-[8-(1,3-benz0thiazol-2—ylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl]({[4-(4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)(beta-D-glucopyranuronosyloxy)benzyl]0xy}carb0nyl) amin0}-1,2-dideoxy-D-arabino-hexitolThe title compound was prepared by substituting Example 2.1431 for Example 2.49.1 ine 2.54. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 8.04 (d, 1H), 7.81 (d, 1H), 7.61 (d,1H), .43 (m, 3H), 7.41-7.35 (m, 2H), 7.29 (s, 1H), 7.18 (m, 1H), 7.03 (s, 2H), 6.97 (d, 1H), 6.93(s, 1H), 6.86 (d, 1H), 5.18-5.05 (m, 3H), 5.03 (d, 1H), 4.97 (s, 2H), 4.01 (s, 2H), 3.91 (d, 1H), 3.87 (t,2H), 3.83 (m, 2H), 3.72 (s, 2H), 3.67 (m, 2H), 3.59 (dd, 2H), 3.50-3.27 (m, 16H), 3.14 (d, 2H), 3.04(m, 4H), 2.09 (s, 3H), 1.68 (m, 2H), 1.52 (m, 2H), 1.44-1.31 (m, 4H), 1.26-1.14 (m, 4H), 1.10 (m,4H), 0.98 (q, 2H), 0.85 (m, 6H). MS (ESI) m/e 1428 (M+H)+, 1426 (M-H)’.2.144 Synthesis of ({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]dec)ethyl]({[4-(4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)(beta-D-glucopyranuronosyloxy)benzyl]oxy}carbonyl)amin0}-1,2—dideoxy-D-erythro-pentitol (Synthon WK)2,144.1 3-(1-((3-(2-((((4—(4-amin0butyl)-2—(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carbonyl)((3S,4R)-3,4,5-trihydroxypentyl)amino)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidMEl 24985843V.1 670117813-12620The title nd was prepared by substituting Example 1.80 for Example 1.25 andExample 2.1245 for Example 2.97.7 in Example 2.97.8. MS (ESI) m/e 1261 (M+H)+, 1259 (M-H)’.2.144.2 1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-azolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl]({[4-(4-{[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}butyl)(beta-D-glucopyranuronosyloxy)benzyl]0xy} carbonyl)amin0}-1,2-dideoxy-D-erythro-pentitolThe title compound was ed by substituting Example 2.1441 for Example 2.49.1 ine 2.54. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 8.08 (t, 1H), 8.03 (d, 1H), 7.79 (d,1H), 7.62 (d, 1H), 7.53-7.42 (m, 3H), 7.38-7.33 (m, 2H), 7.20 (s, 1H), 7.17 (m, 1H), 7.07 (s, 2H),6.97-6.93 (m, 2H), 6.85 (d, 1H), .05 (m, 3H), 5.02 (d, 1H), 4.96 (s, 2H), 3.98 (s, 2H), 3.88 (m,4H), 3.80 (m, 4H), 3.67 (m, 2H), 3.42 (m, 4H), 3.36-3.23 (m, 13H), 3.08-2.99 (m, 5H), 2.09 (s, 3H),1.86 (m, 1H), 1.53 (m, 2H), 1.38 (m, 4H), 1.25 (m, 4H), 1.11 (m, 4H), 0.96 (m, 2H), 0.83 (m, 6H).

MS (ESI) m/e 1398 (M+H)+, 1396 (M-H)’.2.145 Synthesis of N-[(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetyl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalen-Z-yl]-2-carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][27-(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriac0ntan--yl]phenyl}-L-alaninamide (Synthon WP)2.145.1 utyl((S)(((S)((3-(3-(((benzyloxy)carbonyl)amin0)pr0pynyl)xymethyl)phenyl)amino)0x0pr0panyl)amin0)methyl0x0butan-2—yl)carbamateTo a mixture of tert-butyl ((S)(((S)((4-(hydroxymethyl)-3 -iodophenyl)amino)oxopropanyl)amino)methyloxobutanyl)carbamate (0.5 g) in N,N-dimethylformamide (6mL) was added benzyl propynylcarbamate (0.182 g), CuI (9.2 mg),bis(triphenylphosphine)palladium(II) dichloride (35 mg) and N,N-diisopropylethylamine (1.0 mL).

The mixture was stirred at room ature overnight. The mixture was concentrated under vacuum.

The residue was dissolved in ethyl acetate (300 mL), washed with water, brine, dried over anhydroussodium sulfate, filtered and concentrated. Evaporation of the solvent, and purification of the residueby silica gel chromatography, eluting with 30% ethyl acetate in dichloromethane, gave the titlecompound. MS (APCI) m/e 581.2 (M-H)’.

MEl 24985843V.1 671117813-126202.145.2 utyl((S)(((S)((3-(3-amin0pr0pyl)(hydroxymethyl)phenyl)amino)0x0pr0panyl)amin0)methyl0x0butan-2—yl)carbamateTo a mixture of Example 2.145.1 (1.7g) in ethanol (30 mL) was added 5% Pd/C (0.3 g)and cyclohexene (large excess). The reaction was stirred at 100 CC for 45 minutes. The reaction wasfiltered and concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide and purified by reverse-phase HPLC on a Gilson system (C18 column), elutingwith 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound.

MS (ESI) m/e 451.1(M-H)’.3 tert-butyl((S)(((S)((3-(27-(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriacontanyl)-4—(hydroxymethyl)phenyl)amin0)oxopropan-Z-yl)amin0)methyl0x0butanyl)carbamateTo a mixture of Example 2.1452 (45 mg) in dichloromethane (4 mL) was added2,5,8,11,14,17,20,23-octaoxahexacosanal (79 mg) followed by NaH(OAc)3 (63.5 mg). Themixture was stirred at room temperature for 3 hours and then concentrated under d pressure.

The residue was ved in N,N-dimethylformamide and ed by reverse-phase HPLC on aGilson system (C18 column), eluting with 20-80% acetonitrile in water containing 0.1%trifluoroacetic acid, to give the title compound. MS (ESI) m/e 1212.1 (M-H)’.2.145.4 tert-butyl((S)(((S)((3-(27-(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriacontanyl)-4—((((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amin0)0x0pr0panyl)amin0)methyl0x0butanyl)carbamateTo a mixture of e 2.145.3 (80 mg) in N,N-dimethylformamide (2 mL) was addedbis(4-nitrophenyl) carbonate (26 mg) followed by N,N-diisopropylamine (0.012 mL). The mixturewas stirred at room temperature ght and purified ly by reverse phase HPLC on a Gilsonsystem (C18 column), eluting with 20-80% itrile in water containing 0.1% trifluoroacetic acid,to give the title compound. MS (ESI) m/e 1376.97 (M-H)’.2,145.5 3-(1-((3-(2-((((2—(27-(2,5,8,11,14,17,20,23-0ctaoxahexacosanyl)-2,5,8,11,14,17,20,23-0cta0xaazatriac0ntanyl)((S)-2-((S)aminomethylbutanamido)propanamido)benzyl)0xy)carb0nyl)(2-sulf0ethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)naphthalen-Z-yl)picolinicMEl 24985843V.1 672-12620To a mixture of Example 2.1454 (30 mg) in N,N-dimethylformamide (4 mL) was addedExample 1.43 (18.68 mg) followed by 1-hydroxybenzotriazole hydrate (3.4 mg) and N,N-diisopropylamine (3.84 uL). The mixture was stirred at room temperature overnight. Trifluoroaceticacid (0.55 mL) was added to the mixture and stirred at room temperature for 3 hours. The mixturewas purified by e-phase HPLC on a Gilson system (C18 column), eluting with 20-80%acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e1986.6 (M-H)’.2.145.6 N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-L-Valyl-N-{4-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalen-2-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][27—(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriacontanyl]phenyl}-L-amideThe title compound was ed as bed in Example 2.123.21, replacing Example2.123.20 with Example 21455. 1H NMR (400 MHZ, dimethyl ide-d6) 5 ppm 13.10 (s, 1H),9.92 (s, 1H), 9.43 (s, 1H), 9.02 (s, 1H), 8.37 (dd, 1H), 8.30 — 8.14 (m, 5H), 8.07 (d, 1H), 8.02 (d, 1H),7.96 (d, 1H), 7.81 (d, 1H), 7.74 — 7.68 (m, 1H), 7.57 (s, 1H), 7.52 — 7.45 (m, 2H), 7.42 — 7.34 (m,2H), 7.28 (d, 1H), 7.08 (s, 2H), 5.05 (d, 2H), 4.39 (t, 1H), 4.21 (dd, 1H), 4.12 (s, 2H), 3.88 (s, 2H),3.49 (d, 55H), 3.34 (s, 200H), 3.23 (s, 5H), 3.13 (d, 4H), 2.79 — 2.65 (m, 5H), 2.23 (s, 3H), 1.94 (d,8H), 1.47 — 0.94 (m, 15H), 0.92 — 0.76 (m, 12H).2.146 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]({N-[(2S)[3,4-bis(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyloxy)phenyl](2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonic acid (Synthon XD)2,146.1 (S)(((benzyloxy)carb0nyl)amin0)(3,4-dihydroxyphenyl)propanoic acidTo a mixture of (S)amino(3,4-dihydroxyphenyl)propanoic acid (1.00 kg) andNaHCO3 (1.28 kg) in dioxane (5.00 L) and water (5.00 L) was added benzyl carbonochloridate (1.04k) se. The reaction mixture was stirred at 25 CC for 12 hours. The reaction mixture wasadjusted to pH = 3.0 ~ 4.0 by addition of 6 N aqueous HCl and extracted with ethyl acetate (25 L).

The organic layer was dried over NaZSO4, filtered, and concentrated in vacuo to afford the titleMEl 24985843V.1 673117813-12620compound. 1H NMR (400MHz, dimethyl sulfoxide-d6) 5 ppm 8.73 (s, 1H), 7.54-7.26 (m, 8H), 6.64-6.45 (m, 3H), 4.98 (s, 2H), 4.49 (s, 1H), 2.87 (d, J = 9.60 Hz, 1H), 2.68-2.62 (m, 1H).2.1462 (S)-benzyl2-(((benzyloxy)carb0nyl)amin0)(3,4-dihydroxyphenyl)propanoateTo a mixture of Example 2.1461 (800.00 g) and CsZCO3 (1.18 kg) was addedbromomethylbenzene (259.67 g) at 20°C. The reaction mixture was d for 1 hour, and TLCshowed the reaction was complete. The residue was d with H20 (5 L) and extracted with ethylacetate (three times 5 L). The combined organic layers were washed with brine (5 L), dried overNaZSO4 (150 g), filtered, and concentrated under reduce pressure. The residue was purified bycolumn chromatography (SiOz, petroleum ethyl acetate = 100:1 to 1:1) twice to provide the titlend. 1H NMR (400 MHZ, CDCl3) 5 ppm 2.77 - 3.02 (m, 2 H), 4.47 (br. s., 1 H), 4.61 (d,J=7.94 Hz, 1 H), 5.01 - 5.17 (m, 4 H), 5.35 - 5.47 (m, 1 H), 6.32 (br. s., 1 H), 6.38 (d, J=7.94 Hz, 1H), 6.51 (s, 1 H), 6.65 (d, J=7.94 Hz, 1 H), 7.17 - 7.42 (m, 9 H).2.146.3 (S)-benzyl2-(((benzyloxy)carb0nyl)amin0)(3,4-bis(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanphenyl)pr0panoateTo a mixture of KZCO3 (27.04 g) and K1 (5.95 g) in N,N-dimethylformamide (150 mL)was added Example 2.1462 (8.12 g) and 2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyl 4-methylbenzenesulfonate (27.00 g) in dimethylformamide (150 mL). The mixture was stirred at75 CC for 12 hours under N2. Two additional vials were set up as described above. All three reactionmixtures were combined for purification. The mixture was poured into NH4Cl aqueous e (9 L),and extracted with ethyl acetate (five times with 900 mL). The combined organic layers were washedwith brine (1500 mL), dried over NaZSO4 (150 g), filtered, and concentrated under reduce re toafford the crude residue. The e was purified by column chromatography (SiOz,dichloromethane/methanol=100/1 to 20: 1) to provide the title compound. 1H NMR (400 MHZ,CDCl3) 5 ppm 2.95 - 3.08 (m, 2 H), 3.38 (s, 6 H), 3.57 - 3.68 (m, 80 H), 3.78 (t, J=4.85 Hz, 2 H), 3.83(t, J=5.29 Hz, 2 H), 4.01 (t, J=5.07 Hz, 2 H), 4.10 (t, J=5.07 Hz, 2 H), 4.58 - 4.70 (m, 1 H), 5.09 (s, 2H), 5.14 (d, J=3.53 Hz, 2 H), 6.55 (d, J=8.38 Hz, 1 H), 6.62 (d, J=1.76 Hz, 1 H), 6.74 (d, J=7.94 Hz, 1H), 7.27 - 7.49 (m, 10 H).2.146.4 (S)amin0(3,4-bis(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyloxy)phenyl)pr0pan0ic acidTo a mixture of Example 2.1463 (16.50 g) in methanol (200 mL) was added Pd/C (9.00g), and the mixture was stirred at 50 CC under H2 (50 psi) for 16 hours. An additional reaction was setup as described above. LC/MS showed the reaction was complete, and both reaction mixtures werecombined for purification. The mixture was filtered and concentrated. The crude title compound wasused in the next step t further purification.

MEl 24985843V.1 674117813-126202.1465 (S)(3,4-bis(2,5,8,11,14,17,20,23,26,29,32—undeca0xatetratriac0ntanyloxy)phenyl)(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)pr0pan0ic acidTo a mixture of Example 2.1464 (5.94 g) in H20 (60.00 mL) was added Na2C03 (790.67mg) and methyl 2,5-dioxopyrrolecarboxylate (1.19 g). The mixture was stirred at 25 CC for 3hours. Four additional reactions were set up as described above. All five reaction es wereed for purification. Aqueous 4M HCl was added to adjust the pH to 2. The combined mixturewas purified by atory reverse-phase HPLC (trifluoroacetic acid conditions) to provide the titlend. 1H NMR (400 MHz, CDCl3) 5 ppm 3.35 - 3.40 (m, 6 H), 3.51 - 3.58 (m, 4 H), 3.58 - 3.75(m, 78 H), 3.81 (q, J=4.70 Hz, 4 H), 4.11 (dt, J=10.14, 5.07 Hz, 4 H), 4.91 (dd, J=11.47, 5.29 Hz, 1H), 6.53 - 6.69 (m, 3 H), 6.71 - 6.89 (m, 2 H). MS (ESI) m/e6 38.0 (M+H)+.2.146.6 (6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]({N-[(2S)[3,4-bis(2,5,8,11,14,17,20,23,26,29,32-undeca0xatetratriac0ntanyloxy)phenyl](2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pr0pan0yl]-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonicacidA mixture of Example 2.1465 (0.020 mL), O-(7-azabenzotriazolyl)-N,N,N’ ,N’-tetramethyluronium hexafluorophosphate (0.014 g) and N-ethyl-N-isopropylpropanamine (0.020mL) was stirred in N,N-dimethylformamide (0.4 mL) for 5 minutes. The mixture was added to amixture of Example 2.123.20 (0.042 g) and N-ethyl-N-isopropylpropanamine (0.020 mL) in N,N-dimethylformamide (0.4 mL) and it was stirred at room ature for 3 hours. The reaction wasdiluted with a mixture of water (1.5 mL), N,N-dimethylformamide (0.5 mL) and 2,2,2-trifluoroaceticacid (0.054 mL) and purified by preparatory reverse-phase HPLC on a Gilson 2020 system, using ant of 5% to 85% acetonitrile/water. The product-containing fractions were lyophilized to givethe title compound. 1H NMR (501 MHz, dimethyl sulfoxide-d6) 5 12.86 (s, 4H), 9.92 (s, 2H), 8.26 (d,1H), 8.10 (s, 1H), 8.02 (dd, 1H), 7.77 (d, 1H), 7.64 (s, 1H), 7.54 — 7.49 (m, 1H), 7.49 — 7.39 (m, 2H),7.39 — 7.31 (m, 2H), 7.28 (s, 1H), 7.20 (d, 1H), 6.94 (d, 1H), 6.87 (s, 2H), 6.77 (d, 1H), 6.60 — 6.53(m, 1H), 5.05 — 4.91 (m, 5H), 4.80 (dd, 2H), 4.37 (t, 2H), 4.21 (t, 2H), 3.97 (dt, 3H), 3.86 (t, 3H), 3.78(d, 3H), 3.68 (dt, 4H), 3.65 — 3.28 (m, 102H), 3.20 — 3.08 (m, 2H), 2.99 (t, 2H), 2.92 (d, 2H), 2.68 (dd,2H), 2.07 (d, 4H), 1.54 (s, 2H), 1.37 — 0.71 (m, 16H). MS (ESI) m/e 2631.2 (M-H)’.2.147 Synthesis of 5-di0x0-2,5-dihydr0-1H-pyrr01yl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyl)-betaalanyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-MEl 24985843V.1 675117813-126203,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)phenyl}-L-alaninamide (Synthon XK)2.147.1 benzyl2,5,8,11,14,17,20,23,26,29,32—undecaoxaatriacontanoateTo a mixture of 2,5,8,l 1,14,l7,20,23,26,29,32-undecaoxatetratriacontanamine (l g) inN,N-dimethylformamide (4 mL) and water (3 mL) was added benzyl acrylate (0.377 g), dropwise.

The reaction mixture was stirred overnight purified by reverse-phase HPLC on a Gilson system (C18), eluting with 20-70% acetonitrile in water containing 0.1% roacetic acid, to give thetitle compound. MS (ESI) m/e 678.4 (M+H)+.2.147.2 2,5,8,11,14,17,20,23,26,29,32-undecaoxaazaoctatriac0ntan-38-0ic acidExample 2147.1 (220 mg) and 10% Pd/C (44 mg, dry) in tetrahydrofuran (10 mL) wasshaken in a pressure bottle for 1 hour under 50 psi of hydrogen gas. The reaction was filtered, and thefiltrate was concentrated. The residue was dried under high vacuum to provide the title compound.

MS (ESI) m/e 588.3 (M+H)+.3 2,5-di0x0pyrrolidinyl35-(2-(2,5-di0x0-2,5-dihydr0-1Hl-yl)acetyl)-2,5,8,11,14,17,20,23,26,29,32-undecaoxaazaoctatriacontanoateA cold (0 CC) mixture of oxopyrrolidin-l-yl 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetate (566 mg), l-hydroxybenzotriazole hydrate (229 mg), oxypyrrolidine-2,5-dione (86mg) and Example 2.1472 (440 mg) in N,N-dimethylformamide (3mL) was treated with N,N-diisopropylethylamine (785 uL) for 25 minutes. The reaction was diluted with dimethyl sulfoxideand purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 5-55%itrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS (ESI) m/e822.3 (M+H)+.2.147.4 N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriac0ntanyl)-beta-alanyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl](2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50-heptadecaoxatripentacontanyl)phenyl}-L-alaninamideMEl 24985843V.l 676117813-12620To a cold (0 CC) mixture of Example 2.1414 (28 mg), Example 2.1473 (27.1 mg) and 1-hydroxybenzotriazole hydrate (6.6 mg) in N,N-dimethylformamide (0.8 mL) was added N,N-diisopropylethylamine-2 (20.1 uL). The mixture was stirred for 10 minutes and was ed byreverse-phase HPLC on a Gilson system (C18 column), eluting with 30-70% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. 1H NMR (400 MHz, dimethylsulfoxide-dé) 5 12.81 (s, 1H), 9.84 (s, 1H), 8.21 — 7.86 (m, 2H), 7.75 (d, 1H), 7.57 (d, 1H), 7.52 — 7.28(m, 7H), 7.27 — 7.15 (m, 2H), 7.04 (d, 2H), 6.91 (d, 1H), 4.94 (d, 4H), 4.36 (dt, 3H), 4.19 (dt, 1H),3.84 (t, 2H), 3.75 (d, 2H), 3.63 (d, 1H), 3.46 (dd, 104H), 3.36 (s, 2H), 3.19 (s, 5H), 2.97 (t, 2H), 2.57(t, 5H), 2.42 — 2.26 (m, 1H), 2.03 (s, 7H), 2.00 — 1.83 (m, 1H), 1.70 (t, 2H), 1.38 — 0.96 (m, 13H),0.96 — 0.69 (m, 13H). MS (ESI) m/e 1327.7 (M-2H)2’.2.148 Synthesis of N-[(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyl)-beta-alanyl-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazol-Z-ylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-inamide (Synthon XL)The title nd was prepared using the procedure in Example 2.147.4, replacingExample 2.1414 with Example 21122. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 12.83 (s, 1H),9.96 (d, 1H), 8.18 — 7.85 (m, 3H), 7.75 (d, 1H), 7.64 — 7.37 (m, 7H), 7.32 (td, 2H), 7.28 — 7.20 (m,3H), 7.04 (s, 2H), 6.92 (d, 1H), 5.17 — 4.79 (m, 4H), 4.59 — 4.31 (m, 3H), 4.21 (dt, 1H), 3.84 (t, 2H),3.77 (d, 2H), 3.52 (s, 4H), 3.39 (d, 2H), 3.19 (s, 5H), 2.94 (dt, 4H), 2.60 (t, 3H), 2.43 — 2.27 (m, 1H),2.05 (s, 4H), 1.60 (d, 2H), 1.44 — 0.57 (m, 22H). MS (ESI) m/e 1964.8 (M-H)’.2.149 Synthesis of 5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetyl]-L-valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-lyl)methyl]-5,7—dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][27-(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriac0ntan-30-yl]phenyl}-L-alaninamide (Synthon YJ)2.149.1 3-(1-((3-(2-((((2—(27-(2,5,8,11,14,17,20,23-0ctaoxahexacosan,8,11,14,17,20,23-0cta0xaazatriac0ntanyl)((S)-2-((S)amin0methylbutanamido)propanamid0)benzyl)0xy)carb0nyl)(2-sulfoethyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)-S-methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)picolinic acidMEl 24985843V.1 677117813-12620The title compound was prepared as described in Example 5, replacing Example1.43 with e 1.2.9. MS (ESI) m/e 1991.4 (M-H)’.2.149.2 N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][27—(2,5,8,11,14,17,20,23-0ctaoxahexac0sanyl)-2,5,8,11,14,17,20,23-0ctaoxaazatriacontanyl]phenyl}-L-alaninamideThe title compound was prepared as described in Example 2.145, replacing Example2.1455 with Example 21491. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 ppm 12.83 (s, 1H), 9.90(s, 1H), 9.41 (s, 1H), 8.24 (d, 2H), 8.01 (d, 1H), 7.77 (d, 1H), 7.67 — 7.29 (m, 8H), 7.26 (s, 2H), 7.06(s, 2H), 6.93 (d, 1H), 5.03 (d, 2H), 4.93 (s, 2H), 4.37 (t, 1H), 4.19 (dd, 1H), 4.11 (s, 2H), 3.86 (t, 2H),3.79 (s, 2H), 3.70 — 3.26 (m, 226H), 3.21 (s, 6H), 3.11 (s, 5H), 2.99 (t, 2H), 2.66 (d, 4H), 2.08 (s, 3H),1.89 (s, 8H), 1.44 — 0.90 (m, 14H), 0.89 — 0.68 (m, 11H).2.150 Synthesis of N-{(3S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[1-,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]propanoyl}-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon YQ)2.150.1 3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)pentyn0ic acidTo a mixture of 3-aminopentynoic acid trifluoroacetic acid salt (1.9 g) intetrahydrofuran (30 mL) was added methyl 2,5-dioxo-2,5-dihydro-1H-pyrrolecarboxylate (1.946g), followed by the rapid addition of N,N-diisopropylethylamine (8.04 mL). The ing mixturewas stirred at 60 CC for 16 hours. The mixture was concentrated to dryness. The residue was purifiedby reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80% acetonitrile in watercontaining 0.1% trifluoroacetic acid, to give the title compound. MS (LC-MS) m/e 194 (M+H). 1H-NMR (dimethyl sulfoxide-dg, 400 MHz) 8 2.92-3.07 (m, 2H), 3.38 (d, 1H), 5.07-5.12 (m, 1H), 7.08 (s,2H), 12.27 (bs, 0.6H).2.1502 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl)(2,5-2,5-dihydr0-lH-pyrrol-l-yl)pr0pan0ic acidMEl 24985843V.1 678117813-12620To Example 2.1501 (700 mg) in a mixture of t—butanol/HZO, (2:1, 15 mL) was added 37-azido-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontane (2123 mg). Sodium (R)((S)-hydroxyethyl)hydroxyoxo-2,5-dihydrofuranolate (71.8 mg) and copper(II) sulfate (28.9mg) were sequentially added to the mixture. The resulting mixture was stirred at room temperaturefor 16 hours and concentrated. The residue was purified by reverse-phase HPLC on a Gilson system(C18 column), eluting with 20-80% acetonitrile in water containing 0.1% trifluoroacetic acid, to givethe title nd. 1H NMR (400 MHz, yl sulfoxide-d6) 5 3.24 (s, 3H), 3.15-3.28 (m, 2H),3.41-3.52 (m, 44H), 3.79 (t, 2H), 4.48 (t, 2H), 5.56-5.60 (m, 1H), 7.05 (s, 2H), 8.03 (s, 1H). MS (LC-MS) m/e 779 (M+H)+.2.150.3 N-{(3S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]propanoyl}-L-valyl-N-{4-[({[2-({3-[(4—{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]phenyl}-N5-carbamoyl-L-0rnithinamideTo a mixture of O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluroniumhexafluorophosphate (8.45 mg), and Example 2.1502 (20 mg) in N,N-dimethylformamide (0.3 mL)at 0 CC was slowly added N,N-diisopropylethylamine (22.19 uL)., and the reaction mixture wasstirred for 1 minute. A cold (0 CC) mixture of Example 2.1122 (20 mg) and N,N-diisopropylethylamine (22 uL) in N,N-dimethylformamide (0.4 mL) was added. The resultingmixture was stirred for 10 minutes and was purified by reverse-phase HPLC on a Gilson system (C18column), eluting with 20-80% acetonitrile in water containing 0.1% roacetic acid, to give thetitle compound. (The absolute configuration of the 3-position was arbitrarily assigned.) 1H NMR(501 MHz, dimethyl sulfoxide-dé) 5 9.95 (s, 1H), 8.07 (d, 3H), 8.04 — 7.96 (m, 2H), 7.77 (d, 1H), 7.64— 7.53 (m, 3H), 7.50 (s, 1H), 7.48 — 7.39 (m, 2H), 7.34 (q, 2H), 7.30 — 7.23 (m, 3H), 6.98 (s, 2H), 6.93(d, 1H), 5.61 (t, 1H), 4.96 (d, 4H), 4.54 — 4.27 (m, 3H), 4.14 (t, 1H), 3.86 (t, 2H), 3.77 (q, 4H), 3.43(d, 71H), 3.21 (s, 6H), 3.00 (d, 5H), 2.61 (s, 2H), 2.07 (d, 3H), 1.92 (s, 1H), 1.60 (d, 2H), 1.47 — 0.86(m, 10H), 0.85 — 0.67 (m, 12H). MS (ESI) m/e 1010.6 (M-2H)2’.2.151 Synthesis of N-{(3R)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]propanoyl}-L-Valyl-N-{4-[({[2-({3-[(4-{6-[8-(1,3-hiazolylcarbam0yl)-3,4-dihydr0isoquinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-MEl 24985843V.1 679117813-12620sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbam0yl-L-ornithinamide (Synthon YR)e 2.151 was ed during the preparation of 2.1503. (The absoluteconfiguration of the 3-position was arbitrarily assigned.) 1H NMR (501 MHZ, dimethyl sulfoxide-dé)9.91 (s, 1H), 8.11 (dd, 2H), 8.04 — 7.99 (m, 1H), 7.96 (s, 1H), 7.77 (d, 1H), 7.58 (t, 3H), 7.54 — 7.39(m, 2H), 7.39 — 7.31 (m, 2H), 7.31 — 7.24 (m, 3H), 7.00 (s, 2H), 6.94 (d, 1H), 5.61 (dd, 1H), 5.08 —4.79 (m, 4H), 4.40 (dt, 3H), 4.16 (s, 1H), 3.86 (t, 2H), 3.82 — 3.73 (m, 4H), 3.51 — 3.30 (m, 46H), 3.21(s, 7H), 3.05 — 2.87 (m, 3H), 2.62 (t, 2H), 2.07 (d, 3H), 1.95 (s, 2H), 1.69 (s, 1H), 1.51 — 0.86 (m,10H), 0.88 — 0.70 (m, 13H). MS (ESI) m/e 1010.6 (M-2H)2’.2.152 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-({[(2-{2-[(2S,3R,4R,5S,6S)carboxy-3,4,5-trihydroxytetrahydr0-2H-pyranyl]ethyl}{[(2S){[(2S){[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]amin0}methylbutanoyl]amin0}pr0pan0yl]amin0}benzyl)0xy]carbonyl}[(3R,4S,5R)-3,4,5,6-tetrahydr0xyhexyl]amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon YS)1 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamid0)(2-((2S,3R,4R,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)benzyl)0xy)carb0nyl)((3R,4S,5R)-3,4,5,6-tetrahydroxyhexyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acidThe title compound was prepared by substituting Example 1.77.2 for e 1.25 andExample 2.123.19 for Example 2.97.7 in Example 2.97.8. MS (ESI) m/e 1417 (M+H)+, 1415 (M-H)+.2.152.2 6-[8-(1,3-benzothiazolylcarbamoyl)-3,4—dihydr0is0quinolin-2(1H)-yl][1-({3-[2—({[(2—{2-[(2S,3R,4R,5S,6S)carb0xy-trihydr0xytetrahydr0-2H-pyranyl]ethyl}{[(2S){[(2S){[(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetyl]amin0}-methylbutanoyl]amin0}pr0pan0yl]amin0}benzyl)0xy]carbonyl}S,5R)-3,4,5,6-tetrahydr0xyhexyl]amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acidThe title compound was prepared by substituting Example 2152.1 for Example 2.49.1 inExample 2.54. 1H NMR (400 MHZ, dimethyl sulfoxide-d6) 5 ppm 9.85 (m, 1H), 8.18 (t, 2H), 7.96 (d,MEl 24985843V.1 680117813-126201H), 7.73 (d, 1H), 7.55 (d, 1H), 7.46-7.25 (m, 8H), 7.21 (s, 1H), 7.15 (d, 1H), 7.00 (s, 1H), 6.99 (d,1H), 6.88 (d, 1H), 4.95 (bs, 2H), 4.88 (s, 2H), 4.32 (m, 1H), 4.15 (t, 1H), 4.05 (s, 2H), 3.82 (t, 2H),3.72 (m, 4H), 3.58-3.29 (m, 6H), 3.19 (m, 4H), 3.11-3.00 (m, 6H), 2.97 (t, 2H), 2.91 (t, 2H), 2.72 (m,2H), 2.55 (m, 2H), 2.04 (s, 3H), 2.02-1.85 (m, 3H), 1.54 (m, 4H), 1.44 (s, 1H), 1.33 (bs, 1H), 1.22 (m,6H), 1.04 (m, 6H), 0.86 (m, 2H), 0.77 (m, 12H). MS (ESI) m/e 1554 (M+H)+, 1552 (M-H)’.2.153 Synthesis of 6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-({[(2-{2-[(2S,3R,4R,5S,6S)y-3,4,5-trihydroxytetrahydro-ZH-pyranyl]ethyl}{[(2S)({(2S)-2—[({(3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulfoethoxy)methyl]pyrrolidinyl}acetyl)amin0]methylbutanoyl}amin0)propanoyl]amin0}benzyl)0xy]carbonyl}[(3R,4S,5R)-3,4,5,6-tetrahydr0xyhexyl]amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon YY)Example 2.119.15 (11 mg) was dissolved in N,N-dimethylformamide (0.1 mL). 2—(3H-[l,2,3]triazolo[4,5-b]pyridin-3 -yl)-l,1,3,3-tetramethylisouronium hexafluorophosphate(V) (11 mg)and N,N-diisopropylethylamine (7.4 mg) were added. The mixture was stirred at room temperaturefor five minutes. The mixture was then added to another mixture of Example 2152.1 (34 mg) andN,N-diisopropylethylamine (16.3 mg) in methylformamide (0.2 mL). The reaction was stirredfor 60 minutes at room temperature and quenched with trifluoroacetic acid (36 mg). The mixture wasdiluted with water (0.75 mL) and yl sulfoxide (0.75 mL) and purified by reverse-phase HPLCusing 10-75% acetonitrile in water % TFA) over 30 minutes on a Grace Reveleris equippedwith a Luna column: , 100 A, 150 x 30 mm. Product fractions were , frozen, andlized to yield the title compound as the trifluoroacetic acid salt. 1H NMR (400 MHz, dimethylsulfoxide-dg) 5 ppm 9.85 (m, 1H), 8.18 (d, 1H), 8.05 (d, 1H), 8.04 (d, 1H), 7.79 (d, 1H), 7.53-7.39 (m,8H), 7.36 (q, 2H), 7.29 (s, 1H), 7.22 (d, 1H), 7.07 (s, 1H), 6.96 (d, 1H),5.18 (bs, 2H), 4.96 (s, 2H),4.65 (t, 1H), 4.37 (t, 1H), 4.19 (t, 1H), 4.16 (s, 1H), 4.01 (d, 2H), 3.89 (t, 2H), 3.78 (m, 4H), 3.73 (m,2H), 3.49-3.44 (m, 4H), 3.40-3.20 (m, 8H), 3.24 (m, 4H), 3.17-3.07 (m, 4H), 3.02 (t, 2H), 2.95 (t,2H), 2.76 (m, 4H), 2.62 (m, 1H), 2.37 (m, 1H), 2.09 (s, 3H), 1.99 (m, 2H), 1.86 (q, 1H), 1.62 (m, 4H),1.38 (bs, 2H), 1.28 (m, 6H), 1.18-1.02 (m, 6H), 0.96 (m, 2H), 0.91-0.79 (m, 12H). MS (ESI) m/e1773 (M-H)’.2.154 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-thyl)carbam0yl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32—MEl 24985843V.1 681117813-12620undecaoxatetratriacontan—34-yl)-beta-alanyl-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonic acid (Synthon YT)2.154.1 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamid0)(2-((2S,3R,4R,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)benzyl)0xy)carbonyl)(2-sulf0ethyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidA mixture of Example 1.2.9 (200 mg), Example 2.123.19 (288 mg), and 1-hydroxybenzotriazole hydrate (50.2 mg) in N,N-dimethylformamide (2 mL) was cooled in an ice-bath, and N,N-diisopropylethylamine (143 uL) was added. The reaction mixture was stirred at roomtemperature for 2.5 hours and concentrated. Tetrahydrofuran (0.5 mL) and methanol (0.5 mL) wereadded into the residue. The resulting mixture was cooled in ice-bath and lithium hydroxide hydrate(147 mg) in water (2.5 mL) was slowly added. The mixture was d at room temperature for 1.5hours, and cooled in ice bath. Trifluoroacetic acid (361 uL) was added dropwise until the pH reached6. The mixture was purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with-45% itrile in water containing 0.1% trifluoroacetic acid, to give the title compound. MS(ESI) m/e 1375.5 (M-H)’.2.1542 (6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-yltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriac0ntanyl)-beta-alanyl-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonicTo a mixture of 1-hydroxybenzotriazole hydrate (5.22 mg), Example 2.1541 (23.5 mg)and Example 2.1473 (24 mg) in N,N-dimethylformamide (1 mL) at 0 CC was slowly added N,N-ropylethylamine (23.84 uL). The reaction mixture was stirred at room ature for 15minutes and ed by e-phase HPLC on a Gilson system (C18 column), eluting with 35-50%acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. 1H NMR (501MHz, dimethyl sulfoxide-dé) 5 12.83 (s, 1H), 9.88 (s, 1H), 8.23 — 8.04 (m, 2H), 8.02 (dd, 1H), 7.92 (s,1H), 7.77 (d, 1H), 7.59 (d, 1H), 7.55 — 7.30 (m, 7H), 7.27 (s, 1H), 7.20 (d, 1H), 7.07 (d, 2H), 6.93 (d,1H), 5.07 — 4.88 (m, 4H), 4.47 — 4.32 (m, 3H), 4.22 (dt, 1H), 3.97 — 3.73 (m, 4H), 3.62 — 3.45 (m,MEl 24985843V.1 682117813-1262035H), 3.31 (t, 3H), 3.21 (s, 3H), 3.06 (d, 2H), 2.83 — 2.54 (m, 5H), 2.47 — 2.29 (m, 1H), 2.13 — 1.84(m, 5H), 1.52 (d, 1H), 1.43 — 0.69 (m, 26H). MS (ESI) m/e 1043.0 (M-2H)2'.2.155 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][(N-{2-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]pr0pan0yl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid (Synthon YU)2,155.1 2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl)(2,5-di0x0-2,5-dihydr0-lH-pyrrol-l-yl)pr0pan0ic acidThe title compound was prepared using the procedure in Example 2.150.2, replacingExample 2.1501 with 2-(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)pentynoic acid.2,155.2 (6S)-2,6-anhydr0(2-{2-[({[2-({3-[(4-{6-[8-(1,3-benz0thiazolamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][(N-{2—(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]pr0pan0yl}-L-Valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonicThe title compound was ed using the procedure in Example 3, replacingExample 2.1502 and e 2.1122 with Example 2.1551 and Example 2.1541, respectively. 1HNMR (400 MHz, dimethyl sulfoxide-dé) 5 12.83 (s, 1H), 9.87 (d, 1H), 8.25 — 8.06 (m, 2H), 8.00 (d,1H), 7.75 (d, 1H), 7.71 (s, 1H), 7.57 (d, 1H), 7.54 — 7.28 (m, 6H), 7.25 (s, 1H), 7.18 (d, 1H), 6.98 —6.85 (m, 3H), 5.09 — 4.89 (m, 4H), 4.76 (ddd, 1H), 4.36 (ddd, 3H), 4.17 (q, 1H), 3.84 (t, 2H), 3.76 (d,2H), 3.72 — 3.66 (m, 2H), 3.49 — 3.44 (m, 37H), 3.20 (s, 5H), 3.01 — 2.82 (m, 3H), 2.13 — 1.81 (m,5H), 1.52 (s, 1H), 1.39 — 0.50 (m, 23H). MS (ESI) m/e 1069.7 (M+2H)2+.2.156 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][(N-{(3S)(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-MEl 24985843V.1 683117813-12620oxaheptatriacontanyl)-1H-1,2,3-triazolyl]propanoyl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid (Synthon YV)Example 2.156 was isolated as a pure diastereomer during the preparation of Example2.1552. (The assignment of absolute configuration at the 3-position is arbitrary.) 1H NMR (400MHz, dimethyl sulfoxide-dé) 5 12.82 (s, 1H), 9.85 (s, 1H), 8.08 (d, 2H), 8.03 — 7.95 (m, 2H), 7.75 (d,1H), 7.57 (d, 1H), 7.51 — 7.29 (m, 6H), 7.24 (s, 1H), 7.18 (d, 1H), 6.95 (s, 2H), 6.91 (d, 1H), 5.59 (dd,1H), 5.06 — 4.86 (m, 4H), 4.43 (dt, 2H), 4.32 (t, 1H), 4.11 (t, 1H), 3.84 (t, 2H), 3.75 (t, 3H), 3.55 —3.41 (m, 43H), 3.41 — 3.36 (m, 2H), 3.19 (s, 5H), 3.10 (t, 1H), 3.03 — 2.86 (m, 3H), 2.59 (s, 3H), 2.13— 1.82 (m, 6H), 1.52 (s, 1H), 1.37 — 0.65 (m, 26H). MS (ESI) m/e 1067.8 (M-2H)2'.2.157 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl][(N-{(3R)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)[1-(2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-1H-1,2,3-triazolyl]pr0pan0yl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid (Synthon YW)e 2.157was isolated as a pure diastereomer during the preparation of Example2.1552. (The assignment of absolute configuration at the 3-position is arbitrary.) 1H NMR (400MHz, yl sulfoxide-dé) 5 12.81 (s, 1H), 9.81 (s, 1H), 8.10 (d, 2H), 8.00 (d, 1H), 7.94 (s, 1H),7.75 (d, 1H), 7.57 (d, 1H),7.51— 7.28 (m, 6H), 7.24 (s, 1H), 7.18 (d, 1H), 6.98 (s, 2H), 6.91 (d, 1H),.59 (t, 1H), 5.06 — 4.87 (m, 4H), 4.46 — 4.26 (m, 2H), 4.12 (d, 1H), 3.84 (t, 2H), 3.75 (d, 3H), 3.46 (d,27H), 3.40 — 3.36 (m, 2H), 3.19 (s, 5H), 3.01 — 2.85 (m, 3H), 2.60 (s, 3H), 1.99 (d, 4H), 1.52 (s, 1H),1.35 — 0.65 (m, 23H). MS (ESI) m/e 1067.8 (M-2H)2'.2.158 sis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl][(N-{(3S)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)[1-(3-sulf0pr0pyl)-1H-1,2,3-triazol-4—yl]propanoyl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid on ZB)2.158.1 sodium 3-azid0pr0panesulf0nateTo a mixture of sodium azide (3.25 g) in water (25 mL) was added 1, 2-oxathiolane 2,2-dioxide (6.1 g) in acetone (25mL). The ing mixture was stirred at room temperature for 24hours and concentrated to dryness. The solid was suspended in diethyl ether (100 mL) and stirred atreflux for 1 hour. The suspension was cooled to room temperature, and the solid was collected byMEl 24985843V.1 684-12620tion, washed with acetone and diethyl ether, and dried under vacuum to afford the titlend. MS (LC-MS) m/e 164 (M-H)’.2,158.2 isopropyl3-azid0pr0panesulf0nateA mixture of Example 2.1581 (6.8 g) in concentrated HCl (90 mL) was stirred at roomtemperature for 1 hour. The mixture was concentrated to dryness. The residue was ved inromethane (350 mL), and triisopropoxymethane (42.0 mL) was added in one portion to themixture. The resulting e was stirred at 50 CC for 2 hours and concentrated to s. Thecrude residue was purified by silica gel chromatography, eluting with 10/1 petroleum ether/ethylacetate, to give the title compound. 1H-NMR (CDCl3, 400 MHz): 1.42 (s, 3H), 1.44 (s, 3H), 2.08-2.15(m, 2H), 3.17 (t, 2H), 3.51 (t, 2H), 4.95-5.01 (m, 1H).2,158.3 3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)(1-(3-sulf0pr0pyl)-1H-1,2,3-triazolyl)pr0pan0ic acidTo a mixture of Example 2.1501 (450 mg) in t—butanol/HZO (2:1, 9 mL) was addedExample 2.1582 (483 mg) followed by copper(II) sulfate (18.59 mg) and sodium (R)((S)-1,2-dihydroxyethyl)hydroxy-5 -oxo-2,5-dihydrofuran-3 -olate (46.2 mg). The resulting mixture wasstirred at room temperature for 16 hours, and the mixture was concentrated to dryness. The residuewas purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 20-80%acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title compound. 1H-NMR(dimethyl sulfoxide-d6, 400 MHz): 2.06-2.10 (m, 2H), 2.45-2.48 (m, 2H), 3.21-3.23 (m, 2H), 4.40-4.44 (m, 2H), 5.55-5.59 (m, 1H), 7.05 (s, 2H), 8.10 (s, 1H). MS (LCMS) m/e 359 (M+H)+.2.158.4 (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl][(N-{(3S)(2,5-di0x0-2,5-o-1H-pyrrolyl)[1-(3-sulf0pr0pyl)-1H-1,2,3-triazol-4-yl]pr0pan0yl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acidThe title compound was prepared using the procedure in Example 2.1503, replacingExample 2.1502 and Example 2.1122 with Example 2.1583 and Example 2.1541, respectively. Thecompound was isolated as a pure reomer. (The absolute configuration of the 3-position wasarbitrarily assigned.) 1H NMR (400 MHz, dimethyl ide-d6) 5 10.14 — 9.66 (m, 1H), 8.07 (d,2H), 8.04 — 7.96 (m, 2H), 7.75 (d, 1H), 7.57 (d, 1H), 7.52 — 7.29 (m, 7H), 7.26 (s, 1H), 7.18 (d, 1H),6.92 (d, 3H), 5.58 (t, 1H), 5.09 — 4.84 (m, 4H), 4.35 (dt, 3H), 4.15 — 4.02 (m, 1H), 3.89 — 3.65 (m,4H), 3.28 (d, 1H), 3.21 (dd, 2H), 3.14 — 3.02 (m, 2H), 3.01 — 2.86 (m, 4H), 2.62 (d, 3H), 2.37 (t, 2H),2.29 (s, 0H), 2.02 (dt, 5H), 1.52 (s, 1H), 1.40 — 0.59 (m, 24H). MS (ESI) m/e 1715.3 (M-H)’.

MEl 24985843V.1 685117813-126202.159 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl][(N-{(3R)(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)[1-(3-sulf0pr0pyl)-1H-1,2,3-triazol-4—yl]propanoyl}-L-valyl-L-alanyl)amin0]phenyl}ethyl)-L-gulonic acid (Synthon ZC)Example 2.159 was isolated as a pure diastereomer during the preparation of Example2.158. (The absolute configuration of the 3-position was arbitrarily assigned.) 1H NMR (400 MHZ,dimethyl sulfoxide-dé) 5 9.97 (d, 1H), 8.21 (d, 1H), 8.13 (d, 1H), 8.04 — 7.96 (m, 2H), 7.75 (d, 1H),7.57 (d, 1H), 7.55 — 7.37 (m, 4H), 7.36 — 7.25 (m, 3H), 7.17 (d, 1H), 6.98 (s, 2H), 6.93 (d, 1H), 5.58(t, 1H), 4.94 (d, 4H), 4.50 — 4.26 (m, 3H), 4.10 (s, 1H), 3.98 — 3.73 (m, 3H), 3.51 (d, 1H), 3.42 (s,3H), 3.34 — 3.01 (m, 6H), 3.01 — 2.83 (m, 4H), 2.63 (d, 4H), 2.42 (d, 1H), 2.18 — 1.80 (m, 8H), 1.53(s, 1H), 1.39 — 0.68 (m, 27H). MS (ESI) m/e 1715.4 (M-H)’.2.160 Synthesis of (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13’7]decyl}0xy)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-N-[2-(2-sulf0eth0xy)ethyl]-beta-alanyl-L-valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonic acid (Synthon ZJ)1 4-((tert-butyldiphenylsilyl)oxy)-2,2—dimethylbutyl2-(2—((tertbutoxycarbonyl)amin0)ethoxy)ethanesulf0nateTo a mixture of tert-butyl (2-hydroxyethyl)carbamate (433 mg) in dimethyl sulfoxide (0.9mL) at 20 CC were added 4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutyl ethenesulfonate (500 mg)and KZCO3 (210 mg). The e was warmed to 60 CC and stirred for 16 hours in a capped bottle.

The mixture was diluted with ethyl acetate, washed with water and brine. The organic layer was driedover anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel flashchromatography, eluting with petrol ether/ ethyl acetate (10:l~2: l), to give the title nd. MS(LC-MS) m/e 630.3 (M+Na) +.2.1602 4-((tert-butyldiphenylsilyl)oxy)-2,2—dimethylbutyl2-(2—aminoethoxy)ethanesulf0nateTo a mixture of Example 2.1601 (1.5 g) in anhydrous dichloromethane (100 mL) at 20 CCwas added zinc(II) bromide (0.445 g). The e was stirred at room temperature for 16 hours.

Additional zinc(II) bromide (278 mg) was added to above mixture, and the reaction was stirred foronal 16 hours. The reaction was ed with l M aqueous NazCO3 mixture (5 mL), and theaqueous layer was extracted with ethyl acetate three times. The ed organic layers were driedMEl 24985843V.1 686117813-12620over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel columnchromatography, eluting with dichloromethane/methanol (10: l), to give the title compound. MS (LC-MS) m/e 508.2 .2.160.3 tert-butyl3-((2-(2—((4-((tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)ethyl)amin0)pr0panoateTo a mixture of Example 2.1602 (0.365 g) in N, thylformamide (5.5 mL) andwater (0.55 mL) were added tert-butyl acrylate (0.105 mL) and triethylamine (10.02 uL). Themixture was stirred at 60 CC for 30 hours. The mixture was concentrated. The residue was mixedwith l M aqueous NazCO3 mixture (5 mL). The aqueous layer was extracted with ethyl acetate threetimes. The combined organic layers were dried over sodium e, filtered and concentrated. Theresidue was purified by silica gel column chromatography, eluting with dichloromethane/ ethylacetate( 3:1) and dichloromethane /methanol (10:1), to give the title compound. MS (LC-MS) m/e636.3 (M+H)+.2.160.4 tert-butyl3-(N-(2-(2—((4-((tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)ethyl)(2,5-di0x0-2,5-dihydro-lH-pyrrol-l-yl)acetamid0)pr0panoateTo a mixture of Example 2.1603 (557.5 mg), 2-(2,5-dioxo-2,5-dihydro-lH-pyrrol-l-yl)acetic acid (272 mg) and O-(7-azabenzotriazol-l-yl)-N,N,N’ ,N’-tetramethyluroniumhexafluorophosphate (667 mg) in N, N—dimethylformamide (1.75 mL) at 0 CC was added N,N-diisopropylethylamine (0.459 mL). The resulting mixture was stirred at 0 CC for 1 hour. The reactionmixture was mixed with saturated s NH4Cl mixture, extracted with ethyl acetate and washedwith brine. The organic layer was dried over sodium sulfate, filtered and trated. The residuewas purified by silica gel column chromatography, eluting with petroleum ether/ ethyl acetate (2/1), toprovide the title compound. MS (LC-MS) m/e 795.3 (M+Na) +.2.1605 2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)-N-(2-(2-thoxy)ethyl)acetamid0)pr0pan0ic acidTo a mixture of Example 2.160.4 (230 mg) in dichloromethane (4 mL) was addedroacetic acid (3 mL). The mixture was stirred at 20 CC for 16 hours and was concentrated. Theresidue was purified by reverse-phase HPLC on a Gilson system (C18 column), g with 20-80%acetonitrile in water containing 0.1% trifluoroacetic acid, to give the title nd. MS (LC-MS)m/e 379.0 (M+Na)+.2.160.6 2-(2-(2—(2,5-di0x0-2,5-dihydr0-lH-pyrrol-l-yl)-N-(3-((2,5-dioxopyrrolidinyl)0xy)oxopropyl)acetamid0)eth0xy)ethane-l-sulfonic acidA mixture of l-hydroxypyrrolidine-2,5-dione (16.43 mg), Example 2.1605 (30 mg), l-ethyl[3 -(dimethylamino)propyl]-carbodiimide hydrochloride (45.6 mg) in N,N-dimethylformamidewere stirred overnight. The on mixture was purified by reverse-phase HPLC on a Gilson systemMEl 24985843V.1 687117813-12620(C18 column), g with 2-30% acetonitrile in water containing 0.1% trifluoroacetic acid, to givethe title compound. MS (ESI) m/e M+H)+.2.160.7 (6S)-2,6-anhydr0(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydr0is0quinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec-l-yl}0xy)ethyl](2-sulfoethyl)carbamoyl}0xy)methyl]({N-[(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)acetyl]-N-[2-(2-sulf0eth0xy)ethyl]-betaalanyl-L-Valyl-L-alanyl}amin0)phenyl}ethyl)-L-gulonic acidTo a mixture of 1-hydroxybenzotriazole hydrate (4.45 mg), e 2.1606 (8.97 mg)and Example 2.1541 (20 mg) in N,N-dimethylformamide (0.8 mL) at 0 CC was added N,N-diisopropylethylamine (20 uL dropwise). The reaction mixture was stirred at room temperature for 1hour and purified by reverse-phase HPLC on a Gilson system (C18 column), eluting with 30-55%itrile in water containing 0.1% trifluoroacetic acid, to give the title nd. 1H NMR (500MHz, dimethyl sulfoxide-dé) 5 12.87 (s, 1H), 9.88 (d, 1H), 8.28 — 8.10 (m, 1H), 8.03 (d, 1H), 7.95 (d,1H), 7.78 (d, 1H), 7.60 (d, 1H), 7.56 — 7.31 (m, 7H), 7.28 (s, 1H), 7.21 (d, 1H), 7.06 (d, 2H), 6.95 (d,1H), 5.06 — 4.90 (m, 4H), 4.38 (q, 3H), 4.28 — 4.11 (m, 1H), 3.87 (t, 2H), 3.79 (d, 2H), 3.71 — 3.49 (m,5H), 3.21 (d, 2H), 3.12 (q, 2H), 2.97 (dt, 3H), 2.84 — 2.57 (m, 6H), 2.38 (dd, 1H), 2.13 — 1.86 (m, 5H),1.55 (s, 1H), 1.39 — 0.64 (m, 25H). MS (ESI) m/e 867.6 (M-2H)2'.2.161 Synthesis of 6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydroisoquinolin-2(1H)-yl}[1-({3-[2-({[(2-{2—[(2S,3R,4R,5S,6S)carboxy-3,4,5-trihydr0xy0xanyl]ethyl}{[(2S){[(2S){[(2S)-2—(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl){4-[(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanyl)0xy]phenyl}pr0pan0yl]amin0}methylbutanoyl]amin0}pr0pan0yl]amin0}phenyl)meth0xy]carbonyl}[(3R,4S,5R)-3,4,5,6-tetrahydr0xyhexyl]amin0)eth0xy]-5,7-dimethyltricyclo[3.3.1.13’7]decanyl}methyl)methyl-1H-pyrazolyl]pyridinecarb0xylic acid (Synthon ZE)The title compound was prepared by substituting Example 2.1205 for Example 2.119.15in Example 2.153. 1H NMR (400 MHz, dimethyl ide-d6) 5 ppm 12.84 (bs, 2H), 9.92 (m, 1H),8.26 (d, 1H), 8.13 (d, 1H), 8.03 (d, 1H), 7.79 (d, 1H), 7.61 (d, 1H), 7.52-7.41 (m, 4H), 7.36 (m, 3H),7.27 (s, 1H), 7.21 (d, 1H), 7.02 (d, 2H), 6.95 (d, 1H), 6.89 (s, 2H), 6.78 (d, 2H), 5.02 (bs, 4H), 4.96 (s,2H), 4.59 (dd, 1H), 4.38 (m, 2H), 4.21 (t, 1H), 3.99 (t, 2H), 3.88 (t, 2H), 3.79 (m, 2H), 3.69 (t, 2H),3.64 (m, 1H), 3.57 (m, 4H), 3.53 (m, 4H), 3.50 (s, 40H), 3.42 (m, 2H), 3.38 (m, 1H), 3.30 (m, 2H),3.23 (s, 6H), 3.20-3.08 (m, 6H), 3.01 (t, 2H), 2.94 (t, 1H), 2.76 (m, 1H), 2.61 (m, 1H), 2.08 (s, 3H),MEl 24985843V.1 688117813-126202.06-1.92 (m, 2H), 1.67-1.52 (m, 3H), 1.38 (m, 1H), 1.32-1.22 (m, 6H), 1.18-1.01 (m, 6H), 0.92 (m,2H), 0.84 (m, 6H), 0.78 (m, 6H). MS (ESI) m/e 1078 (M-2H)’.2.162 Synthesis of 4-{[({2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4—oisoquinolin-2(1H)-yl}carb0xypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13’7]decanyl)0xy]ethyl}[(3S)-3,4-dihydr0xybutyl]carbamoyl)0xy]methyl}(2-{2-[2—(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetamid0]ethoxy}eth0xy)phenylbeta-D-glucopyranosiduronic acid (Synthon ZS)2.162.1 3-(1-((3-(2-((((2—(2-(2-amin0eth0xy)eth0xy)(((2S,3R,4S,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-2-yl)0xy)benzyl)0xy)carb0nyl)((S)-3,4-dihydroxybutyl)amino)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acide 21621 was prepared by substituting Example 2.62.6 for (9H-flu0renyl)methyl ((S)-3 -methyl(((S)((4-((((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amino) -1 -0x0--ureid0pentanyl)amin0)0x0butanyl)carbamate and substituting Example 1.85 for Example1.2.9 in Example . MS (ESI) m/e 1261.4 (M-H)’.2,162.2 2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4—dihydroisoquinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13,7]decan-1-yl)0xy]ethyl}[(3S)-3,4-dihydroxybutyl]carbamoyl)0xy]methyl}(2-{2-[2-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetamid0]ethoxy}eth0xy)phenyl-glucopyranosiduronic acidExample 2.1622 was prepared by substituting Example 2162.1 for Example 2.49.1 inExample 2.54. 1H NMR (400 MHz, dimethyl sulfoxide-dé) 5 8.18 (t, 1H), 8.00 (dd, 1H), 7.76 (d, 1H),7.58 (dd, 1H), 7.50 — 7.29 (m, 6H), 7.26 (s, 1H), 7.17 (d, 1H), 7.03 (s, 2H), 6.92 (d, 1H), 6.64 (d, 1H),6.57 (dd, 1H), 4.94 (d, 4H), 4.08 (hept, 2H), 4.00 (s, 2H), 3.92 — 3.68 (m, 8H), 3.51 — 3.13 (m, 12H),2.98 (t, 2H), 2.06 (s, 3H), 1.65 (s, 1H), 1.43 — 0.66 (m, 18H). MS (ESI) m/e 1398.5 (M-H)’.2.163 Synthesis of 2,6-anhydr0[2-({[{2-[(3-{[4-(6-{8-[(1,3-benz0thiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)--methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13’7]decan-1-yl)0xy]ethyl}(2-sulf0ethyl)carbamoyl]0xy}methyl){[(79S,82S)[(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)acetyl]methyl-77,80,83-tri0x0(pr0panyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-MEl 24985843V.1 689117813-12620tetracosaoxa-74,78,81-triazatri0ctac0ntanyl]amin0}phenyl]-7,8—dideoxy-L-glycer0-L-gulo-0ct0nic acid (Synthon ZW)2,163.1 benzyl2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62, 71-tetracosaoxaazaheptaheptac0ntanThe title compound was prepared using the procedure in Example 2.147.1, replacing2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontanamine with2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxatriheptacontanamine. MS (ESI) m/e 625.9 (M+2H)2+.2,163.2 2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56,59,62,65,68,71-tetracosaoxaazaheptaheptacontanoic acidThe title compound was prepared using the procedure in e 2.147.2, replacingExample 2.147.1 with e 2.163.1. MS (ESI) m/e 1160.7 (M+H)+.2,163.3 2,5-di0x0pyrrolidinyl74-(2-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53, 56,59,62,65,68,71-tetrac0sa0xaazaheptaheptacontan0ateThe title compound was prepared using the procedure in Example 2.1473, replacingExample 2.1472 with Example 2.163.2. MS (ESI) m/e 698.1(M+2H)2+.2.163.4 2,6-anhydr0[2-({[{2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.l.13,7]decanyl)0xy]ethyl}(2-sulfoethyl)carbam0yl]0xy}methyl){[(79S,82S)-74—[(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-82—methyl-77,80,83-trioxo-79-(pr0panyl)-2,5,8,11,14,17,20,23,26,29,32,35,38,41,44,47,50,53,56, 65,68,71-tetrac0sa0xa-74,78,81-triazatrioctacontanyl]amin0}phenyl]-7,8-dide0xy-L-glycero-L-gulo-octonic acidThe title compound was prepared using the procedure in Example 2.147.4, replacingExample 2.1473 and e 2.141.4 with e 2.1633 and Example 2.1541, respectively. 1HNMR (400 MHz, dimethyl sulfoxide-dé) 5 9.86 (s, 1H), 8.23 — 7.87 (m, 3H), 7.76 (d, 1H), 7.58 (dd,1H), 7.53 — 7.25 (m, 7H), 7.19 (d, 1H), 7.05 (d, 2H), 6.92 (d, 1H), 5.07 — 4.85 (m, 4H), 4.49 — 4.30(m, 3H), 4.20 (dt, 1H), 3.52 (d, 8H), 3.46 — 3.26 (m, 7H), 3.20 (s, 4H), 3.15 — 2.82 (m, 4H), 2.61 (s,3H), 2.38 (dq, 1H), 2.11 — 1.82 (m, 5H), 1.53 (s, 1H), 1.39 — 0.66 (m, 24H). MS (ESI) m/e 1326.9(M-2H)2'.

MEl 24985843V.1 690117813-126202.164 Synthesis of 6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3-{2-[{[(4-{[(2S,5S)[3-(carbamoylamin0)pr0pyl][(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetyl]-4,7-di0x0(pr0panyl)sulf00xa-3,6,10-triazapentadecanan0yl]amin0}phenyl)meth0xy]carbonyl}(2-sulfoethyl)amin0]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinecarb0xylic acid(Synthon ZX)A mixture of 1-hydroxypyrrolidine-2,5-dione (2.74 mg), 1-ethyl[3-(dimethylamino)propyl]-carbodiimide hydrochloride (4.26 mg) and Example 2.1605 (9.01 mg) inN,N-dimethylformamide (0.3 mL) were stirred at room temperature overnight. The e wascooled in ice bath. 1-Hydroxybenzotriazole hydrate (3.65 mg) and a mixture of Example 2.1122 (20mg) and N,N-diisopropylethylamine (22.19 uL) were added. The resulting mixture was stirred at 0CC for 10 minutes and purified by reverse phase HPLC, eluting with 30%-55% acetonitrile in 0.1%trifluoroacetic acid water, to provide the title compound. 1H NMR (400 MHz, dimethyl ide-dé)9.95 (d, 1H), 8.18 — 7.89 (m, 3H), 7.76 (d, 1H), 7.57 (d, 3H), 7.52 — 7.21 (m, 8H), 7.04 (d, 2H), 6.92(d, 1H), 4.94 (d, 4H), 4.37 (d, 2H), 4.19 (d, 1H), 3.85 (t, 2H), 3.77 (d, 2H), 3.22 (d, 2H), 2.96 (dt, 4H),2.73 (dt, 2H), 2.66 — 2.55 (m, 2H), 2.36 (s, 1H), 2.06 (s, 3H), 1.91 (s, 1H), 1.61 (d, 3H), 1.47 — 0.86(m, 11H), 0.80 (ddd, 12H). MS (ESI) m/e 1617.5 (M-H)’.2.165 This aph was intentionally left blank.2.166 Synthesis of 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)(1-((3-(2—((((2-(2-((2S,3R,4R,5S,6S)carboxy-3,4,5-trihydroxytetrahydro-ZH-pyranyl)ethyl)((S)((S)S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2-sulfoethoxy)methyl)pyrrolidinyl)acetamid0)methylbutanamid0)pr0panamid0)benzyl)0xy)carb0nyl)((S)-3,4-dihydroxybutyl)amin0)eth0xy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)picolinic acid (Synthon AAA)The title compound was prepared by substituting Example 2167.1 for Example 2.119.16in Example 2.119.17. 1H NMR (500 MHz, dimethyl ide-dg) 5 ppm 9.86 (br d, 1H), 8.17 (br d,1H), 8.04 (m, 2H), 7.78 (d, 1H), 7.61 (d, 1H), 7.51 (br d, 1H), 7.49-7.39 (m, 4H), 7.36 (m, 2H), 7.29(s, 1H), 7.21 (d, 1H), 7.07 (s, 2H), 6.95 (d, 1H), 5.00 (s, 2H), 4.96 (s, 2H), 4.64 (t, 1H), 4.36 (m, 1H),4.19 (m, 1H), 4.16 (d, 1H), 4.01 (d, 1H), 3.88 (br t, 2H), 3.82 (br m, 3H), 3.75 (br m, 1H), 3.64 (t,2H), 3.54 (d, 2H), 3.47 (m, 4H), 3.43 (br m, 4H), 3.23 (br m, 5H), 3.13 (t, 1H), 3.10 (br m, 1H), 3.01(br m, 2H), 2.93 (t, 1H), 2.83-2.68 (m, 3H), 2.37 (m, 1H), 2.08 (s, 3H), 1.99 (br m, 2H), 1.85 (m, 1H),1.55 (br m, 1H), 1.37 (br m, 1H), 1.28 (br m, 6H), 1.10 (br m, 7H), 0.93 (br m, 1H), .69 (m,12H). MS (ESI) m/e 1713.6 (M-H)’.

MEl 24985843V.1 691117813-12620Alternative Synthesis of 6-(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3-(2-((((2-(2-((2S,3R,4R,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)((S)((S)(2-((3S,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2—sulfoethoxy)methyl)pyrrolidinyl)acetamid0)methylbutanamid0)propanamido)benzyl)0xy)carb0nyl)((S)-3,4-dihydroxybutyl)amino)ethoxy)-,7-dimethyladamantanyl)methyl)methyl-lH-pyrazolyl)picolinic acid (Synthon AAA)2.166.1 3-(1-((3-(2-((((4-((S)((S)amin0methylbutanamido)propanamid0)(2-((2S,3R,4R,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)benzyl)0xy)carb0nyl)((S)-3,4-dihydroxybutyl)amin0)ethoxy)-,7-dimethyladamantanyl)methyl)methyl-1H-pyrazolyl)(8-(benzo[d]thiazolylcarbam0yl)-3,4-dihydr0is0quinolin-2(1H)-yl)picolinic acidTo a d solution of Example 1.85 (0.065 g), 1-hydroxybenzotriazole (0.013 g) andN,N-diisopropylethylamine (0.06 mL) in methylformamide (0.5 mL) was added Example2.123.19 (0.085 g), and the mixture was stirred at room temperature for 2 hours. The reaction wasconcentrated under reduced pressure. The residue was ved in a solvent mixture of methanol (0.5mL) and tetrahydrofuran (0.5 mL), and lithium hydroxide drate (30 mg) was added. Thereaction was stirred for 1 hour at ambient temperature, after which the reaction was concentratedunder reduced pressure. The residue was dissolved in methanol/water (1 :1, 1mL) ning 0.1 mLtrifluoroacetic acid. The sample was ed by reverse-phase HPLC (Phenomenex® Luna® C18250 x 50 mm column, 100 mL/min), eluting with 20-100% itrile in water containing 0.01%trifluoroacetic acid over 40 minutes. The fractions containing product were lyophilized to give thetitle compound. MS (ESI) m/z 1357.5 (M+H)+.2.166.2 6-(8-(benz0[d]thiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl)-3-(1-((3-(2-((((2—(2-((2S,3R,4R,5S,6S)carb0xy-3,4,5-trihydroxytetrahydro-2H-pyranyl)ethyl)((S)-2—((S)(2—((3S,5S)-3-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2-sulfoethoxy)methyl)pyrrolidinyl)acetamid0)methylbutanamido)propanamid0)benzyl)0xy)carb0nyl)((S)-3,4-oxybutyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)-1H-pyrazolyl)picolinic acid (Synthon AAA)To a solution of Example 2.119.15 (16 mg) in methylformamide (200 uL) was added 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (16mg, HATU) and N,N-diisopropylethylamine (17 uL). The reaction was stirred for 5 minutes, and asolution of Example 2.166.1 (48 mg) and N,N-diisopropylethylamine (20 uL) in N,N-dimethylformamide (200 uL) was added. The reaction was stirred for one hour and diluted with aMEI 24985843v.1 692117813-12620mixture of N,N-dimethylformamide/water (1/ l, 1.5 mL). The sample was purified by reverse-phaseHPLC (Phenomenex® Luna® C18 250 x 50 mm column, 100 mL/min), eluting with 20-70%acetonitrile in water containing 0.01% trifluoroacetic acid over 40 minutes. The fractions containingthe product were lyophilized to give the title compound. 1H NMR (500 MHz, dimethyl sulfoxide-dé)ppm 9.86 (br d, 1H), 8.17 (br d, 1H), 8.04 (m, 2H), 7.78 (d, 1H), 7.61 (d, 1H), 7.51 (br d, 1H), 7.49-7.39 (m, 4H), 7.36 (m, 2H), 7.29 (s, 1H), 7.21 (d, 1H), 7.07 (s, 2H), 6.95 (d, 1H), 5.00 (s, 2H), 4.96 (s,2H), 4.64 (t, 1H), 4.36 (m, 1H), 4.19 (m, 1H), 4.16 (d, 1H), 4.01 (d, 1H), 3.88 (br t, 2H), 3.82 (br m,3H), 3.75 (br m, 1H), 3.64 (t, 2H), 3.54 (d, 2H), 3.47 (m, 4H), 3.43 (br m, 4H), 3.23 (br m, 5H), 3.13(t, 1H), 3.10 (br m, 1H), 3.01 (br m, 2H), 2.93 (t, 1H), 2.83-2.68 (m, 3H), 2.37 (m, 1H), 2.08 (s, 3H),1.99 (br m, 2H), 1.85 (m, 1H), 1.55 (br m, 1H), 1.37 (br m, 1H), 1.28 (br m, 6H), 1.10 (br m, 7H),0.93 (br m, 1H), 0.88 — 0.69 (m, 12H). MS (ESI) m/z 1713.6 (M—H)‘.2.167 Synthesis of 2,6-anhydr0(2-{[({2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}-2—carboxypyridinyl)--methyl-1H-pyrazolyl]methyl}-5,7—dimethyltricyclo[3.3.1.13,7]decan-1-yl)0xy]ethyl}[(3S)-3,4-dihydr0xybutyl]carbamoyl)0xy]methyl}{[(2S)-2-({(2S)[2-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)acetamid0]methylbutanoyl}amin0)propanoyl]amin0}phenyl)-7,8-dide0xy-L-glycer0-L-gulo-octonic acid (Synthon AAD)2.167.1 3-(1-((3-(2-((((4—((S)((S)amin0methylbutanamido)propanamid0)(2-((2S,3R,4R,5S,6S)carboxy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)ethyl)benzyl)0xy)carb0nyl)((S)-3,4—oxybutyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01amoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acide 2.167.l was prepared by substituting Example 19 for (9H-fluorenyl)methyl ((S)-3 -methyl(((S)- l -((4-((((4-nitrophenoxy)carbonyl)oxy)methyl)phenyl)amino)-l -oxo--ureidopentanyl)amino)-l-oxobutanyl)carbamate and substituting Example 1.85 for e1.2.9 in Example 2.49.1. MS (ESI) m/e 1355.5 (M-H)’.2.167.2 2,6-anhydr0(2—{[({2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.l.13,7]decanyl)0xy]ethyl}[(3S)-3,4-dihydroxybutyl]carbamoyl)0xy]methyl}{[(2S)({(2S)-2—[2-(2,5-di0x0-2,5-dihydr0-1H-pyrr01yl)acetamid0]methylbutanoyl}amin0)pr0pan0yl]amin0}phenyl)-7,8-dide0xy-L-glycero—L-gulo-octonic acidMEl 24985843V.1 693117813-12620Example 21672 was prepared by substituting Example 2167.1 for Example 2.49.1 inExample 2.54. 1H NMR (501 MHz, dimethyl sulfoxide-dé) 5 9.90 (d, 1H), 8.25 (m, 2H), 8.01 (d, 1H),7.77 (d, 1H), 7.59 (d, 1H), 7.51 — 7.40 (m, 4H), 7.40 — 7.31 (m, 3H), 7.26 (s, 1H), 7.20 (d, 1H), 7.05(s, 2H), 6.93 (d, 1H), 4.96 (d, 4H), 4.36 (t, 1H), 4.22 — 4.06 (m, 3H), 3.85 (t, 2H), 3.26 — 3.17 (m, 4H),3.14 — 2.88 (m, 5H), 2.78 — 2.55 (m, 2H), 2.10 — 1.88 (m, 5H), 1.69 — 1.49 (m, 2H), 1.39 — 0.73 (m,28H). MS (ESI) m/e 1492.5 (M-H)’.2.168 sis of 2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4—dihydroisoquinolin-2(1H)-yl}carb0xypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13,7]decan]ethyl}[(3S)-3,4-dihydr0xybutyl]carbamoyl)0xy]methyl}{4-[2-(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)acetamid0]butyl}phenyl -glucopyranosiduronic acid (Synthon AAE)2,168.1 3-(1-((3-(2-((((4—(4-amin0butyl)(((2S,3R,4S,5S,6S)carb0xy-3,4,5-trihydr0xytetrahydr0-2H-pyranyl)0xy)benzyl)0xy)carb0nyl)((S)-3,4—dihydroxybutyl)amin0)ethoxy)-5,7-dimethyladamantanyl)methyl)methyl-1H-pyrazol-4—yl)(8-(benzo[d]thiaz01ylcarbamoyl)-3,4—dihydroisoquinolin-2(1H)-yl)pic01inic acide 21681 was prepared by substituting Example 2.1245 for (9H-flu0renyl)methyl ((S)-3 -methyl(((S)((4-((((4-nitr0phen0xy)carbonyl)0xy)methyl)phenyl)amino)0x0--ureid0pentanyl)amin0)0x0butanyl)carbamate and substituting Example 1.85 for Example1.2.9 in Example 2.49.1. MS (ESI) m/e 1229.5 (M-H)’.2.1682 2-{[({2—[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4—dihydroisoquinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13,7]decan-1-yl)0xy]ethyl}[(3S)-3,4-dihydroxybutyl]carbamoyl)0xy]methyl}{4-[2-(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)acetamid0]butyl}phenyl beta-D-glucopyranosiduronic acidExample 21682 was prepared by substituting Example 2.1681 for Example 2.49.1 inExample 2.54. 1H NMR (501 MHZ, dimethyl sulfoxide-dé) 5 8.07 (s, 1H), 8.01 (dt, 1H), 7.77 (dt,1H), 7.63 — 7.57 (m, 1H),7.51— 7.39 (m, 3H), 7.38 — 7.31 (m, 2H), 7.26 (s, 1H), 7.16 (d, 1H), 7.05 (s,2H), 6.93 (d, 2H), 6.84 — 6.80 (m, 1H), 5.14 — 4.98 (m, 3H), 4.94 (s, 2H), 3.79 (d, 2H), 3.48 — 3.19(m, 10H), 3.08 — 2.96 (m, 4H), 2.52 (s, 4H), 2.07 (s, 2H), 1.77 — 0.72 (m, 14H). MS (ESI) m/e 1366.5(M-H)’.

MEl 24985843V.1 694-126202.169 Synthesis of 6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3-{2-[{[(4-{[(2S)(carbamoylamin0){[(2S){[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]amino}methylbutanoyl]amin0}pentan0yl]amin0}phenyl)methoxy]carb0nyl}(2-sulfoethyl)amin0]acetamid0}-5,7-dimethyltricyclo[3.3.1.13’7]decanyl)methyl]methyl-1H-pyrazolyl}pyridine-2—carb0xylic acid (Synthon ABC)The title compound was prepared as described in Example 2.54, replacing e 2.49.1with Example 1.89.12. 1H NMR (501 MHz, dimethyl sulfoxide-dé) 5 ppm 9.95 (d, 1H), 8.10 — 7.96(m, 1H), 7.75 (t, 2H), 7.57 (dd, 3H), 7.51 — 7.18 (m, 8H), 6.95 (d, 3H), 6.92 (s, 0H), 5.03 — 4.86 (m,4H), 4.36 (d, 1H), 3.85 (t, 2H), 3.78 — 3.67 (m, 4H), 3.42 (s, 2H), 3.33 (t, 2H), 3.04 — 2.86 (m, 4H),2.63 (d, 2H), 2.13 (dd, 1H), 2.07 (s, 3H), 1.98 — 1.87 (m, 0H), 1.71 — 1.23 (m, 10H), 1.24 — 0.85 (m,6H), 0.78 (t, 11H). MS (ESI) m/e 1463.5 (M-H)’.2.170 Synthesis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-{4-[({[2-({3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}sulfanyl)ethyl](2-sulfoethyl)carbam0yl}0xy)methyl]phenyl}-N5-carbamoyl-L-ornithinamide (Synthon ABL)The title compound was prepared by substituting Example 1.90.11 for Example 1.2.9 inExample 2.1. 1H NMR (500 MHz, dimethyl sulfoxide-d6) 5 ppm 10.0 (s, 1H), 8.08 (br s, 1H), 8.03(d, 1H), 7.81 (br s, 1H) 7.78 (d, 1H), 7.60 (m, 3H) 7.52 (t, 1H), 7.47 (t, 1H), 7.43 (d, 1H), 7.37 (d,1H), 7.34 (d, 1H) 7.32 (s, 1H), 7.28 (d, 2H), 6.99 (s, 1H), 6.96 (d, 2H), 5.00 (s, 2H), 4.96 (s, 2H), 4.39(m, 1H), 4.18 (m, 2H), 3.88 (m, 2H), 3.82 (s, 1H), 3.77 (s, 1H), 3.46 (br m, 2H), 3.58 (t, 2H), 3.29 (Vbr m, 2H), 3.01 (br m, 3H), 2.95 (br m, 1H), 2.47 (m, 2H), 2.61 (br m, 2H) 2.16 (m, 1H), 2.10 (m,4H), 1.96 (br m, 1H), 1.69 (V br m, 1H), 1.59 (V br m, 1H), 1.53-1.40 (m, 7H), .22 (m, 5H),1.17 (m, 3H), 1.13-0.88 (m, 6H), 0.87-0.77 (m, 9H), 0.75 (s, 3H). MS (ESI) m/e 1466.5 (M-H)’.2.171 sis of N-[6-(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)hexan0yl]-L-valyl-N-[4-({[(3-{3-[(4-{6—[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}pr0pyl)(2-sulfoethyl)carbam0yl]0xy}methyl)phenyl]-N5-carbam0yl-L-ornithinamide (Synthon ABN)The title compound was prepared as described in Example 2.1, ing Example 1.2.9with Example 1.91.13. 1H NMR (501 MHz, DMSO-dé) 5 ppm 12.83 (s, 1H), 9.96 (s, 1H), 8.03 (t,2H), 7.77 (d, 2H), 7.64 — 7.52 (m, 3H), 7.45 (ddd, 3H), 7.34 (td, 2H), 7.29 — 7.21 (m, 3H), 7.03 — 6.91(m, 3H), 4.95 (d, 4H), 4.37 (q, 1H), 4.17 (s, 1H), 3.86 (t, 2H), 3.45 — 3.29 (m, 4H), 3.10 (t, 2H), 2.95MEl 24985843V.1 695117813-12620(dt, 4H), 2.61 (q, 2H), 2.15 (td, 2H), 2.07 (s, 3H), 2.00 — 1.89 (m, 1H), 1.74 — 1.24 (m, 10H), 1.25 —0.87 (m, 13H), 0.88 — 0.70 (m, 12H). MS (ESI) m/e 1450.2 (M+H)+.2.172 sis of 2-[({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbam0yl)-3,4-dihydroisoquinolin-2(1H)-yl]carb0xypyridinyl}methyl-1H-pyrazol-l-yl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}0xy)ethyl][(3S)-3,4-dihydr0xybutyl]carbamoyl}0xy)methyl]{4-,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulfoethoxy)methyl]pyrrolidinyl}acetyl)amin0]butyl}phenyl beta-D-glucopyranosiduronic acid (Synthon AAF)The title compound was prepared as described in Example 2.119.17, ing Example2.1681 for Example 2.119.16. 1H NMR (400 MHZ, dimethyl sulfoxide-dg) 5 ppm 8.03 (d, 1H), 7.84(br t, 1H), 7.78 (d, 1H), 7.61 (d, 1H), 7.50 (br d, 1H), 7.45 (dd, 1H), 7.43 (d, 1H), 7.36 (m, 2H), 7.29(s, 1H), 7.17 (br m, 1H), 7.06 (s, 2H), 6.95 (m, 2H), 6.85 (d, 1H), 5.08 (s, 2H), 5.02 (d, 1H), 4.96 (s,2H), 4.70 (t, 1H), 4.06 (d, 2H), 3.88 (m, 4H), 3.81 (m, 2H), 3.73 (br m, 1H), 3.62 (m, 2H), 3.47 (br m,4H), 3.40 (m, 4H), 3.35 (m, 2H), 3.29 (m, 4H), 3.07 (m, 2H), 3.00 (t, 2H), 2.73 (m, 2H), 2.54 (m, 2H),2.36 (br m, 1H), 2.09 (s, 3H), 1.83 (m, 1H), 1.71 (br m, 1H), 1.55 (br m, 2H), 1.40 (br m, 5H), 1.24(br m, 4H), 1.10 (br m, 5H), 0.94 (br m, 1H), 0.83, 0.81 (both s, total 6H). MS (ESI) m/e 1587.5 (M-2.173 Synthesis of 2,6-anhydr0[2-({[{2-[(3-{[4-(6-{8-[(1,3-benz0thiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)--methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13,7]decan-1-yl)0xy]ethyl}(2-sulf0ethyl)carbamoyl]0xy}methyl){[N-({(3R,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulfoethoxy)methyl]pyrrolidinyl}acetyl)-L-valyl-L-]amin0}phenyl]-7,8-dide0xy-L-glycer0-L-gulo—octonic acid(Synthon ABO)2.173.1 (3R,6R,7aS)azid0phenyltetrahydropyrrolo[1,2-c]0xazol-(3H)-0neThe title compound was prepared by substituting Example 2.1193 for Example 2.1192 inExample 4. MS (DCI) m/e 262.0 (M+NH4)+.2.173.2 (3R,6R,7aS)amin0phenyltetrahydropyrrolo[1,2-c]0xazol-(3H)-0neThe title compound was prepared by substituting Example 2.1731 for Example 2.1194 inExample 2.119.5. MS (DCI) m/e 219.0 (M+H)+.

MEl 24985843V.1 696117813-126202173.3 (3R,6R,7aS)(dibenzylamino)phenyltetrahydropyrrolo[1,2-c]0xazol-5(3H)-0neThe title compound was prepared by substituting Example 2.1732 for Example 2.1195 inExample 2.119.6. MS (DCI) m/e 399.1 (M+H)+.2.173.4 (3R,5S)(dibenzylamino)(hydroxymethyl)pyrrolidin-Z-oneThe title compound was prepared by substituting Example 2.1733 for Example 2.1196 inExample 2.1197, with the exception that the reaction was heated to 65 CC for one day rather than 6days. MS (DCI) m/e 311.1 (M+H)+.2.1735 (3R,5S)(((tert-butyldimethylsilyl)0xy)methyl)(dibenzylamin0)pyrrolidinoneThe title compound was prepared by substituting e 2173.4 for e 2.1197 ine . The title compound was carried on to the next step without purification. MS (DCI)m/e 425.2 (M+H)+.2.173.6 tert-butyl2-((3R,5S)(((tert-butyldimethylsilyl)0xy)methyl)(dibenzylamino)0x0pyrrolidinyl)acetateThe title compound was prepared by substituting Example 2173.5 for Example 2.1198 inExample 2.1199. The title nd was carried on to the next step without purification. MS (DCI)m/e 539.3 (M+H)+.2.173.7 tert-butyl2-((3R,5S)(dibenzylamino)(hydr0xymethyl)oxopyrrolidinyl)acetateThe title compound was prepared by substituting Example 2.1736 for Example 2.1199 inExample 2.119.10. MS (DCI) m/e 425.2 (M+H)+.2.17.3.8 tert-butyl2-((3R,5S)((2-((4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)(dibenzylamino)0x0pyrrolidinyl)acetateThe title compound was prepared by substituting Example 2173.7 for Example 211910in Example 2.119.11.2.173.9 tert-butyl(S)(2-((2-((4-((tert-butyldiphenylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)0x0pyrrolidinyl)acetateThe title nd was ed by tuting Example 2.1738 for Example 2.119.11in Example 2.119.12. MS (ESI) m/e 691.1 (M+H)+.2.173.10 4-(((3R,5S)(2-(tert-butoxy)0x0ethyl)((2-((4—((tert-iphenylsilyl)0xy)-2,2-dimethylbutoxy)sulfonyl)eth0xy)methyl)0x0pyrrolidinyl)amino)0x0buten0ic acidMEl 24985843V.1 697117813-12620The title compound was prepared by substituting Example 2.1739 for e 2.119.12in Example 2.119.13. MS (ESI) m/e 789.0 .2.173.11 tert-butyl 2-((3R,5S)((2-((4-((tert-butyldiphenylsilyl)oxy)-2,2-dimethylbut0xy)sulfonyl)eth0xy)methyl)(2,5-di0x0-2,5-dihydro-1H-pyrrolyl)0x0pyrrolidinyl)acetateThe title compound was prepared by substituting Example 2173.10 for Example 2.119.13in Example 2.119.14.12 ,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0((2-sulf0eth0xy)methyl)pyrrolidinyl)acetic acidThe title compound was prepared by substituting Example 11 for Example 2.119.14in Example 2.119.15. MS (ESI) m/e 377.0 (M+H)+.2.173.13 2,6-anhydr0[2-({[{2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-yltricyclo[3.3.1.13,7]decanyl)0xy]ethyl}(2-sulfoethyl)carbam0yl]0xy}methyl){[N-({(3R,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0[(2-sulfoethoxy)methyl]pyrrolidinyl}acetyl)-L-valyl-L-alanyl]amin0}phenyl]-7,8-dide0xy-L-glycero-L-gulo-octonicacidThe title compound was prepared by substituting Example 20 for Example 2.119.16and Example 2.173.12 for Example 2.1 19. 15 in Example 2.119.17. 1H NMR (400 MHZ, dimethylsulfoxide-dg) 5 ppm 9.94 (d, 1H), 8.28 (br d, 1H), 8.01 (d, 2H), 7.77 (d, 1H), 7.59 (d, 1H), 7.53 (d,1H), 7.43 (m, 4H), 7.34 (m, 3H), 7.19 (d, 1H), 7.06 (s, 2H), 6.96 (d, 1H), 4.99 (m, 2H), 4.95 (s, 2H),4.78 (t, 1H), 4.36 (t, 1H), 4.19 (br m, 1H), 4.16 (d, 1H), 3.98 (d, 1H), 3.87 (br t, 2H), 3.81 (br d, 2H),3.73 (brm, 1H), 3.63 (t, 2H), 3.53 (m, 2H), 3.44 (m, 4H), 3.31 (t, 2H), 3.21 (br m, 2H), 3.17 (m, 2H),3.00 (m, 2H), 2.92 (br m, 1H), 2.75 (m, 3H), 2.65 (br m, 3H), 2.35 (br m, 1H), 2.16 (m, 1H), 2.07 (s,3H), 1.98 (br m, 2H), 1.55 (br m, 1H), 1.34 (br m, 1H), 1.26 (br m, 6H), 1.09 (br m, 7H), 0.93 (br m,1H), 0.87, 0.83, 0.79 (all d, total 12H). MS (ESI) m/e 1733.3 (M-H)’.2.174 Synthesis of 2,6-anhydr0{2-({[{2-[(3-{[4-(6-{8-[(1,3-benzothiazolyl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)--methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13,7]decan-1-yl)0xy]ethyl}(2-sulf0ethyl)carbamoyl]0xy}methyl)[(N-{[(3R,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x0(41-0x0-2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxaazatritetrac0ntanyl)pyrr01idinyl]acetyl}-L-Valyl-L-alanyl)amin0]phenyl}-7,8-dide0xy-L-glycero-L-gulo-octonic acid (Synthon ABM)MEl 24985843V.1 698117813-126202.174.1 tert-butyl [(3R,5S){[bis(tert-butoxycarbonyl)amin0]methyl}(dibenzylamin0)0x0pyrrolidinyl]acetateTo a cold (0 CC) solution of Example 2173.7 (1.6 g) in dichloromethane (15 mL) wasadded triethylamine (0.70 mL) and methanesulfonyl chloride (0.39 mL) dropwise. The ice-bath wasd, and the reaction was stirred at room temperature for two hours. The reaction was quenchedby the addition of saturated aqueous sodium bicarbonate solution. The layers were separated, and theorganic layer was washed with brine. The combined aqueous layers were back-extracted withdichloromethane. The combined organic layers were dried with anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give the intermediate mesylate (1.9 g). The residue wasdissolved in acetonitrile (15 mL), and di-tert-butyl-iminodicarboxylate (1.0 g) and cesium carbonate(2.4 g) were added. The reaction was heated to reflux under nitrogen for one day. The reaction wascooled and quenched by the addition of water and l ether. The layers were separated, and theorganic was washed with brine. The combined aqueous layers were back-extracted with diethyl ether.

The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentratedunder reduced pressure. The residue was purified by silica gel chromatography, eluting with 20%ethyl e in heptanes, to give the title compound. MS (DCI) m/e 624.3 (M+H)+.2.174.2 tert-butyl [(3R,5S)amin0{[bis(tert-butoxycarbonyl)amino]methyl}0x0pyrrolidinyl]acetateTo a solution of Example 2.1741 (1.0 g) in ethyl acetate (6 mL) and methanol (18 mL)was added ium hydroxide on carbon (100 mg, 20% by weight). The reaction was d atroom temperature under a hydrogen balloon for one day. The on was filtered throughdiatomaceous earth, eluting with ethyl acetate. The filtrate was concentrated under reduced pressure,dissolved in dichloromethane (10 mL) and filtered h a syringe-tip Teflon 40 micron filter. Thefiltrate was concentrated under reduced re to give the title compound. MS (DCI) m/e 444.1(M+H)+.3 4-{[(3R,5S){[bis(tert-butoxycarbonyl)amin0]methyl}(2—tert-butoxy-Z-oxoethyl)0x0pyrrolidinyl]amin0}0x0but-2-en0ic acidThe title compound was prepared by substituting Example 2.1742 for Example 2.119.12in Example 2.119.13. MS (ESI) m/e 540.2 (M-H)’.2.174.4 tert-butyl [(3R,5S){[bis(tert-butoxycarbonyl)amin0]methyl}(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)oxopyrrolidinyl]acetateThe title compound was ed by substituting e 2.1743 for Example 13in Example 2.119.14. MS (DCI) m/e 541.1 (M+NH4)+.

MEl 24985843V.1 699117813-126202.174.5 2-((3R,5S)(amin0methyl)(2,5-di0x0-2,5-dihydr0-1H-yl)0x0pyrrolidinyl)acetic acidTo a solution of Example 2174.4 (284 mg) in romethane (10 mL) was addedtrifluoroacetic acid (5 mL). The reaction was d at room temperature for two hours and wastrated under reduced pressure. The residue was dissolved in water/acetonitrile 7/3 (5 mL),frozen and lyophilized to provide the title compound, which was used in the subsequent step withoutfurther cation. MS (ESI) m/e 266.1 (M-H)’.6 2-((3R,5S)(2,5-di0x0-2,5-dihydr0-1H-pyrrolyl)0x00-2,5,8,11,14,17,20,23,26,29,32,35,38-trideca0xaazatritetracontanyl)pyrr01idinyl)acetic acidTo a solution of 2,5,8,11,14,17,20,23,26,29,32,35,38-tridecaoxahentetracontanoic acid(160 mg) in N,N-dimethylformamide (1.0 mL) was added O-(7-azabenzotriazolyl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (85 mg) and N,N-diisopropylethylamine (130 uL). Thereaction mixture was stirred for three minutes at room temperature, and a solution of Example 2174.5(70 mg) and N,N-diisopropylethylamine (130 uL) in N,N-dimethylformamide (1.0 mL) was added.

The reaction was stirred at room temperature for one hour and diluted with N,N-dimethylformamide/water 1/1 (3.5 mL). The solution was purified by reverse phase HPLC on aGilson system (C18 column), eluting with 20-70% acetonitrile in 0.1% TFA water, to provide the titlecompound. MS (ESI) m/e 880.4 (M-H)’.2,174.7 2,6-anhydr0{2-({[{2-[(3-{[4-(6—{8-[(1,3-benzothiazol-2—yl)carbam0yl]-3,4-dihydr0is0quinolin-2(1H)-yl}carboxypyridinyl)methyl-1H-pyrazolyl]methyl}-5,7-dimethyltricyclo[3.3.1.13’7]decan-l-yl)0xy]ethyl}(2-sulfoethyl)carbam0yl]0xy}methyl)[(N-{[(3R,SS)(2,5-di0x0-2,5-dihydr0-lH-pyrrolyl)0x0(41-0x0-2,5,8,11,14,17,20,23,26,29,32,35,38-trideca0xaazatritetracontanyl)pyrrolidinyl]acetyl}-L-valyl-L-alanyl)amin0]phenyl}-7,8-dide0xy-L-glycer0-L-gul0-0ct0nicThe title compound was prepared by substituting Example 2.174.6 for Example 2.119.15and e 2.123.20 for Example 2.119.16 in Example 2.119.17 1H NMR (500 MHz, dimethylsulfoxide-d6) 5 ppm 9.93 (br d, 1H), 8.28 (d, 1H), 8.03 (d, 1H), 8.02 (br s, 1H), 7.91 (br d, 1H), 7.79(d, 1H), 7.61 (d, 1H), 7.51 (br d, 1H), 7.49-7.42 (m, 3H), 7.40 (br d, 1H), 7.36 (m, 2H), 7.28 (s, 1H),7.22 (d, 1H), 7.06 (s, 2H), 6.95 (d, 1H), 5.00 (br d, 2H), 4.95 (s, 2H), 4.70 (t, 1H), 4.39 (m, 1H), 4.28(m, 1H), 4.00 (dd, 2H), 3.88 (br m, 2H), 3.85 (br m, 1H), 3.80 (br m, 2H), 3.62 (t, 2H), 3.50 (s, 44H),3.48 (d, 4H), 3.43 (br m, 2H), 3.34 (br m, 2H), 3.23 (s, 3H), 3.21 (v br m, 2H), 3.14 (t, 2H), 3.10 (v brMEl 24985843V.1 700117813-12620m, 1H), 3.00 (t, 2H), 2.94 (br m, 1H), 2.76 (V br m, 1H), 2.64 (V br m, 3H), 2.34 (br t, 2H), 2.32 (m,1H), 2.17 (m, 1H), 2.09 (br d, 3H), 2.00 (br m, 1H), 1.56 (br m, 1H), 1.39-1.19 (br m, 8H), 1.19-0.92(br m, 8H), 0.88 (br d, 3H), 0.87 (br m, 1H), 0.82 (br d, 6H), 0.79 (br s, 3H). MS (ESI) m/e 1119.2[(M-2H)/2]'.2.175 Synthesis of (6S)-2,6-anhydro(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl][(3S)-3,4-dihydroxybutyl]carbamoyl}oxy)methyl]({N-[(2,5-dioxo-2,5-dihydro-1H-pyrrolyl)acetyl]-N-(2,5,8,11,14,17,20,23,26,29,32-undecaoxatetratriacontan—34-yl)-b-alanyl-L-valyl-L-alanyl}amino)phenyl}ethyl)-L-gulonic acid (Synthon ABU)The title compound was prepared using the procedure in Example 4, replacinge 2.1414 with Example 2.167.l. MS (ESI) m/e 1033.4 (M+2H)2+.2.176 Synthesis of (6S)-2,6-anhydro(2—{2-[({[2-({3-[(4-{6-[8—(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl][(3S)-3,4-dihydroxybutyl]carbamoyl}oxy)methyl]({N-[(2,5-dioxo-2,5-dihydro-rolyl)acetyl]-N-[2-(2—sulfoethoxy)ethyl]-b-alanyl-L-valyl-L-alanyl}amino)phenyl}ethyl)-L-gulonic acid (Synthon ABV)The title compound was ed using the ure in Example 2.160.7, replacingExample 2.1541 with Example 2.167.l. MS (ESI) m/e 859.4 (M+2H)2+.

Example 3: Generation of Mouse Anti-B7-H3 Monoclonal Antibodies by Mouse HybridomaTechnologyB7-H3 specific antibodies were raised using mouse hybridomas technology. Specifically, amouse fibroblast cell line (3Tl2) expressing full length human B7-H3 as well as recombinant humanor mouse B7-H3-ECD-human Fc fusion proteins were used as immunogens, the sequences of whichare provided in Table 1. Human HCTl 16 cell lines sing human B7-H3 were used fordetermining anti-sera titer and for screening antigen-specific antibodies. Cell lines were exposed toapproximately 3000 mREM of gamma source radiation prior to immunization. Two ent strainsof mice were immunized in the hock with dosages containing 5 x 106 cells/mouse/inj ection or 10 ugof protein/mouse/injection in the presence of Gerbu MM adjuvant (Cooper-Casey Corporation, ValleyCenter, CA, US) for both y and boost immunizations. To increase immune response to mouseB7-H3, the mice were further boosted with a mixture of human and mouse B7-H3-ECD-human Fcproteins for the final boosts. Briefly, the antigens were prepared in PBS as follows: 200 x 106MEl 24985843V.1 701117813-12620cells/mL or 400 ug/mL protein. The calculated volume of antigen was transferred to a sterilemicrocentrifuge tube and equal volume of Gerbu MM was then added. The solution was mixed bygently vortexing for 1 minute. The adjuvant-antigen solution was then drawn into a proper syringe foranimal ion. A total of 25 uL of the mixture was ed into the hock of each leg of the mouse.

Each animal was boosted 3 times before serum titer was determined for the groups. All animals weregiven 2 additional boosts with an equal mixture of mouse B7-H3-ECD-human Fc and human B7-H3-ECD-human Fc proteins in adjuvant before fusion.

Table 1: Amino acid se uences of recombinant roteins used for immunization or inAmino Acid SequenceML99RGSPGMGV{VGAADGADWECDLGADfiVQVP9D9VVALVGTDATLCCSFS9E9GFSLAQLNL:WQLTDTKQLVdSFAEGQDQGSAYAN9TALF9DLLAQGNASLRLQ9V9VHGSEiCEVSL9DEGSAAVSLQVAA9YS<9SMTLE 9NKDLRPGDTVT:TCSSYQGY9VEWQDGQGV9LiGNViiSQ AWLQGLEJVHSLLRVVLGAWGTYSCLVRN9VLQiPQ9SPiGAV9VQV99D9VVALVGTDATLRCSFS9I.9GFST.AQDWDIIWDTKQLVHSFTEG9DQGSAYAWI 9DLLAQGWASL9LQ9VI DEGSFTCFVIIDFGSAAVSLQVAA9YS<PSMTLIl I 9PGDTVTITCSSYI )9A9Vb'WQDG9LTGWVTTSQ AWEQGLFDV LGAWGTYSCLVI } DAdGSVTITTFP9EALWVTVGLSVCL: 9 <QSC911 ZDQDG9G9GS<dSDS<9DDGQ9 A 1I : .49)I9RGS9GMGVdVGAADGADWECDiGAD1 91I9VVALVGTDATLCCSFS9E9GFSLAQLNLIWQLTDT<QLVdSFAEGQDQGSAYAW9TALF9DLLAQGNASLRLQ9V9VILGSEiCEVSL9DEGSAAVSLQVAA9YS<9SMTLE9NKDLRPGDTVTIITCSSYQGY' 9VEWQDGQGV9LiGNViiSQ AWLQGLEJVdSLLRVVLGAWGTYSCLVRN9VLQ{SSViLiPQ9SPiGAV9VQV99D9VVALVGTDATLRCSFS9I99GFST.AQDWDIIWDTKQLVHSFTEG9DQGSAYAW9TALF9DLLAQGWASLRLQ9V9VADEGSFTCFVIDFGSAAVSLQVAA9YS<9SMTLE9WKDL99GDTVTITCSSY9GYP9A9VhWQDG9LTGWVTTSQ AWLQGLFDVdSVL9VVLGAWGTYSCLVRN9VLQQDAdGSVT:T} TFAAADKT{TC99C9A99A9GA9SVFLF99<P<DLDM S9i91 iCVVVDVSd' <EWWYVDGVEVdNA<i<P999QYNSiY9VVSVLTVLHQDWL EYKCKVSW9 9K1 S<A<GQP9I9QVYTD99SR99 i<NQVSLTCLVKG' } D AV9W9ENWYKTT9PVLDSDGSFFLYS<LTVD<S9WQQGNVFSCSV I <I < (S9Q 3 NO: 150)9SVGVCVRTATWGVTCTCTiGAV*.VQVS9D9VVALVDTDATLRCSFS9E9GIWQLTDT{QLVHSFTLG9DQGSAYSW9TALF9DLLVQGNASLRLQ9V9Vw+<m<rowe LGSYiCb'VSLQDEDSAAVSLQVAA9YS<9SMTLE} I 9GNMVTITCSSYQGYGQGV9LTGWVTTSQ FDVdSVLI CLVRN9VLQ{GSVTITGQ9LTFAAADKT{TC99C9A99A9GAL 99KPKDLDM S9i99{L'D9L'V<EWWYVDGVEV{WA<i<P999QYNSiY9VVSVLTVLHQDWLW<AD9A9 9K1 29E9QVYTDII 99 iKNQVSLTCLVKGFI 9SNGQP9NWYKL19PVLI DGSFFLYS D<S9WQQGWVFSCSV {I {NHYTQ<SLSLS9G< (S9Q I 90: 151)9FGTSWDFDVAITKGVQCGADLVQV}139VVADVGTDATLCCSFS9E9GFSLAQLWLIIWQLTDTKQLV{SFALGQDQGSAYAW9TALF9DLLAQGNASLRLQ9V9VADLGSFTCFVSII 9DFGSAAVSLQVAA9YS<9SMTLI9NKDLRPGDTVTITCSSYQGYP9A9Vh'WQDGQGV9LTGNVTTSQ ANEQGLFDVdS:LRVVLGAWGTYSCLVRN9VLQQDA{SSVTITPQ9SPiGAV9VQV99D9VVALVGTDATLRCSFS999GFSTAQDWDIIWQDTDTKQLVHSFTEGRDQGSAYAW9TALF9DLLAQGWASLRLQ9V9VADLGSb'iCb'VSLRDEGSMEl 24985843v.1 702117813-12620AAVSLQVAA?YSKPSMTLEPWKDLRPGDTVT:TCSSYRGYP1 fiVEWQDGQGVPLTGNVTTSQMAVEQGLFDVHSVLQVVLGAWGTYSCLVRWPVLQQ, {GSVTITGQPMTHHHiHH (SfiQ D W0: 152)MHFGLSWLFLVA"L<GVQCV£VQVS1,) DTDATLRCSFS???GFSLAQLNL"WQLTDTKQLVHSFTEGRDQGSAYSN' ?DLLVQGNASLRLQQVQVTDEGSYTCF" DFDSAAVSLQVAA?YS<?SMTL;?N<3LR?GWMVTITCSSYQGYPfiA?LTGNVTTSQ ANERGLFDVHSVLRVVLGAWGTYSQWPVLQQDAIGSVTITGQ?LTFiiiHii (Si D NO: 153)'QGSPGMGVIVGAALGALWECL .fiVQVPfi,?VVALVGTDATLRCSFSLI?GLAQLNL:WQLTDTKQLViSFTEGQDQGSAYANQTALFLDLLAQGNASLRLQ' QV,jGSEICEVSHQDEGSAAVSLQVAA?YS<?SMTLL?NKDLRPGDTVTITCSSYQGYfiVEWQDGQGA?LTGNVTTSQ AWEQGLFDVHSVLRVVLGAVGTYSCLVRN?VLQ{GS l lPQQSPlGAVfiVQV?£3?VVALVGT3ATLRCSFS?T?GFSLAQLWL"WDTKQLVHSFTEGRDQGSAYAWQTALFLDLLAQGWASLRLQQVQVADEGSFTCFVDFGSAAVSLQVAA?YS<PSMTLI?NKDLQPGDTVTITCSSYQGYPfiAfiVEWQDGTTSQ ANEQGLF, {SVLRVVLGANGTYSCLVRN?VLQQ3AIGSVTITTFAAAHHHHIHHI (SfiQ 3 NO: 154)Note: leader sequence, Fc, and His s qi nc s ar und rlin dHybridoma fusion and screeningCells of murine myeloma cell line (NS-0, ECACC No. 85110503) were cultured to reach thelog phase stage right before fusion. Popliteal and inguinal lymph nodes were d from eachmouse and single cell suspensions were prepared ely. Lymphocytes were fused with myelomacells (E. , D. Lane, Antibody: A Laboratory Manual, Cold Spring Harbor Laboratory Press,Cold Spring Harbor, NY, 1998); Kohler G. and Milstein C., “Continuous cultures of fused cellsecreting antibody of predefined specificity,” , 256:495-497 (1975); BTX Harvard tus(Holliston, MA, US) ECM 2001 technical manual). Fused hybrid cells were dispensed into lplates in DMEM/10% FBS/HAT media. Supernatants from surviving hybridoma colonies weresubjected to cell-based ing using human cell lines expressing the recombinant human B7-H3.

Briefly, a human cell line expressing the human B7-H3 was thawed and directly dispensed into 96well (black with clear bottom for imaging) plates at 50,000 cells/well in growth media and incubatedfor 2 days at 37 CC to reach 50% confluency. Hybridoma supernatants (50 uL/well) were transferredto respective plates and incubated at room temperature for 30 minutes. Media was removed fromeach well and goat anti-mouse IgG-AF488 (Invitrogen, No. A11029, Grand Island, NY, US) was usedfor detection using the InCell Analyzer 2000 (GE). Hits were expanded and binding was confirmedby FACS using a different human cell line or a mouse cell line expressing the human B7-H3 and goatanti-mouse IgG-PE for detection. Species icity was ined using the ELISA formataccording to the following procedure. ELISA plates were coated with human B7-H3-ECD-human Fc,cynomolgous B7-H3-ECD-his, or mouse B7-H3-ECD-human Fc proteins overnight at roomature. Plates were washed and hybridoma supes (100 ML) was added to each well, andMEl 24985843V.1 703117813-12620incubated at room temperature for 1 hour. Plates were washed, donkey anti-mouse IgG-HRP(Jackson Immunochemicals, No. 115071, West Grove, PA, US) was used for detection, andbinding ODs were observed at 650 nm.

A selection of hits were subcloned using the MoFlo an, Indianapolis, IN, US) bydepositing a single cell per well into 96 well cell culture plates to ensure clonality of the cell line.

Resulting colonies were screened for specificity by FACS using mouse 3T12 fibroblast cell linesexpressing the human B7-H3, cynomolgous B7-H3 or mouse B7-H3. Isotype of each monoclonalantibody was determined using the Mouse Monoclonal Isostyping Kit (Roche, No. 11027-001,Indianapolis, IN, USA). Hybridoma clones producing antibodies that showed high ic bindingactivity against human and cynomolgus B7-H3 antigen were subcloned and purified (Table 2).

Table 2: List of Anti-B7-H3 antibodies enerated usin mouse h bridoma technoloFACS Binding (EC50 nM)CynomolgousHuman B7'H3 M01133 B7-H3Clone Name Species / Isotype 37-1.13Abl mouse IgGl/k 299-0Abz mouse IgGl/k 1-00Ab3 mouse I-G1/k 0-94Ab4 mouse Ingb/k 1-75AbS mouse IgGl/k 6-01Abo mouse IgGl/k No bindingAb7 mouse IgGl/k 67-13Ab8 mouse IGI/k 193-0Ab9 0-72AblO 3-80Abii 568-60Abiz 8-72New 25-80Ab14 102-2Ab15 4-61Abio 318-7Ab17 mouse Ingb/k 2-39Ab18 mouse IgGl/k No bindingExample 4: In Vitro Characterization of Anti-B7-H3 Mouse onal Antibodies.

The g affinity of the purified anti-B7-H3 monoclonal antibodies was determined bysurface plasma nce. Table 3 shows the association rate constants (ka) dissociation rate constants(kd) and equilibrium dissociation constants (KD) for a series of mouse hybridoma derived anti-B7-H3monoclonal antibodies (mAbs) g to the soluble ECDs of human B7-H3 and cyno B7-H3. Thebinding kinetics were derived from SPR measurements using a Biacore T200 instrument and a mAbcapture approach (as described in the als and methods below).

MEl 24985843V.1 704117813-12620Table 3: Biacore cs of 7-H3 mouse h bridoma antibodies bindin to human andcynomolgus monkey B7-H3.cynoB7-H3MurineAntibodyName kd (1/8) KD (M) ka (l/MS) kd (1/5) KD (M).4E+05 1.9E-05 5.1E+05 1.0E-052.1E+05 3.6E-05 2.4E+05 2.9E-058.0E+04 3.4E-05 7.7E+04 7.0E-056.9E+05 1.1E-03 5.4E+05 9.6E-04.8E+04 9.9E-05 1.6E+05 2.6E-044.1E+04 1.9E-04 2.0E+05 4.2E-033.8E+04 2.5E-04 5.5E+04 1.0E-051.3E+06 1.2E-02 1.4E+06 2.8E-011.1E+05 3 . 3.0E-036.6E+04 1.1E-03 ' ' '3.3E+05 5.8E-03 4.4E+05 3.7E-03.2E+05 1.0E-02 3. 8E+05 1.0E-021.4E+05 3.2E-03 7.5E+05 5.6E-031.2E+05 2.9E-03 2.3E+05 1.1E-022.0E+04 8.9E-04 2.7E+04 7.2E-051.2E+04 2 2. 8E+04 1.2E-02no noobservable observableg bindinglittle littleobservable ablebinding bindingPair-wise binding assays performed on Biacore T200 SPR instruments were used todetermine the relative epitope grouping for the murine anti-B7-H3 mAbs as described in the methodsbelow. Figure 1 shows an epitope grouping depiction, which describes the relative human B7-H3epitope diversity and overlap for a series of anti-B7-H3 mAbs identified herein. Epitope groups arerepresented as individual ovals, some of which overlap with each other. Antibodies in differentepitope groups can bind to B7-H3 simultaneously and likely bind to different epitopes whileantibodies within a given epitope group cannot bind to B7-H3 aneously and likely bind tooverlapping epitopes. The grouping information was derived from a simultaneous binding assay asbed in materials and s. Ab3, Ab4, Ab5, Ab11, Ab12, and Ab8 groupings wereambiguous.

Materials and methods: Binding kineticsBiacore T200 SPR instruments were used to measure the binding kinetics of human B7-H3(analyte) binding to various mAbs (ligands). The assay format was Fc-based capture Via lizedouse (Fc) (Pierce 31170) or immobilized anti-human (Fc) (Pierce . A standard amineng protocol was employed to lize the capture reagents Via primary amines to theMEl 24985843V.1 705117813-12620carboxy-methyl (CM) dextran surface of CM5 sensorchips (Biacore); capture antibodies were coupledto a level of approximately 5000RU. For binding kinetic measurements the assay buffer was HBS-EP+ (Biacore): 10 mM Hepes, pH7.4, 150 mM NaCl, 3 mM EDTA, 0.05% rbate 20. Duringthe assay, all ements were referenced against the capture surface alone. Each assay cycleconsisted of the following steps: 1) Capture of ligand to approximately 50RU; 2) Analyte injectionover both reference and test e, 240 uL at 80 uL/min, after which the iation was monitoredfor 900 seconds at 80 uL/min; 3) Regeneration of capture surface with low pH glycine. For kineticdeterminations analyte injections were 3-point, 9-fold dilution series of 900 nM, 100 nM and 11.11nM, buffer only injections were included for secondary referencing. Data were processed and fit to a1:1 binding model using Biacore T200 Evaluation re to determine the binding kinetic rateconstants, ka (on-rate) and kd (off-rate), and the equilibrium dissociation constant (affinity, KD).

Materials and methods: e groupingPair-wise binding assays performed on Biacore T200 SPR instruments were used todetermine the relative epitope grouping for a series of anti-B7-H3 mAbs. The assay format was Fc-based capture via immobilized anti-mouse(Fc) (Pierce 31170) or lized anti-human (Fc) (Pierce31125). A standard amine ng protocol was employed to immobilize the capture reagents viaprimary amines to the carboxy-methyl (CM) dextran surface of CM5 sensorchips (Biacore); captureantibodies were coupled to a level of approximately 2000RU. Epitope grouping ements weredone at 12 CC (low temperature allows for grouping information on fast off-rate mAbs), the assaybuffer was HBS-EP+ (Biacore): 10 mM Hepes, pH7.4, 150 mM NaCl, 3 mM EDTA, 0.05%polysorbate 20. Each assay cycle consisted of the following steps in a four flowcell system: 1)separate test mAbs were captured in flowcells 2, 3 & 4 ll l was reference, no test mAb); 2) all4 flowcells were then blocked by injection with e control mAb or isotype mAb cocktail at 50ug/mL; 3) all 4 flowcells were then injected with antigen or buffer only (buffer only is for doublereferencing, done for each mAb pair individually); 4) all 4 flowcells were then injected with 2nd testmAb at 10 ug/mL; 5) all 4 ls were then regenerated with glycine, le.5. The assay was donefor each test mAb pair in reciprocal orientations. Simultaneous binding was evaluated examining theratio of the 2nd test mAb response to the Ag response (RUmAbZ/RUAg); if this ratio was equal to orgreater than 0.2 the interaction was scored as a simultaneous binder. From this pair-wise bindingassay data a “venn” style diagram was constructed manually to depict ve epitope groupings.

Example 5: Generation of Anti-hB7-H3 Chimeric Antibodiesing the identification of mouse anti-B7-H3 hybridoma antibodies, heavy and lightchain variable regions (VH and VL) corresponding to the secreted dies were determined fromcells using reverse transcriptase-polymerase chain reaction (RT-PCR). Murine variable s wereexpressed in ian host cells in the context of a human immunoglobulin constant region toMEl 24985843V.1 706117813-12620provide chimeric antibodies. Table 4 below provides the variable region amino acid sequences for themouse chimerized hybridomas.

Table 4: le re ion amino acid se uences of anti-B7-H3 antibodies from mouse h bridomasMine ACid sequence0- QVQLQQPGAELVK?GASV{LSCKASGYTFTSYWMHWVKQR?GQGR%W GMIHPDVH SGTTNYNEKFRSKATLTV DKSSSTAYMQLSSLTSEDSAVYYCAVYYGSTYWYFDVWGTGTTVTVSSlilll 'Re51dues 2 6 — 35GYTFTS* 1 3 NO:"lilll ' ' 50—66MIHPDSGTTNYNEKFRS3 NO:"’IHIII OU”Km w 99 —1 99WYFDV4Q 3 NO:"DVVMTQTPLSL?VSLGDQAYIISCRSSQSLVHINGNTYLHWYRQKPGQSPKLLIYVL KVSNRFSGVPDQFSGSGSGTDFTLK:SlGVYFCSQSTHFPFTFGSGTK-OUR—LlRes1dues 24 39RSSQSLVHINGNTYLHO7 - SfiQ '3 NO : 5lilll C,R—Lz ae51dues 55 — 61KVSNRFS0* S {Q ) NO:5OU”KH w sidue 94—1020’ S 4Q 3 NO:5QVQLQQPGAELVK?GASV<LSCKASGYMHWVKQR?GQGR£W GLIHPDVH SGSTNYNEMFKNKATLTVDRSSSTAYVQLSSLTSEDSAVYFCAGGGRLYFDYWGQGTTLTVSSOUR—Hl Res1dues 26—35GYTFSSYWMHo~ sao 3 NO:9C,R—HZ a€81dues 50 — 66'_l LIHPDSGSTNYNEMFKNO“ S fiQ 3 NO:9OU”Km w a Sldue' 8 99—106N GGRLYFDY0’ sao 3 NO:9DVVMTQTPLSL?VSLGDQASIISCRSSQSLVHSNGDTYLRWYLQKPGQSPKLLIYl3 ChAb3 VL KVSNRFSGVPDRFSGSGSGTDFTLKITfiAfiDKGVYFCSQSTHVPYTFGGGTK'. KCDR—Ll Residues 24—39F RSSQSLVHSNGDTYLRO“ SfiQ D NO:13MEl 24985843v.1 707117813-12620Residues Amino Acid SequenceResidues 55—6;\] KVSNRFS0’ 1 D NO:L|_| SQSTHVPYTQVQLQQPGAELVK'9GASV<LSCKASGYMHWVKQR9GQGK£W GMIHPN6 SGSNNYNEKFKSKATLTVJKSSNTAYMQLSSLTSEDSAVYYCARRLGLHFDYWGQGTTLTVSSU Residues 26—35\] GYSFTSYWMHRLGLHFDYWVMTQSQKFMSTPVGDRVS_TCKASQNVGTAVAWYQQKPGQS9KLL:YSASNRYTGVPDRFTGSGSGLDELT.1 SN QSfiDLADYFCQQYSSYPYTbGGGiKTw.

Residues 24—34KASQNVGTAVA3 NO: 20Residues 50—56SASNRYT3 NO: 20A) (D '_l. Q.C (D 89— 97(A) PYTn (I) I0 D No.20QVQLQQSAAH R9GASV<MSCKASGYIHWVKQR9GQGK£W GYINPN24 SRNTDYNQKFKDIETTLTADRSSSTAYMQ1 SliSfiDSAVYYCARYSGSTPYWYFDVWGAGTTVTVSSResidues 26—35(II GYSFTSYTIHD NO:24YINPNSRNTDYNQKFKD(1'; YSGSTPYWYFDV«VLLQSPA LSASPG_EKVTMTCRASSSVSYMNWYQQKPGSSP<PWIYATSNLASGVPARFSVSVSGLSHST.1 SRV“A“DQQWSSNPLTFGAGTKLER—Ll Residues 24—33k0 RASSSVSYMN3 NO: 28,R—L2 Residues 49—55O: SfiQ D NO:28MEI 24985843V.1 708117813-12620Residues Amino Acid SequenceResidues 88—96F QQWSSNPLTO“ SfiQ D NO:28DVQLQESGPDLVKPSQSLSLTCTVTGYSITSGYSWHW:RQFPGNKLEWMGYIHS32 SGSTNYNPSLKSR S NRDiSKNQEFLQLNSVTTEDTATYYCAGYDDYFEYWGQGTTLTVSSResidues 26—36(A) (A) GYSITSGYSWH~ SfiQ 3 NO 32liill GSldues 51—66YIHSSGSTNYNPSLKS, z 3 NO 32' ' 99—105(A) (II Y3 NO 32DIVMTQSQKFMSTSVGJRVSVTCKASQNVGFNVAWYQQKPGQS?KALIYSASYRYSGVPDRFTGSGSGLDELRL SNVQSfiDLAEYFCQQYNSYPFTEGSGLKR: Kaes1dues 24 _ 34KASQNVGFNVA* 1 D NO:3650—56\ SASYRYSD NO:3689—97182 .3 NO:36 IEillllllllllllllllllllllYNSYPFTfiVQKVfiSGGGWVK' SGFTFSSYAMSWVRQLLI '.fiWVATISSG4O TNYTYYPDSVKGRFT: LYLQMTSLRSEDTAMYYCAQQGRYSWIAYWGQGTLVTVSAIIIII '3' RGSldues 2 6 — 35|_| YAMS* 1 3 NO:4liall TISSGTNYTYYPDSVKGIIIII(A) QGRYSWIAYDIVLTQSPASLAVSLGQRATISCRASKSVSTSDYSYMHWNQQKPGQ?PKLL:YL44 ChAblZ VL ASNLESGVPARFSGSGSGTDFTLNIH?VfififiDAAiYYCQHSRELLTFGAGTKL,3 QeSldueS' 2 L— 38I\ (II RASKSVSTSDYSYMH7 1 D NO:4'l\ LASNLESMEI 24985843V.1 709117813-12620IIHHHHHII Residues Amino Acid SequenceCDR—L3 Residues 93—10047 ChAblZF LT‘ ' D NO:44fiVKRVfiSGGGKVKL {LSCAASGFTFSSYGMSWVRQL}: .fiWVATISGG48 C GTNTYYPDSVEGRFT: DNAKNFLYLQMSSLRSEDTALYYCA’KHYGSQTMDYWGQGTSVTVSSKesidues 26—357’ A GFTFSSYGMS3 NO:4:- TISGGGTNTYYPDSVEG(II :- HYGSQTMDYPASLSASVG4'1V1 iCRTSGNIHNYLTWYQQKQGKS9QLLVYNAKTLADGVPSRFSGSGSGLQESTK NST.QP£DFGSYYCQHFWSIMWTE'GGGiKTH.

(II (A)Kesi 50—56«2Q ,K s i dues 89— 97(II (IIO S' 3 NO: 52QVQLQQSGA_ELMK?GASV<:SCKATGYTFSRYWIEWVKQR9GHGKfiW GEILPG56 SGSTNYNEKFKGKATFTADTSSNTAYMQVSSLTSEDSAVHYCARRGYGYVPYALDYWGQGTSVTVSSKesidues 26—35(II \1 GYTFSRYWIE3 NO: 56es 50- 66f” 'hA EILPGSGSTNYNEKFKG3 NO: 5699—110(II RGYGYVPYALDY3 NO: 56QMiQiiSSLSASLGDRVTI SCRASQDISNSLNWYQQKPDGTVNLLIYYTSRLYSGVPSRFSGSGSGLDYST.1 SNm fiQ:4DIATYFCQQGNTLPYTbGGGiKT:Klll: Kesidues 24—34Ch |_| RASQDISNSLND NQ 6OKesidues 50-56L151 3 v: YTSRLYSD NQ 6O89— 97QQGNTLPYTD NO:6OMEI 24985843V.1 710117813-12620Re51dues Amino Acid cefiVKlVfiSGGGWVQ?GGSLKLSCATSGFTFTNYYMSWVKQP?GKALEWLGFIRNK4 ANDYTTEYSASVKGRFT:SRDNSQSILYLQMNTLRAEDSATYYCAKESPGNPFAYWGQGTLVTVSAKesidues 26—35GFTFTNYYMSD NO:64FIRNKANDYTTEYSASVKGMVMTQSPSSLTVTAG_EKVTMTCKSSQSLLNSGTQKNFLTWYQQKPGQ?PKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYFCQNDYIYPLTFGAGTKesidues 24— 4OKSSQSLLNSGTQKNFLT3 NO: 68Kesidues 56— 62O ’ 73 NO: 68(D QC(D 95— 1037 7 QNDYIYPLTn 3 NO: 68*WVKTT*SGGGTVQ?GGSL<LSCAASGFMSWVRQA?GKGK%W GEINPD2 SSTINYTPSLKDKE SRDNAKNTLYLQMSKVRSEDTALYYCARPGFGNYIYAMDYWGQGTSVTVSSKesidues 26—35'4' *77‘7. -L3 NO: 72Kesidues 50— 66.J> EINPDSSTINYTPSLKD3 NO: 72(D QC(D 99—110L1>1A3 d: I, PGFGNYIYAMDYn 3 NO: 72DIIQMTQTTSSLSASLGDRVTINCRASQDISNFLNWYQQKPDGTVKLLIYYTSRLRFSGSGSGLDYST.1 SNRKQKDIWATYFCQQGNTLPPTbGGGiKTKesidues 24—34\] RASQDISNFLN3 NO: 76Kesidues 50—56A YTSRLYL3 NO: 7689— 97QQGNTLPPTD NO:76MEI 24985843V.1 711117813-12620Amj-no ACid sequenceDVQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNW:RQFPGNKLEWMGHINYSGITNYNPSLKSR S iKDiSKNQEFLQLYSVTTEDTATYFCARRSLFYYYGSSLYAMDYWGQGTSVTVSS,K—Hl Kesidues 26—36OO |—‘ GYSITSDYAWND NO: 80es 51— 6600 N HINYSGITNYNPSLKS3 NO: 8099— 11400 (A) RSLFYYYGSSLYAMDYD NO:8ODVVMTQSPFSL9VSLGDQAS:SCRSSQSLVHSNGNTYLHWYLQKPGQSPKLLIY84 ChAblO VL KVSNRFSGVPDKFSGSGSGTDFTLK:SRVfiAfiDKGVYFCSQSTHVPWTFGGGTK4. .« Kg 24—39OO §Sl§ues RSSQSLVHSNGNTYLH\1 SSQSTHVPWTfiVQKVfiSGfiNKVK?GGSL{LSCAASGFSFRGYGMSWVRQT?DKKLEWVAAISTG87 ChAb7 GNYTYYPDSVQGRFT:SRDNANNTLYLQMSSLKSEDTAMYYCAKRGGNYAGFAYWGQGTLVTVSA-C fE'_| Qesidues 26—35GFsFRGYGMS3 NO. 87-CfEN Kesidues 50 66AISTGGNYTYYPDSVQG3 NO: 87OUTmm (D 99108RGGNYAGFAYO D NO:87DIQMTQSPASLSVSVGfiiVi iCRPSENIYSNLAWYQQKQGKS?QLLVYAATNL91 ChAb7ADGVPSRFSGSGSGTQYSKK NSKQSfiDFGTYYCQHFWGTPFTEGSGLKK: KO U f L_.1 |_| s. q 24 _N 34’ RPSENIYSNLAO7 1 J N029"fL_' N(A) -C AATNLADMEI 24985843V.1 712117813-12620Re51dues Amino Acid SequenceCDR—L3 Residues 89 97Oh D NO. 91.fiVKKVfiSGGGKVKL SGFTFSSYGMSWVRQL}: .fiWVATISGG95 IHHHHEIIIIVO.I GNYTYCPDSVKGRFT: DNAKNNLYLQMSSLRSEDTALYYCTQQRGYDYHYAMDFWGQGTSVTVSSResidues 26—35.J> GFTFSSYGMS3 NO: 95QC(D 50— 66Iiiafifillllc TISGGGNYTYCPDSVKG3 NO: 958”Kmm (D QC(D 99—11097 QRGYDYHYAMDF3 NO: 95IHHHHEIIII :QMTQSPASLSVSVGfiiVi iCRASENIYSNLAWHQQKQGKS9QLLVYAATNLADGVPSRFSGNGSDTQYSWK NSKQSfiDFGSYFCQNFWGTSWTEGGGLKK: KIHHEHEIIIICU .k0 3 IiiafifillllcIHHEHEIIIIC8”KHw 89—97D NO:98fiSGGGWVQL {LSCAASGFTFSSYIMSWVRQLLI '.%WVASIVSSChAbl7 DSMKGRFT: QDWARNILYLQMSSLKSEDTAMYYCARSGTRAWFAYWGQGTLVTVSAIafiilllllcU. Residues 26—35IO N GFTFSSYIMSIOIiiilllll (A) ITYYPDSMKGIaiilllll CIIO uh FAYMVLTQSPASLAVSLGQRAT SCRASKSVSTSAYSYMHWYQQKPGQ9PKLL:YLASNLESGVPARFSGSGSGTDFTLNIHPVfi1fiDAAiYYCQHSRELPYTFGGGTKL44 <CDR—Ll Residues 24—38ChAbl7 RASKSVSTSAYSYMHo: SfiQ D NO:105MEI 24985843V.1 713117813-12620Residues Amino Acid SequenceResidues 54—60LASNLES* 1 D NO:"05QHSRELPYTQVQLQQPGDELVK?GASV{LSCKTSGYTFTTDWMHWVKQR?GQGK%W GMIHPNSGTTNYNEKFKSKAALTVJKSSSTACMQLSSLTSEDSAVYYCARSYWKWYFDVWGTGTTVTVSSa§Sléues' 2 6 — 3?GYTFTTDWMHSYWKWYFDVQHVLLQSPA MSASKGfifi lliCSASSSVSYMHWYQQKSGTSP{LLIYSTSNLASGVPSRFSGSGSGLEYSKL SSVfiAfiDSADYYCHQWTSYMYTEGGGLKKZ KSASSSVSYMHHQWTSYMYTExample 6: Binding Characterization of Chimeric Anti-B7-H3 AntibodiesTo generate purified chimeric antibodies, expression vectors were transiently transfected intoHEK293 6E suspension cell es in a ratio of 60% to 40% light to heavy chain construct. 1 mg/mlof polyethylenimine (PEI) or 2.6 uL/mL of Expifectamine was used to transfect the cells. Cellsupernatants were harvested after five days in shaking flasks, spun down to pellet cells, and filteredthrough 0.22 pm s to separate IgG from culture inants. Antibody-containing supernatantswere purified on Akta Pure using protein A mAb SelectSure. Columns were equilibrated in PBS pH7.4, atants were then passed through the column and a wash was performed with PBS pH 7.4.

IgG were eluted with 0.1 M acetic acid pH 3.5 and collected in several aliquots. Fractions containingIgG were pooled and dialyzed in PBS ght at 4 CC. Anti-B7-H3 ic antibodies that weresuccessfully expressed were characterized for the ability to bind the B7-H3 overexpressing humannon-small cell lung cancer cell line NCI-Hl650 (ATCC® N0. CRL-5883) by FACS using the methodsdescribed below. Table 5 summarizes the binding properties of the ic 7-H3 antibodies.

MEl 24985843V.1 714117813-12620TABLE 5: In vitro characterization of B7-H3 chimeric antibodiesChimeric Ab Name e Parental Hybridoma FACS binding (ECSO nM)FACS binding methodsCells were harvested from flasks when approximately 80% confluent using Gibco® Celliation Buffer. Cells were washed once in PB S/1% FBS (FACS buffer) then resuspended at2.5x106 cells/mL in FACS buffer. 100 uL of cells/well were added to a round bottom 96-well plate.uL of a 10x concentration of mAb/ADC (final concentrations are indicated the figures). Wellswere washed twice with FACS buffer and resuspended in 50 uL of secondary Ab (AlexaFluor 488)diluted in FACS buffer. The plate was ted at 4°C for one hour and washed twice with FACSbuffer. Cells were ended in 100 uL of PBS/1% formaldehyde and analyzed on a BectonDickinson LSRII flow cytometer. Data was analyzed using WinList flow cytometry analysissoftware.

Example 7: Characterization of Chimeric Anti-B7-H3 Antibodies as Bcl-xL Inhibiting AntibodyDrug atesNine anti-B7-H3 ic antibodies were conjugated to the Bcl-xL inhibiting (Bcl-xLi)synthon CZ (Example 2.1) using conjugation Method A bed below. The resulting ADCs (anti-B7-H3 antibodies conjugated to synthon CZ) were tested for binding to cell surface human B7-H3 byFACS (as described in Example 6) and for cell cytotoxicity in cell lines expressing B7-H3. Of thenine antibodies, three antibodies (chAb2, chAb6, and ) itated following conjugation tosynthon CZ and showed weak cytotoxicity in cells expressing human B7-H3. Table 6 provides cellsurface binding and cytotoxicity actiVity of anti-B7-H3 chimera ADCs against breast cancer cellHCC38 expressing human B7-H3.

MEI 24985843V.1 715117813-12620TABLE 6: In vitro characterization of B7-H3 chimeric-CZ conjugatesADC Name Conjugation FACS Binding Cytotoxicity Conjugationobservation Human B7-H3 (HCC38 cellEC50 nM line IC50nM)chAb3-CZchAb18-CZchAb13-CZchAbll-CZchAb6-CZchAb16-CZchAb14-CZMaterials and methods: Conjugation of Bcl-xL tory ADCsADCs were synthesized using one of the methods described below. Exemplary ADCs weresynthesized using one of nine exemplary methods, described below.

Method A. A solution of Bond-BreakerTM -carboxyethyl)phosphine (TCEP) solution (10 mM,0.017 mL) was added to a solution of antibody (10 mg/mL, 1 mL) preheated to 37 CC. The onmixture was kept at 37 CC for 1 hour. The on of reduced antibody was added to a solution ofsynthon (3.3 mM, 0.160 mL in DMSO) and gently mixed for 30 minutes. The reaction solution wasloaded onto a desalting column (PD10, washed with Dulbecco’s phosphate-buffered saline [DPBS] 3xbefore use), followed by DPBS (3 mL). The purified ADC solution was filtered through a 0.2 micron,low protein-binding 13 mm syringe-filter and stored at 4 CC.

Method B. A solution of Bond-BreakerTM tris(2-carboxyethyl)phosphine (TCEP) solution (10 mM,0.017 mL) was added to the solution of antibody (10 mg/mL, 1 mL) ted to 37 CC. The reactionmixture was kept at 37 CC for 1 hour. The solution of reduced antibody was adjusted to pH=8 byadding boric buffer (0.05 mL, 0.5 M, pH 8), added to a solution of synthon (3.3 mM, 0.160 mL inDMSO) and gently mixed for 4 hours. The reaction solution was loaded onto a desalting column(PD10, washed with DPBS 3x before use), followed by DPBS (1.6 mL) and eluted with additionalDPBS (3 mL). The purified ADC solution was filtered through a 0.2 micron, low protein-binding 13mm syringe-filter and stored at 4 CC.

Method C. Conjugations were performed using a PerkinElmer Janus (part 1) robotic liquidhandling system ed with an 1235/96 tip ModuLar se Technology (MDT), disposablehead (part 70243540) containing a gripper arm (part 7400358), and an 8-tip Varispan pipetting arm(part 7002357) on an expanded deck. The PerkinElmer Janus system was controlled using theWinPREP version 4.8.3.315 Software.

ME1 24985843V.1 716117813-12620A Pall Filter plate 5052 was pre-wet with 100 uL lx DPBS using the MDT. Vacuum wasapplied to the filter plate for 10 seconds and was followed by a 5 second vent to remove DPBS fromfilter plate. A 50% slurry of Protein A resin (GE MabSelect Sure) in DPBS was poured into an 8 wellreservoir equipped with a magnetic ball, and the resin was mixed by passing a traveling magnetunderneath the reservoir plate. The 8 tip Varispan arm, equipped with 1 mL conductive tips, was usedto aspirate the resin (250 uL) and transfer to a 96-well filter plate. A vacuum was applied for 2 cyclesto remove most of the buffer. Using the MDT, 150 uL of leBS was aspirated and dispensed to the96-well filter plate holding the resin. A vacuum was applied, removing the buffer from the resin. Therinse/vacuum cycle was repeated 3 times. A 2 mL, 96-well collection plate was mounted on the Janusdeck, and the MDT transferred 450 uL of 5x DPBS to the collection plate for later use. Reducedantibody (2 mg) as a solution in (200 uL) DPBS was prepared as described above for Conditions Aand preloaded into a 96 well plate. The solutions of reduced antibody were erred to the filterplate wells containing the resin, and the mixture was mixed with the MDT by repeatedtion/dispensation of a 100 uL volume within the well for 45 seconds per cycle. Theaspiration/dispensation cycle was repeated for a total of 5 times over the course of 5 s. Avacuum was applied to the filter plate for 2 cycles, thereby ng excess antibody. The MDT tipswere rinsed with water for 5 cycles (200 uL, 1 mL total volume). The MDT aspirated and dispensed150 uL of DPBS to the filter plate wells containing resin —bound antibody, and a vacuum was appliedfor two cycles. The wash and vacuum sequence was repeated two more times. After the last vacuumcycle, 100 uL of lx DPBS was dispensed to the wells containing the bound antibody. The MDTthen collected 30 uL each of 3.3 mM dimethyl ide solutions of ns plated in a lformat and dispensed it to the filter plate containing resin-bound antibody in DPBS. The wellscontaining the ation mixture were mixed with the MDT by repeated aspiration/dispensation ofa 100 uL volume within the well for 45 seconds per cycle. The aspiration/dispensation sequence wasrepeated for a total of 5 times over the course of 5 minutes. A vacuum was applied for 2 cycles toremove excess synthon to waste. The MDT tips were rinsed with water for 5 cycles (200 uL, 1 mLtotal volume). The MDT aspirated and sed DPBS (150 uL) to the conjugation mixture, and avacuum was applied for two cycles. The wash and vacuum sequence was repeated two more times.

The MDT gripper then moved the filter plate and collar to a holding n. The MDT placed the 2mL collection plate containing 450 uL of 10x DPBS inside the vacuum manifold. The MDTreassembled the vacuum manifold by placement of the filter plate and collar. The MDT tips wererinsed with water for 5 cycles (200 uL, 1 mL total ). The MDT aspirated and dispensed 100uL of IgG Elution Buffer 3.75 (Pierce) to the conjugation mixture. After one minute, a vacuum wasapplied for 2 cycles, and the eluent was captured in the receiving plate containing 450 uL of 5xMEl 24985843V.1 717117813-12620DPBS. The aspiration/dispensation sequence was repeated 3 additional times to deliver ADC sampleswith concentrations in the range of 1.5-2.5 mg/mL at pH 7.4 in DPBS.

Method D. Conjugations were performed using a PerkinElmer Janus (part 1) robotic liquidhandling system equipped with an 1235/96 tip ModuLar Dispense Technology (MDT), disposablehead (part 70243540) containing a gripper arm (part 7400358), and an 8-tip Varispan pipetting arm(part 7002357) on an expanded deck. The PerkinElmer Janus system was controlled using theWinPREP version 4.8.3.315 re.

A Pall Filter plate 5052 was prewet with 100 uL 1x DPBS using the MDT. Vacuum wasapplied to the filter plate for 10 seconds and was followed by a 5 second vent to remove DPBS fromfilter plate. A 50% slurry of Protein A resin (GE MabSelect Sure) in DPBS was poured into an 8-wellreservoir equipped with a magnetic ball, and the resin was mixed by passing a traveling magnetunderneath the reservoir plate. The 8 tip Varispan arm, equipped with 1 mL conductive tips, was usedto aspirate the resin (250 uL) and transfer to a 96-well filter plate. A vacuum was applied to the filterplate for 2 cycles to remove most of the buffer. The MDT aspirated and dispensed 150 uL of DPBSto the filter plate wells containing the resin. The wash and vacuum ce was repeated two moretimes. A 2 mL, 96-well tion plate was d on the Janus deck, and the MDT transferred450 uL of 5x DPBS to the collection plate for later use. Reduced antibody (2 mg) as a solution in(200 uL) DPBS was prepared as described above for ions A and dispensed into the 96-wellplate. The MDT then collected 30 uL each of 3.3 mM dimethyl sulfoxide solutions of synthons platedin a l format and dispensed it to the plate loaded with reduced antibody in DPBS. The mixturewas mixed with the MDT by twice repeated aspiration/dispensation of a 100 uL volume within thewell. After five minutes, the conjugation reaction mixture (230 uL) was transferred to the 96-wellfilter plate containing the resin. The wells containing the ation mixture and resin were mixedwith the MDT by repeated aspiration/dispensation of a 100 uL volume within the well for 45 secondsper cycle. The aspiration/dispensation ce was repeated for a total of 5 times over the course ofminutes. A vacuum was applied for 2 cycles to remove excess synthon and protein to waste. TheMDT tips were rinsed with water for 5 cycles (200 uL, 1 mL total volume). The MDT aspirated andsed DPBS (150 uL) to the conjugation mixture, and a vacuum was applied for two cycles. Thewash and vacuum sequence was repeated two more times. The MDT gripper then moved the filterplate and collar to a holding station. The MDT placed the 2 mL collection plate containing 450 uL of10x DPBS inside the vacuum manifold. The MDT reassembled the vacuum manifold by placementof the filter plate and collar. The MDT tips were rinsed with water for 5 cycles (200 uL, 1 mL total). The MDT aspirated and dispensed 100 uL of IgG Elution Buffer 3.75 (P) to the conjugatione. After one minute, a vacuum was applied for 2 cycles, and the eluent was captured in thereceiving plate containing 450 uL of 5x DPBS. The aspiration/dispensation sequence was repeated 3MEl 24985843V.1 718117813-12620additional times to deliver ADC samples with concentrations in the range of 1.5-2.5 mg/mL at pH 7.4in DPBS.

Method E. A solution of Bond-BreakerTM tris(2-carboxyethyl)phosphine (TCEP) solution (10 leI,0.017 mL) was added to the on of antibody (10 mg/mL, 1 mL) at room temperature. Thereaction mixture was heated to 37 CC for 75 minutes. The on of reduced antibody cooled toroom temperature and was added to a solution of synthon (10 leI, 0.040 mL in DMSO) followed byaddition of boric buffer (0.1 mL, 1M, pH 8). The reaction solution was let to stand for 3 days at roomtemperature, loaded onto a desalting column (PD10, washed with DPBS 3x5mL before use), followedby DPBS (1.6 mL) and eluted with additional DPBS (3 mL). The purified ADC solution was filteredthrough a 0.2 micron, low protein-binding 13 mm e-filter and stored at 4 CC.

Method F. Conjugations were performed using a Tecan Freedom Evo c liquid handling system.

The solution of antibody (10 mg/mL) was preheated to 37 CC and aliquoted to a heated 96 ellplate in amounts of 3 mg per well (0.3 mL) and kept at 37°C. A on of reakerTM tris(2-carboxyethyl)phosphine (TCEP) solution (1 leI, 0.051 mL/well) was added to antibodies, and thereaction mixture was kept at 37 CC for 75 minutes. The solution of reduced antibody was transferredto an unheated 96 ell plate. Corresponding solutions of synthons (5 leI, 0.024 mL in DMSO)were added to the wells with reduced antibodies and treated for 15 minutes. The reaction solutionswere loaded onto a platform (8 x 12) of desalting columns (NAP5, washed with DPBS 4x before use),followed by DPBS (0.3 mL) and eluted with additional DPBS (0.8 mL). The purified ADC solutionswere further aliquoted for analytics and stored at 4 CC.

Method G. Conjugations were performed using a Tecan Freedom Evo robotic liquid handling system.

The solution of antibody (10 mg/mL) was preheated to 37 CC and aliquoted onto a heated 96 deep-well plate in amounts of 3 mg per well (0.3 mL) and kept at 37 C. A solution of Bond-BreakerTMtris(2-carboxyethyl)phosphine (TCEP) on (1 leI, 0.051 mL/well) was added to dies, andthe on mixture was kept at 37 CC for 75 minutes. The solutions of reduced antibody weretransferred to an unheated 96 deep-well plate. Corresponding solutions of synthons (5 leI, 0.024mL/well in DMSO) were added to the wells with d antibodies followed by addition of boricbuffer (pH=8, 0.03 l) and treated for 3 days. The reaction solutions were loaded onto arm (8 x 12) of desalting columns (NAP5, washed with DPBS 4x before use), followed by DPBS(0.3 mL) and eluted with additional DPBS (0.8 mL). The purified ADC solutions were furtheraliquoted for analytics and stored at 4 CC.

Method H. A solution of Bond-BreakerTM tris(2-carboxyethyl)phosphine (TCEP) solution (10 lel,0.17 mL) was added to the solution of antibody (10 mg/mL, 10 mL) at room temperature. TheMEl 24985843V.1 719117813-12620on mixture was heated to 37 CC for 75 minutes. The solution of synthon (10 lel, 0.40 mL inDMSO) was added to a solution of reduced antibody cooled to room temperature. The reactionsolution was let to stand for 30 minutes at room temperature. The solution of ADC was treated withsaturated ammonium sulfate solution (~2 — 2.5 mL) until a slightly cloudy solution formed. Thissolution was loaded onto butyl sepharose column (5 mL of butyl sepharose) equilibrated with 30%phase B in phase A (phase A: 1.5 M ammonium sulphate, 25 mM phosphate; phase B: 25 mMphosphate, 25% isopropanol V/V). IndiVidual fractions with DAR2 (also referred to as “E2”) andDAR4 (also referred to as “E4”) eluted upon applying gradient A/B up to 75% phase B. Each ADCsolution was concentrated and buffer switched using centrifuge trators or TFF for larger scales.

The purified ADC solutions were filtered through a 0.2 micron, low protein-binding 13 mm syringe-filter and stored at 4 CC.

Method I. A solution of Bond-BreakerTM tris(2-carboxyethyl)phosphine (TCEP) solution (10 lel,0.17 mL) was added to the solution of antibody (10 mg/mL, 10 mL) at room temperature. Thereaction mixture was heated to 37 CC for 75 minutes. The on of synthon (10 lel, 0.40 mL inDMSO) was added to a solution of reduced antibody cooled to room temperature. The onsolution was let to stand for 30 minutes at room temperature. The solution of ADC was treated withsaturated um sulfate solution (~2 — 2.5 mL) until a slightly cloudy solution . Thissolution was loaded onto a butyl sepharose column (5 mL of butyl sepharose) equilibrated with 30%phase B in Phase A (phase A: 1.5 M ammonium sulphate, 25 mM ate; phase B: 25 mMphosphate, 25% isopropanol V/V). IndiVidual fractions with DAR2 (also referred to as “E2”) andDAR 4 (also referred to as “E4”) eluted upon applying a gradient A/B up to 75% phase B. Each ADCsolution was trated and buffer switched using centrifuge concentrators or TFF for larger scales.

The ADC solutions were treated with boric buffer (0.1 mL, 1M, pH8). The reaction solution was letstand for 3 days at room temperature, then loaded onto a desalting column (PD10, washed with DPBS3x5mL before use), followed by DPBS (1.6 mL) and eluted with additional DPBS (3 mL). Thepurified ADC solution was filtered through a 0.2 micron, low protein-binding 13 mm syringe-filterand stored at 4 CC.

DAR and ation of ADCsThe DAR and percentage aggregation of ADCs synthesized were determined by LC-MS andsize ion chromatography (SEC), respectively.

LC-MS general ologyLC-MS analysis was performed using an Agilent 1100 HPLC system interfaced to an AgilentLC/MSD TOF 6220 E81 mass spectrometer. The ADC was reduced with 5 mM (final concentration)Bond-Breaker® TCEP solution o Scientific, Rockford, IL), loaded onto a Protein MicrotrapMEl 24985843V.1 720-12620(Michrom Bioresorces, Auburn, CA) desalting cartridge, and eluted with a gradient of 10% B to 75%B in 0.2 minutes at ambient temperature. Mobile phase A was H20 with 0.1% formic acid (FA),mobile phase B was acetonitrile with 0.1% FA, and the flow rate was 0.2 mL/min. Electrospray-ionization f-flight mass spectra of the co-eluting light and heavy chains were ed usingAgilent MassHunterTM acquisition software. The extracted intensity vs. m/z spectrum wasdeconvoluted using the Maximum Entropy feature of MassHunter re to determine the mass ofeach d antibody fragment. DAR was calculated from the deconvoluted spectrum by summingintensities of the naked and modified peaks for the light chain and heavy chain, normalized bymultiplying intensity by the number of drugs attached. The summed, normalized intensities weredivided by the sum of the intensities, and the summing results for two light chains and two heavychains produced a final average DAR value for the full ADC.

Thiosuccinimide hydrolysis of a bioconjugate can be monitored by electrospray massspectrometry, since the on of water to the conjugate results in an increase of 18 Daltons to theobservable molecular weight of the conjugate. When a conjugate is prepared by fully reducing theinterchain disulfides of a human IgG1 antibody and conjugating the maleimide derivative to each ofthe resulting cysteines, each light chain of the antibody will contain a single maleimide modificationand each heavy chain will contain three maleimide modifications, as described in Figure 2. Uponcomplete ysis of the resulting thiosuccinimides, the mass of the light chain will thereforeincrease by 18 Daltons, while the mass of each heavy chain will increase by 54 Daltons. This isillustrated in Figure 5 with the conjugation and subsequent hydrolysis of an exemplary maleimideinker (synthon TX, molecular weight 1736 Da) to the fully reduced huAb13v1 antibody.

Size exclusion tography general ologySize exclusion chromatography was performed using a Shodex KW802.5 column in 0.2 Mpotassium phosphate pH 6.2 with 0.25 mM potassium chloride and 15% IPA at a flow rate of 0.75ml/min. The peak area absorbance at 280 nm was determined for each of the high molecular weightand monomeric eluents by integration of the area under the curve. The % aggregate fraction of theconjugate sample was determined by ng the peak area absorbance at 280 nM for the highmolecular weight eluent by the sum of the peak area absorbances at 280 nM of the high larweight and monomeric eluents multiplied by 100%.

In vitro cell viability assay methodsThe tumor cell lines HCC38 (breast ), NCI-H1650 (NSCLC) and NCI-H847 (small celllung cancer cell line) were obtained from American Type Culture Collection (ATCC). Cells weregrown in 96-well culture plates using recommended growth media overnight at a y of 5 x 103(HCC38) or 20 x 103 (NCI-H847) or 40 x 103 (NCI-H1650) per well. The ing day, treatmentswere added in fresh media to triplicate wells. Cellular viability was determined 5 days later using theMEl 24985843V.1 721117813-12620CellTiter-Glo Luminescent Cell ity Assay kit (Promega), as ed in the manufacturer’sprotocol. Cell ity was assessed as percentage of l untreated cells.

Example 8: In vivo Efficacy of Anti-B7-H3 Antibody Drug ConjugatesOf the nine chimeric antibodies tested in vitro conjugtaed to CZ synthons, four showedsubnanomolar cytotoxicity (Table 6). chAb3-CZ, chAbl8-CZ, and chAbl3-CZ achieved DARSranging from 2.6 to 4.2 (see Table 7) and were assessed for anti-tumor activity in a mouse small celllung cancer cell line xenograft model NCI-Hl46, of human origin, using the s describedbelow. dy MSL109 (an IgGl antibody that binds to cytomegalovirus (CMV) glycoprotein H)was used as a control, both as a naked antibody and as an ADC (conjugated to the same n (CZ)as the chAb3, chAbl8, and chAbl3 antibodies). MSL109 is an isotype matched non-targetingcontrol. The methods of this xenograft assay are described below. The results are presented in Table7. The s show that each of the anti-B7-H3 Bcl-xL inhibiting ADCs were able to significantlyinhibit tumor growth relative to the naked antibody control (MSL109) or non-target specific Bcl-xLADC l (MSL109-CZ).

Tbl7'I' ' ' ' ' ' BlLdMSL109 -_[a] dose is given in mg/kg/dayEvaluation of efficac in xeno raft models methodsNCI-Hl46 cells, NCI-l650 cells, and EBC-l cells were obtained from the American TypeCulture Collection (ATCC, Manassas, VA). The cells were cultured as monolayers in RPMI-l640(NCI-Hl46, NCI-Hl650) or MEM (EBC-l) culture media (Invitrogen, Carlsbad, CA) that wassupplemented with 10 % Fetal Bovine Serum (FBS, Hyclone, Logan, UT). To generate xenografts,5x106 viable cells were inoculated subcutaneously into the right flank of immune deficient femaleSCID/bg mice (Charles River Laboratories, Wilmington, MA) respectively. The injection volumewas 0.2 mL and composed of a 1:1 mixture of S MEM and el (BD, Franklin Lakes, NJ).

Tumors were size matched at approximately 200 m3. Antibodies and conjugates were formulated in0.9% sodium chloride for injection and ed intraperitoneally. Injection volume did not exceed200 uL. Therapy began within 24 hours after size matching of the . Mice weighedapproximately 22 g at the onset of therapy. Tumor volume was estimated two to three times weekly.

Measurements of the length (L) and width (W) of the tumor were taken via electronic caliper and theMEl 24985843v.1 722117813-12620volume was calculated according to the following equation: V = L x W2/2. Mice were euthanizedwhen tumor volume reached 3,000 mm3 or skin ulcerations occurred. Eight mice were housed percage. Food and water were available ad libitum. Mice were acclimated to the animal facilities for aperiod of at least one week prior to commencement of experiments. Animals were tested in the lightphase of a r light: 12-hour dark schedule (lights on at 06:00 hours). As described above,human IgG control antibody (MSL109) was used as a negative control agent.

To refer to efficacy of therapeutic agents, ters of amplitude (TGImaX), durability (TGD)of therapeutic response are used. TGImX is the maximum tumor growth inhibition during theexperiment. Tumor growth inhibition is calculated by 100*(l-TV/CV) where TV and CV are the meantumor volumes of the treated and control groups, respectively. TGD or tumor growth delay is theextended time of a treated tumor needed to reach a volume of 1 cm3 relative to the control group.

TGD is calculated by 100*(Tt/Ct-l) where Tt and CK are the median time periods to reach 1 cm3 of thetreated and control groups, respectively.e 9: zation 0f Anti-B7-H3 Antibody chAblSAnti-B7-H3 chimeric antibody chAbl8 was selected for humanization based on its bindingcharacteristics and favorable properties as an ADC, including its properties when conjugated to a Bcl-xL tor (described above as exemplary conjugate CZ).zed antibodies were generated based on the variable heavy (VH) and variable light(VL) CDR ces of chAb18. Specifically, human germline sequences were selected forconstructing CDR-grafted, humanized chAbl8 antibodies, where the CDR s of the VH and VLchains were grafted onto different human heavy and light chain or sequences. Based on thealignments with the VH and VL sequences of monoclonal dy chAb18, the following humansequences were selected as acceptors:0 IGHVl-69*06 and IGHJ6*01 for constructing heavy chain acceptor sequences0 IGKVl-9*01 and IGKJ2*01 for constructing light chain acceptor sequences0 IGKV6-21*01and IGKJ2*01 as backup acceptor for constructing light chainThus, the VH and VL CDRs of chAbl8 were grafted into said acceptor sequences.

To generate humanized antibodies, framework back-mutations were identified and introducedinto the CDR-grafted antibody ces by de novo synthesis of the variable domain, or mutagenicucleotide primers and polymerase chain reactions, or both by methods well known in the art.

Different ations of back mutations and other mutations were constructed for each of the CDR-grafts as described below. Residue numbers for these mutations are based on the Kabat numberingsystem.

For heavy chains huAbl8VH.l, one or more of the following Vernier and VH/VL interfacingresidues were back mutated as follows: L46P, L47W, G64V, F7lH. Additional mutations include thefollowing: QlE, N60A, K64Q, D65G. For light chains VL.l, one or more of the followingMEl 24985843v.1 723117813-12620Vernier and VH/VL interfacing residues were back mutated as follows: A438, L46P, L47W, G64V,G66V, F71H. For light chains huAblSVL.2, one or more of the following Vernier and VH/VLinterfacing residues were back mutated as follows: L46P, L47W, K49Y, G64V, G66V, F71H.

The variable region and CDR amino acid sequences of the humanized antibodies aredescribed in Table 8 below.

TABLE 8: VH and VL amino acid se uences of humanized versions of chAbl87 Amino ACid sequence|—‘ I—‘"Ch huAbl 8VH 1 VH avowosGA‘2VKK’9GSSVKVSCYTIHWVRQAPGQGLEWINPNSRNTDYNQKFKDRVT :: TAUs ST.RST.DTAVYYCAGSTPYWYFDVWGQGTTVTVSSN (II 'huAb’ 8VH.‘ GYSFTSYTIH, es 26—35’” S41Q D NOH’N '- ,7 YINPNSRNTDYNQKFKDN VI V YSGSTPYWYFDV117 8VH.’a VVQKVQSGA?VKK?GSSVKVSC{ASGYSFTSYTIHWVRQAPGQGKfiW GYINPNSRNTDYNQKFKDRTTLTADRSTSTAYMVRSSKRSVDTAVYYCAQYSGSTPYWYFDVWGQGTTVTVSSIlilll(J‘I Residues 26—35 GYSFTSYTIHf S*Q 3 NO:”llilll ' 7 YINPNSRNTDYNQKFKDN YSGSTPYWYFDVSGA?VKK?GSSVKVSC{ASGYSFTSYTIHWVRQAPGQGLEW GYINPNSRNTDYAQKFQGRVTLTADKSTSTAYMVKSSKRSVDTAVYYCAQYSGSTPYWYFDVWGQGTTVTVSSResidues 26—35 GYSFTSYTIHf S*Q 3 NO:”' ' YINPNSRNTDYAQKFQGYSGSTPYWYFDVIi DIQLTQS?SFLSASVGD?VTITCRASSSVSYMNWYQQKPGKA?{LLIYATSNLASGV?SRFSGSGSG1%E111 SSLQ?EDFATYYCQQWSSNPLTFGQGlKlfi KMEl 24985843V.1 724117813-12620Amino Acid Sequence_ RASSSVSYMND NO:L20ATSNLASQQWSSNPLT:QLTQS9SFLSASVGDRVT:SSSVSYMNWYQQKPGKSP{PWIYATSNLASGV9SRFSVSVSGifiHiKi SSLQ9EDFATYYCQQWSSNPLTFGQGiKT.4VL. SYMN, Residues 24—33f ’, NO:’I V— ATSNLAS122 SSSVSYMNWYQQKPGKA9{PWIYAT:QLTQS9SFLSASVGD9VSNLASGV9SRFSVSGSGifiHili SSLQ9EDFATYYCQQWSSNPLTFGQGiKT.4Residues 24—33 RASSSVSYMNf 1 3 NO:;22(A) O ' '— ATSNLAS(A) QQWSSNPLT.VTiQS9DbQSVi9K41KVi iCRASSSVSYMNWYQQKPDQSPKLLIKATSNLASGV9SRFSGSGSGTDFTLTINST.fiA“DAAiYYCQQWSSNPLTFGQGiKT.4Residues 24—33 RASSSVSYMNf 1 3 NO:;23' '— ATSNLASQQWSSNPLT.VTiQS9DbQSVi9K41KVi iCRASSSVSYMNWYQQKPDQSPKPWIYATSNLASGV9SRFSVSVSGTDHTLTINDAAiYYCQQWSSNPLTFGQGiKT.4lhuAbl8VL.2a CDR—Ll Residues 24—33 RASSSVSYMND NO: 124MEI 24985843V.1 725-12620Clone Protei Residues Amino Acid SequenceReggion Residues 49—55 ATSNLASof 4Q J NO:; 21,hUAb:_ 8V1]. 2a 7 QQWSSNPLTHumanized variable s of the murine monoclonal Abl8 (described above) were clonedinto 1gG expression vectors for functional characterization:0 Humanized Abl8VH.l (huAbl8VH.l) is a CDR-grafted, humanized Abl8 VH containing1GHVl-69*06 and 1GHJ6*01 ork sequences. It also contains a QlE change toprevent pyroglutamate formation. The variable and CDR sequences of VH.l aredescribed in Table 8.0 Humanized Abl8VHl.a (huAbl8VH. la) is a humanized design based on huAbl8VH.l andcontains 4 proposed framework utations: M481, V67T, L691, K73R. The variable andCDR sequences of huAbl8VH.la are described in Table 8.0 Humanized Abl8VHl.b (huAbl8VH.lb) is a humanized design based on VH.l andhuAbl8VH. la and contains 1 ed framework back-mutation L691 and 3 HCDR2germlining changes N60A, K64Q, D65G. The variable and CDR sequences ofhuAbl8VH. lb are described in Table 8.0 Humanized Abl8VL.l (huAbl8VL.l) is a CDR-grafted, humanized Abl8 VL containing1GKVl-9*01 and 1GKJ2*01 framework sequences. The variable and CDR sequences ofhuAbl8VL.l are described in Table 8.0 Humanized Abl8VL. la (huAbl8VL.la) is a humanized design based on huAbl8VL.l andcontains 6 ed framework back-mutations: A43S, L46P, L47W, G64V, G66V, F7lH.

The variable and CDR sequences of huAbl8VL. 11 are described in Table 8.0 Humanized Abl8VL. lb (huAbl8VL.lb) is a humanized design based on huAbl8VL.l andVL.la contains 4 proposed framework back-mutations: L46P, L47W, G64V, F7lH.

The variable and CDR sequences of huAbl8VL. lb are described in Table 8.0 Humanized Abl8VL.2 (huAbl8VL.2) is a CDR-grafted, humanized Abl8 VL containing1GKV6-2l*01 and 1GKJ2*01 framework ces. The variable and CDR sequences ofhuAbl8VL.2 are described in Table 8.0 zed Abl8VL.2a 8VL.2a) is a humanized design based on huAbl8VL.2 andcontains 6 proposed framework back-mutations: L46P, L47W, K49Y, G64V, G66V, F7lH.

The variable and CDR sequences of huAbl8VL.2a are described in Table 8.

Thus, the humanization of chAbl8 resulted in 10 humanized antibodies, including huAbl8vl,huAb l 8V2, huAb l 8V3, huAb l 8v4, huAb l 8v5, huAb l 8v6, huAb l 8v7, huAb l 8v8, huAb l 8V9, andMEl 24985843v.l 726117813-12620huAbl8v10. The variable and heavy light chains for each of these humanized versions of Abl8 areprovided below:Table 9: Anti-B7-H3 Abl8 humanized antibodiesExample 10: In vitro Characterization of Anti-B7—H3 chAblS Humanized VariantsThe humanization of chAbl8 generated 10 variants (described above in Table 9) that retainedbinding to human and cyno B7-H3 as ed by FACS (the method of which is described above inExample 6). These variants were further characterized for binding by SPR and were sfullyconjugated to the Bcl-XL inhibitor synthon CZ using Method A (described above) and assessed forcell cytotoxicity as described in Example 7. Table 10 summarizes the in vitro characteristics of thevarious humanized Abl8 variants. The parental chAbl8 from which the variants were derived wasalso tested as a comparator. All zed variants had similar binding ties as assessed bybiacore, and retained g activity to cell surface expressed as conjugates with the CZ synthon.

The cytotoxicity of all of the variants as CZ synthons were similar to the chAbl8 from which theywere derived.

TABLE 10: In vitro characterization of humanized anti-B7-H3 Abl8 tsAffinity ofnaked CytotoxicityVariant name mAbs (HCC38 Cell(Biacore, line IC50)chAb l 8-CZ 0.28huAb 1 8v 1 -CZ 0.39huAb l 8v2-CZ 1.19huAb l 8v3-CZ 0.32huAb l 8v4-CZ "mm 0.29huAb l 8v5-CZ 0.12huAb l 8v6-CZ 0.14huAb l 8v7-CZ 0.03huAb l 8v8-CZ 1.3huAb l 8v9-CZhuAb l 8v10-CZ 0.57MEl 24985843V.l 727117813-12620Humanized chAbl8 variants were conjugated to the CZ synthon and tested for cytotoxicity inHCC38 cell line. As described in Table 10, most zed antibodies showed potent cytotoxicity,similar to those observed with l antibody chAb18.

Example 11: In Vivo Efficacy of Humanized Ab18 Variants as Bcl-xL Inhibitor ADCsSix of the humanized chAbl8 variants were selected based on in vitro cytotoxicity resultsdescribed in Example 10. Specifically, antibodies huAb18vl, huAbl8v3, huAb18v4, huAbl8v6,huAb18v7, and huAbl8v9 were each conjugated to the CZ synthon (to form an anti-B7-H3 CZ ADC)for tion in an in vivo xenograft model of small cell lung cancer (using NCI-Hl46 cells), asdescribed in Example 8. Single dose treatment of the tumor bearing mice ed in tumor growthinhibition and tumor growth delay and the results are summarized in Table 11. Ab095 was used as anegative control for the effect of administering IgG, as it is an isotype matched rget specificantibody raised against tetanus toxoid. See Larrick er al., 1992, Immunological Reviews 69-85. Micewere administered 6 mg/kg of the ADC intraperitoneally QDxl.

Table 11: In vivo efficacy of anti-B7-H3 ADCS {humanized chAbl8-CZ variants}Conjugation DAR by Dose[“]//route/ Number of TGImaxADC TGD (%)Method MS n mice (%)[a] dose is given in mg/kg/dayAs described in Table 11, each of the tested humanized antibodies was able to t tumorgrowth in the mouse xenograft model.

Example 12: Humanization of Anti-B7-H3 Antibody chAb3Anti-B7-H3 ic antibody chAb3 was selected for humanization based on its favorableproperties as a Bcl-xL ting (Bcl-xLi) conjugate. Humanized dies were generated based onthe variable heavy (VH) and variable light (VL) CDR sequences of chAB3. Specifically, humangermline sequences were selected for constructing afted, humanized chAb3 dies wherethe CDR domains of the VH and VL chains of chAb3 were grafted onto different human heavy andlight chain acceptor sequences. Based on the alignments with the VH and VL sequences ofmonoclonal antibody chAb3 the following human sequences were ed as acceptors:0 IGHVl-69*06 and IGHJ6*01 for constructing heavy chain acceptor sequences0 IGKV2-28*01 and IGKJ4*01 for constructing light chain acceptor sequencesMEl 24985843v.1 728-126201GHV1-69*06 IGHJ6QVQLVQSGAEVKKPGSSVKVSCKASggtfssyaisWVRQAPGQGLEWMGgiipifgtanyaqqugRVTITADKSTSTAYMELSSLRSEDTAVYYCARXXXXXXXXWGQGTTVTVSS (SEQ ID NO: 174);where XXXXXXXX represents the CDR-H3 region.1GKV2-28*01 IGKJ4DIVMTQSPLSLPVTPGEPASISCrssqsllhsngynyldWYLQKPGQSPQLLIYlgsnrasGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCXXXXXXXXXFGGGTKVEIK (SEQ ID NO: 175);where XXXXXXXXX represents the CDR-L3 region.

By ng the corresponding VH and VL CDRs of chAb3 into said acceptor sequences,afted, humanized, and modified VH and VL sequences were prepared. To generatehumanized antibodies with potential framework back-mutations, the mutations were identified andintroduced into the CDR-grafted antibody sequences by de novo synthesis of the variable domain, ormutagenic oligonucleotide primers and polymerase chain reactions, or both. Different combinationsof back mutations and other mutations are constructed for each of the CDR-grafts as follows. Residuenumbers for these ons are based on the Kabat numbering .

The amino acid ces of the various humanized heavy and light chain variable regionsare described below in Table 12.

For heavy chains huAb3VH.l, one or more of the following Vernier and VH/VL interfacingresidues were back mutated as follows: M481, V67A, 169L, A71V, K73R, M80V, Y91F, R94G. Forlight chains huAb3l VL.1, one or more of the following Vernier and VH/VL interfacing residueswere back mutated as follows: 12V, Y87F.

The following zed variable regions of the murine onal chAb3 antibody werecloned into IgG expression vectors for functional characterization:0 Humanized Ab3 VH.1 (huAb3VH.l) is a CDR-grafted, humanized Ab3 VH containing1GHV1-69*06 and 1GHJ6*01 framework sequences. It also contains a QlE change toprevent pyroglutamate formation.0 zed Ab3 VH. la (huAb3VH.la) is a humanized design based on H.l andcontains 8 proposed framework back-mutations: M481, V67A, 169L, A71V, K73R, M80V,Y9 1 F, R94G.0 Humanized Ab3 VH.lb (huAb3VH.lb) is a humanized design between huAb3VH.l andhuAb3VH. la and contains 6 proposed framework back-mutations: M481, V67A, 169L, A71V,K73R, R94G.0 Humanized Ab3 VL.1 (huAb3VL.l) is a CDR-grafted, humanized Ab3 VL containing1GKV2-28*01 and 1GKJ4*01 framework sequences.0 zed Ab3 VL.la (huAb3VL. la is a humanized design based on huAb3VL.l andcontains 2 proposed framework back-mutations: 12V, Y87F.0 Humanized Ab3 VL.lb (huAb3VL.lb) is a zed design ns only 1 proposedframework back-mutations: 12V.

MEl 24985843v.1 729117813-12620The variable region and CDR amino acid sequences of the foregoing humanized antibodiesare described in Table 12 below.

TABLE 12: VH and VL seuences of humanized versions of chAb3125IiiiiillllllllVHhuAbBVH. l Residues Amino Acid ce3VQKVQSGA3VKKPGSSV<VSCKASGYTFSSYWMHWVRQAPGQGLEWMGLIHPDSGSTNYNEMilADKSlSlAYMjLSSLRSEDTAVYYCARGGRLYFDYWGQGTTVTVSSliiiiiiiillll C es 26—35 GYTFSSYWMH' ’ D NO:L 25liilllliiiiiiiillll LIHPDSGSTNYNEMFKNliilll GGRLYFDYN OW liiiiiiiil!llhuAbBVH. 3VQT.VQSGA3VKKPGSSV<VCKASGYTFSSYWMHWVRQAPGQGK3W GLIHPDSGSTNYNEMFKNRATLTVJRSTSTAYVELSSLRSEDTAVYFCAGGGRLYFDYWGQGTTVTVSSliiiiiiiillll es 26—35 GYTFSSYWMHT ' D NO:L 26liilllliiiiiiiillll LIHPDSGSTNYNEMFKNliilllliiiiiiiil!llhuAbBVH. GGRLYFDYN \l 3VQT.VQSGA3VKKPGSSV<VCKASGYTFSSYWMHWVRQAPGQGK3W GLIHPDSGSTNYNEMFKNRATLTVJRSTSTAYMELSSLRSEDTAVYYCAGGGRLYFDTVTVSSliiiiiiiillll Residues 26—35 GYTFSSYWMH’" ' 3 NO: L27liilllliiiiiiiillll LIHPDSGSTNYNEMFKNliilllliiiiiiiillll GGRLYFDYMEl 24985843V.1 730117813-126207 Amino ACid sequencehuAb3VL 1 DIIVMTQSPLSL9V1PG41PASSCRSSQSLVHSNGDTYLRWYL<9GQSPQLLIIYKVSNRFSGV.33FssssssiabiT.K SvaGEDVGVYYCSQSTHVPYTFGG|_l .J> huAbBVL Cr' Residues 24—39 RSSQSLVHSNGDTYLR’ 1 D NO:L28\l VI V— KVSNRFSr :_liilllN k0 huAbBVL, DVVMTQSPLSL9VlPG*1PASSCRSSQSLVHSNGDTYLRWYL<9GQSPQLL__YKVSNRFSGVLD9FSGSGSGiDblTK SRV“GlEDVGVYFCSQSTHVPYTFGG.lillll 'L. , es 2 4—3 9 RSSQSLVHSNGDTYLRf 1 D NO:LZ9lllllll VI V— :_ KVSNRFSliilll(A) O huAb3VL DWMTQSPLSL9V1PG4.PASSCRSSQSLVHSNGDTYLRWYLQLLIIYKVSNRFSGV'. DRFSGSGSGL )1: N.K Sva.

EDVGVYYCSQSTHVPYTFGGGl .|_l 'huAbBVL. , Residues 2 4—3 9 RSSQSLVHSNGDTYLRf 1 D NO:L3Ol VI V— :_ KVSNRFSlillll(J‘IThe humanization of chAb3 resulted in 6 humanized antibodies, including huAb3vl,huAb3v2, 3, huAb3v4, huAbl8v5, and huAb3v6. The variable and heavy light chains foreach of these humanized versions of Abl8 are provided below in Table 13.

MEl 24985843v.1 731117813-12620Table 13: Humanized Ab3 antibodieshuAb3V1 huAb3 VH1 / huAb3 VL1huAb3V2 huAb3 VH1b / huAb3 VL1huAb3V3 huAb3 VH1a / huAb3 VL1ahuAb3V4 huAb3 VH1 / huAb3 VL1bhuAb3V5 huAb3 VH1b / huAb3 VL1bhuAb3V6 huAb3 VH1a / huAb3 VL1bExample 13: In vitro characterization of chAb3 humanized variantsThe humanization of chAb3 generated 6 ts (described in Table 13) that retainedg to human B7-H3 as assessed by FACS (as described in Example 6). These variants werefurther characterized for binding by SPR and as ADCs conjugated to the Bcl-XL inhibitor synthon(linker warhead) CZ. The humanized Ab3 antibodies were also assessed for cell cytotoxicity (usingthe assay bed above in e 7). Table 14 summarizes in vitro characteristics of chAb3humanized variants. An ADC comprising chAb3 conjugated to synthon CZ was used as a control.

TABLE 14: In vitro characterization of humanized variants of chAb3FACS CytotoxicityAffinity ofSeq. Id. Conjugati (Binding to (HCC38 CellADC naked mAbsNumber on Method hu B7-H3) line [(350)(Biacore K )ECso (11M) ’ D (11M)chAb3-CZhuAb3V1-huACbZ3V3- 1.68 9.22e 14: In vivo Efficacy of chAb3 Humanized Variants as Bcl-xL ADCsTwo of the humanized variants (huAb3V2 and huAb3V6) were selected based on potent invitro cytotoxicity as CZ conjugates and acceptable aggregation properties for evaluation in an in vivamurine aft model of small cell lung cancer cells (NCI-H146 cells) as described in materials andmethods in Example 8. Single dose treatment of tumor bearing mice resulted in tumor growthinhibition and tumor growth delayfor both zed dies conjugated to an exemplary Bcl-XLinhibitor, and the results are summarized in Table 15.

MEI 24985843v.1 732117813-12620Table 15: In vivo efficac of humanized chAb3-CZ variantsConJugatlon. . Dose e/[aADC DAR Number of TGImax (%) TGD ((70)Method regimen mice———-n-_n——-———n——-———n[a] dose is given in mg/kg/dayExample 15: Modifications of the CDRs of Humanized Variant dy huAb3v22 showed favorable binding and cell killing properties. An examination of thevariable region amino acid sequences of huAb3v2, however, revealed potential deamidation and/orisomerization sites.

The amino acid sequences of huAb3 le regions are described below, including the lightchain (huAb3VL1) and the heavy chain (huAb3VH1b). The potential deamidation and/orisomerization sites in CDRs of the VH (CDR2 at amino acids “ds” and VL (CDRI at amino acids“ng”) are italicized and were thus engineered to improve dy manufacturing. The CDRs aredescribed in lower case letters in the sequences below.

To make huAb3v2 ts lacking these potential deamidation and/or isomerization sites,each of the amino acids indicated below (X and z; representing the potential sites in the CDRI of theVL and the CDR2 of the VH) were nized. The resulting 30 VL variants were paired with theoriginal huAb3v2 VH and tested for g. The resulting 29 VH variants were paired with theoriginal huAb3v2 VL and tested for g. Successful VH variants were combined and tested withproductive VL variants harboring changes in LCDRI to make the final humanized variants lackingthe potential deamidation and/or isomerization sites in CDRs. The amino acid sequences of thevariants are provided in Table 16 below. The full length amino acid sequences of the heavy chain andlight chain of the huAb3v2 variant, huAb3v2.5 are provided in SEQ ID NOs: 170 and 171,tively. The full length amino acid sequences of the heavy chain and light chain of the huAb3v2variant, huAb3v2.6 are provided in SEQ ID NOs: 172 and 173, respectively.huAb3 VL1DIVMTQSPLSLPVTPGEPASISCrssqslvhsngdtylrWYLQKPGQSPQLLIYkvsnrstVPDRFSGSGSGTDFTLKISRVEAEDVGVYYqusthvpthGGGTKVEIK (SEQ ID NO: 128)xg (15 variants) (SEQ ID NO: 178)nz (15 variants) (SEQ ID NO: 179)huAb3 VHlbEVQLVQSGAEVKKPGSSVKVSCKASgytfssywthVRQAPGQGLEWIGlihpdsgstnynemfknRATLTXDRSTSTAYMELSSLRSEDTAVYYCAQggrlyfdyWGQGTTVTVSS (SEQ ID NO: 127)(15 variants) xs (SEQ ID NO: 180)(14 variants) dz (SEQ ID NO: 181)MEI 24985843v.1 733117813-12620Where (for both the VL and VH),x = All amino acids, except: M, C, N, D, or Q.z = All amino acids, except: M, C, G, S, N, or P.

Proposed framework back ons are underlined (see Example 12).

Table 16: Variable re ion se uences of huAb3V2 d variantsA. Amino ACid sequencehuAb3V2 1 EVQLVQSGAEVK<PGSSVKVSC<ASGYTFSSYWMHWVRQA?GQGLEWIGLIHPWSGSTNYNEMFKNRATLTVDRSTSTAYMTT.SST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTV2 C, GYTFSSYWMH. __ Residues 26— 35O' 1, NO:Z. ,7 ' '— GSTNYNEMFKNhuAbBVZ. 77 ' '— GGRLYFDY(A) (A) huAb3v2. MVMTQSPLSLPVlRSSQSLVHSSGDTYLRWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGlDb'lTK SRV4'A“DVGVYYCSQSTHVPYTE'GGGlKV'|_l 'huAvaZ. , Re sidues 2 4—3 9 RSSQSLVHSSGDTYLROf 1 D NO:L33IIIIIII huAb3v2.:_ii“.7' ' '_ ; KVSNRFSliillll huAb3v2. 7' ' ' SQSTHVPYThuAb3v2_ 2 .EVQLVQSGA'WK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLIWIGLIHPWSGSTNYNEMFKNRATLTVDRSTSTAYMVLSSLRSVDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 2 Residues 26—35 GYTFSSYWMHof z 3 No:’3’huAb3v2. 2 - ,_ LIHPWSGSTNYNEMFKN22 |!i||||-uAb3v2.2-_uAb3v2.2 ' '_ GGRLYFDY* 4'.Q 3 N05 3’2.3 MVMTQSPLSLPVlRSSQSLVHSNRDTYLRWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGlDb'lTK SRV4A“DVGVYYCSQSTHVPYTE'GGGlKVfi KMEI 24985843V.1 734-12620II ReSTdues Amino Acid SequencehuAb3v2. 2 Residues 24—39 RSSQSLVHSNRDTYLR’ 1 D NO:T352. 2 ' ’ '— KVSNRFShuAb3v2. 2 SQSTHVPYThuAb3v2. 3 ITVQLVQSGAIWK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLITWTGLIHPWSGSTNYNEMFKNRATLTVDRSTSTAYMTT.SST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 3 Residues 26—35 GYTFSSYWMH’ 1, NO:IhuAb3v2. 3 ' '— LIHPWSGSTNYNEMFKN-huAb3v2. 3 GGRLYFDYIhUAb3V2 3-RSSQSLVHSNQDTYLRWMVMTQSPLSLPVL YLQKPG QSPQLLTYKVSNRFSGVPDRFSGSGSGiDb'iTK SRVT'ATDVGVYYCSQSTHVPYTE'GGGLKV'huAb3v2. 3 Residues 24— 39 RSSQSLVHSNQDTYLR’ 1 D NO:T372.3 ' ' KVSNRFS-huAb3v2. 3 SQSTHVPYTIhUAb3V2 4'-ITVQLVQSGAIWK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLITWTGLIHPESGSTNYNEMFKNRATLTVDRSTSTAYMTTSST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTV2. Z Residues 26— 35 GYTFSSYWMH* 1 D NO:L39huAb3v2 A ' '— LIHPESGSTNYNEMFKNhuAb3v2 2 GGRLYFDYhuAb3v2 2. RSSQSLVHSSGDTYLRWDVWTQSPLSLPVL. YLQKPGQSPQLLTYKVSNRFSGVPDRFSGSGSGiDb'iTK SRVTATDVGVYYCSQSTHVPYTE'GGGLKVT KMEI 24985843V.1 735117813-12620II ReSTdues Amino Acid SequencehuAb3v2. 1 VI Residues 24—39 RSSQSLVHSSGDTYLR’ 1 D NO:T332.Z ' ’ '— KVSNRFShuAb3v2. Z SQSTHVPYThuAb3v2. 5 ITVQLVQSGAIWK<PGSSVKVSC<SSYWMHWVRQA9GQGLITPESGSTNYNEMFKNRATLTVDRSTSTAYMTT.SST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 5 Residues 26—35 GYTFSSYWMHf 1 D N02T39huAb3v2. 5 ' '— LIHPESGSTNYNEMFKNhuAb3v2. 5 GGRLYFDYIhUAb3V2 SLVHSNRDTYLRWMVMTQSPLSLPVL YLQKPG QSPQLLTYKVSNRFSGVPDRFSGSGSGiDb'iTK SRVT1ATDVGVYYCSQSTHVPYTE'GGGLKV1huAb3v2. 5 Residues 24— 39 RSSQSLVHSNRDTYLR* 1 D NO:L35huAb3v2.5 ' ' KVSNRFS-huAb3v2. 5 SQSTHVPYTIhUAb3V2 QLVQSGAIWK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLITWTGLIHPESGSTNYNEMFKNRATLTVDRSTSTAYMTTSST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 6 Residues 26— 35 GYTFSSYWMH* 1 D NO:L39huAb3v2.6 ' '— LIHPESGSTNYNEMFKNhuAb3v2. 6 GGRLYFDYIhUAb3V2 6-RSSQSLVHSNQDTYLRWVWTQSPLSLPVi. YLQKPG QSPQLLTYKVSNRFSGVPDRFSGSGSGiDb'iTK SRVTATDVGVYYCSQSTHVPYTE'GGGLKVT KMEI 24985843V.1 736117813-12620II ReSTdues Amino Acid SequencehuAb3v2. 6 Residues 24—39 RSSQSLVHSNQDTYLR’ 1 D NO:T37huAb3v2. 6 KVSNRFS-huAb3v2. 6 SQSTHVPYTIhUAb3V2 QLVQSGAIWK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLITWTGLIHPISGSTNYNEMFKNRATLTVDRSTSTAYMTT.SST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 7 Residues 26— 35 GYTFSSYWMH* 1 NO: VI ,2.7 ' '— LIHPISGSTNYNEMFKNhuAb3v2. 7 GGRLYFDYIhUAbBVZ 7'-RSSQSLVHSSGDTYLRWMVMTQSPLSLPVL IYLQKPG QSPQLLTYKVSNRFSGVPDRFSGSGSGiDb'iTK SRVT'ATDVGVYYVPYTE'GGGLKV'huAb3v2. 7 Residues 24— 39 RSSQSLVHSSGDTYLR* 1 D NO:L33huAb3v2.7 ' ' KVSNRFSv2. 7 SQSTHVPYTIhUAb3V2 8'-ITVQLVQSGAIWK<PGSSVKVSC<ASGYTFSSYWMHWVRQA9GQGLITWTGLIHPISGSTNYNEMFKNRATLTVDRSTSTAYMTTSST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 8 Residues 26— 35 GYTFSSYWMH* 1 NO: VI ,huAb3v2.8 ' '— LIHPISGSTNYNEMFKNhuAb3v2. 8 GGRLYFDYIhUAb3V2 8'-RSSQSLVHSNRDTYLRWVWTQSPLSLPVi. IYLQKPG QSPQLLTYKVSNRFSGVPDRFSGb'iTK SRVTATDVGVYYCSQSTHVPYTE'GGGLKVT KMEl 24985843V.1 737117813-12620’. Residues Amino Acid Sequence'I '. .3 NO 2 I 3 5huAb3v2. 8 '- ,_ ;_ KVSNRFS2. 8 '' ' SQSTHVPYThuAb3v2_ 9 QSGA'WK<PGSSVKVSC<ASGYTFSSYWMHWVRQA?GQGL.EWIGLIHPISGSTNYNEMFKNQATLTVDRSTSTAYMTT.SST.RSTDTAVYYCAGGGRLYFDYWGQGTTVTVhuAb3v2. 9 'Residues 26—35 GYTFSSYWMH*" '.

, NOE 7huAb3v2. 9 '- ,_ LIHPISGSTNYNEMFKN-huAb3v2. 9 - , - GGRLYFDYhuAb3v2. 9 DIV?MTQSPLSLPVi '?ASRSSQSLVHSNQDTYLRWYLQKPGQSPQLLIYKVSNRFSGV?DRFSGSGSGiDb' 1TK SRV“.AfiDVGVYYCSQSTHVPYTE'GGGiKV'.7 -. 3 NO:I37-huAb3v2. 9 '- , KVSNRFShuAb3v2 . 9 c, '- , SQSTHVPYTExample 16: In vitro characterization of huAb3v2 VariantsRemoval of potential deamidation and/or ization sites (described in Example 15)generated only 6 variants that retained binding to both human and cyno B7-H3 exogenously expressedon mouse 3T12 fibroblasts as assessed by FACS (as described in the s of Example 6).

These new anti-B7-H3 antibodies were further characterized for binding by SPR andconjugated to the Bcl-xLi synthon CZ and assessed for cell cytotoxicity (using the methods bedin Example 7). Table 17 es in vitro characteristics of six 2 humanized variants.

MEI 24985843V.1 73 8117813-12620Table 17: In vitro characterization of humanized huAb3v2 variants includin naked dies andSequence Conjugation FACS (ECSO ty Cyto-number Method nM) of toxicitynaked (H847 CellA | ine IC50)my. CVB7- (lgi‘actieH3 H3huAb3V2- 127, 128 A 3.5 0.44 5.11 2.87 2.30E- 1.49CZ 092.3- 0.11 6.50 4.03huAb3v2.5— 15.6 0.13 5.14 4.86huAb3v2.8- 0.14 3.94 3.01huAb3v2.9— . . 6.16 4.64As described in Table 17, the results showed that all six huAb3v2 variants had similar bindingproperties to cells expressing human or cynoB7-H3 as compared to the parental huAb3v2. Of the sixhuAb3v2 variants, four antibodies (huAb3v2.5, huAb3v2.6, huAb3v2.8, huAb3v2.9) showed potentcytotoxicity in H847 cells when conjugated to exemplary Bcl-xLi synthon CZ.

Example 17: zation 0f Anti-B7-H3 Antibody chAb13The anti-B7-H3 chimeric antibody chAbl3 was selected for humanization based on itsbinding characteristics and favorable properties as an ADC (conjugated to a Bcl-xL inhibitor).

Prior to humanization, chAbl3 was modified in order to minimize potential deamidation inthe light chain CDR3 (QQYNSYPFT (SEQ ID ); potential deamidation site is ted asresidues “NS” (italicized)). Point mutations in the amino acid position corresponding to “N” and/or“S” within the light chain CDR3 of chAbl3 were introduced, resulting in 30 variants. diescontaining these CDR3 light chain variants were then screened for their ability to retain the bindingcharacteristics of chAbl3. Variants comprising a CDR3 having a tryptophan (W) point mutationd of the serine “S” in the “NS” motif (i.e., QQYNWYPFT (SEQ ID NO: 39)) retained thebinding es of the parent chAbl3 antibody. The substitution of the S e with a W residuewithin the CDR3was surprising given the structural differences between serine and tryptophan as wellas the significant role the CDR3 plays in antigen binding.

MEI 24985843v.1 739117813-12620Humanized antibodies were generated based on the variable heavy (VH) and variable light(VL) CDR sequences of chAbl3, ing the “NW” light chain CDR3. Specifically, humangermline sequences were selected for constructing CDR-grafted, zed chAbl3 antibodies,where the CDR domains of the VH and VL chains were grafted onto ent human heavy and lightchain acceptor sequences. Based on the alignments with the VH and VL sequences of monoclonalantibody chAbl3, the following human ces were selected as acceptors:0 IGHV4-b*Ol(O-l) and IGHJ6*01 for constructing heavy chain acceptor sequences0 IGKVl-39*01 and 01 for constructing light chain acceptor sequencesIGHV4-b_IGHJ6QVQLQESGPGLVKPSETLSLTCAVSgysissgyngWIRQPPGKGLEWIGsiyhsgstyynpslksRVTISVFSLKLSSVTAADTAVYYCARXXXXXXXWGQGTTVTVSS (SEQ ID NO: 176);where XXXXXXX ents the CDR-H3 region.

IGKV l -39_IGKJ2DIQMTQSPSSLSASVGDRVTITCrasqsissyanYQQKPGKAPKLLIYaasslqsGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCXXXXXXXXXFGQGTKLEIK (SEQ ID NO: 177);where XXXXXXXXX represents the CDR-L3 region.

By grafting the “NW” light chain CDR3 and the remaining five corresponding VH and VLCDRs of chAbl3 into said acceptor sequences, afted, humanized, and modified VH and VLsequences were prepared. To generate humanized antibodies with potential framework back-mutations, mutations were identified and introduced into the CDR-grafted dy sequences by denovo synthesis of the variable domain, or mutagenic oligonucleotide primers and polymerase chainreactions, or both by methods well known in the art. Different combinations of back mutations andother mutations were constructed for each of the CDR-grafts as follows. Residue s for thesemutations are based on the Kabat numbering system.

The following humanized variable regions of the murine monoclonal chAbl3 antibodies werecloned into IgG expression vectors for functional characterization:0 Humanized Abl3 VH.l (huAbl3VH. l) is a CDR-grafted, humanized Abl3 VH containingIGHV4-b*Ol(O-l) and IGHJ6*01 framework sequences. It also contains a QlE change toprevent pyroglutamate ion.0 Humanized Abl3 VH.l (huAbl3 VH.la) is a humanized design based on huAbl3VH.l andcontains 9 proposed ork back-mutation(s): S25T, P40F, K43N, I48M, V671, T68S,V7lR, S79F, R94G.0 Humanized Abl3 VH. lb (huAbl3VH. lb) is an intermediate design between on huAbl3VH.land huAbl3VH.la and contains 4 proposed framework back-mutation(s): K43N, I48M, V671,V7 1 R.0 Humanized Abl3 VL.l (huAbl3VL. l) is a CDR-grafted, humanized Abl3 VL containing40 IGKVl-39*01 and IGHJ6*01 ork sequences.

MEl 24985843V.1 740117813-126200 Humanized Abl3 VL.la (huAbl3VL. la) is a humanized design based on huAbl3VL.l andcontains 4 proposed framework back-mutation(s): A438, L46A, T85E, Y87F.0 Humanized Abl3 VL.lb (huAbl3VL.lb) is an intermediate design between on huAbl3VL.land huAbl3VL.la and contains 1 proposed framework back-mutation(s): Y87F.

The variable region and CDR amino acid sequences of the foregoing are described in Table18 below.

Table 18: Amino acid variable re ion se uences of humanized Abl3Amino Acid SequenceSPSSLSASVGDQVTZTVGFNVAWYQQ<?GKAPKLL:YSASYRYSGV?SQFSGSGSGTDFTWTusstPVDFATYYCQQYNWYPFTEGQGL<R£ KResidues 24—34 KASQNVGFNVA’ '. 3 NO: :.4SASYRYS.-DIQMTQSPSSLSASVG: DRVTITCKASQNVGFNVAWYQQ<?GKSPKAL:YSASYRYSGV?SRFSGSGSGTDFTRT"SSRQP£DEA£YECQQYNWYPFTEGQG1<14 <Residues 24—34 KASQNVGFNVAV '- 3 NO2 :_ A ,' ' SASYRYSI 89—97 QQYNWYPFT4Q 3 NO:;44||||||||||ii{ fiVQRQfiSGPGKVKPSVTKSKTCAVSGYSITSGYSWHWIRQPPGKGlfiw GYIHSSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAYCARYDDYFEYWGQGTTVTVSSGYSITSGYSWH, R—Hl 'Residues 26—36o: S41Q D NO:146YIHSSGSTNYNPSLKS, R—HZ es 51—66MEl 24985843V.1 741117813-12620Amino Acid Sequencew 0" YDDYFEY:QMTQSPSSLSASVGDRVTITCKASQNVGFNVAWYQQ<?GKAPKLL IYSASYRYSGV?SRFSGSGSGTDFTT.T"SSTQPRDFATYFCQQYNWYPFTEGQGL {Tut K(A) \l Residues 24—34 KASQNVGFNVA’ '- 3 NO: LA(A) OO ' ' S(A) k0 QQYNWYPFTfiVQKQfiSGPGKVKPSVTKSKTCITSGYSWHWIRQFPGNGLEWMGYIHSSGSTNYNPSLKSR S SRDiSKNQEFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSS(A) (A) Residues 26—36 GYSITSGYSWH’ '- ,7 NO: 2.

(A) uh ' ' YIHSSGSTNYNPSLKS(A) (J‘I YDDYFEY|—‘ uh OO fiVQKQfiSGPGKVKPSVTKSKTCAVSGYSITSGYSWHWIRQPPGNGLEWMGYIHSSGSTNYNPSLKSR i NQESLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSS(A) (A) Residues 26—36 GYSITSGYSWH’ '- ,7 NO: 2.

(A) uh ' ' YIHSSGSTNYNPSLKS(A) (II YDDYFEYMEI 24985843V.1 742117813-12620Example 18: Generation of huAb13 variantsThe 3 VH and 3 VL region amino acid sequences of humanized Ab13 variants described inTable 18 were paired er to generate 9 huAb13 variants described in Table 19. The full lengthamino acid sequences of the heavy chain and light chain of the huAb13v1 variant, huAb13v1 areprovided in SEQ ID NOs: 168 and 169, respectively.

Table 19: Variable re ion se uences of en ineered huAb13 variantsClone ' Residues Amino acid sequence147 huAblel SGPGWVKPSVTWSWTCAVTGYSITSGYSWHW:RQF?GNGLEWGYIHSSGSTNYNPSLKSR S SRFFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSSo.) (A) huAb C R—Hl Residues 2 6— 36 GYSITSGYSWH* '. ,, NO : Z.

(A) - ,_ YIHSSGSTNYNPSLKS7 2—142(A) (II144 huAb HQMTQSPSSLSASVGDRVTFNVAWYQQKPGKSPKAL:YSGVPSQFSGSGSGTDFTT. T" SST.QP *iDb'AfiYb'CQQYNWYPFTbGQGiKT37 huAb ', 'Residues 2 4—34 KASQNVGFNVA, -. 3 NO : :_ A ,(A) 00(A) rI r QQYNWYPFThuAb13v2 fiVQTQfiSGPGTVKPSVTTSTTCAVSGYSITSGYSWHW:RQP?GKGLEW:: GYIHSSGSTNYNPSLKSRVT :: svDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSS(A) (A) Cf Residues 26—36 GYSITSGYSWH* '.

, NO:Z_rU) as ,- ,_ YIHSSGSTNYNPSLKS(A) VI V— YDDYFEYMEI 24985843v.1 743117813-12620Clone 'L Residues Amino acid sequence143 huAbl3v2 DIQMTQSPSSLSASVGDRVTITCKASQNVGFNVAWYQQKPGKAPKLL:YSASYRYSGVPSRFSGSGSGTDFTT.T"SST.QP7DFATYYCQQYNWYPFTbGQGiKT(A) hUAb" OVfH|_\ Residues 24— 34 KASQNVGFNVAo: S41Q 3 N034(A) 00 OVfHN(A) k0 hUAb O v Residues 89— 97 QQYNWYPFTD NO: 143huAb13v3 *VQTQ4SGPGTVKPSTTTSTTCAVSGYSITSGYSWHWIIRQP'9GKGLEWIIGYIHSSGSTNYNPSLKSRVTIISVDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVS s(A) (A) huAb__ OVfm|—‘ es 2 6— 36 GYSITSGYSWH* 1, NO:;rOVfmN - ,_ YIHSSGSTNYNPSLKS(A) (II OVfm (A) YDDYFEY144 huAbL3V3 <L—' HQMTQSPSSLSASVGDRVTASQNVGFNVAWYQQKPGKSPKAL:YSASYRYSGVPSQFSGSGSGTDFTT. T" SST.QP *ZDb'AfiYb'CQQYNWYPFTbGQGiKT37 liiiiilllll OvfH H Residues 24—34 KASQNVGFNVA* '. 3 N034(A) 00 llll OufHN ' '— S(A) k0 llll{OufHw QQYNWYPFT146 huAb < fiVQTQfiSGPGTVKPSTTTSTTCAVSGYSITSGYSWHWIRQP?GKGLEW:GYIHSSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSShuAb13v4 CDR—H1 Residues 26— 36 GYSITSGYSWHO: SfiQ D NO:146MEI 24985843V.1 744117813-12620Residues Amino acid sequence(A) »J> es 51—66 YIHSSGSTNYNPSLKS’ 1, NO:;r(A) (II ' ' YDDYFEYDIQMTQSPSSLSASVGDRVTII :TCKASQNVGFNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFT1T"SSRQPRDFATYFCQQYNWYPFKlfi KResidues 24—34 KASQNVGFNVA’ 1 3 N02;4(A) 00 ' ' SASYRYS(A) k0 QQYNWYPFTfiVQRQfiSGPGKVKPSRTKSKTCAVTGYSITSGYSWHWIRQF?GNGLEWGYIHSSGSTNYNPSLKSR S SRDTSKNQFFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSSResidues 26—36 GYSITSGYSWH’ 1, NO:;r' ' YIHSSGSTNYNPSLKSDIQMTQSPSSLSASVGDRVTI3 :TCKASQNVGFNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFT1T"SSRQPRDFATYYCQQYNWYPFTEGQGiKlfi KResidues 24—34 KASQNVGFNVA’ 1 3 N02;4' ' SASYRYSQQYNWYPFTMEI 24985843V.1 745-12620Clone 'L Residues Amino acid ce147 huAbl3V6 fiVQLQfiSGPGLVKPSVTLSLTCAVTGYSITSGYSWHWIRQF?GNGLEWGYIHSSGSTNYNPSLKSR S SRDTSKNQFFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSSw (A) huAb__ C V Residues 2 6— 36 GYSITSGYSWH* 1, NO:;r(A) '- ,_ STNYNPSLKS(A) (II145 huAbL3V6 <L—' HQMTQSPSSLSASVGDRVTASQNVGFNVAWYQQKPGKAPKLL:YSASYRYSGVPSRFSGSGSGTDFTT.T"SSTQPTDFATYFCQQYNWYPFTbGQGiKT37 liiiiilllll OVf L—' H Residues 24—34 KASQNVGFNVA’ 1 3 N02;4Iiiiilllll OVf L—' N ' '— SASYRYShuAbL3V6 OVf L—' m QQYNWYPFT148 huAbL3v7 < #4 fiVQLQfiSGPGLVKPSVTLSLTCAVSGYSITSGYSWHWIRQP?GNGLEWGYIHSSGSTNYNPSLKSR 1 SRDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSS3:IiiiilllllchuAb13v7 vfm H Residues 26—36 GYSITSGYSWH’ 1, NO:;rOVfmN ' '— YIHSSGSTNYNPSLKS(A) llllVLOVfmw YDDYFEY143 huAb IQMTQSPSSLSASVGDRVTASQNVGFNVAWYQQKPGKAPKLL:YSASYRYSGVPSRFSGSGSGTDFTT.T"SSTQPTDFATYYCQQYNWYPFTbGQGiKThuAb13v7 CDR—L1 Residues 24- 34 KASQNVGFNVAD NO. 143MEI 24985843V.1 746117813-12620Iiiiiillll ; Residues Amino acid sequencew m huAbL3v7 Residues 50—56 SASYRYSD NO:L Z,(A) k0 huAbL3v7 QQYNWYPFT148 huAbL3v8 fiVQTQfiSGPGTVKPSRTTSTTCAVSGYSITSGYSWHW:RQP?GNGLEWGYIHSSGSTNYNPSLKSR 1 SRDTSKNQFSLKLSSVTAA DTAVYYCARYDDYFEYWGQGTTVTVSS(A) (A) huAbL3v8 es 26—36 GYSITSGYSWHNO:;r4Iiiiilllll YIHSSGSTNYNPSLKS(A) Iiiiilllll YDDYFEY144 huAbL3v8 PSSLSASVGDRVTASQNVGFNVAWYQQKPGKSPKAL:YSASYRYSGVPSRFSGSGSGTDFTT. T" SST.QP fiYb'CQQYNWYPFTbGQGiKT37 liiiiilllll Residues 24—34 KASQNVGFNVAD NO:L Z,(A) Iiiiilllll SASYRYS(A) k0148IiiiilllllvhuAb13v9 QQYNWYPFTfiVQTQfiSGPGTVKPSVTTSTTCAVSGYSITSGYSWHW:RQP?GNGLEWGYIHSSGSTNYNPSLKSR 1 SRDTSKNQFSLKLSSVTAA DTAVYYCARYDDYFEYWGQGTTVTVSS(A) Iiiiilllll C Residues 26—36 GYSITSGYSWHNO:;r(A) 4Iiiiilllll STNYNPSLKS(A) Iiiiilllll YDDYFEYMEI 24985843V.1 747117813-12620Clone ''- Residues Amino acid sequence145 huAbl3v9 VL DIQMTQSPSSLSASVGDRVTIITCKASQNVGFNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFTT.T"SSTQPTDFATYFCQQYNWYPFTb'GQGlKTm:Residues 24—343 NO : :.4Example 19: Characterization of huAb13 VL.1a Humanized VariantsNine huAbl3 variants described in Examples 17 and 18 were generated and tested for bindingto B7-H3 by FACS (according to s described in Example 6). Six variants did not bind tohuman B7-H3. The remaining three variants were further characterized for g by SPR andconjugated (via Method A) to the Bcl—xL inhibitor (specifically the linker warhead (0r n) CZ)and assessed for cell xicity (according to methods described in Example 7). Table 20 providesthe in vitro characteristics of these variants.

Table 20: In vitro terization of huAbl3 VL.la variants con‘u ated to s nthon 0r linkerpayload) CZAffinity of Cytotoxicitynaked H847 CellmAbs line IC50)(Biacore,6 6.2HuAbl3vl was selected for further study due in part to its potent and superior cytotoxicityagainst H847 cells and similar binding teristics as chAbl3 from which it was derived. Incontrast, huAbl3v5 and huAbl3v6 showed poor fit kinetics in Biacore experiments ting theirbinding properties are more divergent from the parental chAbl3 than huAbl3vl and have reducedactivity in the cell killing assay.

MEl 24985843V.1 748117813-12620Example 20: In vitro potency of Selected Humanized B7-H3 dies with Exemplary Bcl-xLInhibitor Linker Warheads (Synthons)Humanized antibodies huAb13v1, huAb3v2.5 and huAb3v2.6 were selected to be conjugatedwith several Bcl-xL inhibitor payloads (0r synthons) at a 3 mg scale using Methods A, E or G, asdescribed in Example 7. The anti-tumor activity of these ADCs was tested in cytotoxicity assaysusing the NCI-H1650 non-small cell lung cancer cell line as described in Example 7. As control, thein vitro anti-tumor activity of ADCs comprising the non-targeting antibody MSL109 (a monoclonalantibody that binds to the CMV glycoprotein H conjugated to Bcl-xL inhibitor payloads (0r synthons)was also evaluated. The s are bed in Table 21.

Table 21: In vitro tumor cell c totoxicit of selected humanized B7-H3 ADCs with exem lar Bcl-sinhibitorxL linker warheads nthonsation DAR by MS %agg byMethod SEChuAb13V1CZhuAb13V1TXhuAb13V1TVhuAb13V1AAAhuAb13V1-AA!)huAb13V1WE)CDJ>FHCDCDCDCDCDCDJ>H1>J>CDCDCD>MEI 24985843V.1 749-12620MSL10§~XWMSL109~$EMSL109-SRMSL109-VGMSL109—K2In contrast to the low anti-tumor activity exhibited by the ADCs comprising the non-targetingantibody MSL109 conjugated to a Bcl-xL inhibitor d, the B7-H3-targeting ADCs exhibitedgreater tumor cell killing, which reflects the antigen-dependent delivery of the B7-H3-targeting ADCsto the B7-H3-expressing tumor cells.

The anti-tumor actiVity of two of these ADCs was tested in cytotoxicity assays using the NCI-H146 small cell lung cancer cell line as described in e 7. The results are described in TableMEl 24985843V.1 750-12620Table 22: In vitro tumor cell c totoxicit of selected humanized B7-H3 ADCs with exem lar Bcl-xL inhibitor synthons.

ConjugationMethodhuAbl3v1—AAA E2 and huAb13v1—WD E2 were tested for cytotoxicity using H146cells. Both conjugates show potent and comparable cytotoxicity.

Example 21: In vivo is of anti-B7-H3 ADCsHumanized anti-B7-H3 antibodies huAbl3vl, huAb3v2.5 and huAb3v2.6 were selected to beconjugated with several Bcl-xL inhibitor payloads and were evaluated in xenograft models of smallcell lung cancer (H146) as conjugates using a number of Bcl-xL inhibitor warheads (synthons) usingthe s described in Example 7 and Example 8. The results are summarized in Table 23 andTable 24.

Table 23: In vivo efficac of zed anti-B7-H3 ADCsConjugation. . Dose[a]lroute/ Number TGImaxADC DAR TGD (%)Method regimen of mice (%)————nnn—n———lmn[a] dose is given in mg/kg/dayTable 24: In vivo efficac of zed anti-B7-H3 ADCsConjugation Dosem/route/ Number ofADC DAR TGImaX ( %)Method regimen micehuAb3v2XW 6mg/kg/IP/QDx1“—huAb l 3vl-AAA 6ng“—MEl 24985843v.1 751117813-12620Conjugation. . Dose[a]Iroute/ Number ofADC DAR TGImax (% )Method regimen mice[a] dose is given in mg/kg/dayHumanized anti-B7-H3 antibody vl was conjugated with the Bcl-xL torsynthon WD and evaluated in a xenograft model of the B7-H3 -positive small cell lung cancer(H1650) as conjugates using the methods described in Example 7 and Example 8. As control, the invivo anti-tumor activity of a non-targeting IgG isotype matched dy (AB095) was also evaluated.

The results are summarized in Table 25.

Table 25: In vivo efficac of humanized anti-B7-H3 ADC huAbl3vl-WD in H1650DAR/ route/. . DoseADC Conjugatlo .reglmen TGImax (%) TGD (%)mgfl<g/dayn Method4095* ———-_-_huAb13v1-WD-E2 2/1 46* 47*huAb13v1-WD-E2 2/1 48* 47*huAb13v1-WD-E2 2/1 62* 77*(*0 IgGl mAb= p < 0.05 as compared to control treatment )= p < 0.05 as compared to the most active partner in a drug combinationNA. = not applicableIn contrast to the lack of ty observed using the non-targeting IgG isotype-matchedantibody Ab095, the B7-H3-targeting Bcl-xL ADCs exhibited tumor growth inhibition (TGI) andtumor growth delay (TGD), as shown in Tables 24 and 25, reflecting the antigen-dependent deliveryof the B7-H3 -targeting ADCs which deliver the Bcl-xL inhibitor to the B7-H3 -expressing tumor cellsin this xenograft mouse model. As an additional l, the in vivo umor activity of ADCscomprising the non-targeting antibody MSL109 conjugated with Bcl-xL inhibitor synthons wasevaluated in the xenograft model of the B7-H3-positive small cell lung cancer ). The activityof these ADCs was compared that of the non-targeting IgG isotype matched antibody, AB095, ascontrol. As shown in Table 26, the ADCs comprising the non-targeting antibody MSL109 conjugatedwith Bcl-xL inhibitor synthons exhibited very modest tumor growth inhibition and low or no tumorgrowth delay. In contrast, the B7-H3-targeting Bcl-xL ADCs (as shown in Table 25) exhibited, muchgreater tumor growth inhibition (TGI) and tumor growth delay (TGD), reflecting the antigen-dependent delivery of these ADCs to expressing cells in this mouse aft model.

MEl 24985843v.1 752117813-12620Table 26. In vivo efficac of non-tar etin MSL109 BCL-XL inhibitin ADCs in NCI-H1650 modelOf NSCLCGrowthInhibitionTreatment Dose[“]/route/regimen TGImax TGD(%) (%)18* nT Non-targeting antibody3] dose is given in mg/kg/day= p < 0.05 as compared to control treatment (AB095)Q4DX6 indicates one dose every 4 days for a total of 6 dosesExample 22: B7-H3 Combination TherapyThe umor ty of v1 as CZ or TX conjugates as purified DAR2 (E2)conjugates were characterized in aft models of non-small cell lung cancer (H1650, H1299,H1975, and EBCl) of human origin using the methods described in Example 8. The anti-tumoractivity was assessed as monotherapy and in combination with docetaxel (H1650, H1299, H1975, andEBCl). The results are presented in Table 27.

Table 27: In vivo efficac of humanized huAb13v1 anti-B7-H3 con‘u ates as monothera and ination with docetaxelDAR/ route/ADC ConJugatlon. . Dose .regimen TGImax (%) TGD (%)mg/kg/dayMethod58 67huAb13v1-TX E2 Q4Dx6/IP+Q+Docetaxel 10+7 5. Dxl/IV 1 40 140AB095 ——-_huAb13v1-TX E2 2/1 ——m_ 24Docetaxel ———87 48huAb13v1-TX E2 2/I Q4Dx6/IP+Q+Docetaxel 10+7 5 Dxl/IV 97 83MEl 24985843v.1 753117813-12620DAR/ route/ADC Conjugation /Zay regimen TGImax(%) TGD(%)MethodNCI-H1975AB095 1—1 0 Q4Dx6/IPhuAb13V1-TX E2 1—1 0 IP 52Docetaxel \1 LI] QDXI/IV 81 \]O\ \INhuAb13V1-TX E2 Q4Dx6/IP+Q+Docetaxel 10+7.5 Dxl/IV 92NCI-H1650AB095 Q7Dx6/IPhuAb13V1-CZ _ 1 P 100Docetaxel >1 U] QDxl/IV 84 143QDxl/IP+QhuAb13V1-CZ +Docetaxel 10+7.5 Dxl/IV >600NCI-H1650huAb13V1-WD E2 2/1 10 113/ Q14DX3+ + + + 98*¥ >717*¥DTX) NA. 7.5 IV/Q14Dx3huAb13V1-WD E2 2/1 3 IP/ Q14DX3+ + + + 99*¥ >717*¥DTX) NA. 7.5 IV/Q14Dx3huAb13V1-WD E2 2/1 1 113/ Q14DX3+ + + + 88*¥ 467*¥DTX NA 7.5 IV/Q14Dx3huAb13V1-AAA E2 2/1 10 IP/ Q14DX3+ + + + 99*¥ >717*¥DTX NA 7.5 IV/Q14DX3huAb13V1-AAA E2 2/1 3 IP/ Q14DX3+ + + + 99*¥ >717*¥DTX NA 7.5 IV/Q14DX3huAb13V1-AAA E2 2/1 1 113/ Q14Dx3+ + + + 92*¥ >717*¥DTX NA 7.5 IV/Q14Dx3MEI 24985843V.1 754117813-12620DAR/ route/ADC Conjugation regimen TGImalx (%) TGD (%)mgfl<g/dayMethod(a) IgGl mAb= p < 0.05 as compared to control treatment (AB095)= p < 0.05 as compared to the most active partner in a drug combinationNA. = not applicableThe results presented in Table 27 demonstrate that above, huAbl3vl as CZ, TX, WD 0r AAApurified DAR2 (E2) conjugates inhibited the growth of all four NSCLC xenograft models asmonotherapy. In addition, huAbl3vl as CZ, TX, WD 0r AAA purified DAR2 (E2) conjugatesively combined with docetaxel to produce more sustained tumor growth inhibition. This is mostdramatically illustrated in the H1650 xenograft model where the combination therapy resulted in aTGD of n 467% and >7l7%, whereas the dual erapies ed in TGD in therange of 67% -l58%. These results support the clinical utility of Bcl-XL inhibitor (Bcl-XLi) ADCs tobe dosed in combination with chemotherapy.

MEl 24985843V.1 755117813-12620CE SUMMARYDescription Amino Acid SequencechAbZ VH amino acid sequence QVQLQQPGAELVKPGASVKLSCKASGYTFTSYWMHWVKQR?GQGR£WSGTTNYNEKFRSKATLTVAYMQLSSLTSEDSAVYYCAVYYGSTYWYFDVWGTGTTVTVSS2 chAbZ VH C311 amino acid sequence GYTFTSYWMH3 chAbZ VH C312 amino acid sequence IHPDSGTTNYWEKFRS4 chAbZ VH C313 amino acid sequence YYGSTYWYFDVchAbZ VL anino acid sequence TPLSL?VSLGDQAYISCRSSQSLVHINGNTYLHWYRQKPGQS?KLLIYKVSNRFSGVPDRFSGSGSGiDEiRK SRVfiAfiDRGVYFCSQSTHFPFTEGSG1<R£ KchAbZ VL CDRl amino acid sequence RSSQSLVHINGNTYLHchAbZ, chAbB, chAblO, huAbBVL.l,huAbBVL.la, huAbBVL.lb, huAb3v2.l,huAb3v2.2, huAb3v2.3, huAb3v2.4,huAb3v2.5, huAb3v2.6, huAb3v2.7,huAb3v2.8, and huAb3v2.9 VL CDRZ aminoacid ceeheez ve ceee eeee eeeeneee MChAb3 VH amino acid sequence QVQLQQPGAELVKPGASVKLSCKASGYTFSSYWMHWVKQR?GQGK%WGLIHPDSGSTNYNEMFKNKATLTVDRSSSTAYVQLSSLTSEDSAVYFCAGGGRLYFDYWGQGTTLTVSSH o 1Ab3, huAbBVH.l, huAbBVH.la, GYTFSSYWMHJAbBVH.lb, huAb3v2.l, huAb3v2.2,JAb3V2.3, huAb3v2.4, huAb3v2.5,JAb3V2.6, huAb3v2.7, huAb3v2.8, andJAb3V2.9 VH CD11 amino acid sequence\ 1Ab3, huAbBVH.L, huAb3VH.La, and LIHPDSGSTNYNEMFKNJAb3VH.lb VH CDRZ amino acid sequence1Ab3, huAbBVH.L, H.La, GGRLYFDYJAbBVH.lb, huAb3v2.l, huAb3v2.2,JAb3V2.3, huAb3v2.4, huAb3v2.5,JAb3V2.6, huAb3v2.7, huAb3v2.8, and.9 VH CDR3 amino acid ceME1 24985843V.1 756117813-12620a Description Amino Acid SequencechAb3 VL amino acid sequence TPLSL?VSLGDQAS"SCRSSQSLVHSNGDTYLRWYLQKPGQS?KLL__YKVSNRFSGVPDRFSGSGSGiDb'iLK iRVnAnDLGVYFCSQSTHVPYTEGGGi<Kfi KchAbB, huAbBVL.L, huAb3VL.La, and RSSQSLVHSNGDTYLRhuAbBVL.;b VL CDRl amino acid sequence, huAbBVL.L, huAb3VL.La, SQSTHVPYTL.;b, huAb3v2.l, huAb3v2.2,huAb3v2.3, huAb3v2.4, huAb3v2.5,huAb3v2.6, huAb3v2.7, huAb3v2.8, andhuAb3v2.9 VL CDR3 amino acid sequencechAb4 VH amino acid sequence QVQLQQPGAELVKPGASVKLSCKASGYSFTSYWMHWVKQR?GQGLKWGMIHPNSGSNNYNEKFKSKATLTVDKSSNTAYMQLSSLTSEDSAVYYCARRLGLHFDYWGQGTTLTVSSE:- chAbZ VH CD3K1 amino acid sequence GYSFTSYWMHchAbZ VH CDR2 amino acid sequenceu chAbZ VH CK3 amino acid sequence RLGLHFDYN O nino acid sequence MVMTQSQ<FMSTPVGDRVSASQNVGTAVAWYQQKPGQSPKLL_ZYSASNRYTGVPDKFTGSGSGTDFTLTISNMQSEDLADYFCQQYSSYPYTEGGGiKKfi KchAbZ VL CDR1 amino acid sequence GTAVAchAbZ VL CDR2 amino acid sequence SASNRYT23 chAbZ VL CCK3 amino acid sequence QQYSSYPYTN »J> ChAblB VH anino acid sequence QVQLQQSAAELARPGASV<MSCKASGYSFTSYTIHWVKQR9GQGT.*‘WGYINPNSRNTDYNQKFKDETTLTAQSSSTAYMQL SLiSfiDSAVYYCKYSGSTPYWYFDVWGAGTTVTVSN (J‘I 2.8, huAb’8VH.’, huAblBVH.la, and YTIH;8VH.lb VH CDRl amino acid sequence26 ChAbLB, huAb’BVH.’, and huAblBVH.la VH YINPNSRNTDYNQKFKDCDRZ amino acid sequenceN \] 2.8, huAb’8VH.’, VH.la, and YSGSTPYWYFDVZ.8VH.lb VH CDR3 amino acid sequence—MEI 24985843V.1 757-12620Description Amino Acid SequencechAb18 VL amino acid sequence Q VliQS?A KSAS?GEKVTMTCRASSSVSYMNWYQQK?GSSPKPWIYATSNLASGVPARFSVSVSGTSHSLi SRVfiAfiDAAiYYCQQWSSNPLTFGAGT<LELKN k0 lAbLB, huAblBVL.L, huAblBVL.la, RASSSVSYMNJAbLBVL.lb, huAbLBVL.2, andJAb’8V1.?a, V1 CDR1 amino acidequenceIIIII(A) lAbLB, huAblBVL.L, huAblBVL.la, ATSNLASJAbLBVL.lb, huAbLBVL.2, andJAb’8V1.?a, V1 CDR? amino acidequenceIliill ClAbLB, huAblBVL.L, huAblBVL.la, PLThJAbLBVL.lb, VL.2, andh iAb;8VL.2a, VL CDR3 amino acidS equenceIliill L3 VH amino acid sequence SGPDLVKPSQSLSLTCTVTGYSITSGYSWHW:RQF9GNKLGSTNYNPSLKSR S WRDTSKNQFFLQLNSVTT.ZDTATYYCAGYDDYFEYWGQGTTLTVSSIliil L3, huAblBVh.L, hJAbLBVh.la, ITSGYSWH;3Vh.lb, huAb;3vl, huAbleZ,L3v3, huAbL3v4, hJAb;3V5, huAb13v6,L3v7, huAbL3v8, aid huAbl3v9 VHamino acid ceIIIII(A) lAbL3, huAblBVh.;, hJAbLBVh.la, :HSSGSTNYNPSLKSiAbLBVh.lb, huAbLBvl, huAbleZ,JAbL3v3, v4, hiAbL3v5, huAbl3v6,7, huAbL3v8, and huAb13v9 VH3R2 amino acid sequelce(A) (II ;3, huAblBVh.;, hJAb;3Vh.la,;3Vh.lb, huAb;3vl, huAbleZ,L3v3, huAbL3v4, hJAb;3V5, huAb13v6,L3v7, huAbL3v8, aid huAbl3v9 VHamino acid sequelce(A) OW ;3 VL amino acid sequence DIVMTQSQ<FMSTSVGDRVSVTCKASQNVGFNVAWYQQKPGQSPKALIYSASYRYSGVPDRFTGSGSGTDFTLTISNVQS%DRA%YECQQYNSYPFTEGSGiKm: KMEI 24985843V.1 758117813-12620Description Amino Acid ce(A) \] L3, huAblBVL.1, hJAbL3VL.1a, KASQNVGFNVA13VL.1b, v1, huAb13v2,13v3, huAb13v4, hJAb13v5, huAb13v6,13v7, huAb13v8, aid huAb13v9 VLamino acid ceIlill 13, huAblBVL.1, hJAbL3VL.la, SASYRYS13VL.1b, huAb13v1, huAb13v2,13v3, huAb13v4, hJAb13v5, v6,13v7, huAb13v8, aid huAb13v9 VLamino acid sequelce(A) k0 L.1, huAblBVL.la, huAbl3VL.1 QQYNWYPFTJAb13v1, huAb13v2, huAb13v3, huAbZJAb13V5, huAb13v6, huAb13v7, huAbL1d huAb13v9 VL CDR3 amino acidequence.J> O 1Ab12 VH amino acid ce fiVQRVfiSGGGRVK1GGSLKLSCAASGFTFSSYAMSWV1Q1?£KRR£WVATISSGTNYTYYPDSVKGRFTISRDNAKNTLYLQMTSLRSEDTAMYYCARQGRYSWIAYWGQGTLVTVSAl\ NH chAbLZ VH C311 amino acid sequence GFTFSSYAMSchAbLZ VH C312 amino acid sequence TISSGTNYTYYPDSVKG(A) chAbLZ VH C313 amino acid sequence QGRYSWIAYg nino acid sequence DIVLTQSPASLAVSLGQRATISCRASKSVSTSDYSYMHWNQQKPGQPPKLLIYLASNLESGVPARFSGSGSG1DE11N HPVfififiDAAiYYCQHSRELLTFGAGTKLELKmm chAbLZ VL C311 amino acid sequence RASKSVSTSDYSYMHchAbLZ and c1Ab17 VL CDRZ amino acid LASNLES\] chAbLZ VL C313 amino acid sequence QHSRELLTa nino acid sequence fiVKRVfiSGGGRVK1GGSLKLSCAASGFTFSSYGMSWV1Q1?£KRR£WVATISGGGTNTYYPDSVEGRFTISR3NAKNFLYLQMSSLRSE3TALYYCARHYGSQTMDYWGQGTSVTVSS49 chAbLi 1Ab8 VH CDR1 amino acid GFTFSSYGMSsequer50 ChAbLL 12 amino acid ce TISGGGTNTYYPDSVEG51 chAbLA 13 amino acid sequence HYGSQTMDYMEI 24985843V.1 759117813-12620Description Amino Acid Sequence2 chAb14 VL amino acid sequence DIQMTQS?ASLSASVG%1V1 1CRTSGNIHNYLTWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQFS1K"NSRQ?1DFGSYYCQHFWSIMWTEGGGLKRfi K-53 chAbLi VL C311 amino acid sequence RTSGNIHWYLT-54 chAbZr_Z VL C312 amino acid ce NAKTLAD-55 chAbZr_Z VL C313 amino acid sequence MWChAb6 VH amilo acid sequence QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQR?GHGK%WGEILPGSGSTNYNEKFKGKATFTADTSSNTAYMQVSSLTSEDSAViYCARRGYGYVPYALDYWGQGTSVTVS-57 chAb6 VH C311 amino acid sequence YW %-58 chAb6 VH C312 amino acid sequence EILPGSGSTNYNEKFKG59 chAb6 VH C313 amino acid sequence 1GYGYVPYAL3YI chAb6 VL anino acid sequence % QMLQLLSSLSASLG3RVTISCRASQDISNSLNWYQQKP3GTVNLL:YSGV?SRFSGSGSGTDYSm1 SNEfiQfiD AiYECQQGNTLPYTEGGG1<Rfi <-61 chAb6 VL C311 amino acid sequence RASQDISNSLW-62 chAb6 VL C312 amino acid sequence YTSRLYS-63 chAb6 VL C313 amino acid ce QQGNTLPYTchAbll VH anino acid sequence fiVKRVfiSGGGRVQ?GGSL1LSCATSGFTFTNYYMSWV1QP?G<ALEWLGFIRNKANDYTTEYSASVKGRFT:SRDNSQS"RYKQMWTR1A1DSATYYCARESPGNPFAYWGQGTLVTVSA-65 chAb” VH C711j amino acid sequence GFTFTNYYMSm chAb” VH C,12j amino acid sequence FI1NKAN3YTTEYSASVKG-67 chAb” VH C313 amino acid ce T ?GNPFAYnino acid sequence 3IVMTQS?SSLTVTAGEKVTMTCKSSQSLLNSGTQKNFLTWYQQKPGQ1P<LLIYWASTRESGV1DRFTGSGSGTDFTLTISSVQAIDLAVYFCQN_‘4ADYIYPLTFGAGTKLIL<_‘4Am chAb11 VL CDR1 amino acid sequence KSSQSLLNSGTQKNFLTMEI 24985843V.1 760117813-12620Mine ACid sequence-70 chAb” V1 C312 amino acid ce WASTRES-71 chAb” V1 C313 amino acid sequence QNDYIYPLTnino acid sequence fiVKREfiSGGGRVQ1GGSLKLSCAASGFDFSRYWMSWV1QA1GKGR£WSSTINYTPSLKDKE SRDNAKNTLYLQMSKVRSEDTALYYCARPGFGNYIYAMDYWGQGTSVTVS-73 chAb16 VH C311 amino acid sequence GFDFSRYWMS-74 chAb16 VH C312 amino acid sequence % NPDSSTINYTPSLK3-75 chAb16 VH C313 amino acid sequence IYAM3Ynino acid sequence VIQMTQTTSSLSASLG3RVTINCR3:ASQDISNFLNWYQQKPDGTVKLL:YYTSRLYLGV?SRFSGSGSGTDYSmi SNEfiQfiD AiYECQQGNTLPPTEGGG1<11 <-77 chAb16 VL C311 amino acid sequence SNFLW-78 chAb16 VL C312 amino acid ce YTSRLYL-79 chAb16 VL C313 amino acid sequence QQGNTLPPTnino acid sequence 3VQLQESGPGLVKPSQSLSLTCTVTGYSITSDYAWNWIRQF?GNRLEWGHINYSGITNYNPSLKSR S 1RDTSKNQFFLQLYSVTTEDTATYFCARRSLFYYYGSSLYAMDYWGQGTSVTVSS-81 chAbLO VH C311 amino acid sequence GYSITSDYAWN-82 chAbLO VH C312 amino acid sequence { NYSG 1NYN?SLKS-83 chAbLO VH C313 amino acid sequence 1SLFYYYGSSLYAMDYnino acid sequence 3VVMTQSPFSL1VSLG3QASISCRSSQSLVHSNGNTYLHWYLQKPGQS1KLLIYKVSNRFSGVP3RFSGSGSG1DE11K SRVfiAfiDRGVYFCSQSTHVPWTEGGG1<K 41K-85 chAbLO VL C311 amino acid sequence 1SSQSLVHSNGWTYLHm chAbLO VL C313 amino acid sequence SQSTHVPWTOO \] chAb7 VH amilo acid sequence fiVQRVfiSGfiNRVKPGGSLKLSCAASGFSFRGYGMSWVRQT?3KRLEWVAAISTGGNYTYYPDSVQGRFTISRDNANNTLYLQMSSLKSEDTAMYYCYAGFAYWGQGTLVTVSA88 chAb7 VH C311 amino acid sequence GFSFRGYGMSchAb7 VH C312 amino acid sequence AISTGGNYTYYPDSVQGchAb7 VH C313 amino acid sequence RGGNYAGFAYMEI 24985843V.1 761117813-12620Description Amino Acid Sequencek0 |—‘ chAb7 VL amino acid sequence DTQ LSVSVG4'1V1 iCRPSENIYSNLAWYQQKQGKSPQLLVYAATNLADGVPSRFSGSGSGTQYSRK'WSTQSTDFGTYYCQHFWGTPFTb'GSGiKlfi K92 chAb7 VL C3391 amino acid sequence RPS4' SWT.A93 chAb7 and mm; VL cm amino acid94 chAb7 VL C393 amino acid ce QHFWGT9Fk0 (II chAb8 VH anino acid sequence fiVKRVfiSGGGRVK9GGSLKLSCAASGFTFSSYGMSWV9Q19£KRR£WVATISGGGNYTYCPDSVKGRFTTSRDNAKNWLYLQMSSLRS_33TALYYCTRQRGYDYHYAMDFWGQGTSVTVSchAb8 VH C3392 amino acid sequence TTSGGGNYTYCPDSVKG97 chAb8 VH C93 amino acid sequence MRGYDYHYAMchAb8 VL anino acid ce ASENIYSNLAWHQQKQGKS9QLLVTQSPASLSVSVG4'1V1 iCRADGV9SRFSGWGS3TQYSEKTWSRQS9DFGSYFCQNFWGTSWKKfi <chAb8 VL C391 amino acid sequence 9AS£N YSWRAchAb8 VL C393 amino acid sequence QNFWGTSWT:\ O |_| chAbl7 VH anino acid sequence fiVKRVfiSGGGRVQ9GGSLKLSCAASGFTFSSYIMSWV9Q19£KRR£WVASIVSSNITYYPDSMKG9FTTWARNTYTQMSST<S4.3TAMYYCA9SGTRAWFAYWGQGTLVTVSA:\l\l\l\ R1 amino acid sequence GFTFSSYT392 amino acid sequence VSSN iYYPDSMKG,93 amino acid sequence SGTRAWFAYO (II nino acid sequence MVLTQSPASLAVSLGQRAT SCRASKSVSTSAYSYMHWYQQKPGQPPKLLTYLASNLESGVPARFSGSGSGiDb'iT.N HPVfifi4'DAAiYYCQHSRELPYTb'GGGi .% K,91 amino acid sequence RASKSVSTSAYSYMHII ,93 amino acid sequence QHSRELPYTMEI 24985843V.1 762117813-12620Description Amino Acid SequenceChAbS VH amino acid sequence QVQLQQPGDELVKPGASVKLSCKTSGYTFTTDWMHWVKQR?GQGK%WGMIHPNSGTTNYNEKFKSKAALTVDKSSSTACMQLSSLTSEDSAVYYCWYFDVWGTGTTVTVSSchAbS VH CD3K1 amino acid sequence GYTFTTDWMHchAbS VH CD3K2 amino acid sequence HPNSGTTNYNEKFKS\ \ chAbS VH CK3 amino acid sequence SYWKWYFD\ \ \) chAbS VL anino acid ce ASSSVSYMHWYQQKSGTSPKLL__YWVTLQS MSASTG iTiCSSTSNLASGVPSKFSGSGSGTFYSLi DSADYYCHQWTSYMYTJ: 'GGGi<lfi K3 chAbS VL CD3K1 amino acid sequence SASSSVSYMHchees m ce2 eeie eeeeneee mchAbS VL CDK3 amino acid sequence HQWTSYMYThuAblBVH.l,huAb18vl, and huAb18v5 VH TVQTVQSGATVKK9GSSVKVSCKAamino acid sequence SGYSFTSYTIHWVKQA9GQGLEWMGYINPNSRNTDYNQKFKDRVTITADKSTSTAYMKRSSRRSKDTAVYYCARYSGSTPYWYFDVWGQGTTVTVSL8VH.la, huAb18V3, V8, and KVQKVQSGAKVKK?GSSVKVSCKAL8v9 VH amino acid ce SGYSFTSYTIHWVKQA?GQGR£WGYINPNSRNTDYNQKFKDRTTLTA,KSTSTAYMKKSSKRSKDTAVYYCPYWYFDVWGQGTTVTVShuAbL8VH.lb, huAb18v2, huAb18v4, KVQKVQSGAKVKK?GSSVKVSCKAhuAbL8v6, huAb18v7, and huAblelO VH SGYSFTSYTIHWVKQA?GQGLEWMamino acid sequence GYINPNSRNTDYAQKFQGRVTLTADKSTSTAYMKKSSKRSKDTAVYYCARYSGSTPYWYFDVWGQGTTVTVS’b VH CDRZ amino acid sequence YINPNSRNTDYAQKFQGN O huAb’8V1.’, huAblel, and huAb18v2 VL DIQLTQS?SFLSASVGDRVTITCRamino acid sequence ASSSVSYMNWYQQKPGKAPKLLIYATSNLASGVPSRFSGSGSGTEFTLT"SSRQPKDFATYYCQQWSSNPLTEGQGiKRfi KMEI 24985843V.1 763117813-12620Description Amino Acid SequencehuAblBVL.la, v3, and v4 VL ?SFLSASVGDRVTITCRamino acid sequence SSSVSYMNWYQQKPGKSPK?WIYTSNLASGVPSRFSVSVSGTEHTL"SSKQPVDFATYYCQQWSSNPLT.fi KhuAblBVL.lb, huAb18v8, and huAblelO VL D- 9SFLSASVGDRVTITCRamino acid sequence ASSSVSYMNWYQQKPGKAPK?W"YATSNLASGVPSRFSVSGSGTEHTLT "SSKQPVDFATYYCQQWSSNPLTEGQGiKlfi KhuAblBVL.2, v5, and huAb18v6 VE 1 V11QS?DEQSV1?K%KV1 iCRamino acid sequence SSSVSYMNWYQQK?DQSPKLLIKTSNLASGVPSRFSGSGSGTDFTLNsm: fiJAAiYYCQQWSSNPLT.4'. KhuAblBVL.2a, huAb18v7, and huAb18v9 V1 9DEQSV1?K%KV1 iCRamino acid sequence SSSVSYMNWYQQK?DQSPK?W YTSNLASGV?SRFSVSVSGTDHTLNsm: fiJAAiYYCQQWSSNPLT.4'. <huAbBVH.l, huAval, and huAb3v4 VH VVQKVQSGA?VKK?GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVQQA?GQGLEWMGLIHPDSGSTNYNEMFKNRVTITADKSTSTAYMVKSSKRSVDTAVYYCARGGRLYFDYWGQGTTVTVSShuAbBVH.la, huAb3v3, and huAb3v6 VH SGA?VKK?GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVQQA?GQGK%WGLIHPDSGSTNYNEMFKNRATLTVDRSTSTAYVVKSSKRSVDTAVYFCAGGGRLYFDYWGQGTTVTVSShuAbBVH.lb, huAb3v2, and huAb3v5 VH SGA?VKK?GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVQQA?GQGK%WGLIHPDSGSTNYNEMFKNRATLTVDRSTSTAYMVKSSKRSVDTAVYYCAGGGRLYFDYWGQGTTVTVSSMEI 24985843V.1 764117813-12620Description Amino Acid SequencehuAb3VL.l, huAval, and huAb3v2 VL QSPLSL9V19G%9AS SCRamino acid sequence HSNGDTYLRWYLQKPGQS9QLL_YKVSNRFSGVPDRFSGSGSGiDb'iLK SRVfiAfiDVGVYYCSQSTHVPYTEGGGL<V£ KL.la and huAb3v3 VL amino acid DVVMTQSPLSL. 9Gfi9AS SCRsequence SSQSLVHSNGDTYLRWYLQKPGQS9QLL.YKVSNRFSGVPDQFSGSGSGiDb'iLK SRVnAfiDVGVYFCSQSTHVPYTEGGGL<V£ KhuAbBVL.lb, huAb3v4, huAb3v5, and DVVMTQSPLSL. 9Gfi9AS SCRhuAb3v6 VL amino acid sequence SSQSLVHSNGDTYLRWYLQKPGQS9QLL_YKVSNRFSGVPDRFSGSGSGiDb'iLK DVGVYYCSQSTHVPYTEGGGL<V£ KhuAb3v2.l, huAb3v2.2, and huAb3v2.3 VH 9VQLVQSGA9VKK9GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVRQA9GQGLfiwGLIHPWSGSTNYNEMFKNRATLTVDRSTSTAYM9LSSLRS9DTAVYYCAGGGRLYFDYWGQGTTVTVSS.32 2. huAb3v2.2, and huAb3v2.3 VH LIHPWSGSTNYNEMFKNCDRZ amino acid sequenceI (A) (A) huAb3v2.L, huAb3v2.4, and huAb3v2.7 VL 3:.VMTQSPLSL9VL9Gfi9AS SCRamino acid sequence SSQSLVHSSGDTYLRWYLQKPGQS9QLL_YKVSNRFSGVPDRFSGSGSGiDb'iLK SRVfiAfiDVGVYYCSQSTHVPYTEGGGL<V£ K.34 huAb3v2. l, huAb3v2.4, and huAb3v2.7 VL RSSQSLVHSSGDTYLRCDRl amino acid sequenceI (A) (II huAb3v2.2, huAb3v2.5, and huAb3v2.8 VL 3:.VMTQSPLSL9VL9Gfi9AS SCRamino acid ce SSQSLVHSNRDTYLRWYLQKPGQS9QLL_YKVSNRFSGVPDRFSGSGSGiDb'iLK DVGVYYCSQSTHVPYTEGGGL<V£ K136 huAb3v2.2, huAb3v2.5, and huAb3v2.8 VL RSSQSLVHSNRDTYLRCDRl amino acid sequenceMEI 24985843V.1 765117813-12620Description Amino Acid SequencehuAb3v2.3, huAb3v2.6, and huAb3V2.9 VL SPLSL?VL?G%?AS SCRamino acid sequence SSQSLVHSNQDTYLRWYLQKPGQS?QLLIYKVSNRFSGVPDQFSGSGSGiDEiKK SRVfiAfiDVGVYYCSQSTHVPYTEGGGL<V£ KL38 huAb3v2.3, huAb3v2.6, and huAb3v2.9 VL VHSNQDTYLRCDRl amino acid sequencehuAb3v2.4, huAb3v2.5, and huAb3V2.6 VH SGAVVKK?GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVRQA?GQGR£WGLIHPESGSTNYNEMFKNRATLTVDRSTSTAYMVKSSKRSVDTAVYYCYFDYWGQGTTVTVSS;VO huAb3v2.4, huAb3v2.5, and huAb3v2.6 LIHPESGSTNYNEMFKNVH CDRZ amino acid sequenceL7 huAb3v2.7, huAb3v2.8, and huAb3V2.9 VH VVQKVQSGAVVKK?GSSVKVSCKAamino acid sequence SGYTFSSYWMHWVRQA?GQGR£WGLIHPISGSTNYNEMFKNRATLTVDRSTSTAYMVKSSKRSVDTAVYYCAGGGRLYFDYWGQGTTVTVSS;42 huAb3v2.7, huAb3v2.8, and huAb3v2.9 VH GSTNYNEMFKNCDRZ amino acid sequence"BVL.1, huAbleZ, huAbleS, and DIQMTQS?SSLSASVGDRVTITCK;3v7 VL amino acid sequence ASQNVGFNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFT1T"SSRQ??DFATYYCQQYNWYPFKm: KL3VL.la, huAbl3vl, huAbl3V3, and S?SSLSASVGDRVTITCK;3v8 VL amino acid sequence ASQNVGFNVAWYQQKPGKSPKALIYSASYRYSGVPSQFSGSGSGTDFT1T"SSRQ?%DEA%YECQQYNWYPFTEGQGLKRZ K’3V1.1b, huAbl3V4, huAbl3v6, and D:QMTQS?SSLSASVGDRVTITCK;3v9 VL amino acid sequence ASQNVGFNVAWYQQKPGKAPKLLIYSASYRYSGVPSRFSGSGSGTDFT1T"SSRQ??DFATYFCQQYNWYPFTEGQGiKm: KMEI 24985843V.1 766117813-12620a Description Amino Acid Sequence.3VH.1, huAbl3v2, huAbl3v3, and fiVQRQfiSGPGRVKPSVTRSRTCAV.3v4 VH amino acid sequence SGYSITSGYSWHWZZRQP'9GKGLEW:GYIHSSGSTNYNPSLKSRVTISVDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSS.3VH.la, huAbl3vl, huAb13v5, and fiVQRQfiSGPGRVKPSVTRSRTCAV.3v6 VH amino acid ce TGYSITSGYSWHWZZRQF'?GNGLEWGYIHSSGSTNYNPSLKSR S SRDTSKNQFFLKLSSVTAADTAVYYCAGYDDYFEYWGQGTTVTVSS.3VH.lb, huAb13v7, v8, and fiVQRQfiSGPGRVKPSVTRSRTCAV.3v9 VH amino acid ce SGYSITSGYSWHWZZRQP'9GNGLEWGYIHSSGSTNYNPSLKSR 1 SRDTSKNQFSLKLSSVTAADTAVYYCARYDDYFEYWGQGTTVTVSS37—H3 amino acid sequence (human) LRRRGS?GMGVHVGAALGALWFCliGAlfiVQVPfiDPVVALVGTDATLCCSFS???GFSKAQ1NK"WQKTDT{QLVHSFAEGQDQGSAYANQTALF?DLLAQGWASL?LQQVQVADEGSF:QDFGSAAVSLQVAA?YSKI?W<DL??GDTVTITCSSY. fiVEWQDGQGV?LTGWVTTHQGLEDViSHLQVVLGAWG' ' DAHSSVTIT?QALVGTDASKAQKNK"WQTIQDQGSAYANQTAVADEG_ {DLQPGDT :TCS. fiVEWQDGQGV?LTGWVI GLFDVHSVLRVVLGA" ' ?VLQQDA'IALWVTVGLSR< KQSC414'. '.<1ALQPL<MEI 24985843V.1 767117813-12620Description Amino Acid Sequence) LRRRGS9GMGVHVGAALGALWFCLTGAL4'VQVPfiDPVVALVGTDATLCCSFS999GFSTAQTNL'WQLTDTNote: Fc seqience is underlined {QLVHSFAEGQDQGSAYANRTALF9DLLAQGW QLQRVQVADEGSF'DFGSAAVSLQVAA9YSK99GDT ITCSSYDGQGV9LTGWVTT{S__LRVVLGAWGDAHSSVTIT9Q.13PVVALVGTDASLAQLNL"WQTT_ 9DQGSAYAN9TA9DLLAQGW 9LQ9V' ,1SFTCFVS..9DFGSAAVSLQVAALSK9SMTL_E9W 9PGDT 'SY9GYPfiAfiVEWQDGQGVLTTSQMAWEQGLFDVHSVL'LVRWLGQ9MTFAAAGA9SVFLF9L _{WAKTK9911{QDWLWG I {CKVSNKALL1<i SKA<GQ'.9EPQVYTLLL1 TKNQVSLTCLVKGFYPS _. 9EWWY<TTPPVLDSFFLYSKLTVD<S9WQQGNVFSCSV{EALHNiYTQKSLSLSPGKMEI 24985843V.1 768117813-12620Description Amino Acid SequenceFusion) LRGWGG9SVGVCVRTALGVLCLCT.iGAV*'VQVSfiDPVVALVDTDATL9CSFS999GFSLAQKNK'WQKTDTNote: Fc seqience is ined <QLVHSFTEG93QGSAYSN9TALF9DLLVQGWASL9LQRV9VTDEGSYDFDSAAVSLQVAA9YSKF9W<DL9PGNMVTITCSSY. fiVEW<DGQGV9LTGWVTTI9GLFDVHSVL9VVLGANG9W} DAHGSVT:A7 9PC9A.‘9SVFLF9} L{QDWLWG I _<T:SKA<GQ'.'EPQVYTL}}TKNQVSLTCLVKGL'YPSESNGQ9EWVY<TTPPVLDSLYSKLTVD<S9WQQGNVFSCSVEALHN{YTQKSLSLSPGKTFGTWSWTFTVA"T.KGVQCGALE_*_AC)<}AUAD>"UIO'UHWAW>L*JC)<} LVGTDATLCCSFS9m LAQLNLIWQLTDT<QLVHSFH10DQGSAYAN9TALF9DLLAQG9LQ9V9VADLGSE1CEVS_JmAAVSLQVAA9YSK9S TLE.

VTITCSSYQGYPfiAZU10DGQGV9LTGWVTTSQ AW' Q< {S__L9VVLGAWGTYSCLVHQQDAHSSVTIT9Q9S9TGAV<1'UIO<}'T_12UC)UJC)'T_1"U<9%DPVVALVGTDATL9CSFSU _*_i' 'm "121 ST.AQT.NL"WQLTDT<QLV{m '91 H LJ C)9DQGSAYAN9TALF9DLLA::O C)WASL9LQ9V9VADEGSFTCFVSDFGSAAVSLQVAA9YSK9SMTLM 'U/U <DL9PGDTVTITCSSY9GYPEyw FWQDGQGV9LTGWVTTSQMAWM N10 LFDVHSVL9VVLGANGTYSCL< 9VLQQDAHGSVTITGQ9MTHiL A {MEI 24985843V.1 769117813-12620Description Amino Acid ce?FGKSWKFKVA"1KGVQCVEVQVIDPVVALVDTDATLQCSFS?E?GSLAQLNLIWQLTDT<QLVHSFTEYSNQTALF?DLLVQGWALQLQRVQViDjGSYiCEVSHQV'DSAAVSLQVAA?YSK?SMTL_‘,4A.

DLQPGNMVTITCSSYQGYPZAZWKDGQGV?LTGWVTTSQMAW3FDVHSVLQVVLGANGTYSCLVVLQQDAHGSVTITGQPLTFiiCynomolgus I LHRRGS?GMGVHVGAALGALWFCLiGALjVQVPjDPVVALVGTDATLQCSFS???GFSKAQ1NK"WQKTDT{QLVHSFTE QDQGSAYANQTALFGW QLQQVQVADEGSFTCFVSIQDFGSAAVSLQVAA?YSK?S TL7?W ??GDT LTCSSYQGYPfi fiVEWQDGQGA?LTGWVTTSQ AW'QGLFDViSVLQVVLGAWGTYSCLV?W?VLQQDAHGS i i?QQS?1GAV%VQV?%DPVVALVGTDATLQCSFSP??GFSKAQ1WK"WQKTDT<QLV{SFTEGRDQGSAYANQTALFLDLLAQGWASLQLQQVQVADEGSFTCFVIQDFGSAAVSLQVAA?YSK?SMTI?W<DLQPGDTVTITCSSYQGYP. fiVEWQDGQGA?LTGWVTTSQMAIQGLFDVHSVLQVVLGANGTYSCQW?VLQQDAHGSVTITGQ?MTFAiiHHiHHHAmino acid sequence Of 'GHV1—69*O6 SGAEVKK?GSSVKVSCKASGGTFSSYAISWVQQA?GQGLEWMGG P EGLANYAQKFQGRVTITADKSTSTAYMVKSSKRSVDTAVYYC156 Amino acid sequence 0’ 'GHJ6*Ol WGQGTTVTVSSMEI 24985843V.1 770117813-12620Description Amino Acid Sequence157 Amino acid sequence Of 'GKVT—9*OT DTQLTQS9SFLSASVGDRVTTTC9ASQGTSSYLAWYQQKPGKAPKLL:YAASTLQSGVPSRFSGSGSGT.EFTTT'SSTQ9TDFATYYCQQLNSYP9Amino acid sequence 0’: "GKJ7*01 FGQGT59 'g gamma—l constant region ASTKG9SVF9LAPSSKSTSGGTAALGCLV<DYF9_9VTVSWNSGALTSGViTF9AVLQSSGLYSLSSVVTV9SSSLGTQTYICWVNHK9SWT<VD<{VE 9KSCD {TCPPC9A_ELLGG99 } , )fiViCVVVDVS{%,}1 ', TWA<TK99£1{QDWLWG<I } ; 1<T:SKA<GQ LPQVYTF.) '1:T<NQVSLTCLVKGF'YPS 1ESWGQ9EWWY<TTPPVLDSLYSKLTVD<SQWQQGNVFSCSVYTQKSLSLSPGK2g gamma—l constant region mutant ASTKG9SVF9LAPSSKSTSGGTAALGCLV<DYF9_9VTVSWNSGALTSGV{TF9AVLQSSGLYSLSSVVTV9SSSLGTQTYICWVNHK9SWT<VD<{VL 9KSCD {TCPPC9A;EAAGG9SVFLF99 'VVVDVS{%,;{QDWLWG<I _<T:SKA<GQ’.'LPQVYT1_;T<NQVSLTCLVKGF'YPSEWVY<TTPPVLDSLYSKLTVD<S9WQQGNVFSCSVLALHN{YTQKSLSLSPGKMEI 24985843V.1 771117813-12620a Description Amino Acid SequenceIg Kappa constant region RTVAA?SVE"'?PSDLQLKSGTASVVCLLWNFY; EAKVQWKVDNALQSGNSQfiSVi: DSKJSTYSLSSTLYEK{KVYACEVTHQGLSSPVTKSFNRGECIg Lambda constant region QPKAAPSVTLFPPSS'4'TQANKATLVCL:SJFY?GAVTVAWKADSSPVETTTPSKQSNN<YAASSYLS<SHRSYSCQV1H4'GS1VnAmino acid sequence of "GKV6—21*Ol % VTiQSPDEQSViPKfiKVi iCRASQS-.GSSLHWYQQKPDQSPKLL:{YASQSFSGVPSRFSGSGSGTDFTLi NSLfiAfiDAAiYYCiQSSSLPXAmino acid sequence of "GKV7—78*01 QSPLSL?V1?G%?AS SCRSSQSLLHSNGYWYLDWYLQKPGQS?QLL__YLGSNRASGVPDRFSGSGSGiDb'iTK SRV4'AfiDVGVYYCMQALQTPPAmino acid sequence of "GKJ4*Ol EGGGLKV:Amino acid ce of "GHV—b*Ol(O—l) QVQT.QTSGPGT.VK?S?TLSLTCAVSGYS__SSGYYWGWI_RQP?GKGLEWGS YiSGSTYYN?SLKSRVT-'SVDTSKNQFSLKLSSVTAADTAVYYCMEI 24985843V.1 772117813-12620a Description Amino Acid SequenceAmino acid sequence Of "GKVi—39*Ol DIQMTQS9SSLSASVGDRVTITCASQSISSYLNWYQQKPGKAPKLL:YAASSLQSGVPSRFSGSGSGTDFTTTSSTQ9TDFATYYCQQSYSTP9Amino acid sequence of huAblel heavy 41VQT.Q4ISGPGT.VK?S?TT.ST.TCAVChain SGYSWHWIRQF9GNGLEWGYIHSSGSTNYN9SKKSR S SRFFLKLSSVTAADTAVYYCNote: 22g gamma—l constant region mutant AGYDDYFEYWGQGTTVTVSSASTKsequence is underlined. '?SVF?LAPSSKSTSGGTAALGCL<DYF9.9VTVSWNSGALTSGV{T9AVLQSSGLYSLSSVVTV9SSSLGTQTY..CWVNHK9SWT<VD< I}KSC {T {TCPPC9A9I '9L M SRiL'{139 VKbNWYVD _"1fiQYWSiYRVVSVLTVLI <CKVSNKAK9A9 1YTT.9} 911TCLVKGE'YPSD AV: .

{TTPPVLDSDGSFFLYSK9WQQGNVFSCSV {EALH{YTQKSLSLSPGKAmino acid sequence Of huAbi3Vi light D:QMTQS?SSLSASVGDRVT:TCKchain ASQNVGFWVAWYQQKPGKSPKAL:YSASYRYSGVPS RFSGSGSGTDFTQ9*DEA*YECQQYNWY;Note: 22g kappa constant region ibGQGiKT'” KRLVAADSVF" ’-sequenceis underlined_ SDEQLKSGTASVVCLLWNFY.’ :KVQWKVDWALQSGNSQfiSViIKDSTYSLSSTLTLSKADYEKACEVTHQGLSSPVTKSFNQGMEI 24985843V.1 773117813-12620Description Amino Acid SequenceAmino acid ce of huAb3v2.5 heavy VVQT.VQSGAVVKK9GSSVKVSCKAchain SGYTFSSYW HWV'VQA’9GQGR VWG1 H94'SGSlNYN fiME {NRAl LlVDRSTSTAY VT.SST.RS VDTAVYYCNote: fg gamma—l constant region mutant AGGG VLYFDYWGQGTTVTVSSASTsequence is underlined. <G9SVF9LA9SSKSTSGGTAALGCLV<DYF9V9VTVSWNSGALTSGVlTF9AVLQSSGLYSLSSVVTV9 SSSLGTQTYICWVNHK9SWT<VD< {V39KSC {TCPPC9A} -—1 4FLF9LDVSlZ,LlK9V11WLWG I _SKA<GQ'.'VPQVYTK9}NQVSLTCLVKGE'YPSDGQ9VWWY<TTPPVLDSSVWQQGNVFSCSVHNlYTQKSLSLSPGKAmino acid sequence of huAb3v2.5 light DI_VMTQSPLSL9Vl9G £9AS SCRchain SSQSLVlSNVJTYLVWYLQKPGQS9QLLIY<VSWVFSGVPDVFSGSGSDb' lT.’{ S'VV'. VJVGVYYCSQSNote: "g kappa nt region sequence 9YlEGGGl<V V KVlVAA 9SVis underlined. '_'9PSD_LQL<SGlASVVCLLWNF"VAKVQW<VDNALQSGNSQ_ DSKDSTYSLSSTLTLSKAVTlQGLSSPVTKSFNMEI 24985843V.1 774117813-12620a Description Amino Acid SequenceAmino acid sequence of huAb3v2.6 heavy VQSGAT.VKK?GSSVKVSCKAChain SGYTFSSYW HWV9QAPGQGL£WGL HPfiSGSiNYNLMEKWRAiLiVDRSTSTAYMNote: 22g gamma—l constant region mutant 'T-Tu SSTRS'T-DTAVYYCAGGGRLYFDsequence is underlined. TVTVSSASTKG9SVF9LA9SSKSTSGGTAALGCLV<DYF9I9VTVSWWSGALTSGViTF9AVLQSSGLYSLSSVVTV9SSSLGTQTY__VNHK9SWT<VD<<VL 9KSCCPPC9ALEAAGG9SVFLF9L _iLM SR 9%ViCVVVDVSi1,}.

KFNWYV, 7 {WA<1K991%STYRVVSVLTVLiQDWLWGIL9A9 fi<i SKA<GQLTPQVYTL9L 9fifi i<NQVSLKGEYPSJ AVfiWL'SWGQ9EWWYTPPVLDSJGSFFLYSKLTVD<SQQGNVFSCSV {EALHNiYTQKSLSLSPGKAmino acid sequence of huAb3v2.6 light DZ_VMTQSPLSL?V1?G41?AS SCRChain SSQSLViSNQDTYL9WYLQKPGQS9QLL__Y<VSN' DRFSGSGSDb'iL< SRVI iDVGVYYCSQSNote: 22g kappa nt region 'sequence 9Yib'GGGi KRiVAA—DSVis underlined_ 3LQL<SGiASVVCLLWNFL'LAKVQWKVDNALQSGNSQ_ DSKDSTYSLSSTLTLSKADY{VYACLVTiQGLSSPVTKSFNAmino acid ce 0:" QVQLVQSGAIEVKK'9GSSVKVSCKA:GHVl—69*O6_IGHJ6 SGGTFSSYAI_SWV9QA9GQGLEWMGG P b'GiANYAQKFQGRVT.ITADKSTSTAYMTLSSLRSTDTAVYYCARXXXXXXXXWGQGTTVTVSSAmino acid sequence of DZ_VMTQSPLSL?V1?G41?AS SCR"GKV7—78*OT_"GKJ4 SSQSLLHSNGYWYLDWYLQKPGQS9QLL-YLGSNRASGVPD9FSGSGSGiDb' 1TK SRVL'.ALZDVGVYYCXXXXXXXXXE'GGGL<V% KMEI 24985843V.1 775-12620Description Amino Acid SequenceAmino acid "sequence of — _I QVQT.QTSGPGT.VK?S?TRSLTCAVSGYS__SSGYYWGWI_RQP9GKGLEWGS YiSGSTYYN9SLKSRVTLSVDTSKNQFSLKLSSVTAADTAVYYCARXXXXXXXWGQGTTVTVSSAmino acid "sequence 0’" — _" DLQMTQS9SSLSASVGDRVTZZTCRASQS._SSYLNWYQQKPG<APKLLIYAASSLQSGVPSRFSGSGSGTDFTT.T" SSTQ9TDFATYYCXXXXXXXXXb'GQGiKLfi KAmino acid sequence of huAb3 VLl DL_VMTQS9LSL9V19G49AS SCRvariants SSQSLVHSXGDTYLQWYLQKPGQS9QLL.YKVSNRFSGVPDRFSGSGSNote: X can be any amino acid except: LK SRV*'A43VGVYYCSQSM, C, N, D, or Q iHVPYiEGGGi<Vfi KAmino acid sequence of huAb3 VLl QSPLSL_ ?G%?AS SCRvariants SSQSLVHSNXDTYLQWYLQKPGQS9QLL-YKVSNQFSGVPDKFSGSGSNote: X can be any amino acid except: GiDb'iLK SRV4A43VGVYYCSQSM, C, G, S, N, or P iHVPYiEGGGi<Vfi KAmino acid ce of huAb3 VHlb TVQT.VQSGA7V<K?GSSVKVSCKAvariants SGYTFSSYW HWVQQA9GQGL%WGLLH9XSGSTNYN_EMF{NRATLTVNote: X can be any amino acid except: DRSTSTAYM4LSSLRSVDTAVYYCM, c, N, D, or Q AGGGRLYFDYWGQGTTVTVSSAmino acid sequence of huAb3 VHlb iVQtVQSGA?VKK?GSSVKVSCKAts SGYTFSSYW HWVQQA9GQGL%WGLLH9DXGSTNYNEMF<NRATLTVNote: X can be any amino acid except: DRSTSTAYMVLSSLRSVDTAVYYCM, C, G, s, N, or P AGGGQLYFDYWGQGTTVTVSSchAb13 VL CDR3 amino acid sequence QQYNSYPFTINCORPORATION BY REFERENCEThe contents of all references, patents, pending patent applications and published patents,cited throughout this application are hereby sly incorporated by reference.

MEl 24985843V.1 776117813-12620EgQUIVALENTSThose skilled in the art will recognize, or be able to ascertain using no more than routinementation, many equivalents to the specific embodiments of the invention described herein.

Such equivalents are intended to be encompassed by the following claims.

MEl 24985843v.1 777Numbered embodiments of the invention are as s:1. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3 (hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chainvariable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 12 and alight chain variable region comprising a CDR3 having the amino acid sequence of SEQ IDNO: 15.2. The antibody, or antigen binding portion f, of embodiment 1, wherein the antibody, orantigen binding portion thereof, comprises a heavy chain variable region comprising a CDR2having the amino acid sequence of SEQ ID NO: 140 and a light chain variable regioncomprising a CDR2 having the amino acid sequence of SEQ ID NO: 7.3. The antibody, or antigen binding portion thereof, of embodiment 1 or 2, wherein the antibody,or antigen g portion thereof, comprises a heavy chain variable region sing aCDR1 having the amino acid sequence of SEQ ID NO: 10 and a light chain variable regionsing a CDR1 having the amino acid sequence of either SEQ ID NO: 136 or 138.4. An ed antibody, or antigen binding portion thereof, that binds to human B7-H3, whereinthe antibody, or antigen binding portion thereof, comprises a heavy chain variable regioncomprising a CDR3 having the amino acid sequence of SEQ ID NO: 35 and a light chainvariable region comprising a CDR3 having the amino acid sequence of SEQ ID NO: 39.

. The antibody, or antigen binding portion thereof, of ment 4, wherein the antibody, orantigen binding portion thereof, comprises a heavy chain variable region sing a CDR2having the amino acid sequence of SEQ ID NO: 34, and a light chain le regioncomprising a CDR2 having the amino acid sequence of SEQ ID NO: 38.6. The antibody, or antigen binding portion thereof, of embodiment 4 or 5, n the antibody,or antigen binding portion thereof, comprises a heavy chain variable region comprising aCDR1 having the amino acid ce of SEQ ID NO: 33 and a light chain variable regioncomprising a CDR1 having the amino acid sequence of either SEQ ID NO: 37.7. The antibody, or n binding portion thereof, of any one of the preceding embodiments,wherein the antibody, or antigen binding portion f, is an IgG isotype.8. The antibody, or antigen binding portion thereof, of ment 7, wherein the antibody, orantigen binding portion thereof, is an IgG1 or an IgG4 isotype.9. The antibody, or antigen binding portion thereof, of any one of the preceding embodiments,wherein the antibody, or antigen binding portion thereof, has a KD of 1.5 x 10-8 or less asdetermined by surface plasmon resonance.

. An antibody, or antigen-binding portion thereof, that binds to hB7-H3, said antibody, orantigen-binding portion thereof, sing eithera heavy chain variable region sing a CDR set of SEQ ID NOs: 10, 11, and 12,and a light chain variable region comprising a CDR set of SEQ ID NOs: 14, 7, and 15, ora heavy chain variable region comprising a CDR set of SEQ ID NOs: 33, 34, and 35,and a light chain variable region comprising a CDR set of SEQ ID NOs: 37, 38, and 39.11. The antibody, or n g portion thereof, of embodiment 10, n the antibody, orantigen binding portion f, is humanized.12. The antibody, or antigen binding portion thereof, ing to embodiment 11, furthercomprising a human acceptor framework.13. The antibody, or antigen binding portion thereof, of embodiment 12, wherein said humanacceptor framework comprises an amino acid sequence selected from the group consisting ofSEQ ID Nos: 155,156, 164, 165, 166, and 167.14. The antibody, or antigen binding portion thereof, of embodiment 13, wherein said humanacceptor framework comprises at least one framework region amino acid substitution.

. The antibody, or n binding portion f, of embodiment 14, wherein the amino acidce of the framework is at least 65% identical to the sequence of said human orframework and comprises at least 70 amino acid residues identical to said human acceptorframework.16. The antibody, or antigen binding portion thereof, of embodiment 14 or 15, wherein saidhuman acceptor framework comprises at least one framework region amino acid substitutionat a key residue, said key residue selected from the group consisting of:a residue adjacent to a CDR;a glycosylation site residue;a rare residue;a residue capable of interacting with human B7-H3;a residue capable of interacting with a CDR;a canonical residue;a contact residue between heavy chain variable region and light chain le region;a residue within a Vernier zone; anda residue in a region that overlaps between a Chothia-defined variable heavy chain CDR1 anda Kabat-defined first heavy chain framework.17. The antibody, or antigen binding portion thereof, of embodiment 16, wherein said key residueis selected from the group consisting of 48H, 67H, 69H, 71H, 73H, 94H, and 2L.18. The antibody, or antigen binding portion thereof, of embodiment 17, wherein the key residuetution is in the variable heavy chain region and is selected from the group ting ofM48I, V67A, I69L, A71V, K73R, and R94G.19. The antibody, or antigen binding portion thereof, of embodiment 17 or 18, wherein the keyresidue substitution is in the variable light chain region and is I2V.

. An antibody, or antigen-binding n thereof, that binds to hB7-H3 sing a heavychain variable region comprising a CDR set of SEQ ID NOs: 25, 26, and 27, and a light chainvariable region comprising a CDR set of SEQ ID NOs: 29, 30, and 31.21. The antibody, or antigen binding portion thereof, of ment 20, n the antibody, orantigen binding portion thereof, is zed.22. The antibody, or antigen binding portion f, according to embodiment 21, furthercomprising a human acceptor ork.23. The antibody, or antigen binding portion f, of embodiment 22, wherein said humanacceptor framework comprises an amino acid sequence selected from the group consisting ofSEQ ID NOs: 155 to 158.24. The antibody, or antigen binding portion thereof, of embodiment 22 or 23, wherein saidhuman acceptor framework comprises at least one ork region amino acid substitution.

. The antibody, or antigen binding portion thereof, of embodiment 24, wherein the amino acidsequence of the framework is at least 65% identical to the sequence of said human acceptorframework and comprises at least 70 amino acid residues identical to said human acceptorframework.26. The antibody, or antigen binding portion thereof, of embodiment 24 or 25, wherein saidhuman acceptor framework comprises at least one framework region amino acid substitutionat a key residue, said key residue selected from the group consisting of:a residue adjacent to a CDR;a glycosylation site residue;a rare residue;a residue capable of interacting with human B7-H3;a e capable of interacting with a CDR;a canonical residue;a contact e between heavy chain variable region and light chain variable region;a residue within a r zone; anda residue in a region that ps between a Chothia-defined variable heavy chain CDR1 anda Kabat-defined first heavy chain framework.27. The antibody, or antigen binding portion thereof, of embodiment 26, wherein said key residueis selected from the group consisting of 69H, 46L, 47L, 64L, and 71L.28. The antibody, or antigen binding portion thereof, of embodiment 27, n the key residuetution is in the variable heavy chain region and is L69I.29. The antibody, or antigen binding portion thereof, of embodiment 27 or 28, wherein the keyresidue substitution is in the le light chain region and is selected from the groupconsisting of L46P, L47W, G64V, and F71H.

. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chainCDR1 comprising an amino acid sequence as set forth in SEQ ID NO: 10, a heavy chainCDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 140, a heavy chainCDR3 sing an amino acid sequence as set forth in SEQ ID NO: 12, a light chain CDR1comprising an amino acid sequence as set forth in SEQ ID NO: 136 or 138, a light chainCDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 7, and a light chainCDR3 comprising an amino acid ce as set forth in SEQ ID NO: 15.31. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chainCDR1 sing an amino acid sequence as set forth in SEQ ID NO: 33, a heavy chainCDR2 comprising an amino acid sequence as set forth in SEQ ID NO: 34, a heavy chainCDR3 comprising an amino acid sequence as set forth in SEQ ID NO: 35, a light chain CDR1comprising an amino acid sequence as set forth in SEQ ID NO: 37, a light chain CDR2comprising an amino acid sequence as set forth in SEQ ID NO: 38, and a light chain CDR3comprising an amino acid sequence as set forth in SEQ ID NO: 39.32. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chainle domain comprising an amino acid ce set forth in SEQ ID NO: 139 and a lightchain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 135.33. An B7-H3 antibody, or n-binding n thereof, comprising a heavy chaincomprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 139, and/or a light chain comprising an amino acid sequence havingat least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 135.34. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chainvariable domain comprising an amino acid sequence set forth in SEQ ID NO: 139 and a lightchain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 137.

. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chaincomprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 139, and/or a light chain comprising an amino acid sequence havingat least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 137.36. An anti-hB7-H3 antibody, or antigen-binding portion thereof, sing a heavy chainvariable domain comprising an amino acid sequence set forth in SEQ ID NO: 147 and a lightchain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 144.37. An anti-hB7-H3 antibody, or antigen-binding portion thereof, comprising a heavy chaincomprising an amino acid sequence having at least 90%, 95%, 96%, 97%, 98%, or 99%identity to SEQ ID NO: 147, and/or a light chain comprising an amino acid ce havingat least 90%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 144.38. The antibody, or antigen-binding portion thereof, of any one of the preceding embodiments,wherein the dy, or antigen binding portion thereof, binds cyno B7-H3.39. The antibody, or antigen-binding portion thereof, of any one of the preceding ments,wherein the antibody, or antigen binding portion thereof, has a dissociation constant (KD) tohB7-H3 selected from the group consisting of: at most about 10-7 M; at most about 10-8 M; atmost about 10-9 M; at most about 10-10 M; at most about 10-11 M; at most about 10-12 M; and atmost 10-13 M.40. The antibody, or antigen-binding n f, of any one of the preceding embodiments,wherein the antibody, or antigen binding portion thereof, comprises a heavy chainimmunoglobulin constant domain of a human IgM nt domain, a human IgG1 constantdomain, a human IgG2 nt domain, a human IgG3 constant domain, a human IgG4constant domain, a human IgA constant domain, or a human IgE constant domain.41. The antibody of any one of the preceding embodiments, which is an IgG having fourpolypeptide chains which are two heavy chains and two light chains.42. The antibody, or antigen-binding portion thereof, of embodiment 41, wherein the human IgG1constant domain comprises an amino acid sequence of SEQ ID NO: 159 or SEQ ID NO: 160.43. The dy, or antigen-binding portion thereof, of any one of the preceding embodiments,wherein the antibody, or antigen binding portion thereof, further comprises a light chainimmunoglobulin constant domain comprising a human Ig kappa constant domain or a humanIg lambda constant domain.44. An anti-hB7-H3 antibody, or antigen-binding portion thereof, that competes with theantibody, or antigen binding portion thereof, of any one of the preceding embodiments.45. A pharmaceutical composition comprising the anti-hB7-H3 dy, or antigen bindingportion thereof, of any one of embodiments 1-44, and a pharmaceutically acceptable carrier.46. An anti-hB7-H3 Antibody Drug ate (ADC) comprising an B7-H3 antibody ofany one of embodiments 1-44 conjugated to a drug via a .47. The ADC of ment 46, wherein the drug is an auristatin or a pyrrolobenzodiazepine(PBD).48. The ADC of embodiment 46, wherein the drug is a Bcl-xL inhibitor.49. An anti-hB7-H3 antibody drug conjugate (ADC) comprising a drug linked to an umanB7-H3 (hB7-H3) antibody by way of a linker, wherein the drug is a Bcl-xL inhibitoraccording to structural formula (IIa), (IIb), (IIc), or (IId):(IIa)(IIb)(IIc)(IId)wherein:Ar1 is selected from , , , , , , ,, and and is optionally tuted with one or more substituents independentlyselected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C1-4alkoxy, amino, cyano andhalomethyl;Ar2 is selected from , , , ,, , , , ,, , and or an N-oxide thereof, and is allysubstituted with one or more substituents independently selected from halo, hydroxy, nitro, loweralkyl, lower heteroalkyl, C1-4alkoxy, amino, cyano and thyl, wherein the R12-Z2b-, R’-Z2b-, #-N(R4)-R13-Z2b-, or #-R’-Z2b- substituents are attached to Ar2 at any Ar2 atom capable of beingsubstituted;Z1 is selected from N, CH, C-halo, C-CH3 and C-CN;Z2a and Z2b are each , independently from one another, selected from a bond, NR6, CR6aR6b,O, S, S(O), S(O)2, -NR6C(O)-,-NR6aC(O)NR6b-, and –NR6C(O)O-;R’ is or , wherein #, where attached to R’, is attachedto R’ at any R’ atom capable of being substituted;X’ is selected at each occurrence from -N(R10)- , -N(R10)C(O)-, -N(R10)S(O)2-, -S(O)2N(R10)-,and -O-;n is selected from 0-3;R10 is independently ed at each occurrence from hydrogen, lower alkyl, cycle,aminoalkyl, G-alkyl, and -(CH2)2-O-(CH2)2-O-(CH2)2-NH2;G at each ence is independently selected from a polyol, a polyethylene glycol withbetween 4 and 30 ing units, a salt and a moiety that is d at physiological pH;SPa is independently selected at each ence from oxygen, -S(O)2N(H)-, -N(H)S(O)2-,-N(H)C(O)-, -C(O)N(H) -, -N(H)- , arylene, heterocyclene, and optionally substituted methylene;n methylene is optionally substituted with one or more of -NH(CH2)2G, NH2, kyl, andcarbonyl;m2 is selected from 0-12;R1 is ed from hydrogen, methyl, halo, halomethyl, ethyl, and cyano;R2 is selected from hydrogen, methyl, halo, halomethyl and cyano;R3 is selected from hydrogen, methyl, ethyl, halomethyl and haloethyl;R4 is ed from en, lower alkyl and lower heteroalkyl or is taken together with anatom of R13 to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms;R6, R6a and R6b are each, independent from one another, selected from hydrogen, optionallysubstituted lower alkyl, optionally substituted lower heteroalkyl, optionally substituted cycloalkyl andoptionally substituted heterocyclyl, or are taken together with an atom from R4 and an atom from R13to form a cycloalkyl or heterocyclyl ring having between 3 and 7 ring atoms;R11a and R11b are each, independently of one another, selected from hydrogen, halo, methyl,ethyl, halomethyl, hydroxyl, methoxy, CN, and SCH3;R12 is optionally R’ or is selected from hydrogen, halo, cyano, optionally substituted alkyl,optionally substituted heteroalkyl, optionally substituted heterocyclyl, and optionally substitutedcycloalkyl;R13 is selected from optionally substituted C1-8 alkylene, optionally tuted heteroalkylene,optionally substituted heterocyclene, and optionally substituted cycloalkylene; and# represents a point of attachment to a linker.50. The ADC of embodiment 49, which is a compound according to structural formula (I):wherein:D is the Bcl-xL inhibitor drug of formula (IIa), (IIb), (IIc) or (IId);L is the linker;Ab is the anti-hB7-H3 antibody;LK ents a covalent linkage linking the linker (L) to the anti-hB7-H3 antibody(Ab); andm is an integer ranging from 1 to 20.51. The ADC of embodiment 49 or 50, in which G at each occurrence is a salt or a moiety that ischarged at physiological pH.52. The ADC of embodiment 49 or 50, or in which G at each occurrence is a salt of a ylate,a sulfonate, a onate, or ammonium.53. The ADC of embodiment 49 or 50, in which G at each occurrence is a moiety that is chargedat physiological pH selected from the group consisting of ylate, a sulfonate, a phosphonate, andan amine.54. The ADC of embodiment 49 or 50, in which G at each occurrence is a moiety containing apolyethylene glycol with between 4 and 30 repeating units, or a polyol.55. The ADC of embodiment 54, in which the polyol is a sugar.56. The ADC of formula (IIa) or formula (IId) of embodiment 49 or 50, in which R’ includes atleast one substitutable nitrogen suitable for attachment to a linker.57. The ADC of embodiment 56, in which G is ed at each occurrence from:, , , , , ,, , , , , ,, , , , and , wherein M ishydrogen or a positively charged counterion.58. The ADC of embodiment 49 or 50, in which R’ is selected from, , ,, ,, ,, , ,, , ,, , ,, , ,, , ,, , ,, ,, , ,, ,, ,, , , ,, ,, ,, ,, ,, , ,, , and, wherein # represents either a hydrogen atom in the Bcl-xL inhibitor drug ofthe ADCs of formula (IIb) or (IIc) or the point of attachment in the Bcl-xL tor drug of the ADCsof formula (IIa) or (IId) to a linker L.59. The ADC of embodiment 49 or 50, in which Ar1 is selected from , ,and and is optionally substituted with one or more substituents independently selected fromhalo, cyano, methyl, and halomethyl.60. The ADC of embodiment 59, in which Ar1 is .61. The ADC of embodiment 49 or 50, in which Ar2 is , optionallysubstituted with one or more substituents.62. The ADC of embodiment 49 or 50, in which Ar2 is selected from ,, , , , ,, , and ; and is optionallysubstituted with one or more substituents.63. The ADC of ment 61, in which Ar2 is substituted with one or moresolubilizing groups.64. The ADC of embodiment 63, in which each solubilizing group is, ndently ofthe others, selected from a moiety containing a polyol, a polyethylene glycol with between 4 and 30repeating units, a salt, or a moiety that is charged at physiological pH.65. The ADC of embodiment 62, in which Ar2 is substituted with one or moresolubilizing groups.66. The ADC of embodiment 65, in which each solubilizing group is, independently ofthe , ed from a moiety containing a polyol, a polyethylene glycol with between 4 and 30repeating units, a salt, or a moiety that is charged at physiological pH.67. The ADC of embodiment 49 or 50, in which Z1 is N.68. The ADC of embodiment 49 or 50, in which Z2a is O.69. The ADC of embodiment 49 or 50, in which R1 is methyl or chloro.70. The ADC of embodiment 49 or 50, in which R2 is hydrogen or methyl.71. The ADC of embodiment 49 or 50, in which R2 is hydrogen.72. The ADC of embodiment 49 or 50, in which Z2b is O.73. The ADC of embodiment 49 or 50, in which Z2b is NH or CH2.74. The ADC of embodiment 49 or 50, which is a compound according to structuralformula (IIa).75. The ADC of ment 74, which includes a core selected from structures (C.1)-(C.21):(C.1)(C.2)(C.3)(C.4)(C.5)(C.6)(C.7)(C.8)(C.9)(C.10)(C.11)(C.12)(C.13)(C.14)(C.15)(C.16)(C.17)(C.18)(C.19)(C.20)(C.21)76. The ADC of ment 74, which is a compound according to structural formula(IIa.1):(IIa.1)wherein:Y is optionally substituted C1-C8 alkylene;r is 0 or 1; ands is 1, 2 or 3.77. The ADC of embodiment 74, which is a compound according to structural formula(IIa.2):(IIa.2)wherein:U is selected from N, O and CH, with the proviso that when U is O, then Va and R21a areabsent;R20 is selected from H and C1-C4 alkyl;R21a and R21b are each, independently from one another, absent or selected from H, C1-C4alkyl and G, where G is selected from a , PEG4-30, a salt and a moiety that is charged atphysiological pH;Va and Vb are each, independently from one another, absent or ed from a bond, and anoptionally substituted ne;R20 is selected from H and C1-C4 alkyl; ands is 1, 2 or 3.78. The ADC of embodiment 74, which is a compound according to structural formula(IIa.3):(IIa.3)wherein:Rb is selected from H, C1-C4 alkyl and Jb-G or is optionally taken together with an atom of Tto form a ring having between 3 and 7 atoms;Ja and Jb are each, independently from one another, selected from optionally tuted C1-C8alkylene and optionally substituted phenylene;T is selected from optionally substituted C1-C8 alkylene, CH2CH2OCH2CH2OCH2CH2,CH2CH2OCH2CH2OCH2CH2OCH2 and a polyethylene glycol containing from 4 to 10 ethylene glycolunits;G is selected from a polyol, PEG4-30, a salt and a moiety that is charged at logical pH;s is 1, 2 or 3.79. The ADC of embodiment 49 or 50, which is a compound according to structuralformula (IIb).80. The ADC of embodiment 79, which is a compound according to structural formula(IIb.1):(IIb.1)Y is optionally substituted C1-C8 alkylene;G is selected from a polyol, 0, a salt and a moiety that is d at physiological pH;r is 0 or 1; ands is 1, 2 or 3.81. The ADC of embodiment 49 or 50, which is a compound according to structuralformula (IIc).82. The ADC of embodiment 81, which is a compound according to structural formula(IIc.1):(IIc.1)wherein:Ya is optionally substituted C1-C8 alkylene;Yb is optionally substituted C1-C8 alkylene;R23 is selected from H and C1-C4 alkyl; andG is ed from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH.83. The ADC of embodiment 81, which is a compound according to structural a(IIc.2):(IIc.2)wherein:Ya is optionally substituted C1-C8 alkylene;Yb is optionally substituted C1-C8 alkylene;Yc is optionally substituted C1-C8 alkylene;R23 is selected from H and C1-C4 alkyl;R25 is Yb-G or is taken together with an atom of Yc to form a ring having 4-6 ring atoms; andG is selected from a polyol, PEG4-30, a salt and a moiety that is charged at physiological pH.84. The ADC of embodiment 49 or 50, wherein the Bcl-xL inhibitor is selected from thegroup consisting of the following compounds modified in that the hydrogen corresponding to the #position of structural a (IIa), (IIb), (IIc), or (IId) is not present forming a monoradical:6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3-[2-({2-[2-(carboxymethoxy)ethoxy]ethyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-lyl}pyridinecarboxylic acid;2-{[(2-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-2-carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]dec)ethyl]amino}ethyl)sulfonyl]amino}deoxy-D-glucopyranose;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(4-{[(3R,4R,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)tetrahydro-2H-pyranyl]methyl}benzyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2,3-dihydroxypropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;2-({[4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}methyl)phenyl]sulfonyl}amino)deoxy-beta-D-glucopyranose;8-(1,3-benzothiazolylcarbamoyl){6-carboxy[1-({3-[2-({2-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl]ethyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl}methyl)methyl-1H-pyrazolyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline;3-[1-({3-[2-(2-{[4-(beta-D-allopyranosyloxy)benzyl]amino}ethoxy)ethoxy]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl][8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(2-sulfoethyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-phosphonoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-lyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-lyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{2-[(3-phosphonopropyl)amino]ethoxy}ethoxy)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;3-{1-[(3-{2-[L-alpha-aspartyl(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-{4-[({2-[2-(2-aminoethoxy)ethoxy]ethyl}[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino)methyl]benzyl}-2,6-anhydro-L-gulonic acid;4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}methyl)phenyl hexopyranosiduronic acid;6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl-7-{2-[(2-phosphonoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl-7-{2-[methyl(3-sulfo-L-alanyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3,5-dimethyl-7-{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)(piperidinyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;3-{1-[(3-{2-[D-alpha-aspartyl(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[1-(carboxymethyl)piperidinyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;N-[(5S)amino{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl](methyl)amino}oxohexyl]-N,N-dimethylmethanaminium;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[piperidinyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)(3-phosphonopropoxy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[N-(2-carboxyethyl)-L-alpha-aspartyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;3-{1-[(3-{2-[(2-aminoethyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[5-(2-aminoethoxy)(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(3-sulfopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)(piperidinyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(3-sulfo-L-alanyl)(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[{2-[(2-yethyl)amino]ethyl}(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[5,4-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)(carboxymethoxy)-3,4-dihydroisoquinolin-2(1H)-yl][1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-carboxypropyl)(piperidinyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(2-thyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;3-{1-[(3-{2-[L-alpha-aspartyl(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(1,3-dihydroxypropanyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[5-(2-aminoethoxy)(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]-3-{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl){2-[(2-sulfoethyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl){2-[(2-sulfoethyl)amino]ethyl}amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl){2-[(2-carboxyethyl)amino]ethoxy}-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[methyl(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;3-{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)(piperidinyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-thiazolo[4,5-b]pyridinylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylicacid;6-[4-(1,3-benzothiazolylcarbamoyl)-3,4-dihydro-2H-1,4-benzoxazinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)(3-sulfopropoxy)-3,4-dihydroisoquinolin-2(1H)-yl]-3-[1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;3-{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[1-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)-1,2,3,4-ydroquinolinyl]pyridinecarboxylic acid;(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-([1,3]thiazolo[4,5-b]pyridinylcarbamoyl)naphthalenyl]pyridine-2-carboxylic acid;(1)({2-[5-(1-{[3-(2-aminoethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)carboxypyridinyl](1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroisoquinolinyl}methyl)-1,5-anhydro-D-glucitol;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-carboxypropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(3-phosphonopropyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[4-(beta-D-glucopyranosyloxy)benzyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}--methyl-1H-pyrazolyl)pyridinecarboxylic acid;3-(1-{[3-(2-{[4-(beta-D-allopyranosyloxy)benzyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;3-{1-[(3-{2-[azetidinyl(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;(3-{2-[(3-aminopropyl)(2-sulfoethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]pyridinecarboxylic acid;6-[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(N6,N6-dimethyl-L-lysyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;3-{1-[(3-{2-[(3-aminopropyl)(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]pyridinecarboxylic acid;3-{1-[(3-{2-[azetidinyl(methyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}[1-(1,3-benzothiazolylcarbamoyl)-1,2,3,4-tetrahydroquinolinyl]pyridinecarboxylic acid;N6-(37-oxo-2,5,8,11,14,17,20,23,26,29,32,35-dodecaoxaheptatriacontanyl)-L-lysyl-N-[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridin-3-yl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]-L-alaninamide;methyl 6-[4-(3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}propyl)-1H-1,2,3-triazolyl]deoxy-beta-L-glucopyranoside;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[5-(1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3,5-dimethyl{2-[(2-thyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[4-(1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[5-(1,3-benzothiazolylcarbamoyl)quinolinyl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[1-(1,3-benzothiazolylcarbamoyl)-5,6-dihydroimidazo[1,5-a]pyrazin-7(8H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;8-(1,3-benzothiazolylcarbamoyl){6-carboxy[1-({3-[2-({3-[1-(beta-D-glucopyranuronosyl)-1H-1,2,3-triazolyl]propyl}amino)ethoxy]-5,7-dimethyltricyclo[3.3.1.13,7]dec-1-yl}methyl)methyl-1H-pyrazolyl]pyridinyl}-1,2,3,4-tetrahydroisoquinoline;1,3-benzothiazolylcarbamoyl)-1H-indolyl]{1-[(3,5-dimethyl{2-[(2-thyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)[3-(methylamino)propyl]-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]--methyl-1H-pyrazolyl}pyridinecarboxylic acid;-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]ypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}deoxy-D-arabinitol;1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}-1,2-dideoxy-D-arabino-hexitol;6-[4-(1,3-benzothiazolylcarbamoyl)isoquinolinyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[3-hydroxy(hydroxymethyl)propyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}-yl-1H-pyrazolyl)pyridinecarboxylic acid;1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}-1,2-dideoxy-D-erythro-pentitol;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl(2-{[(2S,3S)-2,3,4-trihydroxybutyl]amino}ethoxy)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;6-[8 -(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-3S,4R,5R,6R)-2,3,4,5,6,7-hexahydroxyheptyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[({3-[(1,3-dihydroxypropanyl)amino]propyl}sulfonyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(3-{[1,3-dihydroxy(hydroxymethyl)propanyl]amino}oxopropyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[(3S)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;4-({[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}methyl)phenyl beta-D-glucopyranosiduronic acid;3-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}propyl beta-D-glucopyranosiduronic acid;6-[4-(1,3-benzothiazolylcarbamoyl)oxidoisoquinolinyl][1-({3,5-dimethyl[2-(methylamino)ethoxy]tricyclo[3.3.1.13,7]decyl}methyl)methyl-1H-pyrazolyl]pyridinecarboxylic acid;6-{8-[(1,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]acetamido}tricyclo[3.3.1.13,7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3,5-dimethyl({2-[(2-sulfoethyl)amino]ethyl}sulfanyl)tricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid; and6-{8-[(1,3-benzothiazolyl)carbamoyl]-3,4-dihydroisoquinolin-2(1H)-yl}{1-[(3,5-dimethyl{3-[(2-sulfoethyl)amino]propyl}tricyclo[3.3.1.13,7]decanyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid.85. The ADC of any one of embodiments 49-84, in which the linker is ble by alysosomal enzyme.86. The ADC of embodiment 85, in which the lysosomal enzyme is Cathepsin B.87. The ADC of anyone of embodiments 49-84, in which the linker comprises a segmentaccording to structural formula (IVa), (IVb), (IVc), or (IVd):(IVa)(IVb)(IVc)(IVd)wherein:e represents a peptide (illustrated N→C, wherein peptide includes the amino andcarboxy “termini”) a cleavable by a lysosomal enzyme;T ents a polymer comprising one or more ethylene glycol units or an alkylene chain, orcombinations thereof;Ra is selected from hydrogen, C1-6 alkyl, SO3H and CH2SO3H;Ry is hydrogen or C1-4 alkyl-(O)r-(C1-4 alkylene)s-G1 or C1-4 alkyl-(N)-[(C1-4 alkylene)-G1]2;Rz is C1-4 alkyl-(O)r-(C1-4 ne)s-G2;G1 is SO3H, CO2H, PEG 4-32, or sugar moiety;G2 is SO3H, CO2H, or PEG 4-32 moiety;r is 0 or 1;s is 0 or 1;p is an integer ranging from 0 to 5;q is 0 or 1;x is 0 or 1;y is 0 or 1;represents the point of attachment of the linker to the Bcl-xL inhibitor; and* represents the point of attachment to the remainder of the .88. The ADC of embodiment 87, in which peptide is selected from the group consistingof Val-Cit; l; Ala-Ala; Ala-Cit; a; Asn-Cit; Cit-Asn; Cit-Cit; Val-Glu; Glu-Val; Ser-Cit;Cit-Ser; Lys-Cit; Cit-Lys; Asp-Cit; Cit-Asp; Ala-Val; Val-Ala; Phe-Lys; Lys-Phe; Val-Lys; Lys-Val;Ala-Lys; Lys-Ala; Phe-Cit; Cit-Phe; Leu-Cit; Cit-Leu; Ile-Cit; Cit-Ile; Phe-Arg; Arg-Phe; p;and Trp-Cit.89. The ADC of embodiment 85, in which the lysosomal enzyme is β-glucuronidase orβ-galactosidase.90. The ADC of any one of ments 49-84, in which the linker comprises a segmentaccording to structural formula (Va), (Vb), (Vc), (Vd), or (Ve):wherein:q is 0 or 1;r is 0 or 1;X1 is CH2, O or NH;represents the point of ment of the linker to the drug; and* represents the point of attachment to the remainder of the linker.91. The ADC of any one of embodiments 49-84, in which the linker comprises a segmentaccording to structural formulae (VIIIa), (VIIIb), or ):(VIIIa)(VIIIb)(VIIIc)or a hydrolyzed derivative thereof, wherein:Rq is H or –O-(CH2CH2O)11-CH3;x is 0 or 1;y is 0 or 1;G3 is –CH2CH2CH2SO3H or –CH2CH2O-(CH2CH2O)11-CH3;Rw is –O-CH2CH2SO3H or )-CH2CH2O-(CH2CH2O)12-CH3;* represents the point of attachment to the remainder of the linker; andrepresents the point of ment of the linker to the antibody.92. The ADC of any one of embodiments 49-84, in which the linker comprises apolyethylene glycol segment having from 1 to 6 ethylene glycol units.93. The ADC of any one of embodiments 50-84, in which m is 2, 3 or 4.94. The ADC of embodiment 86, in which linker L is selected from IVa or IVb.95. The ADC of any one of embodiments 49-84, in which linker L is selected from thegroup consisting of IVa.1-IVa.8, IVb.1-IVb.19, IVc.1-IVc.7, IVd.1-IVd.4, Va.1-Va.12, Vb.1-Vb.10,Vc.1-Vc.11, Vd.1-Vd.6, Ve.1-Ve.2, VIa.1, VIc.1-V1c.2, VId.1-VId.4, VIIa.1-VIIa.4, VIIb.1-VIIb.8,VIIc.1-VIIc.6 in either the closed or open form.96. The ADC of any one of embodiments 50-84, in which the linker L is selected fromthe group consisting of IVb.2, IVc.5, IVc.6, IVc.7, IVd.4, Vb.9, VIIa.1, VIIa.3, VIIc.1, VIIc.4, andVIIc.5, wherein the maleimide of each linker has reacted with the antibody Ab, forming a covalentment as either a succinimide (closed form) or succinamide (open form).97. The ADC of any one of embodiments 49-84, in which the linker L is selected fromthe group consisting of IVb.2, IVc.5, IVc.6, IVd.4, VIIa.1, VIIa.3, VIIc.1, VIIc.4, , wherein themaleimide of each linker has reacted with the antibody Ab, forming a covalent attachment as either aimide (closed form) or succinamide (open form).98. The ADC of any one of embodiments 49-84, in which the linker L is selected fromthe group consisting of IVb.2, VIIa.3, IVc.6, and VIIc.1, n is the attachment point to drugD and @ is the attachment point to the LK, wherein when the linker is in the open form as shownbelow, @ can be either at the α-position or tion of the carboxylic acid next to it:, and99. The ADC of any one of embodiments 50-84, in which LK is a linkage formed with anamino group on the anti-hB7H3 antibody Ab.100. The ADC of embodiment 98, in which LK is an amide or a thiourea.101. The ADC of any one of embodiments 50-84, in which LK is a linkage formed with asulfhydryl group on the anti-hB7-H3 antibody Ab.102. The ADC of embodiment 101, in which LK is a thioether.103. The ADC of any one of embodiments 50-84, in which:LK is selected from the group ting of amide, thiourea and thioether; andm is an integer ranging from 1 to 8.104. The ADC of embodiment 50, in which:D is the Bcl-xL tor as defined in embodiment 84;L is selected from the group consisting of linkers IVa.8, IVb.1-IVb.19, IVc.1-IVc.7,IVd.1-IVd.4, Va.1-Va.12, Vb.1-Vb.10, Vc.1-Vc.11, Vd.1-Vd.6, Ve.1-Ve.2, VIa.1, VIc.1-V1c.2,VId.1-VId.4, VIIa.1-VIIa.4, VIIb.1-VIIb.8, and -VIIc.6, wherein each linker has reacted withthe antibody, Ab, forming a covalent attachment;LK is thioether; andm is an integer ranging from 1 to 8.105. The ADC of embodiment 50, in which:D is the Bcl-xL inhibitor selected from the group consisting of the following ndsmodified in that the hydrogen corresponding to the # position of structural formula (IIa), (IIb), (IIc),or (IId) is not present, forming a monoradical:6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridinecarboxylic acid;1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]{1-[(3-{2-[(2-carboxyethyl)amino]ethoxy}-5,7-dimethyltricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazol-4-yl}pyridinecarboxylic acid;6-[8-(1,3-benzothiazolylcarbamoyl)naphthalenyl]{1-[(3,5-dimethyl{2-[(2-sulfoethyl)amino]ethoxy}tricyclo[3.3.1.13,7]decyl)methyl]methyl-1H-pyrazolyl}pyridineylic acid;1-{[2-({3-[(4-{6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl]carboxypyridinyl}methyl-1H-pyrazolyl)methyl]-5,7-dimethyltricyclo[3.3.1.13,7]decyl}oxy)ethyl]amino}-1,2-dideoxy-D-arabino-hexitol;6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[3-hydroxy(hydroxymethyl)propyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}--methyl-1H-pyrazolyl)pyridinecarboxylic acid; and6-[8-(1,3-benzothiazolylcarbamoyl)-3,4-dihydroisoquinolin-2(1H)-yl](1-{[3-(2-{[(3S)-3,4-dihydroxybutyl]amino}ethoxy)-5,7-dimethyltricyclo[3.3.1.13,7]decyl]methyl}methyl-1H-pyrazolyl)pyridinecarboxylic acid;L is selected from the group consisting of linkers IVb.2, IVc.5, IVc.6, IVc.7, IVd.4, Vb.9,Vc.11, VIIa.1, , VIIc.1, VIIc.4, and VIIc.5 in either closed or open forms;LK is thioether; andm is an integer ranging from 2 to 4.106. The ADC of embodiment 50, selected from the group consisting of huAb3v2.5-CZ,huAb3v2.5-TX, huAb3v2.5-TV, huAb3v2.5-YY, huAb3v2.5-AAA, huAb3v2.5-AAD, 2.6-CZ, huAb3v2.6-TX, huAb3v2.6-TV, huAb3v2.6-YY, huAb3v2.6-AAD, huAb13v1-CZ, v1-TX, huAb13v1-TV, huAb13v1-YY, v1-AAA, huAb13v1-AAD, wherein CZ, TX, TV, YY,AAA, and AAD are synthons disclosed in Table B, and wherein the conjugated synthons are either inopen or closed form.107. The ADC of embodiment 50, ed from the group consisting of formulae i-vi:(ii),(iii),(iv),(v), and(vi),wherein m is an integer from 1 to 6.108. The ADC of embodiment 107, wherein m is an integer from 2 to 6.109. The ADC of any one of embodiments 49-108, wherein the anti-hB7-H3 antibodycomprises a heavy chain CDR3 domain comprising the amino acid sequence set forth in SEQ IDNO: 12, a heavy chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO:140, and a heavy chain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO:; a light chain CDR3 domain sing the amino acid ce set forth in SEQ ID NO: 15, alight chain CDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 7, and a lightchain CDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 136 or 138.110. The ADC of any one of embodiments , wherein the antibody ses aheavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 139, and alight chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 135.111. The ADC of any one of embodiments 49-108, wherein the antibody comprises eithera heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 139, and alight chain variable region sing the amino acid sequence set forth in SEQ ID NO: 137; or aheavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 147, and alight chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 144.112. The ADC of any one of embodiments 49-108, wherein the antibody comprises a lightchain CDR3 domain sing the amino acid ce set forth in SEQ ID NO: 39, a light chainCDR2 domain comprising the amino acid sequence set forth in SEQ ID NO: 38, and a light chainCDR1 domain comprising the amino acid sequence set forth in SEQ ID NO: 37; and a heavy chainCDR3 domain comprising the amino acid sequence set forth in SEQ ID NO: 35, a heavy chain CDR2domain comprising the amino acid sequence set forth in SEQ ID NO: 34, and a heavy chain CDR1domain comprising the amino acid sequence set forth in SEQ ID NO: 33.113. The ADC of any one of embodiments 49-108, wherein the antibody is an IgG havingfour polypeptide chains which are two heavy chains and two light .114. A pharmaceutical ition comprising an effective amount of an ADC accordingto any one of embodiments , and a pharmaceutically acceptable carrier.115. A pharmaceutical composition comprising an ADC mixture comprising a plurality ofthe ADC of any one of ments 46-113, and a pharmaceutically acceptable carrier.116. The pharmaceutical composition of ment 115, wherein the ADC mixture hasan average drug to antibody ratio (DAR) of 1.5 to 4.117. The pharmaceutical composition of embodiment 115, wherein the ADC mixturecomprises at least 75% ADCs each having a DAR of 2.118. A method for ng cancer, comprising administering a therapeutically effectiveamount of the ADC of any one of embodiments 46-113 to a subject in need thereof.119. The method of embodiment 118, wherein the cancer is selected from the groupconsisting of small cell lung cancer, non small cell lung cancer, breast cancer, ovarian cancer, aglioblastoma, prostate cancer, pancreatic cancer, colon cancer, gastric cancer, melanoma,cellular carcinoma, head and neck cancer, acute myeloid leukemia (AML), non-Hodgkin'slymphoma (NHL), and kidney cancer120. The method of embodiment 119, wherein the cancer is a squamous cell carcinoma.121. The method of embodiment 120, wherein the squamous cell carcinoma is squamouslung cancer or squamous head and neck cancer.122. The method of embodiment 119, wherein the cancer is triple negative breast cancer.123. The method of embodiment 119, n the cancer is non-small cell lung cancer.124. A method for inhibiting or decreasing solid tumor growth in a subject having a solidtumor, said method comprising administering an effective amount of the ADC of any one ofembodiments 46-114 to the subject having the solid tumor, such that the solid tumor growth isinhibited or decreased.125. The method of embodiment 124, wherein the solid tumor is a non-small cell lungcarcinoma.126. The method of any one of embodiments 119-125, wherein the ADC is administeredin combination with an additional agent or an additional y.127. The method of embodiment 126, wherein the additional agent is selected from thegroup consisting of an anti-PD1 antibody (e.g. pembrolizumab), an anti-PD-L1 antibody (e.g.,izumab), an anti-CTLA-4 antibody (e.g. ipilimumab), a MEK tor (e.g. trametinib), anERK inhibitor, a BRAF inhibitor (e.g. dabrafenib), osimertinib, erlotinib, gefitinib, nib, a CDK9inhibitor (e.g. dinaciclib), a MCL-1 inhibitor, temozolomide, a Bcl-xL inhibitor, a Bcl-2 inhibitor(e.g., venetoclax), ibrutinib, a mTOR inhibitor (e.g. everolimus), a PI3K inhibitor (e.g. buparlisib),duvelisib, idelalisib, an AKT inhibitor, a HER2 inhibitor (e.g. lapatinib), a taxane (e.g. docetaxel,paclitaxel, nab-paclitaxel), venetoclax, an ADC comprising an auristatin, an ADC sing a PBD(e.g. rovalpituzumab tesirine), an ADC comprising a maytansinoid (e.g. TDM1), a TRAIL t, aproteasome inhibitor (e.g. bortezomib), and a nicotinamide phosphoribosyltransferase (NAMPT)inhibitor.128. The method of embodiment 125, n the additional therapy is radiation.129. The method of embodiment 125, wherein the additional agent is a chemotherapeuticagent.130. An ed antibody, or antigen binding portion thereof, that binds to human B7-H3(hB7-H3), wherein the antibody, or antigen binding n thereof, comprises a heavy chaincomprising the amino acid sequence of SEQ ID NO: 168 and a light chain comprising the amino acidsequence of SEQ ID NO: 169.131. An isolated antibody, or antigen binding portion thereof, that binds to human B7-H3(hB7-H3), wherein the antibody, or antigen binding portion thereof, comprises a heavy chaincomprising the amino acid sequence of SEQ ID NO: 170 and a light chain comprising the amino acidsequence of SEQ ID NO: 171.132. An isolated antibody, or antigen g portion thereof, that binds to human B7-H3(hB7-H3), wherein the dy, or n binding portion thereof, comprises a heavy chaincomprising the amino acid sequence of SEQ ID NO: 172 and a light chain comprising the amino acidce of SEQ ID NO: 173.133. The method of any one of ments 118-129, wherein the cancer is characterizedas having an activating EGFR mutation.134. The method of embodiment 133, wherein the activating EGFR mutation is edfrom the group ting of an exon 19 deletion mutation, a single-point substitution mutation L858Rin exon 21, a T790M point mutation, and combinations thereof.135. A process for the preparation of an ADC according to structural formula (I):wherein:D is the Bcl-xL tor drug of formula (IIa), (IIb), (IIc), or (IId);L is the ;Ab is an hB7-H3 antibody, wherein the hB7-H3 dy comprises the heavy and light chainCDRs of huAb3v2.5, huAb3v2.6, or huAb13v1;LK represents a covalent linkage linking linker L to antibody Ab; andm is an integer ranging from 1 to 20;the process comprising:treating an antibody in an aqueous solution with an effective amount of a disulfide reducingagent at 30-40 °C for at least 15 minutes, and then cooling the antibody solution to 20-27 °C;adding to the reduced antibody solution a solution of water/dimethyl sulfoxide comprising asynthon selected from the group of 2.1 to 2.176 (Table B);adjusting the pH of the solution to a pH of 7.5 to 8.5;allowing the reaction to run for 48 to 80 hours to form the ADC;wherein the mass is shifted by 18 ± 2 amu for each hydrolysis of a succinimide to asuccinamide as measured by electron spray mass ometry; andn the ADC is optionally purified by hydrophobic interaction chromatography.136. The process of embodiment 135, wherein m is 2.137. An ADC prepared by the s of embodiment 135 or 136.

Claims (11)

1. An isolated anti-hB7H3 antibody, n the antibody ses a heavy chain variable region comprising a CDR3 having an amino acid sequence selected from the group consisting of SEQ ID NO: 12, SEQ ID NO: 35, and SEQ ID NO: 27, a CDR2 having an amino acid sequence selected from the group ting of SEQ ID NO: 140, SEQ ID NO: 34, SEQ ID NO: 11, and SEQ ID NO: 26, and a CDRI having an amino acid ce selected from the group consisting of SEQ ID NO: 10, SEQ ID NO: 25, SEQ ID NO: 33; and a light chain variable region comprising a CDR3 having the amino acid sequence selected from the group consisting of SEQ ID NO: 15, SEQ ID NO: 39, and SEQ ID NO: 31; a CDR2 having an amino acid sequence selected from the group consisting of SEQ ID NO: 7, SEQ ID NO: 38, and SEQ ID NO: 30; and a CDRI having an amino acid sequence selected from the group consisting of SEQ ID NO: 136, SEQ ID NO: 138, SEQ ID NO: 37, SEQ ID NO: 14, and SEQ ID NO: 29.

2. The antibody according to claim 1, wherein the antibody further comprises a human or framework, said human acceptor framework comprises an amino acid sequence selected from the group consisting of SEQ ID Nos: 155, 156, 164, 165, 166, and 167.

3. The antibody according to claim 1, wherein the antibody further comprises a human acceptor framework, said human acceptor framework comprises an amino acid ce selected from the group consisting of SEQ ID NOs: 155 to 158.

4. The anti-hB7-H3 antibody ing to claim 1, wherein the antibody comprises_a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 139 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 135.

5. The anti-hB7-H3 antibody according to claim 1, wherein the antibody comprises_a heavy chain variable domain comprising an amino acid ce set forth in SEQ ID NO: 139 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 137.

6. The anti-hB7-H3 antibody according to claim 1, n the antibody comprises a heavy chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 147 and a light chain variable domain comprising an amino acid sequence set forth in SEQ ID NO: 144.

7. A ceutical composition comprising the anti-hB7-H3 antibody according to claim 1, and a pharmaceutically acceptable carrier.

8. An anti-hB7-H3 Antibody Drug Conjugate (ADC) comprising the anti-hB7-H3 antibody according to claim 1 conjugated to one or more drugs via a linker.

9. The ADC of claim 8, wherein said one or more drugs is an auristatin or a pyrrolobenzodiazepine (PBD).

10. The ADC of claim 8, wherein said one or more drugs is a Bcl-xL inhibitor.

11. An anti-hB7-H3 dy drug conjugate (ADC) sing a drug linked to an anti-human B7-H3 (hB7-H3) antibody via a linker, wherein the drug is a Bcl-xL inhibitor according to structural formula (Ila), (lib), (Ile), or (Ild): (Ila) z 0 R',,- 2a.,.. R��_,.., # (lib) HN.X0 / R.4 R 11b (Ile) (Ild) wherein: J---- N, and � and is optionally tuted with one or more substituents independently selected from halo, hydroxy, nitro, lower alkyl, lower heteroalkyl, C 1 4alkoxy, amino, cyano and halomethyl; ya en� cNnR3Ny 1 A -/ A -/ 1 A -/ ::., , ".:_ A? is selected from , , , o N N C � ( IIJ 7-IIJ (!I J fl0-� -�Nyr,71 N�/ �/ �/ �/ y� J,., ' JVVV ' JVVV ' JVVV ' JVVV ' ' N2}I .._.,,, Ny NII'Y����\t�� ' and I or an N-oxide thereof, and is optionally substituted with one or more substituents independently selected from halo, hydroxy, nitro, lower alkyl, lower alkyl, C1_4alkoxy, amino, cyano and halomethyl, wherein the R12 Z2b-, R' Z2b-, # N(R4) R13 Z2b-, or # R' z2b- substituents are ed to Ar2 at any Ar2 atom capable of being substituted; Z1 is selected from N, CH, Chalo, C CH3 and CCN; Z2a and z2b are each , independently from one another, selected from a bond, NR6, CR6aR6