HK1221953B - Protein tyrosine kinase modulators and methods of use - Google Patents

Description

Tyrosine protein kinase modulators and methods of use thereof

Technical Field

The present invention relates to heterocyclic pyrimidine compounds having the ability to modulate the kinase activity of selectively mutated Epidermal Growth Factor Receptor (EGFR), by modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemical invasion. More specifically, the pyrimidine compounds provided herein are capable of selectively inhibiting, modulating and/or modulating the activity of kinase receptors, particularly the various EGFR mutants associated with changes in cellular activity as described above. The invention also relates to pharmaceutical compositions comprising the pyrimidine derivatives, and methods of treating diseases associated with protein kinase activity, particularly diseases associated with EGFR kinase activity such as non-small cell lung cancer, comprising administering the pyrimidine derivatives.

Background

Epidermal growth factor receptor (EGFR, Erb-Bl) is a member of the protein family, involved in the proliferation of normal and malignant cells (Artega, C.L.J.Clin Oncol 19,2001, 32-40). Overexpression of Epidermal Growth Factor Receptor (EGFR) is present in at least 70% of human cancers (Seymour, L.K., Curr Drug Targets 2,2001,117-133), such as non-small cell lung cancer (NSCLC), breast cancer, neural cellsGliomas, head and neck squamous cell carcinomas, and prostate cancers, among others (Raymond et al, Drugs 60Suppl 1,2000, discussion 41-2; Salomon et al, Crit RevOncol Hematol 19,1995, 183-. Therefore, it is widely considered to be very attractive to develop and design compounds targeting epidermal growth factor receptor tyrosine kinase (EGFR-TK), which target compounds are developed to be capable of specifically binding to tyrosine kinase and inhibiting its activity, blocking its signal transduction pathway in cancer cells, and thus being used as diagnostic or therapeutic agents. For example, the reversible inhibitor of EGFR tyrosine kinase (EGFR-TK) Tarceva (TARCEVA)^RTM) It has been approved by the FDA in the united states for the treatment of NSCLC and advanced pancreatic cancer. Other anti-EGFR target small molecule drugs, including LAPATINIB (LAPATINIB)^RTM) And Iressa (IRESSA)^RTM) Has also been approved.

Erlotinib and gefitinib have limited efficacy in treating various lung cancer patients. When erlotinib or gefitinib is used to treat various lung cancer patients (no activated (mutant) EGFR selected for presence/absence), the tumor shrinkage probability (response rate) is only 8% -10% and the median tumor progression time is about 2 months (Shepherd et al NEJM 2004, thatcher et al lancet 2005). Erlotinib and gefitinib were found to have very good clinical efficacy in 2004 for the treatment of lung cancer containing EGFR somatic mutations (Paez et al science 2004; Lynch et al NEJM 2004; Pao et al PNAS 2004). Somatic mutations identified to date include point mutations, i.e.changes in individual amino acid residues in the expressed protein (e.g.L 858R, G719S, G719C, G719A, L861Q), as well as expression frame deletions or 20 th exon insertions of small fragments of the 19 th exon. EGFR somatic mutations are present in 10-15% of white people and 30-40% of Asian non-small cell carcinoma patients. EGFR mutations are commonly found in non-smokers, women, adenocarcinoma patients, and patients of the east Asian race (Shigematsu et al JNCCI 2005). These patient groups are the same as those previously clinically considered most likely to benefit from erlotinib or gefitinib drugs (Fukuoka et al JCO 2003; Kris et al JAMA 2003and shepherd et al NEJM 2004). To date, there have been six successful clinical treatment cases in patients with EGFR-mutated tumors treated with erlotinib or gefitinib (Inoue et al JCO 2006, Tamura et al Br. Jcancer 2008; Asahina et al., Br.J. cancer 2006; Sequist et al., JCO 2008). The current study has cumulatively diagnosed and treated over 200 patients with EGFR mutant cancer. In patients treated with gefitinib and erlotinib, the imaging response rate was 60-82% with a median time to progression of 9.4 to 13.3 months. The treatment effect of the patient with advanced non-small cell lung cancer is 3-4 times that of the platinum antineoplastic drugs (the imaging reaction rate is 20-30%, and the median progression time is 3-4 months) (Schiller, et al JCO 2002). Results of recently completed phase iii clinical trials showed that treatment of EGFR-mutated non-small cell lung cancer patients with gefitinib had significantly longer progression-free survival (PFS) (risk ratio 0.48 (95% confidence interval, 0.36-0.64); P <0.0001) and tumor treatment response rates (71.3% versus 47.2%; P0.0001) than conventional chemotherapy (Mok et al. In contrast, gefitinib treatment of EGFR wild-type NSCLC patients was less effective than the initial conventional chemotherapy for advanced NSCLC (Mok et al ESMOmeeting 2008). Thus, EGFR mutations provide an important alternative to treatment of NSCLC patients (EGFR TKIs) that is more effective than conventional systemic chemotherapy. EGFR mutations have been used by many clinical centers as a routine indicator for diagnosing NSCLC patients.

Although gefitinib/erlotinib has initial clinical advantages in treating EGFR-mutated NSCLC patients, most patients eventually develop progressive cancer during treatment with these agents. Preliminary studies have shown that patients with recurrent cancer develop secondary mutations to EGFR, such as T790M, mainly because gefitinib and erlotinib are not potent inhibitors of EGFR T790M kinase activity (Kobayashi et al NEJM 2005and Pao et al PLOS mediien 2005). Further studies have shown that approximately 50% (24/48) of tumors from patients with acquired resistance to gefitinib or erlotinib develop the T790M mutation in EGFR (Kosaka et al CCR 2006; Balak et al CCR 2006and Engelman et al Science 2007). This secondary gene mutation occurs primarily at the "gatekeeper" amino acid residues and at similar positions in other secondary drug-resistant alleles in diseases treated with kinase inhibitors (e.g., the ABL T315I mutation in imatinib-resistant Chronic Myelogenous Leukemia (CML) patients).

Preliminary identification of EGFR T790M also indicates that even though it includes the T790M mutation, the irreversible EGFR inhibitor CL-387,785 can still inhibit EGFR. Further studies have shown that other irreversible EGFR inhibitors EKB-569 and HKI-272 can also inhibit phosphorylation of EGFR T790M and the growth of EGFR mutant NSCLC cell lines containing the T790M mutation (Kwaket al PNAS 2005; Kobayashi et al NEJM 2005). These irreversible EGFR inhibitors are similar in structure to the reversible EGFR inhibitors gefitinib and erlotinib, except that they have a Michael receptor that covalently binds to EGFR at Cys 797. The T790M mutation does not prevent binding of EGFR to irreversible inhibitors, but rather, it is capable of conferring resistance to reversible inhibitors to some extent by increasing affinity for atpase, at least in L858R/T790M mutated EGFR (Yun et al, PNAS 2008). Irreversible inhibitors overcome this resistance mechanism because once they covalently bind, they can no longer compete with ATP. These findings have prompted clinical development of irreversible EGFR inhibitors to treat patients with acquired resistance to gefitinib or erlotinib. Currently, three irreversible EGFR inhibitors (HKI-272, BIBW2992 and PF00299804) are in clinical development. However, to date, preclinical experimental results have shown that these drugs are not effective in inhibiting EGFR containing the T790M mutation.

Recent studies in an EGFR L858R/T790M-mediated mouse model of lung Cancer have shown that these mice with bronchomas are not sensitive to HKI-272 alone (Li et al Cancer Cell 2007). Therefore, even in this single EGFR-driven model, HKI-272 alone did not provide tumor shrinkage. In sharp contrast, erlotinib alone had significant effects in treating mouse models of lung cancer caused only by mutations in EGFR (Ji et al cancer cell2006), while HKI-272 was shown to be potentially ineffective in treating NSCLC patients with EGFR T790M. The same problem was also reported for BIBW2992 (Li et al. oncogene 2008). In addition, HKI-272 required for the growth of Ba/F3 cells inhibiting the EGFR T790M mutation caused by deletion of different bases in exon 19 had an IC50 range of 200-800nM, whereas the mean Cmax in one phase clinical trial was only about 200nM (Yuza et al Cancer biol 2007; Wong et al CCR 2009in press). Therefore, it is necessary to develop EGFR target drugs capable of effectively inhibiting EGFR T790M.

The major drawback of all current EGFR inhibitors is that they are also toxic to normal tissues. Because EGFR T790M has similar ATP affinity to wild-type EGFR, the concentration of irreversible EGFR inhibitor required to inhibit EGFR T790M, while also effectively inhibiting wild-type EGFR. The clear toxicity of current EGFR kinase inhibitors, rash and diarrhea, is the result of inhibition of wild-type EGFR in non-cancerous cell tissues. This toxic effect of inhibiting wild-type EGFR prevents the dose of the inhibitor from being escalated to a plasma level that is effective to inhibit EGFR T790M. It is currently desirable to develop inhibitors that recognize specific mutations of EGFR, but have little effect on wild-type EGFR. Such drugs would be more clinically effective and have better compliance as therapeutic agents for cancer patients.

Anaplastic Lymphoma Kinase (ALK) belongs to the Receptor Tyrosine Kinase (RTK) superfamily of protein kinases. ALK expression in normal adult tissues is restricted to endothelial cells, pericytes and a few neural cells. Oncogenic, constitutively active ALK fusion proteins are expressed in Anaplastic Large Cell Lymphoma (ALCL) and Inflammatory Myofibroblastoma (IMT). ALK has recently been considered an oncogene in a small proportion of non-small cell lung cancers and neuroblastomas (Choi et al, Cancer Res 2008; 68 (13); Webb et al, Expert Rev. anticancer The.9 (3),331-356, 2009).

Anaplastic Large Cell Lymphomas (ALCLs) are a subtype of the highly non-hodgkin lymphoma family with definite morphology, immunophenotype and prognosis. Given that ALCLs are derived from T cells, in a small number of cases, they may also exhibit a B cell phenotype. In addition, cell origin is unknown in 40% of cases, and is classified as "null". Based on the expression of CD30(Ki-1), first described by Stein et al as a histological entity, ALCL appears to be a systemic disease affecting the skin, bone, soft tissues and other organs, including or not including lymph nodes. ALCL can be divided into at least two subtypes characterized by the presence or absence of chromosomal rearrangements between Anaplastic Lymphoma Kinase (ALK) genetic loci and various fusion partners such as Nuclear Phosphoprotein (NPM). About 50-60% of cases of ALCL are associated with t (2; 5) (p 23; q35) chromosomal translocations, which result in a hybrid gene consisting of the intracellular domain of the ALK tyrosine kinase receptor juxtaposed to the NPM. The resulting fusion protein NPM-ALK has constitutive tyrosine kinase activity and has been shown to transform a variety of hematopoietic cell types in vitro and support tumor formation in vivo.

NPM-ALK is an oncogenic fusion protein variant of anaplastic lymphoma kinase, which is produced by chromosomal ectopic events and is implicated in the pathogenesis of human anaplastic large cell lymphoma (Pulford K, Morris SW, TurturroF. anaplastic lymphoma kinase proteins in growth control and cancer. J. CellPhysiol 2004; 199: 330-58). The role of aberrant expression of constitutively active ALK chimeric proteins in the pathogenesis of ALCL has been well established (Weihua Wan, et al. adaptive lymphoma kinase activity infection for the promotion and preservation of adaptive large cell culture, blood First Edition Paper, prepublished online October 27,2005; DOI 10.1182/blood-2005-08-3254). NPM-ALK is closely associated with abnormalities in cell proliferation and apoptosis of lymphoma cells in ALCL (Pulford et al, 2004).

Other less frequent ALK fusion partners, such as tropomyosin-3 and clathrin heavy chain, were also identified in ALCL and CD 30-negative diffuse large cell lymphomas. Despite minor differences in signaling and some biological functions, it appears that all fusions are transformed into fibroblasts and hematopoietic cells. Extensive analysis of the leukemic potential of NPM-ALK in animal models has further confirmed the importance of NPM-ALK and other ALK rearrangements in the development of ALK-positive ALCL and other diseases.

ALK fusion proteins have also been detected in cell lines and/or primary samples representing a variety of other tumors including Inflammatory Myofibroblastoma (IMT), neuroectodermal tumors, glioblastoma, melanoma, rhabdomyosarcoma and esophageal squamous cell carcinoma (see review of Webb TR, Slavish J et al, anticancer lymphoma: roll in cancer and small-molecule inhibitor evaluation for therapy. Ext review of anticancer The R. 2009; 9(3): 331. 356). ALK has also been recently implicated in a Small proportion of Breast, Colorectal and Non-Small Cell Lung cancers (Lin E, Li L et al Exon Array Profiling EML 4-ALKFusation in Breast, Colorectal, and Non-Small Cell Lung Cancer. mol Cancer Res 2009; 7(9): 1466-76).

ALK fusions are present in approximately 3-7% of lung cancers, and many reports confirm the presence of multiple different ALK recombinations in NSCLC. Most ALK fusion variants include a portion of the echinoderm microtubule-associated protein-like 4(EML4) gene and the ALK gene. At least 9 different EML4-ALK fusion variants have been found in NSCLC (Takeuchi et al multiple reverse transcription-PCR screening for EML4-ALK fusion transitions. clincancer res.2008,15(9): 3143-9). In addition, non-EML 4 fusion partners were also found, including KIF5B-ALK (Takeuchi et al. KIF5B-ALK, a novel fusion oncokinase identified by immunological-based diagnostic system for ALK-positional regulator. 2009,15(9):3143-9) and TFG-ALK (Rikova et al. Global summary of phosphorus hybridization activities oncogenic regulators in cellular regulator. Cell2007,131(6): 1190-.

Multiple N-terminal fusion partners promote dimerization and constitutive kinase activity. Downstream signaling of ALK fusions leads to activation of cellular pathways for cell growth and proliferation. (Mosse et al. inhibition of ALK signaling for Cancer therapy. Clin Cancer Res.2009, (15) (18): 5609-14).

Disclosure of Invention

The present invention relates to heterocyclic pyrimidines as EGFR or ALK inhibitors and their use in the treatment of diseases mediated by EGFR or ALK. The compound has a general structure shown in a formula I or pharmaceutically acceptable salt thereof:

wherein the content of the first and second substances,

x is selected from absent, O, S or NR₁₆(ii) a Wherein R is₁₆Is selected from H or C_1-6An alkyl group;

y is selected from halogen, OH, NH₂、CN、N₃、NO₂Or substituted or unsubstituted C_1-6An alkyl group;

z is selected from O, S, NR₂₀Or CR₂₀R₂₁(ii) a Wherein each R₂₀And R₂₁Each independently selected from H, halogen, substituted or unsubstituted C_1-6Alkyl, or substituted or unsubstituted C_1-6An alkoxy group;

R₁selected from OH, N (R)₈)(R₉)、N(R₈)(CH₂)N(R₈)(R₉)、N(R₈)(R₉)CO(R₉)、N(R₈)CO(R₉)、C(O)R₈、C(O)OR₈、C(O)NH₂、C(O)NH(R₈)、C(O)N(R₈)(R₉) Alkyl, haloalkyl, aryl, arylalkyl, alkoxy, heteroaryl, heterocyclyl or cycloalkyl, each optionally substituted or unsubstituted; each R₈And R₉Each independently selected from H, OH, alkyl, alkenyl, vinyl, heterocyclyl, cycloalkyl, or cycloalkyl, and each optionally substituted;

R₂selected from H, F or C_1-4An alkyl group; or

R₂And R₁And the atoms to which they are attached together form a 5-7 membered heterocyclic ring, wherein said heterocyclic ring contains 1-3 substituents each independently selected from P, N, O orS, the heterocycle may be substituted or unsubstituted;

R₃selected from H, halogen or a5 or 6 membered heterocyclic ring containing 1 or 2N atoms, which heterocyclic ring may be substituted or unsubstituted; or

R₂And R₃Taken together to form a 5-12 membered substituted or unsubstituted heterocyclic ring containing 1,2, 3 or 4 heteroatoms each independently selected from N or O;

R₄selected from H, C_1-6Alkoxy radical, C_3-6Alkenyloxy radical, C_3-6Cycloalkoxy, halogen, -O-heterocyclyl, heterocyclyl or-NR₂₄(CH₂)_PNR₂₄R₂₅And each is optionally substituted or unsubstituted; p is selected from 0, 1,2 or 3, and each R₂₄And R₂₅Each independently selected from H, halogen, substituted or unsubstituted C_1-6Alkyl or substituted or unsubstituted C_1-6An alkoxy group;

R₅selected from H, F, C_1-6Alkyl, haloalkyl, C_1-6Alkoxy, cycloalkoxy, alkoxy, cycloalkoxy, and cycloalkoxy,

-NR₁₅C(O)(CH₂)_nCR₁₇＝CR₁₈R₁₉、-NR₁₅C(O)(CH₂)_nOCHR₁₇R₁₈、

-NR₁₅C(O)(CH₂)_nCR₁₇(CH₂)_mCHR₁₈R₁₉、-NR₁₅C(O)(CH₂)_nCR₁₇＝CH(CH₂)_mNR₁₈R₁₉、

-NR₁₅C(O)CR₁₇(CH₂)_mNR₁₈(CH₂)_nNR₁₈R₁₉、-NR₁₅C(O)(CH₂)_nCHR₁₇R₁₈、

-NR₁₅C(O)(CH₂)_nCR₁₇(CH₂)_mCHR₁₈R₁₉Or isAnd each is optionally substituted or unsubstituted; or R₅Is a 5-or 6-membered heterocyclic ring containing 1,2 or 3 heteroatoms each independently selected from N or O, which heterocyclic ring may be substituted or unsubstituted; each R₁₅、R₁₇、R₁₈And R₁₉Each independently selected from the group consisting of absent, -H, -OH, -NH₂Halogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl, a linkage, or heteroaryl, each of which is optionally substituted or unsubstituted; m and n are each independently selected from 0, 1,2 or 3;

R₇selected from H, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_3-6Alkenyloxy radical, C_3-6Cycloalkoxy, -OC (O) N (R)₁₀)(R₁₁)、-NR₁₀C(O)OR₁₁、-NR₂₂C(O)CR₂₃＝CR₁₀R₁₁、-NR₂₂C(O)CR₂₃(CH₂)_sCHR₁₀R₁₁、-NR₂₂C(O)CR₂₃＝CR₁₀(CH₂)_sR₁₁、-NR₂₂C(O)CR₂₃(CH₂)_sNR₁₀(CH₂)_tNR₁₀R₁₁or-NR₂₂C(O)(CH₂)_sCR₂₃＝CH(CH₂)_tNR₁₀R₁₁And each is optionally substituted or unsubstituted; or is a 5-or 6-membered heterocyclic ring containing 1,2 or 3 heteroatoms independently selected from N or O, which heterocyclic ring may be substituted or unsubstituted; each R₁₀、R₁₁、R₂₂And R₂₃Each independently selected from H, alkyl, alkenyl, alkynyl, heterocyclic radical, cycloalkyl, cycloalkoxy, heteroalkylOr a connecting bond, each optionally substituted or unsubstituted; or R₁₀And R₁₁And the atoms to which they are attached together form a 3-, 4-, 5-or 6-membered heterocyclic ring, which may be substituted or unsubstituted; each s and t is independently selected from 0, 1,2 or 3;

R₆can be mixed with R₇Together form a 6-membered heterocyclic ring, or R₆Selected from H, halogen, -CN, -NO₂Cycloalkyl, heteroalkyl, heterocyclyl, heterocycle-CO-alkyl, heterocycle-CO-alkenyl, heteroaryl, -R₁₂、-OR₁₃、-O-NR₁₂R₁₃、-NR₁₂R₁₃、-NR₁₂-NR₁₂R₁₃,、-NR₁₂-OR₁₃、-C(O)GR₁₃、-OC(O)GR₁₃、-NR₁₂C(O)GR₁₃、-SC(O)GR₁₃、-NR₁₂C(＝S)GR₁₃、-OC(＝S)GR₁₃、-C(＝S)GR₁₃、-YC(＝NR₁₂)GR₁₃、-GC(＝N-OR₁₂)GR₁₃、-GC(＝N-NR₁₂R₁₃)GR₁₃、-GP(＝O)(GR₁₂)(GR₁₃)、-NR₁₂SO₂R₁₃、-S(O)_rR₁₃、-SO₂NR₁₂R₁₃、-NR¹SO₂NR₁₂R₁₃、-O(CH₂)_rR₁₃、-O(CH₂)_rNR₁₂R₁₃、-NR₁₂(CH₂)_rNR₁₂R₁₃、-NR₁₂(CH₂)_rR₁₃、-(CH₂)_rNR₁₂R₁₃or-CH₂O(CH₂)_rNR₁₂R₁₃And each is optionally substituted or unsubstituted; or

Each G is independently selected from the group consisting of a bond, -O-, -S-, and-NR-₁₅(ii) a Each of whichR₁₂、R₁₃And R₁₅Each independently selected from H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl or heteroaryl, and each optionally substituted or unsubstituted;

r is selected from 0, 1,2 or 3;

each A₁And A₂Each independently selected from CH or N; r₁₄Selected from alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroalkyl, heterocyclyl or heteroaryl, each of which is optionally substituted or unsubstituted.

The invention further provides some preferable technical schemes for the compound shown in the formula (I).

In some embodiments, Y in formula (I) is selected from halogen or substituted or unsubstituted C_1-6An alkyl group.

In some embodiments, Y in formula (I) is selected from halogen, methyl, or halogen substituted methyl.

In some embodiments, Y in formula (I) is selected from Cl or CF₃。

In some embodiments, Y in formula (I) is CH₃。

In some embodiments, X in formula (I) is NR₁₆。

In some embodiments, R in formula (I)₁₆Is H.

In some embodiments, Z in formula (I) is selected from O or CH₂。

In some embodiments, Z in formula (I) is O.

In some embodiments, r in formula (I) is selected from 0, 1 or 2.

In some embodiments, r in formula (I) is 3.

In some embodiments, each R in formula (I)₆Each independently selected from H, halogen, -R₁₂、-OR₁₃or-NR₁₂R₁₃And each is optionally substituted or unsubstituted.

In some embodiments, each R in formula (I)₆And R₇Taken together to form a 6-membered heterocyclic ring which may optionally be H, OH, alkyl, alkenyl, heterocyclyl, cycloalkyl, -OR₁₃、-C(O)R₁₂、-NR₁₂R₁₃Or cycloalkyl substitution; or R₆Is selected from-O (CH)₂)_rR₁₃、-O(CH₂)_rNR₁₂R₁₃、-NR₁₂(CH₂)_rNR₁₂R₁₃、-NR₁₂(CH₂)_rR₁₃、-(CH₂)_rNR₁₂R₁₃or-CH₂O(CH₂)_rNR₁₂R₁₃And each is optionally substituted or unsubstituted, said substituents being selected from substituted or unsubstituted C_1-6Alkyl, substituted or unsubstituted C_2-6Alkenyl, substituted or unsubstituted C_2-6Alkynyl, haloalkyl, halogen, substituted or unsubstituted alkoxy, -NH₂、–NCH₃CH₃or-NHCH₃。

In some embodiments, each R in formula (I)₁₂、R₁₃Or R₁₅Each independently selected from H and (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_3-6) Cycloalkyl or (C)_3-6) Heterocyclyl, and each is optionally substituted or unsubstituted.

In some embodiments, each R in formula (I)₆Selected from-OH, -OEt, -NH₂、-NHCH₃、-NCH₃CH₃、

In some embodiments, each R in formula (I)₆Selected from-H, -F,

In some embodiments, each R in formula (I)₂And R₃Each independently selected from H or halogen.

In some embodiments, R in formula (I)₂And R₃Are all H.

In some embodiments, R in formula (I)₁Selected from OH, N (R)₈)(R₉) Alkyl, alkoxy or haloalkyl, and each is optionally substituted or unsubstituted.

In some embodiments, each R in formula (I)₈And R₉Each independently selected from H, OH, C_1-6Alkyl or C_2-6An alkenyl group.

In some embodiments, each R in formula (I)₈And R₉Each independently selected from methyl or vinyl.

In some embodiments, each R in formula (I)₈And R₉Each independently selected from heterocyclyl, cycloalkyl or cycloalkyl, and each optionally substituted or unsubstituted.

In some embodiments, each R in formula (I)₁Each independently selected from-OH, -OEt, -NHOH and-NH₂、-NHCH₃、-NCH₃CH₃、-NHCH₂CH₂NCH₃CH₃、-NHCH₂CH₂OH、

In some embodiments, each R in formula (I)₁Are each independently selected from-CH₂CH₃、

In some embodiments, R in formula (I)₂、R₃And R₅Are all H.

In some embodiments, R in formula (I)₄Is selected from C_1-6Alkoxy radical, C_3-6Alkenyloxy or C_3-6A cycloalkoxy group.

In some embodiments, R in formula (I)₄Selected from H, -OCH₃、-OEt、

In some embodiments, R in formula (I)₄Selected from halogen, -O-heterocyclyl, heterocyclyl or-NR₂₄(CH₂)_PNR₂₄R₂₅And each is optionally substituted or unsubstituted; p is selected from 1 or 2, each R₂₄And R₂₅Are each independently selected from C_1-6Alkyl radical, C_1-6Alkoxy, -NHOH, -NH₂、NHCH₃、NCH₃CH₃Or a halogen.

In some embodiments, R in formula (I)₄Selected from the group consisting of H, F, -OCH₃、

In some embodiments, R in formula (I)₅Selected from H, haloalkyl, C_1-6Alkoxy, -NR₁₅C(O)(CH₂)_nCR₁₇＝CR₁₈R₁₉、-NR₁₅C(O)(CH₂)_nOCHR₁₇R₁₈、-NR₁₅C(O)(CH₂)_nCR₁₇＝CH(CH₂)_mNR₁₈R₁₉、-NR₁₅C(O)CR₁₇(CH₂)_mNR₁₈(CH₂)_nNR₁₈R₁₉or-NR₁₅C(O)(CH₂)_nCHR₁₇R₁₈And each is optionally substituted or unsubstituted with a substituent selected from C_1-6Alkoxy, -NH₂、-NHCH₃、-NCH₃CH₃、-NHOH、C_1-6Alkyl, halogen or a linkage; each R₁₅、R₁₇、R₁₈And R₁₉Each independently selected from absent, -H, C_1-6Alkyl, alkenyl, C_1-6Alkoxy, -NHOH, -NH₂、-NHCH₃、-NCH₃CH₃A connecting bond or C_3-6A heterocyclic group; each of m and n is independently selected from 0, 1 or 2.

In some embodiments, R in formula (I)₅Selected from H, methyl, halogen substituted methyl, methoxy,

In some embodiments, R in formula (I)₇Selected from H, C_1-6Alkyl, -NR₂₂C(O)CR₂₃＝CR₁₀R₁₁、-NR₂₂C(O)CR₂₃(CH₂)_sCHR₁₀R₁₁、-NR₂₂C(O)CR₂₃＝CR₁₀(CH₂)_sR₁₁、-NR₂₂C(O)CR₂₃(CH₂)_sNR₁₀(CH₂)_tNR₁₀R₁₁or-NR₂₂C(O)(CH₂)_sCR₂₃＝CH(CH₂)_tNR₁₀R₁₁And each is optionally substituted or unsubstituted; each R₁₀、R₁₁、R₂₂And R₂₃Each independently selected from H, alkyl, alkenyl, heterocyclyl, cycloalkyl, cycloalkoxy, heteroalkyl, or a linkage, and each optionally substituted with a substituent C_1-6Alkyl, alkoxy, heterocyclyl, cycloalkyl, cycloalkoxy, heteroalkyl, or a linkage; each s and t is independently selected from 0, 1 or 2.

In some embodiments, R in formula (I)₇Selected from H, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,

In some embodiments, the compound of formula (I), i.e., the compound of formula (II):

the invention further provides some more preferred technical schemes of the formula (II).

In some embodiments, X in formula (II) is NH.

In some embodiments, Y in formula (II) is selected from halogen or haloalkyl.

In some embodiments, Y in formula (II) is selected from Cl or CF₃。

In some embodiments, Y in formula (II) is C_1-6An alkyl group.

In some embodiments, Y in formula (II) is CH₃。

In some embodiments, each R in formula (II)₁Selected from-OH, -OEt, -NHOH, -NH₂、-NHCH₃、-NCH₃CH₃、-NHCH₂CH₂NCH₃CH₃、-NHCH₂CH₂OH、

In some embodiments, each R in formula (II)₁Are each independently selected from-CH₂CH₃、

In some embodiments, R in formula (II)₂、R₃、R₅And R₇Are all H.

In some embodiments, R in formula (II)₂、R₃And R₅Are all H.

In some embodiments, R in formula (II)₅Selected from H, halogen substituted methyl, methoxy,

In some embodiments, R in formula (II)₄Selected from the group consisting of H, F, -OCH₃、

In some embodiments, each R in formula (II)₆Independently selected from-OH, -OEt, -NHOH, -NH₂、-NHCH₃、-NCH₃CH₃、

In some embodiments, each R in formula (II)₆Independently selected from-H, -F,

The present invention further provides certain particularly preferred embodiments of compounds of formula (I) or formula (II), wherein:

1) ethyl 2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetate;

2)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetic acid;

3)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-hydroxy-2-oxoacetamide;

4)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

5) ethyl 2- (2- (5-chloro-2- (4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) acrylate;

6)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

7)2- (2- ((2- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

8)2- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

9)2- (2- ((5-chloro-2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

10)2- (2- ((2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

11)2- (2- ((2- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

12)2- (2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

13)2- (2- ((2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

14)2- (2- ((2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

15)2- (2- ((2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetic acid;

16)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

17)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

18)1- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-morpholinoethane-1, 2-dione;

19)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N- (2-dimethylaminoethyl) -2-oxoacetamide;

20)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methylaminopiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -N- (2-hydroxyethyl) -2-oxoacetamide;

21)1- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -3-methylbutane-1, 2-dione;

22)1- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) propane-1, 2-dione;

23)1- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -3- (dimethylamino) propane-1, 2-dione;

24)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N- (azetidin-3-yl) -2-oxoacetamide;

25)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-cyclopropyl-2-oxoacetamide;

26)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxo-N- (pyrrolidin-3-yl) acetamide;

27)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxo-N- (piperidin-4-yl) acetamide;

28)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

29)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylic acid;

30)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

31)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylic acid;

32)2- (2- ((5-chloro-2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

33)2- (2- ((5-chloro-2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylic acid;

34)2- (2- ((5-chloro-2- ((2-methoxy-4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

35)2- (2- ((5-chloro-2- ((2-methoxy-4- (1-methylpiperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylic acid;

36)2- (2- ((5-chloro-2- ((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

37)2- (2- ((5-chloro-2- ((2-methoxy-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylic acid;

38)2- (2- ((5-chloro-2- ((4- (4-fluoropiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

39)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methoxypiperidin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) acrylamide;

40) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

41) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- (morpholinylmethyl) acrylamide;

42)1- (2- ((2- (4- (4-acetylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -2-morpholinoethane-1, 2-dione;

43)1- (2- ((2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-morpholinoethane-1, 2-dione;

44)1- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -2-morpholinoethane-1, 2-dione;

45)1- (2- ((2- (4- (4- (dimethylamino) piperidin-1-yl) -2-methoxyphenylamino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-morpholinoethane-1, 2-dione;

46)2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

47)2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

48)2- (2- ((5-chloro-2- (2-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

49)2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-cyclopropyl-2-oxoacetamide;

50)2- (2- ((2- (4- (4-acetylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N-cyclopropyl-2-oxoacetamide;

51)2- (2- ((5-chloro-2- (2-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) amino) phenyl) -N-cyclopropyl-2-oxoacetamide;

52)2- (2- ((5-chloro-2- (2-methoxy-4- (4-propionylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

53)2- (2- ((2- (4- (4-acetylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

54)2- (2- ((5-chloro-2- (2-methoxy-4- (4-propionylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

55) n- (1-acryloylazetidin-3-yl) -2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

56) 2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N- (1-acryloylpiperidin-4-yl) -2-oxoacetamide;

57) n- (3- ((5-chloro-4- (2- (2- (methylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

58) n- (3- ((4- (2- (2-amino-2-oxoacetyl) phenylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide;

59) 2- (2- ((5-chloro-2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N- (1-acryloylpiperidin-4-yl) -2-oxoacetamide;

60)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

61)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

62)2- (2- ((5-chloro-2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

63)2- (2- ((5-chloro-2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

64) n- (5- ((5-chloro-4- (2- (2- (methylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

65) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

66) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide;

67) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

68) n- (5- ((5-chloro 4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-fluoro-2-methoxyphenyl) acrylamide;

69) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-fluoro-2-methoxyphenyl) acrylamide;

70) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) but-2-enamide;

71) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -3-methylbut-2-enamide;

72) (E) -N- (3- (5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -4-methoxyphenyl) -4- (piperidin-1-yl) but-2-enamide;

73) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

74) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

75) n- (5- ((5-chloro-4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

76) n- (3- ((5-chloro-4- (2- (2- (2- (dimethylamino) ethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

77) n- (3- ((5-chloro-4- (2- (2- (2- (dimethylamino) ethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

78) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((dimethylamino) methyl) acrylamide;

79) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -4-morpholinylbut-2-enamide;

80) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -4- (dimethylamino) but-2-enamide;

81) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide;

82) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide;

83) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide;

84) n- (5- ((5-chloro-4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide;

85) n- (3- ((5-chloro-4- (2- (2-morpholinyl-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

86) n- (5- ((5-chloro-4- (2- (2- (2- (dimethylamino) ethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

87)2- (2- ((2- ((4-acryloyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

88)2- (2- ((2- (4- (4-acryloylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

89) n- (3- ((5-chloro-4- (2- (2- (4-methylpiperazin-1-yl) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

90) n- (3- ((5-chloro-4- (2- (2-morpholinyl-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

91) n- (3- ((5-chloro-4- (2- (2- (4-methylpiperazin-1-yl) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

92) n- (5- ((5-chloro-4- (2- (2-morpholinyl-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

93) n- (5- ((5-chloro-4- (2- (2- (4-methylpiperazin-1-yl) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

94)2- (2- ((2- (4- (4-acetylpiperazin-1-yl) -3-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

95)2- ((aziridin-1-yl) methyl) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

96)2- ((azetidin-1-yl) methyl) -N- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

97) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((pyrrolidin-1-yl) methyl) acrylamide;

98) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (2-morpholinoethoxy) phenyl) acrylamide;

99) n- (5- (5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide;

100) n- (3- ((4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) -5-methylpyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((dimethylamino) methyl) acrylamide;

101) n- (5- ((4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) -5-methylpyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

102) n- (5- ((5-chloro-4- (2- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

103) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) -3-methoxypropionamide;

104) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-cyclopropoxyphenyl) acrylamide;

105) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (cyclopentyloxy) phenyl) acrylamide;

106) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((1-methylpyrrolidin-3-yl) oxo) phenyl) acrylamide;

107) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4- (dimethylamino) cyclohexyloxo) phenyl) acrylamide;

108) n- (2- ((azetidin-3-yl) oxo) -5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

109) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((1-methylazetidin-3-yl) oxo) phenyl) acrylamide;

110) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-morpholinylphenyl) acrylamide;

111) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

112) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- (morpholinylmethyl) acrylamide;

113) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

114) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide;

115) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) acrylamide;

116) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (difluoromethoxy) phenyl) acrylamide;

117)2- (2- ((5-chloro-2- (3-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

118)2- (2- ((5-chloro-2- (4- (4-dimethylaminopiperidin-1-yl) -3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

119)2- (2- ((5-chloro-2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

120) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) propionamide;

121) (E) -N- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) -3- (dimethylamino) acrylamide;

122) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-propoxyphenyl) acrylamide;

123) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-fluorophenyl) -3-morpholinylpropanamide;

124) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

125) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- (((2- (dimethylamino) ethyl) (meth) amino) methyl) acrylamide;

126) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- (((2- (dimethylamino) ethyl) (meth) amino) methyl) acrylamide;

127) n- (3- ((5-chloro-4- (2- (2- ((2-dimethylaminoethyl) (methyl) amino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

128) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

129) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-morpholinylphenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

130)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-diethyl-2-oxoacetamide;

131) n- (3- ((5-chloro-4- (2- (2-diethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

132) n- (5- ((5-chloro-4- (2- (2-diethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

133) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -5- (trifluoromethyl) phenyl) acrylamide;

134) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide;

135) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4- (4-methylpiperazin-1-yl) phenyl) acrylamide;

136) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -4- ((tetrahydrofuran-3-yl) oxo) phenyl) acrylamide;

137) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethoxy) methyl) phenyl) acrylamide;

138) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethoxy) methyl) -4-methoxyphenyl) acrylamide;

139) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((dimethylamino) methyl) phenyl) acrylamide;

140) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((dimethylamino) methyl) -4-methoxyphenyl) acrylamide;

141) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((4-methylpiperazin-1-yl) methyl) phenyl) acrylamide;

142) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- ((4-methylpiperazin-1-yl) methyl) phenyl) acrylamide;

143) n- (5- (5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -2- (1-methylpiperidin-4-yl) phenyl) acrylamide;

144) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (1-methylpiperidin-4-yl) phenyl) acrylamide;

145)2- (2- ((5-chloro-2- (3-methoxy-4- (1-methylpiperidin-4-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

146)2- (2- ((2- (4- (1-acetylpiperidin-4-yl) -3-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

147) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethyl) phenyl) acrylamide;

148) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (3- (dimethylamino) propyl) phenyl) acrylamide;

149)2- (2- ((5-chloro-2- (4- (1-isopropylpiperidin-4-yl) -3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

150)2- (2- ((5-chloro-2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of at least one of the above compounds and a pharmaceutically acceptable excipient, such as hydroxypropylmethylcellulose. In some compositions, the weight ratio of the compound to the adjuvant is about 0.0001 to about 10.

In addition, the invention also provides the application of the pharmaceutical composition of the formula (I) or the formula (II) in preparing medicines.

The invention further provides a preferable technical scheme of the application.

In some embodiments, the medicament is for treating, preventing, delaying or arresting the onset or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease or ocular disorder.

In some embodiments, the medicament is for use as a kinase inhibitor.

In some embodiments, the kinase comprises EGFR, ALK fusion protein, Flt3, Jak3, Blk, Bmx, Btk, HER2(ErbB2), HER4(ErbB4), Itk, Tec, or Txk.

In some embodiments, the EGFR is a mutated EGFR; the cancer is an EGFR-induced cancer characterized by the occurrence of one or more mutations selected from the group consisting of: (i) L858R, (ii) T790M, (iii) L858R and T790M, (iv) del E746_ A750, or (v) del E746_ A750 and T790M.

In some embodiments, the EGFR-induced cancer is non-small cell lung cancer (NSCLS), glioblastoma, pancreatic cancer, head and neck cancer (e.g., squamous cell carcinoma), breast cancer, large bowel cancer, epithelial cancer, ovarian cancer, prostate cancer, or adenocarcinoma.

In some embodiments, the ALK fusion protein is MEL4-ALK or NPM-ALK kinase.

In some embodiments, the subject is a human.

The invention also provides methods of administering a compound of formula (I) or formula (II) or a pharmaceutical composition as described above for inhibiting kinase activity in a subject.

The invention further provides a preferable technical scheme of the method.

In some embodiments, the kinase comprises EGFR, ALK fusion protein, Flt3, Jak3, Blk, Bmx, Btk, HER2(ErbB2), HER4(ErbB4), Itk, Tec, or Txk.

In some embodiments, the EGFR is a mutant EGFR and the ALK fusion protein is MEL4-ALK or NPM-ALK kinase.

In addition, the present invention provides a method of treating a disease in a subject, the method comprising administering to the subject a compound of formula (I) or formula (ii) or a pharmaceutical composition as described above.

The invention further provides a preferable technical scheme of the method.

In some embodiments, the disease is caused by a disorder in the regulation of kinases including EGFR, ALK fusion protein, Flt3, Jak3, Blk, Bmx, Btk, HER2(ErbB2), HER4(ErbB4), Itk, Tec, or Txk.

In some embodiments, the disease is an EGFR-induced cancer characterized by one or more mutations selected from the group consisting of: (i) L858R, (ii) T790M, (iii) L858R and T790M, (iv) del E746_ A750, or (v) del E746_ A750 and T790M.

In some embodiments, the EGFR-induced cancer is selected from non-small cell lung cancer (NSCLS), glioblastoma, pancreatic cancer, head and neck cancer (e.g., squamous cell carcinoma), breast cancer, large bowel cancer, epithelial cancer, ovarian cancer, prostate cancer, or adenocarcinoma.

In some embodiments, the ALK fusion protein is MEL4-ALK or NPM-ALK kinase.

In some embodiments, the subject is a human.

The term "EGFR-induced cancer" refers to a cancer caused by a mutation in the EGFR gene that alters the biological activity of the EGFR nucleic acid molecule or polypeptide, including the specific mutations referred to in the present invention. EGFR-induced cancer can occur in any tissue, including brain, blood, connective tissue, liver, oral cavity, muscle, spleen, stomach, testis, and trachea. EGFR-induced cancers include: non-small cell lung cancer (NSCLS) including one or more of squamous cell carcinoma, adenocarcinoma, bronchioloalveolar carcinoma (BAC), locally invasive BAC, adenocarcinoma with BAC characteristics, and large cell carcinoma; neuroma, such as glioblastoma; pancreatic cancer; head and neck cancer (e.g., squamous cell carcinoma); breast cancer; large bowel cancer; epithelial cancers, including squamous cell carcinoma; ovarian cancer; prostate cancer; adenocarcinoma; and other cancers mediated by EGFR.

The term "EGFR mutation" or "mutation" refers to one or more deletions, substitutions or insertions in the amino acid or nucleotide sequence of the EGFR protein or the EGFR coding sequence. EGFR mutations also include deletions, substitutions, or insertions of one or more segments, so long as the mutation retains or increases tyrosine kinase activity as compared to wild-type EGFR. Kinase or phosphorylation activity may be increased (e.g., by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or even 100%) in a particular EGFR mutation as compared to wild-type EGFR. A particular EGFR mutation, as described herein, refers to a mutation at a position relative to an amino acid in human EGFR, as described in NCBI GenBank reference sequence NP-005219.2.

As used herein, the term "inhibiting the proliferation of cells expressing EGFR mutations" refers to measurable slowing, arresting or reversing of the growth rate of cells expressing EGFR in vivo or in vitro. Ideally, the cell growth rate can be reduced by at least 10%, 20%, 30%, 50% or even 70% by measuring the cell growth rate by a suitable assay (such as the cell growth assay described herein). The EGFR mutation may be any EGFR mutation described in the present invention.

Furthermore, the present invention provides the use of at least one compound as described above for the treatment of cancer, the prevention of cancer metastasis, the treatment of cardiovascular diseases, immunological diseases or ocular disorders.

The present invention also provides a method of treating a patient suffering from a condition mediated by protein kinase activity, comprising administering to the patient a therapeutically effective amount of at least one compound of the invention, or a pharmaceutically acceptable salt thereof, as described above. Examples of such protein kinases include mutated EGFR, KDR, Tie-2, Flt3, FGFR3, AbI, Aurora A, c-Src, IGF-IR, ALK, c-MET, RON, PAKl, PAK2 and TAKl.

In some embodiments, the disorder mediated by protein kinase activity is cancer.

Examples of such cancers include solid tumors, sarcomas, fibrosarcomas, osteogenic tumors, melanomas, retinoblastomas, rhabdomyosarcomas, glioblastomas, neuroblastomas, teratomas, hematopoietic malignancies or malignant ascites.

The invention also provides the application of at least one compound or pharmaceutically acceptable salt thereof as a medicine.

The invention further provides the use of at least one of the above compounds or a pharmaceutically acceptable salt thereof for the treatment of cancer.

In addition, the present invention provides a method for treating cancer selected from lung cancer, breast cancer, colorectal cancer, renal cell carcinoma, pancreatic cancer, head and neck cancer, hereditary papillary renal cell carcinoma, childhood hepatocellular carcinoma, and gastric cancer in a mammal, comprising administering to a mammal in need of such treatment a therapeutically effective amount of at least one compound as described above or a pharmaceutically acceptable salt thereof provided herein.

In the present invention, the term "halogen" (halogen) refers to fluorine, chlorine, bromine or iodine unless otherwise indicated. Preferred halogen groups are fluorine, chlorine and bromine.

In the present invention, unless otherwise specified, the term "alkyl" includes straight-chain, branched-chain or cyclic saturated monovalent hydrocarbon groups. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3- (2-methyl) butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-methylpentyl and cyclohexyl. Similarly, C_1-8"C" in alkyl_1-8"refers to a group containing 1,2, 3,4, 5,6, 7, or 8 carbon atoms arranged in a straight or branched chain.

Alkenyl and alkynyl groups include alkenes and alkynes containing straight, branched or cyclic chains. Likewise, "C_2-8Alkenyl "and" C_2-8Alkynyl "means an alkenyl or alkynyl group containing 2, 3,4, 5,6, 7 or 8 carbon atoms arranged in a straight or branched chain.

Alkoxy means an oxygen ether formed from a straight, branched or cyclic alkyl group as described above.

In the present invention, unless otherwise indicated, the term "aryl" refers to a substituted or unsubstituted monocyclic or polycyclic ring system containing carbon atoms. Preferred aryl groups are 6 to 10 membered monocyclic or bicyclic aromatic ring systems. Preferred aryl groups are phenyl and naphthyl. The most preferred aryl group is phenyl.

In the present invention, unless otherwise indicated, the term "heterocycloalkyl" refers to a stable 3 to 8 membered monocyclic saturated ring system, substituted or unsubstituted, consisting of C atoms and 1 to 3 heteroatoms selected from N, O or S, and wherein the N or S heteroatoms are optionally oxidized and the N heteroatoms may optionally be quaternized. The heterocycloalkyl group can be attached to any heteroatom or carbon atom that results in a stable structure. Examples of such heterocycloalkyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, oxopazapinyl, azepinyl, tetrahydrofuranyl, dioxolanyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, and oxadiazolyl.

In the present invention, unless otherwise indicated, the term "heterocycloaryl" means an unsubstituted or substituted stable 5-or 6-membered monoaromatic ring system, or an unsubstituted or substituted 9-or 10-membered benzofused heteroaromatic or diheteroaromatic ring system consisting of carbon atoms and from 1 to 4 heteroatoms selected from N, O or S, wherein the N or S heteroatoms may optionally be oxidized and the N heteroatoms may optionally be quaternized. The heterocyclic aryl group may be attached to any heteroatom or carbon atom that results in a stable structure. Examples of heterocycloaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridazinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenine, quinolinyl, or isoquinolinyl.

The term "carbonyl" refers to a C (O) group.

The term "alkoxycarbonyl" refers to a group containing the indicated number of carbon atoms (e.g., C)_1-6Alkoxycarbonyl) or a linear or branched ester of a carboxylic acid derivative of the invention with any number of carbon atoms within this range, for example, methoxycarbonyl (MeOCO-), ethoxycarbonyl or butoxycarbonyl.

Whenever the term "alkyl" or "aryl" or its prefix root appears in a substituent name (e.g., aralkyl or dialkylamino), the substituent should be construed as previously including those defined for "alkyl" and "aryl". Specified number of carbon atoms (e.g. C)_l-6) Shall independently refer to the alkyl moiety (with alkyl as its prefix root) in the number of carbon atoms of one alkyl moiety or one larger substituent.

The term "alkylsulfinyl" refers to a group containing the indicated number of carbon atoms (e.g., C)_1-6Alkylsulfinyl), or a linear or branched alkyl sulfoxide compound of any number of carbon atoms within this range (e.g., methylsulfinyl (MeSO-), ethylsulfinyl, isopropylsulfinyl).

The term "alkylsulfonyl" refers to radicals containing the indicated number of carbon atoms (e.g., C)_1-6Alkylsulfonyl), or any number of carbon atoms within this range (e.g., methylsulfonyl (MeSO)₂-), ethylsulfonyl, isopropylsulfonyl, etc.).

The term "alkylthio" refers to a group containing the specified number of carbon atoms (e.g., C)_1-6Alkylthio), or a linear or branched alkyl sulfide compound of any number of carbon atoms within this range (e.g., methylthio (MeS-), ethylthio, isopropylthio, etc.).

The term "alkenyloxy" refers to an-O-alkenyl group, wherein alkenyl is as previously defined.

The term "alkynyloxy" refers to-O-alkynyl, wherein alkynyl is as previously defined.

The term "composition" as used herein is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. Therefore, a pharmaceutical composition comprising the compound of the present invention as an active ingredient and a process for preparing the compound are also aspects of the present invention. Furthermore, some of the crystalline forms of the compounds may exist as polymorphic forms, which are also included in the present invention. In addition, some compounds form solvates with water (e.g., hydrates) or common organic solvents, and such solvates are also encompassed by the present invention.

The compounds provided by the present invention may also exist in the form of pharmaceutically acceptable salts. In terms of pharmaceutical applications, the salts of the compounds provided herein are referred to as non-toxic "pharmaceutically acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutically acceptable acid/anion salts or base/cation salts. The pharmaceutically acceptable acid/anion salts are typically present in the basic nitrogen form protonated by inorganic or organic acids. Typical organic or inorganic acids include hydrochloric, hydrobromic, hydroiodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, isethionic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclamic, salicylic, saccharinic or trifluoroacetic acid. Pharmaceutically acceptable base/cation salts include, but are not limited to, aluminum, calcium, chloroprocaine, choline, diethanolamine, ethylenediamine, lithium, magnesium, potassium, sodium and zinc salts.

Prodrugs of the compounds of the present invention are included within the scope of the invention. In general, the prodrug refers to a functional derivative that is readily converted in vivo to the desired compound. Thus, the term "administering" in the treatment methods provided herein includes administering a compound disclosed herein, or, although not specifically disclosed, is capable of being converted in vivo upon administration to a subject to treat the various disorders described herein. Conventional methods for selecting and preparing suitable prodrug derivatives are described, for example, in the Design of Prodrugs (Design of produgs, ed.h. bundgaard, Elsevier, 1985).

It will be apparent that the definition of any substituent or variable at a particular position in a molecule is independent of the other positions in the molecule. It will be readily appreciated that substituents or substituted forms of the compounds of the invention may be selected by one of ordinary skill in the art by means of prior art techniques and methods described herein to provide compounds which are chemically stable and which are readily synthesized.

The compounds of the present invention may contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention includes all possible diastereomers and racemic mixtures thereof, substantially pure resolved enantiomers thereof, all possible geometric isomers thereof, and pharmaceutically acceptable salts thereof.

The above formula (I) does not define the stereostructure of the compound exactly at a certain position. The invention includes all stereoisomers of the compounds of formula (I) and pharmaceutically acceptable salts thereof. Further, mixtures of stereoisomers and isolated specific stereoisomers are also included in the present invention. During synthesis to prepare such compounds, or using racemization or epimerization methods well known to those of ordinary skill in the art, the products produced may be mixtures of stereoisomers.

When a tautomer exists in the compound of formula (I), the present invention includes any possible tautomer and pharmaceutically acceptable salts thereof, and mixtures thereof, unless otherwise specified.

When the compounds of formula (I) and pharmaceutically acceptable salts thereof are in the form of solvates or polymorphs, the present invention includes any possible solvates and polymorphs. The type of solvent forming the solvate is not particularly limited as long as the solvent is pharmacologically acceptable. For example, water, ethanol, propanol, acetone, and the like can be used.

The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids. When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low), ferric, ferrous, lithium, magnesium, manganese (high and low), potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Non-toxic organic bases which can be derivatized to form pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts include ion exchange resins and arginine, betaine, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.

When the compounds provided by the present invention are bases, their corresponding salts can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, for example, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, and p-toluenesulfonic acid, and the like. Preferably, citric, hydrobromic, formic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. More preferably formic acid and hydrochloric acid. Since the compound of formula (I) is to be used as a pharmaceutical, it is preferred to use it in substantially pure form, e.g. at least 60% pure, more suitably at least 75% pure, especially at least 98% pure (% is by weight).

The pharmaceutical composition provided by the invention comprises a compound shown as a formula (I) (or pharmaceutically acceptable salt thereof) as an active component, a pharmaceutically acceptable excipient and other optional therapeutic components or auxiliary materials. Although the most suitable mode of administration of the active ingredient in any given case will depend on the particular host, host nature and severity of the condition being treated, the pharmaceutical compositions of the present invention include those suitable for oral, rectal, topical and parenteral (including subcutaneous, intramuscular, intravenous) administration. The pharmaceutical compositions of the present invention may be conveniently prepared in unit dosage forms well known in the art and by any of the methods of preparation well known in the pharmaceutical arts.

In practice, the compounds of formula (I), or prodrugs, or metabolites, or pharmaceutically acceptable salts thereof, of the present invention may be incorporated as active ingredients in pharmaceutical compositions with pharmaceutical carriers according to conventional pharmaceutical compounding techniques. The pharmaceutical carrier can take a wide variety of forms depending on the desired mode of administration, e.g., oral or parenteral (including intravenous). Thus, the pharmaceutical compositions of the present invention may take the form of discrete units suitable for oral administration, such as capsules, cachets or tablets containing the active ingredient at the predetermined dosage. Further, the pharmaceutical composition of the present invention may take the form of a powder, granules, a solution, an aqueous suspension, a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil emulsion. In addition, in addition to the usual dosage forms mentioned above, the compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered by controlled release means and/or delivery devices. The pharmaceutical composition of the present invention can be prepared by any pharmaceutical method. In general, such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more of the necessary ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or a mixture of both. The product can then be conveniently prepared to the desired appearance.

Accordingly, the pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier and a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The compounds of formula (I) or a pharmaceutically acceptable salt thereof, together with one or more other therapeutically active compounds are also included in the pharmaceutical compositions of the present invention.

The pharmaceutical carrier employed in the present invention may be, for example, a solid carrier, a liquid carrier or a gaseous carrier. Solid carriers including lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid. Liquid carriers, including syrup, peanut oil, olive oil and water. Gaseous carriers, including carbon dioxide and nitrogen. Any convenient pharmaceutical medium may be employed in the preparation of the pharmaceutical oral formulations. For example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like can be used in oral liquid preparations such as suspensions, elixirs and solutions; and carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like may be used in solid preparations for oral administration such as powders, capsules and tablets. In view of ease of administration, oral formulations are preferably tablets and capsules, where solid pharmaceutical carriers are employed. Alternatively, tablet coatings may use standard aqueous or non-aqueous formulation techniques.

Tablets containing a compound or pharmaceutical composition of the invention may be prepared by compression or molding together with optionally one or more accessory ingredients or adjuvants. Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free-flowing form such as a powder or granules, with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by wetting a powdered compound or pharmaceutical composition with an inert liquid diluent and then shaping in a suitable machine. Preferably, each tablet contains about 0.05mg to 5g of active ingredient and each cachet or capsule contains about 0.05mg to 5g of active ingredient. For example, a dosage form intended for oral administration to humans comprises from about 0.5mg to about 5g of the active ingredient, in combination with suitable and conveniently metered amounts of auxiliary materials which constitute from about 5% to about 95% of the total weight of the pharmaceutical composition. Unit dosage forms generally contain from about 1mg to about 2g of the active ingredient, typically 25mg, 50mg, 100mg, 200mg, 300mg, 400mg, 500mg, 600mg, 800mg or 1000 mg.

The pharmaceutical compositions provided by the present invention, which are suitable for parenteral administration, can be prepared as aqueous solutions or suspensions by adding the active ingredient to water. Suitable surfactants such as hydroxypropyl cellulose may be included. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Further, preservatives may also be included in the pharmaceutical compositions of the present invention to prevent the growth of harmful microorganisms.

The present invention provides pharmaceutical compositions, including sterile aqueous solutions or dispersions, suitable for injection. Further, the above pharmaceutical composition may be prepared in the form of a sterile powder for the extemporaneous preparation of sterile injectable solutions or dispersions. In any event, the final injection form must be sterile and must be readily flowable for ease of injection. Furthermore, the pharmaceutical composition must be stable during preparation and storage. Therefore, preservation against microbial contamination such as bacteria and fungi is preferred. The carrier can be a solvent or dispersion medium, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol), vegetable oil, and suitable mixtures thereof.

The pharmaceutical compositions provided herein may be in a form suitable for topical administration, for example, an aerosol, cream, ointment, lotion, dusting powder, or other similar dosage form. Further, the pharmaceutical compositions provided herein may take a form suitable for use in a transdermal delivery device. These formulations can be prepared by conventional processing methods using the compounds of formula (I) of the present invention, or pharmaceutically acceptable salts thereof. As an example, the cream or ointment is prepared by adding a hydrophilic material and water to about 5 to 10 wt% of the above-mentioned compound to make a cream or ointment having a desired consistency.

The pharmaceutical composition provided by the invention can be prepared into a form which takes a solid as a carrier and is suitable for rectal administration. The preferred dosage form is a mixture to form a unit dose suppository. Suitable excipients include cocoa butter and other materials commonly used in the art. Suppositories can be conveniently prepared by first mixing the pharmaceutical composition with the softened or melted excipients, then cooling and moulding.

In addition to the aforementioned carrier components, the above-mentioned pharmaceutical preparations may also contain, as appropriate, one or more additional adjuvant components such as diluents, buffers, flavoring agents, binders, surfactants, thickeners, lubricants, preservatives (including antioxidants), and the like. In addition, other adjuvants may also include penetration enhancers to regulate the osmolality of the drug with blood. The pharmaceutical composition containing the compound represented by the formula (I) or the pharmaceutically acceptable salt thereof can also be prepared in the form of powder or concentrated solution.

In general, the above-identified conditions or disorders are treated with a dosage level of the drug of about 0.01mg/kg body weight to about 150mg/kg body weight per day, or about 0.5mg to about 7g per patient per day. For example, inflammation, cancer, psoriasis, allergy/asthma, diseases and disorders of the immune system, diseases and disorders of the Central Nervous System (CNS), are effectively treated at a drug dose level of 0.01mg/kg body weight to 50mg/kg body weight per day, or 0.5mg to 3.5g per patient per day.

It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.

In order that the foregoing may be more clearly and clearly understood, the present invention will now be further described.

Detailed Description

The following examples serve to better understand the invention. Unless otherwise indicated, all parts and percentages are by weight and all temperatures are in degrees Celsius. The following abbreviations are used in the examples:

ATP: adenosine triphosphate;

DIPEA: n, N-diisopropylethylamine;

DMF: n, N-dimethylformamide;

DMA: n, N-dimethylacetamide;

DMAP: 4-N, N-dimethylaminopyridine;

DMSO, DMSO: dimethyl sulfoxide;

DEAD: diethyl azodicarboxylate;

HATU: o- (7-azobenzotriazol-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate;

DIPEA: n, N-diisopropylethylamine;

EDC: 1-ethyl- (3-dimethylaminopropyl) carbodiimide;

TBAB: tetrabutylammonium bromide;

TEA: triethylamine;

EtOAc: ethyl acetate;

GSR: glutathione-S-transferase;

crk: CT10 (chicken tumor retrovirus 10);

min: the method comprises the following steps of (1) taking minutes;

h or hr: hours;

RT or RT: room temperature;

SDS (sodium dodecyl sulfate): sodium lauryl sulfate;

SDS-PAGE: sodium dodecyl sulfate polyacrylamide electrophoresis gel;

TLC: thin layer chromatography;

EXAMPLE 1 Synthesis of Compound 1

Compound 1a (25g,0.11mol), Compound 1b (20g,0.11mol) and K₂CO₃(37.5g,0.22mol) was dissolved in DMF (200ml) and the mixture was stirred at 70 ℃ for 3 hours. Then, water (300ml) was added to the mixture, extracted with EA (200 ml. times.3), and the aqueous phase was adjusted to pH 3-4 by adding HCl (1mol/L), and the precipitate was collected and washed with methanol (5 ml). After air drying for 5 hours 23g of compound 1c are obtained.

Under the protection of nitrogen, in ice bath (COCl)₂(7.2ml(COCl)₂Dissolved in 10ml of DCM) was added to a solution of compound 1c (5.0g) and 2 drops of DMF in DCM and stirred. After 3.5 hours the solvent was removed and the residue was dissolved in DCM and 10ml ethanol was added. After stirring for 1 hour, the reaction mixture was quenched with water. The organic phase was separated, dried and concentrated. The residue was purified by chromatography to give 4.7g of a yellow solid, Compound 1 d.

A mixture of compound 1d (200mg) and compound 1e was sealed in a sealed tube and stirred at 130 ℃ for 1 hour. Removal of the solvent followed by purification gives compound 1. MS: 552.2(M + H)⁺。

EXAMPLE 2 Synthesis of Compound 2

A solution of Compound 1 and NaOH (0.5ml, 2mol/L) in methanol was stirred at room temperature for 1 hour. The solution was then adjusted to a pH of about 5 by the addition of HCl. Filtration and drying of the solid gave compound 2(37 mg). MS 524.2(M + H)⁺。

EXAMPLE 3 Synthesis of Compound 3

Compound 2(140mg) and NH₂A mixture of OH (72mg), PyBOP (180mg) was dissolved in 10ml of DMF and stirred at 45 ℃ for 3 hours. The reaction solution was purified by preparative HPLC to give 30mg of a solid, compound 3. MS:539.2(M + H)⁺。

EXAMPLE 4 Synthesis of Compound 4

Under the protection of nitrogen, the mixture is cooled in ice bath and stirred (COCl)₂(7.2ml(COCl)₂Dissolved in 10ml of DCM) was added to 50ml of a solution of DCM containing compound 1c (5.0g) and 2 drops of DMF. After 3.5 hours the solvent was removed. The residue was dissolved in DCM and aqueous ammonia was added to the solution. After stirring for 1 hour, the precipitate was collected by filtration to give 6.0g of a white solid, Compound 1 f.

Compound 4 can be obtained by reacting compound 1f instead of 1d with compound 1e in a similar manner to example 1. MS:523.2(M + H)⁺。

EXAMPLE 40 Synthesis of Compound 40

A three-necked round bottom flask equipped with mechanical stirrer, addition funnel and thermometer was charged with Compound 40a (10.0g), TEA (12ml) and DCM (30 ml). After the reaction mixture was cooled to-10 ℃, a solution of acryloyl chloride (5.9g) in DCM (20ml) was added dropwise (through the addition funnel). The reaction mixture was stirred at-10 ℃ until the completion of the reaction was monitored by TLC (PE: EA ═ 3: 1). The reaction was then quenched by the addition of water (30ml) and filtered to give crude compound 40b (8.5g) which was used directly in the next reaction.

A three-necked round bottom flask equipped with a mechanical stirrer, addition funnel and thermometer was charged with Compound 40b (2.0g), SnCl₂(14.1g) and methanol (60 ml). The reaction mixture was then stirred at 80 ℃ to TLC (DCM: MeOH ═ 10:1) to monitor the reaction completion. The reaction mixture was concentrated under reduced pressure, and ethyl acetate (50ml) and K were added₂CO₃Filtering the aqueous solution, collecting the organic phase, washing with water, and removing anhydrous Na₂SO₄Drying and removal of the solvent by evaporation gave 1.5g of a yellow solid, compound 40 c.

Compound 1c (1.03g), dimethylamine hydrochloride (0.54g), HATU (1.51g) and TEA (1.00g) were dissolved in DCM (20ml) and the mixture was stirred at 25 ℃ for 6 hours. The reaction mixture was concentrated under reduced pressure and purified by chromatography to give 0.64g of a yellow solid, Compound 40 d.

Compound 40d (200mg), compound 40c (96mg), con-HCl (3d) and n-BuOH (60ml) were stirred in a sealed tube at 130 ℃ until the completion of the reaction was monitored by TLC (DCM: MeOH ═ 10: 1). The reaction mixture was washed with water, concentrated under reduced pressure, and the residue was purified by column chromatography to give 500mg of a yellow solid, i.e., compound 40. MS 464.1(M + H)⁺。H-NMR(DMSO-d6,400MHz):10.25(s,1H),9.12(s,1H),8.34(s,1H),7.98(s,1H),7.39-7.33(m,2H),7.24-7.19(m,2H),6.54-6.51(m,2H),6.49-6.47(m,1H)，6.54-6.47(m,1H)，6.25-6.21(dd,1H),5.74-5.71(dd,1H),3.00(s,3H),2.90(s,3H)。

EXAMPLE 41 Synthesis of Compound 41

Method 1.

A mixture of 4-methoxy-3-nitroaniline (1.52g, 9.04mmol), triethylamine (1.37g, 13.54mmol) and DCM (60ml) was cooled to 0 deg.C and a solution of acryloyl chloride (0.90g,9.94mmol) in DCM (20ml) was added dropwise and the mixture was stirred at 0-5 deg.C for 20 min. TLC monitored the progress of the reaction. The reaction was quenched by addition of water (50ml), the aqueous solution was extracted with DCM (30 ml. times.2), the organic phases were combined and Na anhydrous₂SO₄Drying and concentration under reduced pressure gave 1.52g of a yellow solid, Compound 41 b.

Compound 41b (1.50g, 6.75mmol), 1, 4-diazabicyclo [2.2.2]A mixture of octane (2.27g, 20.25mmol), paraformaldehyde (1.01g, 33.75mmol), 1, 4-dioxane (100ml) and water (60ml) was heated to 80 ℃ for reaction for 15 hours. Adding water (100ml), EA (100ml × 2) extracting, combining organic phases, washing with brine (100ml), anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and purifying the residue by column chromatography to obtain 1.25g yellow solidCompound 41 c.

A mixture of compound 41c (1.20g, 4.76mmol) dissolved in DCM (130ml) was cooled to 0 deg.C, a solution of phosphorus tribromide (1.54g, 5.71mmol) dissolved in DCM (20ml) was added dropwise, after reaction for 15 minutes, water (50ml) was added to quench the reaction, aqueous DCM (30 ml. times.2) was extracted, the organic phases were combined, washed with brine (50 ml. times.2), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave a residue (compound 41d) which was used in the next step without further purification.

Compound 41d (1.35g) was dissolved in DCM (100ml), and morpholine (1.86g, 21.40mmol) was added dropwise to the solution. The resulting mixture was stirred at room temperature for 15 minutes. Water (50ml) was added and the organic phase was washed with brine (30ml), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 1.28g of a brown solid, Compound 41 e.

Compound 41e (1.25g, 3.89mmol), Fe powder (4.34g, 77.80mmol), ethanol (50ml) and saturated NH₄A mixture of aqueous Cl (20ml) was warmed to 65 ℃ for 30 minutes, cooled, filtered, and extracted with brine (20ml) and ethyl acetate (50 ml. times.3). The combined organic phases were washed with brine (50ml) and anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 0.94g of a brown solid, Compound 41 f.

A mixture of compound 41f (508mg, 1.74mmol), compound 40d (705mg, 2.09mmol), p-toluenesulfonic acid (449mg, 2.61mmol) and n-BuOH (100ml) was warmed to 100 ℃ for 14 hours. The mixture was cooled and concentrated under reduced pressure, the residue was basified with aqueous sodium carbonate (50ml), extracted with EA (50ml, 30 ml. times.2), the organic phases were combined, washed with brine (50 ml. times.2), anhydrous Na₂SO₄Drying, concentration under reduced pressure, and column chromatography purification of the residue yielded 198mg of a yellow solid, i.e., compound 41. MS:593.2(M + H)⁺。HNMR(DMSO-d6,400MHz):11.36(s,1H),11.05(s,1H),8.89(d,1H),8.60(s,1H),8.25(s,1H),7.92(s,1H),7.61(d,1H),7.54-7.56(m,1H),7.49(t,1H),7.14(t,1H),7.04(d,1H),6.02(s,1H),5.54(s,1H),3.77(s,3H),3.55(s,4H),3.24(s,2H),2.99(s,3H),2.88(s,3H),2.35(s,4H)。

Method 2

To a solution of compound 41a (2.0g) in DCM (25ml) was added dropwise morpholine (0.6g) dissolved in DCM (5ml) with stirring at 0 ℃ and the reaction mixture was stirred at 0-5 ℃ for a further 3 hours. The reaction mixture was concentrated under reduced pressure to give 1.5g of a white solid, compound 41b, which was used directly in the next reaction.

Compound 41b (1.45g), LiOH (0.46g), MeOH (10ml) and water (5ml) were combined and the reaction mixture reacted at room temperature for 1 hour, most of the solvent was removed under reduced pressure and concentrated HCl was added to adjust the pH to 1-2 to give a solid which was filtered and the filter cake dried to give 1.5g of Compound 41 c.

A three-necked round-bottomed flask equipped with mechanical stirrer, addition funnel and thermometer was charged with Compound 41c (1.2g) and DCM (25ml), cooled to 0 deg.C and a solution of oxalyl chloride (1.1g) in DCM (15ml) was added dropwise (via the addition funnel) with the temperature in the reaction system controlled at 0-5 deg.C. After the addition was complete, the reaction mixture was warmed to 15 ℃ and continued to TLC (DCM: MeOH 10:1) to monitor the completion of the reaction. The reaction solvent was removed under reduced pressure to obtain 1.3g of compound 41d, which was used directly in the next reaction.

A three-necked round-bottomed flask equipped with a mechanical stirrer, addition funnel and thermometer was charged with 4-methoxy-3-nitroaniline (0.8g) and DCM (25ml), cooled to 0 ℃ and a solution of compound 41d (1.3g) in DCM (15ml) was added dropwise, maintaining the temperature in the reaction system at 0-5 ℃. After the addition was complete, the reaction mixture was allowed to warm naturally and continued until completion of TLC (DCM: MeOH: 10: 1). The reaction mixture was washed with water, the collected organic phase was concentrated under reduced pressure to give a residue, which was purified by column chromatography to give 0.8g of compound 41 e.

Equipped with a mechanical stirrer, addition funnel and temperatureA three-necked round-bottomed flask of the calorimeter was charged with Compound 41e (98mg), Fe powder (347mg) and saturated NH₄Cl solution (15ml) and the reaction mixture warmed to 80 ℃ and stirred until TLC (DCM: MeOH ═ 10:1) monitored completion of the reaction. Most of the reaction solvent was removed under reduced pressure to give a residue, which was partitioned 3 times between ethyl acetate (20ml) and water (10ml), the organic phase was collected, washed with brine, and dried over anhydrous Na₂SO₄Drying gave 62mg of compound 41 f.

Compound 40d (74mg), compound 41f (60mg), TsOH (36mg) and n-BuOH (15ml) were stirred in a sealed tube at 90 ℃ and the reaction was monitored by TLC (DCM: MeOH ═ 10:1) for completion. The reaction mixture was washed with water, the organic phase was concentrated under reduced pressure, and the residue was purified by column chromatography to give 8mg of a yellow solid, i.e., compound 41. MS:593.2(M + H)⁺。

EXAMPLE 72 Synthesis of Compound 72

To a solution of crotonic acid (5.05g, 58.65mmol) and one drop of DMF in DCM (80ml) was added oxalyl chloride (11.12g, 87.98mmol) dropwise, the reaction mixture was stirred at 15 deg.C for 30 min and concentrated under reduced pressure to give residue A (compound 72a) which was used in the next step without further purification.

Compound 72b (4.92g, 29.33mmol) and DIPEA (3.80g, 29.33mmol) were dissolved in DCM (100ml), a solution of A in DCM (30ml) was added dropwise at 0 ℃ and the resulting mixture was stirred at 0-5 ℃ for 30 minutes and quenched with 50ml of water. The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography to give 4.21g of a yellow solid, compound 72 c.

A mixture of compound 72c (402mg, 1.72mmol), NBS (334mg, 1.88mmol) and AIBN (40mg, 0.26mmol) dissolved in benzene (70ml) was reacted at 80 ℃ for 5 hours. The mixture was concentrated under reduced pressure to give a residue, 72d, which was used in the next step without further purification.

Compound 72d was dissolved in DCM (30ml), piperidine (1ml) was added, and the resulting mixture was stirred at room temperature for 2 minutes, concentrated under reduced pressure, and the residue was purified by column chromatography to give 380mg of a pale yellow solid, compound 72 e.

Compound 72e (205mg, 0.64mmol), iron powder (715mg, 12.80mmol) were dissolved in EtOH (20ml), a saturated ammonium chloride solution (5ml) was added, and the mixture was warmed to 65 ℃ for 30 minutes. After cooling, water was added and filtration was carried out, EA (50ml, 30ml) was used to extract the filtrate, the organic phases were combined, washed with brine (30ml), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 108mg of a brown solid, compound 72 f.

A mixture of compound 72f (105mg, 0.36mmol), compound 40d (145mg, 0.43mmol) and p-toluenesulfonic acid (93mg, 0.54mmol) in n-butanol (20ml) was reacted for 13 hours at 100 ℃. After cooling, concentration under reduced pressure, basification of the residue with aqueous sodium carbonate, secondary extraction with EA (50ml, 30ml), combining the organic phases, washing with brine (30ml), anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and purifying the residue by column chromatography to give 38mg of a yellow solidI.e. compound 72. MS:591.2(M + H)⁺。

EXAMPLE 74 Synthesis of Compound 74

H₂Compound 74a (50g) and Pd/C (10g) were dissolved in a methanol solution (100ml) under protection, the solution was stirred at room temperature for 4 hours, filtered, and the filtrate was concentrated under reduced pressure to give 41g of compound 74 b.

Compound 74b (8.05g) was dissolved in concentrated H₂SO₄(40ml), KNO was added under ice-bath₃(5.77g) and stirred for 2 hours. The reaction mixture was poured into NaOH solution, solid precipitated and filtered to give 8.5g of yellow solid, Compound 74 c.

Compound 74c (19.7g), 1-methylpiperazine (15.9g) and K₂CO₃(21.94g) was dissolved in DMF and stirred at 80 ℃ for 8 hours. Water was added to the reaction mixture and extracted with EA, the organic phase was washed with brine, anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 10.2g of a yellow solid, compound 74 d.

Compound 74d (1.02g) and TEA (0.5g) were dissolved in DCM (20ml), and acryloyl chloride (0.38g) was added dropwise over an ice bath and the reaction was stirred for 1 hour. Water was added to the mixture to quench the reaction, and the organic phase was separated, dried, and concentrated under reduced pressure to give 0.98g of a solid, Compound 74 e.

Compound 74e (0.98g), iron powder (0.85g) and NH₄Cl (0.82g) was dissolved in a mixed solvent of ethanol and water, and the reaction was stirred at 50 ℃ for 2 hours. Filtering, extracting the filtrate with EA, anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 0.58g of a solid, Compound 74 f.

Compound 74f (16.5g), compound 40d (23.2g) and p-toluenesulfonic acid (11.75g) were dissolved in butanol (250ml), and the reaction was stirred at 70 ℃ for 8 hours. The solvent was removed and the residue was purified by column chromatography to give 11.3g of a pale yellow solid, i.e., compound 74. MS:592.2(M + H)⁺.HNMR(DMSO-d6,400Mz):8.84-8.82(d,J＝7.76Hz,1H),8.24(s,1H),8.09-8.07(d,J＝6Hz,1H),7.63-7.61(d,J＝8Hz,1H),7.53(s,1H),7.16-7.12(t,J＝7.6Hz,1H),6.87(s,1H),6.63-6.56(dd,J＝10Hz,J＝17.2Hz,1H),6.18-6.13(d,J＝16.8Hz,1H),5.71-5.68(d,J＝10.4Hz,1H),3.77(s,3H),3.00(s,3H),2.89(s,6H),2.55-2.50(m,5H),2.25-2.25(m,3H).

EXAMPLE 79 Synthesis of Compound 79

Morpholine (1ml) was added dropwise to a mixture of compound 72d (0.5g) and DCM (50ml), the reaction stirred at rt for 5 minutes, evaporated to dryness and the residue purified by column chromatography to give 350mg of a pale yellow solid, compound 79 b.

Compound 79b (152mg, 0.47mmol), iron powder (525mg, 9.40mmol), ethanol (20ml) and saturated NH₄A mixture of Cl solution (10ml) was warmed to 65 deg.C for 15 minutes, cooled and filtered, brine (30ml) was added, the product was extracted with EA (50ml, 30ml), the organic phases were combined, washed with brine (30ml), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 102mg of a brown solid, compound 79 c.

A mixture of compound 79c (102mg, 0.34mmol), compound 40d (138mg, 0.41mmol), p-toluenesulfonic acid (87mg, 0.51mmol) and n-butanol (15ml) was heated to 105 ℃ for reaction for 7 hours. Cooling, vacuum concentrating, adding carbonBasification of sodium acid solution (20ml), extraction with EA (50ml, 30ml), combination of organic phases, washing with brine (30ml), anhydrous Na₂SO₄Drying and concentration, and column chromatography of the residue purified 92mg of a yellow solid, Compound 79. MS:594.9(M + H)⁺.HNMR(DMSO-d6,400MHz):11.35(s,1H),9.93(s,1H),8.85(d,1H),8.61(s,1H),8.28(s,1H),7.93(s,1H),7.63(d,1H),7.48(m,2H),7.13(t,1H),7.04(d,1H),6.65-6.68(m,1H),6.24(d,1H),3.77(s,3H),3.59(s,4H),3.11(s,2H),3.01(s,3H),2.90(s,3H),2.38(s,4H)。

EXAMPLE 115 Synthesis of Compound 115

To a stirred solution of N, N-dimethylethanolamine (8.58g, 96mmol) in DMF (80ml) at 0 ℃ NaH (1.54g, 64mmol) was slowly added and after the mixture was stirred for a further 30 minutes at 0-5 ℃ compound 115a (5.01g, 32mmol) was added dropwise to the DMF solution. Then naturally heating to room temperatureThe reaction was stirred for an additional 4 hours and monitored by TLC (PE: EA ═ 1:1) for completion. Excess NaH was quenched by addition of water (80ml), the mixture was extracted with ethyl acetate (80 ml. times.2), the organic phases were combined, washed with brine (80ml), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 6.49g of compound 115 b.

Compound 115b (6.49g, 28.81 mmol) and triethylamine (4.8ml, 34.58mmol) were dissolved in DCM (55ml), stirred at 0 deg.C and a solution of acryloyl chloride (2.3ml, 31.68mmol) in DCM (10ml) was added dropwise. The reaction mixture was stirred at 0 ℃ for 30 minutes. The reaction system was washed with water (60ml), and the organic phase was concentrated under reduced pressure to give 7.32g of Compound 115 c.

Compound 115c (7.32g, 25.93mmol) was dissolved in ethanol (15ml), and iron powder (8.84g, 155.57mmol) and ammonium chloride (2.77g, 51.86mmol) were dissolved in water (70ml) and reacted at 90 ℃ for 30 minutes. Filtration was carried out, and the filtrate was extracted with ethyl acetate (80 ml. times.2), and the organic phases were combined, washed with brine (80ml), anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 2.31g of Compound 115 d.

A mixture of compound 115d (2.30g, 9.23mmol), compound 40d (3.13g, 9.23mmol) and concentrated hydrochloric acid (0.3ml) dissolved in n-butanol (30ml) was reacted at 110 ℃ for 6 hours. The reaction was monitored by TLC (DCM: MeOH ═ 10: 1). After the reaction, the temperature is reduced to room temperature, a crude product is obtained by concentration under reduced pressure, and the crude product is purified by column chromatography to obtain 1.71g of yellow solid, namely the compound 115. MS:551.2(M + H)⁺。H-NMR(DMSO-d6,400MHz):8.35(s,1H),8.29(s,1H),7.88-7.82(m,1H),7.47(s,1H),7.32-7.15(m,4H),7.05-7.02(m,1H),6.25-6.21(m,1H),5.70-5.67(m,1H),4.33-4.32(t,3H)，3.60-3.55(t,3H)，3.00(s,6H),2.90(s,6H)。

EXAMPLE 124 Synthesis of Compound 124

3-Hydroxytetrahydrofuran (203mg) was dissolved in DMF (10ml), and NaH (92mg) was added slowly with stirring at 0 ℃. The mixture was stirred at 0-5 ℃ for 30 minutes, and compound 124a (300mg) in DMF was added dropwise, slowly returning to room temperature after completion of the addition. The completion of the reaction was monitored by TLC (PE: EA ═ 1:1) after 4 hours. 15ml of water were added. EA (15 ml. times.2) extraction of the mixture, combining the organic phases, brine wash, anhydrous Na₂SO₄Drying and concentrating under reduced pressure to give crude compound 124 b. The crude compound was purified by column chromatography to give 226mg of compound 124 b.

Compound 124b (220mg) and TEA (0.2ml) were dissolved in DCM (15ml), a solution of acryloyl chloride (0.1ml) in DCM (2ml) was added dropwise with stirring at 0 ℃ to the reaction mixture, and the reaction was stirred at 0 ℃ for 30 minutes. The completion of the reaction was monitored by TLC (PE: EA ═ 1: 1). The reaction solution was washed with water (20ml) and the organic phase was concentrated under reduced pressure to give 220mg of compound 124 c.

To a solution of compound 124c (220mg) in ethanol (5ml), iron powder (500mg) and saturated NH were added with stirring₄Cl solution (15 ml). The stirred solution was warmed to 90 ℃ for reaction until completion by TLC (DCM: MeOH ═ 10: 1). The reaction solution was filtered, extracted twice with ethyl acetate (20ml) and water (10ml), the organic phases were combined, washed with aqueous NaCl solution and anhydrous Na₂SO₄Drying and concentration under reduced pressure gave 160mg of compound 124 d.

A mixture solution of compound 124d (150mg), compound 40d (205mg) and concentrated HCl (0.05ml) in n-butanol was heated to 85 ℃ and stirred for 3 hours. TLC (DCM: MeOH ═ 10:1) monitored the reaction completion. Cooling to 20 deg.C, filtration and drying of the filter cake yields 115mg of compound 124. MS:550.2(M + H)⁺.H-NMR(DMSO-d6,400MHz):11.38(s,1H),9.81(s,1H),9.19(s,1H),8.90(s,1H),8.40(s,1H),8.22(s,1H),7.64-7.69(m,2H),7.32-7.36(m,1H),7.23-7.27(t,1H)，7.00(d,1H)，6.64-6.71(dd,1H),6.18-6.22(dd,1H),5.71-5.74(dd,1H),5.02(d,1H),3.87-3.94(m,2H)，3.73-3.78(m,2H),3.00(s,3H),2.90(s,3H),2.19(m,1H),2.05-2.10(m,1H)。

EXAMPLE 143 Synthesis of Compound 143

Compound 143a (5.12g, 23.59mmol), tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) carboxylate (7.30g, 23.59mmol), tetrakis (triphenylphosphine) palladium (0) (1.36g, 1.18mmol) and K under vacuum or nitrogen protection₂CO₃(8.15g,58.98mmol) was dissolved in DMF (200 ml). The mixture was warmed to 80 ℃ and reacted for 16.5 hours. Cooled to 10 deg.C, water (300mL) was added, the resulting mixture was extracted with ethyl acetate (300mL, 150 mL. times.2), the organic phases were combined, washed with brine (200 mL. times.2), anhydrous Na₂SO₄Drying, concentration under reduced pressure, and purification by column chromatography of the residue gave 4.82g of a yellow solid, i.e., compound 143 b.

Compound 143b (4.81g, 15.08mmol) and anhydrous acetic anhydride (5ml, 52.89mmol) were dissolved in DCM (300ml) and stirred at 25 ℃ for 20 h. Concentrated under reduced pressure, and the residue was dissolved in a saturated aqueous sodium hydrogencarbonate solution (200ml) and stirred at room temperature for 12 hours. The solid was collected by filtration to obtain 5.28g of compound 143 c.

Compound 143c (5.27g, 14.58mmol) and trifluoroacetic acid (13ml, 175mmol) are dissolved in DCM and the mixture is stirred for 2h at 40 ℃. TLC monitored the progress of the reaction. After completion of the reaction, concentration was performed under reduced pressure, and the residue (compound 143d) was used in the next step without purification.

A mixture of compound 143d (3.80g, 14.54mmol), formaldehyde solution (5ml, 178.90mmol), acetic acid (1ml, 17.48mmol), sodium triacetoxyborohydride (9.25g, 43.65mmol) and DCM (150ml) was stirred at room temperature for 20 min. Addition of saturated K₂CO₃The solution (100ml) gave a mixture which was extracted with DCM (100 ml. times.2), the organic phases were combined, washed with brine (100ml), anhydrous Na₂SO₄The residue (compound 143e) was dried and concentrated under reduced pressure and used in the next step without further purification.

Compound 143e (3.81g, 13.84mmol) was dissolved in EA (100ml) and EtOH (100ml), 10% palladium on carbon (1.05g) was added, and the reaction mixture was reacted at room temperature with stirring under hydrogen gas for 2 hours. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated to obtain 3.21g of compound 143 f.

A mixture of compound 143f (3.21g, 12.99mmol), compound 40d (4.40g, 12.99mmol), p-toluenesulfonic acid (2.68g, 15.59mmol) and n-butanol (150ml) was heated to 100 ℃ and stirred for reaction for 7 hours, after cooling and concentration under reduced pressure, the residue was purified by column chromatography to give 5.02g of a pale yellow solid, i.e., compound 143 g.

143g (1.98g, 3.60mmol) of the compound was dissolved in THF (50ml), concentrated hydrochloric acid (15ml) was added with stirring, and the resulting mixture was reacted with stirring at 65 ℃ for 17 hours. The reaction was monitored by TLC. After the reaction is finished, cooling to 0-5 ℃, and adding saturated K₂CO₃The solution was adjusted to pH 9-10, DCM extracted (100 ml. times.2), the organic phases combined, washed with brine (100ml), anhydrous Na₂SO₄Drying, concentrating under reduced pressure, and purifying the crude product by column chromatography to obtain 0.28g of light yellow solid, namely compound 143 h.

To a solution of compound 143h (255mg, 0.5mmol) and triethylamine (100mg, 1.0mmol) in DCM (100ml) was added acryloyl chloride (69mg, 0.7 mmol) dropwise5mmol), the resulting mixture was stirred at 0-5 deg.C. Addition of saturated K₂CO₃The reaction was quenched with solution (200ml), extracted with DCM (100 ml. times.3), the organic phases combined, washed with brine (100 ml. times.2), anhydrous Na₂SO₄Drying, concentration under reduced pressure and purification of the residue by preparative-TLC gave 138mg of a yellow solid, Compound 143. MS 561.2(M + H) +. HNMR (DMSO-d6,400MHz) 11.32(s,1H),9.61(s,1H),9.02(d,1H),8.33(s,1H),7.63-7.80(m,3H),7.50(d,1H),7.20-7.23(m,2H),6.46-6.53(m,1H),6.19-6.23(dd,1H),5.72-5.75(dd,1H),3.01(s,3H),2.91(s,3H),2.87(s,2H),2.61-2.67(m,1H),2.21(s,3H),1.98(m,2H),1.63-1.65(m, 4H).

Pharmacological experiments

Experimental example A kinase assay (Single dose inhibition assay)

In vitro kinase detection targets comprise EGFR WT, L858R, T790M, L858R/T790M and ALK. The assay conditions were 100nM of test compound reacted with 10. mu.M ATP.

A detection step:

all reactions were initiated by adding MgATP mixture. After incubation at room temperature for 40 minutes, the reaction was stopped by adding a 3% phosphoric acid solution. Then, 10. mu.L of the reaction was spotted on a P30 filter membrane (filtermat) and washed 3 times in 75mM phosphoric acid for 5 minutes each, followed by 1 more wash with methanol before drying and scintillation counting. The test was performed by Millipore. The above experiments are all parallel multiple-hole experiments. The measurement values of the control sample (DMSO) group were set as 100%, and the measurement values of the test compound sample were expressed as relative activities to the control sample.

Kinase-specific detection conditions:

ALK (h) and 8mM propanesulfonic acid (MOPS) pH7.0, 0.2mM ethylenediaminetetraacetic acid (EDTA), 250 μ MKKKSPGEYVNIEFG, 10mM magnesium acetate, [ gamma-³³P-ATP](specific activity of radioactivity)About 500cpm/pmol, concentrated as needed) and 0.1. mu.M test compound.

EGFR (h) and EGFR (L858R) with 8mM propanesulfonic acid (MOPS) pH7.0, 0.2mM ethylenediaminetetraacetic acid (EDTA), 10mM MnCl₂0.1mg/mL poly (Glu, Tyr)4:1, 10mM magnesium acetate, [ gamma-³³P-ATP](specific radioactivity of about 500cpm/pmol, concentrated as required) and 0.1. mu.M of test compound.

EGFR (T790M) (h) and EGFR (T790M, L858R) with 8mM propanesulfonic acid (MOPS) pH7.0, 0.2mM ethylenediaminetetraacetic acid (EDTA), 250. mu. M GGMEDIYFEFMGGKKK, 10mM magnesium acetate, [ gamma-³³P-ATP](specific radioactivity of about 500cpm/pmol, concentrated as required) and 0.1. mu.M of test compound.

TABLE 1

Experimental example B kinase assay (IC)₅₀)

The detection targets of the in vitro kinase inhibition curves comprise EGFR WT, L858R, T790M, L858/T790M and ALK, and the reaction is carried out by using Km ATP concentration and setting 1 μm (EGFR L858R, T790M, L858R/T790M and ALK) or 10 μm (EGFR WT) as the highest concentration (two times of repetition) to carry out 10 concentration data point curve determination.

Kinase assay procedure:

strip-coded Corning low-volume NBS black 384-well plates (Corning Cat, # 4514);

1.2.5 μ L-4X test compound, or a mixture of 100nL 100X test compound and 2.4 μ L kinase buffer;

2.5 μ L of the-2X peptide/kinase mixture;

3.2.5 μ L-4X ATP solution;

4.30 seconds of mixing with a perforated plate;

5. incubation of the kinase reaction for 60 min at room temperature;

6.5 mul-developer solution;

7.30 seconds of mixing with a perforated plate;

8. extension reaction incubation at room temperature for 60 min;

9. the data were read and analyzed on a fluorescence plate reader.

Kinase-specific detection conditions:

ALK

at 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂A2X ALK/Tyr01 mixture was prepared in 1mM EGTA. The final 10. mu.L kinase reaction system was 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂1mM EGTA solution containing 4.25-96ng ALK and 2. mu.M Tyr01, 1 hour after kinase reaction, 5. mu.L of developer B diluted at a ratio of 1:256 was added.

EGFR(ErbB1)

At 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂、4mM MnCl₂2X EGFR (ErbB1)/Tyr 04 mixture was prepared in 1mM EGTA, 2mM DTT. The final 10. mu.L kinase reaction system was 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂,2mM MnCl₂1mM EGTA,1mM DTT solution containing 1.1-8ng EGFR (ErbB1) and 2. mu.M Tyr 04, 1 hour after incubation, 5. mu.L of developer B diluted at a ratio of 1:64 was added.

EGFR(ErbB1)L858R

At 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂、4mM MnCl₂,、1mM EA2X EGFR (ErbB1) L858R/Tyr 04 mixture was prepared from GTA, 2 mMDTT. The final 10. mu.L kinase reaction system was 50mM HEPES pH7.5, 0.01% BRIJ-35,10mM MgCl₂,2mM MnCl₂1mM EGTA,1mM DTT solution containing 0.2-3.36ng EGFR (ErbB1) L858R and 2. mu.M Tyr 04, 1 hour after incubation with kinase, 5. mu.L of developer B diluted at a ratio of 1:64 was added.

EGFR(ErbB1)T790M

At 50mM HEPES pH 6.5, 0.01% BRIJ-35,10mM MgCl₂、1mM EGTA、0.02％NaN₃To prepare a 2X EGFR (ErbB1) T790M/Tyr 04 mixture. The final 10. mu.L kinase reaction system was 50mM HEPES pH7.0, 0.01% BRIJ-35,10mM MgCl₂,1mM EGTA,0.01％NaN₃The solution contained 3.9-34.8ng EGFR (ErbB1) T790M and 2. mu.M Tyr 04, and after 1 hour of kinase reaction incubation, 5. mu.L of developer B diluted at a ratio of 1:64 was added.

EGFR(ErbB1)T790M L858R

At 50mM HEPES pH 6.5, 0.01% BRIJ-35,10mM MgCl2, 1mM EGTA, 0.02% NaN₃The medium 2XEGFR (ErbB1) T790M L858R/Tyr 04 mixture. The final 10. mu.L kinase reaction system was 50mM HEPES pH7.0, 0.01% BRIJ-35,10mM MgCl₂,1mM EGTA,0.01％NaN₃The solution contained 0.36-2.96ng EGFR (ErbB1) T790M L858R and 2. mu.M Tyr 04, after 1 hour of kinase reaction incubation, 5. mu.L of developer B diluted at a ratio of 1:64 was added.

The compounds of formula (I) are potent inhibitors of EGFR mutants in kinase assays. For example, the IC of the previously known inhibitors gefitinib, erlotinib and CO-1686 against the drug-resistant mutant EGFR L858R/T790M₅₀A value of about 16.6nM to>1 μm, and IC of many compounds of formula (I)₅₀It is approximately 4.08 to 22.8 nM. Therefore, the compound shown in the formula (I) has an inhibitory effect on EGFR-caused cancers.

TABLE 2

Experimental example C cell proliferation experiment

NSCLC cell lines were used to test the effect of compounds of formula (I) on 3 common EGFR, namely: wild-type EGFR (naturally occurring form, WT), activation mutant EGFR (Del e746_ a750[ Del ], this type sensitive to first generation EGFR inhibitors), and EGFR with both activation and T790M resistance mutations (L858R/T790M, T790M secondary mutations contribute to their resistance to first generation EGFR inhibitors).

The effect of the test compound on in vitro proliferation can be determined by MTS cell viability assay.

Cell culture

H1975(EGFR L858R/T790M), HCC827(EGFR Del), A549(EGFR WT) and A431(EGFR WT) NSCLC cell lines were all from ATCC.

Both H1975 and HCC827 cells were cultured in RPMI1640(Gibco) medium supplemented with 10% FBS, 100 units/mL penicillin, 100 units/mL streptomycin, and 2mM glutamine.

A549 cells were cultured in Ham's F12K (Gibco) medium supplemented with 10% FBS, 100 units/mL penicillin, 100 units/mL streptomycin, and 2mM glutamine.

A431 cells were cultured in DMEM (Gibco) medium supplemented with 10% FBS, 100 units/mL penicillin, 100 units/mL streptomycin and 2mM glutamine.

MTS cell viability assay:

1. at 2X 10³Inoculating cells into a 96-well plate at a cell density of each well, and culturing for 24 hours;

2. preparing a culture medium with a final volume of 200 mul containing the compound to be detected;

3. continuously exposing and culturing for 3 days;

4. reagents were prepared according to the instructions of the cell proliferation assay kit (Promega);

5. the medium was replaced with serum-free medium and the final volume of each well was 100. mu.l, and another well plate was prepared for background elimination;

6. mu.l of MTS solution containing PMS (final concentration of MTS 0.33mg/ml) was added to each well;

7. the above 96-well plates were humidified at 37 ℃ with 5% CO₂Incubating for 1-4 hours in the cell incubator;

8. the absorbance values were read at 490nm using a Victor X5 microplate spectrophotometer (Perkinelmer).

Three wells were set for all experimental points and all experiments were repeated at least three times.

Examples 40, 65, 66, 67, 74, 112 and 118 all have inhibitory effects on EGFR containing both the sensitive mutation and the T790M resistant mutation in vitro cell experiments. For example, in an independent assay, in vitro proliferation of HCC827 cells expressing EGFR Del, half inhibitory concentrations GI of examples 67 and 118₅₀Respectively at 20 nM; proliferation of H1975 cells expressing EGFR-L858R/T790M in vitro, half inhibitory concentrations GI of examples 67 and 118₅₀20nM and 10nM, respectively, similar to the HCC827 cell line.

In contrast, examples 67 and 118 showed no significant inhibitory activity on proliferation of cells expressing EGFR WT in vitro, e.g., both of the half inhibitory concentrations for proliferation in A549(EGFR WT) cell line were GI₅₀>1500nM, indicating outstanding selectivity for EGFRWT and mutant. However, afatinib, a second generation EFGR TKI inhibitor, has similar inhibitory effects on HCC827(EGFR Del) cell proliferation and a431(EGFR WT) cell proliferation.

TABLE 3

The compounds provided herein are preferably pharmaceutical compositions having multiple modes of administration. Most preferably, the pharmaceutical composition is administered orally. Such pharmaceutical compositions and processes for their preparation are well known in the art, for example, REMINGTON (REMINGTON): science and practice OF PHARMACY (THE SCIENCE AND PRACTICE OF PHARMACY, A. Gennaro, et al, eds., 19)^thed., Mack Publishing co, 1995). The compounds of formula (I) are effective over a relatively wide dosage range.

For example, a normal daily dose range is generally from about 1mg to about 200mg of total daily dose (total daily dose), preferably from 1mg to 150mg of total daily dose, more preferably from 1mg to 50mg of total daily dose. In some cases, dosage levels below the lower limit of the aforesaid range may also be sufficient, while in other cases still larger doses may be useful. The above dosage ranges do not limit the scope of the present invention in any way. It will be understood that the actual dosage of the compounds provided herein will be determined by a physician, in the light of the relevant circumstances, including the conditions to be treated, the choice of route of administration, the actual compounds and complexes administered, the age, weight, response of the individual patient, and the severity of the patient's symptoms.

Claims (39)

1. A compound of formula I or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

x is selected from NR₁₆(ii) a Wherein R is₁₆Is selected from H;

y is selected from halogen, methyl or halogen substituted methyl;

z is selected from O;

R₁is selected from N (R)₈)(R₉) (ii) a Each R₈And R₉Each independently selected from H, OH or C_1-6An alkyl group;

R₂is selected from H;

R₃is selected from H;

R₄selected from H, C_1-6Alkoxy or halogen;

R₅selected from H, C_1-6Alkyl, haloalkyl or C_1-6An alkoxy group;

R₆selected from-H, halogen, -OH, -OEt, -NH₂、-NHCH₃、-NCH₃CH₃、

Or

R₇Selected from H, C_1-6Alkyl, aryl, heteroaryl, and heteroaryl,Or

R₆And R₇Together form a 6-membered heterocyclic ring which is unsubstituted or substituted by-C (O) R₁₂Is substituted in which R₁₂Independently selected from H, (C)_1-6) Alkyl, (C)_2-6) Alkenyl, (C)_3-6) Cycloalkyl or (C)_3-6) A heterocyclic group.

2. The compound of claim 1, wherein Y is selected from Cl or CF₃。

3. The compound of claim 1, wherein Y is CH₃。

4. A compound of claim 1, wherein R is₁₂Is selected from (C)_2-6) An alkenyl group.

5. A compound of claim 1, wherein R is₆Is selected from

6. A compound of claim 1, wherein R is₆Is selected from-H or-F.

7. A compound of claim 1, wherein R is₈And R₉Selected from methyl.

8. A compound of claim 1, wherein R is₁Each independently selected from-NHOH and-NH₂、-NHCH₃or-NCH₃CH₃。

9. A compound of claim 1, wherein R is₁Is selected from

10. The method of claim 1Characterized in that R is₂、R₃And R₅Are all H.

11. A compound of claim 1, wherein R is₄Selected from H, -OCH₃OEt or

12. A compound of claim 1, wherein R is₄Selected from halogens.

13. A compound of claim 1, wherein R is₄Selected from the group consisting of H, F, -OCH₃Or

14. A compound of claim 1, wherein R is₅Selected from H, halogen substituted methyl or methoxy.

15. A compound of claim 1, wherein R is₇Selected from H, C_1-6Alkyl or

16. The compound of claim 1, wherein the compound is of formula II:

17. a compound according to claim 16, wherein X is NH.

18. The compound of claim 16, wherein Y is selected from Cl or CF₃。

19. The compound of claim 16, wherein R is₁Is selected from-NHCH₃or-NCH₃CH₃。

20. The compound of claim 16, wherein R is₂、R₃And R₅Are all H.

21. The compound of claim 16, wherein R is₄Selected from the group consisting of H, F, -OCH₃Or

22. The compound of claim 16, wherein each R is₆Each independently selected from-OH, -OEt, -NHOH and-NH₂、-NHCH₃、-NCH₃CH₃、

23. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

1)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-hydroxy-2-oxoacetamide;

2)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

3)2- (2- ((5-chloro-2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

4)2- (2- ((2- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

5)2- (2- ((5-chloro-2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

6)2- (2- ((5-chloro-2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

7)2- (2- ((2- ((2-methoxy-4- (4-methylpiperazin-1-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

8)2- (2- ((2- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

9)2- (2- ((2- ((2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

10)2- (2- ((2- ((4- ((1- (2-fluoroethyl) azetidin-3-yl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

11)2- (2- ((2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) -2-oxoacetamide;

12)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

13)2- (2- ((5-chloro-2- ((4- (4-dimethylaminopiperidin-1-yl) -2-methoxyphenyl) amino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

14) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

15) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- (morpholinylmethyl) acrylamide;

16)2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

17)2- (2- ((5-chloro-2- (2-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

18)2- (2- ((5-chloro-2- (2-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

19)2- (2- ((5-chloro-2- (2-methoxy-4- (4-propionylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

20)2- (2- ((2- (4- (4-acetylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

21)2- (2- ((5-chloro-2- (2-methoxy-4- (4-propionylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

22) n- (3- ((4- (2- (2-amino-2-oxoacetyl) phenylamino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) phenyl) acrylamide;

23)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

24)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

25)2- (2- ((5-chloro-2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

26)2- (2- ((5-chloro-2- (4-fluoro-3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N-methyl-2-oxoacetamide;

27) n- (5- ((5-chloro-4- (2- (2- (methylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

28) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

29) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-fluoro-4-methoxyphenyl) acrylamide;

30) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

31) n- (5- ((5-chloro-4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-fluoro-2-methoxyphenyl) acrylamide;

32) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-fluoro-2-methoxyphenyl) acrylamide;

33) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) but-2-enamide;

34) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -3-methylbut-2-enamide;

35) (E) -N- (3- (5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -4-methoxyphenyl) -4- (piperidin-1-yl) but-2-enamide;

36) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

37) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

38) n- (5- ((5-chloro-4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

39) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((dimethylamino) methyl) acrylamide;

40) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -4-morpholinylbut-2-enamide;

41) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -4- (dimethylamino) but-2-enamide;

42) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide;

43) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) -4-methoxyphenyl) acrylamide;

44) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide;

45) n- (5- ((5-chloro-4- (2- (2-methylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (3-morpholinopropoxy) phenyl) acrylamide;

46)2- (2- ((2- ((4-acryloyl-3, 4-dihydro-2H-benzo [ b ] [1,4] oxazin-6-yl) amino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

47)2- (2- ((2- (4- (4-acryloylpiperazin-1-yl) -2-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

48)2- (2- ((2- (4- (4-acetylpiperazin-1-yl) -3-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

49)2- ((aziridin-1-yl) methyl) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

50)2- ((azetidin-1-yl) methyl) -N- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

51) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((pyrrolidin-1-yl) methyl) acrylamide;

52) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (2-morpholinoethoxy) phenyl) acrylamide;

53) n- (5- (5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide;

54) n- (3- ((4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) -5-methylpyrimidin-2-yl) amino) -4-methoxyphenyl) -2- ((dimethylamino) methyl) acrylamide;

55) n- (5- ((4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) -5-methylpyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

56) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) -3-methoxypropionamide;

57) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-cyclopropoxyphenyl) acrylamide;

58) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (cyclopentyloxy) phenyl) acrylamide;

59) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((1-methylpyrrolidin-3-yl) oxo) phenyl) acrylamide;

60) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4- (dimethylamino) cyclohexyloxo) phenyl) acrylamide;

61) n- (2- ((azetidin-3-yl) oxo) -5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) acrylamide;

62) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((1-methylazetidin-3-yl) oxo) phenyl) acrylamide;

63) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-morpholinylphenyl) acrylamide;

64) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) acrylamide;

65) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- (morpholinylmethyl) acrylamide;

66) n- (3- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

67) (E) -N- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -4- (dimethylamino) but-2-enamide;

68) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) acrylamide;

69) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (difluoromethoxy) phenyl) acrylamide;

70)2- (2- ((5-chloro-2- (3-methoxy-4-morpholinylphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

71)2- (2- ((5-chloro-2- (4- (4-dimethylaminopiperidin-1-yl) -3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

72)2- (2- ((5-chloro-2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

73) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethoxy) phenyl) propionamide;

74) (E) -N- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) -3- (dimethylamino) acrylamide;

75) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-propoxyphenyl) acrylamide;

76) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-fluorophenyl) -3-morpholinylpropanamide;

77) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((tetrahydrofuran-3-yl) oxy) phenyl) acrylamide;

78) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) phenyl) -2- (((2- (dimethylamino) ethyl) (meth) amino) methyl) acrylamide;

79) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) -2- (((2- (dimethylamino) ethyl) (meth) amino) methyl) acrylamide;

80) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (4-methylpiperazin-1-yl) phenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

81) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-morpholinylphenyl) -2- ((piperidin-1-yl) methyl) acrylamide;

82)2- (2- ((5-chloro-2- (3-methoxy-4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-diethyl-2-oxoacetamide;

83) n- (3- ((5-chloro-4- (2- (2-diethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide;

84) n- (5- ((5-chloro-4- (2- (2-diethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2-methoxyphenyl) acrylamide;

85) n- (3- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -5- (trifluoromethyl) phenyl) acrylamide;

86) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethoxy) methyl) phenyl) acrylamide;

87) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethoxy) methyl) -4-methoxyphenyl) acrylamide;

88) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((dimethylamino) methyl) phenyl) acrylamide;

89) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((dimethylamino) methyl) -4-methoxyphenyl) acrylamide;

90) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- ((4-methylpiperazin-1-yl) methyl) phenyl) acrylamide;

91) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- ((4-methylpiperazin-1-yl) methyl) phenyl) acrylamide;

92) n- (5- (5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-ylamino) -2- (1-methylpiperidin-4-yl) phenyl) acrylamide;

93) n- (5- ((5-chloro-4- (2- (2-dimethylamino-2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -4-methoxy-2- (1-methylpiperidin-4-yl) phenyl) acrylamide;

94)2- (2- ((5-chloro-2- (3-methoxy-4- (1-methylpiperidin-4-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

95)2- (2- ((2- (4- (1-acetylpiperidin-4-yl) -3-methoxyphenylamino) -5-chloropyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

96) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (2- (dimethylamino) ethyl) phenyl) acrylamide;

97) n- (5- ((5-chloro-4- (2- (2- (dimethylamino) -2-oxoacetyl) phenylamino) pyrimidin-2-yl) amino) -2- (3- (dimethylamino) propyl) phenyl) acrylamide;

98)2- (2- ((5-chloro-2- (4- (1-isopropylpiperidin-4-yl) -3-methoxyphenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide;

99)2- (2- ((5-chloro-2- (2-isopropoxy-5-methyl-4- (piperidin-4-yl) phenylamino) pyrimidin-4-yl) amino) phenyl) -N, N-dimethyl-2-oxoacetamide.

24. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-23 and a pharmaceutically acceptable adjuvant.

25. The pharmaceutical composition of claim 24, wherein the weight ratio of the compound to the excipient is 0.0001 to 10.

26. Use of a pharmaceutical composition according to claim 24 or 25 or a compound according to any one of claims 1 to 23 for the manufacture of a medicament for treating, preventing, delaying or arresting the occurrence or progression of cancer, cancer metastasis, cardiovascular disease, immunological disease or an ocular disorder in a subject.

27. Use according to claim 26, wherein the medicament is for use as a kinase inhibitor.

28. The use of claim 27, wherein the kinase comprises EGFR, ALK, or ALK fusion proteins.

29. The use of claim 28, wherein the EGFR is a mutated EGFR; the cancer is an EGFR-induced cancer characterized by a mutation selected from one or more of: (i) L858R, (ii) T790M, (iii) L858R and T790M, (iv) del E746_ A750, or (v) del E746_ A750 and T790M.

30. The use of claim 29, wherein the EGFR-induced cancer is non-small cell lung cancer, glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, epithelial cancer, ovarian cancer, prostate cancer, or adenocarcinoma.

31. The use according to claim 30, wherein the head and neck cancer is a squamous cell carcinoma of the head and neck.

32. The use according to claim 28, wherein the ALK fusion protein is EML4-ALK or NPM-ALK kinase.

33. The use according to any one of claims 26 to 32, wherein the subject is a human.

34. Use of a compound according to any one of claims 1 to 23 or a pharmaceutical composition according to claim 24 or 25 for the preparation of a medicament for the treatment of a disease resulting from a kinase modulation disorder in a subject, wherein the kinase comprises EGFR, ALK or an ALK fusion protein.

35. The use of claim 34, wherein the disease is an EGFR-induced cancer characterized by one or more mutations selected from the group consisting of: (i) L858R, (ii) T790M, (iii) L858R and T790M, (iv) del E746_ A750, or (v) del E746_ A750 and T790M.

36. The use of claim 35, wherein the EGFR-induced cancer is non-small cell lung cancer, glioblastoma, pancreatic cancer, head and neck cancer, breast cancer, colorectal cancer, epithelial cancer, ovarian cancer, prostate cancer, or adenocarcinoma.

37. The use according to claim 36, wherein the head and neck cancer is a squamous cell carcinoma of the head and neck.

38. The use according to claim 37, wherein the ALK fusion protein is EML4-ALK or NPM-ALK kinase.

39. The use according to any one of claims 34 to 38, wherein the subject is a human.