R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[07] In one aspect, the present disclosure provides a compound according to Formula I

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N; R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein R₁₀ is a C₂-C₁₀ alkyl;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and

R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[08] In one embodiment of the above, the compound is according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein:

R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein R₁₀ is a C₂-C₁₀ alkyl;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and

R₈ and R₉ are independently C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₈ and R₉ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[09] In one embodiment of the above, the compound is according to Formula IIIA or IIIB:

or a pharmaceutically acceptable salt thereof, wherein

Q₁ - Q₃ are each independently C or N, provided that at least one of Q₁ - Q₃ is C and at least one of Q₁ - Q₃ is N;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl;

R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and

R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[010] In one embodiment of the above, the compound is according to Formula IV;

or a pharmaceutically acceptable salt thereof, wherein R₁₁ is an optionally substituted C₁-C₁₀ alkyl.

[011] In one embodiment, R₁₁ is an optionally substituted C₁-C₄ alkyl.

[012] In one embodiment, the present disclosure provides a compound having a formula

[013] In one embodiment, Z is S.

[014] In one embodiment, Z is CR₅.

[015] In one embodiment, R₇ is an aryl or heteroaryl.

[016] In one embodiment, R₁ is hydrogen (H).

[017] In one embodiment, R₂ is selected from H, a halide, OH, and CN. In one embodiment, R₂ is fluoro.

[018] In one embodiment, R₃ is selected from H, F, Cl, CN, and CF₃.

[019] In one embodiment, R₄ is selected from H, CN, and CF₃.

[020] In one embodiment, R₅ is H or a C₁-C₁₀ alkyl.

[021] In one embodiment, R₆ is H or a C₁-C₁₀ alkyl.

[022] In one embodiment, R_{1 1} is selected from H and an optionally substituted C₁-C₄ alkyl. [023] In one embodiment, R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[024] In one embodiment, Qi is N, Q₂ is C, and Q₃ is N. In one embodiment, Q₁ is C, Q₂ is N, and Q₃ is N. In one embodiment, Qi is N, Q₂ is C, and Q₃ is C.

[025] In another aspect, the present disclosure provides a pharmaceutical composition comprising the compound according to any one of the above embodiments, together with one or more excipients.

[026] In another aspect, the present disclosure provides a pharmaceutical dosage form comprising the compound according to any one of the above embodiments, or the composition according to the above embodiment.

[027] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula A; or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein Rio is a C₂-C₁₀ alkyl;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

12 [028] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula I: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein R₁₀ is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[029] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula II A or IIB:

or a pharmaceutically acceptable salt thereof, wherein:

R? is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and R₈ and R₉ are independently C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₈ and R₉ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[030] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula III A or IIIB:

or a pharmaceutically acceptable salt thereof, wherein:

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety. [031] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound selected from the group consisting of:

[032] In one embodiment, modulating the HSD17B 13 protein comprises inhibiting the HSD17B 13 protein.

[033] In one embodiment, the compound does not modulate one or more ofHSD17Bl, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6, HSD17B7, HSD17B8, HSD17B9, HSD17B10, HSD17B11, HSD17B12, or HSD17B14.

[034] In one embodiment, the compound does not modulate one or more ofHSD17Bl, HSD17B2, HSD 17B4, HSD 17B 10, and HSD 17B 13. [035] In one embodiment, the cell is a mammalian cell. In one embodiment, the cell is a human cell. In one embodiment, the cell is a liver cell.

[036] In one embodiment, the compound inhibits the HSD17B13 protein with an IC50 of less than 10 μmol. In one embodiment, the compound inhibits the HSD17B13 protein with an IC50 of less than 2 μmol. In one embodiment, the compound inhibits the HSD17B13 protein with an IC50 of less than 0.1 μmol.

[037] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula A: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[038] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula I: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[039] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[040] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IIIA or IIIB:

or a pharmaceutically acceptable salt thereof, wherein

R? is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[041] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IV: or a pharmaceutically

acceptable salt thereof, wherein R₁₁ is an optionally substituted C₁-C₁₀ alkyl.

[042] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound selected from the group consisting of:

, or a pharmaceutically acceptable salt thereof.

[043] In another aspect, the present disclosure provides a protein-drug conjugate comprising: (a) an antigen binding protein that specifically binds a tumor-associated antigen (TAA); (b) a compound according to any of the above embodiments; and (c) a suitable linker that connects said antigen binding protein and said amanitin or analog thereof.

[044] In one embodiment, the linker is a cleavable linker. In one embodiment, the linker is a non- cleavable linker.

[045] In one embodiment, the linker is connected to the antigen-binding protein using a transglutaminase reaction.

[046] In one embodiment, the TAA is selected from the group consisting of: an anti-HER2 antibody, an anti-STEAP2 antibody, an anti-MET antibody, an anti-EGFRVIII antibody, an anti- MUC16 antibody, an anti-PRLR antibody, an anti-PSMA antibody, an anti-FGFR2 antibody, an anti-FOLRl antibody, an anti-HER2/HER2 bispecific antibody, an anti-ASGRl antibody, an anti- MET/MET bispecific antibody, or an antigen-binding fragment thereof.

[047] These and other aspects will become apparent to those skilled in the art after a reading of the following detailed description, including the appended claims.

DETAILED DESCRIPTION

[048] Detailed embodiments are disclosed herein, however, it is to be understood that the disclosed embodiments are merely illustrative of the disclosure, which can be embodied in various forms. In addition, each of the examples given in connection with the various embodiments of the disclosure is intended to be illustrative, and not restrictive. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a representative basis for teaching one skilled in the art to variously employ the present disclosure. [049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs.

[050] As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. Thus, for example, a reference to “a method” includes one or more methods, and/or steps of the type described herein and/or which will become apparent to those persons skilled in the art upon reading this disclosure. [051] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and/or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that can be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder, or condition (e.g., arresting, reducing or delaying the development of the disease or a relapse thereof or at least one clinical or sub-clinical symptom thereof); or (3) relieving the disease (e.g., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms). The benefit to a subject to be treated is either statistically significant or at least perceptible to the subject or to the physician.

[052] A “subject” or “patient” or “individual” or “animal,” as used herein, refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animals used to model diseases (e.g., mice, rats, rabbits, dogs, monkeys). In any embodiment, the subject may be a human.

[053] As used herein the term “effective” applied to dose or amount refers to that quantity of a compound or pharmaceutical composition that is sufficient to result in a desired activity upon administration to a subject. Note that when a combination of active ingredients is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[054] The phrase “pharmaceutically acceptable,” as used in connection with compositions of the disclosure, refers to molecular entities and other ingredients of such compositions that are physiologically tolerable and, in certain embodiments, do not typically produce untoward reactions when administered to a mammal (e.g., a human). As used herein, in certain embodiments, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in mammals, and more particularly in humans.

[055] Ranges can be expressed herein as “about” or “approximately” one particular value and/or to “about” or “approximately” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. As used herein, the term “about,” when used in reference to a particular recited numerical value, means that the value can vary from the recited value by no more than 10%. For example, as used herein, the expression “about 100” includes 90 and 110 and all values in between (e.g., 91, 92, 93, 94, etc.).

[056] “Comprising” or “containing” or “including” are used to mean that at least the named compound, element, particle, or method step is present in the composition or article or method, but does not exclude the presence of other compounds, materials, particles, or method steps, even if the other such compounds, material, particles, or method steps have the same function as what is named.

[057] Compounds of the present disclosure include those described generally herein, and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75^th Ed. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[058] The term “aliphatic” or “aliphatic group,” as used herein, means a straight-chain (i.e., unbranched), branched, or cyclic (also referred to herein as “carbocycle,” “cycloaliphatic” or “cycloalkyl”) hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon, bicyclic hydrocarbon, tricyclic hydrocarbon, and polycyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that is attached to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1 to 30 aliphatic carbon atoms. In any embodiment, unless otherwise specified, an aliphatic group may contain 1 to 20 aliphatic carbon atoms, 1 to 10 aliphatic carbon atoms, 1 to 6 aliphatic carbon atoms, or 1, 2, 3, or 4 aliphatic carbon atoms. Suitable aliphatic groups include, but are not limited to, linear or branched alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. [059] In any embodiment, an aliphatic group may be a cycloaliphatic group. The term “cycloaliphatic,” as used herein, refers to saturated or partially unsaturated cyclic aliphatic monocyclic, bicyclic, or polycyclic ring systems, as described herein, having 3 to 14 carbons. Cycloaliphatic groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cyclooctyl, cyclooctenyl, norbomyl, adamantyl, and cyclooctadienyl. A cycloalkyl may have 3 to 6 carbons. The terms “cycloaliphatic,” can also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic ring. A carbocyclic group may, in any embodiment, be bicyclic. A cycloaliphatic group may be tricyclic. A cycloaliphatic group may be, in any embodiment, polycyclic. “Cycloaliphatic” (or “carbocycle” or “cycloalkyl”) may refer to a monocyclic C_3-6 hydrocarbon, or a C_8-10 bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule, or a C_9-16 tricyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule.

[060] As used herein, the term “alkyl” is given its ordinary meaning in the art and can include saturated aliphatic groups, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In any embodiment, unless otherwise specified, a straight chain or branched chain alkyl has 1 to 20 carbon atoms in its backbone (e.g., C_1-20 for straight chain, C_2-20 for branched chain), and alternatively, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. In any embodiment, unless otherwise specified, a cycloalkyl ring may have 3 to 10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, or alternatively 5, 6, or 7 carbons in its ring structure. In any embodiment, unless otherwise specified, a cycloalkyl group is a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl group. In any embodiment, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1 to 4 carbon atoms (e.g., C_1-4 for straight chain lower alkyls). When used in the context of a divalent alkyl group, it is to be understood that “alkyl” refers to an alkylene group.

[061] As used herein, the term “alkenyl” refers to an alkyl group, as defined herein, including straight-chain alkenyl groups, branched-chain alkenyl groups, and cycloalkenyl groups having one or more double bonds. In any embodiment, unless otherwise specified, a straight chain or branched chain alkenyl has 1 to 20 carbon atoms in its backbone (e.g., C_2-20 for straight chain, C_3-20 for branched chain), or alternatively, 2 to 10 carbon atoms, or 2 to 6 carbon atoms. In any embodiment, unless otherwise specified, an alkenyl group may have 1, 2, 3, 4, 5, or 6 double bonds. In any embodiment, a cycloalkenyl ring may have 3 to 10 carbon atoms in its ring structure where such rings are monocyclic or bicyclic, or alternatively 5, 6 or 7 carbons in its ring structure and 1, 2, or 3 double bonds. In any embodiment, a cycloalkenyl group may be, for example, a cyclopropenyl, a cyclobutenyl, a cyclobutadienyl, a cyclopentenyl, a cyclopentadienyl, a cyclohexenyl, or a cyclohexadienyl group. In any embodiment, unless otherwise specified, an alkenyl group can be a lower alkenyl group, wherein a lower alkenyl group comprises 2 to 4 carbon atoms e.g., C_2-4 for straight chain lower alkenyls). For example, in any embodiment, a cycloalkenyl group may have six carbon atoms and one double bond.

[062] As used herein, the term “alkynyl” refers to an alkyl group, as defined herein, including straight-chain alkynyl groups, branched-chain alkynyl groups, and cycloalkynyl groups having one or more triple bonds. In any embodiment, unless specified otherwise, a straight chain or branched chain alkynyl may have 2 to 20 carbon atoms in its backbone (e.g., C_2-20 for straight chain, C_3-20 for branched chain), or alternatively, 2 to 10 carbon atoms or 2 to 6 carbon atoms. In any embodiment, an alkynyl group may have 1, 2, 3, 4, 5, or 6 triple bonds. In any embodiment, a cycloalkynyl ring may have 6 to 12 carbon atoms in its ring structure where such rings are monocyclic or bicyclic, or alternatively 8, 9, or 10 carbons in its ring structure and 1, 2, or 3 triple bonds. In any embodiment, unless otherwise specified, an alkynyl group can be a lower alkynyl group, wherein a lower alkynyl group comprises 2 to 4 carbon atoms (e.g., C_2-4 for straight chain lower alkynyls).

[063] The term “heteroalkyl” is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more carbon atoms is replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, and the like). Tn any embodiment, unless otherwise specified, a heteroalkyl group can have one or more of its methylene groups replaced with -O-, -S-, or -N(H)-, wherein the hydrogen of-N(H)- is optionally substituted. Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[064] The term “haloalkyl” is given its ordinary meaning in the art and refers to alkyl groups as described herein in which one or more hydrogen atoms is replaced by a halogen atom, i.e., F, Cl, Br, or I. In any embodiment, unless specified otherwise, a haloalkyl group can be a perfluoroalkyl group, i.e., a group where all hydrogen atoms are replaced with fluoride atoms. In any embodiment, unless otherwise specified, a haloalkyl group can be a halomethyl group, i.e., a C₁ group with 1, 2, or 3 halogen atoms, e.g., -CF₃, -CF₂H, -CH₂F, -CH₂CI, -CH₂Br; -CH₂I. Other examples of haloalkyl groups include, without limitation, e.g., -CF₃, -CF₂H, -CH₂F, -CH₂CI, -CH₂Br; -CH₂I, - CH₂CF₃, CH₂CH₂F, -CH₂CH₂Br, -CH₂CH₂CI, -CH₂CH₂I, etc.

[065] The term “haloalkoxy” is given its ordinary meaning in the art and refers to alkoxy groups as described herein, i.e., alkyl groups bonded to an oxygen atom, in which one or more hydrogen atoms is replaced by a halogen atom, i.e., F, Cl, Br, or I. A haloalkoxy group can be a perfluoroalkoxy group, i.e., a group where all hydrogen atoms are replaced with fluoride atoms. A haloalkoxy group may be, e.g., -OCF₃, -OCF₂H, -OCH₂F, -OCH₂CI, -OCH₂Br; -OCH₂I, -OCH₂CF₃, -OCH₂CH₂F, -OCH₂CH₂Br, -OCH₂CH₂CI, -OCH₂CH₂I, etc.

[066] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,” “aralkoxy,” “aryloxy” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of 5 to 14 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” can be used interchangeably with the term “aryl ring.” In any embodiment, “aryl” may refer to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which can bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[067] The term “aralkyl” refers to alkyl groups as described herein in which one or more hydrogen atoms is substituted by an aryl group, where the radical or point of attachment is on the alkyl group. The alkyl part of an aralkyl group may be optionally substituted as described in the term “alkyl” above. The aryl part of the aralkyl group may be optionally substituted as described in the term “alkyl” above.

[0681 The term “alkylaryl” refers to aryl groups, as described herein, in which one or more hydrogen atoms is substituted by an alkyl group, where the radical or point of attachment is on the aryl group. The aryl part of the alkylaryl group may be optionally substituted as described in the term “aryl” above. The alkyl part of an alkylaryl group may be optionally substituted as described in the term “alkyl” above.

[069] The terms “heteroaryl” and “heteroar-,” used alone or as part of a larger moiety, e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms (e.g., monocyclic or bicyclic), such as 5, 6, 9, or 10 ring atoms. In any embodiment, such rings may have 6, 10, or 14 it electrons shared in a cyclic array; and having, in addition to carbon atoms, from 1 to 5 heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur and any quatemized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. In any embodiment, a heteroaryl may be a heterobiaryl group, such as a bipyridyl group or the like. The terms “heteroaryl” and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H — quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group can be monocyclic, bicyclic, tricyclic, tetracyclic, and/or otherwise polycyclic. The term “heteroaryl” can be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[070] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic moiety that is saturated, partially unsaturated, or aromatic, and having, in addition to carbon atoms, one or more, e.g., one to four, heteroatoms, as defined above. As used herein, the term “heterocycle” encompasses heteroaryl groups, as defined above. In any embodiment, a heterocycle can be a saturated, partially unsaturated, or aromatic, 5- to 7- membered monocyclic moiety comprising 1 to 3 nitrogen atoms, e.g., a pyrrole, an imidazole, a pyrazole, a pyrazole, a triazole, a piperidine, a piperazine, a pyridazine, a pyridine, 2H-pyridine, a pyridone, a pyrimidine, or a pyrazine, including monovalent or divalent radicals thereof. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. In any embodiment, unless specified otherwise, a heterocycle may be a saturated, partially unsaturated, or aromatic, 5- to 7-membered monocyclic moiety comprising 1 to 3 oxygen atoms, e.g., a tetrahydrofuran (e.g., oxolane), a furan, a dihydrofuran, a di oxolane, a tetrahydropyran (e.g., oxane), a pyran, a dihydropyran, a dioxane, a dioxine, a trioxane, an oxepane, or an oxepine, including monovalent or divalent radicals thereof. In any embodiment, unless indicated otherwise, a heterocycle can be thiophene, oxazole, thiazole, or morpholine, including monovalent or divalent radicals thereof.

[071] A heterocyclic ring can be attached, e.g., to its pendant group, at any heteroatom or carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as phenyl, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, tetracyclic, and/or otherwise polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl.

[072] As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as herein defined. [073] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen. In any embodiment, unless specified otherwise, a heteroatom can be a substitutable nitrogen of a heterocyclic ring.

[074] The term “unsaturated,” as used herein, means that a moiety has one or more units of unsaturation.

[075] The term “halogen” means F, Cl, Br, or I atom, and/or its radical or substituent, namely -F, -Cl, -Br, or -I.

[076] The compounds disclosed herein may be described herein as comprising “optionally substituted” moieties. When indicated, in general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[077] As used herein, a substituent, e. ., -B, can be represented as a

, where denotes a point of attachment.

[078] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure.

[079] Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the disclosure (e.g., keto- and enol tautomeric forms). For example, compounds including carbonyl — CH₂(C=0) — or — NH(C=O) — groups (keto forms) can undergo tautomerization to form hydroxyl — CH=C(OH) — or — N=C(OH) — groups (enol forms). Both keto and enol forms, individually as well as mixtures thereof, are included within the scope of the present disclosure.

[080] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a¹¹C- or¹³C- or¹⁴C-enriched carbon are within the scope of this disclosure.

[081] It is also to be understood that the mention of one or more method steps does not preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a device or system does not preclude the presence of additional components or intervening components between those components expressly identified.

[082] Unless otherwise stated, all crystalline forms of the compounds disclosed herein and salts thereof are also within the scope of the disclosure. The compounds disclosed herein can be isolated in various amorphous and crystalline forms, including without limitation forms which are anhydrous, hydrated, non-solvated, or solvated. Example hydrates include hemihydrates, monohydrates, dihydrates, and the like. In any embodiment, the compounds disclosed herein may be anhydrous and non-solvated. By "anhydrous" is meant that the crystalline form of the compound contains essentially no bound water in the crystal lattice structure (i.e., the compound does not form a crystalline hydrate).

[083] As used herein, "crystalline form" is meant to refer to a certain lattice configuration of a crystalline substance. Different crystalline forms of the same substance typically have different crystalline lattices (e.g., unit cells) which are attributed to different physical properties that are characteristic of each of the crystalline forms. In some instances, different lattice configurations have different water or solvent content. The different crystalline lattices can be identified by solid state characterization methods such as by X-ray powder diffraction (PXRD). Other characterization methods such as differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), solid state NMR, and the like further help identify the crystalline form as well as help determine stability and solvent/water content. [084] Crystalline forms of a substance include both solvated (e.g., hydrated) and non- solvated (e.g., anhydrous) forms. A hydrated form is a crystalline form that includes water in the crystalline lattice. Hydrated forms can be stoichiometric hydrates, where the water is present in the lattice in a certain water/molecule ratio such as for hemihydrates, monohydrates, dihydrates, etc. Hydrated forms can also be non-stoichiometric, where the water content is variable and dependent on external conditions such as humidity.

[085] In any embodiment, a disclosed compound may be substantially isolated, which is used to describe a particular compound is at least partially isolated from impurities. For example, a compound may comprise less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2.5%, less than about 1%, or less than about 0.5% of one or more impurities. Impurities generally include anything that is not the substantially isolated or named compound including, for example, other crystalline forms and other substances.

[086] The present disclosure also provides salts of the compounds described herein. As used herein, “salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form. Examples of salts include, but are not limited to, mineral acid (such as HC1, HBr, H2SO4) or organic acid (such as acetic acid, benzoic acid, trifluoroacetic acid salts of basic residues such as amines); alkali (such as Li, Na, K, mg, Ca) or organic (such as trialkylammonium) salts of acidic residues such can be synthesized from the parent compound which contains a basic or acidic as carboxylic acids; and the like. The salts of the present application may be prepared by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. In some embodiments, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (ACN) can be used.

[087] The present application also includes pharmaceutically acceptable salts of the compounds described herein. The “pharmaceutically acceptable salts” include a subset of the salts described above that are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. By way of an example, in any embodiment, a pharmaceutically acceptable salt can comprise a suitable anion selected from F", Cl", Br , I", OH , BF4, CF₃SO₃- , monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO₃- , PF₆-, NO2", carboxylate, C_eF_fSO₃- , (where e = 2- 10 and f = 2e+l), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, oxalate, palmitate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide. By way of another example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamine, or zinc. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[088] Preparation of any compound disclosed herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Greene Protective Groups in Organic Synthesis, 4th Ed., John Wiley & Sons: New York, 2006. In one non-limiting embodiment, protecting groups can include 1 -chloroethyl carbonyl (ACE), acetoyl, benzyl (Bn), benzyloxy carbonyl (CBz), formyl, methyl carbonyl, trifluoroacetyl, t-butoxy carbonyl (Boc), and fluorenylmethyloxy carbonyl (Fmoc).

[089] Compounds of the Disclosure

[090] In one aspect, the present disclosure provides a compound according to Formula A: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

[091] In one aspect, the present disclosure provides a compound according to Formula I: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

[092] In one embodiment, R₇ is an aryl or heteroaryl.

[093] In another aspect, the present disclosure provides a compound according to Formula I, which may be referred to as a compound according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein

R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein Rio is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[094] In another aspect, the present disclosure provides a compound according to Formula I, which may be referred to as Formula IIIA or IIIB:

or a pharmaceutically acceptable salt thereof, wherein Q₁ - Q₃ are each independently C or N, provided that at least one of Q₁ - Q₃ is C and at least one of Q₁ - Q₃ is N;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl;

R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[095] In one embodiment of any of the above compounds, Ri is hydrogen (H).

[096] In one embodiment of any of the above compounds, R₂ is a halide.

[097] In one embodiment of any of the above compounds, R₂ is fluoro.

[098] In one embodiment of any of the above compounds, R3 is selected from H, F, Cl, CN, and CF₃ In one embodiment, R3 is H. In one embodiment of any of the above compounds, R3 is CN. [099] In one embodiment of any of the above compounds, R4 is selected from H, CN, and CF₃. In one embodiment, R4 is CN.

[0100] In one embodiment of any of the above compounds, R₅ is H or a C₁-C₁₀ alkyl. In one embodiment of any of the above compounds, R₅ is hydrogen (H).

[0101] In one embodiment of any of the above compounds, R₆ is H or a C₁-C₁₀ alkyl. In one embodiment of any of the above compounds, R₆ is hydrogen (H)

[0102] In one embodiment, R₁₁ is selected from H and an optionally substituted C₁-C₄ alkyl. In one embodiment, R₁₁ is an optionally substituted C₁-C₄ alkyl. In one embodiment, R₁₁ is methyl.

[0103] In one embodiment, R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[0104] In one embodiment, Qi is N, Q₂ is C, and Q₃ is N. In one embodiment, Qi is C, Q₂ is N, and Q₃ is N. In one embodiment, Qi is N, Q₂ is C, and Q₃ is C.

[0105] In one embodiment, the compound of Formula IIIA has a structure according to Formula IV: or a pharmaceutically acceptable salt thereof,

wherein R₁₁ is an optionally substituted C₁-C₁₀ alkyl.

[0106] In one embodiment of the compound of Formula IV, R₁₁ is an optionally substituted C₁-C₄ alkyl.

[0107] In another aspect, the present disclosure provides a compound, or a pharmaceutically acceptable salt thereof, selected from those in Table 1 below.

Table 1: compounds of the present disclosure

Pharmaceutical Compositions and Dosage Forms

[0108] The present disclosure also provides a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound as described herein, and at least one pharmaceutically acceptable excipient that may be utilized to treat a condition, disease, or disorder in a subject in need thereof.

[0109] For example, the present disclosure provides a pharmaceutical composition comprising a compound according to Formula A:

wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety. [0110] For example, the present disclosure provides a pharmaceutical composition comprising a compound according to Formula I: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

R? is H or an optionally substituted C₁-C₁₀ alkyl;

[0111] Some examples of pharmaceutically acceptable excipients include, without limitation, diluents, lubricating agents, wetting agents, emulsifying and/or suspending agents, sweetening agents, preserving agents, flavoring agents, binders, fillers, disintegrants, glidants, coloring agents, compression aids, granulating agents, anti-adherents, viscosity-altering agents, buffers, humectants, pH adjusting agents, chelating agents, antioxidants, emollients, rheology modifying agents, thickeners, solvents (e.g., water), and the like. Many common excipients may function to control properties of a pharmaceutical composition in more than one manner. Examples of pharmaceutically acceptable excipients include, without limitation, lactose, dextrose, sucrose, sorbitol, mannitol, magnesium stearate, talc, mineral oil, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxy benzoate, propylhydroxy-benzoate, and the like.

[0112] Forms: The form of the pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient is not particularly limited, and may be provided as, e.g., a liquid such as a solution, emulsion, suspension, syrup, slurry, dispersion, colloid, or the like. In another example, a pharmaceutical composition may be provided in a semi-solid form, such as a gel, gel matrix, cream, ointment, paste, plaster, rigid foam, or the like. In yet another example, a pharmaceutical composition may be provided in a solid form, such as a tablet, capsule (hard or soft), disintegrating tablet, lozenge, reconstitutable powder, inhalable powder, chewable, granules, sachet, suppository, or the like.

[0113] A pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient, can be formulated for administration to a subject by any administration route. For example, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient, can be formulated for systemic delivery, such as, but not limited to, parenteral, topical, transdermal, oral, by inhalation/pulmonary, rectal, nasal, buccal, or sublingual administration. The term “parenteral,” as used herein, includes subcutaneous, intradermal, intravenous, intramuscular, intracranial, and intraperitoneal administration. A liquid or solid pharmaceutical composition can contain suitable pharmaceutically acceptable excipients as described supra. In another example, a pharmaceutical composition may be formulated for administration to the nasal respiratory route for a local or systemic effect. In such embodiments, a pharmaceutical composition can comprise inert gases for nebulization of the pharmaceutical composition during administration. In another example, a pharmaceutical composition formulated for inhalation or insufflation may be formulated as one or more solutions or suspensions of the one or more active pharmaceutical ingredients in an aqueous solvent, organic solvent, or a mixture thereof, or as a powder.

[0114] Methods of Preparation: A pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient, can be prepared in a manner well known in the pharmaceutical art. [0115] A pharmaceutical composition may be prepared by combining the one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, with the at least one pharmaceutically acceptable excipient, which may be any listed supra. For example, the one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, may be mixed with the at least one pharmaceutically acceptable excipient. The proportion or concentration of the one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table Imay vary depending upon a number of factors including desired dosage, chemical characteristics of the one or more active pharmaceutical ingredients (e. ., hydrophobicity, solubility, stability), and the intended route of administration. It will be understood that use of certain pharmaceutically excipients as disclosed herein may result in the formation of a pharmaceutical salt of the one or more active pharmaceutical ingredients.

[0116] For example, in any embodiment, the one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may be milled to provide a desired particle size prior to combining with an additional active pharmaceutical ingredient and the at least one pharmaceutically acceptable excipient. If the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 is substantially insoluble in the chosen at least one pharmaceutically acceptable excipient, it may, for example, be milled to a particle size of 200 mesh or less. If the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 is substantially soluble in the chosen at least one pharmaceutically acceptable excipient, it may, for example, be milled to provide a particle size that results in a substantially uniform distribution in the composition, e.g. about 40 mesh.

[0117] For preparing a solid pharmaceutical composition such as a tablet, the one or more active pharmaceutical ingredients can be mixed with the pharmaceutically acceptable excipient to form a solid pre-formulation composition containing a homogeneous mixture of the compound according to the disclosure, e.g., the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. When referring to these pre-formulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid pre-form ulati on is then subdivided into unit dosage forms of the type described above containing from, for example, 0.000001 to about 2000 mg of the one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1.

[0118] The tablets or pills containing the compound according to the disclosure, e.g., the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.

[0119] The compositions of the disclosure can be formulated so as to provide rapid, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. For example, the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0120] In any embodiment, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient, can be provided in a unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages for a subject, each unit containing a predetermined quantity of the one or more active pharmaceutical ingredient (at least one of which is a compound disclosed herein) calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0121] A pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may comprise an effective amount of a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. For example, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may comprise about 0.01 mg to about 10 mg (e.g., about 0.1 mg to about 10 mg, about 0.25 mg to about 5 mg, about 0.25 mg to about 2.5 mg, about 1 mg to about 2 mg, about 2 mg to about 3 mg, about 0.5 mg to about 2 mg, about 1 mg to about 2 mg, about 1 mg, or about 2 mg of a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1.

[0122] In any embodiment, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may alternatively comprise about 5 mg and about 500 mg of a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1.

[0123] a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may be, if compatible with the composition, sterilized by conventional sterilization techniques or can be sterile filtered. Aqueous solutions may be packaged for use as is, or lyophilized for reconstitution with a sterile aqueous carrier prior to administration. Where applicable, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient typically will typically have a pH of about 3 to about 11 or from about 5 to about 9.

[0124] In any embodiment, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may be provided in a kit useful, for example, in the treatment of liver disease (e.g, liver diseases where HSD17B13 plays a role), which may include one or more containers containing a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.

[0125] In any embodiment, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and at least one pharmaceutically acceptable excipient may be provided in a device for delivery. Delivery devices are important not only for delivering the various active pharmaceutical ingredients disclosed herein, but also for providing an appropriate environment for storage. This would include protection from microbial contamination and chemical degradation. The device and formulation should be compatible so as to avoid potential leaching or adsorption. The delivery device (or its packaging) can be optionally provided with a label and/or with instructions for use indicating that the composition should be used intranasally.

Methods of Use

[0126] In another aspect, the present disclosure provides a method of modulating the activity of the 17-beta-hydroxysteroid dehydrogenase 13 (17 -HSD type 13, referred to herein as HSD17B13) in a cell comprising administering an effective amount of a compound according to Formula A:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

R? is H or an optionally substituted C₁-C₁₀ alkyl;

Rfi is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[0127] In another aspect, the present disclosure provides a method of modulating the activity of the 17-beta-hydroxysteroid dehydrogenase 13 (17β-HSD type 13, referred to herein as HSD17B13) in a cell comprising administering an effective amount of a compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N;

[0128] In any embodiment, HSDB13 may be inhibited in a mammalian cell, such as, for example, a human cell. In any embodiment, the cell may be a liver cell. The inhibiting may be carried out ex vivo (e.g. , in vitro) or in vivo.

[0129] In another aspect, the present disclosure provides a method of modulating HSD17B13 in a cell comprising administering an effective amount of a compound according to Formula IIA or I IB:

or a pharmaceutically acceptable salt thereof, wherein

[0130] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula III A or IIIB:

or a pharmaceutically acceptable salt thereof, wherein

R₆ is H or an optionally substituted C₁-C₁₀ alkyl; R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₁ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

[0131] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula IV: or a pharmaceutically

[0132] In another aspect, the present disclosure provides a method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound of Table 1 .

[0133] A compound according to Formula A, Formula I (or any subgenera thereof) is suitable for the methods disclosed herein, namely inhibiting the activity of HSD17B13, including those of all the Formulas as described in the Compounds of the Disclosure section above (i.e., compounds of Table 1).

[0134] As used herein, “modulate,” “modulating,” and any grammatical variation thereof refers to changing the native endogenous activity of a named compound, such as HSD17B13. For example, modulating may comprise inhibiting activity of HSD17B13. Inhibition may be described by an IC₅₀ value, which is the concentration of an inhibitor (i.e., a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1) that inhibits the activity of the HSD17B protein being described by half. This may be determined by generating a curve that describes the activity of the protein versus the concentration of the inhibitor. Such a curve may comprise a top plateau at low concentrations of inhibitor (0% or close to 0% inhibition) and a bottom plateau at high concentrations of inhibitor (representing maximum inhibition), where the ICso may be determined as the intersection (on the x-axis) of the curve halfway between the top and bottom plateau. There are various ways of approximating the exact value of each of the plateaus depending use of and methods of including control (no inhibitor) data that generally generate similar results. Therefore, in any embodiment, unless otherwise indicated, any IC₅₀ value reported is an approximate value and may vary from the recited value by 10% in either the positive or negative direction.

[0135] The class of compounds according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 are selective for modulating (e.g., inhibiting) the activity of HSD17B13 and are less effective at modulating (e.g., inhibiting) the activity of other HSD17B family proteins. For example, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may be effective in modulating (e.g., inhibiting) the activity of HSD17B13 with an IC₅₀ of less than about 10 μmol, and are less effective at modulating (e.g., inhibiting) the activity of one or more of 17p-hydroxysteroid dehydrogenase 1 (HSD17B1), 17β-hydroxysteroid dehydrogenase 2 (HSD17B2), 17P-hydroxy steroid dehydrogenase 3 (HSD17B3), 17(3- hydroxysteroid dehydrogenase type IV (HSD17B4), 17β-hydroxy steroid dehydrogenase type 5 (HSD17B5), hydroxysteroid 17-β dehydrogenase 6 (HSD17B6), 3-keto-steroid reductase (HSD17B7), estradiol 17β-dehydrogenase 8 (HSD17B8), retinol dehydrogenase 5 (HSD17B9), 17-β -hydroxysteroid dehydrogenase X (HSD17B10), estradiol 17P-dehydrogenase 11 (HSD17B11), estradiol 17-β -dehydrogenase 12 (HSD17B12), and 17p-hydroxysteroid dehydrogenase type 14 (HSD17B14). For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may not modulate the activity of one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6, HSD17B7, HSD17B8, HSD17B9, HSD17B10, HSD17B11, HSD17B12, and HSD17B14 (i.e., a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 modulates the activity of one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6, HSD17B7, HSD17B8, HSD17B9, HSD17B10, HSD17B11, HSD17B12, HSD17B13, and HSD17B14 with an IC₅₀ of greater than about 50 μmol, or greater than about 40 μmol, or greater than about 30 μmol, or greater than about 20 μmol, or greater than about 10 μmol, or greater than about 8 μmol, or greater than about 5 μmol). In another example, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 are selective for modulating (e.g., inhibiting) the activity of HSD17B13 and are less effective at modulating (e.g., inhibiting) the activity of one or more of HSD17B1 , HSD17B2, HSD17B4, and HSD17B10. For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 do not modulate the activity of one or more of HSD17B1, HSD17B2, HSD17B4, and HSD17B10.

[0136] For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may have an IC₅₀ for modulating the activity of one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6, HSD17B7, HSD17B8, HSD17B9, HSD17B10, HSD17B11, HSD17B12, HSD17B13, and HSD17B14 of greater than about 10 μmol. In another example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may have an IC₅₀ for modulating the activity of one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6, HSD17B7, HSD17B8, HSD17B9, HSD17B10, HSD17B11, HSD17B12, HSD17B13, and HSD17B14 of greater than about 30 μmol.

[0137] In any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may modulate the activity of HSD17B13, but may not modulate the activity of HSD17B1. For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B 13, but may not inhibit HSD17B 1 activity. In another example and in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity with an IC₅₀ of less than about 10 μmol, and do not inhibit the activity of HSD17B1 (e.g., inhibit HSD17B1 activity with an IC₅₀ of greater than about 10 μmol).

[0138] In any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may modulate HSD17B13 activity, but may not modulate HSD17B2 activity. In any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity, but not HSD17B2 activity. For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity with an IC₅₀ of less than about 10 μmol, and not inhibit HSD17B2 activity, (e.g. inhibit HSD17B2 with an IC₅₀ of greater than about 10 μmol).

[0139] In any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may modulate HSD17B13 activity, but not modulate HSD17B4 activity. For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity, but not inhibit HSD17B4 activity. In another example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity with an IC₅₀ of less than about 10 μmol and not inhibit HSD17B4 (e.g., inhibit HSD17B4 activity with an IC₅₀ of greater than about 10 μmol).

[0140] In any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may modulate HSD17B13 activity but notHSD17B10 activity. For example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity but not HSD17B10 activity. In another example, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may inhibit HSD17B13 activity (e.g. inhibit HSD17B13 activity with an IC₅₀ of less than about 10 μmol) but not inhibit HSD17B4 activity (e.g.. inhibit HSD17B4 activity with an IC₅₀ of greater than about 10 μmol).

[0141] A compound according to Formula A, Formula I (including subgenera thereof) may inhibit HSD17B13 activity with an IC₅₀ of less than about 10 μmol, less than about 9 μmol, less than about 8 μmol, less than about 7 μmol, less than about 6 μmol, less than about 5 μmol, less than 4 μmol, less than 3 μmol, less than 2 μmol, or less than about 1 μmol of the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 . For example, in some embodiments, a compound according to Formula A, Formula I (such as a compound of a subgenera thereof) may inhibit HSD17B13 activity with an IC₅₀ of less than about 1 μmol, less than about 0.9 μmol, less than about 0.8 μmol, less than about 0.7 μmol, less than about 0.6 μmol, less than about 0.5 μmol, less than about 0.4 μmol, less than about 0.3 μmol, less than about 0.2 μmol, or less than about 0.1 μmol of the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 .

[0142] In any embodiment, a compound according to Formula A, Formula I (such as a compound of a subgenera thereof) may inhibit HSD17B13 activity with an IC₅₀ of less than 1 μmol of the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. In any embodiment, a compound according to Formula A, Formula I (such as a compound of a subgenera thereof) may inhibit HSD17B13 activity with an IC₅₀ of less than 0.5 μmol of the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 . In any embodiment, a compound according to Formula A, Formula I (such as a compound of a subgenera thereof) may inhibit HSD17B13 activity with an IC₅₀ of less than 0.1 μmol of the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 .

[0143] In any embodiment, a compound according to Formula A, Formula I (including any subgenera thereof) may be effective to modulate the activity of 150 nM HSD17B13 with an IC₅₀ of less than about 10 μmol, such as less than about 8 μmol, less than about 7 μmol, less than about 6 μmol, less than about 5 μmol, less than about 4 μmol, less than about 3 μmol, less than about 2 μmol, less than about 1 μmol, less than about 0.8 μmol, less than about 0.6 μmol, less than about 0.4 μmol, or less than about 0.2 μmol.

[0144] In any embodiment, a compound according to Formula A, Formula I (including any subgenera thereof) may be effective to modulate the activity of 50 nM HSD17B13 with an IC₅₀ of less than about 10 μmol, such as less than about 8 μmol, less than about 7 μmol, less than about 6 μmol, less than about 5 μmol, less than about 4 μmol, less than about 3 μmol, less than about 2 μmol, less than about 1 μmol, less than about 0.8 μmol, less than about 0.6 μmol, less than about 0.4 μmol, or less than about 0.2 μmol.

Methods of Treatment

[0145] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having the liver disease comprising administering to the subject an effective amount of a compound according to Formula A:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N;

Z is selected from C and S;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl; R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[0146] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having the liver disease comprising administering to the subject an effective amount of a compound according to Formula I:

wherein:

X and Y are independently selected from O and N;

R? is H or an optionally substituted C₁-C₁₀ alkyl; R₆ is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

[0147] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having the liver disease comprising administering to the subject an effective amount of a compound according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein

Ri - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein R₁₀ is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

[0148] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IIIA or IIIB :

or a pharmaceutically acceptable salt thereof, wherein

[0149] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IV:

[0150] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound of Table 1.

[0151] In another aspect, the present disclosure provides a method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to any one of Formulas A, I-IV or Table 1 . The compound according to any one of Formulas A, I-IV or Table 1 may be administered via a pharmaceutical composition, as described herein, comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to any one of Formulas A, I-IV or Table 1, and at least one pharmaceutically acceptable excipient. In any embodiment, the liver disease may be chronic liver disease. The subject may be a mammal, for example, a human.

[0152] A pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or Table 1, and at least one pharmaceutically acceptable excipient can be administered to a subject in need thereof, by any administration route. For example, a pharmaceutical composition comprising one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof, such as a compound according to any of Formulas II-IV or Table 1), and at least one pharmaceutically acceptable excipient may be administered to a subject by systemic administration, which includes parenteral, topical, transdermal, oral, by inhalation/pulmonary, rectal, nasal, buccal, and sublingual administration. For example, a pharmaceutical composition comprising an effective amount of one or more active pharmaceutical ingredients, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or Table 1, and at least one pharmaceutically acceptable excipient may be administered orally, topically, intranasally, intravenously, intramuscularly, or subcutaneously to treat the liver disease (e.g., chronic liver disease in which HSD17B13 plays a role) in a subject diagnosed therewith.

[0153] Nebulized solutions comprising a compound according to any one of Formulas A, I-IV or Table 1 can be breathed directly by the subject from a nebulizing device or a nebulizing device can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from a device which delivers the composition in an appropriate manner. A compound according to any one of Formulas A, I-IV or Table 1 can be provided in a liquid forms for administration orally or by parenteral injection.

[0154] A compound according to any one of Formulas A, I-IV or Table 1 can be effective over a wide dosage range and can be generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual subject, the severity of the subject’s symptoms, and the like. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0155] For example, in any embodiment, an effective amount of a compound according to any one of Formulas A, I-IV or Table 1 may be about 0.000001 mg to about 2000 mg, about 0.00001 mg to about 1000 mg, or about 0.0001 mg to about 750 mg, about 0.001 mg to about 500 mg, about 0.01 mg to about 250 mg, about 0.1 mg to about 100 mg, about 0.5 mg to about 75 mg, about 1 mg to about 50 mg, about 2 mg to about 40 mg, about 5 mg to about 20 mg, or about 7.5 mg to about 15 mg of the compound, which may be administered to the subject on a per-day or per-dose basis. In yet another example, an effective amount of a compound according to any one of Formulas A, I-IV or Table 1 may be about 0.05 mg to about 50 mg, about 0.25 mg to about 20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, or about 0.25 mg to about 5 mg (e.g., about 0.1 to about 5 mg, about 0.25 to about 2.5 mg, about 0.3 mg to about 2 mg, about 0.5 mg to about 1 mg, about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg, about 1.25 mg, or about 1.5 mg or about 2 mg of the compound, which may be administered to the subject on a per-day or per-dose basis.

[0156] In yet another example, an effective amount of a compound according to any one of Formulas A, I-IV or Table 1 may be about 0.5 mg to about 3 mg, about 0.5 mg to about 4 mg, or about 0.35 mg to about 4 mg of the compound, which may be on a per-day or per-dose basis. In yet another example, an effective amount of a compound according to any one of Formulas A, I- IV or Table 1 may be about 1 mg to about 3 mg, about 1 mg to about 2 mg, or about 2 mg to about 3 mg of the compound. In yet another example, an effective amount of a compound according to any one of Formulas A, I-IV or Table 1 may be about 5 mg to about 300 mg of the compound. In yet another example, an effective amount of a compound according to any one of Formulas A, I- IV or Table 1 may be about 5 mg to about 250 mg, about 5 mg to and about 200 mg, about 5 mg to about 150 mg, about 5 mg to about 100 mg, or about 5 mg to about 50 mg of the compound.

[0157] As used herein, “chronic liver disease” include diseases of the liver which last over a period of six months and can include, for example, diseases of the liver involving progressive destruction and regeneration of the liver parenchyma that can lead to fibrosis and cirrhosis. Chronic liver diseases can be alcoholic liver diseases or nonalcoholic liver diseases. Liver pathologies encompassed by chronic liver diseases can include, for example, inflammation (e.g., chronic hepatitis), liver cirrhosis, and hepatocellular carcinoma. Types of chronic liver disease are disclosed elsewhere herein and include, for example, fatty liver disease, nonalcoholic fatty liver disease, alcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. Symptoms and signs of chronic liver diseases are known and can include, for example, enlarged liver, fatigue, pain in the upper right abdomen, abdominal swelling (ascites), enlarged blood vessels just beneath the skin's surface, enlarged breasts in men, enlarged spleen, red palms, and yellowing of the skin and eyes (jaundice). Testing for chronic liver diseases can involve blood tests, imaging of the liver, and biopsy of the liver. An individual is at increased risk of a chronic liver disease if the subject has at least one known risk-factor (e.g., genetic factor such as a disease-causing mutation) placing individuals with that risk factor at a statistically significant greater risk of developing the disease than individuals without the risk factor. Risk factors for chronic liver diseases are also well known and can include, for example, excessive alcohol use, obesity, high cholesterol, high levels of triglycerides in the blood, polycystic ovary syndrome, sleep apnea, type 2 diabetes, underactive thyroid (hypothyroidism), underactive pituitary gland (hypopituitarism), and metabolic syndromes including raised blood lipids.

[0158] Any of the compounds disclosed herein (i.e., any of a compound according to any of Formulas A, I-IV or Table 1) may be effective to treat a chronic liver disease selected from one or more of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, and hepatocellular carcinoma. The compounds disclosed herein may be particularly effective to treat a chronic liver disease selected from one or more of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, or steatosis. In some embodiments, the liver disease can be an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease can be a non-alcoholic liver disease. In some embodiments, the non-alcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disease can be non-alcoholic steatohepatitis (NASH). In some embodiments, the liver disease can be nonalcoholic fatty liver disease (NAFLD). In some embodiments, the liver disease can be alcoholic liver disease (ALD). In some embodiments, the liver disease can be cirrhosis. In some embodiments, the liver disease can be steatosis. In some embodiments, the liver disease can be hepatocellular carcinoma. In some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, or hepatocellular carcinoma not caused by alcohol consumption.

[0159] In any of the methods described herein, administration of a compound according to Formula A, Formula I (including any subgenera thereof) or Table 1 which is capable of inhibiting HSD17B13 activity can effectively treat liver disease, for example, reduce one or more of inflammation and fibrosis.

Genetic Variations Modulate Susceptibility to Liver Disease

HSD17B13 Variants

[0160] A compound according to any of Formulas A, LIV or Table 1 may be effective for modulating wild-type HSD17B13. In any embodiment, however, a compound according to any of Formulas A, I-IV or Table 1 may also be effective to modulate a variant of wild-type HSD17B13. It has been observed that a splice variant (rs72613567:TA) in HSD17B13, which encodes hepatic lipid droplet protein 17-β hydroxy steroid dehydrogenase 13, is reproducibly associated with reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. It has also been observed that this variant is associated with a reduced risk of alcoholic and nonalcoholic liver disease and alcoholic and nonalcoholic cirrhosis for each rs72613567:TA allele in an allele dosagedependent manner. These observations were confirmed in two independent cohorts. rs72613567:TA was associated with a decreased severity of histological features of nonalcoholic steatohepatitis (NASH) for each rs72613567:TA allele among individuals with fatty liver disease and mitigated liver injury associated with PNPLA3 Ilel48Met. rs72613567:TA results in a truncated isoform deficient in enzymatic activity against steroid substrates. That is, a loss-of- function variant in HSD17B13 was associated with a reduced risk of alcoholic and nonalcoholic liver disease as well as a reduced risk of progression from steatosis to NASH. U.S. Patent Application Publication No. US2018/0216084 (corresponding to PCT Publication No. WO2018/136702), PCT Publication No. WO2018/136758, and PCT Publication No. W02019/075181, which disclose the splice variant, are incorporated herein by reference in their entirety. Therefore, in any embodiment, a compound according to any of Formulas A, LIV or Table 1 may be effective to modulate a HSD17B13 rs72613567 variant. In any embodiment, a compound according to any of Formulas A, I-IV or Table 1 may be effective to treat or inhibit liver disease in a subject who is not a carrier of the HSD17B13 rs72613567 variant and has or is susceptible to developing a chronic liver disease. In any embodiment, a compound according to any of Formulas A, I-IV or Table 1 may be effective to treat or inhibit liver disease in a subject who is homozygous or heterozygous for functional HSD17B13.

HSD17B13 Isoforms

[0161] As described above, a HSD17B13 rs72613567 variant carrier may have a reduced risk for developing liver disease. Therefore, the present disclosure also provides methods of detecting a variant HSD17B13 rs72613567 gene, variant HSD17B13 transcripts (such as Transcript D), and variant HSD17B13 Isoforms (such as Isoform D).

[0162] In any embodiment, the method may comprise detecting the presence of one or more HSD17B13 variant gene transcripts (e.g., RNA or cDNA thereof, mRNA or cDNA thereof) selected from transcript C, transcript D, transcript E, transcript F, transcript G, and transcript H, particularly transcript D, in a biological sample, and/or detecting the presence or quantifying protein levels of one or more HSD17B13 isoforms selected from isoform C, isoform D, isoform F, isoform G, and isoform H, particularly isoform D, in a biological sample comprising protein prior to administration of a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 to a subject via a pharmaceutical composition as disclosed herein. In any embodiment, detecting an HSD17B 13 isoform comprises quantifying the expression level of one or more of HSD17B13 isoforms C, D, F, G, and H in a subject’s biological sample, wherein an increased expression level of one or more of HSD17B13 isoforms C, D, F, G, and H, compared to a control sample from a control subject homozygous for a wild type HSD17B13 allele, indicates a decreased risk for developing liver disease. Conversely, a decreased expression level or no change in expression level of one or more of HSD17B13 isoforms C, D, F, G, and H, compared to a control sample from a control subject homozygous for a wild type HSD17B13 allele, may indicate an increased risk for developing liver disease. Therefore, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, may be effective in treating or preventing liver disease in a subject where one or more of Isoform C, D, F, G, and H are not detected in a biological sample obtained from the subject.

[0163] In any embodiment, detecting an HSD17B 13 isoform comprises quantifying the expression level of one or more of HSD17B13 Isoforms A, B, and E or one or more of HSD17B13 Isoforms A, B, E, and F’ in a subject’s biological sample, wherein an increased expression level of one or more of Isoforms A, B, and E or one or more of Isoforms A, B, E, and F' compared to a control sample from a control subject homozygous for the HSD17B13 rs72613567 variant allele indicates an increased risk for developing liver disease. Conversely, a decreased expression level or no change in expression level of Isoform A, B, or E or Isoform A, B, E, or F', compared to a control sample from a control subj ect homozygous for the HSD 17B 13 rs72613567 variant allele, indicates a decreased risk for developing liver disease. Therefore, in any embodiment, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, may be effective in treating or preventing liver disease in a subject where one or more of Isoform A, B, or E or Isoform A, B, E, or F' are not detected in a biological sample obtained from the subject.

[0164] Transcripts and isoforms of HSD17B13 are described in more detail in WO2018/136702, the contents of which are incorporated herein by reference in their entirety. In particular, WO2018/136702 describes each transcript. Transcript A includes all seven exons of the HSD17B13 gene, whereas exon 2 is skipped in Transcript B. Transcript A is the dominant transcript in wild type subjects. In Transcript C, exon 6 is skipped compared to Transcript A. In Transcript D, there is an insertion of a guanine 3' of exon 6, resulting in a frameshift in and premature truncation of exon 7 compared to Transcript A. In Transcript E, there is an additional exon between exons 3 and 4 compared to Transcript A. In Transcript F, which is expressed only in HSD17B13 rs72613567 variant carriers, there is read-through from exon 6 into intron 6 compared to Transcript A. In Transcript G, exon 2 is skipped, and there is an insertion of a guanine 3' of exon 6, resulting in a frameshift in and premature truncation of exon 7 compared to Transcript A. In Transcript H, there is an additional exon between exons 3 and 4, and there is an insertion of a guanine 3' of exon 6, resulting in a frameshift in and premature truncation of exon 7 compared to Transcript A. Transcripts C, D, F, G, and H are dominant in HSD17B13 rs72613567 variant carriers, with Transcript D being the most abundant.

[0165] WO2018/136702 also describes each isoform. Protein Isoform C is formed from the region encoded by Exon 1 (AA 1-70), the region encoded by Exon 2 (AA 71-106, the region encoded by Exon 3 (AA 107-150, the region encoded by Exon 4 (AA 151-185, the region encoded by Exon 5 (AA 186-232, Exon 6 is skipped, and the region encoded by Exon 7 (AA 233-261). Protein Isoform D is formed from the region encoded by Exon 1 (AA 1-70), the region encoded by Exon 2 (AA 71-106), the region encoded by Exon 3 (AA 107-150), the region encoded by Exon 4 (AA 151- 185), the region encoded by Exon 5 (AA 186-232), the region encoded by Exon 6v2 (AA 233- 271), and the region encoded by Exon 7 (AA 272-274). Protein Isoform E is formed from the region encoded by Exon 1 (AA 1-70), the region encoded by Exon 2 (AA 71-106), the region encoded by Exon 3 (AA 107-150), the region encoded by Exon 3' (AA 151-174), the region encoded by Exon 4 (AA 175-209), the region encoded by Exon 5 (AA 210-256), the region encoded by Exon 6vl (AA 257-295, and the region encoded by Exon 7 (AA 296-324). Protein Isoform F is formed from the region encoded by Exon 1 (AA 1-70), the region encoded by Exon 2 (AA 71-106), the region encoded by Exon 3 (AA 107-150), the region encoded by Exon 4 (AA 151-185), the region encoded by Exon 5 (AA 186-232), the region encoded by Exon 6v3 (AA 233- 284, and the region encoded by read-through into Intron 6 (AA 272-284). Protein Isoform F' is formed from the region encoded by Exon 1 (AA 1-70), the region encoded by Exon 2 (AA 71- 106), the region encoded by Exon 3 (AA 107-150), the region encoded by Exon 4 (AA 151-185), the region encoded by Exon 5 (AA 186-232, and the region encoded by Exon 6v4 (AA 233-271). Protein Isoform G is formed from the region encoded by Exon 1 (AA 1-70, Exon 2 is skipped, the region encoded by Exon 3 (AA 71-114), the region encoded by Exon 4 (AA 115-149), the region encoded by Exon 5 (AA 150-196), the region encoded by Exon 6v2 (AA 197-235, and the region encoded by Exon 7 (AA 236-238). Protein Isoform H is formed from the region encoded by Exon 1 (AA 1- 70), the region encoded by Exon 2 (AA 71-106), the region encoded by Exon 3 (AA 107- 150), the region encoded by Exon 3' (AA 151-174), the region encoded by Exon 4 (AA 175-209), the region encoded by Exon 5 (AA 210- 256), the region encoded by Exon 6v2 (AA 257-295, and the region encoded by Exon 7 (AA 296-298).

[0166] It has been discovered that, in some cases, the presence or absence of HSD17B13 Isoform D influences risk of progression to a more clinically advanced stage of fatty liver disease. Therefore, provided herein is a method of mediating risk for progression to more clinically advanced stages of fatty liver disease in a subject lacking expression of HSD17B 13 Isoform D, the method comprising administering to the subject an effective amount of a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. In any embodiment, such a method may comprise a step of collecting a biological sample from the subject and performing an assay to detect the presence of and/or quantify the expression of HSD17B13 Isoform D and either a) classifying the subject as being at decreased risk for developing the liver disease if HSD17B13 Isoform D is detected in the biological sample or b) classifying the human subject as being at increased risk for developing the liver disease if HSD17B13 Isoform D is not detected in the biological sample. In any embodiment, the method may further comprise a step of diagnosing the subject with a higher risk for developing liver disease where variant HSD17B13 rs72613567 gene, variant HSD17B 13 transcripts (such as Transcript D), and/or vari ant HSD17B 13 Isoforms (such as Isoform D) are not found in a biological sample.

[0167] In any embodiment, the liver disease may be a chronic liver disease, such as, but not limited to, fatty liver disease, nonalcoholic fatty liver disease (NAFLD), alcoholic liver fatty liver disease, cirrhosis, viral hepatitis, hepatocellular carcinoma, simple steatosis, steatohepatitis, fibrosis, and non-alcoholic steatohepatitis (NASH). One of skill in the art will be familiar with methods for assaying a biological sample to detect and/or quantify expression of HSD17B13. For example, amino acid sequencing or immunoassay may be utilized

[0168] Combination Treatment

[0169] As described above, a pharmaceutical composition comprising one or more active pharmaceutical agents, at least one of which is a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, and a pharmaceutically acceptable excipient may be administered to a subject in need thereof to treat liver disease. In any embodiment, said pharmaceutical composition may comprise the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 and a second active pharmaceutical agent. In any embodiment, the second active pharmaceutical ingredient may be effective for the treatment of liver disease. For example, in any embodiment, the second active pharmaceutical ingredient may be capable of modulating HSD17B13 activity. In any embodiment, the second active pharmaceutical ingredient may comprise more than one active pharmaceutical agent, effectively being a second active pharmaceutical ingredient and at least a third active pharmaceutical ingredient.

[0170] Alternatively, a second active pharmaceutical ingredient may be provided and administered to the subject in a pharmaceutical composition separate from the pharmaceutical composition comprising the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. As such, a method of treating liver disease in a subject in need thereof may comprise administering to the subject an effective amount of a first active pharmaceutical ingredient comprising a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 and administering to the subject an effective amount of a second active pharmaceutical agent. Examples of second active pharmaceutical agents suitable administration in combination with a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 include one or more of (but are not limited to) acamprosate, amiloride, amoxicillin-clavulanate, atenolol, azathioprine, bumetanide, carvedilol, ceftriaxone, ciprofloxacin, chlorothiazide, deferoxamine, disulfiram, furosemide, hydrochlorothiazide, metoprolol, nadolol, naltrexone, norofloxacin, octreotide, ofloxacin, phytonadione, prednisone, penicillamine, propranolol, spironolactone, timolol, triamterene, and trientine.

[0171] Additional examples of second active pharmaceutical agents suitable administration in combination with a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, for example to treat Hepatitis C, include one or more of (but are not limited to) daclatasvir (e.g., DAKLINZA®), dasabuvir, elbasvir, glecaprevir, grazoprevir, interferon alfa- 2b, ledipasvir, ombitasvir, paritaprevir, peginterferon alfa-2a, peginterferon alfa-2b, pibrentasvir, ribavirin, ritonavir, simeprevir (e.g., OLYSIO®), sofosbuvir, velpatasvir, and voxilaprevir.

[0172] Additional examples of second active pharmaceutical agents suitable administration in combination with a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 , for example to treat nonalcoholic fatty liver disease include one or more of (but are not limited to) weight loss inducing agents such as orlistat or sibutramine; insulin sensitizing agents such as thiazolidinediones (TZDs), metformin, and meglitinides; lipid lowering agents such as statins, fibrates, and omega-3 fatty acids; atioxidants such as, vitamin E, betaine, N-acetyl-cysteine, lecithin, silymarin, and beta-carotene; anti-TNF agents such as pentoxifylline; probiotics, such as VSL#3® from Alfasigma (Covington, LA, USA); and cytoprotective agents such as ursodeoxycholic acid (UDCA). Other suitable second active pharmaceutical agents include ACE inhibitors/ ARBs, oligofructose, and incretin analogs.

[0173] Additional examples of second active pharmaceutical agents suitable administration in combination with a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1, for example to treat NASH include one or more of (but are not limited to) ACQT 1127 (SLC22A12 protein inhibitor, xanthine oxidase inhibiotor developed by Acquits Therapeutics), aldafermin, ALT 801 (GLP1 receptor agonist developed by Altimmune and Velocity Pharmaceutical Development), apararenone, arachidyl amido cholanoic acid (e.g., ARAMCHOL™), azemiglitazone, BC 556 (cyclophilin D inhibitor developed by Abliva, Arbutus Biopharma, and Karolinska Institute), belapectin, BI 1467335 (AOC₃ protein inhibitor, chemical name 4-[[(2E)-2-(aminomethyl)-3-fluoro-2-propen-l-yl]oxy]-N-(l,l-dimethylethyl)-benzamide hydrochloride), BMS986171 (FGF replacement developed by Bristol-Myers Squibb), BMS986263 (HSP inhibitor developed by Bristol-Myers Squibb and Nitto Denko), CB4209 (angiogenesis inhibitor developed by Albert Einstein College of Medicine, CohBar, and University of Southern California), CB4211 (insulin receptor modulator developed by CohBar), cenicriviroc, CER-209 (P2RY13 protein agonist developed by ABIONYX Pharma), cilofexor, clesacostat, DUR-928 (DNA methylation inhibitor, inflammation mediator modulator, lipid modulator developed by DURECT Corporation), EDP-305 (farnesoid X-activated receptor agonist developed by Enanta Pharmaceuticals, CAS No. 1933507-63-1), elafibranor, elobixibat, emricasan, ervogastat, firsococstat, foralumab, gemcabene, GRI-0621 (natural killer cell receptor antagonist developed by GRIBio), HepaStem, 5-hydroxyeicosapentaenoic acid, IMM124E, isosabutate, ION 224 (diacylglycerol-O-acyltransferase inhibitor developed by lonis Pharmaceuticals), ION 839 (adiponutrin inhibitor developed by AstraZeneca), INT 767 (farnesoid X-activated receptor agonist developed by Intercept Pharmaceuticals), KBP 042 (amylin receptor agonist, calcitonin receptor agonist; developed by Eli Lilly and Company and Key BioScience), lanifibranor, licoglifozin, MK 3655 (KLB protein stimulant, antibody developed by Merck & Co., NGM Biopharmaceuticals), nalmefene, namodenoson, namacizumab, nidufexor, nimacimab, nitazoxanide, obeticholic acid (e. ., OCALIVA®), pegbelfermin, deuterated R-pioglitazone, PXL 770 (AMP activated protein kinase stimulant developed by Proxel), resmetirom, RTU-1096 (AOC₃ protein inhibitor developed by Hokkaido University, Kyushu University, Sucampo Pharmaceuticals), SAR425899 (GLP1 receptor agonist developed by Sanofi), saroglitazar, seladepar, selonsertib, semaglutide, sentanaxib, sotagliflozin, TERN-101 (farnesoid X-activated receptor agonist, chemical name 6-(4-((5-cyclopropyl-3-(2,6-dichlorophenyl)-4- isoxazolyl)methoxy)-l-piperidinyl)-l-methyl-lH-Indole-3-carboxylic acid), TERN-201 (AOC₃ protein inhibitor developed by Eli Lilly and Company), TGFTX4 (receptor PTK modulator developed by Genfit), tipelukast, tropifexor, VK0214 (thyroid hormone receptor beta agonist developed by Viking Therapeutics), VK2809 (thyroid hormone receptor beta agonist, chemical name (2R,4S)-4-(3-chlorophenyl)-2-[(4-{[4-hydroxy-3-(propan-2-yl)phenyl]methyl}-3,5- dimethylphenoxy)methyl]-l,3,21ambda5-dioxaphosphinan-2-one), volixibat, and vonafexor.

[0174] Additional examples of second active pharmaceutical agents suitable administration in combination with a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 include one or more of (but are not limited to) ursodiol, norursodiol, UDCA, ursodeoxycholic acid, chenodeoxycholic acid, cholic acid, taurocholic acid, ursocholic acid, glycocholic acid, glycodeoxycholic acid, taurodeoxycholic acid, taurocholate, glycochenodeoxycholic acid, tauroursodeoxycholic acid, cholestyramine/resins, antihistamine agents (e.g., hydroxyzine, diphenhydamine), rifampin, naloxone, phenobarbital, dronabinol (CB1 agonist), methotrexate, corticosteroids, cyclosporine, colchicine, TPGS - vitamin A, D, E, or K optionally with polyethylene glycol, zinc, and a resin or sequestrant for absorbing bile acids.

[0175] In any embodiment of any of the above methods, the method can comprise administering a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 to a subject to prevent or alleviate one or more symptoms associated with progression to more clinically advanced stages of chronic liver disease (e.g., progression from simple steatosis to more clinically advanced stages of chronic liver disease, or progression from simple steatosis to one or more of steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma). For example, such treatments could be focused on preventing or reducing inflammation or preventing or reducing fibrosis. In any embodiment, a second active pharmaceutical ingredient may be co- administered with the compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1. Examples of such second active pharmaceutical ingredients include OCA (obeticholic acid) (OCALIVA®), cilofexor, simtuzumab, selonsertib, firsocostat, elafibraor, aramchol, cenicriviroc, belapectin, GB0139 (developed by Galecto Inc, University of Edinburgh), volixibat, BI 1467335 (A0C₃ protein inhibitor developed by Boehringer Ingelheim), and RP103 (cysteamine bitartrate).

[0176] The present disclosure also provides any of the methods described herein further comprising administering to the subject a first active pharmaceutical ingredient comprising a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 and a second active pharmaceutical ingredient comprising a second inhibitor of HSD17B13 activity (where the compound according to Formula A, Formula I or any subgenera thereof is the first inhibitor of HSD17B13 activity). Examples of effective second HSD17B13 inhibitor include, but are not limited to, naturally occurring and synthetic ligands, antagonists, agonists, antibodies, peptides, cyclic peptides, nucleic acids, functional polynucleotides, small organic molecules, and the like. Functional polynucleotides are nucleic acid molecules that have a specific function, such as binding a target molecule or catalyzing a specific reaction. Examples of functional polynucleotides include, but are not limited to, antisense molecules, aptamers, ribozymes, and triplex forming molecules. The functional polynucleotides can act as inhibitors of a specific activity possessed by a target molecule. Antisense molecules are designed to interact with a target nucleic acid molecule through either canonical or non-canonical base pairing. The interaction of the antisense molecule and the target molecule is designed to promote the destruction of the target molecule through, for example, RNase-H-mediated RNA-DNA hybrid degradation. Alternately, the antisense molecule is designed to interrupt a processing function that normally would take place on the target molecule, such as transcription or replication. Antisense molecules can be designed based on the sequence of the target molecule. Numerous methods for optimization of antisense efficiency by identifying the most accessible regions of the target molecule exist. Exemplary methods include, but are not limited to, in vitro selection experiments and DNA modification studies using DMS and DEPC. Antisense molecules generally bind the target molecule with a dissociation constant (Ka) less than or equal to about 10-6, less than or equal to about 10-8, less than or equal to about 10-10, or less than or equal to about 10-12. A representative sample of methods and techniques which aid in the design and use of antisense molecules, and antisense molecules, can be found in the following non-limiting list of U.S. Patents and applications: 5,135,917; 5,294,533; 5,627,158; 5,641,754; 5,691,317; 5,780,607; 5,786,138; 5,849,903; 5,856,103; 5,919,772; 5,955,590; 5,990,088; 5,994,320; 5,998,602; 6,005,095; 6,007,995; 6,013,522; 6,017,898; 6,018,042; 6,025,198; 6,033,910; 6,040,296; 6,046,004; 6,046,319; 6,057,437; and U.S. Serial No. 62/645,941 filed March 21, 2018, each of which is incorporated herein by reference in its entirety. Examples of antisense molecules include, but are not limited to, antisense RNAs, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). For example, the antisense RNAs, siRNAs, or shRNAs can be designed to target a region unique of the HSD17B13 genomic DNA or mRNA. In any embodiment, the second HSD17B13 inhibitor may be an antisense molecule. In any embodiment, the inhibitor of HSD17B13 may be an shRNA molecule. In any embodiment, the second HSD17B13 inhibitor may be an siRNA molecule.

[0177] In any embodiment, the second HSD17B13 inhibitor may comprises a functional polypeptide, an antisense DNA, RNA, an siRNA, or an shRNA that hybridizes to the endogenous HSD17B13 genomic DNA or mRNA and decreases expression of HSD17B13 polypeptide in a cell in the subject. In any embodiment, the second HSD17B13 inhibitor may further inhibit one or more additional members of the short-chain dehydrogenases/reductases (SDR) family, of which HSD17B13 is a member. Such other members include, but are not limited to, HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B6, HSD17B7, HSD17B8, HSD17B10, HSD17B11, HSD17B12, HSD17B14, HSD11B1, HSD11B2, HSD3B1, HSD3B2, and HSD3B7, as well as close homologs dehydrogenase/reductase 3 (DHRS3) and retinol dehydrogenase 10 (RDH10). In any embodiment, the first and/or second inhibitor of HSD17B13 activity may be administered to inhibit liver disease in the subject. In any embodiment, the first and/or second inhibitor of HSD17B13 activity may be administered to treat liver disease in the subject. In any embodiment, the liver disease may be a chronic liver disease, for example, one or more of nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), non-alcoholic steatohepatitis (NASH), cirrhosis, steatosis, and hepatocellular carcinoma. In some embodiments, the liver disease is an alcoholic liver disease. In some embodiments, the alcoholic liver disease comprises one or more of cirrhosis, steatosis, and hepatocellular carcinoma resulting from alcohol consumption. In some embodiments, the liver disease is a non-alcoholic liver disease. In some embodiments, the nonalcoholic liver disease comprises nonalcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). Tn some embodiments, the non-alcoholic liver disease comprises one or more of cirrhosis, steatosis, and hepatocellular carcinoma not caused by alcohol consumption. In any embodiment, the subject may be homozygous for the gene encoding the Ilel48Met variation of PNPLA3. Alternatively, in any embodiment, the subject may be heterozygous for the gene encoding the Ilel48Met variation of PNPLA3. In any embodiment, the subject may be homozygous for the gene encoding functional HSD17B13. Alternatively, in any embodiment, the subject may be heterozygous for the gene encoding functional HSD17B13, comprising a gene encoding a loss of function variant of HSD17B13.

[0178] The second active pharmaceutical ingredient (which may, in any embodiment, comprise two or more different active pharmaceutical ingredients, effectively being a second and at least a third active pharmaceutical ingredient) may be administered just prior to, concurrent with, or shortly after the administration of a compound according Formula A, Formula I (or any subgenera thereof) or a compound of Table 1; for purposes of the present disclosure, such administration regimens are considered the administration of a compound described herein “in combination with” the second active pharmaceutical ingredient. Embodiments include pharmaceutical compositions in which a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 is co-formulated with one or more of the second active pharmaceutical ingredients as described elsewhere herein.

Protein-Drug Conjugates

[0179] In one aspect, the present disclosure provides a protein-drug conjugate comprising: (a) an antigen binding protein that specifically binds a tumor-associated antigen (TAA); (b) a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1; and (c) a suitable linker that connects said antigen binding protein and said amanitin or analog thereof.

[0180] In one embodiment, the linker is a cleavable linker.

[0181] In another embodiment, the linker is a non-cleavable linker.

[0182] In one embodiment, the linker is connected to the antigen-binding protein using a transglutaminase reaction.

[0183] In one embodiment, the TAA is selected from the group consisting of: an anti-HER2 antibody, an anti-STEAP2 antibody, an anti-MET antibody, an anti-EGFRVIII antibody, an anti- MUC16 antibody, an anti-PRLR antibody, an anti-PSMA antibody, an anti-FGFR2 antibody, an anti-FOLRl antibody, an anti-HER2/HER2 bispecific antibody, an anti-ASGRl antibody, an anti- MET/MET bispecific antibody, or an antigen-binding fragment thereof.

[0184] In some embodiments, a compound according to Formula A, Formula I (or any subgenera thereof) or a compound of Table 1 may be linked to a protein (e.g., an antibody or an antigenbinding fragment thereof) with any linker L deemed suitable. Linkers are any group or moiety that links, connects, or bonds the antibody or antigen-binding proteins described herein with a therapeutic moiety, e.g. a rifamycin analog. Suitable linkers may be found, for example, in Antibody-Drug Conjugates and Immunotoxins, Phillips, G. L., Ed.; Springer Verlag: New York, 2013; Antibody-Drug Conjugates,' Ducry, L., Ed.; Humana Press, 2013; Antibody-Drug Conjugates, Wang, J., Shen, W.-C., and Zaro, J. L., Eds.; Springer International Publishing, 2015, the contents of each incorporated herein in their entirety by reference. Generally, suitable binding agent linkers for the antibody conjugates described herein are those that are sufficiently stable to exploit the circulating half-life of the antibody and, at the same time, capable of releasing its payload after antigen-mediated internalization of the conjugate. Linkers can be cleavable or non- cleavable. Cleavable linkers include linkers that are cleaved by intracellular metabolism following internalization, e.g., cleavage via hydrolysis, reduction, or enzymatic reaction. Non-cleavable linkers include linkers that release an attached payload via lysosomal degradation of the antibody following internalization. Suitable linkers include, but are not limited to, acid-labile linkers, hydrolysis-labile linkers, enzymatically cleavable linkers, reduction labile linkers, self-immolative linkers, and non-cleavable linkers. Suitable linkers also include, but are not limited to, those that are or comprise peptides, glucuronides, succinimide-thioethers, polyethylene glycol (PEG) units, hydrazones, mal-caproyl units, dipeptide units, valine-citruline units, and para-aminobenzyl (PAB) units.

[0185] Any linker molecule or linker technology known in the art can be used to create or construct an ADC of the present disclosure. In certain embodiments, the linker is a cleavable linker. According to other embodiments, the linker is a non-cleavable linker. Exemplary linkers that can be used in the context of the present disclosure include, linkers that comprise or consist of e.g., MC (6-maleimidocaproyl), MP (maleimidopropanoyl), val-cit (valine-citrulline), val-ala (valinealanine), dipeptide site in protease-cleavable linker, ala-phe (alanine-phenylalanine), dipeptide site in protease-cleavable linker, PAB (p-aminobenzyloxycarbonyl), SPP (N-Succinimidyl 4-(2- pyridylthio) pentanoate), SMCC (N-Succinimidyl 4-(N-maleimidomethyl)cyclohexane-l carboxylate), SIAB (N-Succinimidyl (4-iodo-acetyl)aminobenzoate), and variants and combinations thereof. Additional examples of linkers that can be used in the context of the present disclosure are provided, e.g., in US 7,754,681 and in Ducry, Bioconjugate Chem., 2010, 27:5-13, and the references cited therein, the contents of which are incorporated by reference herein in their entireties.

[0186] In certain embodiments, the linkers are stable in physiological conditions. In certain embodiments, the linkers are cleavable, for instance, able to release at least the payload portion in the presence of an enzyme or at a particular pH range or value. In some embodiments, a linker may comprise an enzyme-cleavable moiety. Illustrative enzyme-cleavable moieties include, but are not limited to, peptide bonds, ester linkages, hydrazones, and disulfide linkages. In some embodiments, the linker may comprise a cathepsin-cleavable linker.

[0187] In some embodiments, the linker may comprise a non-cleavable moiety.

[0188] Suitable linkers also include, but are not limited to, those that are chemically bonded to two cysteine residues of a single binding agent, e.g., antibody. Such linkers can serve to mimic the antibody’s disulfide bonds that are disrupted as a result of the conjugation process.

[0189] In some embodiments, the linker may comprise one or more amino acids. Suitable amino acids include natural, non-natural, standard, non-standard, proteinogenic, non-proteinogenic, and L- or D- cc-amino acids. In some embodiments, the linker may comprise alanine, valine, glycine, leucine, isoleucine, methionine, tryptophan, phenylalanine, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, or citrulline, a derivative thereof, or combination thereof. In certain embodiments, one or more side chains of the amino acids is linked to a side chain group, described below. In some embodiments, the linker may comprise valine and citrulline. In some embodiments, the linker may comprise lysine, valine, and citrulline. In some embodiments, the linker may comprise lysine, valine, and alanine. In some embodiments, the linker may comprise valine and alanine.

[0190] In some embodiments, the linker may comprise a self-immolative group. The self- immolative group may be any such group known to those of skill. In particular embodiments, the self-immolative group may be >-aminobenzyl (PAB), or a derivative thereof. Useful derivatives include /?-aminobenzyloxycarbonyl (PABC). Those of skill will recognize that a self-immolative group is capable of carrying out a chemical reaction which releases the remaining atoms of a linker from a payload. [0191] In some embodiments, the linker may be:

wherein is a bond to the antibody or antigen-binding protein e.g., via lysine residue) and

is a bond to the payload (i.e., a compound of Formula A, I-IV or a compound of Table 1). In

some embodiments, the linker may be:

wherein is a bond to the antibody or antigen-binding protein (e.g., via lysine residue) and

is a bond to the payload. In certain embodiments, the linker may be:

[0192] In certain embodiments, the linker may be:

[0193] In some embodiments, the linker may be derived from maleimidylmethyl-4-trans- cyclohexanecarboxysuccinate:

[0194] In some embodiments, the linker may be:

wherein is a bond to the antibody or antigen-binding protein (e.g., via a lysine or a serine residue) and is a bond to the payload.

[0195] In some embodiments, linker L may be a cleavable linker. In some embodiments, L may be a non-cleavable linker. In some embodiments, L may comprise a dipeptide. In some embodiments, L may comprise a

moiety.

[0196] In some embodiments, L may comprise a moiety having the following structure:

[0197] In some embodiments, L may comprise a moiety having the following structure:

[0198] In some embodiments, L may comprise a moiety having the following structure:

[0199] In some embodiments, L may comprise a moiety having a structure selected from:

EXAMPLES

[0200] The following examples illustrate specific aspects of the instant description. The examples should not be construed as limiting, as the examples merely provide specific understanding and practice of the embodiments and their various aspects.

Example 1: 2-(3-((2-ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4J/)-yl)methyl) isoxazol-5- yl)-4-hydroxybenzonitrile (2035)

Step 1: Ethyl 5-(2-cyano-5-methoxyphenyl)isoxazoIe-3-carboxylate (2035-2)

[0201] A solution of 2035-1 (1g, 4.72 mmol), 2-bromo-4-methoxybenzonitrile (2.2 g, 5.2 mmol) and Pd(t-Bu₃P)₂ (241.2 mg, 472 μmol) in Tol. (20 mL) was degassed and purged with N2 for 3 times, the resulting mixture was stirred at 90 °C for 3 h under N2. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue. The reaction mixture was poured into Petroleum ether (20 mL) and then the precipitate was separate out. The reaction mixture was filtered and the filter cake was washed with 20 mL of Petroleum ether, dried in vacuum to give Compound 2035-2 (1.1 g, 4.04 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d₆) 5 = 8.01 (d, J = 8.8 Hz, 1H), 7.67 - 7.58 (m, 2H), 7.35 - 7.25 (m, 1H), 4.42 (q, J = 7.1 Hz, 2H), 3.94 (s, 3H), 1.41 - 1.32 (m, 3H)

Step 2: 2-(3-(Hydroxymethyl)isoxazol-5-yl)-4-methoxybenzonitrile (2035-3)

[0202] To a solution of 2035-2 (500 mg, 1.8 mmol) in THF (20 mL), was added NaBH₄ (173.7 mg, 4.6 mmol) at 0°C under N2. The resulting mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into NH4CI aqueous (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give 2035-3 (410 mg, 4.04 mmol) as a white solid.

Step 3: 2-(3-(Chloromethyl)isoxazol-5-yl)-4-methoxybenzonitrile (2035-4)

[0203] To a solution of 2035-3 (200 mg, 868.74 μmol) in CHCl₃ (6.0 mL), was added SOCh (341.1 mg, 2.9 mmol) and DMF (6.4 mg, 86.9 μmol). The resulting mixture was stirred at 70 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 2035-3 (200 mg, 804.3 μmol) as a white solid.

Step 4: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) yl)methyl)isoxazo l-5-yl)-4- methoxybenzonitrile (2035-5)

[0204] To a solution of 2035-3 (200 mg, 804.3 μmol) and 2-ethyl-5,6,7,8-tetrahydroquinazolin- 4(3/Z)-one (157.7 mg, 884.7 μmol) in acetone (6.0 mL) was added Nal (12.1 mg, 80.4 μmol) and K₂CO₃ (555.8 mg, 4.0 mmol). The mixture was stirred at 50 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (60 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 2035-5 (160 mg, 409.8 μmol) as a white solid.

Step 5: 2-(3-((2-ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxa zol-5-yl)-4- hydroxybenzonitrile (2035)

[0205] To a stirred solution of 2035-5 (50 mg, 128.1 μmol) in DCM (2.0 mL) was added a solution of BBrs (962.5 mg, 3.8 mmol) in DCM (1.0 mL) at -78°C. The resulting mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (3.0 mL) and extracted with DCM (3.0 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2035 (7.7 mg, 20.46 umol) as a white solid. ESI [M+H]⁺ = 377.1 (LCMS);¹HNMR (400 MHz, DMSO-d₆) 5 = 11.30 - 10.91 (m, 1H), 7.84 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 2.4 Hz, 1H), 7.14 (s, 1H), 7.04 (dd, J = 2.5, 8.6 Hz, 1H), 5.38 (s, 2H), 2.82 (q, J = 7.3 Hz, 2H), 2.39 - 2.32 (m, 2H), 1.75 - 1.61 (m, 4H), 1.22 - 1.14 (m, 3H). Example 2: 3-((3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)methyl)-5,6-dimethylpyrimid in- 4(3H) -one (1706)

Step 1: (E)-4-Fluoro-3-methoxybenzaldehyde oxime (1706-2)

[0206] To a solution of NH₂OH.HC1 (2.7 g, 39.3 mmol) in EtOH (8.0 mL) and H₂O (40 mL) was added Na₂CO₃ (4.2 g, 39.3 mmol) and the mixture was stirred for 5 min to obtain a clear solution. Then 1706-1 (5 g, 32.4 mmol) was added and the solution was stirred at 15 °C for 1 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO4, filtered and concentrated in vacuum to give Compound 1706-2 (5.2 g, crude) as a white solid.¹H NMR (400MHz, CHLOROFORM-d) = 8.09 (s, 1H), 7.33 - 7.25 (m, 1H), 7.15 - 7.00 (m, 2H), 3.93 (s, 3H).

Step 2: Ethyl 3-(4-fluoro-3-methoxyphenyl)isoxazole-5-carboxylate (1706-3)

[0207] To a solution of 1706-2 (5.0 g, 29.6 mmol) in ethyl methyl ketone (50 mL) was added ethyl propiolate (3.6 g, 36.4 mmol) followed by isopentyl nitrite (4.0 g, 34.3 mmol). After 5 min stirring at 15 °C, the turbid reaction mixture was stirred at 65 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (60 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO4, filtered and concentrated under vacuum to give a residue which was purified by triturated with EtOAc to give Compound 1706-3 (1.95 g, 7.35 mmol) as a white solid.

Step 3: (3-(4-Fluoro-3-inethoxyphenyl)isoxazol-5-yl)methanol (1706-4)

[0208] To a solution of 1706-3 (1.0 g, 3.8 mmol) in THF (20 mL) was added NaBH₄ (356.6 mg, 9.4 mmol) at 0°C. The mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give Compound 1706-4 (900 mg, crude) as a white solid.

Step 4: 5-(Chloromethyl)-3-(4-fluoro-3-methoxyphenyl)isoxazole (1706-5)

[0209] To a solution of 1706-4 (900 mg, 4.0 mmol) in CHCI3 (10 mL) was added SOCh (1.6 g, 13.3 mmol) and DMF (29.5 mg, 403.2 μmol) , then the mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give Compound 1706-5 (900 mg, crude) as a pale yellow solid.

Step 5: 3-((3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)methyl)-5,6-dimethylpyri midin- 4(3H) -one (RG N-1706-6)

[0210] To a solution of 4,5-dimethyl-lH-pyrimidin-6-one (51.4 mg, 413.8 μmol) in acetone (5.0 mL) was added K₂CO₃ (286 mg, 2.1 mmol) and Nal (6.2 mg, 41.4 μmol). 1706-5 (100 mg, 413.8 μmol) was added to the mixture and stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (6.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give Compound 1706-6 (130 mg, crude) as a white solid.

Step 6: 3-((3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)methyl)-5,6-dimethylp yrimidin- 4(3H)-one (1706)

[0211] To a solution of 1706-6 (50 mg, 151.8 μmol) in DCM (6.0 mL) was added a solution of BBn (304 mg, 1.2 mmol) in DCM (2.0 mL) at -78 °C under N2. The resulting mixture was stirred at 25 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (6.0 mL) and extracted with DCM (2.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 1706-6 (14 mg, 45 μmol) as a white solid. ESI [M+H]⁺ = 316.0 (LCMS);¹HNMR (400MHz, DMSO-d₆) δ = 10.22 (s, 1H), 8.45 (s, 1H), 7.50 - 7.38 (m, 1H), 7.31 - 7.18 (m, 2H), 6.92 (s, 1H), 5.29 (s, 2H), 2.24 (s, 3H), 1.95 (s, 3H).

Example 3: 3-(l-(3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)ethyl)quinazolin-4(3H)-one

(1708)

Step 1: 3-(4-Fuoro-3-methoxyphenyl)isoxazole-5-carboxylic acid (1708-1)

[0212] To a stirred solution of 1706-3 (1.8 g, 6.8 mmol) in THF (35 mL) and H₂O (7.0 mL) was added LiOH.HzO (854.3 mg, 20.4 mmol) at 0 °C. The resulting mixture was stirred at 20 °C for 4 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was added H₂O (40 mL), extracted with petroleum ether (10 mL x 2). The combined organic layers were discarded, the water phase was added HC1 (IM) to make pH=4, and extracted with EtOAc (15mL x 3). The combined organic layers dried over Na₂SO₄ and concentrated under vacuum to give a Compound 1708-1 (1.5 g, crude) as a white solid.¹H NMR (400MHz, DMSO-d₆) δ = 7.86 (s, 1H), 7.70 (br d, J=8.3 Hz, 1H), 7.55 (ddd, J=2.1, 4.2, 6.2 Hz, 1H), 7.37 (dd, J=8.4, 11.3 Hz, 1H), 3.93 (s, 3H)

Step 2: 3-(4-Fuoro-3-methoxyphenyl)-A-methoxy-A-methylisoxazole-5-carbo xamide (1708- 2)

[0213] To a solution of 1708-1 (400 mg, 1.7 mmol) and A,(9-dimethylhydroxylamine (271.2 mg, 2.0 mmol) in DCM (12 mL) was added TEA (512 mg, 5.1 mmol) and T3P (2.2 g, 3.4 mmol, 50% purity in EtOAc), then the mixture was stirred at 25 °C for 1 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (12 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give a Compound 1708-2 (700 mg, crude) as a white solid.

Step 3: l-(3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)ethan-l-one (1708-3)

[0214] To a solution of 1708-2 (70 mg, 249.2 μmol) in THF (2.0 mL) was added MeMgBr (3 M, 166.52 μL) at -78 °C .The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (3.0 mL) and extracted with EtOAc (3.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give Compound 1708-3 (60 mg, crude) as a white solid.

Step 4: l-(3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)ethan-l-ol (1708-4)

[0215] To a solution of 1708-3 (60 mg, 255.1 μmol) in MeOH (1.0 mL) was added NaBH₄ (24.1 mg, 637.7 μmol) at 0 °C The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (3.0 mL) and extracted with EtOAc (2.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give Compound 1708-4 (40 mg, crude) as a white oil.

Step 5: 5-(l-Chloroethyl)-3-(4-fluoro-3-inethoxyphenyl)isoxazole (1708-5)

[0216] To a solution of 1708-4 (40 mg, 168.6 μmol) in CHCI3 (1.0 mL) was added SOCI2 (66.2 mg, 556.43 μmol) and DMF (1.3 mg, 16.9 μmol). Then the mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (2.0 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give Compound 1708-5 (50 mg, crude) as a white oil.

Step 6: 3-(l-(3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)ethyl)quinazolin-4 (3H) -one (1708- 6)

[0217] To a solution of quinazolin-4(3H) -one (28.6 mg, 195.6 μmol) in acetone (3.0 mL) was added Nal (2.9 mg, 19.6 μmol), K₂CO₃ (135.1 mg, 977.8 μmol) and 1708-5 (50 mg, 195.56 μmol). The mixture and stirred at 50 °C for 72 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give Compound 1708-6 (50 mg, crude) as a brown solid.

Step 7: 3-(l-(3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)ethyl)quinazolin-4(3 //)-one (1708) [0218] To a stirred solution of 1708-6 (50 mg, 136.85 μmol) in DCM (5.0 mL) was added BBri (342.9 mg, 1.4 mmol) in DCM (2.0 mL) at -78 °C. The resulting mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 1708 (3.1 mg, 8.46 μmol) as a brown oil. ESI [M-H] = 350.1 (LCMS);¹H NMR (400MHZ, DMSO-d₆) δ = 10.23 (br s, 1H), 8.47 (s, 1H), 8.18 (dd, J=1.3, 8.0 Hz, 1H), 7.95 - 7.82 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.50 - 7.44 (m, 1H), 7.33 - 7.23 (m, 2H), 7.13 (s, 1H), 6.18 (q, J=7.2 Hz, 1H), 1.92 (d, J=7.1 Hz, 3H).

Example 4: 5-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-3-methyl-2-phenylpy rimidin-4(3/Z)-one (1909)

Step 1: (5-(4-Fluoro-3-methoxyphenyl)isoxazol-3-yl)methanol (1909-2)

[0219] To a solution of 1909-1 (3 g, 11 mmol) in THF (75 mL) was added LAH (859 mg, 23 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated the reaction was completed. After the reaction mixture was cooled to 0 °C, the reaction mixture was quenched by addition of 0.9 mL of H₂O, followed by 0.9 mL of 10% aqueous NaOH, 2.7 mL of H₂O, After being stirred at room temperature for 5 min, then added MgSCL, the mixture was filtered through Celite pad, then was dryness to give Compound 1909-2 (4.5 g, crude) as a white solid.

Step 2: 5-(4-Fluoro-3-methoxyphenyl)isoxazole-3-carbaldehyde (1909-3)

[0220] To a solution of 1909-3 (2.5 g, 11 mmol) in ACN (65 mL) was added DMP (5.2 g, 12 mmol), then the mixture was stirred at 20 °C for 3 h. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1909-4 (2 g, crude) as a white solid. Step 3: Methyl (E)-3-(5-(4-fluoro-3-methoxyphenyl)isoxazol-3-yl)acrylate (1909-4)

[0221] A solution of methyl 2-diethoxyphosphorylacetate (1.4 g, 6.8 mmol) in THF (25 mL) was added NaH (271 mg, 6.8 mmol, 60% purity) at 0 °C, after 1 h, 1909-3 (1 g, 4.5 mmol) was added, then the mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1909-4 (3 g, crude) as a white solid. ESI [M+H]+ = 278.2(LCMS).

Step 4: Methyl 3-(5-(4-fluoro-3-methoxyphenyl)isoxazol-3-yl)propanoate (1909-5)

[0222] To a solution of 1909-4 (1.5 g, 5.4 mmol) in MeOH (15 mL) was added Pd/C (50 mg, 5.4 mmol, 10% purity), then the mixture was stirred at 20 °C for 2 h under H2 atmosphere 15 psi. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1909-5 (800 mg, crude) as brown oil. ESI [M+H]¹ = 280.3(LCMS); 1H NMR (400 MHz, DMSO-d6) 8 = 7.56 (dd, J = 1.7, 8.2 Hz, 1H), 7.45 - 7.33 (m, 2H), 6.97 (s, 1H), 3.93 (s, 3H), 3.61 (s, 3H), 2.99 - 2.89 (m, 2H), 2.80 - 2.71 (m, 2H).

Step 5: Methyl (Z)-3-(dimethylamino)-2-((5-(4-fluoro-3-methoxyphenyl)isoxazol- 3-yl)methyl)acrylate (1909-6)

[0223] A solution of 1909-5 (600 mg, 2.2 mmol) in t-BuOCH(N(CH3)2)2 (3.7 g, 22 mmol, 4.4 mL) was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated to give crude 1909-6 (650 mg, crude) as a white solid. ESI [M+H]⁺= 334.1(LCMS).

Step 6: 5-((5-(4-fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)-2-phenylpyrimid in-4(3H) -one (1909-7)

[0224] To a solution of benzimidamide (47 mg, 2997 μmol) in EtOH (1.0 mL) was added NaOEt (51 mg, 748 μmol) in EtOH (1.0 mL) and 1909-6 (50.00 mg, 149.55 μmol), then the mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1909-7 (120 mg, crude) as a white solid. ESI [M+H]⁺= 378.2 (LCMS); Step 7 : 5-((5-(4-Fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)-3-methyl-2-phEny lpyrimidin-4(3//)-one (1909-8)

[0225] To a solution of 1909-7 (50 mg, 133 μmol) in acetone (1 mL) was added K₂CO₃ (22 mg, 159 μmol), Mel (21 mg, 146 μmol), then the mxiture was stirred at 55 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (5.0 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1909-8 (100 mg, crude) as a white solid. ESI [M+H]⁺= 392.2(LCMS).

Step 8: 5-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-3-methyl-2-phen ylpyrimidin-4(3H)-one (1909)

[0226] To a solution of 1909-8 (60 mg, 153.30 μmol) in DCM (1.0 mL) was added BBr? (384 mg, 1.5 mmol) in DCM (1.0 mL) at -78 °C, after 1 h, the mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1909 (21 mg, 52 μmol) as a white solid. ESI [M+H]⁺ = 378.0(LCMS);¹HNMR (400MHz, DMSO-d₆) δ =10.31 (s, 1H), 8.59 (s, 1H), 8.40 (dd, J=2.9, 6.6 Hz, 2H), 7.58 - 7.48 (m, 3H), 7.42 - 7.34 (m, 1H), 7.32 - 7.24 (m, 2H), 6.84 (s, 1H), 4.08 (s, 3H), 4.00 (s, 2H).

Example 5: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-methyl-5,8-dihydro-

3//-pyr:iiio|3.4-d|pyriniidin-4(6//)-one (1910)

Step 1: Ethyl 5-(tributylstannyl) isoxazole-3-carboxylate (1910-2)

[0227] To a solution of 1910-1 (5 g, 15 mmol) and (Z)-ethyl-2-chl oro-2- (hydroxyimino)acetate (2.6 g, 17 mmol) in toluene (50 mL) was added TEA (1.6 g, 17 mmol) under N2. The resulting mixture was stirred at 25 °C for 4 h. TLC indicated that the starting material was completely. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1910-2 (4.5 g, crude) as a colorless oil.

Step 2: Ethyl 5-(4-fluoro-3-methoxyphenyl)isoxazole-3-carboxylate (1910-3)

[0228] To a solution of 1910-2 (4.2 g, 9.7 mmol) and 4-bromo-l-fluoro-2-methoxy benzene (2 g, 9.7 mmol) in toluene (40 mL) was added Pd (t-Bu₃P)₂ (249 mg, 488 umol) under N2. The mixture was stirred at 90 °C for 3 h. TLC indicated that the starting material was completely. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1910-3 (2 g, 7.6 mmol) as a yellow solid.

NMR (400 MHz, DMSO-d₆) 5 = 7.74 - 7.68 (m, 1H), 7.56 - 7.50 (m, 2H), 7.38 (dd, J=8.4, 11.2 Hz, 1H), 4.45 - 4.35 (m, 2H), 3.94 (s, 3H), 1.34 (t, J=7.1 Hz, 3H).

Step 3: (5-(4-Fluoro-3-methoxyphenyl) isoxazol-3-yl) methanol (1910-4)

[0229] To a solution of 1910-3 (3 g, 10 mmol) in THF (60 mL) was added LiAlH4 (860 mg, 22 mmol) at 0 °C. The mixture was stirred at 20 °C for 1 h. TLC indicated that the starting material was completely. After the reaction mixture was cooled to 0°C, the reaction mixture was quenched by addition 0.9 mL H₂O, followed by 0.9 mL 10 % aqueous NaOH and 1.8 mL H₂O. After stirred at 25 °C for 5 min, 5 g MgSO₄ was added, then the mixture was filtered through Celite pad, the filtrate was dryness to give Compound 1910-4 (2 g, 9 mmol) as a yellow solid.¹HNMR (DMSO- d₆, 400 MHz): 5 = 7.61 (dd, J=8.3, 1.9 Hz, 1H), 7.48-7.41 (m, 1H), 7.35 (dd, J=11.3, 8.4 Hz, 1H), 7.05 (s, 1H), 5.57 (t, J=5.8 Hz, 1H), 4.55 (d, J=5.8 Hz, 2H), 3.93 ppm (s, 3H).

Step 4: 3-(Chloromethyl)-5-(4-fluoro-3-methoxyphenyl) isoxazole (1910-5)

[0230] To a solution of 1910-4 (0.5 g, 2.0 mmol) in CHCI3 (5.0 mL) was added SOCI2 (879 mg, 7.4 mmol) and DMF (16 mg, 224 μmol), then the mixture was stirred at 70 °C for 12 h. TLC indicated that the starting material was completely. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1910- 5 (809 mg, 3.0 mmol) as a yellow solid.¹H NMR (400 MHz, CHLOROFORM-d) 5 = 7.39 (dd, J=2.0, 8.0 Hz, 1H), 7.32 (ddd, J=2.1, 4.3, 8.4 Hz, 1H), 7.17 (dd, J=8.4, 10.8 Hz, 1H), 6.59 (s, 1H), 4.64 (s, 2H), 3.97 (s, 3H)

Step 5: 3-((5-(4-Fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)-2-methyl-5,8-dihydro-3H - pyrano[3,4-d|pyrimidin-4(6H )-one (1910-6)

[0231] To a solution of 2-methyl-5,8-dihydro-3H -pyrano[3,4-d]pyrimidin-4(6H) -one (125 mg, 752 μmol), K₂CO₃ (343.16 mg, 2.5 mmol) and Nal (6.2 mg, 41 μmol) in acetone (5.0 mL) was added 1910-5 (100 mg, 414 μmol). The mixture was stirred at 60 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and filtered, the filter cake was concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 1910-6 (120 mg, crude) as a brown solid.

Step 6: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-methyl-5,8-dihydro-3H - pyrano[3,4-d]pyrimidin-4(6//)-one (1910)

[0232] AICI3 (172 mg, 1.3 mmol, 70 μL) was added to a mixture of EtSH (2.0 mL) and DCM (6.0 mL) at 0 °C, then 1910-6 (80 mg, 216 μmol) was added at 0°C. The mixture was stirred at 25 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H₂O (20 mL) and extracted with DCM (10 mL x 4). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give Compound 1910 (29.5 mg, 81.22 μmol) as a white solid. ESI [M+H]⁺ = 358.0(LCMS);¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.43 (br d, J = 8.0 Hz, 1H), 7.27 - 7.22 (m, 1H), 7.19 - 7.07 (m, 1H), 6.58 (s, 1H), 6.40 - 6.13 (m, 1H), 5.33 (s, 2H), 4.45 (s, 2H), 3.93 (br t, J = 5.3 Hz, 2H), 2.66 (s, 5H).

Example 6: 2-Ethyl-3-((5-(4-fluoro-5-hydroxy-2(trifluoromethyl)phenyl)isoxazol-3-yl) methyl)-6-phenylpyrimidin-4(3H) -one (1925)

Step 1: l-Bromo-4-fluoro-5-methoxy-2-(trifluoromethyl)benzene (1925-2)

[0233] To a solution of the 1925-1 (1.0 g, 3.0 mmol) in DMF (40 mL) was added Cui (3.5 g, 18.1 mmol) and methyl 2,2-difluoro-2-fluorosulfonyl-acetate (5.8 g, 30.2 mmol, 3.8 mL), the mixture was degassed and purged with N2 for 3 times, and then the mixture was stirred at 70 °C for 12 h under N2 atmosphere. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 30 mL and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 1925- 2 (0.6 g, 2.0 mmol) as an oil liquid.

Step 2: Ethyl 5-(4-fluoro-5-methoxy-2-(trifluoromethyl)phenyl)isoxazole-3-carboxylate (1925-4)

[0234] To a solution of the 1925-3 (4.7 g, 11.0 mmol), 1925-2 (2.0 g, 7.3 mmol) in Tol. (30 mL), was added Pd(t-Bu₃P)₂ (374.4 mg, 732.5 μmol) under N2 for 3 times, the resulting mixture was stirred at 90 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 30 mL and extracted with EtOAc (5.0 mL x 8). The combined organic layers were dried overl Na₂SO,₄ filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 1925- 4 (1.3 g, 3.9 mmol) as a white solid. ' H NMR (400 MHz, CHLOROFORM-d) δ = 7.55 (d, J= 11.1 Hz, 1H), 7.36 (d, J = 7.9 Hz, 1H), 6.97 (s, 1H), 4.56 - 4.44 (m, 2H), 4.01 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H).

Step 3: (5-(4-Fluoro-5-methoxy-2-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (1925-5) [0235] To a solution of (1925-4) (1.3 g, 3.9 mmol) in THF (20 mL) was added NaBH₄ (368.9 mg, 9.8 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by poured into NH4CI 20 mL and extracted with EtOAc (4.0 mL x 5). the aqueous layer were concentrated under reduced pressure to give Compound (1925-5) (1.1 g, crude) as a yellow solid.

Step 4: 3-(Chloromethyl)-5-(4-fluoro-5-methoxy-2-(trifluoroinethyl)phenyl)isoxa zole (1925-6)

[0236] To a solution of (1925-5) (1 g, 3.4 mmol) in CHCI3 (15 mL) was added SOCl2 (1.4 g, 11.3 mmol, 822.1 μL) and DMF (25.1 mg, 343.4 μmol, 26.4 μL), then the mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 20 mL and extracted with EtOAc (5.0 mL x 4). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound (1925-6) (200 mg, 827.7 μmol) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.5 (d, J = 11.3 Hz, 1H), 7.40 - 7.34 (m, 1H), 6.69 (s, 1H), 4.67 (s, 2H), 4.01 (s, 3H).

Step 5: 2-Ethyl-3-((5-(4-fluoro-5-methoxy-2-(trifluoromethyl)phenyl)isoxazol-3-yl) methyl)- 6-phenylpyrimidin-4(3H)-one (1925-7)

[0237] To a solution of 1925-6 (300.0 mg, 968.9 μmol) in ACETONE (6 mL), was added K₂CO₃ (669.5 mg, 4.8 mmol), Nal (14.5 mg, 96.9 μmol), 2-ethyl-6-phenylpyrimidin-4(3H) -one (194.0 mg, 968.9 μmol), the resulting mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by pouring into H₂O 6.0 mL and extracted with DCM (3.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by TLC to give Compound (1925-7) as a yellow solid.

Step 6: 2-Ethyl-3-((5-(4-fluoro-5-hydroxy-2-(trifluoromethyl)phenyl)isoxazol-3-yl) methyl)- 6-phenylpyrimidin-4(3H) -one (1925)

[0238] To a solution of 1925-7 (110 mg, 232.4 μmol) in DCM (10.0 mL) was added a solution of BBr? (873.1 mg, 3.5 mmol, 335.8 μL) in DCM (10.0 mL) at -70 °C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by pouring into water 10 mL and extracted with EtOAc (5.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give Compound 1925 (50.1 mg, 103.5 μmol) as a white solid. ESI [M-H] = 460.1 (LCMS); NMR (400 MHz, DMSO-d₆) δ = 8.17 - 8.11 (m, 2H), 7.78 (d, J = 11.6 Hz, 1H), 7.54 - 7.49 (m, 3H), 7.32 - 7.27 (m, 1H), 6.98 (s, 1H), 6.81 (s, 1H), 5.42 (s, 2H), 2.93 (q, J = 7.3 Hz, 2H), 1.30 (t, J = 7.2 Hz, 3H).

Example 7: 3-((5-(3-Chloro-4-fluoro-5-hydroxyphenyl)isoxazol-3-yl)methyl)-2-ethyl-6 - phenylpyrimidin-4(3H)-one (1927)

Step 1 : 2-(5-Bromo-3-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-l,3,2-dioxaborolane (1927-2)

[0239] To a solution of 1927-1 (1 g, 4.8 mmol, 578 L), 4,4,5,5-tetramethyl-2-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (1.2 g, 4.8 mmol) in THF (20 mL), was added 4-tert-butyl-2-(4-tert-butyl-2-pyridyl)pyridine (32.0 mg, 119.4 μmol) and (1Z,5Z)- cycloocta-l,5-diene;2,4-dimethyl-BLAHbicyclo[1.1.0]butane (63.3 mg, 95.5 μmol) under N2 ,then the mixture was stirred at 80 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1927-2 (1 g, 3.0 mmol) was obtained as a white solid.

Step 2: 5-Bromo-3-chloro-2-fluorophenol (1927-3) [0240] To a solution of 1927-2 (500 mg, 1.5 mmol) in THF (12.5 mL) and H₂O (0.5 mL) was added NaBO_3.4H₂O (344.1 mg, 2.2 mmol, 430.1 μL). The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude 1927-3 (690 mg, crude) as a white solid.

Step 3: 5-Bromo-l-chloro-2-fluoro-3-methoxybenzene (1927-4)

[0241] To a solution of 1927-3 (345 mg, 1.5 mmol), K₂CO₃ (423 mg, 3.1 mmol) in DMF (5.0 mL) was added Mel (434.4 mg, 3.1 mmol, 190.5 μL), then the mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether at 25 °C for 15 min. Compound 1927-4 (450 mg, 1.9 mmol) was obtained as a white solid.

Step 4: Ethyl 5-(3-chloro-4-fluoro-5-methoxyphenyl)isoxazole-3-carboxylate (1927-5)

[0242] To a solution of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (359.3 mg, 835.2 μmol) and 1927-4 (200 mg, 835.2 μmol) in Tol. (8.0 mL) was added Pd(t-Bu₃P)₂ (42.7 mg, 83.5 μmol), then the mixture was stirred at 90 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The residue was triturated with PE at 25 °C for 25 min to give Compound 1927- 5 (200 mg, 667.4 umol) as a white solid.

Step 5: (5-(3-Chloro-4-fluoro-5-methoxyphenyl)isoxazol-3-yl)methanol (1927-6)

[0243] To a solution of 1927-5 (180 mg, 600.6 μmol) in THF (10 mL), was added NaBH₄ (56.8 mg, 1.5 mmol) at 0 °C, then the mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure to give a residue. Compound 1927-6 (130 mg, crude) was obtained as a white solid. Step 6: 5-(3-Chloro-4-fluoro-5-methoxyphenyl)-3-(chloromethyl)isoxazole (1927-7)

[0244] To a solution of 1927-6 (130 mg, 504.6 μmol) in CHCl₃ (5 mL) was added SOCh (600.3 mg, 5.1 mmol, 366 μL) and DMF (3.7 mg, 50.5 μmol, 3.9 μL). The mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ fdtered and concentrated under reduced pressure to give a residue. Compound 1927-7 (130 mg, crude) was obtained as a white solid.

Step 7: 3-((5-(3-Chloro-4-fluoro-5-methoxyphenyl)isoxazol-3-yl)methyl)-2-ethyl-6 - plieiiylpyriiiiidin-4(3//)-one (1927-8)

[0245] To a solution of 1927-7 (110 mg, 398.4 μmol) and 2-ethyl-6-phenylpyrimidin-4(3H) -one (79.8 mg, 398.4 μmol) in ACETONE (5.0 mL) was added K₂CO₃ (330.4 mg, 2.4 mmol) and Nal (6.0 mg, 39.8 μmol). The reaction was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc at 25 °C for 15 min. Compound 1927-8 (80 mg, 181.9 umol) as a white solid.

Step 8: 3-((5-(3-Chloro-4-fluoro-5-hydroxyphenyl)isoxazol-3-yl)methyl)-2-ethyl-6 - phenylpyriinidin-4(3//)-one (1927)

[0246] To a solution of 1927-8 (80 mg, 181.9 μmol) in DCM (3 mL) was added BBrs (455.6 mg, 1.8 mmol, 175.2 μL) in DCM (1.0 mL) at -78 °C under N2 for 1 h, then the mixture was stirred at 20 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was concentrated to get a residue. The residue was purified by prep-HPLC to give Compound 1927 (15.3 mg, 35.9 μmol) was obtained as a Pale yellow solid. ESI [M+H]⁺ = 426.0 (LCMS);^JH NMR (400 MHz, DMSO-d₆) δ = 10.90 (br s, 1H), 8.18 - 8.07 (m, 2H), 7.60 - 7.47 (m, 4H), 7.37 (dd, J= 2.1, 7.5 Hz, 1H), 7.05 (s, 1H), 6.97 (s, 1H), 5.38 (s, 2H), 2.93 (q, J= 2 Hz, 2H), 1.30 (t, J= 7.3 Hz, 3H).

Example 8: 2-Ethyl-3-((5-(4-fluoro-3-hydroxy-5-(trifluoromethyl) phenyl) isoxazol-3-yl) methyl)-6-phenylpyrimidin-4(3H) -one (1972)

Step 1: (5-Bromo-2-fluoro-3-(trifluoromethyl)phenyl)boronic acid (1972-2)

[0247] To a solution of 1972-1 (2 g, 8.2 mmol, 1.2 mL), tri-isopropyl borate (2.32 g, 12.4 mmol, 2.8 mL) in THF (12 mL) was added LDA (2 M, 4.5 mL) at -78 °C under N2. The mixture was stirred at 0 °C for 1 h. TLC indicated that the starting material was completely consumed. 12 mL HC1 (5 M) and 13 mL MTBE was added and stirred for 30 min then extracted with MTBE (5 mL x 4). The combined organic layers were washed with brine (5 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude 1972-2 (2 g) as a colorless oil.

Step 2: 5-Bromo-2-fluoro-3-(trifluoromethyl)phenol (1972-3)

[0248] To a solution of 1972-2 (0.7 g, 2.4 mmol) in THF (8.0 mL) and H₂O (0.4 mL) was added NaBO_3.4H₂O (563 mg, 3.7 mmol). The mixture was stirred at 20 °C for 12 h. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was poured into H₂O 10 mL and extracted with EtOAc (5.0 mL x 5). The combined organic layers dried over Na₂SO₄ , filtered and concentrated under concentrated to give crude 1972-3 (0.6 g) as a colorless oil.

Step 3: 5-Bromo-2-fluoro-l-methoxy-3-(trifluoromethyl)benzene (1972-4)

[0249] To a solution of 1972-3 (0.67 g, 2.6 mmol), K₂CO₃ (429 mg, 3.1 mmol) in acetone (15 mL) was added Mel (404 mg, 2.8 mmol, 177 μL). The mixture was stirred at 50 °C for 12 h. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 20 mL and extracted with EtOAc (5.0 mL x 3). The combined organic layers were washed with brine (5.0 mb x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1972-4 (1 g, 3.7 mmol) as a pale yellow solid.

Step 4: Ethyl 5-(4-fluoro-3-methoxy-5-(trifluoromethyl) phenyl) isoxazole-3-carboxylate (1972-5)

[0250] To a solution of ethyl 5-tributylstannylisoxazole-3-carboxylate (2.4 g, 5.5 mmol) and 1972- 4 (1 g, 3.7 mmol) in toluene (25 mL) was added Pd(t-Bu₃P)₂ (94 mg, 183 μmol) under N2. The mixture was stirred at 90 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 25 mL and extracted with EtOAc (10 mL x 5). The combined organic layers were washed with brine (10 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1972-5 (1.2 g, 3.6 mmol) as a white solid. ESI [M+H]⁺ = 334.0 (LCMS);¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.62 - 7.56 (m, 2H), 6.98 (s, 1H), 4.49 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.46 (t, J = 7.2 Hz, 3H)

Step 5: (5-(4-Fluoro-3-methoxy-5-(trifluoromethyl)phenyl)isoxazol-3-yl)methanol (1972-6) [0251] To a solution of 1972-5 (1.15 g, 3.5 mmol) in THF (20 mL) was added NaBH₄ (326 mg, 8.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction was poured into saturated NH4CI aqueous 20 mL and extracted with EtOAc (5.0 mL x 5). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude 1972-6 (1.1 g) as a white solid.¹H NMR (400 MHz, DMSO-de) 6 = 8.03 - 7.88 (m, 1H), 7.79 - 7.66 (m, 1H), 7.28 (s, 1H), 4.56 (s, 2H), 4.01 (s, 3H).

Step 6: 3-(Chloromethyl)-5-(4-fluoro-3-methoxy-5-(trifluoromethyl) phenyl)isoxa zole (1972-7)

[0252] To a solution of 1972-6 (1 g, 3.4 mmol) in CHCI3 (20 mL) was added SOCI2 (1.4 g, 11.3 mmol, 822 μL) and DMF (25 mg, 343.4 μmol, 26 μL). The mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 20 mL and extracted with EtOAc (5 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1972-7 (0.5 g, 1.6 mmol) as a pink solid.

Step 7 : 2-Ethyl-3-((5-(4-fluoro-3-methoxy-5-(trifluoromethyl)phenyl)isoxazol-3-yl)methyl)- 6-phenylpyrimidin-4(3H) -one (1972-8)

[0253] To a solution of 2-ethyl-6-phenylpyrimidin-4(31/)-one (69 mg, 343 μmol), K₂CO₃ (237 mg, 1.7 mmol) and Nal (5 mg, 34.3 μmol) in acetone (4.0 mL) was added 1972-7 (100 mg, 343 μmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 10 mL and extracted with EtOAc (5.0 mL x 2), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 1972-8 (60 mg, 127 μmol) as a white solid. ESI [M+H]⁺ = 474.1 (LCMS).

Step 8: 2-Ethyl-3-((5-(4-fluoro-3-hydroxy-5-(trifluoromethyl)phenyl)isoxazol-3-yl)methyl)- 6-phenylpyrimidin-4(3H) -one (1972)

[0254] To a solution of 1972-8 (50 mg, 106 μmol) in DCM (5.0 mL) was added a solution of BBn (265 mg, 1.1 mmol, 102 μL) in DCM (3.0 mL) at -70 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give Compound 1972 (14.4 mg, 29.5 μmol) as a white solid. ESI [M+H]⁺= 460.0 (LCMS)¹;H NMR (400 MHz, DMSO-d₆) δ=8.14 (br d, J = 3.4 Hz, 2H), 7.72 - 7.59 (m, 2H), 7.51 (br d, J = 2.8 Hz, 3H), 7.16 (s, 1H), 6.98 (s, 1H), 5.39 (s, 2H), 2.97 - 2.88 (m, 2H), 1.30 (br t, J = 7.1 Hz, 3H)

Example 9: 2-Ethyl-3-((3-(4-fluoro-3-hydroxy-5-(trifluoromethyl) phenyl) isoxazol-5-yl) methyl)-6-phenylpyrimidin-4(3H) -one (1992)

Step 1: 4-Fluoro-3-methoxy-5-(trifluoromethyl)benzaldehyde (1992-1)

[0255] To a solution of 1972-4 (2 g, 7.3 mmol) in DMF (40 mL) was added Pd(dppf)Ch (1.1 g, 1.5 mmol), TEA (3.7 g, 36.6 mmol, 5.1 mL) and EtsSiH (3.4 g, 29.3 mmol, 4.7 mL). The mixture was stirred at 80 °C for 12 h under CO (50 psi) atmosphere. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 50 mL and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with brine (15 mL x 3), dried overNa₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1992-1 (1.4 g, 6.3 mmol) as a brown oil.

(400 MHz, CHLOROFORM-d) δ = 9.96 (s, 1H), 7.70 (d, J = 6.6 Hz, 2H), 4.01 (s, 3H)

Step 2: (E)-4-Fluoro-3-methoxy-5-(trifluoromethyl) benzaldehyde oxime (1992-2)

[0256] To a solution of NH₂OHHCl (265 mg, 3.8 mmol) in EtOH (2.0 mL) and H₂O (10 mL) was added Na₂CO₃ (404 mg, 3.8 mmol). The mixture was stirred for 5 min to obtain a clear solution, then 1992-1 (700 mg, 3.2 mmol) was added. The mixture was stirred at 25 °C for 2 h. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was poured into H₂O 10 mL and extracted with EtOAc (5.0 mL x 5). The combined organic layers were washed with brine (5 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude 1992-2 (700 mg) as a white solid.

Step 3: Ethyl 3-(4-fluoro-3-methoxy-5-(trifluoromethyl) phenyl) isoxazole-5-carboxylate (1992-3) [0257] To a solution of ethyl prop-2 -ynoate (203 mg, 2.1 mmol, 204 μL) in butanone (20 mL) was added 1992-2 (400 mg, 1.69 mmol) and isopentyl nitrite (229 mg, 1.9 mmol, 263 μL). After stirred for 5 min at 15 °C, the mixture was stirred at 65 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 20 mL and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1992-3 (550 mg, 1.7 mmol) as a white solid. ESI [M+H]⁺ = 334.0 (LCMS).

Step 4: (3-(4-Fluoro-3-methoxy-5-(trifluoromethyl)phenyl)isoxazol-5-yl)methanol (1992-4) [0258] To a solution of 1992-3 (490 mg, 1.5 mmol) in THF (20 mL) was added NaBH₄ (139 mg, 3.7 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. TLC indicated that the starting material was completely consumed and one new spot formed. The reaction mixture was poured into saturated NH₄CI aqueous 20 mL and extracted with EtOAc (5.0 mL x 5). The combined organic layers were washed with brine (5.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 1992-4 (400 mg, 1.4 mmol) as a white solid.

Step 5: 5-(Chloromethyl)-3-(4-fluoro-3-methoxy-5-(trifluoromethyl) phenyl) isoxazole (1992-5)

[0259] To a solution of 1992-4 (200 mg, 687 μmol) in CHCl₃ (5.0 mL) was added SOCl₂ (270 mg, 2.3 mmol) and DMF (5.02 mg, 68.68 μmol). The mixture was stirred at 65 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 10 mL and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 1992-5 (150 mg, 484 μmol) as a yellow solid. ESI [M+H]⁺ = 310.0 (LCMS).

Step 6: 2-Ethyl-3-((3-(4-fluoro-3-methoxy-5-(trifluoromethyl) phenyl) isoxazol-5-yl) methyl)-6-phenylpyrimidin-4(3H) -one (1992-6)

[0260] To a solution of 2-ethyl-6-phenylpyrimidin-4(3H) -one (97 mg, 484 μmol), K₂CO₃ (335 mg, 2.4 mmol) and Nal (7 mg, 48 μmol) in acetone (5.0 mL) was added 1992-5 (150 mg, 484 μmol, 1 eq). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 10 mL and extracted with EtOAc (5.0 mL x 2), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 1992-6 (60 mg, 126.74 μmol) as a white solid. ESI [M+H]⁺ = 474.1 (LCMS).

Step 7: 2-Ethyl-3-((3-(4-fluoro-3-hydroxy-5-(trifluoromethyl) phenyl) isoxazol-5-yl) methyl)-6-phenylpyrimidin-4(3H) -one (1992)

[0261] To a solution of 1992-6 (60 mg, 127 μmol) in DCM (6.0 mL) was added a solution of BBr.3 (318 mg, 1.3 mmol, 122.12 p.L) in DCM (3.0 mL) at -70 °C. The mixture was stirred at 20 °C for 2.5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give Compound 1992 (19.9 mg, 43 μmol) as a white solid. ESI [M+H]⁺ = 460.0 (LCMS);¹H NMR (400 MHz, DMSO-d₆) 5 = 11.21 - 10.89 (m, 1H), 8.19 - 8.11 (m, 2H), 7.77 (dd, J = 2.0, 7.9 Hz, 1H), 7.63 - 7.58 (m, 1H), 7.55 - 7.44 (m, 3H), 7.19 (s, 1H), 7.00 (s, 1H), 5.48 (s, 2H), 2.95 (q, J = 7.2 Hz, 2H), 1.33 (t, J = 7.2 Hz, 3H).

Example 10: 5-Fluoro-4-hydroxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazo lin- 3(4H) -yl)methyl)isoxazol-5-yl)benzonitrile (2003)

Step 1: 2-Bromo-5-fluoro-4-methoxyaniline (2003-2)

[0262] To a solution of 2003-1 (12.5 g, 88.6 mmol) in DCM (40 mL) was added Br2 (14.2 g, 88.6 mmol, 4.6 mL) and K₂CO₃ (12.9 g, 93.0 mmol) in DCM (80 mL) at -15 °C. The resulting mixture was stirred at 25 °C for 16 h. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2003-2 (23.0 g, 105 mmol) as a red solid.

Step 2: l-Bromo-4-fluoro-2-iodo-5-methoxybenzene (2003-3)

[0263] To a solution of 2003-2 (6.0 g, 27.3 mmol) in H₂O (150 mL) was added H2SO4 (3.0 g, 30.0 mmol), a solution of NaNO₂ (2.3 g, 32.7 mmol) in H₂O (50 mL) was added, and the mixture was dripped in about 1 h. Stirring was continued for 1 h. A solution of KI (5.9 g, 35.5 mmol) in H₂O (50 mL) was added. The mixture was stirred at 25 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2003-3 (2.2 g, 6.7 mmol) as a white solid¹.H NMR (400 MHz, CHLOROFORM-d) δ = 7.51 (d, J= 10.4 Hz, 1H), 7.21 (d, J= 8.0 Hz, 1H), 3.87 (s, 3H).

Step 3: 2-Bromo-5-fluoro-4-methoxybenzonitrile (2003-4)

[0264] To a solution of 2003-3 (2.2 g, 6.7 mmol) in DMF (40 mL) was added CuCN (655 mg, 7.3 mmol, 1.6 mL) under N2. The resulting mixture was stirred at 110 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (30 mL x 3). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether at 25 °C for 15 min. Compound 2003-4 (2.0 g, crude) was obtained as a white solid¹.H NMR (400 MHz, CHLOROFORM-d) δ = 7.36 (d, J= 10.3 Hz, 1H), 7.22 (d, J= 7.5 Hz, 1H), 3.97 (s, 3H)

Step 4: Ethyl 5-(2-cyano-4-fluoro-5-methoxyphenyl)isoxazole-3-carboxylate (2003-5)

[0265] To a solution of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (1.5 g, 3.5 mmol) and 2003-4 (0.8 g, 3.5 mmol) in Tol. (30 mL), was added Pd(t-Bu₃P)₂ (178 mg, 348 umol), then the mixture was stirred at 90 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2003-5 (550 mg, 1.89 mmol) as a white solid.

Step 5: 5-Fluoro-2-(3-(hydroxymethyl)isoxazol-5-yl)-4-methoxybenzonitrile (2003-6)

[0266] To a solution of 2003-5 (550 mg, 1.9 mmol) in THF (16 mL), was added NaBH₄ (179.2 mg, 4.7 mmol) at 0 °C, then the mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2003-6 (120 mg, 483.5 μmol) as a white solid.

Step 6: 2-(3-(Chloromethyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2003-7)

[0267] To a solution of 2003-6 (120 mg, 483.5 umol) in CHCI3 (5 mL) was added SOCh (575.2 mg, 4.8 mmol, 350.7 μL) and DMF (3.5 mg, 48.4 μmol, 3.7 μL), the mixture was stirred at 70 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (15 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude 2003-7 (120 mg, crude) as a white solid.

Step 7: 5-Fluoro-4-methoxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquina zolin-3(4H) - yl)methyl)isoxazol-5-yl)benzonitrile (2003-8)

[0268] To a solution of 2003-7 (120 mg, 450.0 μmol) and 2-methyl-5,6,7,8-tetrahydroquinazolin- 4(3H) -one (73.9 mg, 450.0 μmol), in ACETONE (4.0 mL) was added K₂CO₃ (373.2 mg, 2.7 mmol), Nal (6.8 mg, 45.0 μmol). The reaction was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2003- 8 (110 mg, 278.91 μmol) was obtained as a white solid. 'HNMR (400 MHz, CHLOROFORM-d) 8 = 7.63- 7.47 (m, 2H), 7.31 (s, 1H), 5.58 (s, 2H), 4.05 (s, 3H), 2.77 (m, 2H), 2.60 - 2.57 (m, 5H), 1.85 -1.79 (m, 4H).

Step 8: 5-Fluoro-4-hydroxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin- 3(4H) - yl)methyl)isoxazol-5-yl)benzonitrile (2003)

[0269] To a solution of 2003-8 (110.0 mg, 278.9 μmol) in DCM (4.0 mL) was added BBr.3 (698.7 mg, 2.8 mmol, 268.7 μL) in DCM (1.0 mL) at -78 °C under N2, after 1 h, the mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was concentrated to get crude residue. The residue was purified by prep-HPLC to give Compound 2003 (39.7 mg, 104.4 umol) as an off white solid. ESI [M+H]⁺ = 381.0 (LCMS);

NMR (400 MHz, METHANOL-d₄) 5 = 7.70 (d, J= 10.6 Hz, 1H), 7.50 (d, J= 8.3 Hz, 1H), 7.13 (s, 1H), 5.48 (s, 2H), 2.74 (s, 3H), 2.64 (br t, J = 6.0 Hz, 2H), 2.50 (br t, J = 4.6 Hz, 2H), 1.95 - 1.72 (m, 4H)

Example 11: 5-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxaz ol-5- yl)-2-fluoro-3-hydroxybenzonitrile (2021)

Step 1: 5-Bromo-2-fluoro-3-methoxybenzaldehyde (2021-2)

[0270] To a solution of A-isopropylpropan-2-amine (3.2 g, 32 mmol) in THF (50 mL) was added n-BuLi (2.5 M, 10.7 mL) at -78 °C, then the mixture was stirred at 0 °C for 10 min, 2021-1 (5 g, 24 mmol) in THF (5 mL) was added at -78 °C, after 0.5 h, DMF (2.0 g, 27 mmol) was added at - 78 °C, then the mixture was stirred at 20 °C for 1 h. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (30 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021-2 (5 g, crude) was obtained as white oil.^JH NMR (400 MHz, CHLOROFORM-d) 6 = 10.32 (s, 1H), 7.55 (dd, J = 2.4, 5.0 Hz, 1H), 7.30 (dd, J = 2.3, 7.5 Hz, 1H), 3.94 (s, 3H)

Step 2: (E)-5-bromo-2-fluoro-3-methoxybenzaldehyde oxime (2021-3)

[0271] To a solution of 2021-2 (2.5 g, 11 mmol) in EtOH (30 mL) was added NH₂OH.HCI (895 mg, 13 mmol), Py (1.3 g, 16 mmol), then the mixture was stirred at 70 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021-3 (3 g, crude) was obtained as a white solid. ESI [M+H]⁺= 248.0 (LCMS) Step 3: 5-Bromo-2-fluoro-3-methoxybenzonitrile (2021-4)

[0272] To a solution of 2021-3 (2.3 g, 9 mmol) in DMSO (40 mL) was added K₂CO₃ (2.6 g, 18 mmol), AC2O (1.9 g, 18 mmol), then the mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021- 4 (2 g, crude) was obtained as a white solid.

Step 4: Ethyl 5-(3-cyano-4-fluoro-5-methoxyphenyl)isoxazole-3-carboxylate (2021-5)

[0273] To a solution of ethyl 5-(tributylstannyl)isoxazole-3-carboxylate (4 g, 10 mmol) in Tol. (60 mL) was added 2021-5 (2 g, 8.7 mmol), Pd(t-Bu₃P)₂ (444 mg, 869 μmol), then the mixture was stirred at 90 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021-5 (2 g, crude) was obtained as a white solid. ESI [M+H]⁺ = 291.2 (LCMS).

Step 5: 2-Fluoro-5-(3-(hydroxymethyl)isoxazol-5-yI)-3-methoxybenzonitrile (RG N-2021-6) [0274] To a solution of 2021-5 (1 g, 3.5 mmol) in THF (30 mL) was added NaBH₄ (326 mg, 8.6 mmol) at 0 °C. The mixture was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (30 mL) and extracted with EtOAc (15 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021-6 (1.5 g, crude) as a white solid. ESI [M+H]⁺= 249.1 (LCMS).

Step 6: 5-(3-(Chloromethyl)isoxazol-5-yl)-2-fluoro-3-methoxybenzonitrile (2021-7)

[0275] To a solution of 2021-6 (1 g, 4 mmol) in CHCI3 (35 mL) was added SOCI2 (1.5 g, 12 mmol), DMF (29 mg, 403 μmol), then the mixture was stirred at 70 °C for 1 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to give Compound 2021-7 (1 g, crude) as a white solid. ESI [M+H]⁺= 267.2 (LCMS)

Step 7 : 5-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxa zol-5-yl)-2-fluoro-3-methoxybenzonitrile (2021-8)

[0276] To a solution of 2021-7 (300 mg, 1.1 mmol), 2-ethyl-5,6,7,8-tetrahydroquinazolin-4 (3H) - one (200 mg, 1.1 mmol) in acetone (15 mL) was added Nal (17 mg, 112 μmol), K₂CO₃ (777 mg, 5.6 mmol), then the mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2021-8 (300 mg, crude) as a white solid. ESI [M+H]⁺ = 409.3 (LCMS);¹ H NMR (400 MHz, DMSO-d₆) δ = 8.00 (dd, J = 1.9, 5.1 Hz, 1H), 7.96 - 7.91 (m, 1H), 7.14 (s, 1H), 5.34 (s, 2H), 4.00 (s, 2H), 2.79 (q, J = 7.3 Hz, 2H), 2.43 - 2.33 (m, 2H), 1.81 - 1.63 (m, 5H), 1.20 - 1.15 (m, 3H).

Step 8: 5-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4Z/)-yl)methyl)Isoxazol- 5-yl)-2- fluoro-3-hydroxybenzonitrile (2021)

[0277] To a solution of 2021-8 (200 mg, 490 μmol) in DCM (10 mL) was added BBn (1.8 g, 7.4 mmol) in DCM (2 mL) at -78 °C, after 1 h, the mixture was stirred at 20°C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2021 (40 mg, 87 μmol) as a white solid. ESI [M+H]⁺ = 395.0 (LCMS);¹ HNMR (400 MHz, DMSO-d₆) δ = 11.52 - 11.08 (m, 1H), 7.91 (dd, J = 1.9, 4.8 Hz, 1H), 7.69 (dd, J = 1.8, 8.1 Hz, 1H), 7.05 (s, 1H), 5.32 (s, 2H), 2.79 (q, J = 7.2 Hz, 2H), 2.58 - 2.53 (m, 2H), 2.40 - 2.30 (m, 2H), 1.83 - 1.60 (m, 4H), 1.17 (t, J = 7.3 Hz, 3H).

Example 12: 2-(3-((2-ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxaz ol-5- yl)-5-fluoro-4-hydroxybenzonitrile (2033-02N)

Step 1: 2-Bromo-5-fluoro-4-methoxybenzonitrile (2033-02N-2)

[0278] To a solution of 2033-02N-1 (100 g, 458.7 mmol) and NaOMe (17.4 g, 321.1 mmol) in MeOH (2000 mL), the mixture was stirred at 70 °C for 12 h. TLC indicated the reaction was completed. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (2000 mL) and then the precipitate was separate out. The reaction mixture was filtered and the filter cake was washed with 500 mL of H₂O, dried in vacuum to give a crude product. The crude product and mother solution was triturated with Petroleum ether:EtOAc=10: l. Compound 2033-02N-2 (120 g, 521.7 mmol) was obtained as a white solid.

Step 2: Ethyl 5-(2-cyano-4-fluoro-5-methoxyphenyl)isoxazole-3-carboxylate (2033-02N-3) [0279] To a solution of 2033-02N-2 (40.0 g, 173.9 mmol) and ethyl 5-(tributylstannyl) isoxazole- 3-carboxylate (89.8 g, 208.7 mmol) in Tol. (400 mL) was added Pd(t-Bu₃P)₂ (8.9 g, 17.4 mmol) under N2. The mixture was stirred at 90 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (400 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum ether:EtOAc =5: 1. Compound 2033-02N-3 (100 g, 344.5 mmol) was obtained as a white solid Step 3: 5-Fluoro-2-(3-(hydroxymethyl)isoxazol-5-yl)-4-inethoxybenzonitrile (2033-02N-4) [0280] To a solution of 2033-02N-3 (60.0 g, 206.7 mmol) in THF (1000 mL)/MeOH (100 mL) at 0 °C, was added NaBH₄ (23.5 g, 620.2 mmol), the mixture was stirred at 20 °C for 1 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (1000 mL) and then the precipitate was separate out. The crude product was triturated with Petroleum ether at 25 °C for 15 min. Compound 2033-02N-4 (43 g, crude) was obtained as a white solid.1H NMR (400 MHz, CHLOROFORM-d) δ = 7.60 (d, J= 7.9 Hz, 1H), 7.52 - 7.45 (m, 1H), 7.22 (s, 1H), 4.87 (s, 2H), 4.09 - 4.02 (m, 3H), 2.53 - 2.07 (m, 1H)

Step 4: Ethyl 2-(3-(chloromethyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2033-02N- 5)

[0281] To a solution of 2033-02N-4 (43.0 g, 225.6 mmol) in CHCl₃ (1300 mL) was added SOC1₂ (268.4 g, 2.3 mol, 163.7 mL) and DMF (4.3 g, 58.2 mmol, 4.5 mL), then the mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The mixture was concentrated under reduced pressure to give crude 2033-02N-5 (43 g, crude) as a brown solid.

Step 5: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)niethyl)isoxazol-5 -yl)-5- fluoro-4-methoxybenzonitrile (2033-02N-6)

[0282] To a solution of 2033-02N-5 (15.0 g, 56.3 mmol) and 2-ethyl-5,6,7,8 - tetrahydroquinazolin-4(3H) -one (10.0 g, 56.3 mmol) in dioxane (600 mL) was added t-BuOK (9.5 g, 84.4 mmol) and Nal (843.2 mg, 5.6 mmol). The mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (800 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with Petroleum etherEtOAc =1 : 1. Compound 2033-02N-6 (25 g, 85.7 mmol) was obtained as a pale yellow solid.

Step 6: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxazol-5 -yl)-5- fluoro-4-hydroxybenzonitrile (2033-02N)

[0283] To a solution of 2033-02N-6 (12.0 g, 29.4 mmol) in DCM (240 mL) was added BBr₃ (220.8 g, 881.4 mmol, 84.9 mL) in DCM (100 mL) at -78 °C under N2, the mixture was stirred at 25 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was concentrated to get crude residue. The crude product was purified by re-crystallization from MeCN/MeOH (200 mL/50 ml) at 90 °C for 4 h. Compound 2033-02N (13 g, 31.3 mmol) was obtained as an off-white solid. ESI [M+H]⁺= 395.3 (LCMS);¹H NMR (400 MHz, DMSO-d₆) 5 = 8.00 (d, J= 10.9 Hz, 1H), 7.48 (d, J= 8.3 Hz, 1H), 7.09 (s, 1H), 5.36 (s, 2H), 2.80 (q, J= 7.3 Hz, 2H), 2.50 (br s, 2H), 2.35 (br s, 2H), 1.77 - 1.57 (m, 4H), 1.17 (t, J= 7.3 Hz, 3H).

Example 13: 5-Fluoro-4-hydroxy-2-(3-((2,4,5-triethyl-6-oxopyrimidin-l(6//)-yl)methyl)i soxazol-5-yl)benzonitrile (2037)

Step 1: Ethyl 2-ethyl-3-oxopentanoate (2037-2)

[0284] To a solution of 2037-1 (5.0 g, 34.7 μmol, 5.0 mL) in EtOH (100 mL) was added NaOEt (2.4 g, 34.7 mmol), the reaction mixture was heated to 80 °C. lodoethane (6.0 g, 38.2 mmol) was added to the resulting mixture dropwise at 80 °C. Then the mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with H₂O (30 mL) and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure to give crude Compound 2037-2 (4.0 g) as a white solid.

Step 2: 2,5,6-Triethylpyrimidin-4(3H) -one (2037-3)

[0285] To a solution of NaOMe (282.3 mg, 5.2 mmol) in MeOH (15 mL) was added 2037-2 (450 mg, 2.6 mmol) and propionimidamide (312.1 mg, 2.87 mmol, HC1 salt). The mixture was stirred at 70 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure to give crude Compound 2037-3 (150 mg) as a white solid¹.H NMR (400 MHz, CHLOROF ORM-d) δ = 2.72 - 2.50 (m, 6H), 1.33 (t, J = 1.6 Hz, 3H), 1.25 - 1.20 (m, 3H), 1.12 (t, J= 7.5 Hz, 3H)

Step 3: 5-Fluoro-4-methoxy-2-(3-((2,4,5-triethyl-6-oxopyrimidin-l(6//)-yl)methyl) isoxazol- 5-yl)benzonitrile (2037-4)

[0286] To a solution of 2037-3 (150.0 mg, 832.2 μmol) and 2-(3-(chloromethyl)isoxazol-5-yl) -5- fluoro-4-methoxybenzonitrile (221.9 mg, 832.2 μmol) in dioxane (6.0 mL) was added t-BuOK (140.7 mg, 1.3 mmol) and Nal (12.5 mg, 83.2 μmol). The reaction mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc at 20 °C for 15 min. Compound 2037-4 (90 mg, 219.3 μmol) was obtained as a white solid.^XH NMR (400 MHz, CHLOROFORM-d) δ = 7.60 - 7.40 (m, 2H) , 7.19 - 7.09 (m, 1H) , 5.40 - 5.27 (m, 2H) , 4.02 (s, 3H) , 2.88 (d, J= 7.4 Hz, 2H) , 2.57 (dd, J = 5.8, 7.4 Hz, 4H) , 1.34 (t, J = 7.3 Hz, 3H) , 1.23 (t, J= 7.5 Hz, 3H) , 1.12 (t, J= 7.5 Hz, 3H).

Step 4: 5-Fluoro-4-hydroxy-2-(3-((2,4,5-triethyl-6-oxopyrimidin-l(67/)-yl)methyl) isoxazol- 5-yl)benzonitrile (2037)

[0287] To a solution of 2037-4 (90 mg, 219.3 μmol) in DCM (3 mL) was added BBr, (1.7 g, 6.6 mmol, 633.9 μL) in DCM (1.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2037 (19.2 mg, 48.4 μmol) as a white solid. ESI [M+H]⁺= 397.3 (LCMS);¹H NMR (400 MHz, CHLOROFORM- d) δ = 7.52 - 7.38 (m, 2H) , 7.04 (s, 1H) , 5.35 (s, 2H) , 2.86 (d, J = 7.4 Hz, 2H) , 2.71 - 2.51 (m, 4H) , 1.35 (t, J = 7.3 Hz, 3H) , 1.26 (t, J = 7.5 Hz, 3H) , 1.13 (t, J= 7.4 Hz, 3H) Example 14: 5-Fluoro-4-hydroxy-2-(3-((4-oxo-2-propyl-5,6,7,8-tetrahydroquinazoli n- 3(4H) -yl)methyl)isoxazol-5-yl)benzonitrile (2038)

Step 1: 2-Propyl-5,6,7,8-tetrahydroquinazolin-4(3H) -one (2038-2)

[0288] To a solution of NaOEt (799.6 mg, 11.8 mmol) in EtOH (12 mL) was added butyrimidamide (792.3 mg, 6.5 mmol, HC1 salt) and 2038-1 (1.0 g, 5.9 mmol). The mixture was stirred at 70°C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine 30 mL and extracted with DCM (20 mL x 3). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2038-2 (0.6 g, crude) as a yellow solid. ESI [M+H] = 193.3 (LCMS)

Step 2: 5-Fluoro-4-methoxy-2-(3-((4-oxo-2-propyl-5,6,7,8-tetrahydroquinazolin-3 (4H) - yl)methyl)isoxazol-5-yl)benzonitrile (2038-3)

[0289] To a solution of 2038-2 (216.3 mg, 1.1 mmol) in dioxane (6.0 mL) was added t-BuOK (189.4 mg, 1.7 mmol), Nal (16.9 mg, 112.5 μmol) and 2-(3-(chloromethyl)isoxazol-5-yl)-5-f luoro-4-methoxybenzonitrile (300.0 mg, 1 .1 mmol). The resulting mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (6.0 mL) and extracted with DCM (3.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 2038-3 as a yellow solid. ESI [M+H]⁺ = 423.3 (LCMS) Step 3: 5-Fluoro-4-hydroxy-2-(3-((4-oxo-2-propyl-5,6,7,8-tetrahydroquinazolin-3 (477)- yl)methyl)isoxazol-5-yl)benzonitrile (2038)

[0290] To a solution of 2038-3 (100 mg, 236.7 μmol) in DCM (10.0 mL) was added a solution of BBr₃ (593.1 mg, 2.4 mmol, 228.1 μL) in DCM (2.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2038 (27.4 mg, 67.0 μmol) as a white solid. ESI [M+H]⁺ = 409.3 (LCMS); *H NMR (400 MHz, DMSO-d₆) δ = 7.99 (d, J= 10.9 Hz, 1H), 7.48 (d, J= 8.3 Hz, 1H), 7.09 (s, 1H), 5.36 (s, 2H), 2.74 (t, J= 7.5 Hz, 2H), 2.50 (br t, J= 5.6 Hz, 2H) 2.35 (br t, J= 5.6 Hz, 2H), 1.79 - 1.48 (m, 6H), 0.93 (t, J = 7.4 Hz, 3H)

Example 15: 2-(3-((2-ethyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3 (4H) -yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2039)

Step 1: tert- Butyl 2-ethyl-4-oxo-3, 5, 7, 8-tetrahydropyrido [4, 3-d] pyrimidine -6(4H) - carboxylate(2039-2)

[0291] To a solution of 2039-1 (1 g, 3.7 mmol) and propanamidine (440.2 mg, 4.1 mmol, HC1 salt) in MeOH (15 mL) was added NaOMe (398.3 mg, 7.4 mmol). The mixture was stirred at 60 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (25 mL) and extracted with EtOAc (10 mLx 5). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2039-2 (1.0 g, 3.7 mmol) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ = 4.10 (s, 2H), 3.53 (br t, J= 5.7 Hz, 3H), 2.50 - 2.44 (m, 3H), 1.42 (s, 9H), 1.15 (t, J= 7.6 Hz, 3H).

Step 2: tert- Butyl 3-((5-(2-cyano-4-fluoro-5-methoxy phenyl) isoxazol-3-yl) methyl)-2-ethyl-4- oxo-3,5,7,8-tetrahydropyrido [4, 3-d] pyrimidine-6(4H) -carboxyl ate (2039-3)

[0292] To a solution of the 2039-2 (1.1 g, 3.8 mmol) and 2-(3-(chloromethyl)isoxazol-5-yl) -5- fluoro-4-methoxybenzonitrile (1 g, 3.8 mmol) in dioxane (25 mL) was added t-BuOK (631.2 mg, 5.6 mmol) and Nal (56.2 mg, 375.0 μmol) under N2. The mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (25 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2039-3 (560 mg, 1.1 mmol) as a white solid, ESI [M+H]⁺ = 510.3 (LCMS).

Step 3 : 2-(3-((2-ethyl-4-oxo-5,6,7,8-tetrahy dropyrido [4, 3-d] pyrimidin-3(4H) -yl) methyl)isoxazol-5-yl)-5-fluoro-4-inethoxybenzonitrile (2039-4)

[0293] To a solution of 2039-3 (120 mg, 235.5 μmol) in EtOAc (3.0 mL) was added HCl/EtOAc (4 M, 2.8 mL), the resulting mixture was stirred at 20 °C for 3 h. TLC indicated the reaction was completed and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to give crude Compound 2039-4 (110 mg, HC1 salt) as a yellow solid.

Step 4: 2-(3-((2-ethyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3 (4H)- yl)methyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2039-5)

[0294] To a solution of 2039-4 (30 mg, 73.3 μmol) in MeOH (3 mL) was added TEA (0.1 mL), followed by the addition of formaldehyde (17.8 mg, 219.8 μmol, 16.4 μL). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (17.0 mg, 269.7 μmol) was added, the resulting mixture was stirred at 20 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was diluted with NaHCCL aqueous 0.1 mL concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 2039-5 (20 mg, 47.2 μmol) as a white solid.

Step 5: 2-(3-((2-ethyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3 (4H) - yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2039)

[0295] To a solution of 2039-5 (20 mg, 47.2 μmol) in DCM (2.0 mL) was added BBrs (354.9 mg, 1.4 mmol, 136.5 μL) in DCM (0.6 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2039 (10 mg, 24.4 μmol) as a yellow solid, ESI [M+H]⁺ = 410.1 (LCMS);¹H NMR (400 MHz, METHANOL-d₄) 5 = 7.60 (d, J = 10.6 Hz, 1H), 7.41 (d, J= 8.4 Hz, 1H), 7.04 (s, 1H), 5.45 (s, 2H), 3.52 (s, 2H), 2.97 - 2.87 (m, 4H), 2.85 - 2.77 (m, 2H), 2.58 (s, 3H), 1.30 (t, J= 7.4 Hz, 3H).

Example 16: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4H) yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2040)

Step 1: rt-Butyl 3-((5-(2-cyano-4-fluoro-5-methoxyphenyl) isoxazol-3-yl)methyl) -2-ethyl-4- oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4H) -carboxylate(2040-2) [0296] To a solution of the 2040-1 (1.1 g, 3.8 mmol) and 2-(3-(chloromethyl)isoxazol-5-yl)-5 - fluoro-4-methoxybenzonitrile (1.0 g, 3.8 mmol) in dioxane (25 mL) was added t-BuOK (631.2 mg, 5.6 mmol) and Nal (56.2 mg, 375.0 μmol) under N2. The mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into water 40 mL and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2040-2 (560 mg, 1.1 mmol,) as a white solid, ESI [M+H]⁺ =

510.4 (LCMS).

Step 1 : 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahy dropyrido [4, 3-d] pyrimidin-3(4H) -yl) methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2040)

[0297] To a solution of 2040-2 (58 mg, 113.8 μmol) in DCM (6 mL) was added BBrs (855.5 mg,

3.4 mmol, 329.04 μL) in DCM (0.6 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2040 (15 mg, 37.94 μmol) was obtained as a yellow solid. ESI [M+H]⁺ = 396.1 (LCMS),¹HNMR (400 MHz, DMSO-d₆) δ = 7.61 (d, J= 11.5 Hz, 1H), 7.10 (d, J= 8.5 Hz, 1H), 6.98 (s, 1H), 5.37 (s, 2H), 3.66 (br s, 2H), 3.07 (br t, J = 5.6 Hz, 2H), 2.83 (q, J = 7.1 Hz, 2H), 2.59 (br s, 2H), 1.18 (t, J = 7.3 Hz, 3H)

Example 17: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H) yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2041)

Step 1: tert- Butyl 2-ethyl-4-oxo-4,5,6,8-tetrahydropyrido[3,4-<Z|pyrimidine-7(3H) -ca rboxylate(2041-2)

[0298] To a solution of the 2041-1 (2.0 g, 7.4 mmol), propionimidamide (800.3 mg, 7.3 mmol, HC1 salt) in MeOH (12 mL) and H₂O (4.0 mL) was added K₂CO₃ (2.0 g, 14.7 mmol) under N2, the resulting mixture was stirred at 70 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine (10 mL) and extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to give crude Compound 2041-2 (1.4 g) as a white solid. ESI [M+H]⁺ = 280.1 (LCMS);¹ H NMR ((400 MHz, DMSO-d₆) δ = 4.17 (s, 2H), 3.49 (br t, J = 5.4 Hz, 4H), 2.49 - 2.44 (m, 2H), 2.35 (br t, J = 5.6 Hz, 2H), 1.41 (s, 9H), 1.14 (t, J = 7.6 Hz, 3H).

Step 2: tert-Butyl 3-((5-(2-cyano-4-fluoro-5-methoxyphenyl)isoxazol-3-yl)met hyl)-2-ethyl-4- oxo-4,5,6,8-tetrahydropyrido[3,4-d]pyrimidine-7(3H) -carboxylate(2041-3)

[0299] To a solution of 2041-2 (477 mg, 1.8 mmol) and 2-(3-(chloromethyl)isoxazol-5-yl)-5- fluoro-4-methoxybenzonitrile (500.0 mg, 1.8 mmol) in dioxane (20 mL) was added t-BuOK (301.3 mg, 2.7 mmol) and Nal (26.8 mg, 179 μmol), the resulting mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (10 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2041-3 (450 mg, 883.17 μmol) as a yellow solid. ESI [M+H]⁺ = 510.3 (LCMS) Step 3: 2-(3-((2-Ethyl-4-oxo-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-3(4H) -yl) methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2041)

[0300] To a solution of 2041-3 (110 mg, 196.2 μmol) in DCM (10.0 mL) was added a solution of BBr? (491.7 mg, 2.0 mmol, 189.1 μL) in DCM (2.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2041(17.9 mg, 44.8 μmol) as a white solid, ESI [M+H]⁺ = 396.3 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 8.19 (s, 1H), 7.71 (d, J = 11.5 Hz, 1H), 7.21 (d, J = 8.5 Hz, 1H), 7.01 (s, 1H), 5.38 (s, 2H), 3.76 (s, 2H), 3.05 (br t, J = 5.6 Hz, 2H), 2.83 (q, J = 7.3 Hz, 2H), 2.48 - 2.40 (m, 2H), 1.17 (t, J = 7.3 Hz, 3H).

Example 18: 2-(3-((2-Ethyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin -3(4H) -yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile(2042)

Step 1: 2-(3-((2-Ethyl-6-methyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-rZ]pyramidin-3 (4H) - yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile(2042)

[0301] To a solution of 2041(100.0 mg, 252.9 μmol) in MeOH (5.0 mL) was added TEA (O.lmL), followed by the addition of formaldehyde (22.3 mg, 758.8 μmol). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBH₃CN (79.5 mg, 1.3 mmol) was added. The resulting reaction mixture was stirred at 20 °C for another 10 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was NaHCO₃ aqueous (0.1 mL) and concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 2042 (11.8 mg, 28.8 μmol) as a white solid. ESI [M+H]⁺ = 410.4 (LCMS)¹;H NMR (400 MHz, METHANOL-d4) δ = 8.29 (br s, 1H), 7.66 (d, J= 10.6 Hz, 1H), 7.46 (d, J= 8.1 Hz, 1H), 7.08 (s, 1H), 5.46 (s, 2H), 3.74 (br s, 2H), 3.05 (br t, J= 5.3 Hz, 2H), 2.93 (q, J= 7.3 Hz, 2H), 2.78 - 2.64 (m, 5H), 1.30 (t, J= 7.3 Hz, 3H).

Example 19: 2-(3-((2,6-Diethyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4H) -yl)me thyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2043)

Stepl: 2-(3-((2,6-Diethyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4H) yl)methy l)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2043)

[0302] To a solution of 2041(100 mg, 252.9 μmol) in MeOH (5.0 mL) was added TEA (O.lmL), followed by the addition of acetaldehyde (33.4 mg, 758.8 μmol). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBH₃CN (79.5 mg, 1.3 mmol) was added. The resulting reaction mixture was stirred at 20 °C for another 10 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was NaHCO₃ aqueous (0.1 mL) and concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 2043 (10.4 mg, 24.6 μmol) as a white solid. ESI [M+H]⁺ = 424.4 (LCMS); ' H NMR (400 MHz, METHANOL-d4) δ = 8.36 (s, 1H), 7.63 (d, J = 10.6 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.07 (s, 1H), 5.46 (s, 2H), 3.75 (s, 2H), 3.10 - 3.01 (m, 2H), 2.93 (q, J= 7.3 Hz, 4H), 2.72 (br t, J= 5.7 Hz, 2H), 1.30 (dt, J= 3.3, 7.3 Hz, 6H).

Example 20: 2-(3-((2-Ethyl-6-isopropyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4 H)-yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2044)

Stepl: 2-(3-((2-Ethyl-6-isopropyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3 (4H) - yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2044)

[0303] To a solution of 2041(100 mg, 252.9 μmol) in MeOH (5.0 mL) was added TEA (O.lmL), followed by the addition of acetone (44.1 mg, 758.8 μmol). The resulting mixture was treated with a small amount of AcOH to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBHsCN (79.5 mg, 1.3 mmol) was added. The resulting reaction mixture was stirred at 20 °C for another 10 h. LCMS indicated that the starting material was completely consumed and the desired mass was detected. The mixture was NaHCO₃ aqueous (0.1 mL) and concentrated under vacuum to give a residue which was purified by prep-HPLC to give Compound 2044 (16.4 mg, 37.2 μmol) as a white solid, ESI [M+H]⁺ = 438.4 (LCMS);¹HNMR (400 MHz, METHANOL-d4) δ = 8.40 (s, 1H), 7.61 (d, J= 10.8 Hz, 1H), 7.41 (d, J= 8.3 Hz, 1H), 7.05 (s, 1H), 5.46 (s, 2H), 3.87 (s, 2H), 3.36 - 3.32 (m, 1H), 3.15 (br t, J= 5.7 Hz, 2H), 2.93 (q, J = 7.3 Hz, 2H), 2.73 (br t, J= 5.5 Hz, 2H), 1.36 - 1.21 (m, 9H).

Example 21: 2-(3-((2,6-diethyl-4-oxo-5,6,7,8-tetrahydropyrido [4.3-d|pyrimidin-3(4H) - yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2045)

Step 1: tert-Butyl 3-((5-(2-cyano-4-fluoro-5-methoxyphenyl) isoxazol-3-yl)methy l)-2-ethyl-4- oxo-3,5,7,8-tetrahydropyrido[4,3-d]pyrimidine-6(4H) -carboxylate(2045-2)

[0304] To a solution of the 2045-1 (1.1 g, 3.8 mmol) and 2-(3-(chloromethyl)isoxazol-5-yl)-5 - fluoro-4-methoxybenzonitrile (1.0 g, 3.8 mmol) in dioxane (25 mL) was added t-BuOK (631.2 mg, 5.6 mmol) and Nal (56.2 mg, 375.0 μmol) under N2. The mixture was stirred at 80 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 25 mL and extracted with EtOAc (10 mL x 8). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2045-2 (560 mg, 1.1 mmol) as a white solid. ESI [M+H]⁺ = 509.2(LCMS).

Step 2: 2-(3-((2-ethyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4Z7) yl)methyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2045-3)

[0305] To a solution of 2045-2 (120 mg, 235.5 μmol) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 2.8 mL), the resulting mixture was stirred at 20 °C for 3 h. TLC indicated Reactant 1 was consumed completely and one new spot formed. The reaction was clean according to TLC. The reaction mixture was concentrated under reduced pressure to give crude Compound 2045-3 (110 mg, HC1 salt) as a yellow solid.

Step 3: 2-(3-((2,6-diethyl-4-oxo-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-3(4H) yl)methyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2045-4)

[0306] To a solution of 2045-3 (60 mg, 146.6 μmol) and EtI (45.7 mg, 293.1 μmol, 23.4 μL) in DMF (2.0 mL) was added NaH (14.7 mg, 366.4 μmol, 60 % purity) at 0 °C and stirred for 0.5 h. Then the mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into brine (6 mL) and extracted with EtOAc (3.0 mL x 4). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 2045-4 (40 mg, 91.4 μmol) was obtained as a white solid. ESI [M+H]⁺= 438.3 (LCMS)

Step 4: 2-(3-((2,6-Diethyl-4-oxo-5,6,7,8-tetrahydropyrido [4, 3-d] pyrimidin-3(4H) - yl)methyl)isoxazoI-5-yl)-5-fluoro-4-hydroxybenzonitrile (2045) [0307] To a solution of 2045-4 (40 mg, 91.4 μmol) in DCM (3.0 mL) was added BBr? (687.2 mg, 2.7 mmol, 264.3 μL) in DCM (4 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O drop wise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2045 (5.2 mg, 12.3 μmol, 13.4% yield, 100% purity) was obtained as a white solid, ESI [M+H]⁺= 424.2 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 7.89 (br d, J= 11.4 Hz, 1H), 7.42 - 7.35 (m, 1H), 7.07 (s, 1H), 5.38 (s, 2H), 3.25 (br s, 2H), 2.82 (q, J= 7.3 Hz, 2H), 2.64 (br dd, J= 4.4, 12.4 Hz, 4H), 2.57 - 2.52 (m, 2H), 1.18 (t, J= 7.3 Hz, 3H), 1.07 (t, J= 7.1 Hz, 3H).

Example 22: 2-(3-((2-EthyI-6-isopropyI-4-oxo-5, 6, 7, 8-tetrahydropyrido[4, 3-d]py rimidin- 3(4J/)-yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2046)

Step 1: 2-(3-((2-Ethyl-4-oxo-5, 6, 7, 8-tetr ahydropyrido [4, 3-d] py rimidin-3(4H) -yl)meth yl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2046-1)

[0308] To a solution of 2039-3 (300 mg, 588.7 μmol) in DCM (15.0 mL) was added BBrt (4.4 g, 17.6 mmol) in DCM (7.5 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by flash silica gel chromatography to give Compound 2046-1 (300 mg, 6.0 μmol) as a white solid. ESI [M+H]⁺ = 396.3 (LCMS). Step 2: 2-(3-((2-Ethyl-6-isopropyl-4-oxo-5, 6, 7, 8-tetrahydropyrido[4,3-d]pyrami din-3(4H) - yl)methyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2046)

[0309] To a solution of 2046-1 (0.3 g, 758.7 μmol) and acetone (176.2 mg, 3.0 mmol) in MeOH (6.0 mL) was added HOAc (136.6 mg, 2.2 mmol), the resulting mixture was stirred at 20 °C for 0.5 h. The resulting mixture was added NaBH₃CN (157.3 mg, 2.5 mmol) and stirred at 20 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The mixture was concentrated to get crude residue which was purified by prep-HPLC to give Compound 2046 (28.2 mg, 64.6 μmol) was obtained as a white solid. ESI [M+H]⁺ = 438.2 (LCMS).;¹ H NMR (400 MHz, DMSO-d₆) δ = 7.72 (d, J= 11.2 Hz, 1H), 7.25 (d, J= 8.5 Hz, 1H), 6.99 (s, 1H), 5.35 (s, 2H), 3.47 (s, 2H), 3.04 (td, J= 6.4, 12.9 Hz, 1H), 2.89 - 2.82 (m, 2H), 2.82 - 2.77 (m, 2H), 2.66 (br s, 2H), 1.16 (t, J= 13 Hz, 3H), 1.08 (d, J= 6.6 Hz, 6H).

Example 23: 5-Fluoro-4-hydroxy-2-(3-((4-oxo-2-(3,3,3-trifluoropropyl)-5,6,7,8-tetrah ydroquinazolin-3(4H)-yl)methyl)isoxazol-5-yl)benzonitrile (2047)

Step 1: 4,4,4-Trifluorobutanimidamide (2047-2)

[0310] To a solution of NH4CI (943.2 mg, 17.6 mmol) in toluene (20 mL) was added AlMe3 (2 M, 8.8 mL) dropwise at 0 °C. The mixture was stirred at 15 °C for 2 h. the mixture was added 2047- 1 (1.0 g, 5.8 mmol) in toluene (4.0 mL). The mixture was stirred at 80 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was added MeOH (25 mL) dropwise at 0 °C and stirred for 15 min, filtered, filter cake was washed with MeOH (25 mL x 3). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by prep- HPLC to give Compound 2047-2 (580.0 mg, 4.1 mmol) as a white oil. ESI [M+H]⁺ = 157.1 (LCMS).

Step 2: 2-(3,3,3-Trifluoropropyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (2047-3)

[0311] To a solution of the 2047-2 (500.0 mg, 713.7 μmol) in EtOH (15.0 mL) was added NaOEt (97.1 mg, 1.4 mmol) at 20 °C and stirred for 30 min. The resulting mixture was added ethyl 2- oxocyclohexanecarboxylate (133.6 mg, 785.1 μmol) in EtOH (5.0 mL). The resulting mixture was stirred at 100 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2047-3 (300.0 mg, 1.2 mmol) as a white solid. ESI [M+H]⁺= 247.2 (LCMS).

Step 3: 5-Fluoro-4-methoxy-2-(3-((4-oxo-2-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahy droquinazolin-3(4H) -yl)methyl)isoxazol-5-yl)benzonitrile (2047-4)

[0312] To a solution of (2047-3) (100.0 mg, 406.1 μmol) and 2-(3-(chloromethyl)isoxazol-5-yl) - 5-fluoro-4-methoxybenzonitrile (108.3 mg, 406.1 μmol) in acetone (3.0 mL) was added K₂CO₃ (280.6 mg, 2.0 mmol) and Nal (6.0 mg, 40.6 μmol). The mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by prep- TLC to give Compound 2047-4 (50 mg, 104.95 μmol) as a white solid.

Step 4: 5-Fluoro-4-hydroxy-2-(3-((4-oxo-2-(3,3,3-trifluoropropyl)-5,6,7,8-tetrahydroqui nazolin-3(4Jf)-yl)methyl)isoxazol-5-yl)benzonitrile (2047)

[0313] To a solution of 2047-4 (40.0 mg, 83.9 μmol) in DCM (3.0 mL) was added a solution of BBra (631.0 mg, 2.5 mmol) in DCM (1.5 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2047 (14.3 mg, 30.9 μmol) as a pale yellow solid, ESI [M+H]⁺ = 462.8 (LCMS);¹H NMR (400 MHz, METHANOL-d₄) δ = 7.61 (d, J= 10.8 Hz, 1H), 7.43 (d, J= 8.3 Hz, 1H), 7.07 (s, 1H), 5.44 (s, 2H), 3.22 - 3.15 (m, 2H), 2.81 - 2.67 (m, 2H), 2.62 (br t, J= 5.9 Hz, 2H), 2.48 (br t, J= 5.7 Hz, 2H), 1.86 - 1.72 (m, 4H).

Example 23: 2-(3-((2-Ethyl-4-oxo-4,5,6,8-tetrahydro-3H-pyrano[3,4-d]pyrimidin-3-yl)m ethyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2048)

Step 1: 2-EthyI-5,8-dihydro-3H- pyrano[3,4-d]pyrimidin-4(6/7)-one (2048-2)

[0314] To a solution of 2048-1 (500 mg, 2.9 mmol) and propionimidamide (346.8 mg, 3.2 mmol, HC1 salt) in MeOH (20 mL) was added K₂CO₃ (802.7 mg, 5.8 mmol). The mixture was stirred at 70 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give the crude Compound 2048-2 (600 mg) as a white solid. ESI [M+H]⁺ = 181.3 (LCMS).

Step 2: 2-(3-((2-Ethyl-4-oxo-4,5,6,8-tetrahydro-3H -pyrano[3,4-d]pyrimidin-3-yl)methyl) isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2048-3)

[0315] To a solution of 2048-2 (304.1 mg, 1.7 mmol) and 2-(3 -(chloromethyl) isoxazol-5-yl)-5- fluoro-4-methoxybenzonitrile (300 mg, 1.1 mmol) in acetone (10 mL) was added K₂CO₃ (777.4 mg, 5.6 mmol), Nal (16.9 mg, 112.5 μmol). The mixture was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 2048-3 (200 mg, 487.3 μmol) as a yellow solid. ESI [M+H]⁺ = 411.2 (LCMS).

Step 3: 2-(3-((2-Ethyl-4-oxo-4,5,6,8-tetrahydro-3H -pyrano[3,4-d]pyrimidin-3-yl)met hyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2048)

[0316] A mixture of 2048-3 (80 mg, 194.9 μmol,) and Py.HCl (4.6 g, 39.6 mmol) was stirred at 170 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Compound 2048 (16.4 mg, 41.38 μmol) as a yellow solid. ESI [M+H]⁺ = 396.9 (LCMS)¹;H NMR (400 MHz, DMSO-d₆) δ = 11.72 (s, 1H), 8.02 (d, J= 11.0 Hz, 1H), 7.50 (d, J= 8.2 Hz, 1H), 7.12 (s, 1H), 5.40 (s, 2H), 4.37 (s, 2H), 3.83 (t, J= 5.5 Hz, 2H), 2.84 (q, J= 7.3 Hz, 2H), 2.43 (br t, J= 5.2 Hz, 2H), 1.17 (t, J = 7.3 Hz, 3H).

Example 24: 2-(3-((2-Ethyl-4-oxo-7,8-dihydro-4H-pyrano[4,3-d]pyrimidin-3(577)-yl)met hyl)isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2049)

Step 1: 2-Ethyl-3,5,7,8-tetrahydro-4H -pyrano[4,3-d]pyrimidin-4-one (2049-2)

[0317] To a solution of propioni midamide (378.3 mg, 3.5 mmol, HC1 salt) in MeOH (18 mL) and H₂O (6.0 mL) was added 2049-1 (600 mg, 3.5 mmol) and K₂CO₃ (963.3 mg, 7.0 mmol). The mixture was stirred at 70 °C for 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (30 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2049-2 (500 mg, 2.8 mmol) as a white solid. 'HNMR (400 MHz, CHLOROFORM-d) δ = 4.58 (s, 2H), 4.04 - 3.92 (m, 2H), 2.78 - 2.63 (m, 4H), 1.35 (t, J= 7.6 Hz, 3H).

Step 2: 2-(3-((2-Ethyl-4-oxo-7,8-dihydro-4H-pyrano[4,3-d]pyrimidin-3(5H) -yl)methyl)I soxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (2049-3) [0318] To a solution of 2049-2 (200.0 mg, 1.1 mmol) and 2-(3-(chloromethyl)isoxazol-5-yl)-5 - fluoro-4-methoxybenzonitrile (296.0 mg, 1.1 mmol) in acetone (6.0 mL) was added K₂CO₃ (767.0 mg, 5.6 mmol) and Nal (16.6 mg, 111.0 μmol). The reaction was stirred at 50 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was triturated with EtOAc at 20 °C for 15 min. Compound 2049-3 (200 mg, 487.3 μmol) was obtained as a white solid. ESI [M+H]⁺ = 411.2

Step 3: 2-(3-((2-Ethyl-4-oxo-7,8-dihydro-4H-pyrano [4, 3-d] py rimidin-3(5//)-yl)met hyl) isoxazol-5-yl)-5-fluoro-4-hydroxybenzonitrile (2049)

[0319] A mixture of 2049-3 (100 mg, 243.7 μmol) and Py.HCl (1 g, 8.7 mmol) was stirred at 170 °C for 8 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was diluted with H₂O (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to give Compound 2049 (19.2 mg, 48.4 μmol) as a white solid. ESI [M+H]⁺ = 396.9 (LCMS)¹;H NMR (400 MHz, DMSO-d₆) δ = 11.78 (br s, 1H), 8.10 - 7.94 (m, 1H), 7.63 - 7.45 (m, 1H), 7.22 - 7.05 (m, 1H), 5.49 - 5.36 (m, 2H), 4.45 - 4.33 (m, 2H), 3.90 - 3.85 (m, 2H), 2.92 - 2.79 (m, 2H), 2.65 - 2.57 (m, 2H), 1.20 (t, J= 7.3 Hz, 3H).

Example 25: 2-(3-((3-Ethyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-2(LH)-yl)methyl)isoxazo 1-5- yl)-5-fluoro-4-hydroxybenzonitrile (2050)

Step 1: 3-bromo-l-methoxyisoquinoline (2050-2)

[0320] To a solution of 2050-1 (2.0 g, 7.0 mmol) in MeOH (30 mL) was added NaOMe (1.5 g, 27.9 mmol). The mixture was stirred at 115 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2050-2 (1.5 g, 6.3 mmol) as a white solid, ESI [M+H]⁺ = 240.1 (LCMS).

Step 2: l-Methoxy-3-vinylisoquinoline (2050-3)

[0321] To a solution of 2050-2 (1 g, 4.2 mmol) and 4,4,5,5-tetramethyl-2-vinyl-l,3,2 - dioxaborolane (970.4 mg, 6.3 mmol, 1.1 mL) in DMF (20 mL) was added CsF (1.9 g, 12.6 mmol, 465.1 pF) and Pd(dppf)C12 (614.7 mg, 840.1 μmol) under N2. The mixture was stirred at 100 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by poured into water (20 mL) and extracted with EtOAc (6.0 mL x 6). The combined organic layers were concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2050-3 (770 mg, 4.2 mmol) as a white solid.

NMR (400 MHz, CHLOROFORM-d) δ = 8.38 (d, J= 8.1 Hz, 1H), 7.88 - 7.74 (m, 2H), 7.65 (ddd, J = 1.3, 7.0, 8.2 Hz, 1H), 7.00 (dd, J= 10.4, 16.9 Hz, 1H), 6.59 (dd, J = 2.0, 17.0 Hz, 1H), 5.60 (dd, .7= 2.1, 10.4 Hz, 1H), 4.36 (s, 3H).

Step 3: 3-Ethyl-l-methoxy-5,6,7,8-tetrahydroisoquinoline (2050-4)

[0322] To a solution of 2050-3 (750 mg, 4.1 mmol) in TFA (16 mL) was added PtCh (46.0 mg, 202.5 μmol). The mixture was stirred at 20 °C for 5 h under H² atmospherel5 psi. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was filtered to give a filtrate. The filtrate was added to NaHCCf aqueous 40 mL dropwise, extracted with EtOAc (20.0 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2050-4 (750 mg, 3.9 mmol) as a white solid, ESI [M+H]⁺ = 192.2 (LCMS).

Step 4: 3-Ethyl-5,6,7,8-tetrahydroisoquinolin-l(2Z7)-one (2050-5)

[0323] To a solution of 2050-4 (400 mg, 2.1 mmol) in MeCN (10 mL) was added TMSC1 (681.6 mg, 6.3 mmol, 796.3 LIL , Nal (940.4 mg, 6.3 mmol). The mixture was stirred at 80 °C for 8 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into NaHCCh aqueous (20 mL) and extracted with EtOAc (10 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-HPLC to give Compound 2050-5 (200 mg, 1.1 mmol) as a white solid. ESI [M+H]⁺ = 178.3 (LCMS).

Step 5: 2-(3-((3-Ethyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-2(1H) -yl)methyl)isoxazol-5 -yl)-5- fluoro-4-methoxybenzonitrile (2050-6)

[0324] To a solution of 2-(3-(chloromethyl)isoxazol-5-yl)-5-fluoro-4-methoxybenzonitrile (90 mg, 337.5 μmol) and 2050-5 (59.8 mg, 337.5 μmol) in dioxane (4.0 mL) and t-BuOK (56.8 mg, 506.3 μmol), Nal (5.1 mg, 33.8 μmol). The mixture was stirred at 80 °C for 6 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by pouring into H₂O 8.0 mL and extracted with DCM (5.0 mL x 5), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 2050-6 (60 mg, 147.3 μmol) as a yellow solid, ESI [M+H]⁺ = 408.3 (LCMS).

Step 6: 2-(3-((3-Ethyl-l-oxo-5,6,7,8-tetrahydroisoquinolin-2(TH)-yl)methyl)isoxaz ol-5-yl)-5- fluoro-4-hydroxybenzonitrile (2050) [0325] To a solution of 2050-6 (60 mg, 147.3 Limol) in DCM (6.0 mL) was added BBr.3 (1.1 g, 4.4 mmol, 425.7 μL) in DCM (2 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2050 (11.1 mg, 26.79 μmol) as a yellow solid, ESI [M+H]⁺ = 394.1 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 11.69 (s, 1H), 8.00 (d, J = 11.0 Hz, 1H), 7.49 (d, J = 8.3 Hz, 1H), 7.02 (s, 1H), 5.91 (s, 1H), 5.33 (s, 2H), 2.69 (q, J = 7.3 Hz, 2H), 2.57 - 2.51 (m, 2H), 2.33 (br s, 2H), 1.65 (br s, 4H), 1.17 (t, J = 7.3 Hz, 3H).

Example 26: 5-fluoro-4-hydroxy-2-(3-((l-oxo-3-propyl-5,6,7,8-tetrahydroisoquin ol in-2( 1 //)- yl)methyl)isoxazol-5-yl)benzonitrile (2051)

Step 1: 3-Allyl-l-methoxyisoquinoline (2051-2)

[0326] To a solution of the 2051-1 (1.0 g, 4.2 mmol), 2-allyl-4, 4,5, 5-tetramethyl- 1,3,2- dioxaborolane (1.1 g, 6.3 mmol) in DMF (8.0 mL) was added CsF (1.9 g, 12.6 mmol) and Pd(dppf)Ch (614.6 mg, 840.0 μmol) under N2, the resulting mixture was stirred at 100 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 30 mL and extracted with EtOAc (10 mL x 5). The combined organic layers were dried overNa₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2051-2 (830 mg, 4.1 mmol) as a white solid. ESI [M+H]⁺ = 200.2 (LCMS)

Step 2: l-Methoxy-3-propyl-5,6,7,8-tetrahydroisoquinoline (2051-3)

[0327] To a solution of 2051-2 (720.0 mg, 3.6 mmol) in TFA (3.6 mL) was added PtCh (41.3 mg, 180.6 μmol). The mixture was stirred at 20 °C for 5 h under a H2 atmosphere 15 Psi. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was filtered to give a filtrate. The filtrate was added to NaHCCh aqueous 20 mL dropwise, extracted with EtOAc (5.0 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2051-3 (700 mg, 3.4 mmol) as a white solid. ESI [M+H] = 206.2 (LCMS);^!H NMR (400 MHz, METHANOL-d₄) 8 = 6.98 (s, 1H), 4.25 (s, 3H), 2.90 - 2.78 (m, 4H), 2.62 (br t, J= 5.2 Hz, 2H), 1.87 - 1.79 (m, 4H), 1.79 - 1.71 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H)

Step 3: 3-Propyl-5,6,7,8-tetrahydroisoquinolin-l(2//)-one (2051-4)

[0328] To a solution of 2051-3 (500 mg, 2.4 mmol) in MeCN (5.0 mL) was added TMSC1 (793.8 mg, 7.3 mmol) and Nal (1.1 g, 7.3 mmol). The mixture was stirred at 80 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 5.0 mL and extracted with EtOAc (5.0 mL x 4). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2051-4 (400.0 mg, 2.0 mmol) as a white solid.

Step 4: 5-Fluoro-4-methoxy-2-(3-((l-oxo-3-propyl-5,6,7,8-tetrahydroisoquinolin-2(1H) - yl)methyl)isoxazol-5-yl)benzonitrile (2051-5)

[0329] To a solution of 2051-4 (80.0 mg, 209.1 μmol) and 2-(3-(chloromethyl)isoxazol-5-yl) -5- fluoro-4-methoxybenzonitrile (55.7 mg, 209.1 μmol) in dioxane (6.0 mL) was added t-BuOK (35.2 mg, 313.6 μmol) and Nal (3.1 mg, 20.9 μmol) under N2. The mixture was stirred at 80 °C for 5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 20 mL and extracted with EtOAc (20 mL x 3), dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 2051-5 (70 mg, 232.4 μmol) as a white solid. ESI [M+H]⁺ = 422.2 (LCMS)

Step 5: 5-Fluoro-4-hydroxy-2-(3-((l-oxo-3-propyl-5,6,7,8-tetrahydroisoquinolin-2(lH) - yl)methyl)isoxazol-5-yl)benzonitrile (2051)

[0330] To a solution of 2051-5 (30.0 mg, 71.1 μmol) in DCM (3.0 mL) was added a solution of BBr (534.9 mg, 2.1 mmol) in DCM (2.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2051 (10 mg, 24.54 μmol) as a white solid, ESI [M+H]⁺ = 408.2 (LCMS);¹H NMR (400 MHz, METHANOL-d4) δ = 7.67 (d, J= 10.5 Hz, 1H), 7.49 (d, J= 8.3 Hz, 1H), 7.00 (s, 1H), 6.09 (s, 1H), 5.43 (s, 2H), 2.76 - 2.68 (m, 2H), 2.59 (br t, J= 5.4 Hz, 2H), 2.47 (br t, J= 5.3 Hz, 2H), 1 .82 - 1.72 (m, 4H), 1.72 - 1.63 (m, 2H), 1.03 (t, J= 7.3 Hz, 3H).

Example 27: 2-(3-((3,4-Dimethyl-2-oxo-6-propylpyridin-l(2//)-yl)methyl)isoxazol-5-yl)- 5- fluoro-4-hydroxybenzonitrile (2052)

Step 1: Heptane-2, 4-dione (2052-2)

[0331] To a solution of NaNH₂ (6.7 g, 172.2 mmol) in THF (100 mL) was added 2052-1 (10 g, 86.1 mmol) and acetone (7.50 g, 129.1 mmol, 9.5 mL). The mixture was stirred at 30 °C for 4 h. TLC indicated that the starting material was completely and one new spot formed. The reaction mixture was quenched by addition HC1 (50 mL, IM) and extracted with EtOAc (30 mL x 5). The combined organic layers were dried overNa₂SO4, fdtered and concentrated under reduced pressure to give crude Compound 2052-2 (20 g) as a yellow oil.

Step 2: 4-MethyI-2-oxo-6-propyl-l,2-dihydropyridine-3-carbonitrile (2052-3)

[0332] To a solution of 2052-2 (12.2 g, 95.2 mmol) and 2-cyanoacetamide (8.0 g, 95.2 mmol) in EtOH (90 mL) was added piperidine (8.1 g, 95.2 mmol, 9.4 mL) at 75 ° C. The reaction was stirred at 75 ° C for 1 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (200 mL) and extracted with EtOAc (50 mL x 5). The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue which was purified by reversed-phase HPLC to give Compound 2052-3 (3.0 g, 17.0 mmol) as a yellow oil.

Step 3: 2-(Benzyloxy)-4-methyl-6-propylnicotinonitrile (2052-4)

[0333] To a solution of 2052-3 (790 mg, 4.48 mmol) in toluene (65 mL) was added BnBr (920.1 mg, 5.4 mmol) and Ag₂CO₃ (1.5 g, 5.4 mmol). The mixture was stirred at 110°C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (20 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2052-4 (0.6 g, 2.0 mmol) as a yellow oil.

Step 4: 2-(Benzyloxy)-4-methyl-6-propylnicotinaldehyde (2052-5)

[0334] To a solution of 2052-4 (1.0 g, 3.75 mmol) in DCM (30 mL) was added DIBAL-H (1 M, 5.63 mL) at 0°C. The mixture was stirred 25°C for 3 h under N2. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was cooled to 0 °C. The reaction mixture was added H₂O (0.24 mL), NaOH 10% aqueous (0.24 mL) followed by H₂O (0.6 mL). After being stirred at room temperature for 10 min. The mixture was dried over MgSO₄, filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2052-5 (0.6 g, 2.0 mmol) as a yellow oil. ESI [M+H]⁺ = 270.1 (LCMS)

Step 5: (2-(Benzyloxy)-4-methyl-6-propylpyridin-3-yl)methanol (2052-6)

[0335] To a solution of 2052-5 (760 mg, 2.82 mmol) in MeOH (20 mL) was added NaBH₄ (128.1 mg, 3.4 mmol) at 0°C. Then the mixture was stirred at 25°C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (30 mL) and extracted with DCM (20 mL x 5). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give crude Compound 2052-6 (770 mg, 2.8 mmol) as a white solid.

Step 6: 2-(Benzyloxy)-3-(chloromethyl)-4-methyl-6-propylpyridine (2052-7) [0336] To a solution of 2052-6 (770 mg, 2.8 mmol) in DCM (10 mL) was added SOCI2 (405.1 mg, 3.4 mmol) at 0 °C. The mixture was stirred at 0°C for 0.5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into NaHCO.i aqueous (30 mL) and extracted with DCM (10 mL x 5). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give Compound 2052-7 (600 mg, 2.1 mmol) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.50 (d, J = 7.2 Hz, 2H), 7.40 - 7.30 (m, 3H), 6.60 (s, 1H), 5.47 (s, 2H), 4.72 (s, 2H), 2.66 - 2.59 (m, 2H), 2.37 (s, 3H), 1.77 - 1.69 (m, 2H), 0.95 (t, J= 7.4 Hz, 3H).

Step 7: 3,4-Dimethyl-6-propylpyridin-2(lH)-one (2052-8)

[0337] To a solution of 2052-7 (494.3 mg, 1.9 mmol) in MeOH (10 mL) was added Pd/C (300 mg, 1.9 mmol, 10% purity). The mixture was stirred at 25°C for 30 min under H2 atmosphere (15 Psi). LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was filtered and concentrated under reduced pressure to give Compound 2052-8 (180 mg, 1.1 mmol) as a white oil.¹H NMR (400 MHz, CHLOROFORM-d) 3 = 5.95 - 5.75 (m, 1H), 2.50 (t, J= 7.7 Hz, 2H), 2.14 (s, 3H), 2.09 - 2.02 (m, 3H), 1.69 (sxt, J= 7.5 Hz, 2H), 0.96 (t, J= 7.3 Hz, 3H).

Step 8: 2-(3-((3,4-Dimethyl-2-oxo-6-propylpyridin-l(2/Z)-yI)methyl)isoxazol-5-yl)-5- fluoro- 4-methoxybenzonitrile (2052-9)

[0338] To a solution of 2052-8 (180 mg, 1.1 mmol,) and 2-(3-(chloromethyl)isoxazol-5-yl)-5- fluoro-4-methoxybenzonitrile (290.5 mg, 1.1 mmol) in dioxane (5.0 mL) was added t-BuOK (183.4 mg, 1.6 mmol) and Nal (16.3 mg, 108.9 μmol) under N2 atmosphere. The resulting mixture was stirred at 90 °C for 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 2052-9 (192 mg, 485.6 μmol) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) δ = 7.49 - 7.43 (m, 2H), 7.07 (s, 1H), 5.93 (s, 1H), 5.47 - 5.33 (m, 2H), 4.01 (s, 3H), 2.72 - 2.62 (m, 2H), 2.16 (s, 3H), 2.13 - 2.07 (m, 3H), 1.68 (br dd, J= 7.5, 15.3 Hz, 2H), 1.05 (s, 3H).

Step 9: 2-(3-((3,4-Dimethyl-2-oxo-6-propylpyridin-l (2//)-yl)niethyl)isoxazol-5-yl)-5-f luoro- 4-hydroxybenzonitrile (2052)

[0339] To a solution of 2052-9 (90 mg, 227.6 μmol) in DCM (10 mL) was added BBr? (2.0 g, 8.0 mmol) in DCM (2.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 3 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2052 (37.4 mg, 97.7 μmol) as a white solid. ESI [M+H]⁺ = 382.1 (LCMSj^H NMR (400 MHz, DMSO-d₆) δ = 11.70 (s, 1H), 8.00 (d, J= 11.0 Hz, 1H), 7.49 (d, J= 8.3 Hz, 1H), 7.01 (s, 1H), 6.02 (s, 1H), 5.32 (s, 2H), 2.66 - 2.59 (m, 2H), 2.11 (s, 3H), 1.98 - 1.91 (m, 3H), 1.63 - 1.51 (m, 2H), 0.98 - 0.87 (m, 3H)

Example 28: 4-Hydroxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H)-yl)m ethyl)isoxazol-5-yl)benzonitrile (2053)

Step 1 : 4-Methoxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)meth yl)isoxazol-5-yl)benzonitri!e (2053-1)

[0340] To a solution of 2053-1 (200 mg, 804.3 μmol) and 2-ethyL5,6,7,8-tetrahydroquinazolin- 4(3H) -one (157.7 mg, 884.7 μmol) in acetone (6.0 mL) was added Nal (12.1 mg, 80.4 μmol) and K₂CO₃ (555.8 mg, 4.0 mmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (15 mL) and extracted with EtOAc (10 mLx 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 2053-1 (160 mg, 409.8 μmol) as a white solid¹.H NMR (400 MHz, CHLOROFORM- d) δ = 7.71 (d, J= 8.6 Hz, 1H), 7.44 (d, J= 2.6 Hz, 1H), 7.18 (s, 1H), 7.04 (dd, J= 2.6, 8.7 Hz, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 2.79 - 2.43 (m, 7H), 1.77 (br dd, J = 5.6, 11.1 Hz, 4H).

Step 2: 4-Hydroxy-2-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)meth yl)isoxazol-5-yl)benzonitrile (2053)

[0341] To a stirred solution of 2053 (50 mg, 128.1 μmol) in DCM (2.0 mL) was added a solution ofBBrs (962.5 mg, 3.8 mmol) in DCM (1.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O drop wise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2053 (7.7 mg, 20.46 μmol) as a white solid. ESI [M+H]⁺ = 363.3 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 7.85 (d, J = 8.5 Hz, 1H), 7.33 (s, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 5.39 (s, 2H), 2.58 (s, 3H), 2.55 - 2.51 (m, 2H), 2.40 - 2.31 (m, 2H), 1.70 (br s, 4H).

Example 29: 4-Hydroxy-2-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl) methyl)isoxazol-5-yl)benzonitrile (2054)

Step 1: 2-(3-((2-Isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxazol -5- yl)-4-methoxybenzonitrile (2054-1)

[0342] To a solution of 2035-1 (200 mg, 804.3 μmol) and 2-ethyl-5,6,7,8-tetrahydroquinazolin - 4(3H) -one (157.7 mg, 884.7 μmol) in acetone (6.0 mL) was added Nal (12.1 mg, 80.4 μmol) and K₂CO₃ (555.8 mg, 4.0 mmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (15 mL) and extracted with EtOAc (10 mLx 3). The combined organic layers were dried over Na2SO4, fdtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 2054-1 (160 mg, 409.8 μmol) as a white solid.^!H NMR (400 MHz, CHLOROFORM- d) δ = 7.71 (d, J= 8.8 Hz, 1H), 7.44 (d, J = 2.5 Hz, 1H), 7.14 (s, 1H), 7.03 (dd, J = 2.6, 8.8 Hz, 1H), 5.42 (s, 2H), 3.94 - 3.91 (m, 3H), 2.68 - 2.48 (m, 4H), 1.84 - 1.70 (m, 4H), 1.37 - 1.22 (m, 7H).

Step 2: 4-Hydroxy-2-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)m ethyl)isoxazol-5-yl)benzonitrile (2054)

[0343] To a stirred solution of 2054-1 (50 mg, 128.1 μmol) in DCM (2.0 mL) was added a solution ofBBrs (962.5 mg, 3.8 mmol) in DCM (1.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2054 (7.7 mg, 20.46 μmol) as a white solid. ESI [M+H]⁺ = 391.3 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 7.85 (d, J= 8.5 Hz, 1H), 7.33 (s, 1H), 7.17 (s, 1H), 7.04 (s, 1H), 5.39 (s, 2H), 2.58 (s, 3H), 2.55 - 2.51 (m, 2H), 2.40 - 2.31 (m, 2H), 1.70 (br s, 4H)

Example 30: 4-(3-((2-Ethyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4H) -yl)methyl) isoxazol- 5-yl)-2-hydroxybenzonitrile (2055)

Step 1: Ethyl 5-(4-cyano-3-methoxyphenyl) isoxazole-3-carboxylate (2055-2)

[0344] To a solution of ethyl 2055-1 (6.1 g, 14.2 mmol), 4-bromo-2-methoxy-benzonitrile (3 g, 14.2 mmol) in toluene. (60 mL) was added Pd(t-Bu₃P)₂ (506.13 mg, 990.4 μmol) under N2 for 3 times, the resulting mixture was stirred at 90 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2055-2 (3 g, 11.0 mmol) as a white solid.^JH NMR (400 MHz, DMSO-d₆) 5 = 7.92 (d, J= 8.1 Hz, 1H), 7.81 (s, 1H), 7.77 (s, 1H), 7.67 (dd, J= 1.3, 8.1 Hz, 1H), 4.41 (q, J= 1A Hz, 2H), 4.04 - 4.00 (m, 3H), 1.35 (t, J= 1A Hz, 3H)

Step 2: 4-(3-(Hydroxymethyl) isoxazol-5-yl)-2-methoxybenzonitrile (2055-3)

[0345] To a solution of (2055-2) (3 g, 11.0 mmol) in THF (30 mL) and MeOH (3.0 mL) was added NaBH₄ (833.7 mg, 22.0 mmol) at 0 °C. The mixture was stirred at 20 °C for 2 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was quenched by poured into NH4CI aqueous (30 mL) and extracted with EtOAc (10 mL x 4). The combined organic layers were concentrated under reduced pressure to give crude Compound 2055-3 (1.7 g, 7.4 mmol) as a yellow solid¹.H NMR (400 MHz, CHLOROFORM-d) 5 = 7.71 - 7.63 (m, 1H), 7.42 - 7.36 (m, 2H), 6.74 (s, 1H), 4.85 (s, 2H), 4.03 (s, 3H). Step 3: 4-(3-(Chloromethyl) isoxazol-5-yl)-2-methoxybenzonitrile (2055-4)

[0346] To a solution of (2055-3) (1.7 g, 7.4 mmol) in CHCI3 (30 mL) was added SOCh (2.9 g, 24.4 mmol, 1.8 mL) and DMF (54.0 mg, 738.4 μmol). The mixture was stirred at 70 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into brine (30 mL) and extracted with DCM (20 mL x 5). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 2055-4 (1.7 g, 6.8 mmol) as a white solid.¹H NMR (400 MHz, CHLOROFORM-d) 5 = 7.67 (d, J= 8.4 Hz, 1H), 7.43 - 7.38 (m, 2H), 6.78 (s, 1H), 4.66 (s, 2H), 4.04 (s, 3H).

Step 4: 4-(3-((2-Ethyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4J/)-yl)methyl)isoxazol- 5-yl)- 2-methoxybenzonitrile(2055-5)

[0347] To a solution of 2055-4 (200.0 mg, 804.3 μmol) and 2-ethyl-5,6,7,8-tetrahydroqu inazolin- 4(3 7)-one (143.3 mg, 804.3 μmol) in dioxane (12 mL) was added t-BuOK (135.3 mg, 1.2 mmol) and Nal (12.0 mg, 80.4 μmol). The mixture was stirred at 80 °C for 5 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (12 mL) and extracted with EtOAc (12 mLx 5). The combined organic layers were dried overNa₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by was purified by prep-TLC to give Compound 2055-5 (100.0 mg, 256.1 μmol) as a white solid, *HNMR (400 MHz, METHANOL-d₄) 8 = 7.74 (d, ,/= 8.0 Hz, 1H), 7.62 - 7.48 (m, 2H), 7.01 (s, 1H), 5.43 (s, 2H), 4.04 (s, 3H), 2.89 (q, J = 7.4 Hz, 2H), 2.63 (t, J = 6.0 Hz, 2H), 2.49 (br t, J = 5.8 Hz, 2H), 1.89 - 1.72 (m, 4H), 1.29 (t, J= 7.4 Hz, 3H)

Step 5: 4-(3-((2-Ethyl-4-oxo-5, 6, 7, 8-tetrahydroquin;izolin-3(4//)-yl)methyl)isox azol-5-yl)- 2-hydroxybenzonitrile (2055)

[0348] To a solution of 2055-5 (70.0 mg, 179.2 μmol) in DCM (7.0 mL) was added BBrs (1.3 g, 5.3 mmol) in DCM (3.5 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2055-01N (38.6 mg, 102.5 μmol) was obtained as a white solid. ESI [M+H]⁺ = 377.1 (LCMS);^XH NMR (400 MHz, DMSO-d₆) δ = 11.54 (br s, 1H), 7.77 (d, J= 8.1 Hz, 1H), 7.48 - 7.36 (m, 2H), 7.11 (s, 1H), 5.34 (s, 2H), 2.80 (q, J= 13 Hz, 2H), 2.56 - 2.51 (m, 2H), 2.36 (br t, J= 5.5 Hz, 2H), 1.77 - 1.59 (m, 4H), 1.17 (t, J= 7.3 Hz, 3H).

Example 31 : 2-Hydroxy-4-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl) methyl)isoxazol-5-yl)benzonitrile (2056)

Step 1: 4-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4Z/)-yl)methyl)iso xazol-5- yl)-2-methoxybenzonitrile (2056-1)

[0349] To a solution of 2055-4 (150 mg, 603.2 μmol) in acetone (6 mL) was added K₂CO₃ (416.9 mg, 3.0 mmol), Nal (9.0 mg, 60.3 μmol) and 2-isopropyl-5,6,7,8-tetrahydroquina zolin-4(31/)-one (116.0 mg, 603.2 μmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 6.0 mL and extracted with DCM (4 mL x 3), dried over Na₂SO₄, fdtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound (2056-2) (80 mg, 197.8 μmol) as a yellow solid, ESI [M+H]⁺ = 405.6 (LCMS).

Step 2: 2-hydroxy-4-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4J/)-yl)m ethyl)isoxazol-5-yl)benzonitrile (2056)

[0350] To a solution of 2056-1 (80 mg, 197.8 nmol) in DCM (12 mL) was added a solution of BBra (1.5 g, 5.9 mmol) in DCM (6 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2056 (10 mg, 25.6 μmol) as a yellow solid. ESI [M+H]⁺= 391.1 (LCMS);¹H NMR (400 MHz, DMSO-d₆) 5 = 11.55 (br s, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.51 - 7.33 (m, 2H), 7.10 (s, 1H), 5.38 (s, 2H), 3.16 (td, J= 6.6, 13.2 Hz, 1H), 2.53 - 2.52 (m, 1H), 2.39 - 2.30 (m, 2H), 1.79 - 1.57 (m, 4H), 1.17 (d, 6.6 Hz, 6H).

Example 32: 3-((5-(4-Fluoro-5-hydroxy-2-(trifluoromethyl)phenyl)isoxazol-3-yl)methyl)- 2- methyl-5,6,7,8-tetrahydroquinazolin-4(3H) -one (2061)

Step 1 : 2-Methoxy-4-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4Z/)-yl)methyl) isoxazol-5-yl)benzonitrile (2061-1)

[0351] To a solution of 2055-4 (150 mg, 603.2 μmol) in acetone (9 mL) was added K₂CO₃ (416.9 mg, 3.0 mmol), Nal (9.0 mg, 60.3 μmol) and 2-methyl-5,6,7,8-tetrahydro-3Z/-quina zolin-4-one (99.1 mg, 603.2 μmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by pouring into H₂O (9.0 mL) and extracted with DCM (4.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound (2061-1) (100 mg, 265.7 μmol) as a yellow solid, ESI [M+H]⁺ = 377.3 (LCMS).

Step 2: 3-((5-(4-Fluoro-5-hydroxy-2-(trifluoromethyl) phenyl) isoxazol-3-yl)meth yl)-2- methyl-5,6,7,8-tetrahydroquinazolin-4(3H) -one (2061) [0352] To a solution of 2061-1 (100 mg, 265.7 μmol) in DCM (20 mL) was added BBr, (2.0 g, 8.0 mmol, 768.0 pL) in DCM (10 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2061 (27.5 mg, 75.7 μmol) as a white solid, ESI [M+H]⁺ = 363.3 (LCMS);¹H NMR (400 MHz, METHANOL-d₄) 8 = 7.44 (d, J= 8.1 Hz, 1H), 7.16 (d, J = 1.4 Hz, 1H), 7.00 (dd, J = 1.5, 8.1 Hz, 1H), 6.77 (s, 1H), 5.38 (s, 2H), 2.63 - 2.56 (m, 5H), 2.48 (br t, J = 5.7 Hz, 2H), 1.87 - 1.69 (m, 4H).

Example 33: 3-Hydroxy-5-(3-((2-methyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4/T) - yl)methyl)isoxazol-5-yl)benzonitrile (2066)

Step 1: Ethyl 5-(3-cyano-5-methoxyphenyl)isoxazole-3-carboxylate (2066-2)

[0353] To a solution of 3 -bromo-5-methoxy -benzonitrile (2.4 g, 11.6 mmol) and 2066-1 (5.0 g, 11.6 mmol) in toluene (25 mL) was added Pd(t-Bu₃P)₂ (415.8 mg, 813.6 μmol) under N2. The mixture was stirred at 90 °C for 3 h. LC-MS showed that the reaction was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The mixture was concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography. Compound 2066-2 (2.6 g, 9.5 mmol) was obtained as a yellow solid.^XH NMR (400 MHz, DMSO-d₆) δ = 8.04 (d, J= 1.1 Hz, 1H), 7.87 - 7.81 (m, 1H), 7.72 (s, 1H), 7.67 - 7.62 (m, 1H), 4.41 (q, J = 7.0 Hz, 2H), 3.91 (s, 3H), 1.35 (br t, J= 7.1 Hz, 3H)

Step 2: 3-(3-(Hydroxymethyl)isoxazol-5-yl)-5-methoxybenzonitrile (2066-3)

[0354] To a solution of 2066-2 (1.3 g, 4.7 mmol) in THF (24 mL) and MeOH (2.4 mL) was added NaBH₄ (541.9 mg, 14.3 mmol) at 0 °C, then the mixture was stirred at 20 °C for 2 h. LC-MS showed that the reaction was consumed completely and desired mass was detected. The reaction mixture was poured into NH4CI aqueous (20 mL) and extraced with EtOAc (10 mL x 3). The combined organic layers were dried overNa₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography. Compound 2066-3 (700 mg, 3.0 mmol) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ = 7.95 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 7.23 (s, 1H), 5.62 - 5.57 (m, 1H), 4.56 (d, J= 5.8 Hz, 2H), 3.90 (s, 3H) Step 3: 3-(3-(Chloromethyl)isoxazol-5-yl)-5-methoxybenzonitrile (2066-4)

[0355] To a solution of 2066-3 (700 mg, 3.0 mmol) in CHCI3 (20 mL) was added SOCh (1.0 g, 9.1 mmol, 662.5 μL), DMF (22.2 mg, 304 μmol, 23.3 pmL).The mixture was stirred at 70 °C for 12 h. LC-MS showed that the reaction was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (20 mL) and extracted DCM (15 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography by prep-TLC. Compound 2066-4 (370 mg, 1.4 mmol) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) δ = 7.99 (s, 1H), 7.76 (s, 1H), 7.62 (d, J= 0.8 Hz, 1H), 7.40 (s, 1H), 4.90 (s, 2H), 3.91 (s, 3H)

Step 4: 3-methoxy-5-(3-((2-methyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4H) -yl)me thyl)isoxazol-5-yl)benzonitrile(2066-5)

[0356] To a solution of 2066-4 (110 mg, 442.3 μmol) and 2-methyl-5,6,7,8-tetrahydroquina zolin- 4-ol (79.9 mg, 486.6 μmol) in dioxane (5.0 mL) was added t-BuOK (74.5 mg, 663.5 μmol) and Nal (6.6 mg, 44.2 μmol). The reaction was stirred at 80 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (5.0 mLx 4). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 2066-5 (40 mg, 106.2 μmol) as a white solid.^JH NMR (400 MHz, DMSO-d₆) δ = 7.96 (s, 1H), 7.76 - 7.68 (m, 1H), 7.62 - 7.55 (m, 1H), 7.20 (s, 1H), 5.33 (s, 2H), 3.90 (s, 3H), 2.51 (d, J = 1.8 Hz, 3H), 2.50 - 2.45 (m, 2H), 2.37 (br t, J = 5.4 Hz, 2H), 1.80 - 1.55 (m, 4H).

Step 5: 3-Hydroxy-5-(3-((2-methyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)meth yl)isoxazol-5-yl)benzonitrile (2066)

[0357] To a solution of 2066-5 (40 mg, 106.2 μmol) in DCM (3.0 mL) was added BBn (399.3 mg, 1 .6 mmol, 153.6 μL) in DCM (1 .0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2066 (6.5 mg, 17.49 μmol) as a white solid. ESI [M+H]⁺ = 363.1 (LCMS); H NMR (400 MHz, CHLOROFORM-d) δ = 7.51 - 7.41 (m, 2H), 7.24 - 7.19 (m, 1H), 6.70 (s, 1H), 5.36 (s, 2H), 2.92 (s, 3H), 2.73 (br t, J= 5.8 Hz, 2H), 2.54 (br t, J= 5.3 Hz, 2H), 1.90 - 1.73 (m, 4H).

Example 34: 3-(3-((2-ethyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4H) -yl)methy l)isoxazol- 5-yl)-5-hydroxybenzonitrile (2068)

Step 1: 3-(3-((2-ethyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxa zol-5-yl)- 5-methoxybenzonitrile (2068-1)

[0358] To a solution of 2066-4 (110 mg, 442.3 μmol) and 2-ethyl-5,6,7,8-tetrahydroquina zolin- 4(3H) -one (78.8 mg, 442.3 μmol) in dioxane (10 mL) was added t-BuOK (74.4 mg, 663.5 μmol), Nal (6.6 mg, 44.2 μmol). The reaction mixture was stirred at 80°C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (4.0 mLx 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep- TLC to give Compound 2068-1 (55 mg, 140.87 μmol) as a yellow solid.¹HNMR (400 MHz, DMSO-d₆) δ = 7.96 (t, J = 1.3 Hz, 1H), 7.71 (dd, J = 1.5, 2.4 Hz, 1H), 7.59 (dd, J= 1.3, 2.4 Hz, 1H), 7.18 (s, 1H), 5.34 (s, 2H), 3.90 (s, 3H), 2.80 (q, J= 13 Hz, 2H), 2.38 (br t, J= 5.5 Hz, 2H), 1.78 - 1.63 (m, 4H), 1.18 (t, J = 7.3 Hz, 3H).

Step 2: 3-(3-((2-ethyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(41/)-yl)methyl)is oxazol-5-yl)- 5-methoxybenzonitrile (2068)

[0359] To a solution of 2068-1 (40 mg, 102.4 μmol) in DCM (2.0 mL) was added BBn (769.9 mg, 3.1 mmol, 296.2 μL) in DCM (1.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2068 (26.08 mg, 69.29 μmol) as a white solid. ESI [M+H]⁺= 377.2 (LCMS); 'HNMR (400 MHz, DMSO-d₆) δ = 7.82 (s, 1H), 7.51 (s, 1H), 7.26 (s, 1H), 7.11 (s, 1H), 5.33 (s, 2H), 2.81 (q, J= 7.2 Hz, 2H), 2.53 (br s, 2H), 2.36 (br s, 2H), 1.79 - 1.60 (m, 4H), 1.18 (t, J= 13 Hz, 3H).

Example 35: 2-hydroxy-4-(3-((4-oxo-2-(2,2,2-trifluoroethyl)quinazolin-3(4H) -yl)m ethyl)isoxazol-5-yl)benzonitrile (2072)

Step 1: 2-methoxy-4-(3-((4-oxo-2-(2,2,2-trifluoroethyl)quinazolin-3(4H) -yl)methyl)isoxa zol- 5-yl)benzonitrile (2072-1)

[0360] To a solution of 2061-4 (150 mg, 603.2 μmol) in acetone (6 mL) was added K₂CO₃ (416.9 mg, 3.0 mmol), Nal (9.0 mg, 60.3 μmol) and 2-(2,2,2-trifluoroethyl)-3H-quin azolin-4-one (137.6 mg, 603.2 μmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O 6.0 mL and extracted with DCM (4.0 mL x 3), dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound (2072-1) (140 mg,

317.9 μmol) as a yellow solid, ESI [M+H]⁺ = 441.3 (LCMS).

Step 2: 2-hydroxy-4-(3-((4-oxo-2-(2,2,2-trifluoroethyl)quinazolin-3(4H) -yl)meth yl)isoxazol- 5-yl)benzonitrile (2072)

[0361] To a solution of 2072-1 (130 mg, 295.2 μmol) in DCM (13 mL), was added BB13 (2.2 g,

8.9 mmol, 853.3 μL) in DCM (2 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O drop wise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2072 (32.5 mg, 73.01 μmol) as a yellow solid, ESI [M+H]⁺ = 427.1 (LCMS); 'HNMR (400 MHz, DMSO-d₆) δ = 11.54 (s, 1H), 8.19 - 8.13 (m, 1H), 7.94 - 7.85 (m, 1H), 7.81 - 7.74 (m, 1H), 7.70 (d, J= 7.9 Hz, 1H), 7.64 - 7.56 (m, 1H), 7.46 - 7.38 (m, 2H), 7.20 (s, 1H), 5.50 (s, 2H), 4.19 (q, J = 10.1 Hz, 2H).

Example 36: 3-Hydroxy-5-(3-((2-isopropyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3 (4H) - yl)methyl)isoxazol-5-yl)benzonitrile (2073)

Step 1: 3-(3-((2-Isopropyl-4-oxo-5, 6, 7, 8-tetrahydroquinazolin-3(4H) -yl)methyl)isoxaz ol-5- yl)-5-methoxybenzonitrile (2073-1)

[0362] To a solution of 2066-4 (130 mg, 522.7 μmol) and 2-isopropyl-5,6,7,8-tetrahyd m-3H- quinazolin-4-one (100.5 mg, 522.7 μmol) in acetone (4.0 mL) was added K₂CO₃ (361.2 mg, 2.6 mmol) and Nal (7.8 mg, 52.2 μmol). The reaction was stirred at 50 °C for 12 h. LC-MS showed that the reaction was consumed completely and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (8.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography by prep-TLC. Compound 2073-1 (110 mg, 271.9 μmol) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO-d₆) 5 = 7.96 (s, 1H), 7.71 (br d, J= 1.4 Hz, 1H), 7.63 - 7.56 (m, 1H), 7.18 (s, 1H), 5.39 (s, 2H), 3.89 (s, 3H), 3.17 (td, J= 6.6, 13.1 Hz, 1H), 2.74 (td, J= 6.8, 13.7 Hz, 1H), 2.36 (br s, 2H), 1.68 (br dd, J= 6.4, 12.5 Hz, 5H), 1.16 (s, 6H)

Step 2: 3-Hydroxy-5-(3-((2-isopropyl-4-oxo-5,6,7,8-tetrahydroquinazolin-3(4H) -yl)m ethyl)isoxazol-5-yI)benzonitrile (2073)

[0363] To a solution of 2073-1 (100 mg, 247.2 μmol) in DCM (3.0 mL) was added BBra (1.8 g, 7.4 mmol, 714.6 pmL) in DCM (1.0 mL) at -78 °C and stirred for 1 h under N2. The reaction was stirred at 20 °C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O drop wise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2073 (19.5 mg, 38.6 μmol) as a white solid. ESI [M+H]⁺ = 391.2 (LCMS);¹H NMR (400 MHz, DMSO-d₆) δ = 10.66 (br d, J = 1.1 Hz, 1H), 7.83 (s, 1H), 7.55 - 7.48 (m, 1H), 7.25 (dd, J= 1.4, 2.1 Hz, 1H), 7.10 (s, 1H), 5.37 (s, 2H), 3.21 - 3.11 (m, 1H), 2.56 - 2.51 (m, 2H), 2.36 (br t, J= 5.5 Hz, 2H), 1.79 - 1.61 (m, 4H), 1.17 (d, J= 6.6 Hz, 6H).

Example 37: Synthesis of 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl) quinazolin-4(3H)-one (1651)

Step 1: ethyl 5-(tributylstannyl) isoxazole-3-carboxylate (1651-2)

[0364] To a solution of Compound 1651-1 (5 g, 15 mmol) and (Z)-ethyl 2-chloro-2- (hydroxyimino)acetate (2.6 g, 17 mmol) in Tol. (50 mL) was added TEA (1.6 g, 16 mmol) under N2. The resulting mixture was stirred at 25°C for 4 hrs. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (50 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1651-2 (4.5 g, crude) as a colorless oil.

Step 2: ethyl 5-(4-fluoro-3-methoxyphenyl)isoxazole-3-carboxylate (1651-3) [0365] To a solution of Compound 1651-2 (4.2 g, 9.7 mmol) and 4-bromo-l -fluoro-2- methoxybenzene (2 g, 9.7 mmol) in toluene (40 mL) was added Pd (t-BuaP) (249 mg, 488 umol) under N2. The resulting mixture was stirred at 90°C for 3 hrs under N2 atmosphere. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (40 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1651-3 (2 g, 7.7 mmol) as a yellow solid.¹H NMR (400MHz, DMSO-d₆) δ = 7.74 - 7.68 (m, 1H), 7.56 - 7.50 (m, 2H), 7.38 (dd, >8.4, 11.2 Hz, 1H), 4.45 - 4.35 (m, 2H), 3.94 (s, 3H), 1.34 (t, >7.1 Hz, 3H).

Step 3: (5-(4-fluoro-3-methoxyphenyl) isoxazol-3-yl) methanol (1651-4)

[0366] To a solution of Compound 1651-3 (2 g, 7.7 mmol) in THF (40 mL) was added LAH (580 mg, 12 mmol) at 0°C. The mixture was stirred at 20°C for 1 hr. TLC indicated the reaction was completed. The reaction mixture was cooled to 0°C then quenched by addition of H₂O 0.6 mL, followed by 0.6 mL of 10% aqueous NaOH, 1.8 mL of H₂O, after being stirred at 25°C for 5 min, 2 g MgSCL was added and stirred for 15 min. Then the mixture was filtered through Celite pad, the filtrate was dryness to give Compound 1651-4 (1.6 g, 7 mmol) as a yellow solid.

Step 4: 3-(chloromethyl)-5-(4-fluoro-3-methoxyphenyl) isoxazole (1651-5)

[0367] To a solution of Compound 1651-4 (1 g, 4 mmol) in CHCI3 (10 mL) was added SOCI2 (1.7 g, 15 mmol) and DMF (32 mg, 448 umol), then the mixture was stirred at 70°C for 12 hrs. TLC indicated the reaction was completed. The reaction mixture was poured into H₂O (15 mL) and extracted with DCM (15 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by column chromatography to give Compound 1651-5 (809 mg, 3 mmol) as a yellow solid. ' H NMR (400MHz, CHLOROFORM-d) δ = 7.39 (dd, >2.0, 8.0 Hz, 1H), 7.32 (ddd, >2.1, 4.3, 8.4 Hz, 1H), 7.17 (dd, >8.4, 10.8 Hz, 1H), 6.59 (s, 1H), 4.64 (s, 2H), 3.97 (s, 3H)

Step 5: 3-((5-(4-fluoro-3-methoxyphenyl) isoxazol-3-yl) methyl) quinazolin- 4 (3H)-one (1651-6)

[0368] To a solution of quinazolin-4(3H)-one (121 mg, 828 umol) in acetone (12 mL) was added K₂CO₃ (572 mg, 4 mmol), Nal (12 mg, 83 umol) and Compound 1651-5 (200 mg, 828 umol), the mixture and stirred at 50°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and then the precipitate was separate out. The reaction mixture was filtered and the filter cake was washed with 5 mL of H₂O, dried in vacuum to give Compound 1651-6 (205 mg, 583 umol) as a white solid. ESI [M+H]⁺ = 352.1 (LCMS);¹H NMR (400 MHz, DMSO-d6) 6 ppm) 8.55 (s, 1 H) 8.17 (dd, J=7.94, 1.06 Hz, 1 H) 7.81 - 7.92 (m, 1 H) 7.72 (d, J=8.00 Hz, 1 H) 7.52 - 7.62 (m, 2 H) 7.27 - 7.47 (m, 2 H) 7.08 (s, 1 H) 5.35 (s, 2 H) 3.90 (s, 3 H).

Step 6: 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl) quinazolin -4(3H) -one (1651)

[0369] To a solution of Compound 1651-6 (50 mg, 142 umol) in DCM (3 mL) was added a solution of BBr₃ (535 mg, 2 mmol) in DCM (0.5 mL) at -78°C under N2, after stirred for 1 hr, the mixture was stirred at 25°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1651 (27.8 mg, 82.4 umol) as a white solid. ESI [M+H]⁺ = 338.0 (LCMS);

NMR (400MHz, DMSO-d6) 8 = 10.33 (br s, 1H), 8.54 (s, 1H), 8.17 (dd, J=1.3, 7.9 Hz, 1H), 7.94 - 7.83 (m, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.64 - 7.50 (m, 1H), 7.40 - 7.35 (m, 1H), 7.32 - 7.23 (m, 2H), 6.97 (s, 1H), 5.33 (s, 2H).

Example 38: Synthesis of 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl) -2- methylquinazolin-4(3H)-one (1688)

Step 1: 3-((5-(4-fluoro-3-methoxyphenyl) isoxazol-3-yl) methyl)-2-methyl quinazolin-4(3H)- one (1688-2)

[0370] To a solution of 2-methylquinazolin-4(3H)-one (33 mg, 207 umol) in acetone (3 mL) was added K₂CO₃ (143 mg, 1 mmol) and Nal (3 mg, 21 umol) then Compound 1688-1 (50 mg, 207 umol) was added to the mixture, then the mixture was stirred at 50°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (5 mL) and then the precipitate was separate out. The reaction mixture was filtered and the filter cake was washed with 5 mL of H₂O, dried in vacuum to give Compound 1688-2 (70 mg, 192 umol) as a yellow solid. ESI [M+H]⁺ =366.2 (LCMS);¹H NMR (DMSO-d6, 400MHz): 8 = 8.10- 8.18 (m, 1H), 7.83 (s, 1H), 7.26-7.68 (m, 5H), 7.06 (s, 1H), 5.44 (s, 2H), 3.90 (s, 3H), 2.63 ppm (s, 3H).

Step 2: 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl) -2- methyl quinazolin-4(3H) -one (1688)

[0371] To a stirred solution of Compound 1688-2 (50 mg, 137 umol) in DCM (2 mL) was added a solution of BBr? (274 mg, 1.1 mmol) in DCM (0.5 mL) at -78°C under N2. The resulting mixture was stirred at 25°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1688 (7.9 mg, 23 umol) as a white solid. ESI [M+H]⁺= 352.0 (LCMS);^JH NMR (DMSO-d6, 400MHz): 5 = 8.46 (s, 1H), 8.10-8.18 (m, 1H), 7.83 (s, 1H), 7.64 (s, 1H), 7.52 (t, J=7.5 Hz, 1H), 7.39 (br d, J=9.2 Hz, 1H), 7.22-7.31 (m, 2H), 6.94 (s, 1H), 5.42 (s, 2H), 2.62 ppm (s, 3H).

Example 39: Synthesis of 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl) -5- methylpyrimidin-4(3H)-one (1689)

Step 1: 3-((5-(4-fluoro-3-methoxyphenyl) isoxazol-3-yl) methyl) -5-methyl pyrimidin-4(3H)- one (1689-2)

[0372] To a solution of 5-methylpyrimidin-4(3H)-one(46 mg, 414 umol) in acetone (6 mL) was added K₂CO₃ (286 mg, 2 mmol) and Nal (6 mg, 41 umol) then Compound 1689-1 (100 mg, 414 umol) was added to the mixture, then the mixture stirred at 50°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give residue. The residue was purified by Prep- TLC to give Compound 1689-2 (80 mg, 254 umol) as a yellow solid.

Step 2: 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl)-5- methyl pyrimidin-4(3H)- one (1689) [0373] To a stirred solution of Compound 1689-2 (50 mg, 158 umol) in DCM (2 mL) was added a solution of BBr.3 (596 mg, 2 mmol) in DCM (0.5 mL) at -78°C under N2. The resulting mixture was stirred at 25°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1689 (13.6 mg, 45 umol) as a white solid. ESI [M+H]⁺ =302.0 (LCMS);¹H NMR (DMSO-d6, 400MHz): 8 = 10.10 - 10.71 (m, 1 H) 8.50 (s, 1 H) 7.87 (d, J=0.75 Hz, 1 H) 7.38 (d, =8.88 Hz, 1 H) 7.27 - 7.31 (m, 2 H) 6.91 (s, 1 H) 5.23 (s, 2 H) 1.96 (s, 3 H).

Example 40: Synthesis of 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl)-2- methylpyrimidin-4(3H) -one (1691)

Step 1: 3-((5-(4-fluoro-3-methoxyphenyl) isoxazol-3-yl) methyl) -2-methyl pyrimidin-4(3H) - one (1691-2)

[0374] To a solution of 2-methylpyrimidin-4(3H)-one (46 mg, 414 umol) in acetone (4 mL) was added K₂CO₃ (286 mg, 2 mmol), Nal (6 mg, 41 umol) and Compound 1691-1 (100 mg, 414 umol), then the mixture was stirred at 50°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue. The residue was purified by Prep-TLC to give Compound 1691-2 (50 mg, 158 umol) as a white solid. ESI [M+H]⁺ =316.2 (LCMS);^JH NMR (CHLOROFORM -d, 400MHz): 5 = 7.82 (s, 1H), 7.28-7.38 (m, 2H), 7.15 (dd, J=10.8, 8.5 Hz, 1H), 6.59 (s, 1H), 6.43 (d, J=6.6 Hz, 1H), 5.33 (s, 2H), 3.96 (s, 3H), 2.71 ppm (s, 3H).

Step 2: 3-((5-(4-fluoro-3-hydroxyphenyl) isoxazol-3-yl) methyl)-2-methyl -pyrimidin-4(3H) - one (1691)

[0375] To a stirred solution of Compound 1691-2 (50 mg, 158 umol) in DCM (2 mL) was added a solution of BBr.3 (318 mg, 1 mmol) in DCM (0.5 mL) at -78°C under N2. The resulting mixture was stirred at 25°C for 12 hrs. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1691 (22.4 mg, 74 umol) as a white solid. ESI [M+H]⁺ =302.0 (LCMS)¹;H NMR (DMSO-d6, 400MHz): 5 = 10.19-10.65 (m, 1H), 7.85 (d, J=6.6 Hz, 1H), 7.36-7.43 (m, 1H), 7.22-7.34 (m, 2H), 6.90 (s, 1H), 6.36 (d, J=6.6 Hz, 1H), 5.32 (s, 2H), 2.55 ppm (s, 3H).

Example 41: l-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)piperidin-2-one (1630)

Step 1: l-((5-(4-Fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)piperidin-2-one (1630-2)

[0376] To a solution of piperidin-2-one (100 mg, 1.0 mmol) in DMF (4.0 mL) was added NaH (40.3 mg, 1.0 mmol, 60% purity) at 0 °C for 0.5 h under N2, followed by a solution of 1630-1 (152.0 mg, 504.4 μmol) in DMF (2.0 mL). The resulting mixture was stirred at 25 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H₂O (7.0 mL) and extracted with EtOAc (4.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by TLC to give Compound 1630-2 (65.0 mg, 213.5 μmol) as a white solid.

Step 2: l-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyI)piperidin-2-one (1630)

[0377] To a solution of 1630-2 (55.0 mg, 180.7 μmol) in DCM (3.0 mL) was added a solution of BBrs (452.7 mg, 1.81 mmol) in DCM (1.0 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 4 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (5.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1630 (32.1 mg, 110.5 μmol) as a white solid. ESI [M+H]⁺ = 291.0 (LCMS);¹H NMR (CDCh-d, 400MHz) 8 = 7.44 (dd, J = 8.2, 2.1 Hz, 1H), 7.31 (br s, 1H), 7.17 (dd, J= 4.4, 2.1 Hz, 1H), 7.07 (dd, J = 10.2, 8.6 Hz, 1H), 6.46 (s, 1H), 4.58 (s, 2H), 3.31 (br s, 2H), 2.41 (br s, 2H), 1.76 ppm (br t, J=3.1 Hz, 4H).

Example 42: 3-((3-(4-Fluoro-3-hydroxyphenyl) isoxazol-5-yl) methyl)-2,6-dimethy lpyrimidin-4(3H) -one (1707)

Step 1 3-((3-(4-Fluoro-3-methoxyphenyl) isoxazol-5-yl) methyl)-2,6-dimethylpy rimidin- 4(3//)-one (1707-2)

[0378] To a solution of 2,6-dimethylpyrimidin-4(3H) -one (102.8 mg, 827.7 μmol) in acetone (5.0 mL) was added K₂CO₃ (572.0 mg, 4.1 mmol), Nal (12.4 mg, 82.8 μmol) and 1707-1 (200 mg, 827.7 μmol). The resulting mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature, poured into H₂O (6.0 mL) and extracted with EtOAc (3.0 mL x 4). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by prep-TLC to give Compound 1707-2 (150 mg, 455 5 μmol) as a white solid ESI [M H]^{r ::::} 330 2 (LCMS).

Step 2 3-((3-(4-Fluoro-3-hydroxyphenyl) isoxazol-5-yl) methyl)-2,6-dimethylpy rimidin- 4(3//)-one (1707)

[0379] To a solution of 1707-2 (100 mg, 303.7 μmol) in DCM (5.0 mL) was added BBr? (608.6 mg, 2.4 mmol, 234.1 μL) in DCM (3.0 mL) at -70 °C under N2. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1707 (21.3 mg, 67.2 μmol) as a brown solid. ESI [ X = - 1 H === 314.1 (LCMS),¹H NMR (400MHz, DMSO-d₆) 6 = 7.49 - 7.40 (m, 1H), 7.30 - 7.20 (m, 2H), 6.94 (s, 1H), 6.24 (s, 1H), 5.38 (s, 2H), 2.54 (s, 3H), 2.17 (s, 3H).

Example 43: 3-((3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)inethyl)-2-methyl-6- phenylpyrimidin-4(3/ )-one (1803)

Step 1: 2-Methyl-6-phenylpyrimidin-4(3H) -one (1803-4)

[0380] To a solution of 1803-1 (3.0 g, 15.6 mmol) in EtOH (50 mL) was added NaOEt (2.1 g, 31.2 mmol) and acetamidine (1.5 g, 15.6 mmol, HC1 salt). The mixture was stirred at 70°C for 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (100 mL) and extracted with EtOAc (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under vacuum to give residue. The residue was purified by column chromatography to give Compound 1803-2 (1.5 g, crude) as a white solid.¹H NMR (DMSO-d6, 400MHz) 5 = 7.92 - 8.09 (m, 2H), 7.40 - 7.53 (m, 3H), 6.67 (s, 1H), 2.35 ppm (s, 3H)

Step 2: 3-((3-(4-Fluoro-3-methoxyphenyl)isoxazol-5-yl)methyl)-2-inethyl-6- plieiiylpyriiiiidin-4(3//)-one (1803-3)

[0381] To a solution of 1803-2 (77.1 mg, 413.8 μmol) in acetone (3.0 mL) was added K₂CO₃ (219.3 mg, 1.6 mmol), Nal (6.20 mg, 41.38 μmol) and 1707-1 (100 mg, 413.8 μmol). The mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (5.0 mL) and extracted with EtOAc (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue. The residue was purified by TLC to give Compound 1803-3 (50 mg, 127.8 μmol) as a white solid.

Step 3: 3-((3-(4-Fluoro-3-hydroxyphenyl)isoxazol-5-yl)methyl)-2-methyl-6- plieiiylpyriiiiidin-4(3//)-one (1803)

[0382] To a solution of 1803-3 (50 mg, 127.8 μmol) in DCM (3.0 mL) was added a solution of BBr.3 (256.0 mg, 1.0 mmol,) in DCM (1.0 mL) at -78 °C under N2 atmosphere. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (5.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1803 (12.8 mg, 33.8 μmol) as a white solid. ESI [M+H]⁺ = 378.0 (LCMS); ‘HNMR (DMSO-d6, 400MHz) 8 = 10.18 (s, 1H), 8.03 - 8.18 (m, 2H), 7.42 - 7.62 (m, 4H), 7.18 - 7.36 (m, 2H), 6.99 (d, ,7=17.9 Hz, 2H), 5.46 (s, 2H), 2.68 ppm (s, 3H).

Example 44: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-methyl-5, 6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H) -one (1839)

Step 1: tert-Butyl 2-methyl-4-oxo-4,5,6,8-tetrahydropyrido[3,4-d]pyrimidine-7(3H) - carboxylate (1839-2)

[0383] To a solution of acetimidamide (174.2 mg, 1.84 mmol, HC1 salt) in MeOH (3.0 mL) and H₂O (1.0 mL) was added 1839-1 (500 mg, 1.8 mmol) and K₂CO₃ (509.4 mg, 3.7 mmol). The mixture was stirred at 70 °C for 1.5 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were dried overNa₂SO₄ filtered and concentrated under reduced pressure to give Compound 1839- 2 (0.5 g, crude) as a white solid.

Step 2: rt-Butyl 3-((5-(4-fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)-2-methyl -4-oxo- 4.5.6.8-tetr:ihydropyrido|3.4-d|pyriniidine-7(3//)-carboxylate (1839-3)

[0384] To a solution of 1839-2 (0.4 g, 1.5 mmol) and 3-(chloromethyl)-5-(4-fluoro-3- methoxyphenyl)isoxazole (364.3 mg, 1.5 mmol) in acetone (4.0 mL) was added Nal (45.2 mg, 301.5 μmol) and K₂CO₃ (1.0 g, 7.5 mmol). The mixture was stirred at 50 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (6.0 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 1839-3 (0.4 g, 850.2 μmol) as a brown solid.

Step 3: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-methyl-5,6,7,8- tetrahydropyrido[3,4-d |pyriiiiidin-4(3//)-one (1839) [0385] To a solution of 1839-3 (20 mg, 42.5 μmol) in DCM (2.0 mL) was added a solution of BBn

(85.2 mg, 340.1 μmol) in DCM (2.0 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1839 (13.7 mg, 37.7 μmol) as a white solid. ESI [M-H]’ = 355.1 (LCMS);¹H NMR (400MHz, MeOD-d4) δ = 7.36 (dd, J=2.0, 8.3 Hz, 1H), 7.27 (ddd, J =2.1, 4.3, 8.4 Hz, 1H), 7.21 - 7.14 (m, 1H), 6.75 (s, 1H), 5.44 (s, 2H), 4.17 (s, 2H), 3.50 (t, J =6.2 Hz, 2H), 2.84 (br t, J =5.9 Hz, 2H), 2.72 (s, 3H).

Example 45: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2,7-dimethyl-5,6,7,8- tetrahydropyrido[3,4-d]pyrimidin-4(3H) -one (1848)

Step 1 : 1 :3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2,7-dimethyl-5,6,7,8- tetrahydropyrido[3,4-d |pyrimidin-4(3//)-one (1848)

[0386] To a solution of 1839 (120.0 mg, 336.7 μmol) in MeOH (8.0 mL) was added TEA (0. ImL), followed by the addition of HCHO (75.8 mg, 1.0 mmol, 69.6 uL, 40% purity). The resulting mixture was treated with a small amount of AcOEl to adjust the pH to 6. The mixture was stirred at 20 °C for 30 min, then NaBH CN (105.8 mg, 1.7 mmol) was added. The resulting reaction mixture was stirred at 20 °C for another 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The mixture was added NaHCO.i aqueous (0.1 mL) and concentrated under vacuum to give a residue which was purified by prep- HPLC to give Compound 1848 (16.4 mg, 38.4 μmol, HC1 salt) as a white solid. ESI [M+H]⁺= 37 L 1 (LCMS);^JH NMR (400MHz, MeOD-d4) δ = 7.35 (dd, J =2.1 , 8.2 Hz, 1 H), 7.26 (ddd, J =2.1 , 4.2, 8.4 Hz, 1H), 7.20 - 7.14 (m, 1H), 6.72 (s, 1H), 5.42 (s, 2H), 4.35 - 4.08 (m, 2H), 3.81 - 3.36 (m, 2H), 3.08 (s, 3H), 2.91 (br s, 2H), 2.65 (s, 3H). Example 46: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-(2,2,2-trifluoroethyl) quinazolin-4(3H) -one (1908)

Step 1: 2-(3, 3, 3-Trifluoropropanamido)benzamide (1908-2)

[0387] To a solution of 1908-1 (2.5 g, 18.4 mmol) in DCM (50 mL) was added 3, 3 , 3- trifhioropropanoic acid (2.4 g, 18.4 mmol, 1.6 mL), TEA (4.7 g, 45.907 mmol, 6.4 mL), EDCI (4.2 g, 22.0 mmol) and HOBt (2.9 g, 22.0 mmol). The mixture was stirred at 20 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was poured into H₂O (50 mL) and extracted with DCM (50 mL x 3). The combined organic layers were dried over Na₂SO₄ , filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 1908- 2 (3 g, 12.2 mmol) as a white solid¹.H NMR (400MHz, DMSO-d₆) δ = 8.44 - 8.13 (m, 2H), 7.92 - 7.61 (m, 2H), 7.51 (t, J =7.1 Hz, 1H), 7.27 - 7.13 (m, 1H), 3.65 (q, J=11.2 Hz, 2H)

Step 2: 2-(2, 2 , 2-Trifluoroethyl)quinazolin-4(3H) -one (1908-3)

[0388] To a solution of 1908-2 (500.0 mg, 2.0 mmol) in toluene (30 mL) was added t-BuOK (273.5 mg, 2.4 mmol). The resulting mixture was stirred at 80 °C for 3 h. TLC indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 1908-3 (150 mg, 675.5 μmol) as a white solid.

NMR (400MHz, DMSO-d6) 5 = 12.51 (br s, 1H), 8.12 (d, .7 =7.9 Hz, 1H), 7.89 - 7.78 (m, 1H), 7.68 (d, J =8.0 Hz, 1H), 7.55 (t, J =7.6 Hz, 1H), 3.75 (q, J=10.8 Hz, 2H).

Step 3: 3-((5-(4-Fluoro-3-methoxyphenyl)isoxazol-3-yl)methyl)-2-(2 ,2, 2-trifluoroethyl)quin azolin-4(3H) -one (1908-5)

[0389] To a solution of 1908-3 (51.1 mg, 224.0 μmol) in toluene (3.0 mL) was added 1908-4 (50.0 mg, 224.0 μmol), PPha (117.5 mg, 448.0 μmol) and DIAD (113.2 mg, 560.0 μmol). The mixture was stirred at 110 °C for 12 h under N2. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (10 mL) and extracted with DCM (5.0 mL x 3). The combined organic layers were dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give Compound 1908-5 (60.0 mg, crude) as a white solid.

Step 4: 3-((5-(4-Fluoro-3-hydroxyphenyl)isoxazol-3-yl)methyl)-2-(2 ,2 , 2-trifluoroethyl)quin azolin-4(377)-one (1908)

[0390] To a solution of 1908-5 (41.3 mg, 95.4 μmol) in DCM (2.0 mL) was added BBn (238.9 mg, 953.9 μmol) in DCM (1.0 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 3 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (2.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 1908 (11.8 mg, 28.14 μmol) as a white solid. ESI [M+H]⁺ = 420.0 (LCMS)¹H; NMR (400MHz, DMSO-d₆) δ = 10.38 (br s, 1H), 8.16 (d, >7.9 Hz, 1H), 7.93 - 7.82 (m, 1H), 7.70 (d, >8.1 Hz, 1H), 7.60 (t, >7.5 Hz, 1H), 7.38 (br d, >9.0 Hz, 1H), 7.33 - 7.24 (m, 2H), 6.97 (s, 1H), 5.47 (s, 2H), 4.18 (q, >10.0 Hz, 2H). Example 47: 2-Ethyl-3-((5-(4-fluoro-5-hydroxy-2-(trifluoromethyl) phenyl) isoxazo 1-3-yl) methyl)-5,6,7,8-tetrahydroquinazolin-4(3H) -one (2019)

Step 1: 2-Ethyl-3-((5-(4-fluoro-5-methoxy-2-(trifluoroinethyl) phenyl) isoxazol-3-yl) methyl)-5,6,7,8-tetrahydroquinazolin-4(3H) -one (2019-1)

[0391] To a solution of 2-ethyl-5,6,7,8-tetrahydroquinazolin-4(3H) -one (97.9 mg, 549.5 μmol) in acetone (5.0 mL) was added K₂CO₃ (379.7 mg, 2.8 mmol), Nal (8.2 mg, 55.0 μmol) and 1925-6 (170.1 mg, 549.5 μmol). The resulting mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by pouring into H₂O (6.0 mL) and extracted with DCM (4.0 mL x 3), dried over Na2SCU, filtered and concentrated under reduced pressure to give a residue which was purified by TLC to give Compound 2019-1 (100 mg, 221.5 μmol) as a yellow solid. ESI [M+H]⁺ = 452.1 (LCMS).

Step 2: 2-Ethyl-3-((5-(4-fluoro-5-hydroxy-2-(trifluoromethyl) phenyl) isoxazol-3-yl) methyl)- 5,6,7,8-tetrahydroquinazolin-4(3/Z)-one (2019)

[0392] To a solution of 2019-2 (30 mg, 66.7 μmol) in DCM (3.0 mL) was added BBrs (416.2 mg, 1.7 mmol, 160.1 μL) in DCM (1.0 mL) at -70 °C under N2. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 12 h under N2. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2019 (6.9 mg, 15.2 μmol) was obtained as a pale yellow solid. ESI [M+H]⁺ = 438.0 (LCMS)¹H; NMR (400 MHz, DMSO-d₆) 5 = 11.34 (br s, 1H), 7.79 (d, J = 11.5 Hz, 1H), 7.30 (d, J = 8.3 Hz, 1H), 6.76 (s, 1H), 5.35 (s, 2H), 2.78 (q, J= 13 Hz, 2H), 2.54 - 2.51 (m, 2H), 2.36 (br t, J= 5.5 Hz, 2H), 1.78 - 1.60 (m, 4H), 1.16 (t, J = 7.3 Hz, 3H).

Example 48: 2-(3-((2,5-Diethyl-6-oxopyrimidin-l(6//)-yl)methyl)isoxazol-5-yl)-5-fluoro-4- hydroxybenzonitrile (2020)

Step 1 : 2-(3-((2,5-Diethyl-6-oxopyrimidin-l(677)-yl)methyl)isoxazol-5-yl)-5-fluoro-4- methoxybenzonitrile (2020-1)

[0393] To a solution of 1925-6 (70 mg, 262.5 μmol) and 2,5-diethylpyrimidin-4(3H) -one (40.0 mg, 262.5 μmol) in acetone (3.0 mL) was added Nal (3.9 mg, 26.3 μmol) and K₂CO₃ (217.7 mg, 1.6 mmol). The mixture was stirred at 50 °C for 12 h. TLC indicated the reaction was completed. The reaction mixture was allowed to cool to room temperature. The reaction mixture was poured into H₂O (6.0 mL) and extracted with EtOAc (6.0 mL x 3). The combined organic layers were dried over Na2SO₄, filtered and concentrated in vacuum to give a residue which was purified by prep-TLC to give Compound 2020-1 (27 mg, 70.6 μmol) as a white solid.

Step 2: 2-(3-((2,5-Diethyl-6-oxopyrimidin-l(6//)-yl)methyl)isoxazol-5-yl)-5-fluoro-4- hydroxybenzonitrile (2020)

[0394] To a solution of 2020-1 (27 mg, 70.6 μmol) in DCM (2.0 mL) was added a solution ofBBn (176.9 mg, 706.1 μmol) in DCM (1.0 mL) at -78 °C under N2. The mixture was stirred at -78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 12 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (3.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2020 (4.3 mg, 11.5 μmol) as a white solid. ESI [M+H]⁺ = 369.0 (LCMS);¹H NMR (400 MHz, MeOD-d₄) 5 = 7.82 (s, 1H), 7.69 (d, J= 10.5 Hz, 1H), 7.51 (d, J= 8.1 Hz, 1H), 7.12 (s, 1H), 5.50 (s, 2H), 3.14 - 2.95 (m, 2H), 2.52 (q, .7= 7.4 Hz, 2H), 1.34 (t, J= 7 A Hz, 3H), 1.20 (t, J = 7.5 Hz, 3H).

Example 49: 5-(3-((2, 5-diethyl-6-oxopyrimidin-l(6//)-yl)methyl)isoxazol-5-yl)-2-fluoro-3- hydroxybenzonitrile (2023)

Step 1: 5-(3-((2, 5-diethyl-6-oxopyrimidin-l(6//)-yl)methyl)isoxazol-5-yl)-2-fluoro -3- methoxybenzonitrile (2023-2) [0395] To a solution of 2023-1 (200 mg, 750.0 μmol) and 2,5-diethylpyrimidin-4(3H) -one (114.1 mg, 750.0 μmol) in acetone (5.0 mL) was added K₂CO₃ (518.3 mg, 4.8 mmol) and Nal (14.5 mg, 96.9 μmol). The resulting mixture was stirred at 50 °C for 12 h. LCMS indicated that the starting material was completely consumed, and the desired mass was detected. The reaction mixture was allowed to cool to room temperature. The reaction mixture was quenched by pouring into H₂O (5.0 mL) and extracted with DCM (3.0 mL x 3), dried over Na₂SO₄ , fdtered and concentrated under reduced pressure to give Compound 2023-2 (200.0 mg, crude) as a white solid,^JH NMR (400 MHz, DMSO-d₆) δ = 8.01 (dd, J = 2.0, 5.0 Hz, 1H), 7.93 (dd, J = 1.9, 7.9 Hz, 1H), 7.83 (s, 1H), 7.15 (s, 1H), 5.37 (s, 2H), 4.00 (s, 3H), 2.83 (q, J= 7.3 Hz, 2H), 2.40 (q, J= 7.3 Hz, 2H), 1.21 - 1.08 (m, 6H)

Step 2: 5-(3-((2, 5-Diethyl-6-oxopyrimidin-l(6/Z)-yl)methyl)isoxazol-5-yl)-2-fluoro -3- hydroxybenzonitrile (2023)

[0396] To a solution of 2023-2 (35.0 mg, 91.5 μmol) in DCM (2.0 mL) was added a solution of BBr3 (229.3 mg, 915.3 μmol) in DCM (1.0 mL) at -78 °C under N2. The mixture was stirred at - 78 °C for 1 h then warmed to 25 °C and stirred at same temperature for another 2 h. LCMS showed the reaction was completed and desired mass was detected. The reaction mixture was concentrated in vacuum at 20 °C to give a residue which was diluted with MeOH (2.0 mL) and treated with NH3.H₂O dropwise to adjust pH 7. The mixture was concentrated in vacuum to give a residue which was purified by prep-HPLC to give Compound 2023 (14.7 mg, 39.5 μmol) as a white solid, ESI [M+H]⁺= 369.0 (LCMS¹)H; NMR(400 MHz, DMSO-db) 8 = 11.42 - 11.12 (m, 1H), 7.91 - 7.89 (m, 1H), 7.82 (s, 1H), 7.69 - 7.67 (m, 1H), 7.05 (s, 1H), 5.35 (s, 2H), 2.82 (d, J= 7.3 Hz, 2H), 2.39 (d, J= 7.5 Hz, 2H), 1.24 - 1.07 (m, 6H).

[0397] Select exemplified compounds according to the disclosure are further characterized in Table 2

Table 2: Structural Characterization of Select Exemplified Compounds

Example 41: HSD17B13 - HSD17B13 small molecule inhibitor cell-based assay protocol and results Objective:

[0398] Measure efficacy of HSD17B13 small molecule inhibitors in a cell-based assay using HEK293 cell lines overexpressing either human or mouse isoform HSD17B13. Cell viability assay is also performed to determine compound cytotoxicity.

Method:

[0399] HSD17B13 overexpressing HEK293 cell line is incubated with putative enzyme substrate estradiol (E2) and candidate enzyme inhibitor compound. After 24 hour incubation estradiol (E2) and product estrone (El) concentrations are monitored via LC-MS to measure enzyme inhibition versus vehicle (DMSO) treatment condition. Cytotoxicity assay measures adenosine triphosphate (ATP) levels from live cells via luminescent signal and indicates cytotoxicity of compound versus vehicle (DMSO) treatment condition.

Protocol:

Day 1:

[0400] Reconstitute powder estradiol (E2) to lOOmM concentration in DMSO or use frozen aliquot stored at -20°C. Dilute E2 to 3.25mM in DMSO from lOOmM DMSO stock solution. Reconstitute powder HSD17B 13 compounds to lOmM concentration in DMSO.

[0401] Prepare compound dilution plate from 2.5mM to 0.00 ImM in 96-well dilution plate using 8 concentration points with 3 -fold dilution per concentration point. Dilutions are in DMSO solvent. [0402] Adherent HEK293_humanB13, HEK293_mouseB13, and HEK293 GFP (negative control) cell lines should be grown to 70% confluence in T225 cell culture flasks at 37°C in 5% CO2 sterile incubator. In sterile biosafety cabinet aspirate media from cell culture flasks to waste. Rinse with PBS and aspirate PBS. Add trypsin solution to flasks to dissociate cells from surface. After cells are dissociated, add equal volume complete media (DME high glucose, 10% FBS, lx Pen/Strep/L-glut solution, 0.5mg/mL G418) to flasks and pipet up and down to break cell clumps into single-cell suspension and collect respective cell lines into sterile 50mL tubes. Calculate cell concentration for each cell line solution with automated cell counter. Add 33.4xl0⁶ cells into new sterile 50mL tubes and centrifuge briefly to pellet cells. Aspirate media supernatant without disturbing cell pellet and resuspend pellet in 50mL complete media for desired cell concentration of 0.667xl0⁶ cells/mL. Add 0.5mL cell solution to each well of 24-well PDL cell culture plate for desired 0.333xl0⁶ cells per well in 0.5mL complete media. [0403] Add 1 |iL of 3.25mM E2 to each well of 24-well PDL cell culture plate. Add 1 μL of diluted compound from 96-well dilution plate to appropriate wells of 24-well PDL cell culture plate. Incubate cells with substrate E2 and inhibitor compound at 37°C in 5% CO2 sterile incubator for 24 hours.

[0404] Day 2:

[0405] In sterile biosafety cabinet take 75μL media sample from each well of 24-well PDL cell culture plate into 96-well deep-well sample collection plate and seal with aluminum foil plate seal. Take additional 75 μL media sample in case replicate testing is needed. If not using immediately place sample plates into -80°C freezer.

[0406] Allow cell viability reagent to equilibrate to room temperature and then add 350μL reagent directly to wells of 24-well PDL cell culture plate with cells. Place 24-well PDL cell culture plates onto plate shaker for 10 minutes to lyse cells and stabilize luminescent signal. Transfer 200μL of lysed cell solution from 24-well PDL cell culture plates to 96-well black walled plates. Read luminescence on plate reader and record results.

[0407] To prepare samples for LC-MS analysis add 300μL LC-MS grade methanol to 75μL media samples (4:1 ratio) in 96-well deep-well plate and seal plate. Incubate at 23°C for 20 minutes to precipitate proteins out of solution. Centrifuge plate at 900g for 10 minutes at 23 °C to pellet proteins. Transfer 300μL supernatant into new 96-well deep-well sample plate without disturbing pellet. Place sample plate into vacuum-centrifuge to desiccate samples to complete dryness. Resuspend dried sample pellet in 80μL of 60% LC-MS grade water, 40% LC-MS grade methanol, with 0.05% formic acid, solution. Seal plate and bath sonicate until pellet is completely dissolved into solution. Centrifuge plate at 2500g for 10 minutes at 23°C to pellet insoluble components.

[0408] Inject 20μL sample using Acquity UPLC Lclass system with ACQUITY UPLC Peptide BEH C18 column with flow rate 0.45ml/min, 2 minute isocratic elution, mobile phase A: watecformic acid / 100:0.1 [V:V], mobile phase B: acetonitrile:formic acid / 100:0.1 [V:V] coupled to Q Exactive Plus Orbitrap MS system, selected ion monitoring (SIM) for El and E2.

[0409] From raw mass spec data extract El and E2 chromatograms for area under the curve (AUC) absolute quantitation using standard curve. Plot El concentration values into Prism software using non-linear fit log(inhibitor) vs. response (three parameters) to calculate EC50 value for each compound. Plot corresponding viability data for each concentration point to assess compound cytotoxicity. Inhibition percentage and cell viability percentage are calculated using vehicle control (DMSO) treatment condition as baseline.

[0410] Tables 3, 4 and 5 summarize the results of the inhibition and cell viability assays. Table 3 shows the EC50, inhibition and cell viability results for compound 2033. Table 4 shows IC50, EC50 and Microsomes results for the compounds according to the disclosure. Table 5 shows the IC50 results for the compounds according to the disclosure.

Table 3

Table 4

Table5

* * *

[0411] As various changes can be made in the above-described subject matter without departing from the scope and spirit of the present disclosure, it is intended that all subject matter contained in the above description, or defined in the appended claims, be interpreted as descriptive and illustrative of the present disclosure. Many modifications and variations of the present disclosure are possible in light of the above teachings. Accordingly, the present description is intended to embrace all such alternatives, modifications, and variances which fall within the scope of the appended claims.

[0412] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

WHAT IS CLAIMED IS:

1. A compound according to Formula A: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;

Z is selected from CR₅ and S;

R? is H or an optionally substituted C₁-C₁₀ alkyl;

Ro is H or an optionally substituted C₁-C₁₀ alkyl; and R₇ is an aryl or heteroaryl, each of which is optionally substituted; -NR₁₁R₁₂, wherein R₁₁ and R₁₂ are C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₁₁ and R₁₂ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

2. A compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N;

3. The compound of claim 1 or 2 having a structure according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

4. The compound of claim 2 having a structure according to Formula IIIA or IIIB :

or a pharmaceutically acceptable salt thereof, wherein

5. The compound of claim 3 having a structure according to Formula IV: or a pharmaceutically

6. The compound of claim 5, wherein R₁₁ is an optionally substituted C₁-C₄ alkyl.

7. The compound of claim 1 having a formula

8. The compound of claim 1, wherein Z is S.

9. The compound of claim 1, wherein Z is CR₅.

10. The compound of claim 1 or 2, wherein R₇ is an aryl or heteroaryl.

11. The compound of any one of claims 1-4, wherein Ri is hydrogen (H).

12. The compound of any one of claims 1-4, wherein R₂ is selected from H, a halide, OH, and CN.

13. The compound of any one of claims 1-4, wherein R₂ is fluoro.

14. The compound of claim 4, wherein R3 is selected from H, F, Cl, CN, and CF₃.

15. The compound of any one of claims 1-4, wherein R4 is selected from H, CN, and CF₃.

16. The compound of any one of claims 1-4, wherein R₅ is H or a C₁-C₁₀ alkyl.

17. The compound of any one of claims 1-4, wherein R₆ is H or a C₁-C₁₀ alkyl.

18. The compound of any one of claims 1-5, wherein R₁₁ is selected from H and an optionally substituted C₁-C₄ alkyl.

19. The compound of any one of claims 1-4, wherein R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

20. The compound of any one of claims 1-4, wherein Qi is N, Q₂ is C, and Q₃ is N.

21. The compound of any one of claims 1-4, wherein Qi is C, Q₂ is N, and Q₃ is N.

22. The compound of any one of claims 1-4, wherein Qi is N, Q₂ is C, and Q₃ is C.

23. A pharmaceutical composition comprising the compound according to any one of claims 1 to

22, together with one or more excipients.

24. A pharmaceutical dosage form comprising the compound according to any one of claims 1 to 22 or the composition according to claim 23.

25. A method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula A:

wherein:

X and Y are independently selected from O and N;

Z is selected from CR₅ and S;

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

26. A method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula I: or a pharmaceutically acceptable salt thereof,

wherein:

X and Y are independently selected from O and N;R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein R₁₀ is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

27. A method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula IIA or IIB:

or a pharmaceutically acceptable salt thereof, wherein

R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

28. A method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound according to Formula IIIA or IIIB:

or a pharmaceutically acceptable salt thereof, wherein

Ro is H or an optionally substituted C₁-C₁₀ alkyl; R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

29. A method of modulating a HSD17B13 protein in a cell comprising administering an effective amount of a compound selected from the group consisting of:

30. The method according to any one of claims 25-29, wherein modulating the HSD17B13 protein comprises inhibiting the HSD17B13 protein.

31. The method according to any one of claims 25-29, wherein the compound does not modulate one or more of HSD17B1, HSD17B2, HSD17B3, HSD17B4, HSD17B5, HSD17B6,

HSD 17B7, HSD 17B 8, HSD 17B9, HSD 17B 10, HSD 17B 1 1 , HSD 17B 12, or HSD 17B 14.

32. The method according to any of claims 25-29, wherein the compound does not modulate one or more of HSD 17B 1 , HSD 17B2, HSD 17B4, HSD 17B 10, and HSD 17B 13.

33. The method of any according to claims 25-29, wherein the cell is a mammalian cell.

34. The method according to claim 33, wherein the cell is a human cell.

35. The method according to claim 33, wherein the cell is a liver cell.

36. The method according to claims 25-29, wherein the compound inhibits the HSD17B13 protein with an IC50 of less than 10 μmol.

37. The method according to claims 25-29, wherein the compound inhibits the HSD17B13 protein with an IC50 of less than 2 μmol.

38. The method according to claims 25-29, wherein the compound inhibits the HSD17B 13 protein with an IC50 of less than 0.1 μmol.

39. A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula A:

wherein: X and Y are independently selected from O and N;

Z is selected from CR₅ and S;

40. A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

X and Y are independently selected from O and N;R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein Rio is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl;

41 . A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to formula IIA or

I IB: or a pharmaceutically acceptable salt thereof,

wherein

R? is H or an optionally substituted C₁-C₁₀ alkyl;

Ro is H or an optionally substituted C₁-C₁₀ alkyl; and R₈ and R₉ are independently C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁-C₁₀ heterocyclyl; or R₈ and R₉ are linked together through the attached nitrogen (N) to form an optionally substituted heterocyclic moiety.

42. A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to formula IIIA or IIIB:

or a pharmaceutically acceptable salt thereof, wherein

R₁ - R₄ are each independently selected from H, halide, C₁-C₄ alkyl, C₃-C₆ cycloalkyl, OH, OR₁₀, CN, and CF₃, wherein Rio is a C₂-C₁₀ alkyl; R₅ is H or an optionally substituted C₁-C₁₀ alkyl; 6 is H or an optionally substituted C₁-C₁₀ alkyl; R₁₁ is H or an optionally substituted C₁-C₁₀ alkyl; and R₁₂ and R₁₃ are independently H, C₁-C₁₀ acyl, C₁-C₁₀ alkyl, C₅-C₁₀ aryl, C₅-C₁₀ heteroaryl, C₁- C₁₀ heterocyclyl; or R₁₂ and R₁₃ are linked together to form an optionally substituted cyclic or heterocyclic moiety.

43. A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound according to Formula IV: or a pharmaceutically

44. A method of treating a liver disease in a subject having liver disease comprising administering to the subject an effective amount of a compound selected from the group consisting of:

, or a pharmaceutically acceptable salt thereof.

45. A protein-drug conjugate comprising: (a) an antigen binding protein that specifically binds a tumor-associated antigen (TAA); (b) a compound according to claims 1-22; and (c) a suitable linker that connects said antigen binding protein and said amanitin or analog thereof.

46. The protein-drug conjugate of claim 45, wherein the linker is a cleavable linker.

47. The protein-drug conjugate of claim 45, wherein the linker is a non-cleavable linker.

48. The protein-drug conjugate of claim 45, wherein the linker is connected to the antigenbinding protein using a transglutaminase reaction.

49. The protein-drug conjugate of claim 45, wherein the TAA is selected from the group consisting of: an anti-HER2 antibody, an anti-STEAP2 antibody, an anti-MET antibody, an anti -EGFR VIII antibody, an anti-MUC16 antibody, an anti-PRLR antibody, an anti-PSMA antibody, an anti-FGFR2 antibody, an anti-FOLRl antibody, an anti-HER2/HER2 bispecific antibody, an anti-ASGRl antibody, an anti-MET/MET bispecific antibody, or an antigenbinding fragment thereof.