KIT inhibitors

Abstract

One embodiment of the present disclosure is a compound represented by formula (I) or a pharma- ceutically acceptable salt thereof.The variables in formula (I) are defined herein.The compound of formula (I) is useful for inhibiting mutant KIT protein and treating conditions related to abnormal KIT activity in humans or non-humans. [Formula 1] TIFF2025513372000402.tif64165

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 332,387, filed April 19, 2022, the contents of which are incorporated herein by reference in their entirety.

[0002] The present application is directed to KIT inhibitors and methods of their use, such as to control the activity of mutant forms of the enzyme KIT (also called "CD117") in a subject. [Background technology]

[0003] The present disclosure relates to novel N-(pyridin-2-yl)pyrimidin-4-amine compounds and their use as selective inhibitors of mutant KIT protein kinase for use in pharmaceutical compositions for treating gastrointestinal stromal tumors (GIST).

[0004] The enzyme KIT (also known as CD117) is a receptor tyrosine kinase expressed in a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain induces receptor dimerization, kinase domain activation, and activation of downstream signaling pathways. Mutations in KIT are found in over 80% of primary GIST patients, with the most common KIT mutations found in exon 11 and less commonly in exon 9. These mutations render the KIT enzyme independent of activation by its ligand, SCF, leading to high cell division rates and, in some cases, genomic instability (C.R. Antonescu, The GIST Paradigm: Lessons from Other Kinase-Driven Cancers, J. Pathol. 223, 251–261 (2011)). Constitutive activation of KIT plays a central role in the oncogenic behavior of GIST.

[0005] GIST patients with primary mutations in KIT exons 9 or 11 respond well to first-line imatinib, with an overall response rate of 60%, but after patients progress (or fail after imatinib), subsequent treatments, including sunitinib, regorafenib, and ripretinib, show less robust efficacy, with overall response rates remaining below 10% for each of these treatments (Ther. Adv. Med. Oncol. 2021;13:1758835920986498).

[0006] Patients resistant to imatinib have been observed to most frequently exhibit on-target mutations in KIT, exon 17 (several different amino acids, including D816) or exon 13 (including V654A and N655K). These resistance mutations occur in addition to primary exon 9 or 11 mutations (Debiec-Rychter M, et al. Gastroenterology. 2005;128:270-9) (Roberts KG, et al. Mol Cancer Ther. 2007;6:1159-66) (Tamborini E, et al. Oncogene. 2006;25:6140-6). Clinical trials using small molecules designed to target exon 17 resistance mutations in KIT have observed that patients with KIT exon 13, specifically KIT exon 13 V654A, are less likely to respond to treatment (George, S., Abstract #11511, American Society of Clinical Oncology, June 2018, Chicago, Illinois; Heinrich, M., Abstract #3027631, Connective Tissue Oncology Society, November 2018, Rome, Italy). For transformative therapy of GIST patients, resistance mutations, such as exon 13 mutations within the KIT enzyme, must be inhibited.

[0007] Current KIT inhibitors are insufficient for the treatment of GISTs that have become resistant to inhibitors of primary activating KIT mutations. For example, current KIT inhibitors cannot adequately inhibit mutant exon 13, such as V654A and N655K. Therefore, small molecule therapies targeting resistant KIT mutations, such as exon 13 V654A and / or exon 13 N655K resistance mutations, are needed. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] J. Pathol. 223, 251-261 (2011) [Non-patent document 2] Ther.Adv.Med.Oncol.2021;13:1758835920986498 [Non-patent document 3] Debiec-Rychter M,et al.Gastroenterology.2005;128:270-9. [Non-patent document 4] Roberts KG,et al.Mol Cancer Ther.2007;6:1159-66. [Non-Patent Document 5] Tamborini E,et al.Oncogene.2006;25:6140-6 [Non-patent document 6] George, S., Abstract #11511, American Society of Clinical Oncology, June 2018, Chicago, Illinois; Heinrich, M., Abstract #3027631, Connective Tissue Oncology Society, November 2018, Rome, Italy Summary of the Invention [Problem to be solved by the invention]

[0009] Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions useful for inhibiting mutant KIT protein and treating gastrointestinal stromal tumors (GIST). For example, the IC50 values ​​for inhibiting KIT autophosphorylation in Table 1 are listed below. 50 The values ​​demonstrate that these compounds are potent inhibitors of mutant KIT. [Means for solving the problem]

[0010] A first embodiment of the present disclosure is a compound of formula (I): [ka] or a pharmaceutically acceptable salt thereof, wherein

[0011] R 1 and R 1A are each independently selected from H, halogen, and CH3, or R 1 and R 1A together with the carbon to which they are attached to form a cyclopropyl,

[0012] R 2 But C 1-5 Alkyl, CD3, C 3-6 cycloalkyl, bicyclo[1.1.1]pentane, and 4- to 6-membered heterocycles containing O, wherein the alkyl, cycloalkyl, or heterocycle is selected from 1 to 3 R 4 is optionally replaced by

[0013] Each R 4 are independently halogen, CH3, C 2-3 Alkenyl, OH, CH2OH, C 4-6 cycloalkyl, a 4- to 6-membered heterocycle containing O, and phenyl, wherein the alkyl, cycloalkyl, heterocycle, or phenyl is selected from OH or NH2, C 1-2 optionally substituted with alkyl, CH2NH2, or halogen;

[0014] R 3 But C(O)NHR5 , [ka] and

[0015] X1 is NH or O,

[0016] X2 is N or CH;

[0017] X3 is N or CH;

[0018] R 5 But H, C 1-3 Alkyl, CD3, C 3-4 cycloalkyl, and bicyclo[1.1.1]pentane, wherein the alkyl, cycloalkyl, or bicyclo[1.1.1]pentane is selected from 1 to 2 R 7 is optionally replaced by

[0019] Each R 7 are independently selected from CN, NH, OH, CHOH, cyclopropyl, pyridinyl, and oxazolyl, or two R attached to the same carbon atom; 7 together form a 4-membered N-containing heterocycle,

[0020] R 6 But independently, C 1-5 alkyl, CHF2, CF3, 4- or 5-membered heterocycles containing N or O, and C 3-4 cycloalkyl, wherein the alkyl or heterocycle is selected from one R 8 is optionally replaced by

[0021] R 8 However, independently, OH, NR 9 R 9 , OCH3, CH3, and a 4-membered heterocycle containing N or O, wherein the alkyl or heterocycle is selected from one R 10 is optionally replaced by

[0022] Each R 9is independently selected from H, CH3, and CH2CF3;

[0023] R 10 is selected from CH3 and CF3, or a pharmaceutically acceptable salt thereof.

[0024] Another embodiment of the present disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0025] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST) with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0026] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0027] Another embodiment of the present disclosure is a method for detecting an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation. A method of treating a patient suffering from a malignant disease characterized by a KIT mutation, or a combination thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0028] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective combination comprising: (i) an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and (ii) a second agent.

[0029] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective combination comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and at least one additional agent.

[0030] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor harboring an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof, comprising: (a) obtaining a biological sample from the patient; (b) detecting an exon 13 KIT mutation or an exon 14 KIT mutation; detecting the presence or absence of a KIT mutation; and (c) if a mutation is detected, administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0031] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor harboring an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof, comprising: (a) obtaining a biological sample from the patient; (b) detecting an exon 13 KIT mutation or an exon 14 KIT mutation; detecting the presence or absence of a KIT mutation; and (c) if the mutation is present, administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0032] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease characterized by tumors harboring exon 9 KIT mutations, exon 11 KIT mutations, or exon 17 KIT mutations, or combinations thereof, comprising administering to the patient an exon 13 KIT mutation or exon 14 KIT mutation. If a KIT mutation is detected, the method includes administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0033] 1. A method of treating a patient suffering from a malignant disease characterized by a tumor having an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof, comprising: If a KIT mutation is present, the method comprises administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

[0034] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a compound disclosed herein in combination with a pharmaceutically acceptable carrier or excipient. or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), wherein the GIST has a mutation that is resistant to a KIT inhibitor administered to treat GIST with a primary activating mutation in exon 9 or exon 11.

[0035] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST) characterized by a primary activating mutation in exon 9 KIT or exon 11 KIT, comprising: (i) a pharmaceutical composition comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing); and (ii) a pharmaceutical composition comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), administering to the patient a KIT inhibitor effective against GIST characterized by a primary activating mutation in KIT. DETAILED DESCRIPTION OF THE INVENTION

[0036] The disclosed compounds, or pharmaceutically acceptable salts thereof, are inhibitors of the KIT enzyme and are useful in the treatment of KIT-dependent disorders or diseases.

[0037] definition The following abbreviations and terms have the means indicated throughout:

[0038] The term "alkyl," used alone or as part of a larger moiety such as "alkoxy" or "haloalkyl," means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically contains 1 to 6 carbon atoms (C 1-6 alkyl) (i.e., 1, 2, 3, 4, 5, or 6), or 1 to 3 carbon atoms (C 1-3 alkyl) (i.e., 1, 2, or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[0039] The term "alkenyl" means an aliphatic straight-chain or branched monovalent hydrocarbon radical having one double bond. Unless otherwise specified, an alkenyl group typically contains 1 to 6 carbon atoms (C 1-3 alkenyl), or 1 to 3 carbon atoms (C 1-3 alkenyl).

[0040] "Cycloalkyl" means a saturated aliphatic cyclic hydrocarbon ring group. Unless otherwise specified, cycloalkyl is a group having 3 to 8 ring carbon atoms (C 3-8 cycloalkyl), or 3 to 6 ring carbon atoms (C 3-6 cycloalkyl), or 3 to 5 carbon atoms (C 3-5 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0041] The term "halogen" or "halo" means fluorine or fluoro (F), chlorine or chloro (Cl), bromine or bromo (Br), or iodine or iodo (I).

[0042] The term "heterocycle," unless otherwise specified, refers to a monocyclic non-aromatic ring group containing 3 to 8 ring atoms (i.e., "3-, 4-, 5-, 6-, 7-, or 8-membered") selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxide (e.g., NO), air, and sulfur, including sulfoxides and sulfones. Representative heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[0043] The terms "hydroxyl" or "hydroxy" refer to an OH group.

[0044] The term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of hydrogen substituents in a given structure with non-hydrogen substituents. Thus, for example, a substituted alkyl is an alkyl in which at least one non-hydrogen substituent is present in place of a hydrogen substituent on the alkyl group. For illustrative purposes, a monofluoroalkyl is an alkyl substituted with a fluoro substituent, and a difluoroalkyl is an alkyl substituted with two fluoro substituents. When there are two or more substitutions on a substituent, it should be recognized that each non-hydrogen substituent can be the same or different (unless otherwise specified).

[0045] When a group is described as "optionally substituted," the group can be either (1) unsubstituted or (2) substituted. When a group is described as optionally substituted with up to a specific number of non-hydrogen substituents, the group can be either (1) unsubstituted or (2) substituted with the lesser of either up to the specific number of non-hydrogen substituents or non-hydrogen substituents up to the maximum number of substitutable positions on the substituent. Thus, for example, if a group is described as cycloalkyl optionally substituted with up to three non-hydrogen substituents, any cycloalkyl having less than three substitutable positions can be optionally substituted with up to as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

[0046] Compounds with one or more chiral centers can exist in various stereoisomeric forms, i.e., each chiral center can have an R or S configuration, or a mixture of both. Stereoisomers are compounds that differ only in spatial configuration. Stereoisomers include all diastereomeric and enantiomeric forms of a compound. Enantiomers are stereoisomers that are mirror images of each other. Diastereomers are stereoisomers with two or more chiral centers that are neither identical nor mirror images of each other.

[0047] When the stereochemical configuration at a chiral center of a compound having one or more chiral centers is represented by its chemical name (e.g., when the configuration is indicated in the chemical name by "R" or "S") or structure (e.g., when the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration over the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%.

[0048] The "enrichment of the indicated configuration relative to the opposite configuration" is a mole percent and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center(s) by the total number of all compounds having the same or opposite stereochemical configuration in the mixture.

[0049] When two or more stereoisomers are represented by a chemical name or structure and the names or structures are connected by "or," either one or the other of the two or more stereoisomers, but not both, is intended. Enrichment of one stereoisomer over the other is as described above.

[0050] When a disclosed compound having a chiral center is represented by a structure without indicating the configuration at that chiral center, the structure is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center. When a disclosed compound having a chiral center is represented by a chemical name without indicating the configuration at that chiral center with "S" or "R," the chemical name is meant to encompass compounds having the S configuration at that chiral center, compounds having the R configuration at that chiral center, or compounds having a mixture of R and S configurations at that chiral center.

[0051] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present invention includes all enantiomerically pure, enantiomerically enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, as well as diastereomeric mixtures, of the compounds described herein.

[0052] Enantiomeric and diastereomeric mixtures can be resolved into their component enantiomers or stereoisomers by well-known methods, examples of which include chiral-phase gas chromatography, chiral-phase high-performance liquid chromatography, crystallization of the compound as a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0053] "Peak 1" or "first eluting isomer" in the experimental section refers to an intended reaction product compound obtained from a chromatographic separation / purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as "Peak 2" or "second eluting isomer."

[0054] If a compound is designated by a name or structure that denotes a single enantiomer, unless otherwise specified, the compound is at least 60%, 70%, 80%, 90%, 99%, or 99.9% optically pure (also called "enantiomerically pure"). Optical purity is the weight of the mixture of the named or represented enantiomer divided by the total weight of the mixture of both enantiomers.

[0055] When the stereochemistry of a disclosed compound is designated or depicted by structure, and this designated or depicted structure encompasses more than one stereoisomer (e.g., as in the case of a diastereomeric pair), it is to be understood that one of the encompassed stereoisomers or any mixture of the encompassed stereoisomers is included unless otherwise indicated. It is further understood that the stereoisomeric purity of the named or depicted stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. Stereoisomeric purity in this case is determined by dividing the total weight of the mixture of stereoisomers encompassed by the name or structure by the total weight of the mixture of all stereoisomers.

[0056] As used herein, the term "pharmaceutically acceptable salt" refers to pharmaceutical salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and commensurate with a reasonable benefit / risk ratio.

[0057] Pharmaceutically acceptable salts are known in the art. For example, S.M. Berge et al. describe pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of the present disclosure having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and salts of organic acids (such as acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present disclosure having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts).

[0058] A "subject" or "patient" is a mammal in need of medical treatment, preferably a human, but may also be an animal in need of veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cows, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In one aspect, the patient is a human. In one aspect, the patient is an adult human.

[0059] The term "effective amount" refers to an amount that, when administered to a subject or patient, produces beneficial or desired results, including clinical results, e.g., inhibits, suppresses, or reduces the symptoms of the condition being treated in the subject compared to a control. For example, a therapeutically effective amount can be provided in a unit dosage form (e.g., 0.1 mg to about 50 g per day, or 1 mg to about 5 grams per day). The exact amount of a compound or pharmaceutically acceptable salt thereof administered to provide an "effective amount" to a subject will depend on the mode of administration, the type and severity of the disease or condition, and the subject's characteristics, such as general health, age, sex, weight, and tolerance to drugs. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., in combination with an anti-cancer or antiviral agent, the "effective amount" of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and are based on the subject's condition, the type of condition(s) being treated, and other factors, as reported in the literature and published in the Physician's Desk Reference (57 th The dosages of the compounds of the present invention and their pharmaceutically acceptable salts used can be adjusted by those skilled in the art according to the dosages recommended in the "Medicine of the Year" (ed., 2003).

[0060] As used herein, "malignant disease" refers to a disease in which abnormal cells divide uncontrollably and can invade nearby tissues. Malignant cells can also spread to other parts of the body via the blood or lymphatic system. Examples of malignant diseases are carcinoma, sarcoma, leukemia, and lymphoma. Cancer is a malignant disease. Systemic mastocytosis is a malignant disease. Asymptomatic systemic mastocytosis is a malignant disease.

[0061] Examples of cancer include, but are not limited to, gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

[0062] As used herein, "inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that inhibits a protein, e.g., an enzyme, such that a decrease in the activity of the protein can be observed, for example, by a biochemical assay. In certain embodiments, the inhibitor has an IC50 of less than 1 mM, less than 500 nM, less than 250 nM, less than 100 nM, less than 50 nM, less than 20 nM, less than 10 nM, less than 5 nM, and less than 1 nM.

[0063] The term "KIT" refers to a human tyrosine kinase that may be called the obesity / stem cell growth factor receptor (SCFR), the proto-oncogene c-KIT, the tyrosine-protein kinase KIT, or CD117.

[0064] As used herein, the term "KIT mutation" refers to a KIT gene, cDNA, mRNA, or protein that differs in sequence from the KIT gene sequence of the human reference genome hg19, or the corresponding cDNA, mRNA, or protein. In some embodiments, when considering a KIT mutation in a nucleotide sequence encoding a KIT polypeptide, the mutation is described in terms of the change produced in the sequence of the polypeptide encoded by the nucleotide. In some embodiments, the KIT mutation is V654A, N655K, or K642E in exon 13. As used herein, the term "exon 9 KIT mutation" refers to a mutation in exon 9 of KIT. As used herein, the term "exon 11 KIT mutation" refers to a mutation in exon 11 of KIT. As used herein, the term "exon 13 KIT mutation" refers to a mutation in exon 13 of KIT. As used herein, the term "exon 17 KIT mutation" refers to a mutation in exon 17 of KIT. As used herein, the term "exon 18 KIT mutation" refers to a mutation in exon 18 of KIT. A829P is the first mutation in exon 18 KIT, although in some embodiments, A829P is referred to as an "exon 17" KIT mutation. In some embodiments, the KIT mutations are N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D in exon 17. In some embodiments, the KIT mutation is A829P in exon 18 or exon 17.

[0065] As used herein, a "selective KIT inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that selectively inhibits KIT protein kinase over another protein kinase and exhibits at least 2-fold selectivity for KIT protein kinase over another kinase. For example, a selective KIT inhibitor exhibits at least 10-fold selectivity, at least 15-fold selectivity, at least 20-fold selectivity, at least 30-fold selectivity, at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity, at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, or at least 200-fold selectivity for KIT kinase over another kinase. In some embodiments, a selective KIT inhibitor exhibits at least 150-fold selectivity over another kinase, such as VEGFR2 (vascular endothelial growth factor receptor 2), SRC (non-receptor protein tyrosine kinase), and FLT3 (Fms-like tyrosine kinase 3). See, e.g., Evans et al. (2017). In some embodiments, selectivity for KIT kinase versus another kinase is measured in a cellular assay (e.g., the cellular assays provided herein). In other embodiments, selectivity for KIT kinase or for another kinase is measured in a biochemical assay (e.g., the biochemical assays provided in Evans, et al. (2017)). In some embodiments, the KIT inhibitor is a selective KIT inhibitor. In some embodiments, the selective KIT inhibitor is a compound disclosed herein, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the selective KIT inhibitor is avapritinib. In some embodiments, the selective KIT inhibitor is bezucrastinib. In some embodiments, the selective KIT inhibitor is BLU-263. In some embodiments, the KIT inhibitor is a pan-KIT inhibitor.In one embodiment, the pan-KIT inhibitor is AZD3229.

[0066] Compound Embodiments Exemplary embodiments include the following:

[0067] First embodiment: Formula (I): [ka] or a pharmaceutically acceptable salt thereof. The variables of formula (I) are described in the Summary above.

[0068] Second embodiment: A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A are each independently selected from H, halogen, and CH; R 2 But C 1-5 Alkyl, CD3, C 3-6 cycloalkyl, and 4- to 6-membered heterocycles containing O, wherein the alkyl, cycloalkyl, or heterocycle is selected from 1 to 3 R 4 and each R 4 are independently halogens, CH3, OH, NH2, C 4-6 cycloalkyl, a 4- to 6-membered heterocycle containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH; and each R 7 are independently selected from CN, OH, CHOH, cyclopropyl, pyridinyl, and oxazolyl, or two R attached to the same carbon atom; 7 together form a 4-membered heterocycle containing N, and R 10 is CH3, or a pharmaceutically acceptable salt thereof. The remainder of the variables in formula (I) are as described above in the first embodiment. In some second embodiments, each R 4 are independently halogens, CH3, OH, C 4-6It is selected from cycloalkyl, 4-6 membered heterocycles containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH2.

[0069] Third embodiment: Formula (II): [ka] or a pharmaceutically acceptable salt thereof. The variables of formula (II) are as described in the first and / or second embodiment.

[0070] Fourth embodiment: Formula (III): [ka] or a pharmaceutically acceptable salt thereof. The variables of formula (III) are as described in the first and / or second embodiment.

[0071] Fifth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A are each independently selected from H, halogen, and CH; R 2 But C 1-5 Alkyl, CD3, C 3-4 cycloalkyl, and 4- to 6-membered heterocycles containing O, wherein the alkyl, cycloalkyl, or heterocycle is selected from 1 to 3 R 4 and each R 4 is independently selected from halogen, CH3, and phenyl; R 5 But H, C 1-3 Alkyl, CD3, C 3-4 cycloalkyl, and bicyclo[1.1.1]pentane, wherein the alkyl, cycloalkyl, or bicyclo[1.1.1]pentane is selected from 1 to 2 R 7 and each R 7are independently selected from CN, OH, CHOH, cyclopropyl, pyridinyl, and oxazolyl, or two R attached to the same carbon atom; 7 taken together form a 4-membered N-containing heterocycle, or a pharmaceutically acceptable salt thereof. The remainder of the variables of formula (I) are as described above in the first or second embodiment.

[0072] Sixth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is selected from 1 to 3 R 4 or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formulas (I), (II), and (III) are as described above in the first, second, and / or fifth embodiments.

[0073] Seventh embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formulas (I), (II), and (III) are as described above in the first, second, and / or fifth embodiments.

[0074] Eighth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R 4is independently selected from F, CH, cyclobutyl, and phenyl, or a pharmaceutically acceptable salt thereof. The remainder of the variables of formulas (I), (II), and (III) are described above in the first, second, fifth, sixth, and / or seventh embodiments.

[0075] Ninth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from H, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, and bicyclo[1.1.1]pentanyl, and said CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, or bicyclo[1.1.1]pentanyl is selected from H, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, or bicyclo[1.1.1]pentanyl, and 7 or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formulas (I), (II), and (III) are as described above in the first, second, fifth, sixth, seventh, and / or eighth embodiments.

[0076] Tenth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 5 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formulas (I), (II), and (III) are as described above in the first, second, fifth, sixth, seventh, and / or eighth embodiments.

[0077] Eleventh embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein each R 7 are independently CN, CH2OH, cyclopropyl, [ka] or two R bonded to the same carbon atom7 Together, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (II), and (II) are as described above in the first, second, fifth, sixth, seventh, eighth, ninth, and / or tenth embodiments.

[0078] Twelfth embodiment: A compound represented by formula (I), (II), or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A are each independently selected from H, F, and CH3, or a pharmaceutically acceptable salt thereof. The remainder of the variables of formulas (I), (II), and (II) are as described above in the first, second, fifth, sixth, seventh, eighth, ninth, tenth, and / or eleventh embodiments.

[0079] Thirteenth embodiment: Formula (IV), (V), or (VI): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables of formulas (IV), (V), and (VI) are as described above in the first and / or second embodiments.

[0080] Fourteenth embodiment: Formula (VII), (VII), (IX), or (X): [ka] or a pharmaceutically acceptable salt thereof, wherein the variables of formulas (VII), (VIII), (IX), and (X) are as described above in the first and / or second embodiments.

[0081] Fifteenth embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R1 and R 1A are each independently selected from H, halogen, and CH; R 2 But C 1-3 Alkyl, CD3, C 3-4 cycloalkyl, and a 4- to 6-membered heterocycle containing one O, wherein the alkyl, cycloalkyl, or heterocycle is selected from 1 to 3 R 4 and each R 4 is independently selected from halogen, OH, cyclopropyl, a 4- to 6-membered heterocycle containing one O, and phenyl, wherein said cyclopropyl or phenyl is optionally substituted with OH or NH; R 6 But C 1-4 alkyl, CHF2, CF3, 4- or 5-membered heterocycles containing N or O, and C 3-4 cycloalkyl, wherein said alkyl, heterocycle, or cycloalkyl is selected from R 8 optionally replaced by R 8 But, OH, NR 9 R 9 , OCH, CH, and a 4-membered heterocycle containing N or O, said heterocycle being optionally substituted with CH; and each R 9 is independently selected from H, CH, and CHCF, or a pharmaceutically acceptable salt thereof. The remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are described above in the first and / or second embodiments.

[0082] Sixteenth embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is selected from 1 to 3 R 4or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, and / or fifteenth embodiments.

[0083] 17th embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 2 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, and / or fifteenth embodiments.

[0084] 18th embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein each R 4 is independently selected from F, OH, cyclobutyl, oxetanyl, phenyl, tetrahydrofuranyl, and tetrahydropyranyl, wherein said cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranyl, or tetrahydropyranyl is optionally substituted with OH or NH, or a pharmaceutically acceptable salt thereof. The remainder of the variables of Formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are described above in the first, second, fifteenth, sixteenth, and / or seventeenth embodiments.

[0085] Nineteenth embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein each R 4 But independently, F, OH, [ka] and *- represents OH or NH2, or a pharmaceutically acceptable salt thereof. The remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, fifteenth, sixteenth, and / or seventeenth embodiments.

[0086] 20th embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CH2CH2CH(CH3)2, CHF2, CF3, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, tetrahydrofuranyl, and pyrrolidinyl, each of which is selected from R 8 or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0087] 21st embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 6 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments.

[0088] 22nd embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from OH, OCH3, CH3, NH2, NHCH3, N(CH3)2, NHCH2CF3, N(CH3)CH2CF3, azetidinyl, azetidinyl, and oxetanyl, or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of Formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments.

[0089] 23rd embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 8 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables of formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments.

[0090] 24th embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A is each independently selected from H, F, and CH3, or a pharmaceutically acceptable salt thereof. The remainder of the variables of Formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, and / or twenty-third embodiments.

[0091] Twenty-fifth embodiment: Formula (III) or (VII): [ka] or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A are each independently selected from H, F, and CH3; R 2 But C 1-3 Alkyl, CD3, C 3-4 cycloalkyl, and a 4-membered heterocycle containing one O, wherein the alkyl is optionally substituted with one to three halo; R 5 is selected from CH3, CH2CH3, and cyclopropyl; R 6 But C 1-5 alkyl, CHF2, CF3, and a 4- to 5-membered heterocycle containing O or N, wherein the alkyl or heterocycle is selected from R 8 optionally replaced by R 8 But, OH, NR 9 R 9 , OCH, CH, and a 4-membered heterocycle containing O or N; 9 is independently selected from H and CH3, or a pharmaceutically acceptable salt thereof.

[0092] 26th embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 2 are CH3, CHF2, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2F, CH(CH3)CHF2, cyclobutyl, cyclopropyl, and [ka] The remainder of the variables in formula (III) or (VII), or a pharmaceutically acceptable salt thereof, are as described above in the twenty-fifth embodiment.

[0093] 27th embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, CHF2, azetidinyl, oxetanyl, tetrahydrofuranyl, and pyrrolidinyl, each of which is selected from one R 8 or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables in formula (III) or (VII) are as described above in the twenty-fifth and / or twenty-sixth embodiments.

[0094] 28th embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 but, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables in formula (III) or (VII) are as described above in the twenty-fifth and / or twenty-sixth embodiments.

[0095] 29th embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8 is, OH, OCH3, NH2, NHCH3, N(CH3)2, CH3, [ka] or a pharmaceutically acceptable salt thereof, wherein the remainder of the variables in formula (III) or (VII) are as described above in the twenty-fifth, twenty-sixth, twenty-seventh, and / or twenty-eighth embodiments.

[0096] Thirty embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8is selected from OH, OCH3, NH2, NHCH3, N(CH3)2, and CH3, or a pharmaceutically acceptable salt thereof. The remainder of the variables in formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, and / or twenty-ninth embodiments.

[0097] 31st embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, and CHF2, each of which is selected from one R 8 The remainder of the variables in formula (III) or (VII) are as described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, and / or thirtieth embodiments. In some thirty-first embodiments, R 6 is selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, and CHF2, each of which is selected from one R 8 In some thirty-first embodiments, R 6 is selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, and CH2CH2CH(CH3)2, each of which is selected from one R 8 is replaced by .

[0098] 32nd embodiment: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6is selected from CH3, CH2CH2OH, CH2CH2N(CH3)2, CH2CH2NHCH3, CH2CH2NH2, CH2CH(N(CH3)2)CH3, CH2CH(NHCH3)CH3, CH2C(NHCH3)(CH3)2, CH2C(NH2)(CH3)2, CH2CHOCH3, CH2CH(OH)(CH3), CH2C(OH)(CH3)2, CH2CH2C(OH)(CH3)2, and C(CH3)2CH2OH, or a pharmaceutically acceptable salt thereof. The remainder of the variables in formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, and / or thirty-first embodiments.

[0099] Thirty-third embodiment: A compound represented by formula (III), or a pharmaceutically acceptable salt thereof, wherein the variables in formula (III) are as described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, and / or thirty-second embodiments.

[0100] Thirty-fourth embodiment: A compound represented by formula (VII), or a pharmaceutically acceptable salt thereof, wherein the variables in formula (VII) are as described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirty-first, and / or thirty-second embodiments.

[0101] The present disclosure also includes the compounds shown in Table 1 and prepared in the Examples, both their neutral forms and pharmaceutically acceptable salts.

[0102] In one embodiment, compounds 204-211 in Table 2, and pharmaceutically acceptable salts thereof, are excluded from the present disclosure.

[0103] The present disclosure also includes pharmaceutical compositions containing a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound set forth in Table 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0104] Another embodiment of the present disclosure is a compound disclosed herein, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more hydrogen atoms are replaced with deuterium. The deuterium enrichment at any one of the sites where hydrogen is replaced with deuterium is at least 50%, 75%, 85%, 90%, 95%, 98%, or 99%. Deuterium enrichment is a molar percentage and is obtained by dividing the number of compounds having deuterium enrichment at the enrichment site by the number of compounds having hydrogen or deuterium at the enrichment site.

[0105] Usage example Compounds of the present disclosure (e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds in Table 1, or pharmaceutically acceptable salts of any of the foregoing) are useful as KIT inhibitors. For example, KIT inhibitors of the present disclosure inhibit mutant KIT protein kinases in which the mutation is in exon 13, e.g., K642E, V654A, or N655K KIT mutations, or in exon 14, e.g., T680K KIT mutation. K642E is an exon 13 KIT mutation that may be a primary activating mutation. It is less common than the primary activating KIT mutations in exon 9 and exon 11. Thus, KIT inhibitors of the present disclosure can treat conditions associated with aberrant KIT activity in human or non-human patients. KIT inhibitors of the present disclosure (also referred to as compounds of the present disclosure) include compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), and / or (X), as well as pharmaceutically acceptable salts thereof, and the compounds set forth in Table 1. The compounds of the present disclosure are selective for exon 13 KIT over wild-type KIT and PDGFR and are therefore expected to exhibit minimal side effects attributable to wild-type inhibition (such as anemia, thrombocytopenia, and edema). The compounds of the present disclosure also exhibit reduced brain penetration. Reduced or absent brain penetration is expected to provide safety benefits and minimize undesirable cognitive effects. The method includes administering to the patient an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient a pharmaceutical composition comprising an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and a pharmaceutically acceptable carrier or excipient.

[0106] In one aspect, the present disclosure relates to a method of treating a patient suffering from a malignant disease (or cancer) characterized by a KIT mutation, e.g., an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. Examples of malignant diseases or cancers treatable by the compounds of the present disclosure include gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma. In one aspect, the malignant disease (or cancer) is selected from gastrointestinal stromal tumor (GIST), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, and pancreatic cancer. In one aspect, the malignant disease (or cancer) is selected from AML (acute myeloid leukemia), intercranial germ cell tumor, and mediastinal B-cell lymphoma. In one aspect, the cancer is a gastrointestinal stromal tumor (GIST), in another aspect, the cancer is AML (acute myeloid leukemia), in another aspect, the cancer is melanoma, in yet another aspect, the cancer is lung cancer, in yet another aspect, the cancer is uterine cancer, in yet another aspect, the cancer is astrocytoma, in yet another aspect, the cancer is liver cancer, in yet another aspect, the cancer is seminoma, in yet another aspect, the cancer is renal cell carcinoma (RCC), in one aspect, the RCC is a pancreatic neuroendocrine tumor (pNET), in yet another aspect, the cancer is intercranial germinoma, in yet another aspect, the cancer is pancreatic cancer, and in yet another aspect, the cancer is mediastinal B-cell lymphoma. In one aspect, the cancer treatable by a compound of the disclosure (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing) is advanced. In another aspect, the cancer is adjuvant.

[0107] In certain aspects, the present disclosure provides a method for detecting an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation.

[0013] Provided are methods of treating a patient suffering from a malignant disease (or cancer) characterized by a KIT mutation, or a combination thereof, comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the malignant disease (or cancer) is selected from gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma. In some embodiments, the malignant disease (or cancer) is gastrointestinal stromal tumor (GIST). In some embodiments, the method further comprises administering to the patient an effective amount of one or more agents (e.g., 1, 2, 3, or 4 additional agents). In some embodiments, the patient has received one or more prior treatments for the malignant disease (or cancer) (e.g., treatments prior to administering a compound of the present disclosure). In some embodiments, the malignant disease (or cancer) has progressed after the prior treatment. In some embodiments, the prior treatment comprises administering one or more agents (e.g., 1, 2, 3, or 4 additional agents). In some embodiments, the agent is a KIT inhibitor. In some embodiments, the malignancy (or cancer) has a mutation that is resistant to a drug (eg, a KIT inhibitor).In some embodiments, the agent is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the one or more agents comprises avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering one or more agents, each independently selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, rivocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof.In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the malignant disease (or cancer) has an imatinib-resistant mutation. In some embodiments, the pretreatment comprises administering sunitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering regorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering bezucrastinib or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, the pretreatment comprises administering BLU-263 or a pharmaceutically acceptable salt thereof.

[0108] In one aspect, a malignant disease (or cancer) treatable by the disclosed methods (e.g., GIST) is characterized by a primary activating KIT mutation. A "primary activating mutation" is an early mutation that converts or contributes to the conversion of a normal cell to a cancer cell; i.e., a primary activating mutation is involved in the initiation of tumorigenesis and / or driving cancer. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, or an exon 11 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, and an exon 17 KIT mutation. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In one embodiment, the exon 17 KIT mutation is D816V. In some embodiments, the primary activating mutation is A829P. A829P is the first mutation in exon 18 KIT, but is commonly referred to as an "exon 17" mutation. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In some embodiments, the primary activating KIT mutation is an exon 13 KIT mutation, such as V654A, N655K, or K642E.In another embodiment, the cancer is GIST, and the primary activating mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. In another embodiment, the cancer is GIST, and the primary activating mutation is selected from an exon 9 and / or exon 11 mutation. In another embodiment, the cancer is GIST, and the primary activating mutation is an exon 9 KIT mutation or an exon 11 KIT mutation, or a combination thereof. In another embodiment, the cancer is GIST, and the primary activating mutation is an exon 13 KIT mutation. In another embodiment, the cancer is GIST, and the primary activating mutation is an exon 17 KIT mutation.

[0109] For primary GIST patients, complete surgical resection is the initial treatment of choice, and surgery is effective in approximately 50% of GIST patients. As used herein, the term "primary GIST" refers to a GIST that has only a primary activating mutation (e.g., does not have a secondary resistance-conferring mutation). Among the remaining patients, tumor recurrence is frequent. For patients with GIST recurrence after surgical resection, the patient is administered one or more anticancer drugs for the treatment of GIST. In one embodiment, the one or more anticancer drugs are administered before treatment with the KIT inhibitor of the present disclosure. For example, the KIT inhibitor of the present disclosure is administered after the GIST has progressed after prior treatment. For example, the patient's tumor became resistant (or refactored) to the previous drug, or the patient had GIST that was intolerant to treatment with the previous drug or recurred after prior treatment. Examples of agents that have been studied and used in the pretreatment of GIST are selected from imatinib (e.g., methanesulfonate), sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the drugs studied and used in the pre-treatment of GIST are selected from imatinib (e.g., methanesulfonate), sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, and bezucrastinib, and larotrectinib, and pharmaceutically acceptable salts thereof (Vallilas, C., et al. International Journal of Molecular Sciences. 2021; 22, 493). Further examples of drugs studied and used in the pre-treatment of GIST are selected from the following:AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol (also known as BLU-263 and elenestinib) is another KIT inhibitor for use in the treatment of GIST. N-(4-{[5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (also known as AZD3229 and NB003) is another KIT inhibitor for use in the treatment of GIST. In some embodiments, the agent studied and used in the pretreatment of GIST is selected from the following: AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof.

[0110] In some embodiments, patients with GIST are administered a "primary KIT inhibitor." Specifically, the primary KIT inhibitor is administered to inhibit primary activating KIT mutations in patients with primary GIST. For example, imatinib is used as a primary KIT inhibitor to inhibit primary activating KIT mutations in exon 9 and / or exon 11. Treatment with a primary KIT inhibitor such as imatinib has also been shown to be sufficient for initial treatment, i.e., for treating primary GIST patients, for example, patients with exon 9 and / or exon 11 activating KIT mutations. However, despite the beneficial effects of targeted therapy such as imatinib, 50% of patients eventually develop primary or secondary resistance to imatinib after two years. These secondary imatinib-resistant mutations are most frequently located in KIT exons 11, 13, 14, 17, 18, or a combination thereof.

[0111] Sunitinib is the standard of second-line therapy for most imatinib-resistant tumors and is used to treat GIST containing KIT mutations in exons 11, 13, and 14. However, secondary KIT mutations in exons 17 and 18 are resistant to sunitinib treatment, and tumors containing tertiary resistance mutations in exons 17 and 18 appear several months after sunitinib treatment.

[0112] Regorafenib has shown promising results in phase 3 clinical trials of imatinib- and sunitinib-resistant GIST, and is active against some, but not all, exon 17 and 18 mutations, including D816. Regorafenib is approved for the treatment of third-line GIST.

[0113] Ripretinib is a KIT and PDGFRA kinase inhibitor approved for fourth-line GIST treatment.

[0114] Additional options for treating GIST include cabozantinib, dasatinib, everolimus, nilotinib, pazopanib, sorafenib, and larotrectinib.

[0115] Avapritinib is a selective exon 17 and exon 18 KIT inhibitor currently approved for patients with GIST harboring exon 18 PDGFRA mutations. Avapritinib has been reported to be active against one or more KIT mutations in exon 17 (e.g., D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D820A, D820E, D820G, N822K, N822H, Y823D, and A829P); see U.S. Patent No. 9,200,002, the entire contents of which are incorporated herein by reference.

[0116] Bezucrastinib, also known as CGT9486 and PLX9486, has the following structure: [ka]

[0117] AZD3229, also known as NB003, has the following structure: [ka]

[0118] In some embodiments, pretreatment of a patient with a GIST involves treating the patient with one or more agents (e.g., 1, 2, 3, or 4 agents) prior to treatment with a KIT inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or prior to treatment with a pharmaceutical composition containing a KIT inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof (e.g., a compound of the present disclosure, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In one embodiment, the prior treatment comprises administering one or more agents selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, rivocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, everolimus, larotrectinib, bezucrastinib, AZD3229, and BLU-263, and pharmaceutically acceptable salts thereof. In one embodiment, the prior treatment comprises administering a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof; imatinib mesylate is a pharmaceutically acceptable salt of imatinib). The prior treatment is continued until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to the primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). In another embodiment, the prior treatment comprises administering an exon 17 KIT inhibitor. Examples of exon 17 inhibitors are avapritinib, BLU-263, ripretinib, and AZD3229. Examples of selective exon 17 inhibitors are avapritinib, BLU-263, and bezucrastinib. In one embodiment, the prior treatment comprises administering an exon 13 KIT inhibitor. An example of an exon 13 KIT inhibitor is sunitinib.In some embodiments, the exon 17 KIT inhibitor is selected from avapritinib, BLU-263, ripretinib, bezucrastinib, and AZD3229. In some embodiments, the exon 17 KIT inhibitor is avapritinib. In some embodiments, the exon 17 KIT inhibitor is BLU-263. In some embodiments, the exon 17 KIT inhibitor is ripretinib. In some embodiments, the exon 17 KIT inhibitor is bezucrastinib. In some embodiments, the exon 17 KIT inhibitor is AZD3229. Examples of alternative exon 17 inhibitors are avapritinib, BLU-263, and bezucrastinib. In some embodiments, the exon 17 KIT inhibitor is an alternative exon 17 KIT inhibitor. In some embodiments, the alternative exon 17 KIT inhibitor is selected from avapritinib, BLU-263, and bezucrastinib. In some embodiments, the alternative exon 17 KIT inhibitor is avapritinib. In some embodiments, the alternative exon 17 KIT inhibitor is BLU-263. In some embodiments, the alternative exon 17 KIT inhibitor is bezucrastinib. In another embodiment, the prior treatment comprises administering one or more agents selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, rivocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, everolimus, larotrectinib, bezucrastinib, AZD3229, and BLU-263, and pharmaceutically acceptable salts thereof. In another embodiment, the prior treatment comprises administering one or more agents selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, rivocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof.

[0119] In another embodiment, the pretreatment comprises administering a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The pretreatment is continued until the GIST is identified as having progressed or is resistant, refractory, or intolerant to the primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), after which the pretreatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as having progressed or is resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof).

[0120] In another embodiment, the pretreatment comprises administering a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The pretreatment is continued until the GIST is identified as having progressed or is resistant, refractory, or intolerant to the primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), and thereafter the pretreatment further comprises administering an exon 17 KIT inhibitor or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as having progressed or is resistant, refractory, or intolerant to the exon 17 inhibitor or a pharmaceutically acceptable salt thereof).

[0121] In another embodiment, the pretreatment comprises administering a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The pretreatment is continued until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to the primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), and thereafter the pretreatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof), and thereafter the pretreatment further comprises administering regorafenib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to regorafenib or a pharmaceutically acceptable salt thereof).

[0122] In another embodiment, the pretreatment comprises administering a primary KIT inhibitor (eg, imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), and then the prior treatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof), and then the prior treatment further comprises administering regorafenib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to regorafenib or a pharmaceutically acceptable salt thereof), and then the prior treatment further comprises administering ripretinib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to ripretinib or a pharmaceutically acceptable salt thereof).

[0123] In another embodiment, the pretreatment comprises administering an effective amount of a primary KIT inhibitor (eg, imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to the first-line KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), after which the prior treatment further comprises administering at least one agent selected from nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, and crenolanib, or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as having progressed or becomes resistant, refractory, or intolerant to the agent(s) or a pharmaceutically acceptable salt(s) thereof).

[0124] The tumor is or has become mutationally resistant to the drug used in the previous treatment due to the presence of a mutation present in the tumor that renders the tumor resistant or refractory to the previous drug, i.e., a "resistance mutation." For example, the tumor may have mutational resistance to a primary KIT inhibitor. In some embodiments, the tumor has a mutation that confers resistance to an exon 9 KIT inhibitor or an exon 11 KIT inhibitor, or a combination thereof. In some embodiments, the tumor has a mutation that confers resistance to an exon 9 KIT inhibitor, an exon 11 KIT inhibitor, an exon 13 KIT mutation, an exon 17 KIT mutation, or an exon 14 KIT mutation, or a combination thereof. In some embodiments, the previous drug is imatinib, and the mutation is an imatinib-resistant mutation. In one embodiment, the tumor has a mutation that confers resistance to the previous drug. In one embodiment, the mutation that confers resistance to the previous drug is selected from an exon 13 KIT mutation, an exon 17 KIT mutation, an exon 18 KIT mutation, and an exon 14 KIT mutation, and a combination thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K, and K642E, and combinations thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K, and combinations thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and combinations thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from, e.g., N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D, and combinations thereof.In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the mutation resistant to the preceding drug is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, and combinations thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P, and combinations thereof. In some embodiments, the mutation resistant to the preceding drug is an exon 14 KIT mutation, e.g., an exon 14 KIT mutation such as N680K. In some embodiments, the tumor is resistant or has become resistant to the preceding drug with one or more mutations.

[0125] In some embodiments, the tumor is mutation-resistant to prior treatment as a result of one or more exon 17 mutations. Examples of exon 17 inhibitors that can inhibit such exon 17 mutation(s), rendering the tumor resistant to prior treatment and thereby treating the tumor are selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib. Other mutations that can be inhibited by the above-mentioned exon 17 inhibitors include N655K, N680K, or a combination thereof.

[0126] In some embodiments, the pre-treated tumor (e.g., with a primary KIT inhibitor such as imatinib) has one or more exon 13 mutations, such as exon 13 KIT mutations selected from V654A, N655K, and K642E, and combinations thereof. In some embodiments, the pre-treated tumor (e.g., with a primary KIT inhibitor such as imatinib) has one or more exon 13 mutations, such as exon 13 KIT mutations selected from V654A, N655K, and combinations thereof.

[0127] In one embodiment, the disclosure provides a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the patient has received one or more prior therapies for GIST. In some embodiments, the GIST has progressed after the prior treatment. In some embodiments, the pretreatment comprises administering one or more agents. In some embodiments, the one or more agents comprises imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more agents comprises avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering one or more agents, each independently selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, rivocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof.In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering sunitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering regorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering bezucrastinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering BLU-263 or a pharmaceutically acceptable salt thereof. In some embodiments, the GIST is characterized by tumors harboring one or more KIT mutations. In some embodiments, the tumors harbor primary activating KIT mutations.In some embodiments, the GIST is characterized by tumors harboring one or more KIT mutations, each independently selected from exon 9, exon 11, exon 13, and exon 17 KIT mutations, and combinations thereof. In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, K642E, V654A, and N655K, and combinations thereof. In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, and K642E, and combinations thereof. In some embodiments, the tumor has an exon 9 KIT mutation. In some embodiments, the tumor has an exon 11 KIT mutation. In some embodiments, the tumor has an exon 17 KIT mutation. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In some embodiments, the exon 17 KIT mutation is D816V. In some embodiments, the tumor has an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is selected from K642E, V654A, and N655K, and combinations thereof. In some embodiments, the exon 13 KIT mutation is K642E. In some embodiments, the exon 17 mutation is A829P. In some embodiments, the exon 18 mutation is A829P. In some embodiments, the tumor is mutation-resistant to one or more prior therapies.In some embodiments, the tumor is resistant to imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof, or a mutation thereof. In some embodiments, the tumor is resistant to imatinib by a mutation. In some embodiments, the tumor has an imatinib-resistant mutation. In some embodiments, the tumor has an exon 13 inhibitor-resistant mutation. In some embodiments, the tumor has an exon 14 inhibitor resistance mutation. In some embodiments, the tumor has an exon 17 inhibitor resistance mutation. In some embodiments, the exon 17 inhibitor is selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib, and pharmaceutically acceptable salts thereof. In some embodiments, the exon 17 inhibitor is avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the exon 17 inhibitor resistance mutation is N655K. In some embodiments, the exon 17 inhibitor resistance mutation is N680K. In some embodiments, the imatinib resistance mutation is selected from an exon 13 KIT mutation, an exon 17 KIT mutation, and an exon 14 KIT mutation, and combinations thereof. In some embodiments, the imatinib resistance mutation is an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is V654A or N655K. In some embodiments, the imatinib resistance mutation is an exon 17 KIT mutation, hi some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P.In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In some embodiments, the exon 17 KIT mutation is D816V. In some embodiments, the exon 17 KIT mutation is D816E. In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the imatinib-resistant mutation is an exon 14 KIT mutation. In some embodiments, the exon 14 KIT mutation is N680K.

[0128] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient: (i) a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing); and (ii) a combination comprising one additional agent (e.g., one, two, three, or four additional agents).

[0129] In one embodiment, a patient suffering from GIST is administered a combination comprising (i) an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and (ii) a primary KIT inhibitor (e.g., imatinib) as an additional agent. In one embodiment, a patient suffering from GIST is administered a combination comprising (i) a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and (ii) an exon 9 or exon 11 inhibitor as an additional agent.In one embodiment, a patient suffering from GIST is administered a combination comprising (i) an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and (ii) an exon 17 inhibitor as an additional agent.

[0130] In another embodiment, a patient suffering from GIST is administered (i) an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). and a pharmaceutical composition comprising a pharmaceutically acceptable salt thereof) and as an additional agent, (ii) a first-line KIT inhibitor (e.g., imatinib), or a pharmaceutically acceptable salt thereof, and at least one agent selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, sunitinib, avapritinib, BLU-263, ripretinib, AZD3229, bezucrastinib, everolimus, and larotrectinib, and a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, sunitinib, avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is an exon 17 inhibitor. In one embodiment, the additional agent (iii) is selected from avapritinib, BLU-263, lipertinib, AZD3229, and bezucrastinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is avapritinib or a pharmaceutically acceptable salt thereof.In one embodiment, the additional agent (iii) is BLU-263 or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is lipertinib or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is AZD3229 or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is bezucrastinib or a pharmaceutically acceptable salt thereof.

[0131] In another embodiment, a patient suffering from GIST is administered (i) a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutical composition comprising any of the foregoing pharmaceutically acceptable salts) and, as additional agents, (ii) a primary KIT inhibitor (e.g., imatinib), or a pharmaceutically acceptable salt thereof, and (iii) an exon 17 inhibitor, and (iv) at least one agent selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, and sunitinib, and pharmaceutically acceptable salts thereof (e.g., an effective combination). In any of the foregoing embodiments, the exon 17 inhibitor is selected from avapritinib, BLU-263, lipertinib, AZD3229, and bezucrastinib. In one embodiment, the exon 17 inhibitor is selected from avapritinib, BLU-263, lipertinib, AZD3229, and bezucrastinib. In one embodiment, the exon 17 inhibitor is avapritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is BLU-263 or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is lipertinib or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is AZD3229 or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is bezucrastinib or a pharmaceutically acceptable salt thereof.

[0132] In one aspect, the combination therapy described in this paragraph can be administered as a first-line therapy, i.e., before resistance mutations are identified, or as a second-, third-, or fourth-line therapy, i.e., after one or more resistance-conferring mutations have emerged. When a combination of agents is administered, the agents in the combination can be administered simultaneously (in the same or different formulations) or simultaneously in any order.

[0133] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective combination comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and at least one additional agent. In some embodiments, the additional agent is an exon 9 KIT inhibitor or an exon 11 KIT inhibitor. In some embodiments, the additional agent is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the additional agent is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an exon 17 KIT inhibitor. In some embodiments, the additional agent is selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib. In some embodiments, the additional agent is selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib.

[0134] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a combination comprising a pharmaceutical composition comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and one or more agents. In some embodiments, the agent is an exon 9 KIT inhibitor or an exon 11 KIT inhibitor. In some embodiments, the agent is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the agent is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an exon 17 KIT inhibitor. In some embodiments, the agent is selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezucrastinib.

[0135] Another embodiment of the present disclosure is a method for treating a patient suffering from a malignant disease (e.g., GIST) characterized by a tumor having an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. The method includes: (a) obtaining a biological sample from the patient; (b) detecting the presence or absence of an exon 13 KIT mutation or an exon 14 KIT mutation; and (c) if a mutation is detected, administering to the patient an effective amount of a compound of the present disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In one embodiment, the presence or absence of an exon 13 KIT mutation is detected, for example, in step (b), where the exon 13 KIT mutation is V654A or N655K. In another embodiment, the presence or absence of an exon 14 KIT mutation is detected, for example, in step (b), where the exon 14 KIT mutation is N680K. The presence or absence of the exon 13 mutations V654A or N655K or the exon 14 mutation N680K is detected according to the methods disclosed in WO2020 / 102095, the teachings of which are incorporated herein by reference in their entirety.

[0136] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor harboring an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof, comprising: (a) obtaining a biological sample from the patient; (b) detecting an exon 13 KIT mutation or an exon 14 KIT mutation; detecting the presence or absence of a KIT mutation; and (c) if the mutation is present, administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In one embodiment, the presence or absence of an exon 13 KIT mutation is detected, for example, in step (b), wherein the exon 13 KIT mutation is V654A or N655K. In another embodiment, the presence or absence of an exon 14 KIT mutation is detected, for example, in step (b), wherein the exon 14 KIT mutation is N680K. The presence or absence of the exon 13 mutation V654A or N655K or the exon 14 mutation N680K is detected according to the methods disclosed in WO2020 / 102095, the teachings of which are incorporated herein by reference in their entirety.

[0137] Another embodiment of the present disclosure is a method of treating a patient suffering from a malignant disease characterized by tumors harboring exon 9 KIT mutations, exon 11 KIT mutations, or exon 17 KIT mutations, or combinations thereof, comprising administering to the patient an exon 13 KIT mutation or exon 14 KIT mutation. If a KIT mutation is detected, the method comprises administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the exon 13 KIT mutation is V654A or N655K. In some embodiments, the exon 14 KIT mutation is N680K.

[0138] 1. A method of treating a patient suffering from a malignant disease characterized by a tumor having an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof, comprising: If a KIT mutation is present, the method comprises administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the exon 13 KIT mutation is V654A or N655K. In some embodiments, the exon 14 KIT mutation is N680K.

[0139] Another embodiment of the present disclosure is a method of treating a patient afflicted with gastrointestinal stromal tumor (GIST), comprising administering to a patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutically acceptable carrier or excipient, and a compound disclosed herein, or a pharmaceutically acceptable salt thereof. and a pharmaceutically acceptable salt of (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), wherein the GIST has a mutation that is resistant to a KIT inhibitor administered to treat GIST with a primary activating mutation in exon 9 or exon 11. In some embodiments, the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the KIT inhibitor is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is bezucrastinib or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is BLU-263 or a pharmaceutically acceptable salt thereof. In some embodiments, the mutation is an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is V654A or N655K.

[0140] Another embodiment of the present disclosure is a method of treating a patient afflicted with a primary gastrointestinal stromal tumor (GIST) characterized by a primary activating mutation in exon 9 KIT or exon 11 KIT, comprising: (i) a pharmaceutical composition comprising an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing); and (ii) an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or a compound in Table 1, or a pharmaceutically acceptable salt of any of the foregoing), characterized by a primary activating mutation in exon 9 KIT or exon 11 KIT. The present invention relates to a method for treating GIST characterized by a primary activating mutation in KIT, comprising administering to a patient an effective amount of a KIT inhibitor effective against the GIST. In some embodiments, the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, riboclicrib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezucrastinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the KIT inhibitor is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is bezucrastinib or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, the KIT inhibitor is BLU-263 or a pharmaceutically acceptable salt thereof.

[0141] Pharmaceutical Composition Although the compound of the present disclosure can be administered alone, it is preferred that the compound be administered as a pharmaceutical preparation, which is combined with one or more pharmaceutically acceptable excipients or carriers.The compound of the present disclosure or its pharmaceutically acceptable salt can be formulated for administration in any convenient way for use in human or veterinary medicine.In certain embodiments, the compound contained in pharmaceutical preparation can be active itself, or can be a prodrug, for example, can be converted into active compound in physiological environment.

[0142] The phrase "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that 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.

[0143] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; and (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil. (10) oils, (11) glycols, such as propylene glycol; (12) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (13) esters, such as ethyl olein and ethyl laurate; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; (21) cyclodextrins; and (22) other non-toxic, compatible substances used in pharmaceutical formulations.

[0144] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium hydrogen sulfide, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and (3) metal chelators such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0145] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) can include one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as glycerol; or (4) agar. (5) disintegrating agents such as calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (6) solution retarding agents such as paraffin; (7) wetting agents such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0146] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (specifically cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters of sorbitan, and mixtures thereof.

[0147] The suspensions may contain, in addition to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

[0148] The ointments, pastes, creams, and gels may contain, in addition to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0149] Powders and sprays can contain, in addition to the compounds of the present disclosure or pharmaceutically acceptable salts thereof, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants (e.g., chlorofluorohydrocarbons) and volatile unsubstituted hydrocarbons (e.g., butane and propane).

[0150] The formulations can be conveniently provided in unit dosage form and can be prepared by any method known in the pharmaceutical field.The amount of active ingredient that can be combined with carrier materials to produce a single dosage form varies depending on the host treated and the specific mode of administration.The amount of the compound of the present disclosure or its pharmaceutically acceptable salt that can be combined with carrier materials to produce a single dosage form is generally the amount of compound that produces a therapeutic effect.

[0151] Dosage forms for topical or transdermal administration of the compounds of the present disclosure or their pharmaceutically acceptable salts include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants, as may be required.

[0152] When the compound of the present disclosure or a pharmaceutically acceptable salt thereof is administered to humans or animals as a pharmaceutical, it can be administered by itself or in combination with a pharmaceutically acceptable carrier as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient.

[0153] Formulations may be administered topically, orally, transdermally, rectally, intravaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

[0154] Dosage Actual dosage levels of the active ingredients in the pharmaceutical compositions of the present disclosure may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without being toxic to the patient.

[0155] The selected dosage level will depend upon a variety of factors, including the activity of the particular active ingredient used, the route of administration, the time of administration, the rate of excretion of the particular active ingredient used, the duration of treatment, other drugs, compounds and / or materials used in combination with the particular active ingredient used, the age, sex, weight, condition, general health and previous medical history of the patient being treated, and similar factors well known in the medical arts.

[0156] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian can start the dosage of the compound of the present disclosure used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0157] In general, a suitable daily dose of a compound of the disclosure will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[0158] As used herein, the terms "administer," "administering," "administration," and the like refer to methods that can be used to enable delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumor, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, transdermal, rectal, and the like. Administration techniques that can be used with the agents and methods described herein can be found, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0159] The particular mode of administration and dosing regimen will be selected by the attending physician, taking into account the particulars of the case (e.g., the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment may involve daily or multiple daily or less-than-daily (weekly, monthly, etc.) administrations over a period ranging from several days to several months, and in some cases, years.

[0160] The pharmaceutical composition of the present disclosure is formulated to be suitable for its intended route of administration.In some embodiments, the composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous, subcutaneous, intramuscular, oral, intranasal or topical administration to humans.In a preferred embodiment, the pharmaceutical composition is formulated for intravenous administration.

[0161] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the formulation and / or administration of and / or absorption by a subject of an active agent, and refer to substances that can be included in the compositions of the present disclosure without causing adverse toxicological effects to the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal sucrose, binders, fillers, disintegrants, lubricants, coating agents, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidine, and dyes. Such preparations can be sterilized and, if necessary, mixed with auxiliary substances such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring agents, and / or flavoring agents that do not adversely react with or interfere with the activity of the compounds provided herein. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds. [Example]

[0162] The following examples are intended to be illustrative and are not meant to limit the scope of the disclosure in any way.

[0163] Abbreviation Abbreviations and acronyms used herein include the following: AcOH means acetic acid; AIBN means 2,2'-azobis(2-methylpropionitrile); t-AmOH means tert-amyl alcohol; Aq. means aqueous; Boc means tert-butoxycarbonyl; (BPin)2 means 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi-1,3,2-dioxaborolane; br means broad; Brettphos means 2-(dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl; BrettPhos Pd G3 means [(2-dicyclohexylphosphino-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate; BrettPhos Pd G4 means dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl]phenyl]phosphane; methanesulfonic acid; N-methyl-2-phenylaniline; palladium. n-BuOH means butan-1-ol; t-BuOK means potassium tert-butoxide; d means doublet; dd means double doublet; DAST means diethylaminosulfur trifluoride; DCM means dichloromethane; DIAD means diisopropyl azodicarboxylate; DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine; DMA means N,N-dimethylacetamide; DMF means N,N-dimethylformamide; DMSO means dimethyl sulfoxide; EtOAc means ethyl acetate; EtOH means ethanol; EtONa means sodium ethoxide; Eq. means equivalent; FA means formic acid; HATU means 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; IPA means 2-propanol; [Ir(OMe)(1,5-cod)]2 means bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I); KOAc means potassium acetate; LCMS means liquid chromatography mass spectrometry; m means multiplet; MeCN means acetonitrile; MeI means iodomethane; MeNH2 means methylamine; MeOH means methanol; MeOH-d4 means deuterated methanol; MPLC means medium pressure liquid chromatography; MS m / z means mass spectral peak; NBS means N-bromosuccinimide; NMP means N-methylpyrrolidine; PE means petroleum ether; Pd(amphos)Cl2 means bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II); Pd(t-Bu3P)2 means bis(tri-tert-butylphosphine)palladium(0); Pd2(dba)3 means tris(dibenzylideneacetone)dipalladium(0); Pd(dppf)Cl2 means [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); PG means a protecting group; i-PrMgCl means isopropyl magnesium chloride; q means quartet; rt means room temperature; RT means retention time; s means singlet; sat. means saturated; SFC means supercritical fluid chromatography; t means triplet; T3P means 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBAF means tetrabutylammonium fluoride; TBDMS means tert-butyldimethylsilane; TBDMSCl means tert-butyl(chloro)dimethylsilane; TEA means triethylamine; TFA means trifluoroacetic acid; TfOH means trifluoroethanesulfonic acid; THF means tetrahydrofuran; TLC means thin layer chromatography; TMSN3 means trimethylsilyl azide; Xantphos means 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; XPhos Pd G2 means chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II).

[0164] General Synthetic Methods and Intermediates According to a first process, compounds of formula (I) may be prepared from compounds of formula (ii) and (iii), as shown by Scheme 1.

[0165] [ka] Scheme 1 Compounds of formula (I) may be prepared from compounds of formula (ii) and (iii) by Buchwald-Hartwig cross-coupling in process step (a). Typical conditions include reacting an amine of formula (iii) with a chloride of formula (ii) in the presence of a suitable inorganic base, a suitable catalyst, in a suitable solvent at elevated temperature. Preferred conditions include reacting compounds of formula (ii) and (iii) in the presence of BrettPhos Pd G3, BrettPhos Pd G4, Pd(t-BuP)2, or Xantphos, optionally in conjunction with Pd2(dba)3 or BrettPhos in the presence of a suitable base, such as Cs2CO3, K2CO3, or KOAc, in a suitable solvent, such as dioxane, toluene, t-AmOH, NMP, or DMF, at temperatures between 90°C and 130°C.

[0166] According to a second process, compounds of formula (I) may be prepared from compounds of formulae (ii), (iv), and (v), as shown in Scheme 2. [ka] Scheme 2 PG is a suitable amine protecting group, preferably 2,4-dimethoxybenzyl or t-butyl.

[0167] Compounds of formula (v) may be prepared from compounds of formula (ii) and (iv) according to the Buchwald-Hartwig cross-coupling reaction in process step (a), as previously described in Scheme 1.

[0168] Compounds of formula (I) may be prepared from protected compounds of formula (v) by process step (b), a deprotection reaction. Typical conditions include reacting compounds of formula (v) with a suitable acid, such as HCl or TFA, in a suitable solvent, such as dioxane, THF, or DCM, at about room temperature.

[0169] According to a third process, compounds of formula (v) may be prepared from compounds of formula (vi) and (vii), as shown in Scheme 3.

[0170] [ka] Scheme 3 Compounds of formula (v) may be prepared from compounds of formula (vi) and (vii) by process step (a), a Buchwald-Hartwig cross-coupling reaction, as previously described in Scheme 1.

[0171] According to a fourth process, compounds of formula (vi) may be prepared from compounds of formula (ii) and (viii), as shown in Scheme 4. [ka] Scheme 4 PG 2 is a suitable nitrogen protecting group, preferably benzyl or diphenylmethylene.

[0172] The compound of formula (viii) can be prepared by reacting a compound of formula (ii) with PG 2 NH2 by an amination reaction, process step (c), wherein PG 2is a benzyl group. A typical condition is to convert the compound of formula (ii) to PG under high temperature such as 200°C and microwave irradiation. 2 This involves reacting with NH2.

[0173] Or, PG 2 is a diphenylmethylene group, compounds of formula (viii) can be prepared by process step (a), a cross-coupling reaction, to give compounds of formula (ii) and PG 2 It may be prepared from the compound NH2.

[0174] Compounds of formula (vi) may be prepared from compounds of formula (viii) by the deprotection reaction in process step (d). Typical conditions include reacting compounds of formula (viii) with a suitable acid, such as triflic acid or HCl, in a suitable solvent, such as DCM, at about room temperature.

[0175] According to a fifth process, compounds of formula (ii) may be prepared from compounds of formulae (ix), (x), (xi), (xii), (xiii), (xiv), (xv), and (xvi), as shown in Scheme 5. [ka] Scheme 5 Hal 1 is a halogen, preferably Br or I Hal 2 is a halogen, preferably Cl or F W is Sn(n-Bu)3 or B(Pin) Alk is a C1-C4 alkyl group,

[0176] wherein X is O, compounds of formula (xi) may be prepared from compounds of formula (ix) by process step (e). Typical conditions include reacting compounds of formula (ix) with a suitable alkyl fluorinating agent, such as ethyl 2-bromo-2,2-difluoroacetate, in the presence of a suitable base, such as KCO, in a suitable solvent, such as DMF, at elevated temperature, typically about 60°C.

[0177] Compounds of formula (xi) may be prepared from compounds of formula (x) by process step (f). Typical conditions include reacting compounds of formula (x) with R in a suitable solvent such as THF, DMF, DMA, DMSO, dioxane, n-BuOH, or MeCN, optionally in the presence of a suitable organic or inorganic base such as DIPEA or TEA, CsCO, t-BuOK, NaH, or KF, at temperatures between 0° C. and 140° C., optionally under microwave irradiation. 2 This involves reacting with X1H.

[0178] Compounds of formula (xii) may be prepared from compounds of formula (xi) according to process step (g), boronate ester formation achieved by treatment with a suitable boronate, such as (BPin) in the presence of a suitable inorganic base, such as KCO or KOAc, and a suitable catalyst, such as Pd(dppf)Cl in a suitable non-polar solvent, at between room temperature and elevated temperature. Preferred conditions include treating compounds of formula (xi) with (BPin) in the presence of Pd(dppf)Cl and KOAc in dioxane at 90° C.

[0179] In the formula, R 3 is a 5-membered aromatic heterocycle, as previously defined, and compounds of formula (ii) may be prepared from compounds of formula (xi) by process step (h), which is a palladium-catalyzed cross-coupling reaction. Such cross-coupling reactions may include Suzuki-type reactions, where W is a boronic acid or ester, or Stille-type cross-coupling reactions, where W is an alkylstannane.

[0180] Typical cross-linking conditions are EtOH, dioxane in the presence of a compound of formula (xvi) 、 It involves a palladium catalyst containing a suitable phosphine ligand, such as Pd(amphos)Cl, Pd(dppf)Cl, Pd(PPh)Cl, or Xphos Pd G, in the presence of an inorganic or organic base, such as CsCO, KCO, NaCO, KPO, TEA, or KOAc, in a suitable solvent, such as aqueous dioxane or DMF, at between room temperature and elevated temperatures.

[0181] In the formula, R 3 is a 5-membered aromatic heterocycle, as described above, and a compound of formula (ii) can be prepared by reacting a compound of formula (xii) and R according to process step (h), as described above. 3 -Hal 1 It may also be prepared from

[0182] In the formula, R 3 is C(O)NHR 5 and compounds of formula (ii) may be prepared from compounds of formulae (xiii), (xiv), and (xv).

[0183] Compounds of formula (xiv) can be prepared by reacting compounds of formula (xiii) and R according to process step (f), as described above. 2 It may also be prepared from X1H.

[0184] Compounds of formula (xv) may be prepared from compounds of formula (xiv) by process step (i), a hydrolysis reaction. Typical conditions include reacting compounds of formula (xiv) with an alkali metal hydroxide, such as LiOH or NaOH, in an aqueous solvent, such as MeOH, EtOH, or THF, at room temperature to about 80°C.

[0185] The compound of formula (ii) can be prepared according to process step (j) by reacting a compound of formula (xv) and R 5 Amide bond formation may be prepared from NH. Typical conditions are by reacting an acid of formula (xv) with R in a suitable polar aprotic solvent in the presence of a suitable coupling agent and an organic base. 5Preferred conditions include reacting an acid of formula (xv) with R in the presence of HATU or T3P in the presence of a suitable organic base, typically DIPEA or TEA, in a suitable solvent such as DMF or DCM at room temperature. 5 This involves reacting with NH2.

[0186] Alternatively, compounds of formula (ii) may be prepared by in situ formation of the acid chloride of an acid of formula (xv), typically using oxalyl chloride or thionyl chloride in a suitable solvent such as THF or DCM at room temperature, followed by reaction of the acid chloride and an amine R in the presence of a suitable organic base, typically DIPEA, at 0° C. 5 An amide bond of NH2 is formed.

[0187] According to a sixth process, compounds of formula (ii) may be prepared from compounds of formulae (x), (xvi), (xvii), (xviii), (xix), and (xx), as shown in Scheme 6.

[0188] [ka] Scheme 6 In the formula, R 3 is a 5-membered aromatic heterocycle, as defined above. Compounds of formula (xviii) may be prepared from compounds of formulae (x) and (xvi) according to process step (h), as described above in Scheme 5.

[0189] In the formula, R 3 is a 5-membered aromatic heterocycle, as defined above, and a compound of formula (xviii) can be prepared by reacting a compound of formula (xvii) and R according to process step (h), as described above in Scheme 5. 3 -Hal 1 It may also be prepared from

[0190] In the formula, R 3 is C(O)NHR 5and a compound of formula (xviii) can be prepared by reacting a compound of formula (xix) and R 5 It may be prepared from the compound NH2.

[0191] In the formula, R 3 is C(O)NHR 5 and the compound of formula (xviii) can be prepared according to process step (k) by reacting a compound of formula (xx) and R 5 The aminolysis reaction may be carried out by reacting a compound of formula (xx) with R at elevated temperature, such as 70°C, in a sealed vessel. 5 This involves reacting with NH2.

[0192] Compounds of formula (ii) can be prepared by reacting compounds of formula (xviii) and R according to process step (f), as previously described in Scheme 5. 2 It may also be prepared from X1H.

[0193] According to a seventh process, compounds of formula (vi) may be prepared from compounds of formula (xxi) and (xxii), as shown by Scheme 7.

[0194] [ka] Scheme 7 Compounds of formula (xxii) may be prepared from compounds of formula (xxi) by a halogenation reaction, preferably a bromination reaction, in process step (1). Typical conditions include reacting compounds of formula (xxi) with NBS in DMF at room temperature.

[0195] Compounds of formula (vi) may be prepared from compounds of formula (xxii) and (xvi) according to process step (h), as previously described in Scheme 5.

[0196] According to an eighth process, compounds of formula (I) may be prepared from compounds of formula (iii), (xviii) and (xxiii), as shown in Scheme 8.

[0197] [ka] Scheme 8 Compounds of formula (xxiii) may be prepared from compounds of formula (iii) and (xviiii) by process step (a), Buchwald-Hartwig coupling, as previously described in Scheme 1.

[0198] Compounds of formula (I) can be prepared by process step (f) to give compounds of formula (xxiii) and R 2 It may also be prepared from X1H.

[0199] According to the ninth process, a compound of formula (v) (wherein R 3 is C(O)NHR 5 (wherein R is an integer from 0 to 10; R is an integer from 1 to 2; R is an integer from 2 to 3; R is an integer from 3 to 4; R is an integer from 4 to 5; R is an integer from 5 to 6; R is an integer from 6 to 7; R is an integer from 7 to 8; R is an integer from 8 to 9; R is an integer from 9 to 10; R is an integer from 1 to 2; R

[0200] [ka] Scheme 9 Compounds of formula (xxiv) may be prepared from compounds of formulae (xiv) and (iv) according to process step (a), as previously described in Scheme 1.

[0201] Compounds of formula (v) may be prepared from compounds of formula (xxiv) according to process step (k), the aminolysis reaction, as previously described in Scheme 6.

[0202] Compounds of formula (iii), (iv), (vii), (ix), (x), (xiii), (xvi), (xvii), (xix), (xx), and (xxi) are either commercially available or may be prepared by methods known in the literature or analogously to the methods described in the experimental section below.

[0203] Compounds of formula (I), (ii), (v), (vi), (viii), (xviii), and (xxiii) may be converted to alternative compounds of formula (I), (ii), (v), (vi), (viii), (xviii), and (xxiii) by standard chemical transformations known to those skilled in the art. Examples of these transformations include, but are not limited to, reductive amination reactions, reduction of esters to secondary alcohols using NaBH4, fluorination using DAST, bromination using AIBN and NBS, and synthetic methods for five-membered heterocycles from functional groups such as nitriles described in generic heterocyclic chemistry or in the literature.

[0204] It will be appreciated by those skilled in the art that it may be necessary to utilize a suitable protecting group strategy to prepare compounds of formula (I). Typical protecting groups may include carbamates, preferably Boc, for the protection of aliphatic amines, or TBDMS groups for the protection of primary alcohols.

[0205] It will further be understood that it may be necessary or desirable to perform the transformations in an order different from that set forth in the schemes, or to modify one or more of the transformations, to provide the desired compounds disclosed herein.

[0206] The method for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis.Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out (for example, temperatures ranging from the freezing point of the solvent to the boiling point of the solvent).A given reaction can be carried out in one solvent or in a mixture of two or more solvents.Depending on the specific reaction step, those skilled in the art can select a suitable solvent for the specific reaction step.

[0207] The preparation of the compounds of the present disclosure 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 easily determined by those skilled in the art. The chemical properties of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th ed., John Wiley & Sons: New Jersey, (2014), the entire contents of which are incorporated herein by reference.

[0208] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C), can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical Instruments and Methods for Compound Characterization:

[0209] Those skilled in the art will recognize that gradients, column lengths, and flow rates can be varied and that, depending on the chemical species being analyzed, some conditions may be more suitable for compound characterization than others.

[0210] Preparative LC-MS: Preparative HPLC was performed using the conditions described below.

[0211] [Table 1]

[0212] Preparation of intermediates Preparation 1: 2-(Difluoromethyl)pyrimidine-4,6-diol [ka] To a solution of malonamide (600 g, 5.88 mol) in EtOH (12 L) was added EtONa (799 g, 11.75 mol) and the solution was stirred at 25° C. for 1 h. Ethyl 2,2-difluoroacetate (875.11 g, 7.05 mol) was added dropwise and the reaction was heated at 90° C. for 15 h. The cooled reaction mixture was filtered, and the solid was washed with EtOH / EtOAc (1:1) and dried in vacuo to give the title compound (800 g, 71.4%) as a yellow solid.

[0213] Preparation 2: 4,6-Dichloro-2-(difluoromethyl)pyrimidine [ka] To a solution of 2-(difluoromethyl)pyrimidine-4,6-diol (Preparation 1, 150 g, 740.31 mmol) in toluene (3 L), POCl (300.15 mL, 3.23 mol) was added dropwise, followed by DIPEA (526.95 mL, 3.03 mol), and the reaction was heated at 120 °C for 16 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (900 mL), and saturated aqueous NaHCO was added to adjust the pH to 7-8. The layers were separated, and the organic layer was washed with brine (300 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ISCO 0-5% EtOAc / PE) to give the title compound (85 g, 57.1%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.18-6.83 (m, 1 H) 8.31 (s, 1 H)

[0214] Preparation 3: 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine [ka] To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 50.0 g, 251 mmol) and 2,4-dimethoxybenzylamine (46.2 g, 276 mmol) in NMP (250 mL) was added DIPEA (64.9 g, 502 mmol), and the reaction was stirred at 140 °C for 2 h. The cooled reaction mixture was poured into water (500 mL) and extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (500 mL), dried over NaSO, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE / EtOAc = 50 / 1 to 10 / 1) to give the title compound (60.0 g, 70.3% yield) as a yellow solid. LCMS m / z = 330 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ:8.61-8.23(m,1H),7.24-7.06(m,1H),6.80-6.44(m,4H),4.50-4.23(m,2H),3.79(s,3H),3.74(s,3H).

[0215] Preparation 4: 6-chloro-2-(difluoromethyl)pyrimidin-4-amine [ka] A solution of 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (Preparation 3, 60.0 g, 176 mmol) in HCl / EtOAc (4 M, 257 mL) was stirred at 25° C. for 12 h. The pH of the mixture was adjusted to 8 with saturated NaHCO solution, the mixture was extracted with EtOAc (500 mL×3), and the combined organic layers were evaporated under reduced pressure to give 30 g of the title compound, which was used without further purification. LCMS m / z = 180 [M+H] +

[0216] Preparation 5: 2-(Difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 6-chloro-2-(difluoromethyl)pyrimidin-4-amine (Preparation 4) and 2,4-dimethoxybenzylamine as an off-white solid (25.31 g, 47.8% yield) following a procedure similar to that described in Preparation 3. LCMS m / z = 311.1 [M+H] + ; 1 H NMR(400 MHz, DMSO-d6) δ 7.16 (t, 1H), 7.07 (d, 1H), 6.58-6.19 (m, 5H), 5.35 (s, 1H), 4.24 (s, 2H), 3.80 (s, 3H), 3.73 (s, 3H).

[0217] Preparation 6: N,N'-(2-(difluoromethyl)pyrimidine-4,6-diyl)bis(1,1-diphenylmethanimine) [ka] To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 145 g, 721.41 mmol) in dioxane (2 L) under N was added diphenylmethanimine (326.86 g, 1.80 mol), CsCO (705.15 g, 2.16 mol), Xantphos (41.74 g, 72.14 mmol), and Pd(dba) (33.03 g, 36.07 mmol), and the reaction was heated at 100 °C for 8 h. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO, 0-10% EtOAc / PE) to give the title compound (250 g, 67%) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ ppm 6.39-6.57 (m, 2H) 7.27-7.60 (m, 20H)

[0218] Preparation 7: 2-(Difluoromethyl)pyrimidine-4,6-diamine hydrochloride [ka] To a solution of N,N'-(2-(difluoromethyl)pyrimidine-4,6-diyl)bis(1,1-diphenylmethanimine) (Preparation 6, 250 g, 511.74 mmol) in dioxane (1.5 L) was added HCl / dioxane (4 M, 800 mL) and the reaction was stirred at 25° C. for 16 h. The reaction was concentrated under reduced pressure and the residue was triturated with THF (1 L) at 25° C. for 30 min. The solid was filtered to give the title compound (113 g, 68.6% yield) as a brown solid. LCMS m / z= 160 [M+H] +

[0219] Preparation 8: 2-(Difluoromethyl)pyrimidine-4,6-diamine [ka] 7M NH3 in MeOH was added to a solution of diethyl malonimidate dihydrochloride (10 g, 43.9 mmol) in MeOH (20 mL), and the reaction was stirred at 50 °C for 16 h. The mixture was evaporated under reduced pressure to give crude malonimidate amide, 7 g. This was dissolved in EtOH (40 mL), ethyl 2,2-difluoroacetate (4.5 g, 36.26 mmol), and EtONa (7.5 g, 110.3 mmol), and the reaction was heated at 80 °C for 2 h. The cooled mixture was extracted with DCM, and the combined organic extracts were concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with MeOH / DCM (1 / 10) to give the title compound (700 mg, 12.6% yield).

[0220] Preparation 9: 2-(1-fluoroethyl)pyrimidine-4,6-diol [ka] To a solution of malonamide (30 g, 294 mmol) in EtOH (300 mL), EtONa (40.0 g, 588 mmol) was added and the solution was stirred at 20° C. for 1 h. Ethyl 2-fluoropropanoate (38.7 g, 323 mmol) was added dropwise and the reaction was stirred at 100° C. for 2 h. The pH of the mixture was adjusted to pH=6 with 1N HCl and then concentrated in vacuo. The residue was adjusted to pH=2 with 1N HCl and filtered to give the title compound (31 g, 66% yield) as a yellow solid, which was used in the next step without further purification. LCMS m / z = 159 [M+H] + .

[0221] Preparation 10: 4,6-Dichloro-2-(1-fluoroethyl)pyrimidine [ka] To a stirred solution of 2-(1-fluoroethyl)pyrimidine-4,6-diol (Preparation 9, 31 g, 196 mmol) in toluene (300 mL) was added POCl (72.8 mL, 784 mmol) at 25 °C. TEA (54.4 mL, 392 mmol) was added dropwise and the reaction was stirred at 100 °C for 2 h. The reaction mixture was poured into warm water and extracted with EtOAc (x3). The combined organic layers were washed with brine, dried over NaSO, filtered, and the filtrate was evaporated under reduced pressure to give 40 g of the title compound.

[0222] Preparation 11: 6-chloro-N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4-amine [ka] A solution of 4,6-dichloro-2-(1-fluoroethyl)pyrimidine (Preparation 10, 40 g, 196 mmol), 2,4-dimethoxybenzylamine (32.7 g, 196 mmol), and DIPEA (50.5 g, 392 mmol) in NMP (150 mL) was stirred at 100° C. for 1 h. The mixture was poured into water (500 mL) and extracted with EtOAc (300 mL×3). The combined organics were washed with brine (300 mL×3), dried over NaSO, and evaporated under reduced pressure to give the title compound (22 g, crude) as a yellow solid, which was used directly in the next step. LCMS m / z = 326 [M+H] + .

[0223] Preparation 12: 6-chloro-2-(1-fluoroethyl)pyrimidin-4-amine [ka] A solution of 6-chloro-N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4-amine (Preparation 11, 22 g, 67.6 mmol) in HCl / EtOAc (4.0 M, 85 mL) was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo, the pH of the residue was adjusted to pH = 8 with saturated NaHCO3 solution, and the mixture was extracted with DCM (300 mL x 3). The combined organics were washed with brine (300 mL), dried over Na2SO4, and concentrated in vacuo. The residue was triturated with PE / EtOAc = 1 / 1 and filtered to give the title compound (10 g, 84% yield) as a gray solid. LCMS m / z = 176 [M+H] + .

[0224] Preparation 13 and Preparation 14: (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine and (R)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine [ka] A solution of 6-chloro-2-(1-fluoroethyl)pyrimidin-4-amine (Preparation 12, 10.0 g, 57 mmol), 2,4-dimethoxybenzylamine (9.5 g, 57 mmol), and DIPEA (29.3 g, 228 mmol) in NMP (60 mL) was stirred at 140 °C for 2 h. The cooled mixture was poured into water (500 mL) and extracted with EtOAc (300 mL × 3), and the combined organics were washed with brine (300 mL × 2), dried over Na SO , and concentrated. The residue was purified by silica gel chromatography to give N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (6.6 g, 37%) as a yellow solid. The product was further purified by SFC using an 0Z 20 x 250 mm, 10 μm (Daicel) column eluting with 35% MeOH (0.2% MeOH / NH) at 100 g / min to give the first eluting enantiomer: (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (2.1 g) as a yellow solid. LCMS m / z = 307 [M+H] + . (Preparation 13) Further elution gave the second eluting enantiomer, (R)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine. (Preparation 14) The stereochemistry of preparation 13 was confirmed by X-ray.

[0225] Preparation 15: 2-(Fluoromethyl)pyrimidine-4,6-diol [ka] To a solution of malonamide (60.0 g, 588 mmol) in EtOH (600 mL) was added EtONa (80.0 g, 1.18 mol) and the solution was stirred for 1 h. Ethyl 2-fluoroacetate (68.6 g, 646 mmol) was added dropwise and the reaction was stirred at 100 °C for 2 h. The pH of the reaction mixture was adjusted to 6 using 1 N HCl and concentrated under reduced pressure. The pH of the residue was adjusted to 2 using 1 M HCl and the mixture was filtered to give the title compound as a yellow solid, 32.0 g, 37.8% yield. 1 H NMR: (400 MHz, DMSO-d6) δ 11.91 (brs, 2H), 5.26 (d, 2H), 5.14 (s, 1H).

[0226] Preparation 16: 4,6-Dichloro-2-(fluoromethyl)pyrimidine [ka] To a solution of 2-(fluoromethyl)pyrimidine-4,6-diol (Preparation 15, 32.0 g, 222 mmol) in toluene (300 mL) was added dropwise POCl (82.8 mL, 891 mmol) at 25 °C. TEA (61.8 mL, 444 mmol) was added dropwise, and the reaction was stirred at 100 °C for 2 h. The reaction mixture was poured into hot water (500 mL) and extracted with EtOAc (300 mL × 3). The combined organic layers were washed with brine (300 mL), dried over Na SO , filtered, and the filtrate was concentrated in vacuo. The residue was purified by MPLC (silica gel, PE / EtOAc = 100 / 1 to 10 / 1) to give the title compound (30.0 g, 74.6% yield) as a white solid. 1 H NMR: (400 MHz, CDCl3) δ: 5.43 (s, 1H), 5.54 (s, 1H), 7.40 (s, 1H).

[0227] Preparation 17: N4,N6-bis(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diamine [ka] To a solution of 4,6-dichloro-2-(fluoromethyl)pyrimidine (Preparation 16, 1.10 g, 6.08 mmol) in DMSO (15 mL) was added 2,4-dimethoxybenzylamine (5.08 g, 30.39 mmol), and the reaction was stirred at 100 °C for 24 h. The cooled reaction was quenched with HO (30 mL) at 0 °C and extracted with EtOAc (20 mL × 5). The combined organic layers were washed with brine (10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE: EtOAc = 5:1 to 1:1) to afford the title compound (940 mg, 35.0%) as a yellow solid.

[0228] Preparation 18: 2-(Fluoromethyl)pyrimidine-4,6-diamine [ka] To a solution of N4,N6-bis(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diamine (Preparation 17, 940 mg, 2.12 mmol) in DCM (9 mL) was added TFA (3 mL) and the reaction was stirred for 1 h at 25° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC-1 to give the title compound (130 mg, 43.1%) as a white solid. 1 H-NMR (400 MHz, DMSO-d6) δ: 6.19 (s, 4H), 5.31 (s, 1H), 5.05-4.93 (m, 2H).

[0229] Preparation 19: N4-(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diamine [ka] A solution of 4,6-dichloro-2-(fluoromethyl)pyrimidine (Preparation 16, 30.0 g, 166 mmol), 2,4-dimethoxybenzylamine (27.7 g, 166 mmol), and DIPEA (42.8 g, 332 mmol) in NMP (150 mL) was stirred at 100° C. for 1 h. The mixture was poured into water (500 mL) and extracted with EtOAc (300 mL×3). The combined organics were washed with brine (300 mL×3), dried over NaSO, and evaporated under reduced pressure to give the title compound (50.0 g, crude) as a yellow solid. LCMS m / z = 312 [M+H] +

[0230] Preparation 20: 5-Bromo-2-chloro-4-methoxypyridine [ka] To a solution of MeOH (704 mg, 22.0 mmol) in THF (30 mL) at 0° C. was added NaH (60% dispersion, 1.76 g, 44.0 mmol), the mixture was stirred at 0° C. for 30 minutes, and then 5-bromo-2,4-dichloropyridine (5 g, 22.0 mmol) in THF (10 mL) was added. The reaction was stirred at room temperature for 12 hours. The solution was quenched with HO, extracted with EtOAc, and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound (3.5 g, 72%) as a white solid. LCMS m / z = 222 [M+H] + .

[0231] Preparation 21: 5-Bromo-2-chloro-4-isopropoxypyridine [ka] To a solution of IPA (1.32 g, 22.0 mmol) in THF (30 mL) was added NaH (1.76 g, 44.0 mmol) at 0° C. The solution was stirred for 30 minutes, and then 5-bromo-2,4-dichloropyridine (5 g, 22.0 mmol) in THF (10 mL) was added. The mixture was stirred at room temperature for 12 hours, diluted with EtOAc (300 mL), and then washed with water (80 mL) and brine (80 mL). The combined organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc = 10 / 1 to 2 / 1) to give the title compound (4.0 g, 73%) as a white solid. LCMS m / z = 250 [M+H] + .

[0232] Preparation 22: 2-chloro-5-iodo-4-methoxypyridine [ka] To a solution of 2-chloro-4-fluoro-5-iodopyridine (800 mg, 3.11 mmol) in MeOH (10 mL) was added a solution of MeONa in MeOH (4 M, 1.16 mL), and the reaction was stirred at room temperature for 4 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated in vacuo to give the crude product. This was purified by silica gel chromatography (PE: EtOAc = 5:1) to give the title compound (750 mg, 90%) as a yellow solid. LCMS m / z = 270 [M+H] + .

[0233] Preparation 23: 2-chloro-5-iodo-4-(methoxy-d3)pyridine [ka] A mixture of methanol-d3 (511 mg, 14.6 mmol) and NaH (875 mg, 21.9 mmol) in THF (50 mL) was stirred at 0° C. for 30 min. 2,4-Dichloro-5-iodopyridine (2 g, 7.30 mmol) was added and the reaction was stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 4) to give the title compound (1.8 g, 90%) as a white solid. LCMS m / z = 273 [M+H] + .

[0234] Preparation 24: 2-Chloro-4-cyclopropoxy-5-iodopyridine [ka] To a suspension of NaH (420 mg, 10.5 mmol) in DMF (10 mL) at 0° C., a solution of cyclopropanol (406 mg, 7 mmol) in DMF (2 mL) was added, and the mixture was stirred at room temperature for 30 minutes. 2-Chloro-4-fluoro-5-iodopyridine (1.8 g, 7 mmol) in DMF (10 mL) was added, and the reaction was stirred at room temperature for 2 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL×3). The combined organic layers were concentrated in vacuo, and the crude product was purified by silica gel chromatography (PE:EtOAc=3:1) to give the title compound (1.2 g, 58.3%) as a yellow solid. LCMS m / z = 296 [M+H] + .

[0235] Preparation 25: 2-chloro-4-((1-fluoropropan-2-yl)oxy)-5-iodopyridine [ka] To a solution of 2-chloro-4-fluoro-5-iodopyridine (350 mg, 1.36 mmol) in THF, NaH (65.3 mg, 2.72 mmol) was added and the solution was stirred at 0° C. for 30 minutes. 1-Fluoropropan-2-ol (106.2 mg, 1.36 mmol) was added and the reaction was stirred at room temperature overnight. The reaction was quenched with water and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound (320 mg, 75% yield). LCMS m / z = 316 [M+H] + .

[0236] Preparation 26: 2-Chloro-5-iodo-4-isopropoxypyridine [ka] The title compound was obtained from 2-chloro-4-fluoro-5-iodopyridine and isopropanol according to the procedure described in Preparation 25 as a white solid, 140 mg, 61% yield. LCMS m / z = 298 [M+H] +

[0237] Preparation 27: 5-Bromo-2-chloro-4-cyclopropoxypyridine [ka] To a solution of cyclopropanol (8.70 g, 150 mmol) in THF (200 mL) was added NaH (5.99 g, 150 mmol, 60% in mineral oil) at 0 °C, and the mixture was stirred at 0 °C for 0.5 h. 5-Bromo-2,4-dichloropyridine (34.0 g, 150 mmol) was added, and the reaction was stirred at 60 °C for 3 h. The reaction mixture was cooled to 0 °C and quenched by adding saturated aqueous NH Cl (100 mL), followed by extraction with EtOAc (100 mL × 3). The combined organic layers were dried over Na SO , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PE / EtOAc = 1:0 to 80:1 to give the title compound (10.5 g, 27.4% yield) as a colorless oil. LCMS m / z = 250 [M+H] + .

[0238] Preparation 28: 5-Bromo-2-chloro-4-(oxetan-3-yloxy)pyridine [ka] From oxetan-3-ol and 5-bromo-2,4-dichloropyridine, following the procedure described in Preparation 27, the title compound was obtained as a white solid, 1.97 g, 67.6%.

[0239] Preparation 29: 2-chloro-4-(difluoromethoxy)-5-iodopyridine [ka] A mixture of 2-chloro-5-iodopyridin-4-ol (1.0 g, 3.92 mmol), ethyl 2-bromo-2,2-difluoroacetate (1.59 g, 7.84 mmol), and K2CO3 (1.62 g, 11.76 mmol) in DMF (20 mL) was stirred at 60 °C under N2 for 16 h. The cooled mixture was diluted with EtOAc, washed with water, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title product (500 mg, 42%). LCMS m / z = 306 [M+H] + .

[0240] Preparation 30: 1,1-diphenyl-N-(4-(trifluoromethoxy)pyridin-2-yl)methanimine [ka] To a mixture of 2-chloro-4-(trifluoromethoxy)pyridine (2.8 g, 14.2 mmol), Pd(dba) (280 mg, 0.306 mmol), XantPhos (560 mg, 0.968 mmol), and CsCO (6.93 g, 21.3 mmol) in dry dioxane (400 mL) was added diphenylmethanimine (2.83 g, 15.6 mmol), and the reaction was stirred at 100 °C under N for 16 h. The cooled mixture was concentrated in vacuo and purified by silica gel chromatography to give the title product (2.6 g, 53%). LCMS m / z = 343 [M+H] + .

[0241] Preparation 31: 4-(trifluoromethoxy)pyridin-2-amine [ka] To a mixture of 1,1-diphenyl-N-(4-(trifluoromethoxy)pyridin-2-yl)methanimine (Preparation 30, 2.6 g, 7.6 mmol) in DCM (20 mL) was added HCl / dioxane (20 mL, 4 M) and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and purified by silica gel chromatography to give the title product (850 mg, 62%). LCMS m / z = 179 [M+H] + .

[0242] Preparation 32: 5-Bromo-4-(trifluoromethoxy)pyridin-2-amine [ka] To a mixture of 4-(trifluoromethoxy)pyridin-2-amine (Preparation 31, 850 mg, 4.78 mmol) in DMF (20 mL) was added NBS (1.02 g, 5.74 mmol) and the reaction was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc, washed with water, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title compound (1.1 g, 89%). LCMS m / z = 257 [M+H] + .

[0243] Preparation 33: 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (1 g, 4.2 mmol), 1H-imidazole (571 mg, 8.4 mmol), and TBDMSCl (945 mg, 6.3 mmol) in DCM (20 mL) was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 5) to give the title compound (1 g, yield: 63%) as a white solid. LCMS m / z = 353 [M+H] + .

[0244] Preparation 34: 1-(oxetan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (800 mg, 4.12 mmol), 2-(bromomethyl)oxetane (622 mg, 4.12 mmol), and CsCO (2.68 g, 8.24 mmol) in MeCN (20 mL) was stirred at 80 °C for 16 h. The cooled mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound (700 mg, 65% yield) as a colorless oil. LCMS m / z = 265 [M+H] + .

[0245] Preparation 35: 2-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol [ka] The title compound was obtained as a brown oil (800 mg, 61% yield) from 2-methyl-4-((4-methylbenzenesulfonyl)oxy)butan-2-ol and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a procedure similar to that described in Preparation 34. LCMS m / z = 281 [M+H] +

[0246] Preparation 36: 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-one [ka] The title compound was obtained from 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 1-chloropropan-2-one (1 g, 77% yield) according to the procedure described in Preparation 34. LCMS m / z = 251 [M+H] + .

[0247] Preparation 37: tert-Butyl methyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate [ka] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.50 g, 23.19 mmol) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (4.06 g, 23.19 mmol) in THF (30 mL) was added DIAD (5.16 g, 25.51 mmol) and PPh (6.69 g, 25.51 mmol), and the reaction was stirred under N at 25 °C for 12 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-2 to afford the title compound (2.11 g, 25.9%) as a yellow oil.

[0248] Preparation 38: tert-Butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate [ka] To a mixture of 2 tert-butyl 2-(hydroxymethyl)azetidine-1-carboxylate (300 mg, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (315 mg, 1.6 mmol) in THF (20 mL) was added PPh3 (630 mg, 2.4 mmol), the mixture was stirred at 0 °C, and DIAD (0.3 mL) was added. The reaction was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 3) to give the title compound (300 mg, 52% yield). LCMS m / z = 364 [M+H] + .

[0249] Preparation 39: tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate [ka] A mixture of 4-bromo-1H-pyrazole (2.5 g, 17.0 mmol), tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (4.69 g, 18.7 mmol), and CsCO (8.35 g, 25.5 mmol) in anhydrous DMF (50 mL) was stirred at 80 °C overnight. The cooled mixture was partitioned between water and EtOAc, the layers were separated, and the organic phase was concentrated in vacuo. The residue was purified by silica gel chromatography EtOAc / PE (1 / 5) to give the title compound (4.4 g, 81% yield) as a colorless oil. LCMS m / z = 318, 320 [M+H] +

[0250] Preparation 40: tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-yl)(methyl)carbamate [ka] To an ice-cooled mixture of tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Preparation 39, 2.3 g, 7.23 mmol) in dry THF (50 mL) was added NaH (578 mg, 14.4 mmol) and the mixture was stirred at 0° C. for 1 h. MeI (1.54 g, 10.84 mmol) was added and the reaction was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with water and the organic layer was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound (1.7 g, 71% yield). LCMS m / z = 332 [M+H] + .

[0251] Preparation 41: tert-butyl methyl (2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate [ka] A mixture of tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-yl)(methyl)carbamate (Preparation 40, 1.7 g, 5.14 mmol), bis(pinacolato)diboron (1.96 g, 7.71 mmol), KOAc (1.51 g, 15.4 mmol), and Pd(dppf)Cl (200 mg, 2.6 mmol) in dioxane (20 mL) was stirred at 100 °C under N for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound (600 mg, 30% yield). LCMS m / z = 380 [M+H] + .

[0252] Preparation 42: 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 2-chloro-5-iodo-4-methoxypyridine (Preparation 22, 750 mg, 2.79 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (891 mg, 3.35 mmol), Pd(dppf)Cl (204 mg, 0.279 mmol), and KCO (770 mg, 5.58 mmol) in dioxane (12 mL) and HO (3 mL) was stirred at 90 °C under N for 4 h. The cooled mixture was concentrated in vacuo to give the crude product, which was purified by silica gel chromatography (PE: EtOAc = 1:2) to give the title compound (560 mg, 71.5%) as a yellow oil. LCMS m / z = 282 [M+H]+.

[0253] Preparation 43: 1-(4-(6-chloro-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 2-chloro-5-iodo-4-(methoxy-d3)pyridine (Preparation 23, 2 g, 7.33 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (2.14 g, 8.06 mmol), K2CO3 (2.01 g, 14.6 mmol), and Pd(dppf)Cl2 (536 mg, 0.733 mmol) in dioxane / water (40 mL / 8 mL) was stirred at 80 °C under N2 for 6 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE = 2 / 1 to give the title compound (1.2 g, yield: 57%) as a white solid. LCMS m / z = 285 [M+H] + .

[0254] Preparation 44: 2-chloro-4-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine [ka] A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 120 mg, 0.479 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (79.73 mg, 0.383 mmol), Pd(dppf)Cl (35.05 mg, 0.048 mmol), and KCO (132.40 mg, 0.958 mmol) in dioxane (2 mL) and HO (0.10 mL) was degassed and purged with N, and the reaction was stirred at 90 °C for 2 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE: EtOAc = 1:1) to give the title compound (50 mg, 41.5%) as a yellow solid. Alternative synthesis: A mixture of NaH (60%, 53 mg, 1.32 mmol) in IPA (5 mL) was stirred at 0° C. for 2 hours, and then 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 70 mg, 0.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE=1 / 2 to give the title compound (60 mg, 72% yield) as a white solid. LCMS m / z = 252 [M+H] + .

[0255] Preparation 45: 1-(4-(6-chloro-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 2.0 g, 8.06 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (2.15 g, 8.06 mmol), K2CO3 (3.34 g, 24.2 mmol), and Pd(dppf)Cl2 (592 mg, 0.81 mmol) in dioxane / water (20 mL / 4 mL) was stirred at 80 °C for 3 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (PE / EtOAc = 10 / 1 to 2 / 1) to give the title compound (2.2 g, 88% yield) as a yellow solid. LCMS m / z = 310 [M+H] + .

[0256] Preparation 46: 1-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 2-chloro-4-cyclopropoxy-5-iodopyridine (Preparation 24, 1.18 g, 4 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (1.28 g, 4.8 mmol), Pd(dppf)Cl (150 mg, 0.2 mmol), and KCO (1.1 g, 8 mmol) in dioxane (20 mL) and HO (3 mL) was stirred at 90 °C under N for 4 h. The cooled mixture was concentrated to give the crude product, which was purified by silica gel chromatography (PE: EtOAc = 1:2) to give the title compound (900 mg, 73.3%) as a beige solid. LCMS m / z = 308 [M+H] + .

[0257] Preparation 47: 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 2-chloro-4-(difluoromethoxy)-5-iodopyridine (Preparation 29, 100 mg, 0.33 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (105 mg, 0.39 mmol), Pd(dppf)Cl (20 mg, 0.027 mmol), and KCO (45 mg, 0.66 mmol) in dioxane / water (10 mL / 1 mL) was stirred at 70 °C under N for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give the title compound (50 mg, 47%). LCMS m / z = 318 [M+H] + .

[0258] Preparation 48: 2-chloro-4-isopropoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridine [ka] A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 300 mg, 1.19 mmol), 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (355 mg, 1.42 mmol), Pd(dppf)Cl (174 mg, 0.238 mmol), and KCO (492 mg, 3.56 mmol) in dioxane / HO (15 mL / 5 mL) was stirred at 100° C. for 4 h. The reaction mixture was diluted with water and extracted with DCM (200 mL × 3), and the organic phase was washed with brine, dried over anhydrous NaSO, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE / EtOAc=2 / 1) to give the title compound (140 mg, 40.1%) as a white solid. LCMS m / z = 294 [M+H] + .

[0259] Preparation 49: 2-chloro-4-isopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine [ka] The title compound was obtained from 2-chloro-5-iodo-4-isopropoxypyridine (Preparation 26) following a procedure similar to that described in Preparation 48 as a white solid, 100 mg, 32% yield. LCMS m / z = 308 [M+H] +

[0260] Preparation 50: tert-Butyl 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] The title compound was obtained from 2-chloro-4-(difluoromethoxy)-5-iodopyridine (Preparation 29) and tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate according to the procedure described in Preparation 48 in 210 mg, 77% yield. LCMS m / z = 415 [M+H] + .

[0261] Preparation 51~74 A mixture of the appropriate chloropyridine (1.0 equiv.) and alkylated (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1 equiv. to 1.2 equiv.), KCO (2.0 to 3.0 equiv.), and Pd(dppf)Cl (0.03 to 0.2 equiv.) in dioxane / water (10 / 1 to 3 / 1 v / v) was stirred at 70 to 100 °C until the starting material was consumed. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (eluting with PE / EtOAc or MeOH / DCM) to give the desired compound.

[0262] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7]

[0263] Preparation 75: 2-chloro-4-methoxy-5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridine [ka] A mixture of 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (348 mg, 1.079 mmol), 5-bromo-2-chloro-4-methoxypyridine (Preparation 20, 200 mg, 0.899 mmol), and PdCl(dppf):DCM (73.4 mg, 0.090 mmol) was purged with N. 2 M aqueous NaCO (1.349 mL, 2.70 mmol) and dioxane (3.60 mL) were added, and the reaction was stirred under N at 90 °C overnight. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography (0–70% EtOAc in hexanes) to afford the title compound (256 mg, 84.2%) as a light brown glass. LCMS m / z = 338 [M+H] +

[0264] Preparation 76: tert-Butyl 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate [ka] A mixture of tert-butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 38, 400 mg, 1.10 mmol), 5-bromo-2-chloro-4-methoxypyridine (Preparation 20, 244 mg, 1.10 mmol), Pd(dppf)Cl (34 mg, 0.0465 mmol), and TEA (260 mg, 2.57 mmol) in dioxane (6 mL) and HO (1.5 mL) was stirred at 80° C. for 2 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give the title compound (150 mg, 36%) as a yellow solid. LCMS m / z = 379 [M+H] + .

[0265] Preparation 77: tert-butyl (2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate [ka] The title compound was obtained from 5-bromo-2-chloro-4-methoxypyridine (Preparation 20) and tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate as a yellow solid, 180 mg, 50%, according to the procedure described in Preparation 76. LCMS m / z = 353 [M+H] +

[0266] Preparation 78: tert-Butyl 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate [ka] The title compound was obtained from 5-bromo-2-chloro-4-cyclopropoxypyridine (Preparation 27) and tert-butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 38) according to the procedure described in Preparation 76 as a white solid, 120 mg, 43% yield. LCMS m / z = 405 [M+H] +

[0267] Preparation 79: tert-butyl (2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate [ka] To a solution of 5-bromo-2-chloro-4-methoxypyridine (Preparation 20, 46 mg, 0.207 mmol), tert-butyl methyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (Preparation 37, 79.89 mg, 0.227 mmol) in EtOH (3 mL) and HO (0.20 mL) was added Pd(amphos)Cl (14.64 mg, 0.0207 mmol) and KOAc (40.59 mg, 0.413 mmol), and the reaction was stirred at 80 °C under N for 2 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (PE: EtOAc = 0:1) to give the title compound (50 mg, 65.9%) as a yellow oil.

[0268] Preparation 80~86 The compounds in the following table were prepared from the appropriate pyrazole pinacol ester and bromopyridine following a procedure similar to that described in Preparation 79.

[0269] [Table 3-1] [Table 3-2]

[0270] Preparation 87: tert-Butyl 3-(4-(6-chloro-4-(oxetan-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate [ka] To a solution of 5-bromo-2-chloro-4-(oxetan-3-yloxy)pyridine (Preparation 28, 500 mg, 1.89 mmol) and tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (990.25 mg, 2.84 mmol) in dioxane (5 mL) and HO (0.50 mL) was added Xphos Pd G (148.73 mg, 0.189 mmol) and KPO (802.51 mg, 3.78 mmol), and the reaction was stirred at 80 °C under N for 3 h. The cooled reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC-6 to give the title compound (120 mg, 15.6%) as a white solid.

[0271] Preparation 88: tert-butyl (1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate [ka] A mixture of tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Preparation 39, 543 mg, 1.706 mmol), bis(pinacolato)diboron (520 mg, 2.048 mmol), Pd(dppf)Cl:DCM (209 mg, 0.256 mmol), and KOAc (502 mg, 5.12 mmol) in dioxane (6.83 mL) was stirred at 90° C. for 9 h. After the reaction was cooled to room temperature, more bis(pinacolato)diboron (200 mg, 0.787 mmol) was added. The reaction mixture was stirred for an additional 2 h at 90° C. 5-Bromo-2-chloro-4-methoxypyridine (Preparation 20, 380 mg, 1.706 mmol) and 2 M aqueous NaCO (2.56 mL, 5.12 mmol) were added. The reaction mixture was stirred at 90 °C overnight, then concentrated in vacuo onto silica and purified by silica gel chromatography (0-100% EtAOc in hexanes) to give the title compound (135 mg, 20.8% yield). LCMS m / z = 381 [M+H] +

[0272] Preparation 89: N-(2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoroethan-1-amine [ka] To a solution of tert-butyl (2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate (Preparation 77, 180 mg, 0.510 mmol) in dioxane (5 mL) was added HCl / dioxane (5 mL) and the reaction was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure. The residue was dissolved in MeOH (5 mL) and DCM (5 mL), 2,2,2-trifluoroacetaldehyde (347 mg, 3.55 mmol) and AcOH (0.2 mL) were added and the solution was stirred at room temperature for 5 min. Na(CN)BH (5.0 equiv) was added and the reaction was stirred at room temperature for 16 h. The solution was quenched with HO, extracted with DCM, and the combined organic layers were concentrated in vacuo and purified by preparative HPLC-3 to give the title compound (25 mg, 11%) as a colorless oil. LCMS m / z = 335 [M+H] + .

[0273] Preparation 90: 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-N-methylpropan-2-amine [ka] The title compound was obtained from 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 52) and methanamine according to a procedure similar to that described in Preparation 89 as a yellow solid, 200 mg, 64%. LCMS m / z = 281 [M+H] +

[0274] Preparation 91: 2-chloro-4-(difluoromethoxy)-5-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridine [ka] To a solution of tert-butyl 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 50, 200 mg, 0.482 mmol) in DCM, TFA (274 mg, 2.4 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE / EtOAc=1 / 1) to give 2-chloro-4-(difluoromethoxy)-5-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridine trifluoroacetate. To a solution of 2-chloro-4-(difluoromethoxy)-5-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridine trifluoroacetate (200 mg) in MeOH (4 mL) was added formaldehyde (95 mg, 3.2 mmol) and AcOH (2 drops), and the solution was stirred for 10 minutes. Na(CN)BH3 (201 mg, 3.2 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with 1 M HCl, concentrated in vacuo, and the residue was purified by column chromatography on silica gel (MeOH / DCM=5%) to give the title compound (130 mg, 62%). LCMS m / z = 329 [M+H] + .

[0275] Preparation 92: 2-chloro-4-methoxy-5-(1-(1-methylpyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridine [ka] The title compound was obtained from tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 55) as a colorless oil (120 mg, 64%) following a procedure similar to that described in Preparation 91. LCMS m / z = 293 [M+H] + .

[0276] Preparation 93: 5-(1-(azetidin-2-ylmethyl)-1H-pyrazol-4-yl)-2-chloro-4-methoxypyridine [ka] To a solution of tert-butyl 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 76, 280 mg, 0.739 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 12 hours. The mixture was concentrated in vacuo and purified by preparative HPLC-3 to give the title compound (160 mg, 78%) as a white solid. LCMS m / z = 279 [M+H] +

[0277] Preparations 94 and 95: (R)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine and (S)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine [ka] To a solution of 5-(1-(azetidin-2-ylmethyl)-1H-pyrazol-4-yl)-2-chloro-4-methoxypyridine (Preparation 93, 160 mg, 0.574 mmol) in MeOH (5 mL) and DCM (5 mL) at room temperature, HCHO (5.0 equiv.) and AcOH (0.2 mL) were added and the solution was stirred for 5 minutes. Na(CN)BH (5.0 equiv.) was added and the reaction was stirred at room temperature for 16 hours. The solution was quenched with HO, the mixture was extracted with DCM, and the combined organic layers were concentrated in vacuo. The residue was purified by preparative HPLC-3 to give 2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine (80 mg, 48%) as a colorless oil. LCMS m / z = 293 [M+H] + . The compound was further purified by SFC using an IG20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 50 / 50, flow rate of 100 g / min to give: First eluting enantiomer 1 (Preparation 94): (S)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine or (R)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine, 30 mg Second eluting enantiomer 2 (Preparation 95): (R)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine or (S)-2-chloro-4-methoxy-5-(1-((1-methylazetidin-2-yl)methyl)-1H-pyrazol-4-yl)pyridine, 30 mg.

[0278] Preparation 96: 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine [ka] A mixture of 2-chloro-4-fluoropyridine (10 g, 76.0 mmol), bis(pinacolato)diboron (9.64 g, 38.0 mmol), [Ir(OMe)(1,5-cord)] (251 mg, 0.380 mmol), and dtbpy (270 mg, 0.760 mmol) in THF (150 mL) was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 10) to give the title compound (15 g, 77% yield) as a colorless oil. LCMS m / z = 258 [M+H] + .

[0279] Preparation 97: 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine [ka] A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (Preparation 96, 15 g, 58.36 mmol), 4-bromo-1-methyl-1H-pyrazole (9.4 g, 58.36 mmol), KCO (16.1 g, 116.73 mmol), and Pd(dppf)Cl (4.27 g, 5.83 mmol) in dioxane / water (80 mL / 20 mL) was stirred at 80° C. for 6 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 2) to give the title compound (5 g, 41% yield) as a brown solid. 1 H-NMR (400 MHz, DMSO-d6) δ ppm 8.83-8.80 (m, 1H), 8.27-8.26 (m, 1H), 8.00 (s, 1H), 7.69-7.67 (m, 1H), 3.90 (s, 3H).

[0280] Preparation 98: 2-chloro-4-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine [ka] A mixture of 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 1.0 g, 4.73 mmol) and EtONa (643 mg, 9.45 mmol) in EtOH (20 mL) was stirred at 80° C. for 16 hours. The cooled mixture was concentrated in vacuo and purified by silica gel column chromatography to give the title compound (900 mg, 80%). LCMS m / z = 238 [M+H] +

[0281] Preparation 99: 2-chloro-4-cyclopropoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine [ka] A mixture of 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 100 mg, 0.47 mmol), cyclopropanol (54 mg, 0.94 mmol), and CsCO (308 mg, 0.95 mmol) in MeCN (15 mL) was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 2) to give the title compound (70 mg, 59% yield). LCMS m / z = 250 [M+H] + .

[0282] Preparation 100: 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 5-bromo-4-(trifluoromethoxy)pyridin-2-amine (Preparation 32, 100 mg, 0.39 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (155 mg, 0.58 mmol), Pd(dppf)Cl (20 mg, 0.027 mmol), and KCO (108 mg, 0.78 mmol) in dioxane / water (10 mL / 1 mL) was stirred at 100 °C under N for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography eluting with MeOH / DCM (1 / 20) to give the title compound (110 mg, 89%). LCMS m / z = 317 [M+H] + .

[0283] Preparation 101~105 The compounds in the following table were prepared from 5-bromo-4-(trifluoromethoxy)pyridin-2-amine (Preparation 32) and the appropriate pyrazole pinacol ester following a procedure similar to that described in Preparation 100.

[0284] [Table 4-1] [Table 4-2]

[0285] Preparation 106: 5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-amine [ka] A mixture of 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 105, 140 mg, 0.46 mmol) and MeNH (1 mL, 2 M in THF) in DCM (10 mL) was stirred at room temperature for 0.5 h. Na(CN)BH (58 mg, 0.92 mmol) was added and the reaction was stirred at room temperature for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with MeOH / DCM (1 / 10) to give the title compound (110 mg, 75% yield). LCMS m / z = 316 [M+H] + .

[0286] Preparation 107: 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-ol [ka] To a solution of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 72, 140 mg, 0.464 mmol) in THF was added NaBH4 (69.9 mg, 1.85 mmol) at 0 °C, and the reaction was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (100 mL × 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography on silica gel (DCM / MeOH = 5%) to give the title compound (45 mg, 32%) as a white solid. LCMS m / z = 304 [M+H] + .

[0287] Preparation 108: 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 100, 110 mg, 0.34 mmol), 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (Preparation 3, 132 mg, 0.40 mmol), BrettPhos Pd G4 (20 mg, 0.0278 mmol), and Cs2CO3 (248 mg, 0.76 mmol) in dry dioxane (10 mL) was stirred at 100 °C under N2 for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by silica gel chromatography to give the title compound (180 mg, 77%). LCMS m / z = 610 [M+H] + .

[0288] Preparations 109-113 The compounds in the following table were prepared from 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (Preparation 3) and the appropriate pyridin-2-amine following a procedure similar to that described in Preparation 108.

[0289] [Table 5-1] [Table 5-2]

[0290] Preparation 114: (S)-1-(4-(6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-chloro-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 45, 800 mg, 2.59 mmol), (S)—N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (Preparation 13, 800 mg, 2.59 mmol), BrettPhos Pd G (397 mg, 0.26 mmol), and CsCO (2.54 g, 7.77 mmol) in dioxane (20 mL) was stirred at 100° C. for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (EtOAc / MeOH = 10 / 1 to 3 / 1) to give the title compound (840 mg, 56% yield) as a yellow solid. LCMS m / z = 580 [M+H] + .

[0291] Preparation 115: 1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 47, 50 mg, 0.16 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 54 mg, 0.17 mmol), BrettPhos Pd G (10 mg, 0.0109 mmol) and CsCO (104 mg, 0.32 mmol) in dry dioxane (4 mL) was stirred at 100° C. under N for 16 h. The cooled mixture was concentrated in vacuo and the crude product was purified by silica gel chromatography to give the title compound (50 mg, 52%). LCMS m / z = 592 [M+H] + .

[0292] Preparation 116: tert-Butyl (1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate [ka] A mixture of tert-butyl (1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Preparation 88, 135 mg, 0.354 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 110 mg, 0.354 mmol), BrettPhos Pd G (32.7 mg, 0.035 mmol), and CsCO (346 mg, 1.063 mmol) in dioxane (2 mL) was purged with N and the reaction was stirred at 80 °C overnight. Additional BrettPhos Pd G4 (12 mg, 0.013 mmol) and Cs2CO3 (115 mg, 0.353 mmol) were added and the reaction was stirred at 100 °C for an additional 10 h. The cooled mixture was concentrated onto silica gel and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (178 mg, 77%). LCMS m / z = 655 [M+H] +

[0293] Preparation 117: (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] A mixture of 2-chloro-4-isopropoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridine (Preparation 48, 100 mg, 0.340 mmol), (S)—N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (Preparation 13, 124 mg, 0.407 mmol), BrettPhos Pd G4 (62.56 mg, 0.068 mmol), and Cs2CO3 (221 mg, 0.680 mmol) in dioxane (2 mL) was stirred at 70 °C for 12 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (MeOH / DCM = 0-10%) to give the title compound (80 mg, 42% yield) as a white solid. LCMS m / z = 564 [M+H] + .

[0294] Preparations 118-137 The appropriate chloropyridine (1 equiv.), the appropriate protected pyrimidine-4,6-diamine (1.2 equiv.), BrettPhos Pd G4 (0.03 equiv.-0.2 equiv.), and CsCO3 (2-3 equiv.) in dioxane were stirred at 70-100 °C until the starting material was consumed. The cooled mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using an appropriate solvent system (e.g., MeOH / DCM or PE / EtOAc) to give the desired compound.

[0295] [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7]

[0296] Preparation 138: 1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one [ka] A mixture of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 72, 140 mg, 0.46 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 143 mg, 0.28 mmol), BrettPhos Pd G (10 mg, 0.011 mmol), and CsCO (300 mg, 0.92 mmol) in dioxane (5 mL) was stirred at 100 °C under N for 16 h. The cooled mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with MeOH / DCM (100% to 10%) to give the title compound (110 mg, 41% yield). LCMS m / z = 576 [M+H] + .

[0297] Preparation 139: 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-chloro-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 43, 400 mg, 1.40 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 434 mg, 1.40 mmol), Cs2CO3 (910 mg, 2.80 mmol), and Brettphos Pd G4 (100 mg) in dioxane (10 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with MeOH / DCM (1 / 20) to give the title compound (300 mg, 38%) as a white solid. LCMS m / z = 559 [M+H] + .

[0298] Preparations 140 and 141: tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl 3-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 66, 180 mg, 0.44 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 137 mg, 0.44 mmol), CsCO (290 mg, 0.89 mmol) and Brettphos Pd G (40 mg, 0.043 mmol) in dioxane (4 mL) was stirred at 100° C. under N for 16 h. The cooled reaction mixture was concentrated in vacuo and the residue was purified by preparative HPLC-3. The product was further purified by SFC using an AD20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / MeOH (1% MeOH / NH3) = 50 / 50 (100 g / min) to give the following: First eluting enantiomer 1: tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 140), (20 mg, 7% yield) as a white solid. LCMS m / z=679 [M+H] + and Second eluting enantiomer 2: tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 141), (20 mg, 7% yield) as a white solid. LCMS m / z = 679 [M+H] + .

[0299] Preparations 142 and 143: tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate and tert-butyl (S)-2-(((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate [ka] A mixture of tert-butyl 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 78, 100 mg, 0.246 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 76.0 mg, 0.245 mmol), KCO (67.7 mg, 0.491 mmol), and Brettphos Pd G (20 mg) in dioxane (4 mL) was stirred at 100° C. under N for 16 h. The cooled reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC-3. The product was further purified by chiral SFC using an AD20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / EtOH (1% MeOH / NH3) = 50 / 50 (100 g / min) to give: First eluting enantiomer 1: tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate or tert-butyl (S)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 142) (12 mg, 7% yield) as a white solid. LCMS m / z=679 [M+H] + and Second eluting enantiomer 2: tert-butyl (S)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate or tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 143) (12 mg, 7% yield) as a white solid. LCMS m / z = 679 [M+H] + .

[0300] Preparations 144 and 145: N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] A mixture of 2-chloro-4-isopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine (Preparation 49, 100 mg, 0.325 mmol), (S)—N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (Preparation 13, 120 mg, 0.390 mmol), BrettPhos Pd G (0.2 equiv.), and CsCO (212 mg, 0.650 mmol) in dioxane was stirred at 100 °C overnight. The cooled solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (DCM / MeOH=10%) to give N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (50 mg, 27%). LCMS m / z = 578 [M+H] + This was further separated by preparative SFC using an AD20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / EtOH (0.2% MeOH / NH3) = 55 / 45, 100 g / min to give: First eluting diastereoisomer 1: N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 144), 16 mg, and Second eluting diastereoisomer 2: N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or N4-(2,4-dimethoxybenzyl)-2-((S)-1-fluoroethyl)-N6-(4-isopropoxy-5-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 145), 12 mg.

[0301] Preparation 146: 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 42, 560 mg, 1.99 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 679 mg, 2.19 mmol), Pd(t-BuP) (200 mg, 0.392 mmol), and CsCO (1.29 g, 3.98 mmol) in dioxane (12 mL) was stirred at 100 °C under N for 16 h. The mixture was poured into water (80 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated in vacuo and the crude product was purified by silica gel chromatography (PE: EtOAc = 1:10) to give the title compound (480 mg, 43.6%) as a yellow oil. LCMS m / z = 556 [M+H] + .

[0302] Preparation 147: 1-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol [ka] A mixture of 1-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 46, 900 mg, 2.93 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 1 g, 3.22 mmol), Pd(t-BuP) (300 mg, 0.586 mmol), and CsCO (1.9 g, 5.86 mmol) in dioxane (20 mL) was stirred at 100 °C under N for 16 h. The cooled mixture was poured into water (80 mL) and extracted with EtOAc (100 mL × 3). The combined organic layers were concentrated in vacuo and the crude product was purified by silica gel chromatography (PE: EtOAc = 1:10) to give the title compound (800 mg, 47.1%) as a beige solid. LCMS m / z = 582 [M+H] + .

[0303] Preparation 148: 2-(Difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 2-chloro-4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 74) and 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) following a procedure similar to that described in Preparation 147 in 80 mg, 44% yield. LCMS m / z = 544 [M+H] +

[0304] Preparation 149: N4-(5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-4-cyclopropoxypyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 5-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-1H-pyrazol-4-yl)-2-chloro-4-cyclopropoxypyridine (Preparation 57) and 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) following a procedure similar to that described in Preparation 147 in 80 mg, 29% yield. LCMS m / z = 668 [M+H] +

[0305] Preparation 150: N4-(4-(difluoromethoxy)-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 138) and MeNH2 following a procedure similar to that described in Preparation 106 in 80 mg, 71% yield. LCMS m / z = 591 [M+H] + .

[0306] Preparation 151: 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propan-2-ol [ka] To a solution of 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 121, 100 mg, 0.185 mmol) in MeOH (5 mL) was added NaBH4 (21.0 mg, 0.56 mmol) and the reaction was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound (50 mg, 50%) as a white solid. LCMS m / z = 542 [M+H] + .

[0307] Preparation 152: 2-(Difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(1-(2-(dimethylamino)propyl)-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)pyrimidine-4,6-diamine [ka] To a solution of 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 121, 100 mg, 0.185 mmol) in DCM / MeOH (1 / 1, 5 mL) was added dimethylamine in THF (2 mL, 2 N) and AcOH (5 drops) and the solution was stirred for 5 min. Na(CN)BH3 (34.85 mg, 0.56 mmol) was added and the reaction was stirred at room temperature for 16 h. The solution was concentrated in vacuo and the residue was purified by silica gel chromatography to give the title compound (65 mg, 62%) as a yellow solid. LCMS m / z=569 [M+H]+ .

[0308] Preparation 153: N4-(4-cyclopropoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 1-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propan-2-one (Preparation 130) and MeNH2 following a procedure similar to that described in Preparation 106 in 50 mg, 61% yield. LCMS m / z = 581 [M+H] + .

[0309] Preparation 154: tert-Butyl 3-(4-(6-((6-amino-2-(fluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate [ka] To a solution of 2-(fluoromethyl)pyrimidine-4,6-diamine (Preparation 18, 15.58 mg, 0.11 mmol), tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 83, 50 mg, 0.137 mmol) in dioxane (2 mL) was added BrettPhos Pd, G4 (12.62 mg, 0.0137 mmol) and CsCO (89.31 mg, 0.274 mmol), and the reaction was stirred at 90 °C under N for 2 h. The cooled reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative TLC (EtOAc:MeOH = 10:1) to give the title compound (15 mg, 23.26%) as a yellow oil.

[0310] Preparation 155~160 The compounds in the following table were prepared from 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) and the appropriate chloro-pyridine following a procedure similar to that described in Preparation 154.

[0311] [Table 7-1] [Table 7-2]

[0312] Preparations 161 and 162: tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate [ka] A mixture of tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 55, 160 mg, 0.422 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 67.5 mg, 0.422 mmol), BrettPhos Pd G4 (77.65 mg, 0.084 mmol), and Cs2CO3 (412 mg, 1.266 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 h. The cooled mixture was purified by silica gel chromatography and preparative HPLC-3 to give tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate as a white solid (100 mg, 47%). LCMS m / z = 503 [M+H] + This was further purified by chiral SFC using an AD20 x 250 mm, 10 μm (Daicel) column, mobile phase: COMeOH (0.2% MeOH / NH) = 60 / 40, 80 g / min to give: First eluting enantiomer 1: tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or tert-butyl (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 161) and Second eluting enantiomer 2: tert-butyl (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate or tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 162).

[0313] Preparations 163 and 164: tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate and tert-butyl (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate [ka] tert-Butyl 2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate was obtained from 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) and tert-butyl 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 76) according to the procedures described in Preparations 161 and 162 as a white solid, 80 mg, 40%. This was further purified by SFC using an AY20 × 250 mm, 10 μm (Daicel) column, mobile phase: CO / EtOH (0.5% MeOH / NH) = 65 / 35, flow rate: 80 g / min to give: First eluting enantiomer 1: tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate or tert-butyl (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 163). Second eluting enantiomer 2: tert-butyl (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate or tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azetidine-1-carboxylate (Preparation 164).

[0314] Preparation 165: tert-Butyl 3-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate [ka] To tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (1.5 g, 7.13 mmol) and 5-bromo-2-chloro-4-fluoropyridine (4.32 g, 12.8 mmol) in dioxane (30 mL) was added NaCO (3.78 g, 35.64 mmol), HO (5 mL), and Pd(PPh) (4.12 g, 3.56 mmol) under N, and the mixture was stirred at 100 °C for 16 h. The reaction was diluted with EtOAc (50 mL) and extracted with HO (3 × 20 mL). The combined organics were washed with HO (3 × 10 mL), dried (NaSO), and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO®; 0-25% EtOAc / PE) to give the title compound (1.6 g, 57%) as a yellow oil.

[0315] Preparation 166: tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate [ka] The title compound was prepared from (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate and 5-bromo-2-chloro-4-fluoropyridine using a method similar to that described in Preparation 165. 1 H NMR(400MHz,DMSO-d6)δ:8.83(d,1H),8.23(d,1H),8.05(s,1H),7.69(d,1H),7.02-6.89(m,1H),4.30-4.11(m,2H),3.39-3.34(m,2H),1.34(s,9H)

[0316] Preparation 167: tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate [ka] tert-Butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate (Preparation 166, 1.0 g, 2.93 mmol) was dissolved in THF (10.0 mL), then NaH (176.0 mg, 4.40 mmol, 60.0% purity) and MeI (625.0 mg, 4.40 mmol) were added at 0 °C under N, and the reaction was stirred at 25 °C for 2 h. The reaction mixture was washed with HO (5 mL), dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ISCO®, 0–20% EtOAc / PE) to afford the title compound (0.86 g, 74.3% yield) as a white solid.

[0317] Preparation 168: tert-Butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate [ka] To a solution of tert-butyl 3-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 165, 1.6 g, 4.08 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 726 mg, 4.08 mmol) in t-AmOH (30 mL) was added BrettPhos Pd G (370 mg, 0.408 mmol) and CsCO (2.66 g, 8.16 mmol) under N and the mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with 30 mL of HO (10 mL × 3). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography ((ISCO®, 0-75% EtOAc / PE)) to give the title compound (800 mg, 41%) as a yellow solid.

[0318] Preparation 169: tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate [ka] The title compound was prepared from tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)carbamate (Preparation 166) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) as a white solid (380 mg, 40%) using a method similar to that described in Preparation 168. 1 H NMR(400MHz,DMSO-d6)δ:10.09 (s, 1H) 8.59 (d, 1H), 8.14-8.04 (m, 1H), 7.95 (s, 1H), 7.57-7.48 (m, 1H), 7.02-6.96 (m, 2H), 6.68-6.64 (m, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 4.19 (br t, 2H), 3.41 (br d, 2H), 1.36 (s, 10H).

[0319] Preparation 170: tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate [ka] The title compound was prepared as a yellow solid (860 mg, 42.7%) from tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate (Preparation 167) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) using a method similar to that described in Preparation 168. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.09 (s, 1H) 8.58 (d, 1H) 8.10 (d, 1H) 7.95 (s, 1H) 7.52 (d, 1H) 6.99 (br s, 1H) 6.64 (s, 1H) 6.54 (s, 1H) 4.35-4.23 (m, 3H) 3.63-3.54 (m, 3H) 2.75-2.64 (m, 4H) 1.36 (s, 9H)

[0320] Preparation 171: 2-(Difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] To a solution of 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 1.9 g, 8.98 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 1.73 g, 10.77 mmol) in t-AmOH (40 mL) was added CsCO (8.78 g, 26.93 mmol) and BrettPhos Pd G (407 mg, 0.449 mmol) under N, and the mixture was stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with HO (30 mL) and extracted with EtOAc (3 × 20 mL). The combined organics were washed with HO (3 × 20 mL), dried (NaSO), and evaporated to dryness in vacuo to give the title compound (1.7 g, 54%) as a brown solid. LCMS m / z = 336 [M+H] + .

[0321] Preparation 172: (4,6-Dichloropyrimidin-2-yl)methyl acetate [ka] A mixture of 4,6-dichloro-2-(chloromethyl)pyrimidine (1.5 g, 7.59 mmol) and NaI (1.69 g, 11.3 mmol) in acetone (50 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, the residue was diluted with dioxane / HO (1:1, 50 mL), KOAc (1.48 g, 15.1 mmol) was added, and the reaction was stirred at 60 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (1:10 EtOAc / PE) to give the title compound (1.5 g, 89%) as a colorless oil. LCMS m / z = 221 [M+H] + .

[0322] Preparation 173: (4,6-bis((diphenylmethylene)amino)pyrimidin-2-yl)methanol [ka] A mixture of (4,6-dichloropyrimidin-2-yl)methyl acetate (Preparation 172, 700 mg, 3.16 mmol), diphenylmethanimine (1.14 g, 6.32 mmol), CsCO (2.05 g, 6.32 mmol), Pd(dba) (289 mg, 0.316 mmol), and Xantphos (182 mg, 0.316 mmol) in dioxane (20 mL) was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (1:10 MeOH / DCM) to give the title compound (500 mg, 33%) as a yellow solid. LCMS m / z = 469 [M+H] + .

[0323] Preparation 174: (4,6-Diaminopyrimidin-2-yl)methanol [ka] A mixture of (4,6-bis((diphenylmethylene)amino)pyrimidin-2-yl)methanol (Preparation 173, 500 mg, 1.06 mmol) in dioxane / HCl (10 mL) was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and the residue was treated with NH3 in MeOH to adjust the pH to approximately 10. The resulting mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography (1:10 MeOH / DCM) to give the title compound (120 mg, 81%) as a white solid. LCMS m / z = 141 [M+H] + .

[0324] Preparation 175: 6-Chloro-4-fluoronicotinic acid [ka] To a solution of 2-chloro-4-fluoro-5-iodopyridine (70.0 g, 272 mmol) in THF (700 mL) was added i-PrMgCl (2.00 M, 136 mL) at 0 °C under N. After 1 h at 0 °C, the reaction mixture was stirred at 0 °C under CO for 30 min. The reaction mixture was poured into H0 (1 L) and washed with EtOAc (2 x 500 mL). The combined aqueous phase was then adjusted to pH = 1-2 with 1 N HCl (600 mL) and extracted with EtOAc (3 x 400 mL). The combined organics were dried (NaSO) and concentrated under reduced pressure to give the title compound (25.5 g, 52%) as a yellow solid. LCMS m / z = 176 [M+H] + .

[0325] Preparation 176: 6-chloro-4-fluoro-N-methylnicotinamide [ka] To a solution of 6-chloro-4-fluoronicotinic acid (Preparation 175, 11.48 g, 65.40 mmol) and methylamine hydrochloride (4.42 g, 65.40 mmol) in MeCN (120 mL) was slowly added T3P (83.23 g, 130.79 mmol, 50% purity) and DIPEA (16.9 g, 130.79 mmol), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with HO (50 mL) and extracted with EtOAc (3 × 100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4), and evaporated to dryness to afford the title compound (8.7 g, 71%) as a yellow solid, which was used without further purification. 1 H NMR (400 MHz, DMSO-d6) δ:8.63(d,1H)8.54(brs,1H)7.77(d,1H)2.79(d,3H)

[0326] Preparation 177: 4,6-Dichloro-N-methylnicotinamide [ka] A drop of DMF was added to a mixture of 4,6-dichloronicotinic acid (10 g, 52 mmol) in SOCl (50 mL), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was diluted with THF (50 mL) and added to a solution of MeNH.HCl (4.21 g, 62.4 mmol) and DIPEA (20.1 g, 156 mmol) in THF (50 mL). The resulting mixture was stirred at room temperature for 16 h. The reaction was quenched with H O and extracted with EtOAc. The combined organics were washed with H O and brine, dried (Na SO ), and evaporated to dryness in vacuo. The residue was purified by column chromatography (10:1 to 5:1 PE / EtOAc) to give the title compound (8 g, 75%) as a yellow solid. LCMS m / z = 205 [M+H] + .

[0327] Preparation 178: 4,6-Dichloro-N-cyclopropylnicotinamide [ka] A mixture of 4,6-dichloronicotinic acid (1 g, 5.2 mmol), cyclopropanamine (297 mg, 5.2 mmol), HATU (3 g, 7.8 mmol), and TEA (1.6 g, 15.6 mmol) in DMF (20 mL) was stirred at room temperature under N for 12 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography (50% EtOAc / PE) to give the title compound (800 mg, 66%). LCMS m / z = 231 [M+H] + .

[0328] Preparation 179: tert-Butyl 6-(4,6-dichloronicotinamido)-2-azaspiro[3.3]heptane-2-carboxylate [ka] A solution of 4,6-dichloronicotinic acid (600 mg, 3.1 mmol), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (658 mg, 3.1 mmol), HATU (1.8 g, 4.7 mmol), and TEA (951 mg, 9.4 mmol) in DMF (10 mL) was stirred at room temperature under N for 12 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography (50% EtOAc / PE) to give the title compound (900 mg, 74%). LCMS m / z = 386 [M+H] + .

[0329] Preparation 180: 6-chloro-N-methyl-4-(methylamino)nicotinamide [ka] MeNH2 in THF (20 mL, 2N) was added to a mixture of 4,6-dichloro-N-methylnicotinamide (Preparation 177, 300 mg, 1.46 mmol) in DCM (20 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was evaporated to dryness in vacuo and purified by column chromatography (1:5 EtOAc / PE) to give the title compound (300 mg, 100%) as a colorless oil. LCMS m / z = 200 [M+H] + .

[0330] Preparation 181: 6-chloro-4-(isopropylamino)-N-methylnicotinamide [ka] A mixture of 4,6-dichloro-N-methylnicotinamide (Preparation 177, 1.0 g, 4.88 mmol), isopropylamine (0.419 mL, 4.88 mmol), N,N-dimethylacetamide (1 mL), and DIPEA (0.937 mL, 10.76 mmol) was stirred at 70° C. overnight. The reaction was evaporated to dryness in vacuo, and the residue was purified by silica gel chromatography to give the title compound (450 mg, 41%). LCMS m / z = 228 [M+H] + .

[0331] Preparation 182: 6-chloro-N-cyclopropyl-4-(methylamino)nicotinamide [ka] A solution of 4,6-dichloro-N-cyclopropylnicotinamide (Preparation 178, 800 mg, 3.5 mmol), methanamine (323 mg, 10.4 mmol), and DIPEA (1.3 g, 10.4 mmol) in MeCN (20 mL) was stirred at room temperature under N for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography (50% EtOAc / PE) to give the title compound (500 mg, 64%). LCMS m / z = 226 [M+H] + .

[0332] Preparation 183: tert-Butyl 6-(6-chloro-4-(ethylamino)nicotinamido)-2-azaspiro[3.3]heptane-2-carboxylate [ka] The title compound was prepared from tert-butyl 6-(4,6-dichloronicotinamido)-2-azaspiro[3.3]heptane-2-carboxylate (Preparation 179) and ethylamine using a method similar to that described in Preparation 182. Yield: 600 mg, 65%; LCMS m / z = 395 [M+H] + .

[0333] Preparation 184: 6-chloro-4-(ethylamino)-N-methylnicotinamide [ka] To a solution of 4,6-dichloro-N-methylnicotinamide (Preparation 177, 190 mg, 0.927 mol) and ethylamine hydrochloride (90.7 mg, 1.11 mmol) in n-BuOH (5 mL) was added DIPEA (359 mg, 2.78 mmol) and the mixture was heated at 100 °C for 1 h. The reaction mixture was evaporated to dryness, diluted with HO, and extracted with EtOAc (3 x 10 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo to give the title compound (150 mg) as a yellow solid. LCMS m / z = 214 [M+H] + .

[0334] Preparation 185: 6-chloro-N-cyclopropyl-4-(ethylamino)nicotinamide [ka] To a mixture of ethanamine hydrochloride (186 mg, 2.28 mmol) and 4,6-dichloro-N-cyclopropylnicotinamide (Preparation 178, 440 mg, 1.90 mmol) in n-BuOH (4 mL) was added DIPEA (738 mg, 5.71 mmol), and the resulting mixture was stirred at 100° C. for 1 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue that was purified by preparative HPLC-6 to give the title compound (100 mg, 22%) as a gray gum. LCMS m / z = 240 [M+H] + .

[0335] Preparation 186: (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-methylnicotinamide [ka] A mixture of 4,6-dichloro-N-methylnicotinamide (Preparation 177, 200 mg, 0.975 mmol), (2S)-1-fluoropropan-2-amine hydrochloride (110 mg, 0.975 mmol), and DIPEA (376 mg, 2.92 mmol) in dioxane (5 mL) was stirred in a sealed tube at 140 °C for 16 h. The reaction was quenched with HO and extracted into EtOAc. The combined organics were washed (HO and brine), dried (NaSO), and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (10:1 to 1:1 PE / EtOAc) to give the title compound (210 mg, 82%) as a white solid. LCMS m / z = 246 [M+H] + .

[0336] Preparation 187: 6-chloro-4-((1,3-difluoropropan-2-yl)amino)-N-methylnicotinamide [ka] The title compound was prepared from 4,6-dichloro-N-methylnicotinamide (Preparation 177) and 1,3-difluoropropan-2-amine using a method similar to that described in Preparation 186. The compound was further purified by preparative HPLC-3 to give the title compound (60 mg, 18%) as a white solid. LCMS m / z = 264 [M+H] + .

[0337] Preparation 188: (R)-6-chloro-4-((1,1-difluoropropan-2-yl)amino)-N-methylnicotinamide [ka] A mixture of (R)-1,1-difluoropropan-2-amine (120 mg, 1.26 mmol), 4,6-dichloro-N-methylnicotinamide (Preparation 177, 258 mg, 1.26 mmol), and DIPEA (489 mg, 3.78 mmol) in dioxane (5 mL) was stirred at 140° C. for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative HPLC-3 to give the title compound (80 mg, 24%) as a white solid. LCMS m / z = 264 [M+H] + .

[0338] Preparation 189~198 The title compound was prepared from the appropriate chloropyridine (RCl) and amine (RNH2) using a method similar to that described in Preparation 188.

[0339] [Table 8-1] [Table 8-2] [Table 8-3]

[0340] Preparation 199: (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-(pyridin-2-ylmethyl)nicotinamide [ka] Part 1: A mixture of 4,6-dichloropyridine-3-carboxylic acid (500 mg, 2.60 mmol) and oxalyl chloride (659 mg, 5.20 mmol) in THF (10 mL) was stirred at room temperature for 2 hours. The mixture was concentrated in vacuo, and the residue was dissolved in THF (10 mL) and DIPEA (1006 mg, 7.80 mmol). 1-(pyridin-2-yl)methanamine (421 mg, 3.90 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography (SiO, 25% EtOAc / PE) to give 4,6-dichloro-N-(pyridin-2-ylmethyl)nicotinamide as a white solid (470 mg, 63%). Part 2: A mixture of 4,6-dichloro-N-(pyridin-2-ylmethyl)nicotinamide (200 mg, 0.708 mmol), (2S)-1-fluoropropan-2-amine hydrochloride (96.4 mg, 0.849 mmol), and DIPEA (273 mg, 2.12 mmol) in dioxane (4 mL) was stirred at 140° C. for 16 hours. The cooled mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 3) to give the title compound (180 mg, 79% yield) as a white solid. LCMS mz=323 [M+H] + .

[0341] Preparation 200: 6-chloro-4-(ethylamino)-N-(oxazol-4-ylmethyl)nicotinamide [ka] 4,6-Dichloro-N-(oxazol-4-ylmethyl)nicotinamide was prepared from 1-(1,3-oxazol-4-yl)methanamine hydrochloride and 4,6-dichloropyridine-3-carboxylic acid using a method similar to that described in Preparation 199, part 1, as a yellow solid, 300 mg, 67%. A mixture of 4,6-dichloro-N-(oxazol-4-ylmethyl)nicotinamide (300 mg, 1.10 mmol), ethanamine (74.3 mg, 1.65 mmol), and DIPEA (650 mg, 3.3 mmol) in MeCN (10 mL) was stirred at room temperature for 16 hours. The mixture was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 3) to give the title compound (200 mg, 65%) as a white solid. LCMS m / z = 281 [M+H] + .

[0342] Preparation 201: 6-chloro-4-(isopropylamino)nicotinic acid [ka] A mixture of 6-chloro-4-fluoronicotinic acid (Preparation 175, 1 g, 5.70 mmol), propan-2-amine (840 mg, 14.2 mmol), and DIPEA (4 mL) in EtOH (20 mL) was stirred at 80° C. for 16 h. The mixture was concentrated and purified by column chromatography on silica gel (10:1 DCM / MeOH) to give the title compound (980 mg, 80%). LCMS m / z = 215 [M+H] + .

[0343] Preparation 202: 6-chloro-4-(ethylamino)nicotinic acid [ka] A mixture of methyl 6-chloro-4-(ethylamino)nicotinate (600 mg, 2.79 mmol) and NaOH (6 mL, 2 M in water) in EtOH (6 mL) was stirred at 80° C. for 1 h. The mixture was cooled to 0° C., the pH was adjusted to 4-5 with HCl (2 M), and the solid was filtered to give the title compound (500 mg, yield: 89%). LCMS m / z = 201 [M+H] + .

[0344] Preparation 203: 6-chloro-4-(cyclopropylamino)nicotinic acid [ka] A solution of methyl 4,6-dichloronicotinate (3.0 g, 14.5 mmol), cyclopropanamine (1.65 g, 29.0 mmol), and DIPEA (5.61 g, 43.5 mmol) in dioxane (30 mL) was stirred at room temperature under N for 16 h. The mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give methyl 6-chloro-4-(cyclopropylamino)nicotinate (1.2 g, 36.5%) as a white solid. A solution of methyl 6-chloro-4-(cyclopropylamino)nicotinate (1.2 g, 5.29 mmol) and LiOH (378 mg, 15.8 mmol) in MeOH (6 mL), HO (6 mL), and THF (6 mL) was stirred at room temperature under N for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (1.1 g, 98%) as a white solid. LCMS m / z = 213 [M+H] + .

[0345] Preparation 204: 6-chloro-N-cyclopropyl-4-(cyclopropylamino)nicotinamide [ka] HATU (535 mg, 1.41 mmol) and TEA (213 mg, 2.11 mmol) were added to a mixture of 6-chloro-4-(cyclopropylamino)nicotinic acid (Preparation 203, 150 mg, 0.705 mmol) and cyclopropanamine (59.9 mg, 1.05 mmol) in DMF (8 mL), and the mixture was stirred at room temperature under N for 16 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (1:1 EtOAc / PE) to give the title compound (110 mg, 62%) as a white solid. LCMS m / z = 252 [M+H] + .

[0346] Preparation 205~220 The title compound was prepared from the appropriate carboxylic acid and amine using a method similar to that described in Preparation 204.

[0347] [Table 9-1] [Table 9-2] [Table 9-3] [Table 9-4]

[0348] Preparation 222: Methyl (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)nicotinate [ka] A mixture of 4,6-dichloropyridine-3-carboxylate methyl (300 mg, 1.45 mmol), (2S)-1-fluoropropan-2-amine hydrochloride (246 mg, 2.17 mmol), and DIPEA (561 mg, 4.35 mmol) in dioxane (5 mL) was stirred at 140° C. for 16 h. The cooled reaction was quenched with water and extracted with EtOAc. The combined organic layers were washed with water and brine, dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 2) to give the title compound (200 mg, 53% yield) as a white solid. LCMS m / z = 247 [M+H] + .

[0349] Preparation 223: (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)nicotinic acid [ka] A mixture of methyl (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)nicotinate (Preparation 222, 200 mg, 0.81 mmol), LiOH (57.9 mg, 2.42 mmol), and HO (1 mL) in THF (4 mL) was stirred at room temperature for 16 h. HCl (1 N) was added to adjust the pH to 3, and the mixture was diluted with water and extracted with EtOAc. The combined organic layers were dried over NaSO, filtered, and concentrated to give the title compound (200 mg, 100% yield) as a white solid. LCMS m / z = 233 [M+H] + .

[0350] Preparation 224: (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)nicotinamide [ka] A mixture of (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)nicotinic acid (Preparation 223, 150 mg, 0.644 mmol), DIPEA (248 mg, 1.93 mmol), and HATU (293 mg, 0.772 mmol) in DCM (10 mL) was stirred at room temperature for 5 minutes. (3-aminobicyclo[1.1.1]pentan-1-yl)methanol (87.3 mg, 0.772 mmol) was added, and the reaction was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with EtOAc / PE (1 / 1) to give the title compound (150 mg, 71% yield) as a white solid. LCMS m / z = 328 [M+H] + .

[0351] Preparation 225: 5-Bromo-2-chloro-N-(oxetan-3-yl)pyridin-4-amine [ka] To a mixture of 5-bromo-2,4-dichloropyridine and oxetan-3-amine (580 mg, 7.93 mmol) in DMF (5 mL) was added TEA (2.01 g, 19.83 mmol), and the reaction was heated at 70 °C for 12 h. The mixture was diluted with HO (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organics were dried (NaSO) and evaporated to dryness in vacuo. The residue was purified by column chromatography on silica gel (1:20 to 1:1 EtOAc / PE) to give the title compound (800 mg, 46%) as a yellow solid. LCMS m / z = 263 [M+H] + .

[0352] Preparation 226: 5-Bromo-2-chloro-N-methylpyridin-4-amine [ka] The title compound was prepared from 5-bromo-2,4-dichloropyridine and methylamine using a method similar to that described in preparation 225. LCMS m / z = 221 [M+H] +

[0353] Preparation 227: 2-chloro-5-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(oxetan-3-yl)pyridin-4-amine [ka] Part 1. To a solution of bis(pinacolato)diboron (925 mg, 3.64 mmol) and 5-bromo-2-chloro-N-(oxetan-3-yl)pyridin-4-amine (Preparation 225, 800 mg, 3.04 mmol) in dioxane (5 mL), Pd(dppf)Cl.DCM (248 mg, 0.304 mmol) and KOAc (596 mg, 6.07 mmol) were added, and the reaction was heated at 90 °C under N for 2 h. The reaction mixture was evaporated to dryness in vacuo to give 2-chloro-N-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine as a yellow oil (crude). Part 2. To a solution of 2-chloro-N-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-4-amine (Part 1) and 2-bromo-5-methyl-1,3,4-thiadiazole (470 mg, 2.63 mmol) in dioxane (5 mL) and HO (0.20 mL), XPhos Pd G (207 mg, 0.263 mmol) and KPO (1.12 g, 5.25 mmol) were added, and the resulting mixture was heated at 80 °C under N for 2 h. The reaction mixture was evaporated to dryness, and the residue was purified by preparative HPLC-9 to give the title compound (60 mg, 8%) as a yellow oil. LCMS m / z = 283 [M+H] +

[0354] Preparation 228: 2-chloro-N-methyl-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridin-4-amine [ka] The title compound was prepared from 5-bromo-2-chloro-N-methylpyridin-4-amine and 2-bromo-5-methyl-1,3,4-thiadiazole using a method similar to that described in Preparation 227, but using preparative HPLC-3. LCMS m / z = 241 [M+H] +

[0355] Preparation 229: 2,4-Dichloro-5-((trimethylsilyl)ethynyl)pyridine [ka] A mixture of 2,4-dichloro-5-iodopyridine (1 g, 3.65 mmol), ethynyltrimethylsilane (358 mg, 3.65 mmol), Pd(PPh3)Cl2 (512 mg, 0.73 mmol), CuI (139 mg, 0.73 mmol), and TEA (1.1 g, 10.95 mmol) in THF (5 mL) was stirred at 40 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (800 mg, 90%) as a yellow solid. LCMS m / z = 244 [M+H] +

[0356] Preparation 230: 2,4-Dichloro-5-ethynylpyridine [ka] TBAF (2 mL) was added to a solution of 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyridine (Preparation 229, 800 mg, 3.27 mmol) in THF and the mixture was stirred at room temperature for 1 h. The solution was diluted with EtOAc (100 mL) and washed with water and brine. The combined organics were evaporated to dryness and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (380 mg, 68%) as a yellow solid. LCMS m / z = 172 [M+H] +

[0357] Preparation 231: 2,4-Dichloro-5-(1H-1,2,3-triazol-4-yl)pyridine [ka] To a solution of 2,4-dichloro-5-ethynylpyridine (Preparation 230, 380 mg, 2.2 mmol) in DMF (4 mL) and MeOH (1.5 mL) was added CuI (83.8 mg, 0.44 mmol) and TMSN3 (380 mg, 3.3 mmol), and the mixture was stirred at 40 °C for 16 h. The reaction was quenched with NH4OH and extracted with EtOAc. The combined organics were concentrated and purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (200 mg, 42%) as a yellow solid. LCMS m / z = 215 [M+H] +

[0358] Preparations 232 and 233: 2,4-dichloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine and 2,4-dichloro-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine [ka] To a solution of 2,4-dichloro-5-(1H-1,2,3-triazol-4-yl)pyridine (Preparation 231, 100 mg, 0.47 mmol) in THF (5 mL) was added TBAF (243 mg, 0.93 mmol) and MeI (792 mg, 0.56 mmol) at 0° C., and the mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine and water. The combined organics were concentrated and purified by column chromatography on silica gel (50% EtOAc / PE) to give 2,4-dichloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine as a yellow solid (70 mg, 45%). LCMS m / z=229 [M+H] + and 2,4-dichloro-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine as a yellow solid (40 mg, 28%). LCMS m / z = 229 [M+H]+

[0359] Preparation 234: 2-chloro-N-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-4-amine [ka] A mixture of 2,4-dichloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (Preparation 232, 70 mg, 0.31 mmol), methanamine (28 mg, 0.92 mmol), and DIPEA (118 mg, 0.915 mmol) in MeCN (2 mL) was stirred at 120° C. for 16 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (50 mg, 73%) as a white solid. LCMS m / z = 224 [M+H] +

[0360] Preparation 235: 2-chloro-N-methyl-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-amine [ka] The title compound was obtained from 2,4-dichloro-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (Preparation 233) following the procedure described in Preparation 234 as a white solid, 30 mg, 77% yield. LCMS m / z = 224 [M+H] +

[0361] Preparation 236: 2-Chloro-5-iodo-N-methylpyridin-4-amine [ka] Methanamine (34 mg, 1.1 mmol) was added to a solution of 2,4-dichloro-5-iodopyridine (300 mg, 1.1 mmol) and DIPEA (426 mg, 3.3 mmol) in MeCN (5 mL), and the resulting mixture was stirred at room temperature under N for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (240 mg, 81%). LCMS m / z = 269 [M+H] +

[0362] Preparation 237: 2-chloro-N-methyl-5-(5-methylthiazol-2-yl)pyridin-4-amine [ka] A solution of 2-chloro-5-iodo-N-methylpyridin-4-amine (Preparation 236, 120 mg, 0.45 mmol), 5-methyl-2-(tributylstannyl)thiazole (173.5 mg, 0.447 mmol), Pd(PPh3)Cl2 (470.3 mg, 0.67 mmol), and K2CO3 (180 mg, 1.3 mmol) in DMF (4 mL) was stirred at 100 °C under N2 for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (100 mg, 93%). LCMS m / z = 240 [M+H] +

[0363] Preparation 238: 2-(6-chloro-4-fluoropyridin-3-yl)-5-methyl-1,3,4-thiadiazole [ka] Under an inert atmosphere of N, 2-bromo-5-methyl-1,3,4-thiadiazole (160 g, 894 mmol), dioxane (2.4 L), DMF (0.48 L), 2-chloro-4-fluoro-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (340 g, 1.32 mol), NaCO (285.8 g, 2.70 mol), Pd(dppf)Cl. DCM (36.6 g, 44.91 mmol), and CuCl (89 g, 899 mmol) were combined and the resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with EtOAc (2 L). The solids were removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel (5-50% EtOAc / PE) and the resulting solid was recrystallized from toluene to afford the title compound (45 g, 22%) as a yellow solid.

[0364] Preparation 239: 2-(Bromomethyl)-5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazole [ka] A mixture of 2-(6-chloro-4-fluoropyridin-3-yl)-5-methyl-1,3,4-thiadiazole (Preparation 238, 200 mg, 0.87 mmol), NBS (195 mg, 0.87 mmol), and AIBN (14 mg, 0.08 mmol) in CCl4 (10 mL) was stirred at 90 °C for 16 h. The mixture was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (10:1 PE / EtOAc) to give the title compound (50 mg, 18%). LCMS m / z = 308 [M+H] +

[0365] Preparation 240: 5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate [ka] A mixture of 2-(bromomethyl)-5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazole (Preparation 239, 50 mg, 0.16 mmol) and KOAc (32 mg, 0.32 mmol) in dioxane (5 mL) was stirred at 110° C. for 16 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (10:1 PE / EtOAc) to give the title compound (20 mg, 43%). LCMS m / z = 288 [M+H] +

[0366] Preparation 241: (5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol [ka] A mixture of (5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)methyl acetate (Preparation 240, 20 mg, 0.07 mmol), MeNH2 (0.5 mL, 2 M in THF), and DIPEA (18 mg, 0.14 mmol) in dioxane (2 mL) was stirred at 80 °C for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (11 mg, 61%). LCMS m / z = 257 [M+H] +

[0367] Preparation 242: (5-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol [ka] A mixture of (5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol (Preparation 241, 11 mg, 0.04 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 14 mg, 0.04 mmol), BrettPhos Pd G (2 mg), and CsCO (39 mg, 0.12 mmol) in dioxane (2 mL) was stirred at 100 °C under N for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (1:20 MeOH / DCM) to give the title compound (12 mg, 56%). LCMS m / z = 531 [M+H] + .

[0368] Preparation 243~246 The title compound was prepared from 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) and the appropriate chloropyridine (RCl) using a method similar to that described in Preparation 242.

[0369] [Table 10-1] [Table 10-2]

[0370] Preparations 247 and 248: N-(cyanomethyl)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)nicotinamide and 6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)nicotinamide [ka] A solution of 6-chloro-N-(cyanomethyl)-4-(methylamino)nicotinamide (Preparation 212, 195 mg, 0.868 mmol), 2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 296 mg, 0.955 mmol), BrettPhos Pd G4 (80 mg, 0.087 mmol), and CsCO3 (848 mg, 2.60 mmol) in dioxane (4.34 mL) was purged with N2 for 5 minutes and then stirred at 100 °C overnight. The reaction mixture was filtered, and the filtrate was washed with 10% MeOH in DCM. The combined organics were concentrated, and the residue was purified by reverse-phase chromatography on silica gel (20–100% MeCN / HO (+0.1% TFA)) to give the title compound. N-(cyanomethyl)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)nicotinamide (Preparation 247, 29 mg, 6.7%), LCMS m / z=499 [M+H] + . 6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)nicotinamide (Preparation 248, 47 mg, 11.8%), LCMS m / z=460 [M+H] + .

[0371] Preparation 249: (R)-6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-methylnicotinamide [ka] A mixture of 6-chloro-4-(isopropylamino)-N-methylnicotinamide (Preparation 181, 50 mg, 0.22 mmol), (R)-N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (Preparation 14, 67.3 mg, 0.22 mmol), BrettPhos Pd G (40.5 mg, 0.044 mmol), and CsCO (215 mg, 0.659 mmol) in dioxane (2 mL) was stirred at 100 °C under N for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (50 mg, 45%). LCMS m / z = 498 [M+H] + .

[0372] Preparation 250: (R)-6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-(ethylamino)-N-methylnicotinamide [ka] A mixture of 6-chloro-4-(ethylamino)-N-methylnicotinamide (Preparation 184, 60 mg, 0.280 mmol), (R)-N-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (Preparation 14, 85.7 mg, 0.280 mmol), CsCO (182 mg, 0.560 mmol), and Pd(t-BuP) (71.5 mg, 0.140 mmol) in dioxane (2 mL) was stirred at 100 °C under N for 16 h. The reaction mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel eluting with MeOH / DCM (1 / 20) to give the title compound (60 mg, 44%) as a white solid. LCMS m / z = 484 [M+H] + .

[0373] Preparations 251-254 The title compounds were prepared from the appropriate chloropyridine (RCl) and the appropriate amine (RNH2) using a method similar to that described in preparation 250. Alternative catalyst systems used are listed in the table.

[0374] [Table 11-1] [Table 11-2]

[0375] Preparation 255: N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine [ka] A solution of 6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 330 mg, 1.65 mmol), 2-methylpropan-2-amine (361 mg, 4.94 mmol), and DIPEA (252 mg, 4.95 mmol) in NMP was stirred at 100° C. for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine and HO. The combined organics were evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (50% EtOAc / PE) to give the title compound (300 mg, 77%) as a yellow solid. LCMS m / z = 236 [M+H] + .

[0376] Preparation 256: 6-((diphenylmethylene)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide [ka] A mixture of 6-chloro-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide (Preparation 220, 500 mg, 1.81 mmol), diphenylmethanimine (360 mg, 1.99 mmol), Pd(dba) (50 mg), XantPhos (50 mg), and CsCO (1.18 g, 3.62 mmol) in dioxane (100 mL) was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (20:1 DCM / MeOH) to give the title product (398 mg, 50%). LCMS m / z = 440 [M+H] + .

[0377] Preparation 257: 6-amino-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide [ka] HCl / dioxane (2 mL, 4 M) was added to a solution of 6-((diphenylmethylene)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide (Preparation 256, 398 mg, 0.9 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo, and the residue was purified by column chromatography on silica gel (10:1 DCM / MeOH) to give the title compound (198 mg, 80%). LCMS m / z = 440 [M+H] + .

[0378] Preparation 258: 6-((6-(tert-butylamino)-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide [ka] A mixture of compound N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine (Preparation 255, 120 mg, 0.509 mmol), 6-amino-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide (Preparation 257, 150 mg, 0.509 mmol), Pd(dba) (93.2 mg, 0.102 mmol), XantPhos (58.9 mg, 0.102 mmol), and CsCO (498 mg, 1.5 mmol) in dioxane (2 mL) was stirred at 100° C. for 12 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (100 mg, 41%) as a yellow solid. LCMS m / z = 475 [M+H] + .

[0379] Preparation 259: 6-((6-amino-2-(hydroxymethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-methylnicotinamide [ka] A mixture of (4,6-diaminopyrimidin-2-yl)methanol (Preparation 174, 60 mg, 0.428 mmol), 6-chloro-4-(isopropylamino)-N-methylnicotinamide (Preparation 181, 97.4 mg, 0.428 mmol), CsCO (278 mg, 0.856 mmol), and Brettphos Pd G (40 mg, 0.043 mmol) in NMP (3 mL) was stirred at 100° C. for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by preparative HPLC-3 to give the title compound (40 mg, 28%) as a white solid. LCMS m / z = 332 [M+H] + .

[0380] Preparation 260: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoro-N-methylnicotinamide [ka] A mixture of 6-chloro-4-fluoro-N-methylnicotinamide (Preparation 176, 1.4 g, 7.45 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 4.77 g, 29.8 mmol), and CsCO (7.26 g, 22.35 mmol) was added to BrettPhos Pd G3 (337.49 mg, 0.373 mmol) in t-AmOH (60 mL) in a degassed and purged solution with N (×3). The mixture was stirred at 120 °C under N for 2 h. The reaction mixture was concentrated under reduced pressure, and HO (30 mL) was added. The mixture was extracted with EtOAc (3 × 30 mL). The resulting solid was removed by filtration, and the filtrate was evaporated to dryness in vacuo to give the title compound (1.5 g, 45%), which was used without further purification. LCMS m / z = 313 [M+H] + .

[0381] Preparation 261: 5-(4,6-dichloropyridin-3-yl)-3-methyl-1,2,4-oxadiazole [ka] Part 1. A mixture of compounds 4,6-dichloronicotinamide (2 g, 10 mmol) and 1,1-dimethoxy-N,N-dimethylethan-1-amine (1.67 g, 12 mmol) in DMF (20 mL) was stirred at 70° C. for 2 hours. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organics were evaporated to dryness in vacuo to give (E)-4,6-dichloro-N-(1-(dimethylamino)ethylidene)nicotinamide (2 g) without further purification. LCMS m / z = 260 [M+H] + . Part 2. A mixture of Part 1 (2 g, 7.7 mmol), NHOH (492 mg, 15.4 mmol), and AcOH (1 mL) in dioxane / water (20 mL / 1 mL) was stirred at 70° C. for 1 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (5:1 PE / EtOAc) to give the title compound (700 mg, 39%). LCMS m / z = 230 [M+H] + .

[0382] Preparation 262: 2-chloro-N-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-amine [ka] A mixture of 5-(4,6-dichloropyridin-3-yl)-3-methyl-1,2,4-oxadiazole (700 mg, 3.0 mmol) and propan-2-amine (360 mg, 6.1 mmol) in EtOH (20 mL) was stirred at 80° C. for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (20:1 DCM / MeOH) to give the title compound (600 mg, 79%). LCMS m / z = 253 [M+H] + .

[0383] Preparation 263: N2-Benzyl-N4-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine [ka] A mixture of 2-chloro-N-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-amine (Preparation 262, 220 mg, 0.870 mmol) and benzylamine (932 mg, 8.70 mmol) was stirred at 200° C. for 1 hour under microwave irradiation. The reaction was diluted with EtOAc and washed with brine and water. The organics were evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (230 mg, 82%) as a yellow solid. LCMS m / z = 324 [M+H] + .

[0384] Preparation 264: N4-Isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine [ka] To a solution of N2-benzyl-N4-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine (Preparation 263, 230 mg, 0.711 mmol) in DCM (10 mL) was added TfOH (534 mg, 3.6 mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with aqueous NaHCO3 to adjust the pH to approximately pH 10. The solution was evaporated in vacuo, and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (110 mg, 67%) as a white solid. LCMS m / z = 234 [M+H] + .

[0385] Preparation 265: N4-(tert-butyl)-2-(difluoromethyl)-N6-(4-(isopropylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] A mixture of N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine (Preparation 255, 100 mg, 0.424 mmol), N-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine (Preparation 264, 98.9 mg, 0.424 mmol), Pd(t-BuP) (43.3 mg, 0.085 mmol), and CsCO (414 mg, 1.3 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (5% MeOH / DCM) to give the title compound (80 mg, 44%) as a white solid. LCMS m / z = 433 [M+H] + .

[0386] Preparation 266: tert-Butyl 6-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(ethylamino)nicotinamido)-2-azaspiro[3.3]heptane-2-carboxylate [ka] The title compound was prepared from tert-butyl 6-(6-chloro-4-(ethylamino)nicotinamido)-2-azaspiro[3.3]heptane-2-carboxylate (Preparation 183) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) using a method similar to that described in Preparation 265. Yield: 120 mg, 45%; LCMS m / z = 519 [M+H] + .

[0387] Preparation 267: Methyl 6-chloro-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinate [ka] A mixture of methyl 6-chloro-4-fluoropyridine-3-carboxylate (300 mg, 1.58 mmol), (1R,2S)-2-fluorocyclopropan-1-amine hydrochloride (176 mg, 1.58 mmol), and DIPEA (611 mg, 4.74 mmol) in dioxane (10 mL) was stirred at room temperature for 16 hours. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (1:5 EtOAc / PE) to give the title compound (120 mg, 31%) as a white solid. LCMS m / z = 245 [M+H] + .

[0388] Preparation 268: Methyl 6-chloro-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinate [ka] The title compound was prepared from methyl 6-chloro-4-fluoropyridine-3-carboxylate and (1S,2R)-2-fluorocyclopropan-1-amine 4-methylbenzenesulfonate as a white solid (100 mg, 26%) using a method similar to that described in Preparation 267. LCMS m / z = 245 [M+H] + .

[0389] Preparation 269: Methyl 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinate [ka] The title compound was prepared from methyl 6-chloro-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinate (Preparation 267) and 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) using a method similar to that described in Preparation 242 as a white solid (60 mg, 28%). LCMS m / z = 519 [M+H] + .

[0390] Preparation 270: Methyl 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinate [ka] The title compound was prepared from methyl 6-chloro-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinate (Preparation 268) and 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) using a method similar to that described in Preparation 242 as a white solid (60 mg, 28%). LCMS m / z = 519 [M+H] + .

[0391] Preparation 271: 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-N-methylnicotinamide [ka] Methyl 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinate (60 mg, 0.115 mmol) in MeNH2 (30% in MeOH, 5 mL) was stirred at 70°C in a sealed vessel for 16 hours. The mixture was concentrated in vacuo to give the title compound (60 mg, 100%) as a white solid. LCMS m / z = 518 [M+H] + .

[0392] Preparation 272: 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-N-methylnicotinamide [ka] The title compound was prepared from methyl 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinate (Preparation 270) using a method similar to that described in Preparation 271 as a white solid (60 mg, 100%). LCMS m / z = 518 [M+H] + .

[0393] Preparation 273: N-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoro-N-methylethan-1-amine [ka] A mixture of 2-(4-bromo-1H-pyrazol-1-yl)-N-methylethan-1-amine hydrochloride (1 g, 4.16 mmol), triethylamine (2.318 mL, 16.63 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (3.59 mL, 24.95 mmol) in DMF (8 mL) was stirred overnight at 80 °C under microwave irradiation. The cooled mixture was diluted with EtOAc, washed with water and brine, dried (Na SO ), and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc / hexanes) to afford the title compound (888 mg, 74.7%) as a colorless oil. LCMS m / z = 286.0 [M+H] + .

[0394] Preparation 274: 2,2,2-trifluoro-N-methyl-N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethyl)ethan-1-amine [ka] A mixture of N-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoro-N-methylethan-1-amine (Preparation 273, 445 mg, 1.555 mmol), bis(pinacolato)diboron (474 ​​mg, 1.867 mmol), and PdCl2(dppf). DCM (191 mg, 0.233 mmol) and potassium acetate (458 mg, 4.67 mmol) in 1,4-dioxane (6 ml) was stirred at 90 °C overnight. The crude material in solution was used directly without further purification. LCMS m / z = 334.1 [M+H] + .

[0395] Preparation 275: 1-(3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole [ka] A 1.3 M solution of iPrMgCl.LiCl in THF (4.89 ml, 6.35 mmol) was added dropwise to a solution of 1-(3-(benzyloxy)cyclobutyl)-4-iodo-1H-pyrazole (prepared according to US2016 / 0256448, 1.8 g, 5.08 mmol) in THF (20.33 ml) at 0 °C. After 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.555 ml, 7.62 mmol) was added dropwise. The reaction mixture was then allowed to warm to room temperature. After 48 h, the reaction mixture was diluted with 50% saturated ammonium chloride solution (25 mL) and then extracted with EtOAc (50 mL × 2). The combined organics were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give the title compound (635 mg, 35.3%) as a colorless solid. LCMS m / z = 355.0 [M+H] + ; 1H NMR (500 MHz, CDCl3) δ ppm 7.85 (d, 1H), 7.74 (d, 1H), 7.38 (t, 5H), 4.97 (t, 1H), 4.49 (d, 2H), 4.47 - 4.41 (m, 1H), 2.90 - 2.73 (m, 2H), 2.65 (m, 2H), 1.34 (d, 12H).

[0396] Preparation 276: tert-Butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-yl)carbamate [ka] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (358 mg, 1.845 mmol), tert-butyl 4,4-dimethyl-1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (464 mg, 1.845 mmol), and cesium carbonate (1202 mg, 3.69 mmol) in acetonitrile (6 mL) was stirred overnight at 70°C under microwave irradiation. The cooled reaction mixture was filtered, and the residue was washed with DCM. The combined filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give the title compound (112 mg, 16.6%). LCMS m / z = 366.2 [M+H] + .

[0397] Preparation of the exemplified compounds Example 1: (S)-1-(4-(6-((6-amino-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (167) [ka] To a solution of (S)-1-(4-(6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 114, 840 mg, 1.45 mmol) in DCM (5 mL) was added TFA (10 mL) and the reaction was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-3 to give the title compound (421.1 mg, 67% yield) as a white solid. LCMS m / z = 430 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:9.54(s,1H),8.34(s,1H),8.05(s,1H),7.88(s,1H),7.55(s,1H),6.67(s,1H),6.62(s,2H),5. 37-5.23(m,1H),4.71(s,1H),4.68(q,1H),4.04(s,2H),1.57(dd,3H),1.40(d,6H),1.08(s,6H).

[0398] Example 2: (S)-2-(1-fluoroethyl)-N4-(4-isopropoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (129) [ka] To a solution of (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 117, 80 mg, 0.141 mmol) in DCM (1 mL) was added TFA (5 equivalents) and the reaction was stirred at room temperature for 4 hours. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC-3 to give the title compound (13.1 mg, 23% yield) as a white solid. LCMS m / z = 414 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:9.57(s,1H),8.36(s,1H),8.19(s,1H),8.04(s,1H),7.55(s,1H),6.67(s,1H),6.64(s,2H),5.67 -5.60(m,1H),5.39-5.22(m,1H),4.95-4.90(m,4H),4.73-4.67(m,1H),1.57(dd,3H),1.41(d,6H).

[0399] Example 3: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (120) [ka] A solution of 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 146, 480 mg, 0.86 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and saturated aqueous NaHCO3 (20 mL) was added. The precipitate was filtered and the solid was dissolved in MeOH (30 mL). The precipitate was filtered and the filtrate was concentrated to give the crude product, which was washed with DCM. The precipitate was filtered to give the title compound (294 mg, 84%) as a pale yellow solid. LCMS m / z = 406 [M+H] + . 1 HNMR (500 MHz, DMSO-d6) δ 9.79 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.38 (s, 1H), 6.95-6.90 (m, 3H), 6.64-6.37 (m, 1H), 4.70 (s, 1H), 4.03 (s, 2H), 3.89 (s, 3H), 1.08 (s, 6H).

[0400] Example 4: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (173) [ka] A mixture of 1-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 147, 800 mg, 1.37 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at room temperature for 2 h. The mixture was concentrated in vacuo and saturated aqueous NaHCO3 (20 mL) was added. The precipitate was filtered and the solid was dissolved in MeOH (30 mL). The mixture was filtered and the filtrate was concentrated in vacuo. The crude product was washed with DCM and the precipitate was filtered to give the title compound (440 mg, 74.6%) as a beige solid. LCMS m / z = 432 [M+H] + . 1H NMR (500 MHz, DMSO-d6) δ 9.84 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 6.89 (s, 3H), 6.50 (t, 1H), 4.70 (s, 1H), 4.03 (s, 2H), 3.96 - 3.86 (m, 1H), 1.08 (s, 6H), 0.93 - 0.75 (m, 4H).

[0401] Example 5: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (126) [ka] A mixture of 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 139, 300 mg, 0.537 mmol) in DCM (10 mL) and TFA (2.5 mL) was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and Na2CO3 (aq) was added to the residue to adjust the pH to 10. The mixture was filtered and the solid was washed with water and DCM and dried to give the title compound (147.4 mg, yield: 67%) as a white solid. LCMS m / z = 409 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ:9.82(s,1H),8.38(s,1H),8.06(s,1H),7.91(s,1H),7.37(s,1H),6.9 6-6.92(m,3H),6.51(t,1H),4.74(br,s,1H),4.04(s,2H),1.08(s,6H).

[0402] Example 6: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (198) [ka] To a mixture of 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 108, 180 mg, 0.3 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the crude was purified by preparative HPLC-3 to give the title product (85 mg, 62%). LCMS m / z = 460 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:10.20 (s, 1H), 8.63 (s, 1H), 8.05-8.00 (m, 2H), 7.88 (s, 1H), 7.21-6.96 (m, 2H), 6.74 (s, 1H), 6.50 (t, 1H), 4.74 (s, 1H), 4.07 (s, 2H), 1.08 (s, 6H).

[0403] Example 7: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (181) [ka] A mixture of 1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Preparation 115, 50 mg, 0.08 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and purified by preparative HPLC-3 to give the title product (26.2 mg, 69%). LCMS m / z = 442 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:10.06 (s, 1H), 8.55 (s, 1H), 8.05 (s, 1H), 7.90 (s, 1H), 7.63 (s, 1H), 7.38 (t, 1H), 6.97 (br s, 2H), 6.84 (s, 1H), 6.50 (t, 1H), 4.73 (s, 1H), 4.06 (s, 2H), 1.08 (s, 6H).

[0404] Examples 8 to 38 The following compounds were prepared from the appropriate protected starting material (SM) and purified by HPLC-3 following a procedure similar to that described in Example 7.

[0405]

Table 12-1

Table 12-2

Table 12-3

Table 12-4

Table 12-5

Table 12-6

Table 12-7

Table 12-8

Table 12-9

Table 12-10

Table 12-11

Table 12-12

Table 12-13

Table 12-14

Table 12-15

[0406] Examples 39 and 40: (S)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine [ka] To a mixture of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 112, 100 mg, 0.16 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was purified by HPLC-3 to give 2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (50.0 mg, 61% yield). The product was further purified by preparative SFC using an AD-H (250 × 4.6 mm 5 μm) column, mobile phase: n-hexane (0.1% diethylamine):EtOH (0.1% diethylamine) = 70:30, 1.0 mL / min, to give the first eluate (S)-2-(difluoromethyl)-N-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (195) (12.8 mg, 25% yield). Further elution afforded a second elution of (R)-2-(difluoromethyl)-N-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine, (196) (12.1 mg, 24% yield). LCMS m / z = 459 [M+H]+. 1 H-NMR (400 MHz, DMSO-d6) δ:10.20 (s, 1H), 8.61 (s, 1H), 8.10 (s, 1H), 7.99 (s, 1H), 7.87 (s, 1H), 7.01 (s, 2H), 6.74 (s, 1H), 6.49 (t, 1H), 4.13-4.03 (m, 1H), 2.90-2.89 (m, 1H), 2.27 (s, 1H), 0.92 (d, 3H).

[0407] Examples 41 and 42: (S)-2-(difluoromethyl)-N4-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] To a solution of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 148, 80 mg, 0.147 mmol) in DCM was added TFA (84 mg, 0.736 mmol) and the solution was stirred at room temperature overnight. The reaction was concentrated in vacuo and the crude product was purified by preparative HPLC-3 to give the title product (40 mg) as a white solid, which was further separated by SFC using an IG20×250 mm, 10 μm (Daicel) column, mobile phase CO2 / MeOH (0.2% MeOH / NH3)=50 / 50 at 100 g / min to give the following: First eluting enantiomer 1, (S)-2-(difluoromethyl)-N4-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(4-(((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (87) (3.0 mg, 5% yield) LCMS m / z = 394 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:9.74(s,1H),8.37(s,1H),8.03(s,1H),7.89(s,1H),7.44(s,1H),6.89(d,3H),6.50(t,1H),4.77-4.75(m,3H),3.87(s,3H),1.37(d,3H). Second eluting enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4-(4-((1-fluoropropan-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (88) (5.5 mg, 9% yield). 1 H-NMR (400 MHz, DMSO-d6) δ:9.75(s,1H),8.37(s,1H),8.03(s,1H),7.89(s,1H),7.44(s,1H),6.89(d,3H),6.50(t,1H),4.77-4.63(m,3H),3.87(s,3H),1.36(d,3H).

[0408] Examples 43 and 44: (S)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine and (R)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine [ka] A mixture of N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 137, 150 mg, 0.26 mmol) in DCM / TFA (8 mL / 2 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. The residue was purified by preparative HPLC-3 to give N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (50 mg, 44% yield) as a white solid. LCMS m / z = 430 [M+H] + This was further purified by SFC using an OJ20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / MeOH (1% MeOH / NH3) = 50 / 50 (100 g / min) to give: First eluting enantiomer 1: (S)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine or (R)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (164) as a white solid (16.5 mg). 1H-NMR (400 MHz, DMSO-d6) δ:9.85(s,1H),8.37(m,1H),8.06(s,1H),7.88(s,1H),7.80(s,1H),6.89-6.87(m,3H),6.50(t,1H) ),5.06-5.04(m,1H),4.01-3.97(m,2H),3.91-3.89(m,3H),2.35-2.26(m,2H),0.89-0.82(m,4H) and Second eluting enantiomer 2: (R)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine or (S)—N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (165) as a white solid (22.5 mg). 1 H-NMR (400 MHz, DMSO-d6) δ:9.85(s,1H),8.37(m,1H),8.06(s,1H),7.88(s,1H),7.80(s,1H),6.89-6.87(m,3H),6.50(t,1H) ),5.06-5.04(m,1H),4.01-3.97(m,2H),3.91-3.89(m,3H),2.35-2.26(m,2H),0.89-0.82(m,4H).

[0409] Example 45: 2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethan-1-ol trifluoroacetate (59) [ka] To a solution of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-methoxy-5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 122, 68 mg, 0.111 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol) and the reaction was stirred at room temperature for 10 minutes. The reaction mixture was concentrated under reduced pressure, diluted with DMSO, and purified by reverse phase chromatography (10-90% MeCN in water with 0.01% TFA) to afford the title compound as a white solid. LCMS m / z = 378 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.23 (s, 1H), 7.16 (s, 3H), 6.64 (t, 2H), 4.18 (t, 2H), 3.99 (s, 3H), 3.77 (t, 2H).

[0410] Example 46: 2-(difluoromethyl)-N4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (95) [ka] To a mixture of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 109, 50 mg, 0.09 mmol) in DCM (2 mL) was added HCl / dioxane (2 mL, 4 M) and the reaction was stirred at room temperature for 1 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel. The product was further purified by preparative HPLC-3 to give the title compound (24.9 mg, 68% yield). LCMS m / z = 402 [M+H] + . 1 H-NMR (400 MHz, DMSO-d6) δ ppm 10.19 (s, 1H), 8.59 (s, 1H), 8.07 (s, 1H), 7.97 (s, 1H), 7.84 (s, 1H), 7.01 (br s, 2H), 6.76 (s, 1H), 6.49 (t, 1H), 3.90 (s, 3H).

[0411] Example 47: 2-(Difluoromethyl)-N4-(4-methoxy-5-(1-(pyrrolidin-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (97) [ka] Following a procedure similar to that described in Example 46, tert-butyl 3-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 123) gave the title compound as a white solid, 5.1 mg, 7% yield. LCMS m / z = 403 [M+H] + . 1H-NMR (400 MHz, DMSO-d6) δ:9.67(s,1H),9.51(s,1H),8.55(s,1H),8.40(s,1H),8.04(s,1H),7.45-7.12(m,3H),6.92-6.69(m,1H),6.45(br s,1H),5.27-5.25(m,1H),4.05(s,3H),3.67-3.65(m,2H),3.53-3.38(m,2H),2.42-2.37(m,1H),2.27-2.25(m,1H).

[0412] Example 48: 2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (122) [ka] Following a procedure similar to that described in Example 46, 2-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (Preparation 124) gave the title compound as a white solid, 41.2 mg, 48% yield. LCMS m / z = 406 [M+H] +. 1 H-NMR (500 MHz, DMSO-d6) δ:9.80(s,1H),8.37(s,1H),8.10(s,1H),7.89(s,1H),7.40(s,1H),6.94(s,1H) ,6.90(s,2H),6.51(t,1H),4.98(t,1H),3.89(s,3H),3.61(d,2H),1.50(s,6H).

[0413] Example 49: N4-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (154) [ka] Following the procedure described in Example 46, N4-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 110) gave the title compound 25.4 mg, 54%. LCMS m / z = 428 [M+H] + 1 H-NMR (400 MHz, DMSO-d6) δ:10.20 (s, 1H), 8.59 (s, 1H), 8.17 (s, 1H), 7.99 (s, 1H), 7.81 (s, 1H), 7.01 (br s, 2H), 6.74 (s, 1H), 6.49 (t, 1H), 3.82-3.78 (m, 1H), 1.10-0.97 (m, 4H).

[0414] Example 50: N4-(5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine formate (76) [ka] To a solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 156, 50 mg, 0.102 mmol) in DCM (2 mL) was added TFA (1 mL, 13.51 mmol) and the reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC-8 to give the title compound (13.40 mg, 27%) as a yellow oil. LCMS m / z = 389 [M+H] + 1H-NMR (400MHz, DMSO-d6) δ:9.83(s,1H),8.39(s,1H),8.27(s,1H),8.07(s,1H),7.41(s,1H),6.94(d,3H),6.71-6.33(m,1H),5.39(s,2H),4.22(s,4H),3.91(s,3H).

[0415] Examples 51 to 53 The compounds in the following table were prepared from the appropriate Boc-protected compounds following procedures similar to those described in Example 50.

[0416] [Table 13-1] [Table 13-2]

[0417] Example 54: 2-(Difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (80) [ka] To a solution of tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate (Preparation 155, 50 mg, 0.102 mmol) in DCM (2 mL), TFA (1 mL, 13.51 mmol) was added and the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue that was then adjusted to pH 5-6 with NH3.HO to give the title compound (9.80 mg, 24.6%) as a pale yellow solid. 1H-NMR (400MHz, DMSO-d6) δ:9.80(s,1H),8.36(s,1H),8.10(s,1H),7.90(s,1H),7.38(s,1H),7.02-6. 86(m,3H),6.50(t,1H),4.19(t,2H),3.90(s,3H),2.89(t,2H),2.30(s,3H).

[0418] Example 55: N4-(5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine formate (168) [ka] To a solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(oxetan-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 159, 62 mg, 0.117 mmol) in DCM (1.0 mL) was added TFA (0.50 mL, 6.75 mmol) and the reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue and the pH was adjusted to pH 5-6 with NH3.H2O. The residue was purified by preparative HPLC-8 to give the title compound (25.0 mg, 42.9%) as a colorless oil. LCMS m / z = 431 [M+H] + 1 H-NMR (400MHz, DMSO-d6) δ:9.81(s,1H),8.45(s,1H),8.34(s,2H),8.13(s,1H),7.05-6.85(m,4H),6.73-6 .36(m,1H),5.51-5.31(m,2H),5.00(t,2H),4.83-4.69(m,2H),4.25-4.07(m,4H).

[0419] Example 56: 2-(Difluoromethyl)-N4-(5-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (175) [ka] To a solution of (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(oxetan-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate (Preparation 160, 26 mg, 0.0488 mmol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue, which was then adjusted to pH 7-8 with NH4OH. The residue was purified by preparative HPLC-11 to give the title compound (5.0 mg, 23.7%) as a grey oil. LCMS m / z = 433 [M+H] + 1 H-NMR (400MHz, DMSO-d6) δ:9.77(s,1H),8.42(s,1H),8.19(s,1H),7.95(s,1H),7.04-6.85(m,4H),6.69-6.35(m, 1H), 5.36 (quin, 1H), 4.99 (t, 2H), 4.73 (dd, 2H), 4.21 (t, 2H), 2.89 (t, 2H), 2.30 (s, 3H).

[0420] Example 57: N4-(5-(1-(2-amino-2-methylpropyl)-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine trifluoroacetate (116) [ka] Following the procedure described in Example 45, tert-butyl (1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-yl)carbamate (Preparation 116) gave the title compound 20 mg, 43.5%. LCMS m / z = 405.2 [M+H] + ; 1H NMR (500 MHz, DMSO-d6) δ:10.16 (s, 1H), 8.47 (s, 1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.90 (s, 3H), 7.44 (s, 1H), 7.02 (s, 2H), 6.75 (s, 1H), 6.58 (t, 1H), 3.95 (s, 3H), 3.36 (d, 2H), 1.62 (s, 6H).

[0421] Example 58: 2-(Difluoromethyl)-N4-(5-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (183) [ka] To a solution of N4-(5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-(oxetan-3-yloxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine formate (Example 55, 15.0 mg, 0.0315 mmol) in MeOH (2.0 mL) was adjusted to pH 5-6 with AcOH (9.00 uL, 0.157 mmol). HCHO (3.07 mg, 0.0378 mmol) was added and the mixture was stirred at 25 °C for 1 hour. Na(CN)BH3 (2.97 mg, 0.047 mmol) was added and the reaction was stirred at 25 °C for 1 hour. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC-11 to give the title compound (9.30 mg, yield: 64.3%) as a grey oil. LCMS m / z = 445 [M+H]+ 1H-NMR (400MHz, DMSO-d6) δ:9.80(s,1H),8.44(s,1H),8.30(s,1H),8.05(s,1H),7.05-6.85(m,4H),6.71-6.39(m,1H),5 .37(q,1H),5.12-4.95(m,3H),4.79-4.68(m,2H),3.80-3.69(m,2H),3.43(t,2H),2.36(s,3H).

[0422] Example 59: 2-(difluoromethyl)-N4-(4-isopropoxy-5-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (56) [ka] To a solution of 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7, 17.81 mg, 0.111 mmol) and 2-chloro-5-(1-isopropyl-1H-pyrazol-4-yl)-4-methoxypyridine (Preparation 80, 40.0 mg, 0.159 mmol) in dioxane (3 mL) was added BrettPhos Pd, G4 (14.63 mg, 0.0159 mmol) and CsCO (103.55 mg, 0.318 mmol), and the reaction was stirred at 90 °C under N for 2 h. The cooled reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC-11 to give the title compound (12.50 mg, 21.0%) as a brown oil. LCMS m / z = 375 [M+H] + 1 H-NMR (400MHz, DMSO-d6) δ:9.76(s,1H),8.32(s,1H),8.07(s,1H),7.84(d,1H),7.35(s,1H),6. 89(d,3H),6.62-6.33(m,1H),4.49(td,1H),3.86(s,3H),1.41(d,6H).

[0423] Example 60: N4-(5-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (52) [ka] Following a procedure similar to that described in Example 59, 2-chloro-5-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methoxypyridine (Preparation 81) and 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) gave the title compound as a brown gum (10.50 mg, 19.2%). LCMS m / z = 373 [M+H] + 1 H-NMR (400MHz, DMSO-d6) δ:9.76(s,1H),8.31(s,1H),8.08(s,1H),7.82(s,1H),7.33(s,1H),6.89(d,2H) ),6.47(t,2H),3.86(s,3H),3.72-3.69(m,1H),1.01(d,2H),0.96-0.91(m,2H).

[0424] Example 61: 2-(Difluoromethyl)-N4-(4-methoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (78) [ka] Following a procedure similar to that described in Example 59, 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) and 2-chloro-4-methoxy-5-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyridine (Preparation 82) gave 4.3 mg, 8.17% of the title compound. LCMS m / z = 390 [M+H] + 1H-NMR (400MHz, DMSO-d6) δ:9.78(s,1H),8.35(s,1H),8.20(s,1H),8.01(s,1H),7.35(s,1H),6.90 (brd,3H),6.64-6.31(m,1H),5.59(quin,1H),4.90(d,4H),3.86(s,3H).

[0425] Examples 62 to 72 To a mixture of the appropriate 2-chloropyridine starting material (SM) and 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7, 1-1.5 equiv.) in dioxane, BrettPhos Pd, G4 (0.02-0.2 equiv.), and CsCO (2.0-3.0 equiv.) were added, and the reaction was heated at 90-100 °C under N until the starting material was consumed. The cooled reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to give the desired compound.

[0426] [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6]

[0427] Examples 73 and 74: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] A mixture of 2-chloro-4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine (Preparation 54, 160 mg, 0.572 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 91.5 mg, 0.572 mmol), BrettPhos-Pd G4 (20 mg, 0.0217 mmol) and CsCO3 (230 mg, 0.708 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated in vacuo and the residue was purified by preparative HPLC-3 to give N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine as a white solid (80 mg, 35%). LCMS m / z = 404 [M+H] + . This was further purified by SFC using an OZ20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 65 / 35, 100 g / min to give: First eluting enantiomer 1: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (109), 22 mg. 1H-NMR (500 MHz, DMSO-d6) δ:9.79(s,1H),8.36(s,1H),8.13(s,1H),7.93(s,1H),7.39(s,1H),6.95-6.90 (m,3H),6.51(t,1H),5.06-5.04(m,1H),4.02-3.82(m,7H),2.36-2.29(m,2H). Second eluting enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (110), 29 mg. 1H-NMR (500 MHz, DMSO-d6) δ:9.79(s,1H),8.37(s,1H),8.13(s,1H),7.93(s,1H),7.39(s,1H),6.95-6.90 (m,3H),6.51(t,1H),5.07-5.04(m,1H),4.02-3.82(m,7H),2.36-2.29(m,2H).

[0428] Examples 75 and 76: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine [ka] The title compound was obtained from 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-N-methylpropan-2-amine (Preparation 90) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) according to the procedures described in Examples 73 and 74. LCMS m / z = 405 [M+H] + . The compound was further purified by SFC using a 0Z20 x 250 mm, 10 μm (Daicel) column, mobile phase: CO2 / MeOH (0.2% MeOH / NH3) = 65 / 35, 100 g / min to give: First eluting enantiomer 1: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (117), 16 mg. 1 H-NMR (500 MHz, DMSO-d6) δ:9.79(s,1H),8.36(s,1H),8.083(s,1H),7.90(s,1H),7.38(s,1H),6.95-6.90(m,3H),6.51(t,1 H),4.12-4.07(m,H),4.00-3.96(m,1H),3.89(s,1H),2.92-2.90(m,1H),2.50(s,3H),0.93(d,3H). Second eluting enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (118), 12 mg 1H-NMR (500 MHz, DMSO-d6) δ:9.79(s,1H),8.36(s,1H),8.08(s,1H),7.90(s,1H),7.38(s,1H),6.95-6.90(m,3H),6.51(t,1H) ),4.12-4.07(m,H),4.00-3.96(m,1H),3.89(s,1H),2.92-2.90(m,1H),2.50(s,3H),0.93(d,3H).

[0429] Example 77: N4-(4-(difluoromethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (69) [ka] A mixture of 2-chloro-4-(difluoromethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 67, 50 mg, 0.218 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8), Pd(t-BuP) (20 mg, 0.050 mmol), and CsCO (100 mg, 0.218 mmol) in dioxane (20 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated and purified by preparative HPLC-3 to give 18.1 mg, 20.8%, of the title compound as a white oil. LCMS m / z = 399 [M+H]. 1 H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.61(s, 1H), 7.37 (t, 1H), 7.19 (s, 2H), 6.86 (s, 1H), 6.50 (t, 1H), 3.89 (s, 3H)

[0430] Examples 78 to 86 Following procedures similar to those described in Example 45 and using procedures similar to those described in Preparations 122 and 75, the compounds in the following table were prepared.

[0431] [Table 15-1] [Table 15-2] [Table 15-3] [Table 15-4]

[0432] Examples 87 to 89 The title compounds were prepared using a two-part chemical protocol using the appropriate fluoropyridine (RF) and EtOH as outlined in the scheme and table below. [ka] Part 1. To a mixture of the appropriate fluoride (RF, 0.22 mmol, 1 equiv.) in THF (1 mL), EtOH (0.33 mmol, 1.5 equiv.) and t-BuOK (73.9 mg, 0.66 mmol, 3 equiv.) were added, and the mixture was stirred at 100 °C under microwave irradiation for 4 h. The reaction was quenched with HO (3.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were evaporated to dryness by Speedvac, and the residue was used in Part 2 without further purification. Part 2. A solution of Part 1 compound (crude, 0.22 mmol, 1 equiv) in DCM (3 mL) and TFA (1 mL) was stirred for 2 h at 30° C. The volatiles were removed by Speedvac and the residue was purified by preparative HPLC-4 to give the title compound.

[0433] [Table 16-1] [Table 16-2]

[0434] Examples 90 to 93 The title compound was prepared using the three-part chemical protocol outlined below. [ka] Part 1. A solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (Preparation 168, 283.3 mg, 0.5 mmol, 1 equiv.) in DCM (3 mL) and TFA (1 mL) was stirred at 30° C. for 2 hours. The solvent was evaporated by Speedvac to give N4-(5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-fluoropyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine, which was used in Part 2 without further purification. Part 2. A solution of N4-(5-(1-(azetidin-3-yl)-1H-pyrazol-4-yl)-4-fluoropyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (Part 1, 188 mg, 0.5 mmol, 1 equiv) and CH3CO2H (150 mg, 2.5 mmol, 5 equiv) and HCHO (48.6 mg, 0.6 mmol, 1.2 equiv, 37% purity) in MeOH (5 mL) was stirred at 30 °C for 1 h. To this was added NaBH3CN (47.1 mg, 0.75 mmol, 1.5 equiv) and the mixture was stirred at 30 °C for 1 h. The volatiles were removed in vacuo by Speedvac to give 2-(difluoromethyl)-N4-(4-fluoro-5-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine, which was used in Part 3 without further purification. Part 3. To a solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(1-(1-methylazetidin-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Part 2, 85.9 mg, 0.22 mmol, 1 equiv.) in THF (1 mL) was added the appropriate alcohol (ROH, 0.33 mmol, 1.5 equiv.) and t-BuOK (73.9 mg, 0.66 mmol, 3 equiv.), and the mixture was heated at 100° C. under microwave irradiation for 4 h. The reaction mixture was evaporated to dryness by Speedvac, and the residue was purified by preparative HPLC-4 to give the title compound.

[0435] [Table 17-1] [Table 17-2]

[0436] Example 94: 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-ethoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (152) [ka] Part 1. To a solution of 5-bromo-2-chloro-4-fluoropyridine (315 mg, 1.5 mmol) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (478 mg, 1.8 mmol) in dioxane (10 mL), NaCO (2.6 mL, 15 mmol, 2 M) and Pd(PPh) (86.6 mg, 0.075 mmol) were added under a N atmosphere, and the mixture was stirred at 100 °C for 5.5 h. The reaction was diluted with HO (5.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were evaporated to dryness by Speedvac and 1-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol was used in Part 2 without further purification. Part 2. To a solution of 1-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Part 1, 351 mg, 1.3 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 416 mg, 2.6 mmol) in t-AmOH (10 mL) was added CsCO (1.27 g, 3.9 mmol) and Brettphos Pd G (59 mg, 0.065 mmol) under N, and the mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with HO (5.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were evaporated to dryness by Speedvac to give 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol, which was used in Part 3 without further purification. Part 3. To a mixture of 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropan-2-ol (Part 2, 86.5 mg, 0.22 mmol) in THF (1 mL) was added EtOH (0.33 mmol), t-BuOK (73.9 mg, 0.66 mmol) and the mixture was heated at 100° C. under microwave irradiation for 4 h. The reaction was evaporated to dryness by Speedvac and the residue was purified by preparative HPLC-4 to give the title compound (23.7 mg, 26%). LCMS m / z = 420 [M+H] + .

[0437] Examples 95-96 The title compound was prepared using the one-step protocol outlined below. [ka] To a mixture of the appropriate alcohol (ROH, 0.33 mmol, 1.5 equiv.) in DMF (4 mL), NaH (61.6 mg, 1.54 mmol, 7 equiv., 60%) was added and the mixture was stirred at 30° C. for 2 h. 2-(Difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 171, 73.7 mg, 0.22 mmol, 1 equiv.) was added to the mixture and the reaction was stirred at 100° C. for 3 h. The reaction was quenched with HO (1.0 mL) and evaporated to dryness using a Speedvac. The residue was purified by preparative HPLC-4 to give the title compound.

[0438] [Table 18]

[0439] Example 97: 2-(Difluoromethyl)-N4-(5-(1-methyl-1H-pyrazol-4-yl)-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)pyrimidine-4,6-diamine (172) [ka] To a solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 171, 73.7 mg, 0.22 mmol) in DMA (4 mL) was added (tetrahydro-2H-pyran-2-yl)methanol (38.3 mg, 0.33 mmol) and t-BuOK (73.9 mg, 0.66 mmol) and the mixture was stirred at 100° C. for 6 h. The volatiles were removed by Speedvac and the residue was purified by preparative HPLC-4 to give the title compound. Yield: 11%; LCMS m / z = 432 [M+H] + .

[0440] Examples 98 to 108 The title compound was prepared from 2-(difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 171) and the appropriate alcohol (ROH) using a method similar to that described in Example 97, using the solvents and heating methods listed in the table. (Method A = DMA, 100 °C, 6 hours; Method B = THF, 100 °C, microwave, 4 hours; C = DMA, 100 °C, microwave, 4 hours). The crude product was purified by preparative HPLC-4.

[0441] [Table 19-1] [Table 19-2] [Table 19-3] [Table 19-4]

[0442] Example 109: (1s,3s)-3-((2-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutan-1-ol (107) [ka] Part 1. To a solution of (1s,3s)-cyclobutane-1,3-diol (39.6 mg, 0.45 mmol) in THF (4 mL) was added NaH (60%, 84.0 mg, 2.1 mmol) and the mixture was stirred at 30 °C for 1 h. To this was added 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 73.7 mg, 0.3 mmol) and the mixture was stirred at 30 °C for 2 h. The reaction was quenched with HO (3.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were concentrated by Speedvac to give (1s,3s)-3-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutan-1-ol, which was used in Part 2 without further purification. Part 2. To a solution of (1s,3s)-3-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutan-1-ol (Part 1, 0.27 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL), CsCO (263.9 g, 0.81 mmol) and Brettphos Pd G (12.24 mg, 0.014 mmol) were added, and the mixture was stirred at 120 °C under N for 2 h. The reaction was diluted with HO (3.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were evaporated to dryness by Speedvac, and the residue was purified by preparative HPLC-4 to give the title compound. Yield: 22%; LCMS m / z = 404 [M+H] + .

[0443] Example 110: 2-(difluoromethyl)-N4-(4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (16) [ka] Part 1. A mixture of 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Preparation 97, 73.7 mg, 0.3 mmol), MeOH (14.4 mg, 0.45 mmol) in THF (4 mL) was added to t-BuOK (101 mg, 0.9 mmol) and the mixture was stirred at 100° C. for 3 hours. The reaction mixture was concentrated by Speedvac to give 2-chloro-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine, which was used in Part 2 without further purification. Part 2. To a solution of 2-chloro-4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine (Part 1, 0.27 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL), CsCO (263.9 g, 0.81 mmol) and Brettphos Pd G (12.24 mg, 0.014 mmol) were added, and the mixture was stirred at 120 °C under N for 2 h. The reaction was diluted with HO (3.0 mL) and extracted with EtOAc (3 × 10 mL). The combined organics were evaporated to dryness by Speedvac, and the residue was purified by preparative HPLC-4 to give the title compound (14 mg, 9%, LCMS m / z = 348 [M+H]). + .

[0444] Examples 112 to 123 The title compounds were prepared from the appropriate protected starting material (SM) using a method similar to that described in Example 111. Alternative conditions (Method B) using HCl (2N in EtOAc) as noted in the table.

[0445] [Table 20-1] [Table 20-2] [Table 20-3] [Table 20-4] [Table 20-5]

[0446] Example 124: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclopropyl-4-(cyclopropylamino)nicotinamide (57) [ka] A mixture of 6-chloro-N-cyclopropyl-4-(cyclopropylamino)nicotinamide (Preparation 204, 65 mg, 0.258 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8), Pd(dba) (47.2 mg, 0.052 mmol), Xantphos (29.8 mg, 0.52 mmol), and CsCO (251 mg, 0.774 mmol) in dioxane (10 mL) was stirred at 100 °C under N for 16 h. The reaction mixture was evaporated to dryness in vacuo, and the residue was purified by column chromatography on silica gel (1:1 EtOAc / PE) to give the title compound (15 mg, 15%) as a white solid. LCMS m / z = 376 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ:9.78(s,1H),8.41(s,1H),8.33(d,1H),8.29(s,1H),7.44(s,1H),6.89(s,2H),6.78(s,1H),6.49(t ,1H),2.77-2.75(m,1H),2.45-2.40(m,1H),0.82-0.78(m,2H),0.67-0.65(m,2H),0.55-0.47(m,4H).

[0447] Example 125: (S)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-((1-fluoropropan-2-yl)amino)-N-methylnicotinamide (48) [ka] (S)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-methylnicotinamide (Preparation 186, 150 mg, 0.610 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 117 mg, 0.731 mmol), CsCO (397 mg, 1.22 mmol), and Pd( t A mixture of (Bu3P)2 (155 mg, 0.305 mmol) and (H,N) was stirred at 100 °C under N2 for 16 h. The reaction mixture was purified by column chromatography on silica gel (10:1 DCM / MeOH) followed by preparative HPLC-3 to give the title compound (41 mg, 18%) as a white solid. LCMS m / z = 370 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ:9.68(s,1H),8.56-8.54(m,1H),8.34-8.33(m,2H),7.09(s,1H),6.91(s,2H),6.79(s,1H) ),6.62-6.35(m,1H),4.54-4.40(m,2H),3.78-3.72(m,1H),2.73-2.72(m,3H),1.22(d,3H).

[0448] Example 126: (R)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-((1-fluoropropan-2-yl)amino)-N-methylnicotinamide (49) [ka] (R)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-methylnicotinamide (Preparation 190, 75 mg, 0.305 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 48.8 mg, 0.305 mmol), CsCO (298 mg, 0.92 mmol), and Pd( t A mixture of (Bu3P)2 (31.2 mg, 0.061 mmol) and (H,N) was stirred at 100 °C under N2 for 3 h. The reaction mixture was purified by column chromatography on silica gel (10:1 DCM / MeOH) followed by preparative HPLC-3 to give the title compound (22.6 mg, 20%) as a white solid. LCMS m / z = 370 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ:9.69(s,1H),8.56(d,1H),8.35-8.33(m,2H),7.10(s,1H),6.92(s,2H),6.80(s,1H) ),6.49(t,1H),4.55-4.41(m,2H),3.77-3.71(m,1H),2.73(d,3H),1.30-1.21(m,3H).

[0449] Examples 127 to 146 The title compounds were prepared from the appropriate 2-chloropyridines (RCl) and...

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, in the formula, R １ and R １Ａ However, each is independent of H, halogen, and CH ３ Selected from or R １ and R １Ａ However, together with the carbon atoms to which they bond, they form cyclopropyl, R ２ is C １－５ alkyl, CD ３ , C ３－６ cycloalkyl, bicyclo[1.1.1]pentane, and a 4- to 6-membered heterocycle containing O, wherein the alkyl, cycloalkyl, or heterocycle is optionally substituted with 1 to 3 R ４ and is optionally substituted with Each R ４ However, independently, halogen, CH ３ , C ２－３ Alkenyl, OH, CH ２ OH, C ４－６ Selected from cycloalkyl groups, 4-6 membered heterocycles containing oxygen, and phenyl groups, wherein the alkyl group, cycloalkyl group, heterocycle, or phenyl group contains OH or NH ２ , C １－２ Alkyl, CH ２ NH ２ , or optionally replaced with halogen, R ３ However, C(O)NHR5, 【Chemistry 2】 And, X １ However, it is NH or O, X ２ However, it is N or CH, X ３ However, it is N or CH, R ５ However, H, C １－３ Alkyl, CD ３ , C ３－４ Selected from cycloalkyl and bicyclo[1.1.1]pentane, wherein the alkyl, cycloalkyl, or bicyclo[1.1.1]pentane contains 1 to 2 R ７ Replaced by optional selection, Each R ７ However, they became independent, CN, NH ２ OH, CH ２ Selected from OH, cyclopropyl, pyridinyl, and oxazolyl, or two R atoms bonded to the same carbon atom ７ Together, they form a four-membered heterocycle containing N. R ６ However, C １－５ Alkyl, CHF ２ CF ３ , a 4 or 5-membered heterocycle containing N or O, and C ３－４ Selected from cycloalkyl groups, the alkyl or heterocycle has one R ８ Replaced by optional selection, R ８ However, OH, NR ９ R ９ , OCH ３ ,CH ３ A selection from a four-membered heterocycle containing N or O, wherein the alkyl or heterocycle contains one R １０ Replaced by optional selection, Each R ９ However, independently, H, CH ３ , and CH ２ CF ３ Selected from, R １０ However, CH ３ and CF ３ A compound selected from, or a pharmaceutically acceptable salt thereof.

2. R １ and R １Ａ However, each is independent of H, halogen, and CH ３ Selected from, R ２ However, C １－５ Alkyl, CD ３ , C ３－６ A cycloalkyl group and a 4-6 membered heterocycle containing oxygen are selected, wherein the alkyl, cycloalkyl, or heterocycle contains 1-3 R atoms. ４ Replaced by optional selection, Each R ４ However, independently, halogen, CH ３ OH, C ４－６ Selected from cycloalkyl groups, 4-6 membered heterocycles containing oxygen, and phenyl groups, wherein the cycloalkyl group or phenyl group contains OH or NH ２ Replaced by optional selection, Each R ７ However, independently, CN, OH, CH ２ Selected from OH, cyclopropyl, pyridinyl, and oxazolyl, or two R atoms bonded to the same carbon atom ７ Together, they form a four-membered heterocycle containing N. R １０ However, CH ３ The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. The compound is of formula (II) or (III): 【Transformation 3】 【Chemistry 4】 A compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

4. R １ and R １Ａ However, each is independent of H, halogen, and CH ３ Selected from, R ２ However, C １－５ Alkyl, CD ３ , C ３－４ A cycloalkyl group and a 4-6 membered heterocycle containing oxygen are selected, wherein the alkyl, cycloalkyl, or heterocycle contains 1-3 R atoms. ４ Replaced by optional selection, Each R ４ However, independently, halogen, CH ３ Selected from , and phenyl, R ５ However, H, C １－３ Alkyl, CD ３ , C ３－４ Selected from cycloalkyl and bicyclo[1.1.1]pentane, wherein the alkyl, cycloalkyl, or bicyclo[1.1.1]pentane contains 1 to 2 R ７ Replaced by optional selection, Each R ７ However, independently, CN, OH, CH ２ Selected from OH, cyclopropyl, pyridinyl, and oxazolyl, or two R atoms bonded to the same carbon atom ７ The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein the two elements together form a four-membered heterocycle containing nitrogen.

5. R ２ is CH ３ , CD ３ , CH ２ CH ３ , CH ２ CH ２ CH ３ CH(CH ３ ), ２ CH ２ CH(CH ３ ), ２ CH(CH ３ ), CH ２ CH ３ selected from cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which is optionally substituted with 1 to 3 R ４ or, R2, 【Transformation 5】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from the above.

6. Each R ４ However, independently, F, CH ３ A compound according to claim 3, selected from cyclobutyl and phenyl, or a pharmaceutically acceptable salt thereof.

7. R ５ However, H, CH ３ CD ３ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ Selected from cyclobutyl, cyclopropyl, and bisilo[1.1.1]pentanyl, the CH ３ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ , cyclobutyl, cyclopropyl, or bisilo[1.1.1]pentanyl, 1 to 2 R ７ It is replaced by an optional selection, or R 5, 【Transformation 6】 A compound according to claim 3, or a pharmaceutically acceptable salt thereof, selected from the above.

8. Each R ７ However, independently, CN, CH ２ OH, cyclopropyl, 【Transformation 7】 Select from or two R atoms bonded to the same carbon atom ７ They came together, 【Transformation 8】 The compound according to claim 3, or a pharmaceutically acceptable salt thereof, forming a compound.

9. The compound is of formula (IV), (V), or (VI): 【Chemistry 9】 Represented by, or The aforementioned compound is of formula (VII), (VIII), (IX), or (X): 【Chemistry 10】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

10. The compound is of formula (VII): 【Chemistry 11】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, represented by [the specified formula].

11. R １ and R １Ａ However, each is independent of H, halogen, and CH ３ Selected from, R ２ However, C １－３ Alkyl, CD ３ , C ３－４ Selected from cycloalkyl groups and 4- to 6-membered heterocycles containing one oxygen atom, wherein the alkyl, cycloalkyl, or heterocycle contains 1 to 3 R atoms. ４ Replaced by optional selection, Each R ４ However, independently selected from halogen, OH, cyclopropyl, a 4-6 membered heterocycle containing one oxygen atom, and phenyl, wherein the cyclopropyl or phenyl is OH or NH ２ Replaced by optional selection, R ６ However, C １－４ Alkyl, CHF ２ CF ３ , a 4 or 5-membered heterocycle containing N or O, and C ３－４ Selected from cycloalkyls, wherein the alkyl, heterocycle, or cycloalkyl is R ８ Replaced by optional selection, R ８ However, OH, NR ９ R ９ , OCH ３ ,CH ３ A selection from a four-membered heterocycle containing N or O, wherein the heterocycle is CH ３ Replaced by optional selection, Each R ９ However, independently, H, CH ３ , and CH ２ CF ３ A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

12. R ２ However, CH ３ CD ３ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ Selected from cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each of which contains 1 to 3 R ４ It is replaced by an optional selection, or R2, 【Chemistry 12】 A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

13. Each R ４ However, independently selected from F, OH, cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranil, and tetrahydropyranil, wherein the cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranil, or tetrahydropyranil is OH or NH ２ It is replaced by an optional selection, or Each R4 independently controls F, OH, 【Chemistry 13】 A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from, wherein *- represents OH or NH₂.

14. R ６ However, CH ３ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ ,CH ２ CH (CH ３ ) ２ , C (CH ３ ) ３ ,CH ２ CH ２ CH (CH ３ ) ２ CHF ２ CF ３ Selected from cyclopropyl, cyclobutyl, azetidinil, oxetanil, tetrahydrofuranil, and pyrrolidinil, each of these is R ８ It is replaced by an optional selection, or R 6, 【Chemistry 14】 A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

15. R ８ However, OH, OCH ３ ,CH ３ NH ２ , NHCH ３ , N (CH ３ ) ２ , NHCH ２ CF ３ , N (CH ３ )CH ２ CF ３ , selected from azetidinil, azetidinil, and oxetanil, R 8, 【Chemistry 15】 A compound according to claim 9, or a pharmaceutically acceptable salt thereof, selected from the above.

16. The compound is of formula (III) or (VII): 【Chemistry 16】 It is expressed by, in the formula, R １ and R １Ａ However, each is independent of H, F, and CH. ３ Selected from, R ２ However, C １－３ Alkyl, CD ３ , C ３－４ Selected from cycloalkyls and O-containing 4-membered heterocycles, wherein the alkyl is optionally substituted with 1 to 3 halos. R ５ However, CH ３ ,CH ２ CH ３ Selected from , and cyclopropyl, R ６ However, C １－５ Alkyl, CHF ２ CF ３ , and selected from a 4- to 5-membered heterocycle containing O or N, wherein the alkyl or heterocycle is R ８ Replaced by optional selection, R ８ However, OH, NR ９ R ９ , OCH ３ ,CH ３ , and selected from four-membered heterocycles containing O or N, Each R ９ However, independently, H and CH ３ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

17. R ２ However, CH ３ CHF ２ CF ３ CD ３ ,CH ２ CH ３ ,CH ２ CF ３ ,CH ２ CH ２ CH ３ , CH (CH ３ ) ２ , CH (CH ３ )CH ２ F, CH(CH ３ CHF ２ cyclobutyl, cyclopropyl, and 【Chemistry 17】 A compound according to claim 16, or a pharmaceutically acceptable salt thereof, selected from the above.

18. R ６ However, CH ３ ,CH ２ CH ３ ,CH ２ CH ２ CH ３ ,CH ２ CH (CH ３ ) ２ ,CH ２ CH ２ CH (CH ３ ) ２ CHF ２ Selected from azetidinil, oxetanil, tetrahydrofuranil, and pyrrolidinil, each of these contains one R ８ It is replaced by an optional selection, or R 6, [Chemistry 18] A compound according to claim 16, or a pharmaceutically acceptable salt thereof, selected from the above.

19. R ８ Yes, Oh, Oh ３ 、NH ２ 、NHCH ３ 、N(CH ３ ) ２ 、H ３ 、 【Chemistry 19】 A compound according to claim 16, or a pharmaceutically acceptable salt thereof, selected from the above.

20. A compound selected from the group consisting of the compounds in the table below, or a pharmaceutically acceptable salt thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22 Table 1-23 Table 1-24 Table 1-25 Table 1-26 Table 1-27 Table 1-28 Table 1-29 Table 1-30 Table 1-31 Table 1-32 Table 1-33 Table 1-34 Table 1-35 Table 1-36 Table 1-37

21. The compound is 【Chemistry 20】 A compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of the following.

22. A pharmaceutical composition comprising a compound according to claim 1, 20, or 21 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

23. A compound according to any one of claims 1, 20, or 21, or a pharmaceutical composition according to claim 22, for use in the treatment of patients suffering from gastrointestinal stromal tumors (GISTs), The method comprises administering to the patient an effective amount of the compound according to any one of claims 1, 20, or 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22.

24. The compound or pharmaceutical composition for use according to claim 23, wherein the GIST is characterized by a tumor having one or more KIT mutations, and each KIT mutation is independently selected from exon 9 KIT mutations, exon 11 KIT mutations, exon 13 KIT mutations, and exon 17 KIT mutations, and combinations thereof.

25. A compound according to any one of claims 1, 20, or 21, or a pharmaceutical composition according to claim 22, for use in a method of treating a patient suffering from a malignant disease characterized by an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. The procedure involves administering to the patient an effective amount of the compound according to claim 1, 20, or 21, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 22. The aforementioned malignant disease is selected from gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

Images