Kit inhibitors

Abstract

One embodiment of the present disclosure is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are defined herein. # imgabs0 # compounds of formula (I) are useful for the inhibition of mutant KIT proteins and the treatment of human or non-human conditions associated with aberrant KIT activity.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 332,387, filed April 19, 2022, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This application relates to KIT inhibitors and methods of use thereof, such as controlling the activity of the enzyme KIT (also known as "CD117") in a subject with a mutated form. Background Technology

[0004] This disclosure relates to the use of novel N-(pyridin-2-yl)pyrimidine-4-amine compounds and their use as selective inhibitors of mutant KIT protein kinase in pharmaceutical compositions for the treatment of gastrointestinal stromal tumors (GIST).

[0005] The enzyme KIT (also known as CD117) is a receptor tyrosine kinase expressed in a variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. KIT's ligand 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 patients with primary GIST, most commonly in exon 11 and less frequently in exon 9; these mutations render the KIT enzyme independent of activation via its ligand SCF, leading to higher cell division rates and potential genomic instability (CRAntonescu, The GIST paradigm: Lessons for other kinase-driven cancers. J. Pathol. 223, 251–261 (2011)). Constitutive activation of KIT plays a central role in the oncogenic behavior of GIST.

[0006] GIST patients with primary mutations in exons 9 or 11 of KIT responded well to first-line imatinib therapy, with an overall response rate of 60%; however, subsequent therapies, including sunitinib, regorafenib, and ripretinib, showed less robust efficacy after patient progression (or imatinib treatment failure), with the overall response rate for each of these therapies remaining below 10% (Ther. Adv. Med. Oncol. 2021; 13:1758835920986498).

[0007] Patients who develop resistance to imatinib have been observed to typically have intermediate-target mutations in the KIT, most commonly in exon 17 (at multiple different amino acids including D816) or in 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.). In clinical trials using small molecules designed to target exon 17 resistance mutations in KIT, patients with KIT exon 13 mutations, particularly KIT exon 13V654A mutations, were observed to be unresponsive 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 therapies for GIST patients, resistance mutations within the KIT enzyme, such as exon 13 mutations, must be suppressed.

[0008] Current KIT inhibitors are insufficient to treat GIST that has become resistant to inhibitors for primary activating KIT mutations. For example, current KIT inhibitors fail to adequately inhibit mutated exon 13, such as V654A and N655K. Therefore, small molecule therapies targeting resistant KIT mutations, such as exon 13V654A and / or exon 13N655K resistant mutations, are needed. Summary of the Invention

[0009] This article provides compounds, or pharmaceutically acceptable salts and combinations thereof, that can be used to inhibit mutant KIT protein and treat gastrointestinal stromal tumors (GIST). For example, the IC50 inhibitors that inhibit KIT autophosphorylation listed in Table 1... 50 The results demonstrate that these compounds are effective inhibitors of mutant KIT.

[0010] The first embodiment of this disclosure is a compound represented by formula (I):

[0011]

[0012] Or its pharmaceutically acceptable salt, wherein:

[0013] R 1 and R 1A Each is independently selected from H, halogens, and CH3.

[0014] or R 1 and R 1A Together with the carbon atom it is attached to, it forms a cyclopropyl group;

[0015] R 2 Selected from 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 optionally surrounded by 1-3 R... 4 replace;

[0016] Each R 4 Independently selected from halogens, CH3, C 2-3 alkenyl, OH, CH2OH, C 4-6 Cycloalkyl, 4- to 6-membered heterocycles containing O, and phenyl, wherein the alkyl, cycloalkyl, heterocycle, or phenyl is optionally surrounded by OH or NH2, C 1-2 Alkyl, CH2NH2, or halogen substitution;

[0017] R 3 C(O)NHR 5 ,

[0018] X1 is NH or O;

[0019] X2 is either N or CH;

[0020] X3 is either N or CH;

[0021] R 5 Selected from 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 optionally surrounded by 1-2 R... 7 replace;

[0022] Each R 7 Independently selected from CN, NH2, OH, CH2OH, cyclopropyl, pyridyl, and oxazolyl, or two R groups attached to the same carbon atom. 7 Together they form a 4-membered heterocycle containing N;

[0023] R 6 Selected independently from C 1-5 Alkyl groups, CHF2, CF3, 4- or 5-membered heterocycles containing N or O, and C 3-4 Cycloalkyl, wherein the alkyl or heterocycle is optionally separated by an R8 replace;

[0024] R 8 Independently selected from OH and NR 9 R 9 OCH3, CH3 and a 4-membered heterocycle containing N or O, wherein the alkyl or heterocycle is optionally separated by an R 10 replace;

[0025] Each R 9 Independently selected from H, CH3, and CH2CF3; and

[0026] R 10 Selected from CH3 and CF3.

[0027] Another embodiment of this 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., compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds in Table 1, or a pharmaceutically acceptable salt of any of the aforementioned compounds).

[0028] Another embodiment of this disclosure is a method for treating a patient with gastrointestinal stromal tumors (GIST) using an effective amount of the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 aforementioned compounds), or using an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 aforementioned compounds).

[0029] Another embodiment of this disclosure is a method of treating a patient with a malignant disease, comprising administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds).

[0030] Another embodiment of this disclosure is a method of treating a patient with a malignant disease characterized by exon 9KIT mutations, exon 11KIT mutations, exon 13KIT mutations, or exon 17KIT mutations, or combinations thereof, comprising administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or administering to the patient an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds).

[0031] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient an effective combination comprising: (i) an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), and (ii) a second dose.

[0032] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient an effective combination comprising: the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 compounds), and at least one additional agent.

[0033] Another embodiment of this disclosure is a method for treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising (a) obtaining a biological sample from the patient; (b) detecting the presence or absence of an exon 13KIT mutation or an exon 14KIT mutation; and (c) if a mutation is detected, administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., formulas (I), (II), (III), (IV)). (V), (VI), (VII), (VIII), (IX) or (X) compounds, or the compounds in Table 1, or pharmaceutically acceptable salts of any of the aforementioned compounds), or administration of an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein or pharmaceutically acceptable salts thereof (e.g., compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X) compounds, or the compounds in Table 1, or pharmaceutically acceptable salts of any of the aforementioned compounds).

[0034] Another embodiment of this disclosure is a method for treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising (a) obtaining a biological sample from the patient; (b) detecting the presence or absence of an exon 13KIT mutation or an exon 14KIT mutation; and (c) if a mutation is present, administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., formulas (I), (II), (III), (IV), (…). (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) compounds, or compounds in Table 1, or pharmaceutically acceptable salts of any of the aforementioned compounds, or administration of 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., compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X) compounds, or compounds in Table 1, or pharmaceutically acceptable salts of any of the aforementioned compounds).

[0035] Another embodiment of this disclosure is a method for treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising administering to the patient, if an exon 13KIT mutation or an exon 14KIT mutation is detected, an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds).

[0036] A method of treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising administering to the patient, if an exon 13KIT mutation or an exon 14KIT mutation is present, an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), 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., 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 aforementioned compounds).

[0037] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), 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., 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 aforementioned compounds), wherein the GIST is mutationally resistant to a KIT inhibitor administered to treat GIST having a primary activating mutation in exon 9 or exon 11.

[0038] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST) characterized by primary activating mutations in exon 9KIT or exon 11KIT, comprising administering to the patient: (i) a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), and (ii) a KIT inhibitor effective against GIST characterized by primary activating mutations in exon 9KIT or exon 11KIT. Detailed Implementation

[0039] The disclosed compounds or their pharmaceutically acceptable salts are inhibitors of the KIT enzyme and can be used to treat KIT-dependent conditions or diseases.

[0040] definition

[0041] The following abbreviations and terms have their indicative meanings throughout:

[0042] The term "alkyl" used alone or as part of a larger component (e.g., "alkoxy," "hydroxyalkyl," etc.) refers to a saturated aliphatic straight-chain or branched monovalent hydrocarbon group. Unless otherwise specified, alkyl groups typically have 1 to 6 carbon atoms (C60-C60). 1-6 Alkyl groups (i.e., 1, 2, 3, 4, 5, or 6) or 1 to 3 carbon atoms (C 1-3 Alkyl groups (i.e., 1, 2, or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0043] The term "alkenyl" refers to an aliphatic straight-chain or branched monovalent hydrocarbon group having a single double bond. Unless otherwise specified, alkenyl groups typically have 1 to 6 carbon atoms (C60-C60). 1-3 Alkenyl), or 1 to 3 carbon atoms (C 1-3 (alkenyl).

[0044] "Cycloalkyl" indicates a cyclic group in a saturated aliphatic cyclic hydrocarbon. Unless otherwise specified, cycloalkyl groups have 3 to 8 carbon atoms in the ring (C1 to C2). 3-8 cycloalkyl groups, or 3 to 6 cyclic carbon atoms (C 3-6 cycloalkyl groups, or 3 to 5 carbon atoms (C64- ... 3-5Cycloalkyl groups. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0045] The term “halogen” or “halogen group” means fluorine or fluorine group (F), chlorine or chlorine group (Cl), bromine or bromo group (Br), or iodine or iodine group (I).

[0046] Unless otherwise specified, the term "heterocycle" refers to a monocyclic nonaromatic ring group containing 3 to 8 ring atoms selected from carbon atoms (i.e., "3, 4, 5, 6, 7, or 8-membered") and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, nitrogen oxides (e.g., NO); oxygen; and sulfur, including sulfoxides and sulfones. Representative heterocycles include azirrocyclobutyl, morpholino, thiomorpholino, pyrrolidone, pyrrolyl, piperidinyl, piperazine, hydantoin, valeronyl, ethylene oxide, oxadicyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydropyrimidinyl, tetrahydrothiophene, tetrahydrothioranyl, etc.

[0047] The term "hydroxyl" or "hydroxyl group" refers to the OH group.

[0048] The term “substitution,” whether or not preceded by the term “optionally,” means replacing a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl group is an alkyl group in which at least one non-hydrogen substituent replaces a hydrogen substituent on the alkyl group. For illustration, a monofluoroalkyl group is an alkyl group substituted with a fluorine substituent, and a difluoroalkyl group is an alkyl group substituted with two fluorine substituents. It should be recognized that if there is more than one substitution associated with a substituent, each non-hydrogen substituent may be the same or different (unless otherwise stated).

[0049] If a group is described as “optionally substituted,” then the group may be (1) unsubstituted or (2) substituted. If a group is described as being optionally substituted by up to a certain number of non-hydrogen substituents, then the group may be (1) unsubstituted; or (2) substituted by up to the certain number of non-hydrogen substituents or by up to the maximum number of substitutable positions associated with the substituents, whichever is less. Thus, for example, if a group is described as a cycloalkyl group optionally substituted by up to three non-hydrogen substituents, then any cycloalkyl group having fewer than three substitutable positions may optionally be substituted only by up to as many non-hydrogen substituents as the cycloalkyl group has substitutable positions.

[0050] Compounds having one or more chiral centers can exist in various stereoisomeric forms; that is, each chiral center can have an R or S configuration or a mixture of both. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomers and enantiomers of a compound. Enantiomers are stereoisomers that are non-overlapping mirror images of each other. Diastereomers are stereoisomers that are not identical and are not mirror images of each other, having two or more chiral centers.

[0051] When the stereochemical configuration at the chiral center in a compound having one or more chiral centers is described by its chemical name (e.g., where the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., the configuration is indicated by a "wedge" bond), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%.

[0052] "Enrichment of the indicated configuration relative to the opposite configuration" is a molar percentage and is determined by dividing the number of compounds having the indicated stereochemical configuration at the chiral center by the total number of all compounds in the mixture having the same or opposite stereochemical configurations.

[0053] When two or more stereoisomers are described by their chemical names or structures and said names or structures are connected by "or", it is expected to be one or the other of the two or more stereoisomers, rather than both. Enrichment of one stereoisomer relative to the other is as described above.

[0054] When a disclosed compound having a chiral center is described by structure without showing the configuration at the chiral center, the structure is intended to encompass compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center. When a disclosed compound having a chiral center is described by its chemical name without using "S" or "R" to indicate the configuration at the chiral center, the name is intended to encompass compounds having an S configuration at the chiral center, compounds having an R configuration at the chiral center, or compounds having a mixture of R and S configurations at the chiral center.

[0055] A racemic mixture represents a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. This teaching covers all enantiomeric purity, enantiomerically enriched, diastereomeric purity, diastereomeric enriched, racemic mixtures, and diastereomeric mixtures of the compounds described herein.

[0056] Enantiomers and diastereomers can be separated into their component enantiomers or stereoisomers by well-known methods, such as chiral gas chromatography, chiral high-performance liquid chromatography, crystallization of the compound into a chiral salt complex, or crystallization of the compound in a chiral solvent. Enantiomers and diastereomers can also be obtained from diastereomers or enantiomerically pure intermediates, reagents, and catalysts by known asymmetric synthetic methods.

[0057] In the experimental section, "peak 1" or "first eluting isomer" refers to the expected reaction product compound obtained from chromatographic separation / purification, which elutes earlier from the same aforementioned reaction than the second specified reaction product compound. The second expected product compound is referred to as "peak 2" or "second eluting isomer".

[0058] When a compound is specified by the name or structure indicating a single enantiomer, unless otherwise indicated, the compound is optically pure (also known as “enantiomer purity”) of at least 60%, 70%, 80%, 90%, 99%, or 99.9%. Optical purity is the weight of the named or described enantiomer in the mixture divided by the total weight of the two enantiomers in the mixture.

[0059] When the stereochemistry of the disclosed compound is named or described by a structure, and the named or described structure covers more than one stereoisomer (e.g., as in a diastereomer pair), it should be understood that, unless otherwise indicated, it includes one of the covered stereoisomers or any mixture of the covered stereoisomers. It should be further understood that the stereoisomer purity of the named or described stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% by weight. In this case, the stereoisomer purity is determined by dividing the total weight of the stereoisomers covered by the name or structure in the mixture by the total weight of all stereoisomers in the mixture.

[0060] As used herein, the term "pharmaceutically acceptable salt" means a medicinal salt that, within reasonable medical judgment, is suitable for contact with the tissues of humans and lower animals without excessive toxicity, irritation, or allergic reactions, and is commensurate with a reasonable benefit / risk ratio.

[0061] Pharmaceutically acceptable salts are known in the art. For example, SMBerge et al. describe pharmaceutically acceptable salts in J. Pharm. Sci. (1977) 66:1-19. Compounds of this disclosure having a basic group can form pharmaceutically acceptable salts with pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include 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 this disclosure having an acidic group can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. Suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts), and alkaline earth metal salts (such as magnesium and calcium salts).

[0062] "Subject" or "patient" is a mammal requiring medical treatment, preferably a human, but can also be an animal requiring veterinary treatment, such as companion animals (e.g., dogs, cats, etc.), livestock (e.g., cattle, sheep, pigs, horses, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). In one aspect, the patient is a human being. In another aspect, the patient is an adult.

[0063] The term "effective amount" refers to the amount that, when administered to a subject or patient, produces a beneficial or desired outcome (including clinical outcomes, such as inhibition, suppression, or reduction of symptoms of the subject's treated condition compared to a control). For example, a therapeutically effective dose may be administered in a unit dosage form (e.g., 0.1 mg to about 50 g daily, or 1 mg to about 5 g daily). The precise amount of the compound or its pharmaceutically acceptable salt administered to provide an “effective amount” to the subject will depend on the administration regimen, the type and severity of the disease or ailment, and the characteristics of the subject, such as general health, age, sex, weight, and tolerance to the drug. Those skilled in the art will be able to determine the appropriate dose based on these and other factors. When administered in combination with other therapeutic agents, such as when administered in combination with anticancer or antiviral agents, the “effective amount” of any other therapeutic agent will depend on the type of drug used. Appropriate doses of approved therapeutic agents are known and can be adjusted by those skilled in the art based on the subject’s ailment, the type of ailment being treated, and the amount of the compound or its pharmaceutically acceptable salt used, by following, for example, the doses reported in the literature and recommended in Physician's Desk Reference (57th edition, 2003).

[0064] As used in this article, a "malignant disease" is one 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 cancer, sarcoma, leukemia, and lymphoma. Cancer is a malignant disease. Generalized mastocytosis is a malignant disease. Painless generalized mastocytosis is a malignant disease.

[0065] Examples of cancers include, but are not limited to, gastrointestinal stromal tumors (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intracranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma.

[0066] As used herein, "inhibitor" refers to a compound or a pharmaceutically acceptable salt thereof that inhibits a protein, such as an enzyme, to the point that the reduction in protein activity can be observed, for example, by a biochemical assay. In some 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.

[0067] The term "KIT" refers to human tyrosine kinase, which may be called mast / stem cell growth factor receptor (SCFR), proto-oncogene c-KIT, tyrosine protein kinase Kit, or CD117.

[0068] As used herein, the term "KIT mutation" refers to a KIT gene sequence, cDNA, mRNA, or protein whose sequence differs from that of the human reference genome hg19. In some embodiments, when discussing KIT mutations in the 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, a 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 the KIT. As used herein, the term "exon 11 KIT mutation" refers to a mutation in exon 11 of the KIT. As used herein, the term "exon 13 KIT mutation" refers to a mutation in exon 13 of the KIT. As used herein, the term "exon 17 KIT mutation" refers to a mutation in exon 17 of the KIT. As used herein, the term "exon 18 KIT mutation" refers to a mutation in exon 18 of the KIT. A829P is a mutation at the very beginning of exon 18 KIT, but in some embodiments, A829P is referred to as an "exon 17" KIT mutation. In some embodiments, 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 either exon 18 or exon 17.

[0069] As used herein, a “selective KIT inhibitor” means a compound or a pharmaceutically acceptable salt thereof that selectively inhibits KIT protein kinase relative to another protein kinase and exhibits at least 2-fold selectivity for KIT protein kinase relative to that other 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 relative to 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, for example, Evans et al. (2017). In some embodiments, selectivity for KIT kinase relative to another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein). In other embodiments, selectivity for KIT kinase or relative to another kinase is measured in a biochemical assay (e.g., a biochemical assay 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 compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds in Table 1, or a pharmaceutically acceptable salt of any of the foregoing compounds. In some embodiments, the selective KIT inhibitor is avapritinib. In some embodiments, the selective KIT inhibitor is bezuclastinib. 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.

[0070] Compound implementation plan

[0071] The example implementation plan includes:

[0072] First implementation scheme: A compound represented by formula (I):

[0073]

[0074] Or a pharmaceutically acceptable salt thereof. The variables in formula (I) are described in the above description of the invention.

[0075] Second implementation scheme: A compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, halogens, and CH3; R 2 Selected from C 1-5 Alkyl, CD3, C 3-6 Cycloalkyl groups and 4- to 6-membered heterocycles containing O, wherein the alkyl, cycloalkyl, or heterocycle is optionally surrounded by 1-3 R groups. 4 Replace; each R 4 Independently selected from halogens, CH3, OH, NH2, C 4-6 Cycloalkyl, a 4- to 6-membered heterocycle containing O, and a phenyl group, wherein the cycloalkyl or phenyl group is optionally substituted with OH or NH2; each R 7 Independently selected from CN, OH, CH2OH, cyclopropyl, pyridyl, and oxazolyl, or two R groups attached to the same carbon atom. 7 Together they form a 4-membered heterocycle containing N; and R 10 CH3. The remainder of the variables in equation (I) are as described in the first embodiment above. In some second embodiments, each R 4 Independently selected from halogens, CH3, OH, C 4-6 The cycloalkyl group, a 4- to 6-membered heterocycle containing O, and a phenyl group, wherein the cycloalkyl group or phenyl group is optionally substituted with OH or NH2.

[0076] Third implementation scheme: A compound represented by formula (II):

[0077]

[0078] Or a pharmaceutically acceptable salt thereof. The variables in Formula (II) are described in the first and / or second embodiments.

[0079] Fourth implementation scheme: A compound represented by formula (III):

[0080]

[0081] Or a pharmaceutically acceptable salt thereof. The variables in formula (III) are described in the first and / or second embodiments.

[0082] Fifth embodiment: A compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, halogens, and CH3; R 2 Selected from C 1-5 Alkyl, CD3, C 3-4Cycloalkyl groups and 4- to 6-membered heterocycles containing O, wherein the alkyl, cycloalkyl, or heterocycle is optionally surrounded by 1-3 R groups. 4 Replace; each R 4 Independently selected from halogens, CH3, and phenyl; R 5 Selected from 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 optionally surrounded by 1-2 R... 7 Replace; and each R 7 Independently selected from CN, OH, CH2OH, cyclopropyl, pyridyl, and oxazolyl, or two R groups attached to the same carbon atom. 7 Together, they form a 4-membered heterocycle containing N. The remainder of the variables in equation (I) is as described in the first or second embodiment above.

[0083] Sixth embodiment: a compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)CH2CH3, cyclobutyl, cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally marked with 1-3 R... 4 Replacement. The remainder of the variables in equations (I), (II), and (III) are as described in the first, second, and / or fifth embodiments above.

[0084] Seventh embodiment: a compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0085]

[0086] The remainder of the variables in equations (I), (II), and (III) are as described in the first, second, and / or fifth embodiments above.

[0087] Eighth embodiment: a compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R 4 The components are independently selected from F, CH3, cyclobutyl, and phenyl. The remainder of the variables in formulas (I), (II), and (III) are as described in the first, second, fifth, sixth, and / or seventh embodiments above.

[0088] Ninth embodiment: a compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R5 Selected from H, CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, and bicyclo[1.1.1]pentyl, wherein the CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, or bicyclo[1.1.1]pentyl is optionally surrounded by 1-2 R... 7 Replacement. The remainder of the variables in equations (I), (II), and (III) are as described in the first, second, fifth, sixth, seventh, and / or eighth embodiments above.

[0089] Tenth embodiment: A compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from:

[0090]

[0091] The remainder of the variables in equations (I), (II), and (III) are as described in the first, second, fifth, sixth, seventh, and / or eighth embodiments above.

[0092] Eleventh implementation scheme: a compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R 7 Independently selected from CN, CH2OH, cyclopropyl, Or two R atoms connected to the same carbon atom 7 Together The remainder of the variables in equations (I), (II), and (II) are as described in the first, second, fifth, sixth, seventh, eighth, ninth, and / or tenth embodiments above.

[0093] Twelfth embodiment: A compound represented by formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, F, and CH3. The remainder of the variables in equations (I), (II), and (III) are as described in the first, second, fifth, sixth, seventh, eighth, ninth, tenth, and / or eleventh embodiments above.

[0094] Thirteenth implementation scheme: A compound represented by formula (IV), (V) or (VI):

[0095]

[0096] Or a pharmaceutically acceptable salt thereof. The variables in formulas (IV), (V), and (VI) are as described in the first and / or second embodiments above.

[0097] Fourteenth implementation scheme: A compound represented by formula (VII), (VII), (IX) or (X):

[0098]

[0099] Or a pharmaceutically acceptable salt thereof. The variables in formulas (VII), (VIII), (IX), and (X) are as described in the first and / or second embodiments above.

[0100] Fifteenth 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 Each is independently selected from H, halogens, and CH3; R 2 Selected from C 1-3 Alkyl, CD3, C 3-4 Cycloalkyl groups and 4- to 6-membered heterocycles containing one O, wherein the alkyl, cycloalkyl, or heterocycle is optionally surrounded by 1-3 R groups. 4 Replace; each R 4 Independently selected from halogens, OH, cyclopropyl, 4- to 6-membered heterocycles containing one O, and phenyl, wherein the cyclopropyl or phenyl group is optionally substituted with OH or NH2; R 6 Selected from C 1-4 Alkyl groups, CHF2, CF3, 4- or 5-membered heterocycles containing N or O, and C 3-4 Cycloalkyl, wherein the alkyl, heterocyclic or cycloalkyl group is optionally R 8 Replace; R 8 Selected from OH, NR 9 R 9 OCH3, CH3 and a 4-membered heterocycle containing N or O, wherein the heterocycle is optionally substituted with CH3; and each R 9 The variables are independently selected from H, CH3, and CH2CF3. The remainder of the variables in formulas (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first and / or second embodiments above.

[0101] 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 Selected from CH3, CD3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydrofuranyl, and tetrahydropyranyl, each optionally marked with 1-3 R... 4Replacement. The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, and / or fifteenth embodiments above.

[0102] Seventeenth embodiment: a compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from:

[0103] The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, and / or fifteenth embodiments above.

[0104] Eighteenth 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 The variable is independently selected from F, OH, cyclobutyl, oxetane, phenyl, tetrahydrofuranyl, and tetrahydropyranyl, wherein the cyclobutyl, oxetane, oxetane, phenyl, tetrahydrofuranyl, or tetrahydropyranyl is optionally substituted with OH or NH2. The remainder of the variable in formula (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) is as described in the first, second, fifteenth, sixteenth, and / or seventeenth embodiments above.

[0105] 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 Independently selected from F, OH, Where * denotes OH or NH2. The remainder of the variables in formulas (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are as described in the first, second, fifteenth, sixteenth and / or seventeenth embodiments above.

[0106] 20th embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R 6Selected from CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, CH2CH(CH3)2, C(CH3)3, CH2CH2CH(CH3)2, CHF2, CF3, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, tetrahydrofuranyl, and pyrrolidinyl, each optionally R 8 Replacement. The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments above.

[0107] Implementation scheme 21: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from:

[0108] The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, and / or nineteenth embodiments above.

[0109] 22. Embodiment: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R 8 The components are selected from OH, OCH3, CH3, NH2, NHCH3, N(CH3)2, NHCH2CF3, N(CH3)CH2CF3, aziridine, aziridine, and oxacyclobutane. The remainder of the variables in formulas (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments above.

[0110] 23. Implementation method: A compound represented by formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from:

[0111] The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, and / or twenty-first embodiments above.

[0112] Twenty-fourth 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 Each is independently selected from H, F, and CH3. The remainder of the variables in equations (I), (IV), (V), (VI), (VII), (VIII), (IX), or (X) are as described in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second, and / or twenty-third embodiments above.

[0113] Implementation scheme 25: A compound represented by formula (III) or (VII):

[0114]

[0115] Or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, F, and CH3; R 2 Selected from C 1-3 Alkyl, CD3, C 3-4 Cycloalkyl groups and four-membered heterocycles containing one oxygen atom, wherein the alkyl group is optionally substituted with one to three halogen groups; R 5 Selected from CH3, CH2CH3 and cyclopropyl; R 6 Selected from C 1-5 Alkyl groups, CHF2, CF3, and 4- to 5-membered heterocycles containing O or N, wherein the alkyl or heterocycle is optionally replaced by R. 8 Replace; R 8 Selected from OH, NR 9 R 9 , OCH3, CH3 and 4-membered heterocycles containing O or N; and each R 9 It is independently selected from H and CH3.

[0116] 26. Implementation method: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from CH3, CHF2, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2F, CH(CH3)CHF2, cyclobutyl, cyclopropyl and The remainder of the variables in equation (III) or (VII) are as described in the twenty-fifth embodiment above.

[0117] Implementation scheme 27: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, CHF2, aziridine, oxadiidine, tetrahydrofuranyl, and pyrrolidinyl, each optionally marked with an R 8 Replacement. The remainder of the variables in equation (III) or (VII) are as described in the twenty-fifth and / or twenty-sixth embodiments above.

[0118] Implementation scheme twenty-eight: a compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from:

[0119] The remainder of the variables in equation (III) or (VII) are as described in the twenty-fifth and / or twenty-sixth embodiments above.

[0120] Implementation scheme 29: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from OH, OCH3, NH2, NHCH3, N(CH3)2, CH3, The remainder of the variables in equation (III) or (VII) are as described in the above twenty-fifth, twenty-sixth, twenty-seventh and / or twenty-eighth embodiments.

[0121] Thirtieth embodiment: a compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 8 The variables are selected from OH, OCH3, NH2, NHCH3, N(CH3)2, and CH3. The remainder of the variables in formula (III) or (VII) are as described in embodiments 25, 26, 27, 28, and / or 29 above.

[0122] Implementation scheme 31: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, and CHF2, each optionally bounded by an R 8 Replacement. The remainder of the variables in equation (III) or (VII) are as described in embodiments 25, 26, 27, 28, 29, and / or 30 above. In some embodiments 31, R 6Selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2, CH2CH2CH(CH3)2, and CHF2, each optionally bounded by an R 8 Replacement. In some of the thirty-first implementations, R 6 Selected from CH3, CH2CH3, CH2CH2CH3, CH2CH(CH3)2 and CH2CH2CH(CH3)2, each of which is separated by an R 8 replace.

[0123] Thirty-second implementation: A compound represented by formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R 6 The variables are 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, CH2CH2OCH3, CH2CH(OH)(CH3), CH2C(OH)(CH3)2, CH2CH2C(OH)(CH3)2, and C(CH3)2CH2OH. The remainder of the variables in formula (III) or (VII) are as described in embodiments XXV, XXVI, XXVII, XXVIII, XXIX, XXIII, and / or XXXI above.

[0124] Thirty-third embodiment: A compound represented by formula (III), or a pharmaceutically acceptable salt thereof. The variables in formula (III) are as described in embodiments twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first and / or thirty-second above.

[0125] Thirty-fourth embodiment: A compound represented by formula (VII), or a pharmaceutically acceptable salt thereof. The variables in formula (VII) are as described in embodiments twenty-five, twenty-six, twenty-seven, twenty-eight, twenty-nine, thirtieth, thirty-first and / or thirty-second above.

[0126] This disclosure also includes compounds described in Table 1 and prepared in examples, in neutral form and pharmaceutically acceptable salts thereof.

[0127] In one embodiment, compounds 204-211 and their pharmaceutically acceptable salts listed in Table 2 are not included in this disclosure.

[0128] This disclosure also includes pharmaceutical compositions comprising compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or compounds described in Table 1, or pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or excipients thereof.

[0129] Another embodiment of this disclosure is a compound disclosed herein, including compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds in Table 1, or a pharmaceutically acceptable salt of any of the foregoing compounds, wherein one or more hydrogen atoms are replaced by deuterium. The deuterium enrichment at any of the sites where hydrogen is replaced by deuterium is at least 50%, 75%, 85%, 90%, 95%, 98%, or 99%. The 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.

[0130] Applications and Implementation Plans

[0131] The compounds disclosed herein (e.g., compounds of formulas (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 compounds) can be used as KIT inhibitors. For example, the KIT inhibitors of this disclosure inhibit mutant KIT protein kinases, wherein the mutation is in exon 13, such as the K642E, V654A, or N655K KIT mutation, or in exon 14, such as the T680K KIT mutation. K642E is an exon 13 KIT mutation, which can be a primary activating mutation. It is less common compared to primary activating KIT mutations in exons 9 and 11. Therefore, the KIT inhibitors of this disclosure can treat disorders in human or non-human patients associated with abnormal KIT activity. The KIT inhibitors disclosed herein (also referred to as the compounds of this disclosure) include compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and / or (X) and their pharmaceutically acceptable salts, and the compounds described in Table 1. The compounds of this disclosure have selectivity for exon 13 KIT relative to both KIT and PDGFR wild-type and are therefore expected to exhibit minimal side effects (such as anemia, thrombocytopenia, and edema) resulting from wild-type inhibition. The compounds of this disclosure also exhibit reduced brain penetration. Reduced or absent brain penetration is expected to provide a safety benefit and minimize adverse cognitive effects. The method comprises administering to a 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 of Table 1, or a pharmaceutically acceptable salt thereof), or administering to a patient an effective amount of a pharmaceutical composition comprising 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 of Table 1, or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier or excipient.

[0132] In one aspect, this disclosure relates to a method of treating a patient with a malignant disease (or cancer) characterized by, for example, KIT mutations in exon 9KIT, exon 11KIT, exon 13KIT, or exon 17KIT, or combinations thereof. Examples of malignant diseases or cancers that can be treated with the compounds of this disclosure include gastrointestinal stromal tumors (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intracranial germ cell tumor, pancreatic cancer, and mediastinal B-cell lymphoma. In one aspect, the malignant disease (or cancer) is selected from gastrointestinal stromal tumors (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), intracranial germ cell tumor, and mediastinal B-cell lymphoma. In one aspect, the cancer is gastrointestinal stromal tumor (GIST); in another aspect, the cancer is AML (acute myeloid leukemia); in another aspect, the cancer is melanoma; in another aspect, the cancer is lung cancer; in another aspect, the cancer is uterine cancer; in another aspect, the cancer is astrocytoma; in another aspect, the cancer is liver cancer; in another aspect, the cancer is seminoma; in another aspect, the cancer is renal cell carcinoma (RCC); in one aspect, RCC is pancreatic neuroendocrine tumor (pNET); in another aspect, the cancer is intracranial germ cell tumor; in another aspect, the cancer is pancreatic cancer; and in another aspect, the cancer is mediastinal B-cell lymphoma. In one aspect, the cancer that can be treated with the compounds of this 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 compounds) is advanced. In another aspect, the cancer is adjunctive.

[0133] In one aspect, this disclosure provides a method of treating a patient with a malignant disease (or cancer) characterized by exon 9KIT mutations, exon 11KIT mutations, exon 13KIT mutations, or exon 17KIT mutations, or combinations thereof, comprising administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds). In some embodiments, the malignant disease (or cancer) is selected from gastrointestinal stromal tumors (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intracranial 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 includes administering an effective amount of one or more agents (e.g., 1, 2, 3, or 4 additional agents) to the patient. In some embodiments, the patient receives one or more prior treatments for the malignant disease (or cancer) (e.g., treatment prior to administration of the compounds disclosed herein). In some embodiments, the malignant disease (or cancer) progresses after prior treatment. In some embodiments, the prior treatment includes administration of 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 malignant disease (or cancer) has a mutation that makes it resistant to the agent (e.g., 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, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, and larotrectinib, as well as pharmaceutically acceptable salts thereof. In some embodiments, one or more agents comprise avatinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment comprises administration of one or more agents, each independently selected from: imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindole, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, and larotrectinib and pharmaceutically acceptable salts thereof. In some implementations, prior treatment includes administration of imatinib, sunitinib, regorafenib, nilotinib, carbozentib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, repretinib, bezuratinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some implementations, prior treatment includes administration of imatinib, sunitinib, regorafenib, nilotinib, carbozentib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapintoxin, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, repretinib, bezuratinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof. In some implementations, prior treatment includes administration of imatinib or a pharmaceutically acceptable salt thereof. In some implementations, the malignant disease (or cancer) has an imatinib resistance mutation.In some embodiments, prior treatment includes administration of sunitinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of regorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of avatinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of bezuratinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of BLU-263 or a pharmaceutically acceptable salt thereof.

[0134] In one aspect, the malignant disease (or cancer) (e.g., GIST) treatable by the disclosed method is characterized by a primary activating KIT mutation. A “primary activating mutation” is an initial mutation that transforms normal cells into cancer cells or causes said transformation; that is, a primary activating mutation causes tumorigenesis and / or drives 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 exon 9 KIT mutations, exon 11 KIT mutations, exon 13 KIT mutations, and exon 17 KIT mutations. In some implementations, the primary activating KIT mutation is an exon 17 KIT mutation, for example, an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In one implementation, the exon 17 KIT mutation is D816V. In some implementations, the primary activating mutation is A829P. A829P is a mutation at the very beginning of exon 18KIT, but is commonly referred to as an "exon 17" mutation. In some implementations, 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 exon 13 KIT mutations like V654A, N655K, or K642E. In another aspect, 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 yet another aspect, the cancer is GIST and the primary activating mutation is selected from exon 9 and / or exon 11 mutations. In another aspect, the cancer is GIST and the primary activating mutation is an exon 9KIT mutation or an exon 11KIT mutation, or a combination thereof. In another aspect, the cancer is GIST and the primary activating mutation is an exon 13KIT mutation. In yet another aspect, the cancer is GIST and the primary activating mutation is an exon 17KIT mutation.

[0135] For patients with primary GIST, complete surgical resection is the preferred initial treatment, and surgery is effective in approximately 50% of GIST patients. As used herein, the term "primary GIST" refers to GIST with only primary activating mutations (e.g., mutations that do not confer secondary resistance). In the remaining patients, tumor recurrence is frequent. For patients whose GIST recurs after surgical resection, one or more anticancer agents for treating GIST are administered. In one aspect, one or more anticancer agents are administered prior to treatment with a KIT inhibitor of this disclosure. For example, a KIT inhibitor of this disclosure is administered after GIST progression following prior treatment. This may occur if, for example, the patient's tumor is resistant to a prior agent, or becomes resistant (or refractory) after treatment, the patient is intolerant to treatment with a prior agent, or GIST recurs after prior treatment. Examples of agents studied and used in previous treatments of GIST include: imatinib (e.g., mesylate), sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindole, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, and larotrectinib and their pharmaceutically acceptable salts. In some implementations, agents studied and used in prior treatment of GIST are selected from: imatinib (e.g., mesylate), sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, and bezuratinib and their pharmaceutically acceptable salts (Vallilas, C. et al., International Journal of Molecular Sciences. 2021; 22, 493). Further examples of agents studied and used in prior treatment of GIST are selected from: AZD3229, BLU-263, everolimus, and larotrectinib and their pharmaceutically acceptable salts. (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 used to treat GIST.N-(4-{[5-fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propane-2-yl)-1H-1,2,3-triazol-1-yl]acetamide (also known as AZD3229 and NB003) is another KIT inhibitor used to treat GIST. In some embodiments, agents studied and used in prior treatment of GIST are selected from: AZD3229, BLU-263, everolimus, and larotrectinib, and their pharmaceutically acceptable salts.

[0136] In some respects, "primary KIT inhibitors" are administered to patients with GIST. Specifically, primary KIT inhibitors are 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 exons 9 and / or 11. Treatment with primary KIT inhibitors such as imatinib has also proven adequate for initial therapy, i.e., for treating patients with primary GIST, for example, those with activating KIT mutations in exons 9 and / or 11. However, despite the beneficial effects of targeted therapies such as imatinib, ultimately 50% of patients develop primary or secondary resistance to imatinib after 2 years. These secondary imatinib resistance mutations are most frequently located at KIT exons 11, 13, 14, 17, 18, or combinations thereof.

[0137] Sunitinib is the standard of care for second-line treatment of most imatinib-resistant tumors and is used to treat GISTs containing KIT mutations in exons 11, 13, and 14. However, secondary KIT mutations in exons 17 and 18 are resistant to sunitinib treatment, and furthermore, tumors containing tertiary resistance mutations in exons 17 and 18 may develop several months after sunitinib treatment.

[0138] In phase 3 clinical trials of imatinib- and sunitinib-resistant GIST, regorafenib has shown promising results, demonstrating activity against multiple, but not all, exon 17 and 18 mutations, including D816. Regorafenib is approved for third-line treatment of GIST.

[0139] Ripretinib is a KIT and PDGFRA kinase inhibitor approved for fourth-line treatment of GIST.

[0140] Additional options for treating GIST include: carbozentine, dasatinib, everolimus, nilotinib, pazopanib, sorafenib, and larotrectinib.

[0141] Avatinib is a selective exon 17 and exon 18 KIT inhibitor, currently approved for patients with GIST who have exon 18 PDGFRA mutations. Avatinib has been reported to have activity 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.

[0142] Bezuratinib, also known as CGT9486 and PLX9486, has the following structure:

[0143]

[0144] AZD3229, also known as NB003, has the following structure:

[0145]

[0146] In some embodiments, prior treatment in patients with GIST involves treating the patient with one or more agents (e.g., 1, 2, 3, or 4 agents) prior to treatment with a pharmaceutical composition containing a KIT inhibitor of the present disclosure or a pharmaceutically acceptable salt thereof (e.g., compounds of the present disclosure, including compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), or (X), or compounds of formula (I), (VIII), (IX), or (X), or compounds of formula (I), (IX), or (X), or compounds of formula (I), (IX), or (X), or compounds of formula (I), (IX), or (X), or compounds of formula (I), (IX), or (X), or compounds of formula (I), or (X), or compounds of formula (I), or (X), or compounds of formula (I), or (X), or compounds of formula (I), or compounds of formula (IX ... In one embodiment, prior treatment includes administration of one or more agents selected from: imatinib, sunitinib, regorafenib, nilotinib, carbozentib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, repretinib, everolimus, larotrectinib, bezuratinib, AZD3229, and BLU-263, and pharmaceutically acceptable salts thereof. In one embodiment, prior treatment includes administration of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof; imatinib mesylate is a pharmaceutically acceptable salt of imatinib). Continue prior treatment until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). In another embodiment, prior treatment includes administration of an exon 17 KIT inhibitor. Examples of exon 17 inhibitors are avatinib, BLU-263, ripretinib, and AZD3229. Examples of selective exon 17 inhibitors are avatinib, BLU-263, and bezuratinib. In one embodiment, prior treatment includes administration of 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 avatinib, BLU-263, ripretinib, bezuratinib, and AZD3229. In some embodiments, the exon 17 KIT inhibitor is avatinib. In some embodiments, the exon 17 KIT inhibitor is BLU-263. In some implementations, the exon 17KIT inhibitor is ripretinib. In some implementations, the exon 17KIT inhibitor is bezurlatinib. In some implementations, the exon 17KIT inhibitor is AZD3229. Examples of selective exon 17 inhibitors are avatinib, BLU-263, and bezurlatinib.In some embodiments, the exon 17KIT inhibitor is a selective exon 17KIT inhibitor. In some embodiments, the selective exon 17KIT inhibitor is selected from avatinib, BLU-263, and bezurlatinib. In some embodiments, the selective exon 17KIT inhibitor is avatinib. In some embodiments, the selective exon 17KIT inhibitor is BLU-263. In some embodiments, the selective exon 17KIT inhibitor is bezurlatinib. In another embodiment, prior treatment includes administration of one or more agents selected from the following: imatinib, sunitinib, regorafenib, nilotinib, carbozentine, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatotumab, clarabinib, avatinib, repretinib, everolimus, larotrectinib, bezuratinib, AZD3229, and BLU-263, and their pharmaceutically acceptable salts. In another embodiment, prior treatment includes administration of one or more agents selected from the following: regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabib, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof.

[0147] In another embodiment, prior treatment includes administration of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). Prior treatment continues until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof); thereafter, prior treatment further includes administration of sunitinib or a pharmaceutically acceptable salt thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof).

[0148] In another embodiment, prior treatment includes administration of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). Prior treatment continues until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof); thereafter, prior treatment further includes administration of an exon 17 KIT inhibitor or a pharmaceutically acceptable salt thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to an exon 17 inhibitor or a pharmaceutically acceptable salt thereof).

[0149] In another embodiment, prior treatment includes administration of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). Prior treatment continues until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), after which prior treatment further includes administration of sunitinib or a pharmaceutically acceptable salt thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof); subsequently, prior treatment further includes administration of regorafenib or a pharmaceutically acceptable amount thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to regorafenib or a pharmaceutically acceptable salt thereof).

[0150] In another embodiment, prior treatment includes administration of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). Prior treatment continues until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), after which prior treatment further includes administration of sunitinib or a pharmaceutically acceptable salt thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to sunitinib or a pharmaceutically acceptable salt thereof); subsequently, prior treatment further includes administration of regorafenib or a pharmaceutically acceptable amount thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to regorafenib or a pharmaceutically acceptable salt thereof); subsequently, prior treatment further includes administration of ripretinib or a pharmaceutically acceptable amount thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to ripretinib or a pharmaceutically acceptable salt thereof).

[0151] In another embodiment, prior treatment comprises administering an effective amount of a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). Prior treatment continues until GIST is identified as progressing or becomes resistant, refractory, or intolerant to a primary KIT inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof), after which prior treatment further comprises administering at least one agent selected from: nilotinib, carbozentine, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, fulapindo, ribocicib, sorafenib, pexidatinib, olatumumab, and clairabine or a pharmaceutically acceptable salt thereof (e.g., until GIST is identified as progressing or becomes resistant, refractory, or intolerant to said agent or a pharmaceutically acceptable salt thereof).

[0152] A tumor has or becomes mutatedly resistant to an agent used for prior treatment because of the presence of a mutation in the tumor that makes it resistant or refractory to the prior agent; this is known as a "resistance mutation." For example, a tumor may become mutatedly resistant to a primary KIT inhibitor. In some embodiments, the tumor has a mutation that makes it resistant 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 makes it resistant 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 prior agent is imatinib and the mutation is an imatinib resistance mutation. In one embodiment, the tumor has a mutation that makes it resistant to a prior agent. In one embodiment, the mutation that makes it resistant to a prior agent is selected from exon 13 KIT mutations, exon 17 KIT mutations, exon 18 KIT mutations, and exon 14 KIT mutations, and combinations thereof. In some embodiments, the mutation resistant to the prior agent is an exon 13KIT mutation, for example, an exon 13KIT mutation selected from V654A, N655K, and K642E, and combinations thereof. In some embodiments, the mutation resistant to the prior agent is an exon 13KIT mutation, for example, an exon 13KIT mutation selected from V654A, N655K, and combinations thereof. In some embodiments, the mutation resistant to the prior agent is an exon 17KIT mutation, for example, an exon 17KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and combinations thereof. In some embodiments, the mutation resistant to the prior agent is an exon 17KIT mutation, for example, an exon 17KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D, and combinations thereof. In some embodiments, the exon 17KIT mutation is A829P. In some embodiments, the exon 18KIT mutation is A829P. In some embodiments, the mutation resistant to the prior agent is an exon 17KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, and combinations thereof. In some implementations, the mutation that provides resistance to the prior agent is an exon 17KIT mutation, for example, an exon 17KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P and combinations thereof.In some embodiments, the mutation that makes the patient resistant to the prior agent is an exon 14KIT mutation, such as the N680K exon 14KIT mutation. In some embodiments, the tumor that has or becomes resistant to the prior agent has one or more mutations.

[0153] In some implementations, the tumor exhibits mutational resistance to prior treatment due to one or more exon 17 mutations. Examples of exon 17 inhibitors that can inhibit these exon 17 mutations leading to tumor resistance to prior treatment and thereby treat the tumor are selected from avatinib, BLU-263, ripretinib, AZD3229, and bezurlatinib. Other mutations that can be inhibited by the aforementioned exon 17 inhibitors include N655K, N680K, or combinations thereof.

[0154] In some embodiments, the tumor following prior treatment (e.g., using a primary KIT inhibitor such as imatinib) has one or more exon 13 mutations, such as exon 13KIT mutations selected from V654A, N655K, and K642E and combinations thereof.

[0155] In one embodiment, this disclosure provides a method of treating a patient 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., 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 compounds), or 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., 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 compounds). In some embodiments, the patient receives one or more prior treatments for GIST. In some embodiments, GIST progresses following prior treatment. In some embodiments, prior treatment includes administration of one or more agents. In some embodiments, one or more agents comprise imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, one or more agents comprise avatinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment comprises administration of one or more agents, each independently selected from: imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindole, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, and larotrectinib and pharmaceutically acceptable salts thereof. In some implementations, prior treatment includes administration of imatinib, sunitinib, regorafenib, nilotinib, carbozentib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, repretinib, bezuratinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some implementations, prior treatment includes administration of imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapintoxin, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, repretinib, bezuratinib, AZD3229, BLU-263, everolimus, or larotrectinib, or a pharmaceutically acceptable salt thereof. In some implementations, prior treatment includes administration of imatinib or a pharmaceutically acceptable salt thereof.In some embodiments, prior treatment includes administration of sunitinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of regorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of avatinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of bezuratinib or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, prior treatment includes administration of BLU-263 or a pharmaceutically acceptable salt thereof. In some embodiments, GIST is characterized by a tumor having one or more KIT mutations. In some embodiments, the tumor has a primary activating KIT mutation. In some embodiments, GIST is characterized by a tumor having one or more KIT mutations, each mutation independently selected from exon 9 KIT mutations, exon 11 KIT mutations, exon 13 KIT mutations, 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 17KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the exon 17KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In some embodiments, the exon 17KIT mutation is D816V. In some embodiments, the tumor has an exon 13KIT mutation. In some embodiments, the exon 13KIT mutation is selected from K642E, V654A, and N655K, and combinations thereof. In some embodiments, the exon 13KIT mutation is K642E. In some implementations, 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 treatments. In some embodiments, the tumor is mutation-resistant to: imatinib, sunitinib, regorafenib, nilotinib, carbozentine, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapintoxin, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, or larotrectinib, or pharmaceutically acceptable salts thereof, or combinations thereof. In some embodiments, the tumor is mutation-resistant to imatinib. In some embodiments, the tumor has an imatinib resistance mutation. In some embodiments, the tumor has an exon 13 inhibitor resistance 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 avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib, and pharmaceutically acceptable salts thereof. In some embodiments, the exon 17 inhibitor is avatinib 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 exon 13KIT mutations, exon 17KIT mutations, and exon 14KIT mutations, and combinations thereof. In some embodiments, the imatinib resistance mutation is an exon 13KIT mutation. In some embodiments, the exon 13KIT mutation is V654A or N655K. In some embodiments, the imatinib resistance mutation is an exon 17KIT mutation. In some embodiments, the exon 17KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the exon 17KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D. In some embodiments, the exon 17KIT mutation is D816V. In some embodiments, the exon 17KIT mutation is D816E. In some embodiments, the exon 17KIT mutation is A829P. In some implementations, the exon 18KIT mutation is A829P. In some implementations, the imatinib resistance mutation is an exon 14KIT mutation. In some implementations, the exon 14KIT mutation is N680K.

[0156] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient a combination comprising: (i) the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 thereof), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 thereof), and (ii) one or more agents (e.g., 1, 2, 3, or 4 additional agents).

[0157] In one embodiment, a patient with GIST is administered a combination comprising: (i) an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), 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., 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 compounds) and (ii) a primary Kit inhibitor (e.g., imatinib) as an adjunct. In one embodiment, a patient with GIST is given a combination comprising: (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), or (X), or a compound of Table 1, or a pharmaceutically acceptable salt thereof), 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 of Table 1, or a pharmaceutically acceptable salt thereof thereof) and (ii) an exon 9 or exon 11 inhibitor as an adjunct. In one embodiment, a combination comprising the following is administered to a patient with GIST: (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 of Table 1, or a pharmaceutically acceptable salt thereof), 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 of Table 1, or a pharmaceutically acceptable salt thereof); and (ii) an exon 17 inhibitor as an adjunct.

[0158] In another embodiment, a combination comprising the following is administered to a patient with GIST: (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 of Table 1, or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition disclosed herein (e.g., 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)). (ii) a primary Kit inhibitor (e.g., imatinib), or a pharmaceutically acceptable salt thereof, and (iii) at least one of the following: regorafenib, nilotinib, carbozentine, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindole, ribocicib, sorafenib, pexidatinib, olatotumab, clairab, sunitinib, avatinib, BLU-263, ripretinib, AZD3229, bezuratinib, everolimus, and larotrectinib, and a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is selected from regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clairab, sunitinib, avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib, 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 avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is avatinib 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 extra agent (iii) is ripretinib or a pharmaceutically acceptable salt thereof. In one embodiment, the extra agent (iii) is AZD3229 or a pharmaceutically acceptable salt thereof. In one embodiment, the extra agent (iii) is bezuratinib or a pharmaceutically acceptable salt thereof.

[0159] In another embodiment, a patient with GIST is administered a combination comprising (e.g., an effective combination) the following: (i) the compounds disclosed herein or pharmaceutically acceptable salts thereof (e.g., compounds of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or Table 1, or pharmaceutically acceptable salts of any of the foregoing compounds), or a pharmaceutical composition disclosed herein (e.g., comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein or pharmaceutically acceptable salts thereof, e.g., formulas (I), (II), (III), (IV), (V), (VI), (VIII), (VIX), (X ... The pharmaceutical composition comprises (II), (VIII), (IX), or (X) compounds, or the compounds in Table 1, or pharmaceutical compositions of pharmaceutically acceptable salts of any of the foregoing compounds, and as an additional agent the following: (ii) a primary Kit inhibitor (e.g., imatinib), or a pharmaceutically acceptable salt thereof, (iii) an exon 17 inhibitor, and (iv) at least one agent selected from: regorafenib, nilotinib, carboplatinib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindole, ribocicib, sorafenib, pexidatinib, olatotumab, clairab, and sunitinib, and pharmaceutically acceptable salts thereof. In any of the foregoing embodiments, the exon 17 inhibitor is selected from avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib. In one embodiment, the exon 17 inhibitor is selected from avatinib, BLU-263, ripretinib, AZD3229, and bezurlatinib. In one embodiment, the exon 17 inhibitor is avatinib 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 ripretinib 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 bezurlatinib or a pharmaceutically acceptable salt thereof.

[0160] In one aspect, the combination therapy described in this paragraph may be used as a first-line therapy, i.e., administered before a resistance mutation has been identified, or as a second-, third-, or fourth-line therapy, i.e., administered after the appearance of one or more resistance-conferring mutations. When a combination of agents is administered, the agents in the combination may be administered simultaneously (in the same or different formulations) or in any order.

[0161] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient an effective combination comprising: the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compounds disclosed herein, or pharmaceutically acceptable salts thereof (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 compounds), and at least one additional agent. In some embodiments, the additional agent is an exon 9KIT inhibitor or an exon 11KIT inhibitor. In some embodiments, the adjuvant is selected from imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the adjuvant is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the adjuvant is an exon 17KIT inhibitor. In some embodiments, the adjuvant is selected from avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib. In some implementations, the additional agent is selected from avatinib, BLU-263, riprinib, AZD3229, and bezuratinib.

[0162] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient a combination comprising: an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), and one or more agents. In some embodiments, said agent is an exon 9KIT inhibitor or an exon 11KIT inhibitor. In some embodiments, the agent is selected from imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, clarabinib, avatinib, ripretinib, bezuratinib, 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 17KIT inhibitor. In some embodiments, the agent is selected from avatinib, BLU-263, ripretinib, AZD3229, and bezuratinib.

[0163] Another embodiment of this disclosure is a method for treating a patient with a malignant disease (e.g., GIST) characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT 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 13KIT mutation or an exon 14KIT mutation; and (c) if a mutation is detected, administering to the patient an effective amount of a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein. In one aspect, the presence or absence of an exon 13KIT mutation is detected in step (b), for example, where the exon 13KIT mutation is V654A or N655K. In another aspect, the presence or absence of an exon 14KIT mutation is detected in step (b), for example, where the exon 14KIT mutation is N680K. The methods disclosed in WO2020 / 102095 for detecting the presence or absence of exon 13 mutation V654A or N655K or exon 14 mutation N680K are used, and all their teachings are incorporated herein by reference.

[0164] Another embodiment of this disclosure is a method for treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising (a) obtaining a biological sample from the patient; (b) detecting the presence or absence of an exon 13KIT mutation or an exon 14KIT mutation; and (c) if a mutation is present, administering to the patient an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., formulas (I), (II), (III), (IV), (…). Compounds of formula (V), (VI), (VII), (VIII), (IX), or (X), or compounds in Table 1, or pharmaceutically acceptable salts of any of the aforementioned compounds, or administration of 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., 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 aforementioned compounds). In one aspect, the presence or absence of an exon 13KIT mutation is detected in step (b), for example, where the exon 13KIT mutation is V654A or N655K. In another aspect, the presence or absence of an exon 14KIT mutation is detected in step (b), for example, where the exon 14KIT mutation is N680K. The methods disclosed in WO 2020 / 102095 for detecting the presence or absence of exon 13 mutation V654A or N655K or exon 14 mutation N680K are used, and all their teachings are incorporated herein by reference.

[0165] Another embodiment of this disclosure is a method for treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising administering to the patient, if an exon 13KIT mutation or an exon 14KIT mutation is detected, an effective amount of the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds). In some implementations, the exon 13KIT mutation is V654A or N655K. In some implementations, the exon 14KIT mutation is N680K.

[0166] A method of treating a patient with a malignant disease characterized by a tumor having an exon 9KIT mutation, an exon 11KIT mutation, or an exon 17KIT mutation, or a combination thereof, comprising administering to the patient, if an exon 13KIT mutation or an exon 14KIT mutation is present, an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 aforementioned compounds), 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., 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 aforementioned compounds). In some implementations, the exon 13KIT mutation is V654A or N655K. In some implementations, the exon 14KIT mutation is N680K.

[0167] Another embodiment of this disclosure is a method of treating a patient with gastrointestinal stromal tumors (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), wherein the GIST has a mutation resistant to a KIT inhibitor administered to treat GIST having a primary activating mutation in exon 9 or exon 11. In some embodiments, the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, claranib, avatinib, ripretinib, bezurlatinib, 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 bezurlatinib 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 implementations, the exon 13KIT mutation is V654A or N655K.

[0168] Another embodiment of this disclosure is a method of treating a patient with primary gastrointestinal stromal tumors (GIST) characterized by primary activating mutations in exon 9KIT or exon 11KIT, comprising administering to the patient: (i) an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein, or a pharmaceutically acceptable salt thereof (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 compounds); and (ii) an effective amount of an effective KIT inhibitor targeting GIST characterized by primary activating mutations in exon 9KIT or exon 11KIT. In some embodiments, the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, carbozentide, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flapindo, ribocicib, sorafenib, pexidatinib, olatumumab, claranib, avatinib, ripretinib, bezurlatinib, 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 bezurlatinib 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.

[0169] Pharmaceutical Composition

[0170] While the compounds of this disclosure can be administered alone, they are preferably administered as pharmaceutical formulations, wherein the compounds are combined with one or more pharmaceutically acceptable excipients or carriers. The compounds of this disclosure, or pharmaceutically acceptable salts thereof, can be formulated for administration in any convenient manner, whether in human or veterinary medicine. In some embodiments, the compounds contained in the pharmaceutical preparation may be active on their own or may be prodrugs, for example, capable of being converted to the active compound in a physiological environment.

[0171] The phrase “pharmaceutically acceptable” is used in this document to refer to compounds, materials, compositions, and / or dosage forms that, within reasonable medical judgment, are suitable for contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, and in proportion to a reasonable benefit / risk ratio.

[0172] 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 carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered astragalus gum; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution. (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrin; and (22) other non-toxic compatible substances used in pharmaceutical preparations.

[0173] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​salt, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0174] Solid dosage forms (e.g., capsules, tablets, pills, sugar tablets, powders, granules, etc.) may include one or more pharmaceutically acceptable carriers, such as sodium citrate or calcium hydrogen 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 carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants, such as glycerin, sucrose, and / or glutinous rice. (3) Oils; (4) Disintegrants, such as agar, calcium carbonate, potato or cassava starch, alginic acid, certain silicates and sodium carbonate; (5) Dissolution inhibitors, such as paraffin; (6) Absorption accelerators, such as quaternary ammonium compounds; (7) Wetting agents, such as cetyl alcohol and glyceryl monostearate; (8) Absorbents, such as kaolin and bentonite; (9) Lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) Colorants.

[0175] Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerin, tetrahydrofuranol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0176] In addition to the compounds disclosed herein or their pharmaceutically acceptable salts, the suspension may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar and astragalus gum and mixtures thereof.

[0177] In addition to the compounds disclosed herein or their pharmaceutically acceptable salts, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin waxes, starches, astragalus gums, cellulose derivatives, polyethylene glycols, polysiloxanes, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0178] In addition to the compounds disclosed herein or their pharmaceutically acceptable salts, powders and sprays may contain excipients such as lactose, talc, silica, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. Sprays may additionally contain conventional propellants such as chlorofluorocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0179] The formulation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical industry. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will vary depending on the host being treated and the specific administration method. The amount of the disclosed compound or a pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect.

[0180] Dosage forms for topical or transdermal application of the compounds disclosed herein or pharmaceutically acceptable salts thereof include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalers. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier and with any preservatives, buffers, or propellants that may be required.

[0181] When the compounds of this disclosure or their pharmaceutically acceptable salts are administered as a drug to humans and animals, they may be given either on their own or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0182] The formulation can be administered topically, orally, dermally, rectally, vaginally, parenterally, intranasally, intrapulmonaryly, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intrasacrally, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0183] dose

[0184] The actual dose level of the active ingredient in the pharmaceutical composition disclosed herein can be varied to obtain an amount of active ingredient that effectively achieves the desired therapeutic response for a particular patient, composition, and administration mode, and is non-toxic to the patient.

[0185] The selected dose level depends on a variety of factors including: the activity of the specific active ingredient used, the route of administration, the time of administration, the excretion rate of the specific active ingredient used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific active ingredient used, the age, sex, weight, condition, general health status and prior medical history of the patient being treated, and similar factors well known in the medical field.

[0186] A physician or veterinarian with ordinary skills in the art can readily determine and prescribe an effective amount of the desired pharmaceutical composition. For example, a physician or veterinarian may start with a dose of the compound of this disclosure used in the pharmaceutical composition at a level lower than required to achieve the desired therapeutic effect and gradually increase the dose until the desired effect is achieved.

[0187] Generally, the appropriate daily dose of the compounds disclosed herein is the minimum amount of the compound that effectively produces a therapeutic effect. This effective dose typically depends on the factors mentioned above.

[0188] As used herein, the terms “administer,” “administering,” and “administration” refer to methods that enable the delivery of a composition to a desired site of biological action. These methods include, but are not limited to, intra-articular, intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, oral, topical, intrathecal, inhalation, percutaneous, and transrectal administration. Administration techniques that can be used with the agents and methods described herein have been found, for example, in Goodman and Gilman, *The Pharmacological Basis of Therapeutics*, current edition; Pergamon; and Remington's Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[0189] The specific administration method and dosage regimen will be selected by the attending clinician based on the specific circumstances of the case (e.g., the subject, the disease, the disease state involved, the specific treatment, and whether the treatment is prophylactic). Treatment may involve once-daily or multi-daily doses, or less than once-daily doses (such as once-weekly or once-monthly), over periods ranging from several days to several months or even several years.

[0190] The pharmaceutical compositions disclosed herein are formulated to be compatible with their intended route of administration. In one embodiment, the composition is formulated according to conventional procedures to be 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.

[0191] "Pharmaceutically acceptable excipients" and "pharmaceutically acceptable carriers" refer to substances that aid in the formulation and / or administration of active agents to and / or absorption by subjects, and that can be included in the compositions of this disclosure without producing significant adverse toxicological effects on the subjects. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, aqueous saline solutions, lactated Ringer's solution, plain sucrose, plain glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavoring agents, salt solutions (such as Ringer's solution), alcohols, oils, gelatin, carbohydrates (such as lactose, amylose, or starch), fatty acid esters, hydroxymethyl cellulose, polyvinylpyrrolidone, and colorants. Such preparations can be sterilized and, if necessary, mixed with adjuvants that do not adversely react with or interfere with the activity of the compounds provided herein, such adjuvants being lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts affecting osmotic pressure, buffers, colorants, and / or aromatic substances. Those skilled in the art will recognize that other pharmaceutical excipients are suitable for use with the disclosed compounds.

[0192] Example

[0193] The following examples are intended to be illustrative and are not intended to be limiting in any way.

[0194] abbreviation

[0195] The abbreviations and acronyms used in this article include the following:

[0196] AcOH represents acetic acid;

[0197] AIBN stands for 2,2'-azobis(2-methylpropionitrile);

[0198] t-AmOH represents tert-amyl alcohol;

[0199] Aq. indicates an aqueous solution;

[0200] Boc represents tert-butoxycarbonyl;

[0201] (BPin)2 represents 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis-1,3,2-dioxoboronylcyclohexane;

[0202] br indicates a broad peak;

[0203] Brettphos represents 2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl;

[0204] BrettPhos Pd G3 represents [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate;

[0205] BrettPhos Pd G4 represents dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tris(propane-2-yl)phenyl]phenyl]phosphine; methanesulfonic acid; N-methyl-2-phenylaniline; palladium.

[0206] n-BuOH represents butane-1-ol;

[0207] t-BuOK represents potassium tert-butoxide;

[0208] d indicates a double peak;

[0209] dd indicates double peaks;

[0210] DAST stands for diethylaminosulfur trifluoride;

[0211] DCM stands for dichloromethane;

[0212] DIAD stands for diisopropyl azodicarboxylate;

[0213] DIPEA stands for N-ethyl diisopropylamine or N,N-diisopropylethylamine;

[0214] DMA stands for N,N-dimethylacetamide;

[0215] DMF stands for N,N-dimethylformamide;

[0216] DMSO stands for dimethyl sulfoxide;

[0217] EtOAc represents ethyl acetate;

[0218] EtOH represents ethanol;

[0219] EtONa represents sodium ethoxide;

[0220] Eq. indicates equivalent;

[0221] FA stands for formic acid;

[0222] HATU represents 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate;

[0223] IPA stands for 2-propanol;

[0224] [Ir(OMe)(1,5-cod)]2 represents bis(1,5-cyclooctadiene)di-μ-methoxydiiridium(I);

[0225] KOAc represents potassium acetate;

[0226] LCMS stands for Liquid Chromatography-Mass Spectrometry;

[0227] m indicates multiple peaks;

[0228] MeCN represents acetonitrile;

[0229] MeI represents iodomethane;

[0230] MeNH2 represents methylamine;

[0231] MeOH represents methanol;

[0232] MeOH-d4 indicates deuterated methanol;

[0233] MPLC stands for Medium Pressure Liquid Chromatography;

[0234] MS m / z indicates the mass spectrum peak;

[0235] NBS stands for N-bromosuccinimide;

[0236] NMP represents N-methylpyrrolidine;

[0237] PE stands for petroleum ether;

[0238] Pd(amphos)Cl2 represents bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II);

[0239] Pd(t-Bu3P)2 represents bis(tri-tert-butylphosphine)palladium(0);

[0240] Pd2(dba)3 represents tris(dibenzylacetylacetone)dipalladium(0);

[0241] Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) chloride;

[0242] PG indicates a protective group;

[0243] i-PrMgCl represents isopropyl magnesium chloride;

[0244] q represents a quartet;

[0245] rt represents room temperature;

[0246] RT represents the retention time;

[0247] s indicates a single peak;

[0248] sat. indicates saturation;

[0249] SFC stands for Supercritical Fluid Chromatography;

[0250] t represents a triplet;

[0251] T3P represents 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphonic alkyl-2,4,6-trioxide;

[0252] TBAF stands for tetrabutylammonium fluoride;

[0253] TBDMS stands for tert-butyldimethylsilane;

[0254] TBDMSCl represents tert-butyl(chloro)dimethylsilane;

[0255] TEA stands for triethylamine;

[0256] TFA stands for trifluoroacetic acid;

[0257] TfOH represents trifluoroethanesulfonic acid;

[0258] THF stands for tetrahydrofuran;

[0259] TLC stands for Thin Layer Chromatography;

[0260] TMSN3 represents trimethylsilyl azide;

[0261] Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthanium; and

[0262] Xphos Pd G2 represents chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II).

[0263] General synthetic methods and intermediates

[0264] According to the first process, compound (I) can be prepared from compounds (ii) and (iii), as illustrated in scheme 1.

[0265]

[0266] According to process step (a) Buchwald-Hartwig cross-coupling, compound (I) can be prepared from compounds (ii) and (iii). Typical conditions include reacting the amine of formula (iii) with the chloride of formula (ii) at high temperature, in a suitable solvent, in a suitable inorganic base, and in a suitable catalyst. Preferred conditions include reacting the amine of formula (iii) with the chloride of formula (ii) at a temperature between 90°C and 130°C, in the presence of BrettPhos PdG3, BrettPhos PdG4, Pd(t-Bu3P)2, or Xantphos, optionally in conjunction with Pd2(dba)3 or BrettPhos, in a suitable solvent such as dioxane, toluene, t-AmOH, NMP, or DMF, in a suitable solvent such as Cs2CO. 3、 Compounds of formulas (ii) and (iii) react in the presence of a suitable base of K2CO3 or KOAc.

[0267] According to the second process, compound (I) can be prepared from compounds (ii), (iv) and (v), as illustrated in scheme 2.

[0268]

[0269] PG is a suitable amine protecting group, preferably 2,4-dimethoxybenzyl or tert-butyl.

[0270] According to the process step (a) Buchwald-Hartwig cross-coupling reaction as previously described in Scheme 1, compound (v) can be prepared from compounds (ii) and (iv).

[0271] Compound (I) can be prepared from the protected compound (v) via the deprotection reaction in process step (b). Typical conditions involve reacting compound (v) with a suitable acid such as HCl or TFA in a suitable solvent such as dioxane, THF, or DCM at about 100°C.

[0272] According to the third process, compound (v) can be prepared from compounds (vi) and (vii), as illustrated in scheme 3.

[0273]

[0274] Compound (v) can be prepared from compounds (vi) and (vii) via process step (a) Buchwald-Hartwig cross-coupling reaction as previously described in Scheme 1.

[0275] According to the fourth process, compound (vi) can be prepared from compounds (ii) and (viii), as illustrated in scheme 4.

[0276]

[0277] PG 2 A suitable nitrogen protecting group is preferred, preferably benzyl or diphenylmethylene.

[0278] Through the amination reaction in process step (c), compound (viii) can be produced from compound (ii) and PG. 2 It is prepared using NH2, in which PG 2 It is benzyl. Typical conditions include reacting the compound of formula (ii) with PG at high temperatures such as 200°C and under microwave irradiation. 2 NH2 reaction.

[0279] Or, where PG 2 It is a diphenylmethylene compound, which can be produced by cross-coupling reaction of compound (ii) and PG via process step (a) as previously described in Scheme 1. 2 Preparation of NH2.

[0280] Compound (vi) can be prepared from compound (viii) via the deprotection reaction in process step (d). Typical conditions involve reacting compound (viii) with a suitable acid, such as trifluoromethanesulfonic acid or HCl, in a suitable solvent, such as DCM, at about rt.

[0281] According to the fifth process, the compound of formula (ii) can be prepared from the compounds of formulas (ix), (x), (xi), (xii), (xiii), (xiv), (xv) and (xvi), as illustrated in scheme 5.

[0282]

[0283] Hal 1 It is a halogen, preferably Br or I.

[0284] Hal 2 It is a halogen, preferably Cl or F.

[0285] W is either Sn(n-Bu)3 or B(Pin).

[0286] Alk is a C1-C4 alkyl group.

[0287] Where X1 is O, the compound of formula (xi) can be prepared from the compound of formula (ix) via process step (e). Typical conditions include reacting the compound of formula (ix) with a suitable alkyl fluorinating agent such as ethyl 2-bromo-2,2-difluoroacetate in a suitable solvent such as DMF and in the presence of a suitable base such as K2CO3 at a high temperature of about 60°C.

[0288] Compound (xi) can be prepared from compound (x) via process step (f). Typical conditions include reacting compound (x) with R between 0°C and 140°C, optionally under microwave irradiation, optionally in a suitable solvent such as THF, DMF, DMA, DMSO, dioxane, n-BuOH, or MeCN, and in the presence of a suitable organic or inorganic base such as DIPEA or TEA, Cs₂CO₃, t-BuOK, NaH, or KF. 2 X1H reaction.

[0289] According to process step (g), the borate ester formation is achieved by treatment with a suitable boric acid such as (BPin)2, between rt and high temperature, in a suitable nonpolar solvent, in the presence of a suitable inorganic base such as K2CO3 or KOAc and a suitable catalyst such as Pd(dppf)Cl2, and compound (xii) can be prepared from compound (xi). Preferred conditions include treatment of compound (xi) with (BPin)2 at 90°C, in dioxane, in the presence of Pd(dppf)Cl2 and KOAc.

[0290] Among them, R 3 As previously defined, a 5-membered aromatic heterocycle, through a palladium-catalyzed cross-coupling reaction in process step (h), the compound of formula (ii) can be prepared from the compound of formula (xi). These cross-coupling reactions may include Suzuki-type reactions, where W is a boric acid or ester, or Stille-type cross-coupling reactions, when W is an alkyltinane.

[0291] Typical cross-coupling conditions include: between rt and high temperature; in suitable solvents such as EtOH, dioxane, aqueous dioxane, or DMF; in the presence of inorganic or organic bases such as Cs₂CO₃, K₂CO₃, Na₂CO₃, K₃PO₄, TEA, or KOAc; in the presence of compounds of formula (xvi); and palladium catalysts containing suitable phosphine ligands, such as Pd(amphos)Cl₂, Pd(dppf)Cl₂. 2、 Pd(PPh3)Cl2 or Xphos Pd G2.

[0292] Among them, R 3 It is a 5-membered aromatic heterocycle as previously defined, and according to the process step (h) described above, the compound of formula (ii) can be formed from the compound of formula (xii) and R. 3 -Hal 1 preparation.

[0293] Where R 3 It is C(O)NHR 5 Compound (ii) can be prepared from compounds (xiii), (xiv) and (xv).

[0294] According to the process step (f) described above, compound (xiv) can be produced by compound (xiii) and R. 2 Preparation of X1H.

[0295] Compound (xv) can be prepared from compound (xiv) via process step (i) hydrolysis. Typical conditions involve reacting compound (xiv) with an alkali metal hydroxide such as LiOH or NaOH in an aqueous solvent such as MeOH, EtOH, or THF between rt and about 80°C.

[0296] According to process step (j), amide bonds are formed, and compound (ii) can be formed from compound (xv) and R. 5 Preparation of NH2. Typical conditions involve reacting the acid of formula (xv) with R in a suitable polar aprotic solvent, in the presence of a suitable coupling agent and an organic base. 5 NH2 reaction. Preferred conditions include reacting the acid of formula (xv) with R in a suitable solvent such as DMF or DCM, in the presence of a suitable organic base, typically DIPEA or TEA, at room temperature, in the presence of HATU or T3P. 5 NH2 reaction.

[0297] Alternatively, the compound of formula (ii) can be prepared by the following steps: at rt, in a suitable solvent such as THF or DCM, typically using oxaloyl chloride or thionyl chloride, an acidic chloride of formula (xv) is formed in situ, and subsequently at 0°C, in the presence of a suitable organic base, typically DIPEA, the acidic chloride and amine R... 5 Amide bonds are formed in NH2.

[0298] According to the sixth process, compound (ii) can be prepared from compounds of formulas (x), (xvi), (xvii), (xviii), (xix) and (xx), as illustrated in scheme 6.

[0299]

[0300] Among them, R 3 It is a 5-membered aromatic heterocycle as previously defined, and the compound of formula (xviii) can be prepared from the compounds of formula (x) and (xvi) according to process step (h) as previously described in scheme 5.

[0301] Among them, R 3 It is a 5-membered aromatic heterocycle as previously defined, and according to process step (h) as previously described in Scheme 5, the compound of formula (xviii) can be formed from the compound of formula (xvii) and R. 3 -Hal 1 preparation.

[0302] Among them, R3 It is C(O)NHR 5 According to process step (j) as previously described in Scheme 5, compound (xviii) can be produced by compound (xix) and R. 5 Preparation of NH2.

[0303] Among them, R 3 It is C(O)NHR 5 According to the ammonolysis reaction in process step (k), compound (xviii) can be produced by compound (xx) and R. 5 Preparation of NH2. Typical conditions include reacting compound (xx) with R in a sealed container at a high temperature such as 70°C. 5 NH2 reaction.

[0304] According to process step (f) as previously described in Scheme 5, compound (ii) can be produced from compound (xviii) and R. 2 Preparation of X1H.

[0305] According to the seventh process, compound (vi) can be prepared from compounds (xxi) and (xxii), as illustrated in scheme 7.

[0306]

[0307] According to process step (l), halogenation reaction, preferably bromination reaction, compound (xxii) can be prepared from compound (xxi). Typical conditions include reacting compound (xxi) with NBS in DMF at rt.

[0308] According to process step (h) as previously described in Scheme 5, compound (vi) can be prepared from compounds (xxii) and (xvi).

[0309] According to the eighth process, compound (I) can be prepared from compounds (iii), (xviii) and (xxiii), as illustrated in scheme 8.

[0310]

[0311] By means of process step (a) as previously described in Scheme 1, Buchwald-Hartwig coupling, compound (xxiii) can be prepared from compounds (iii) and (xviiii).

[0312] Through process step (f) as previously described in Scheme 5, compound (I) can be produced from compound (xxiii) and R. 2 Preparation of X1H.

[0313] According to the ninth process, compound (v) is given, where R...3 C(O)NHR 5 It can be prepared from compounds of formula (iv), (xiv) and (xxiv), as illustrated in scheme 9.

[0314]

[0315] According to process step (a) as previously described in Scheme 1, compound (xxiv) can be prepared from compounds (xiv) and (iv).

[0316] According to process step (k) as previously described in Scheme 6, ammonolysis reaction, compound (v) can be prepared from compound (xxiv).

[0317] Compounds of formulas (iii), (iv), (vii), (ix), (x), (xiii), (xvi), (xvii), (xix), (xx), and (xxi) are commercially available or can be prepared by methods similar to those known in the literature or by methods described in the experimental section below.

[0318] Compounds of formulas (I), (ii), (v), (vi), (viii), (xviii), and (xxiii) can be converted into alternative compounds of formulas (I), (ii), (v), (vi), (viii), (xviii), and (xxiii) using 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 methods for synthesizing five-membered heterocycles from functional groups such as nitriles, as described in Comprehensive Heterocyclic Chemistry or in the literature.

[0319] Those skilled in the art will understand that a suitable protecting group strategy may be required to prepare compounds of formula (I). Typical protecting groups may include carbamates and, preferably, Boc groups for protecting aliphatic amines, or TBDMS groups for protecting primary alcohols.

[0320] It should be further understood that it may be necessary or desirable to perform the transformations in a different order than that described in the protocol, or to modify one or more transformations to provide the desired compounds disclosed herein.

[0321] The methods for preparing the compounds of this disclosure can be carried out in suitable solvents that can be readily selected by those skilled in the art of organic synthesis. At the temperature at which the reaction is carried out, for example, in a temperature range from the freezing point to the boiling point of the solvent, the suitable solvent is substantially non-reactive with the starting materials (reactants), intermediates, or products. A given reaction can be carried out in one solvent or a mixture of more than one solvent. The suitable solvent for a particular reaction step can be selected by those skilled in the art, depending on the specific reaction step.

[0322] The preparation of the compounds disclosed herein may involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by those skilled in the art. The chemistry of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0323] The reaction can be monitored using any suitable method known in the art. For example, product formation can be detected by methods such as nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13 C) Detection using spectroscopic methods such as infrared (IR) spectroscopy, spectroscopic determinations (e.g., UV-Vis), 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:

[0324] Those skilled in the art will recognize that modifications to the gradient, column length, and flow rate are possible, and that some conditions may be more suitable for compound characterization than others, depending on the chemical being analyzed.

[0325] Preparative LC-MS: Preparative HPLC is performed using the conditions described below.

[0326]

[0327] Preparation of intermediates

[0328] Preparation 1 2-(difluoromethyl)pyrimidin-4,6-diol

[0329]

[0330] EtONa (799 g, 11.75 mol) was added to a solution of malondiamide (600 g, 5.88 mol) in EtOH (12 L) 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, the solid was washed with EtOH / EtOAc (1:1) and dried under vacuum to give the title compound (800 g, 71.4%) as a yellow solid.

[0331] Preparation 2 4,6-Dichloro-2-(difluoromethyl)pyrimidine

[0332]

[0333] To a solution of 2-(difluoromethyl)pyrimidin-4,6-diol (preparation 1, 150 g, 740.31 mmol) in toluene (3 L), POCl3 (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 the pH was adjusted to 7–8 by adding saturated NaHCO3 aqueous solution. The layers were separated, the organic layer was washed with brine (300 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ISCO 0–5% EtOAc / PE) to give the title compound (85 g, 57.1%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6)δppm 7.18-6.83(m,1H)8.31(s,1H)

[0334] Preparation 3 6-Chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine

[0335]

[0336] DIPEA (64.9 g, 502 mmol) was added 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), and the reaction was stirred at 140 °C for 2 h. The cooled reaction mixture was decanted into water (500 mL) and extracted with EtOAc (400 mL x 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, 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(400MHz, 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).

[0337] Preparation 4 6-Chloro-2-(difluoromethyl)pyrimidin-4-amine

[0338]

[0339] 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 NaHCO3 solution, and the mixture was extracted with EtOAc (500 mL x 3). 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] +

[0340] Preparation 5 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine

[0341]

[0342] Following a similar procedure to that described in Preparation 3, 25.31 g of the title compound as a grayish-white solid was obtained from 6-chloro-2-(difluoromethyl)pyrimidin-4-amine (Preparation 4) and 2,4-dimethoxybenzylamine, in 47.8% yield. LCMS m / z = 311.1 [M+H] + ;1 H NMR (400MHz, DMSO-d6) δ7.16(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).

[0343] Preparation of 6 :N,N'-(2-(difluoromethyl)pyrimidin-4,6-diyl)bis(1,1-diphenylmethaneimine)

[0344]

[0345] Under N2, diphenylmethaneimine (326.86 g, 1.80 mol), Cs2CO3 (705.15 g, 2.16 mol), Xantphos (41.74 g, 72.14 mmol), and Pd2(dba)3 (33.03 g, 36.07 mmol) were added to a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (preparation 2,145 g, 721.41 mmol) in dioxane (2 L), 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(400MHz,DMSO-d6)δppm 6.39-6.57(m,2H)7.27-7.60(m,20H)

[0346] Preparation 7 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride

[0347]

[0348] A solution of N,N'-(2-(difluoromethyl)pyrimidin-4,6-diyl)bis(1,1-diphenylmethaneimine) (preparation 6,250 g, 511.74 mmol) in dioxane (1.5 L) was added to 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 milled with THF (1 L) for 30 min at 25 °C. The solid was filtered off to give the title compound (113 g, 68.6% yield) as a brown solid. LCMS m / z = 160 [M+H] +

[0349] Preparation of 8 2-(difluoromethyl)pyrimidin-4,6-diamine

[0350]

[0351] 7M NH3 from MeOH was added to a solution of diethyl malonimide dihydrochloride (10 g, 43.9 mmol) in 20 mL of MeOH, and the reaction was stirred at 50 °C for 16 h. The mixture was evaporated under reduced pressure to give 7 g of crude malonimide. This was dissolved in 40 mL of EtOH, and ethyl 2,2-difluoroacetate (4.5 g, 36.26 mmol) and EtONa (7.5 g, 110.3 mmol) were added, 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 under vacuum. The residue was purified by silica gel column chromatography eluting with MeOH / DCM (1 / 10) to give the title compound (700 mg, 12.6% yield).

[0352] Preparation 9 2-(1-Fluoroethyl)pyrimidin-4,6-diol

[0353]

[0354] EtONa (40.0 g, 588 mmol) was added to a solution of malondiamide (30 g, 294 mmol) in EtOH (300 mL), and the solution was stirred at 20 °C for 1 h. Ethyl 2-fluoropropionate (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 1 N HCl, and then concentrated under vacuum. The residue was adjusted to pH 2 with 1 N 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] + .

[0355] Preparation 10 4,6-Dichloro-2-(1-fluoroethyl)pyrimidine

[0356]

[0357] At 25 °C, POCl3 (72.8 mL, 784 mmol) was added to a stirred solution of 2-(1-fluoroethyl)pyrimidin-4,6-diol (preparation 9, 31 g, 196 mmol) in toluene (300 mL). 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 (x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate was evaporated under reduced pressure to give 40 g of the title compound.

[0358] Preparation 11 6-Chloro-N-(2,4-Dimethoxybenzyl)-2-(1-Fluoroethyl)pyrimidin-4-amine

[0359]

[0360] 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 x 3). The combined organic matter was washed with brine (300 mL x 3), dried over Na2SO4, and evaporated under reduced pressure to give the title compound (22 g, crude matter) as a yellow solid, which was used directly in the next step. LCMS m / z = 326 [M+H] + .

[0361] Preparation 12 6-Chloro-2-(1-Fluoroethyl)pyrimidin-4-amine

[0362]

[0363] 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 under vacuum, 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 organic matter was washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum. The residue was ground with PE / EtOAc = 1 / 1 and filtered to give the title compound as a gray solid (10 g, 84% yield). LCMS m / z = 176 [M+H] + .

[0364] 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

[0365]

[0366] 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), extracted with EtOAc (300 mL x 3), and the combined organic matter was washed with brine (300 mL x 2), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography to give N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine (6.6 g, 37%) as a yellow solid.

[0367] This product was further purified by SFC using an OZ 20 x 250 mm, 10 μm (Daicel) column, eluting with 35% MeOH (0.2% MeOH / NH3) at 100 g / min to obtain the first eluted enantiomeric form: (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidine-4,6-diamine (2.1 g), a yellow solid. LCMS m / z = 307 [M+H] + (Preparation 13)

[0368] Further elution yields a second enantiomer, (R)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine. (Preparation 14)

[0369] The stereochemistry of preparation 13 was confirmed by X-ray diffraction.

[0370] Preparation 15 2-(fluoromethyl)pyrimidin-4,6-diol

[0371]

[0372] EtONa (80.0 g, 1.18 mol) was added to a solution of malondiamide (60.0 g, 588 mmol) in EtOH (600 mL), and the solution was stirred for 1 h. Ethyl 2-fluoroacetate (68.6 g, 646 mmol) was added dropwise. The reaction mixture 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 32.0 g of the title compound as a yellow solid (37.8% yield). 1 H NMR: (400MHz, DMSO-d6) δ11.91(brs,2H),5.26(d,2H),5.14(s,1H).

[0373] Preparation of 16 4,6-Dichloro-2-(fluoromethyl)pyrimidine

[0374]

[0375] At 25 °C, POCl3 (82.8 mL, 891 mmol) was added dropwise to a solution of 2-(fluoromethyl)pyrimidin-4,6-diol (preparation 15, 32.0 g, 222 mmol) in toluene (300 mL). 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 warm water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by MPLC (silica gel, PE / EtOAc = 100 / 1–10 / 1) to give the title compound (30.0 g, 74.6% yield) as a white solid. 1 H NMR: (400MHz, CDCl3) δ: 5.43 (s, 1H), 5.54 (s, 1H), 7.40 (s, 1H).

[0376] Preparation of 17 N4,N6-Bis(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diamine

[0377]

[0378] 2,4-Dimethoxybenzylamine (5.08 g, 30.39 mmol) was added to a solution of 4,6-dichloro-2-(fluoromethyl)pyrimidine (Preparation 16, 1.10 g, 6.08 mmol) in DMSO (15 mL), and the reaction was stirred at 100 °C for 24 h. The cooled reaction was quenched with H₂O (30 mL) at 0 °C and extracted with EtOAc (20 mL x 5). The combined organic layers were washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE:EtOAc = 5:1 to 1:1) to give the title compound (940 mg, 35.0%) as a yellow solid.

[0379] Preparation of 18 2-(fluoromethyl)pyrimidin-4,6-diamine

[0380]

[0381] TFA (3 mL) was added 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), and the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-1 to give the title compound as a white solid (130 mg, 43.1%). 1 H-NMR (400MHz, DMSO-d6) δ: 6.19 (s, 4H), 5.31 (s, 1H), 5.05-4.93 (m, 2H).

[0382] Preparation of 19 N4-(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diamine

[0383]

[0384] 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 x 3). The combined organic matter was washed with brine (300 mL x 3), dried over Na2SO4, and evaporated under reduced pressure to give the title compound (50.0 g, crude matter) as a yellow solid. LCMS m / z = 312 [M+H] +

[0385] Preparation 20 5-Bromo-2-chloro-4-methoxypyridine

[0386]

[0387] At 0 °C, NaH (60% dispersion, 1.76 g, 44.0 mmol) was added to a solution of MeOH (704 mg, 22.0 mmol) in THF (30 mL). The mixture was stirred at 0 °C for 30 min, and then 5-bromo-2,4-dichloropyridine (5 g, 22.0 mmol) in THF (10 mL) was added. The reaction was stirred at rt for 12 h. The solution was quenched with H₂O, extracted with EtOAc, and the combined organic layers were concentrated under vacuum. 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] + .

[0388] Preparation 21 5-Bromo-2-chloro-4-isopropoxypyridine

[0389]

[0390] At 0 °C, NaH (1.76 g, 44.0 mmol) was added to a solution of IPA (1.32 g, 22.0 mmol) in THF (30 mL), and the solution was stirred for 30 min. Then, 5-bromo-2,4-dichloropyridine (5 g, 22.0 mmol) in THF (10 mL) was added. The mixture was stirred at rt for 12 h, diluted with EtOAc (300 mL), and washed with water (80 mL) and brine (80 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. 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] + .

[0391] Preparation 22 2-Chloro-5-iodo-4-methoxypyridine

[0392]

[0393] A solution of MeONa in MeOH (4M, 1.16 mL) was added to a solution of 2-chloro-4-fluoro-5-iodopyridine (800 mg, 3.11 mmol) in MeOH (10 mL), and the reaction was stirred at rt for 4 h. Water (30 mL) was added, the mixture was extracted with EtOAc (50 mL × 3), and the combined organic layers were concentrated under vacuum to give the crude product. This crude product 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] + .

[0394] Preparation 23 2-Chloro-5-iodo-4-(methoxy-d3)pyridine

[0395]

[0396] 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 rt for 4 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 4) to give the title compound (1.8 g, 90%) as a white solid. LCMS m / z = 273 [M+H] + .

[0397] Preparation 24 2-Chloro-4-cyclopropoxy-5-iodopyridine

[0398]

[0399] At 0 °C, a solution of cyclopropanol (406 mg, 7 mmol) in DMF (2 mL) was added to a suspension of NaH (420 mg, 10.5 mmol) in DMF (10 mL), and the mixture was stirred at rt for 30 min. 2-Chloro-4-fluoro-5-iodopyridine (1.8 g, 7 mmol) was added to DMF (10 mL), and the reaction was stirred at rt for 2 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were concentrated under vacuum, 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] + .

[0400] Preparation 25 2-Chloro-4-((1-fluoropropane-2-yl)oxy)-5-iodopyridine

[0401]

[0402] NaH (65.3 mg, 2.72 mmol) was added to a solution of 2-chloro-4-fluoro-5-iodopyridine (350 mg, 1.36 mmol) in THF, and the solution was stirred for 30 min at 0 °C. 1-fluoropropane-2-ol (106.2 mg, 1.36 mmol) was added, and the reaction was stirred overnight at rt. The reaction was quenched with water and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 1) to give the title compound (320 mg, 75% yield). LCMS m / z = 316 [M+H] + .

[0403] Preparation 262-Chloro-5-iodo-4-isopropoxypyridine

[0404]

[0405] Following the procedure described in Preparation 25, 140 mg of the title compound, as a white solid, was obtained from 2-chloro-4-fluoro-5-iodopyridine and isopropanol in 61% yield. LCMS m / z = 298 [M+H] +

[0406] Preparation 27 5-Bromo-2-chloro-4-cyclopropoxypyridine

[0407]

[0408] NaH (5.99 g, 150 mmol, 60% of mineral oil) was added to a solution of cyclopropanol (8.70 g, 150 mmol) in THF (200 mL) 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 a saturated aqueous solution of NH4Cl (100 mL), followed by extraction with EtOAc (100 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography 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] +

[0409] Preparation 28 5-Bromo-2-chloro-4-(oxetane-3-yloxy)pyridine

[0410]

[0411] Following the procedure described in Preparation 27, 1.97 g of the title compound, a white solid (67.6%), was obtained from oxetane-3-ol and 5-bromo-2,4-dichloropyridine.

[0412] Preparation 29 2-Chloro-4-(difluoromethoxy)-5-iodopyridine

[0413]

[0414] 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 for 16 h at 60 °C under N₂. The cooled mixture was diluted with EtOAc, washed with water, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give the title product (500 mg, 42%). LCMS m / z = 306 [M + H] + .

[0415] Preparation 30 1,1-Diphenyl-N-(4-(trifluoromethoxy)pyridin-2-yl)methaneimine

[0416]

[0417] Diphenylmethaneimine (2.83 g, 15.6 mmol) was added to a mixture of 2-chloro-4-(trifluoromethoxy)pyridine (2.8 g, 14.2 mmol), Pd₂(dba)₃ (280 mg, 0.306 mmol), XantPhos (560 mg, 0.968 mmol), and Cs₂CO₃ (6.93 g, 21.3 mmol) in anhydrous dioxane (400 mL), and the reaction was stirred at 100 °C under N₂ for 16 h. The cooled mixture was concentrated under vacuum and purified by silica gel chromatography to give the title product (2.6 g, 53%). LCMS m / z = 343 [M + H] + .

[0418] Preparation 31 4-(trifluoromethoxy)pyridine-2-amine

[0419]

[0420] To a mixture of 1,1-diphenyl-N-(4-(trifluoromethoxy)pyridin-2-yl)methaneimine (preparation 30, 2.6 g, 7.6 mmol) in DCM (20 mL), HCl / dioxane (20 mL, 4 M) was added and the reaction was stirred at rt for 1 h. The mixture was concentrated under vacuum and purified by silica gel chromatography to give the title product (850 mg, 62%). LCMS m / z = 179 [M+H] + .

[0421] Preparation of 32 5-Bromo-4-(trifluoromethoxy)pyridine-2-amine

[0422]

[0423] NBS (1.02 g, 5.74 mmol) was added to a mixture of 4-(trifluoromethoxy)pyridine-2-amine (preparation 31, 850 mg, 4.78 mmol) in DMF (20 mL), and the reaction was stirred at rt for 1 h. The mixture was diluted with EtOAc, washed with water, and concentrated under vacuum. The crude product was purified by silica gel chromatography to give the title compound (1.1 g, 89%). LCMS m / z = 257 [M+H] + .

[0424] Preparation of 33 1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole

[0425]

[0426] A mixture of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)ethane-1-ol (1 g, 4.2 mmol), 1H-imidazolium (571 mg, 8.4 mmol), and TBDMSCl (945 mg, 6.3 mmol) in DCM (20 mL) was stirred at rt for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography 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] + .

[0427] Preparation of 34 1-(oxetane-2-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-pyrazole

[0428]

[0429] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (800 mg, 4.12 mmol), 2-(bromomethyl)oxetane (622 mg, 4.12 mmol), and Cs₂CO₃ (2.68 g, 8.24 mmol) in MeCN (20 mL) was stirred at 80 °C for 16 h. The cooled mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography 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] + .

[0430] Preparation of 35 2-Methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)butane-2-ol

[0431]

[0432] Following a similar procedure to that described in Preparation 34, the title compound (800 mg, 61% yield) was obtained as a brown oil from 2-methyl-4-((4-methylbenzenesulfonyl)oxy)butane-2-ol and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-pyrazole. LCMS m / z = 281 [M+H] +

[0433] Preparation of 36 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-2-one

[0434]

[0435] The title compound (1 g, 77% yield) was obtained from 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole and 1-chloropropane-2-one, following the procedure described in Preparation 34. LCMS m / z = 251 [M+H] + .

[0436] Preparation of 37 : Methyl(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate

[0437]

[0438] DIAD (5.16 g, 25.51 mmol) and PPh3 (6.69 g, 25.51 mmol) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (4.50 g, 23.19 mmol) and N-(2-hydroxyethyl)-N-methyl-carbamate tert-butyl ester (4.06 g, 23.19 mmol) in THF (30 mL), and the reaction was stirred at 25 °C for 12 h under N2. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC-2 to give the title compound (2.11 g, 25.9%) as a yellow oil.

[0439] Preparation of 382-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0440]

[0441] PPh3 (630 mg, 2.4 mmol) was added to a mixture of 2-(hydroxymethyl)azacyclobutane-1-carboxylic acid 2-tert-butyl ester (300 mg, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (315 mg, 1.6 mmol) in THF (20 mL). The mixture was stirred at 0 °C and DIAD (0.3 mL) was added. The reaction was stirred overnight at rt and concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 3) to give the title compound (300 mg, 52% yield). LCMS m / z = 364 [M+H] + .

[0442] Preparation 39 :(1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-2-yl)tert-butyl carbamate

[0443]

[0444] A mixture of 4-bromo-1H-pyrazole (2.5 g, 17.0 mmol), 2,2-dioxide of 4,4-dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester (4.69 g, 18.7 mmol), and Cs₂CO₃ (8.35 g, 25.5 mmol) in anhydrous DMF (50 mL) was stirred overnight at 80 °C. The cooled mixture was partitioned between water and EtOAc, the layers were separated, and the organic phase was concentrated under vacuum. 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] +

[0445] Preparation of 40 (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-2-yl)(methyl)carbamate tert-butyl ester

[0446]

[0447] NaH (578 mg, 14.4 mmol) was added to an ice-cooled mixture of (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-2-yl)carbamate (Preparation 39, 2.3 g, 7.23 mmol) in anhydrous THF (50 mL), 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 rt for 2 h. The mixture was diluted with EtOAc, washed with water, and the organic layer was concentrated under vacuum. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 10) to give the title compound (1.7 g, 71% yield). LCMS m / z = 332 [M+H] + .

[0448] Preparation 41 : Methyl(2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-2-yl)tert-butyl carbamate

[0449]

[0450] A mixture of (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-2-yl)(methyl)carbamate tert-butyl ester (preparation 40, 1.7 g, 5.14 mmol), bis(pinacol)diboron (1.96 g, 7.71 mmol), KOAc (1.51 g, 15.4 mmol), and Pd(dppf)Cl2 (200 mg, 2.6 mmol) in dioxane (20 mL) was stirred at 100 °C under N2 for 16 h. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 10) to give the title compound (600 mg, 30% yield). LCMS m / z = 380 [M+H] + .

[0451] Preparation 42 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0452]

[0453] 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-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-2-ol (891 mg, 3.35 mmol), Pd(dppf)Cl2 (204 mg, 0.279 mmol), and K2CO3 (770 mg, 5.58 mmol) in dioxane (12 mL) and H2O (3 mL) was stirred at 90 °C under N2 for 4 h. The cooled mixture was concentrated under vacuum to give a 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] + .

[0454] Preparation of 43 1-(4-(6-chloro-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0455]

[0456] 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-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-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 under vacuum, and the residue was purified by silica gel column chromatography 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] + .

[0457] Preparation of 44 2-Chloro-4-isopropoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine

[0458]

[0459] 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-dioxoboropentane-2-yl)-1H-pyrazole (79.73 mg, 0.383 mmol), Pd(dppf)Cl2 (35.05 mg, 0.048 mmol), and K2CO3 (132.40 mg, 0.958 mmol) in dioxane (2 mL) and H2O (0.10 mL) was degassed and purged with N2, 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.

[0460] Alternative Synthesis:

[0461] A mixture of NaH (60%, 53 mg, 1.32 mmol) and IPA (5 mL) was stirred at 0 °C for 2 h, followed by the addition of 2-chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (preparation 97, 70 mg, 0.33 mmol). The mixture was stirred at rt for 2 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with EtOAc / PE = 1 / 2 to give the title compound as a white solid (60 mg, 72% yield). LCMS m / z = 252 [M+H] + .

[0462] Preparation of 45 1-(4-(6-chloro-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0463]

[0464] 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-dioxoboropentan-2-yl)-1H-pyrazol-1-yl)propane-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 under vacuum, and the residue was purified by silica gel column chromatography (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] + .

[0465] Preparation of 46 1-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0466]

[0467] 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-dioxoboropentan-2-yl)-1H-pyrazol-1-yl)propane-2-ol (1.28 g, 4.8 mmol), Pd(dppf)Cl2 (150 mg, 0.2 mmol), and K2CO3 (1.1 g, 8 mmol) in dioxane (20 mL) and H2O (3 mL) was stirred at 90 °C under N2 for 4 h. The cooled mixture was concentrated to give a 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] + .

[0468] Preparation 47 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0469]

[0470] 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-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-2-ol (105 mg, 0.39 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and K2CO3 (45 mg, 0.66 mmol) in dioxane / water (10 mL / 1 mL) was stirred at 70 °C under N2 for 16 h. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography to give the title compound (50 mg, 47%). LCMS m / z = 318 [M+H] + .

[0471] Preparation of 48 2-Chloro-4-isopropoxy-5-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)pyridine

[0472]

[0473] A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (preparation 21, 300 mg, 1.19 mmol), 1-(oxecyclobutan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazole (355 mg, 1.42 mmol), Pd(dppf)Cl2 (174 mg, 0.238 mmol), and K2CO3 (492 mg, 3.56 mmol) in dioxane / H2O (15 mL / 5 mL) was stirred at 100 °C for 4 h. The reaction mixture was diluted with water, extracted with DCM (200 mL x 3), the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (PE / EtOAc = 2 / 1) to give the title compound (140 mg, 40.1%) as a white solid. LCMS m / z = 294[M+H] + .

[0474] Preparation 49 2-Chloro-4-isopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine

[0475]

[0476] Following a similar procedure to that described in Preparation 48, 100 mg of the title compound as a white solid was obtained from 2-chloro-5-iodo-4-isopropoxypyridine (Preparation 26), in 32% yield. LCMS m / z = 308 [M+H] +

[0477] Preparation of 50 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0478]

[0479] Following the procedure described in Preparation 48, 210 mg of the title compound was obtained from 2-chloro-4-(difluoromethoxy)-5-iodopyridine (Preparation 29) and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester, in 77% yield. LCMS m / z = 415 [M+H] + .

[0480] Preparation of 51 to 74

[0481] A mixture of appropriate chloropyridine (1.0 equivalent) and alkylation (4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (1 to 1.2 equivalent), K₂CO₃ (2.0 to 3.0 equivalent), and Pd(dppf)Cl₂ (0.03 to 0.2 equivalent) in dioxane / water (10 / 1 to 3 / 1 V / V) was stirred between 70°C and 100°C until the starting material was consumed. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (eluting with PE / EtOAc or MeOH / DCM) to obtain the desired compound.

[0482]

[0483]

[0484]

[0485]

[0486]

[0487]

[0488] A Cs2CO3 is used to replace K2CO3

[0489] Preparation of 75 2-Chloro-4-methoxy-5-(1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-1H-pyrazol-4-yl)pyridine

[0490]

[0491] A mixture of 1-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (348 mg, 1.079 mmol), 5-bromo-2-chloro-4-methoxypyridine (preparation 20, 200 mg, 0.899 mmol), and PdCl2(dppf):DCM (73.4 mg, 0.090 mmol) was purged with N2. 2M Na2CO3 aqueous solution (1.349 mL, 2.70 mmol) and dioxane (3.60 mL) were added, and the reaction was carried out overnight at 90 °C with stirring under N2. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (0-70% EtOAc in hexane) to give the title compound (256 mg, 84.2%) as a light brown glassy substance. LCMS m / z = 338[M+H] +

[0492] Preparation of 76 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0493]

[0494] A mixture of tert-butyl 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylate (preparation 38, 400 mg, 1.10 mmol), 5-bromo-2-chloro-4-methoxypyridine (preparation 20, 244 mg, 1.10 mmol), Pd(dppf)Cl2 (34 mg, 0.0465 mmol), and TEA (260 mg, 2.57 mmol) in dioxane (6 mL) and H2O (1.5 mL) was stirred at 80 °C for 2 h. The cooled mixture was concentrated under vacuum, 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] + .

[0495] Preparation of 77 2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate

[0496]

[0497] Following the procedure described in Preparation 76, 180 mg of the title compound, 50%, was obtained from 5-bromo-2-chloro-4-methoxypyridine (Preparation 20) and (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate, as a yellow solid. LCMS m / z = 353 [M+H] +

[0498] Preparation of 78 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0499]

[0500] Following the procedure described in Preparation 76, 120 mg of the title compound as a white solid was obtained from 5-bromo-2-chloro-4-cyclopropoxypyridine (Preparation 27) and 2-((4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 38), in 43% yield. LCMS m / z = 405 [M+H] +

[0501] Preparation 79 :(2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate tert-butyl

[0502]

[0503] Pd(amphos)Cl2 (14.64 mg, 0.0207 mmol) and KOAc (40.59 mg, 0.413 mmol) were added to a solution of 5-bromo-2-chloro-4-methoxypyridine (preparation 20, 46 mg, 0.207 mmol), methyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)ethyl)carbamate (preparation 37, 79.89 mg, 0.227 mmol) in EtOH (3 mL) and H2O (0.20 mL), and the reaction was stirred at 80 °C under N2 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.

[0504] Preparation of 80 to 86

[0505] The compounds in the table below are prepared from appropriate pyrazolpinaol esters and bromopyridine following a procedure similar to that described in Preparation 79.

[0506]

[0507]

[0508] Preparation of 87 3-(4-(6-chloro-4-(oxetane-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0509]

[0510] Xphos Pd G2 (148.73 mg, 0.189 mmol) and K3PO4 (802.51 mg, 3.78 mmol) were added to a solution of 5-bromo-2-chloro-4-(oxetane-3-yloxy)pyridine (preparation 28, 500 mg, 1.89 mmol) and 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboron-2-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (990.25 mg, 2.84 mmol) in dioxane (5 mL) and H2O (0.50 mL), and the reaction was stirred at 80 °C under N2 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.

[0511] Preparation of 88 :(1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl)tert-butyl carbamate

[0512]

[0513] A mixture of tert-butyl (1-(4-bromo-1H-pyrazol-1-yl)-2-methylpropane-2-yl)carbamate (preparation 39,543 mg, 1.706 mmol), bis(pinacol)diborone (520 mg, 2.048 mmol), Pd(dppf)Cl2: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. The reaction was cooled to rt, and then more bis(pinacol)diborone (200 mg, 0.787 mmol) was added. The reaction mixture was stirred at 90 °C for another 2 h. 5-Bromo-2-chloro-4-methoxypyridine (preparation 20,380 mg, 1.706 mmol) and 2M Na2CO3 aqueous solution (2.56 mL, 5.12 mmol) were added. The reaction mixture was stirred overnight at 90 °C, then concentrated under vacuum onto silica gel and purified by silica gel chromatography (0-100% EtAOc in hexane) to give the title compound (135 mg, 20.8% yield). LCMS m / z = 381 [M+H] +

[0514] Preparation of 89 :N-(2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoroethane-1-amine

[0515]

[0516] To a solution of (2-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate (preparation 77, 180 mg, 0.510 mmol) in dioxane (5 mL), HCl / dioxane (5 mL) was added and the reaction was stirred at rt 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 rt for 5 min. Na(CN)BH3 (5.0 equivalent) was added and the reaction was stirred at rt for 16 h. The solution was quenched with H2O, extracted with DCM, and the combined organic layers were concentrated under vacuum and purified by preparative HPLC-3 to give the title compound (25 mg, 11%) as a colorless oil. LCMS m / z = 335[M+H] + .

[0517] Preparation of 90 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-N-methylpropane-2-amine

[0518]

[0519] Following a procedure similar to that described in Preparation 89, 200 mg of the title compound, a yellow solid (64%), was obtained from 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one (Preparation 52) and methylamine. LCMS m / z = 281 [M+H] +

[0520] Preparation of 91 2-Chloro-4-(difluoromethoxy)-5-(1-(1-methylpyrrolidone-3-yl)-1H-pyrazole-4-yl)pyridine

[0521]

[0522] TFA (274 mg, 2.4 mmol) was added to a solution of tert-butyl 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylate (preparation 50, 200 mg, 0.482 mmol) in DCM, and the reaction was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum and purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give 2-chloro-4-(difluoromethoxy)-5-(1-(pyrrolidine-3-yl)-1H-pyrazole-4-yl)pyridinetrifluoroacetate.

[0523] Formaldehyde (95 mg, 3.2 mmol) and AcOH (2 drops) were added to a solution of 2-chloro-4-(difluoromethoxy)-5-(1-(pyrrolidin-3-yl)-1H-pyrazole-4-yl)pyridine trifluoroacetate (200 mg) in MeOH (4 mL), and the solution was stirred for 10 min. Na(CN)BH3 (201 mg, 3.2 mmol) was added, and the reaction was stirred at rt for 16 h. The reaction was quenched with 1 M HCl, concentrated under vacuum, and the residue was purified by silica gel column chromatography (MeOH / DCM = 5%) to give the title compound (130 mg, 62%). LCMS m / z = 329 [M+H] + .

[0524] Preparation of 92 2-Chloro-4-methoxy-5-(1-(1-methylpyrrolidone-3-yl)-1H-pyrazole-4-yl)pyridine

[0525]

[0526] Following a similar procedure to that described in Preparation 91, the title compound (120 mg, 64%) was obtained as a colorless oil from tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (Preparation 55). LCMS m / z = 293 [M+H] + .

[0527] Preparation of 93: 5-(1-(azacyclobutane-2-ylmethyl)-1H-pyrazol-4-yl)-2-chloro-4-methoxypyridine

[0528]

[0529] TFA (1 mL) was added to a solution of tert-butyl 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylate (preparation 76, 280 mg, 0.739 mmol) in DCM (2 mL), and the reaction was stirred at rt for 12 h. The mixture was concentrated under vacuum and purified by preparative HPLC-3 to give the title compound (160 mg, 78%) as a white solid. LCMS m / z = 279 [M+H] +

[0530] Preparation of 94 and 95 (R)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine and (S)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine

[0531]

[0532] At rest, HCHO (5.0 equivalents) and AcOH (0.2 mL) were added to a solution of 5-(1-(1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)-2-chloro-4-methoxypyridine (preparation 93, 160 mg, 0.574 mmol) in MeOH (5 mL) and DCM (5 mL), and the solution was stirred for 5 min. Na(CN)BH3 (5.0 equivalents) was added, and the reaction was stirred at rest for 16 h. The solution was quenched with H2O, the mixture was extracted with DCM, and the combined organic layers were concentrated under vacuum. The residue was purified by preparative HPLC-3 to give 2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine (80 mg, 48%) as a colorless oil. LCMS m / z = 293 [M+H] + .

[0533] The compound was further purified by SFC using an IG 20 x 250 mm, 10 μm (Daicel) column with a mobile phase of CO2 / MeOH (0.2% MeOH / NH3) = 50 / 50 at a flow rate of 100 g / min to obtain the desired product.

[0534] First eluted enantiomeric form 1 (Preparation 94): (S)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine or (R)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine, 30 mg

[0535] Second eluted enantiomeric form 2 (Preparation 95): (R)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine or (S)-2-chloro-4-methoxy-5-(1-((1-methylazacyclobutane-2-yl)methyl)-1H-pyrazol-4-yl)pyridine, 30 mg.

[0536] Preparation of 96 2-Chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine

[0537]

[0538] A mixture of 2-chloro-4-fluoropyridine (10 g, 76.0 mmol), bis(pinacol)diboron (9.64 g, 38.0 mmol), [Ir(OMe)(1,5-cod)]2 (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 under vacuum, and the residue was purified by silica gel column chromatography 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] + .

[0539] Preparation of 97 2-Chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine

[0540]

[0541] A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-2-yl)pyridine (preparation 96, 15 g, 58.36 mmol), 4-bromo-1-methyl-1H-pyrazole (9.4 g, 58.36 mmol), K₂CO₃ (16.1 g, 116.73 mmol), and Pd(dppf)Cl₂ (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 under vacuum, and the residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 2) to give the title compound (5 g, 41% yield) as a brown solid. 1 H-NMR (400MHz, DMSO-d6) δppm 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).

[0542] Preparation of 98 2-Chloro-4-ethoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine

[0543]

[0544] 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 h. The cooled mixture was concentrated under vacuum and purified by silica gel column chromatography to give the title compound (900 mg, 80%). LCMS m / z = 238 [M+H] +

[0545] Preparation of 99 2-Chloro-4-cyclopropoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridine

[0546]

[0547] 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 Cs₂CO₃ (308 mg, 0.95 mmol) in MeCN (15 mL) was stirred at 80 °C for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 2) to give the title compound (70 mg, 59% yield). LCMS m / z = 250 [M+H] + .

[0548] Prepare 100 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0549]

[0550] A mixture of 5-bromo-4-(trifluoromethoxy)pyridine-2-amine (preparation 32, 100 mg, 0.39 mmol), 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-pyrazol-1-yl)propane-2-ol (155 mg, 0.58 mmol), Pd(dppf)Cl2 (20 mg, 0.027 mmol), and K2CO3 (108 mg, 0.78 mmol) in dioxane / water (10 mL / 1 mL) was stirred at 100 °C under N2 for 16 h. The cooled mixture was concentrated under vacuum, 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] + .

[0551] Preparation of 101 to 105

[0552] The compounds in the table below were prepared from 5-bromo-4-(trifluoromethoxy)pyridine-2-amine (Preparation 32) and appropriate pyrazole pinacol esters, following a procedure similar to that described in Preparation 100.

[0553]

[0554] Preparation of 106 5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridine-2-amine

[0555]

[0556] A mixture of 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one (preparation 105, 140 mg, 0.46 mmol) and MeNH2 (1 mL, 2 M THF) in DCM (10 mL) was stirred at rt for 0.5 h. Na(CN)BH3 (58 mg, 0.92 mmol) was added and the reaction was stirred at rt for 16 h. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography eluting with MeOH / DCM (1 / 10) to give the title compound (110 mg, 75% yield). LCMS m / z = 316 [M+H] + .

[0557] Preparation of 107 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-ol

[0558]

[0559] At 0 °C, NaBH4 (69.9 mg, 1.85 mmol) was added to a solution of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one (preparation 72, 140 mg, 0.464 mmol) in THF, and the reaction was stirred at rt for 1 h. The reaction mixture was diluted with water and extracted with EtOAc (100 mL x 3). The organic phase was washed with brine, dried over anhydrous Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 5%) to give the title compound (45 mg, 32%) as a white solid. LCMS m / z = 304 [M+H] + .

[0560] Preparation of 1081-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0561]

[0562] A mixture of 1-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-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 anhydrous dioxane (10 mL) was stirred at 100 °C under N₂ for 16 h. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography to give the title compound (180 mg, 77%). LCMS m / z = 610 [M+H] + .

[0563] Preparation of 109 to 113

[0564] Following a procedure similar to that described in Preparation 108, the compounds in the table below were prepared from 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin-4-amine (Preparation 3) and a suitable pyridine-2-amine.

[0565]

[0566]

[0567] Preparation of 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-methylpropane-2-ol

[0568]

[0569] A mixture of 1-(4-(6-chloro-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (preparation 45,800 mg, 2.59 mmol), (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine (preparation 13,800 mg, 2.59 mmol), BrettPhos Pd G4 (397 mg, 0.26 mmol), and Cs₂CO₃ (2.54 g, 7.77 mmol) in dioxane (20 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (EtOAc / MeOH = 10 / 1 to 3 / 1) to give the title compound as a yellow solid (840 mg, 56% yield). LCMS m / z = 580 [M+H] + .

[0570] 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-methylpropane-2-ol

[0571]

[0572] A mixture of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (preparation 47, 50 mg, 0.16 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (preparation 5, 54 mg, 0.17 mmol), BrettPhos Pd G4 (10 mg, 0.0109 mmol), and Cs₂CO₃ (104 mg, 0.32 mmol) in anhydrous dioxane (4 mL) was stirred at 100 °C under N₂ for 16 h. The cooled mixture was concentrated under vacuum, and the crude product was purified by silica gel chromatography to give the title compound (50 mg, 52%). LCMS m / z = 592 [M+H] + .

[0573] Preparation of 116 :(1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl)tert-butyl carbamate

[0574]

[0575] A mixture of (1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl) tert-butyl carbamate (preparation 88, 135 mg, 0.354 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (preparation 5, 110 mg, 0.354 mmol), BrettPhos Pd G4 (32.7 mg, 0.035 mmol), and Cs2CO3 (346 mg, 1.063 mmol) in dioxane (2 mL) was purged with N2 and the reaction was stirred overnight at 80 °C. Additional BrettPhos Pd G4 (12 mg, 0.013 mmol) and Cs2CO3 (115 mg, 0.353 mmol) were added and the reaction was stirred again at 100 °C for 10 h. The cooled mixture was concentrated onto silica gel and purified by silica gel chromatography (0-100% EtOAc in hexane) to give the title compound (178 mg, 77%). LCMS m / z = 655 [M+H] +

[0576] Preparation of 117 (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[0577]

[0578] A mixture of 2-chloro-4-isopropoxy-5-(1-(oxetane-3-yl)-1H-pyrazol-4-yl)pyridine (preparation 48, 100 mg, 0.340 mmol), (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-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 under vacuum, and the residue was purified by silica gel column chromatography (MeOH / DCM = 0 to 10%) to give the title compound as a white solid (80 mg, 42% yield). LCMS m / z = 564 [M+H] + .

[0579] Preparation of 118 to 137

[0580] A mixture of appropriate chloropyridine (1 equivalent), appropriate protected pyrimidine-4,6-diamine (1.2 equivalent), BrettPhos Pd G4 (0.03 to 0.2 equivalents), and Cs₂CO₃ (2-3 equivalents) in dioxane was stirred between 70 and 100 °C until the starting material was consumed. The cooled mixture was concentrated under vacuum. The crude product was purified by silica gel column chromatography using a suitable solvent system (e.g., MeOH / DCM or PE / EtOAc) to obtain the desired compound.

[0581]

[0582]

[0583]

[0584]

[0585]

[0586] A -K2CO3 is used to replace Cs2CO3

[0587] Preparation of 138 :1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one

[0588]

[0589] A mixture of 1-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one (preparation 72, 140 mg, 0.46 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidin-4,6-diamine (preparation 5, 143 mg, 0.28 mmol), BrettPhos Pd G4 (10 mg, 0.011 mmol), and Cs₂CO₃ (300 mg, 0.92 mmol) in dioxane (5 mL) was stirred at 100 °C under N₂ for 16 h. The cooled mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with MeOH / DCM (100%–10%) to give the title compound (110 mg, 41% yield). LCMS m / z = 576 [M+H] + .

[0590] Preparation of 1391-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0591]

[0592] A mixture of 1-(4-(6-chloro-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (preparation 43,400 mg, 1.40 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidin-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 under vacuum, and the residue was purified by silica gel column chromatography eluted with MeOH / DCM (1 / 20) to give the title compound (300 mg, 38%) as a white solid. LCMS m / z = 559 [M+H] + .

[0593] Preparation of 140 and 141 (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-carboxylic acid tert-butyl ester and (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-carboxylic acid tert-butyl ester

[0594]

[0595] A mixture of tert-butyl 3-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylate (66, 180 mg, 0.44 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (5, 137 mg, 0.44 mmol), Cs₂CO₃ (290 mg, 0.89 mmol), and BrettPhos Pd G₄ (40 mg, 0.043 mmol) in dioxane (4 mL) was stirred at 100 °C under N₂ for 16 h. The cooled reaction mixture was concentrated under vacuum, and the residue was purified by preparative HPLC-3. The product was further purified by SFC using an AD 20x250mm, 10μm (Daicel) column with a mobile phase of 100g / min: CO2 / MEOH (1% MeOH / NH3) = 50 / 50 to obtain:

[0596] First eluted enantiomeric form 1: (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-carboxylic acid tert-butyl ester or (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-carboxylic acid tert-butyl ester (Preparation 140), (20 mg, 7% yield) as a white solid. LCMS m / z = 679 [M+H] + and

[0597] Second eluted enantiomeric form 2: (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-carboxylic acid tert-butyl ester or (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-carboxylic acid tert-butyl ester (Preparation 141), (20 mg, 7% yield) as a white solid. LCMS m / z = 679 [M+H] + .

[0598] Preparation of 142 and 143(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)azacyclobutane-1-carboxylic acid tert-butyl ester and (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)azacyclobutane-1-carboxylic acid tert-butyl ester

[0599]

[0600] A mixture of tert-butyl 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylate (preparation 78, 100 mg, 0.246 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidin-4,6-diamine (preparation 5, 76.0 mg, 0.245 mmol), K2CO3 (67.7 mg, 0.491 mmol), and BrettPhos Pd G4 (20 mg) in dioxane (4 mL) was stirred at 100 °C under N2 for 16 h. The cooled reaction mixture was concentrated under vacuum. The residue was purified by preparative HPLC-3. The product was further purified by chiral-SFC using an AD 20x 250 mm, 10 μm (Daicel) column with a mobile phase of 100 g / min: CO2 / EtOH (1% MeOH / NH3) = 50 / 50 to obtain:

[0601] First eluted enantiomeric form 1: (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)azacyclobutane-1-carboxylic acid tert-butyl ester or (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)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 142) (12 mg, 7% yield) is a white solid. LCMS m / z = 679 [M+H] + and

[0602] Second eluted enantiomeric form 2: (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)azacyclobutane-1-carboxylic acid tert-butyl ester or (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)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 143) (12 mg, 7% yield) is a white solid. LCMS m / z = 679 [M+H] + .

[0603] Preparation of 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

[0604]

[0605] A mixture of 2-chloro-4-isopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine (49, 100 mg, 0.325 mmol), (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine (13, 120 mg, 0.390 mmol), BrettPhos Pd G4 (0.2 equivalents), and Cs2CO3 (212 mg, 0.650 mmol) in dioxane was stirred overnight at 100 °C. The cooled solution was concentrated under vacuum, and the residue was purified by silica gel column chromatography (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] +

[0606] It was further separated by preparative SFC using an AD 20x 250 mm, 10 μm (Daicel) column and a mobile phase of 100 g / min: CO2 / EtOH (0.2% MeOH / NH3) = 55 / 45 to obtain:

[0607] First eluted diastereomer 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)pyrimidin-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)pyrimidin-4,6-diamine (Preparation 144), 16 mg and

[0608] Second eluted diastereomer 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.

[0609] Preparation of 146 1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol

[0610]

[0611] A mixture of 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (preparation 42,560 mg, 1.99 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (preparation 5,679 mg, 2.19 mmol), Pd(t-Bu3P)2 (200 mg, 0.392 mmol), and Cs2CO3 (1.29 g, 3.98 mmol) in dioxane (12 mL) was stirred at 100 °C under N2 for 16 h. The mixture was then poured into water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum, 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] + .

[0612] Preparation of 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-methylpropane-2-ol

[0613]

[0614] A mixture of 1-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (preparation 46,900 mg, 2.93 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (preparation 5,1 g, 3.22 mmol), Pd(t-Bu3P)2 (300 mg, 0.586 mmol), and Cs2CO3 (1.9 g, 5.86 mmol) in dioxane (20 mL) was stirred at 100 °C under N2 for 16 h. The cooled mixture was poured into water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were concentrated under vacuum, 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] + .

[0615] Preparation of 148 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[0616]

[0617] Following a procedure similar to that described in Preparation 147, 80 mg of the title compound was obtained from 2-chloro-4-((1-fluoropropane-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), in 44% yield. LCMS m / z = 544 [M+H] +

[0618] Preparation of 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

[0619]

[0620] Following a procedure similar to that described in Preparation 147, the title compound was prepared 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), yielding 80 mg in 29% yield. LCMS m / z = 668 [M+H] +

[0621] Prepare 150 N4-(4-(difluoromethoxy)-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidin-4,6-diamine

[0622]

[0623] Following a procedure similar to that described in Preparation 106, the title compound was prepared from 1-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-1H-pyrazol-1-yl)propane-2-one (Preparation 138) and MeNH2, yielding 80 mg in 71% yield. LCMS m / z = 591 [M+H] + .

[0624] Preparation of 1511-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)propane-2-ol

[0625]

[0626] 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)propane-2-one (preparation 121, 100 mg, 0.185 mmol) in MeOH (5 mL), NaBH4 (21.0 mg, 0.56 mmol) was added and the reaction was stirred at rt for 2 h. The mixture was concentrated under vacuum 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] + .

[0627] Preparation 152 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(1-(2-(dimethylamino)propyl)-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)pyrimidin-4,6-diamine

[0628]

[0629] 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)propane-2-one (preparation 121, 100 mg, 0.185 mmol) in DCM / MeOH (1 / 1, 5 mL), dimethylamine in THF (2 mL, 2N) and AcOH (5 drops) were added, 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 rt for 16 h. The solution was concentrated under vacuum, 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] + .

[0630] Preparation 153 N4-(4-cyclopropoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidin-4,6-diamine

[0631]

[0632] Following a procedure similar to that described in Preparation 106, 50 mg of 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)propane-2-one (Preparation 130) and MeNH2, in 61% yield. LCMS m / z = 581 [M+H] + .

[0633] Preparation of 154 3-(4-(6-((6-amino-2-(fluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0634]

[0635] BrettPhos Pd, G4 (12.62 mg, 0.0137 mmol) and Cs2CO3 (89.31 mg, 0.274 mmol) were added to a solution of 2-(fluoromethyl)pyrimidin-4,6-diamine (preparation 18, 15.58 mg, 0.11 mmol), 3-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylic acid tert-butyl ester (preparation 83, 50 mg, 0.137 mmol) in dioxane (2 mL), and the reaction was stirred at 90 °C under N2 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.

[0636] Preparation 155 to 160

[0637] The compounds in the table below were prepared from 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) and appropriate chloropyridine, following a procedure similar to that described in Preparation 154.

[0638]

[0639]

[0640] Preparation of 161 and 162(S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester and (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester

[0641]

[0642] 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)pyrimidin-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 (100 mg, 47%) as a white solid. LCMS m / z = 503 [M+H] +

[0643] It was further purified by chiral SFC using an AD 20x 250 mm, 10 μm (Daicel) column with a mobile phase of 80 g / min: CO2MeOH (0.2% MeOH / NH3) = 60 / 40 to obtain:

[0644] First eluted enantiomeric form 1: (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester or (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation 161) and

[0645] Second eluted enantiomeric form 2: (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester or (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester (Preparation 162).

[0646] Preparation of 163 and 164 (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester and (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester

[0647]

[0648] Following the procedures described in Preparations 161 and 162, 2-(difluoromethyl)pyrimidin-4,6-diamine (Preparation 8) and 2-((4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 76) were prepared as a white solid to obtain 80 mg of 2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester, 40%. It was further purified by SFC using an AY20 x 250 mm, 10 μm (Daicel) column with a mobile phase of CO2 / EtOH (0.5% MeOH / NH3) = 65 / 35 and a flow rate of 80 g / min to obtain:

[0649] First eluted enantiomeric form 1: (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester or (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 163).

[0650] Second eluted enantiomeric form 2: (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester or (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)methyl)azacyclobutane-1-carboxylic acid tert-butyl ester (Preparation 164).

[0651] Preparation of 165 3-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl) tert-butyl aziridine-1-carboxylate

[0652]

[0653] Under N2, tert-butyl 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate (1.5 g, 7.13 mmol) and 5-bromo-2-chloro-4-fluoropyridine (4.32 g, 12.8 mmol) were added to dioxane (30 mL), and Na2CO3 (3.78 g, 35.64 mmol), H2O (5 mL), and Pd(PPh3)4 (4.12 g, 3.56 mmol) were added, and the mixture was stirred at 100 °C for 16 h. The reaction was diluted with EtOAc (50 mL) and extracted with H2O (3 x 20 mL). The combined organic matter was washed with H2O (3 x 10 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was analyzed by column chromatography (…). Purified with 0-25% EtOAc / PE to give the title compound (1.6 g, 57%) as a yellow oil.

[0654] Preparation of 166 2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate

[0655]

[0656] The title compound was prepared from tert-butyl (2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-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. 1H 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)

[0657] Preparation of 167 :(2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate tert-butyl ester

[0658]

[0659] (2-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate (Preparation 166, 1.0 g, 2.93 mmol) was dissolved in THF (10.0 mL), and then NaH (176.0 mg, 4.40 mmol, 60.0% purity) and MeI (625.0 mg, 4.40 mmol) were added under N2 at 0 °C, and the reaction was stirred at 25 °C for 2 h. The reaction mixture was washed with H2O (5 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was analyzed by silica gel column chromatography (…). Purification with 0–20% EtOAc / PE yielded the title compound as a white solid (0.86 g, 74.3% yield).

[0660] Preparation of 168 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl) tert-butyl aziridine-1-carboxylate

[0661]

[0662] Under N2, tert-butyl 3-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate (preparation 165, 1.6 g, 4.08 mmol) and 2-(difluoromethyl)pyrimidin-4,6-diamine (preparation 8, 726 mg, 4.08 mmol) in t-AmOH (30 mL) were added to a solution 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 H2O (10 mL x 3). The combined organic matter was dried (Na2SO4) and evaporated to dryness under vacuum. The residue was analyzed by silica gel chromatography. Purified with 0-75% EtOAc / PE to give the title compound (800 mg, 41%) as a yellow solid.

[0663] Preparation of 169 :(2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)tert-butyl carbamate

[0664]

[0665] The title compound (380 mg, 40%) was prepared as a white solid from (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) 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), 7.5 7-7.48(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).

[0666] Preparation of 170 :(2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate tert-butyl

[0667]

[0668] Using a method similar to that described in Preparation 168, the title compound (860 mg, 42.7%) was prepared as a yellow solid from (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).

[0669] 1H NMR (400MHz, DMSO-d6) δppm 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)

[0670] Preparation of 171 2-(difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[0671]

[0672] Under N2, Cs2CO3 (8.78 g, 26.93 mmol) and BrettPhos Pd G3 (407 mg, 0.449 mmol) were added 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)pyrimidin-4,6-diamine (preparation 8, 1.73 g, 10.77 mmol) in t-AmOH (40 mL), 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 H2O (30 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were washed with H2O (3 x 20 mL), dried (Na2SO4), and evaporated to dryness under vacuum to give the title compound (1.7 g, 54%) as a brown solid. LCMS m / z = 336[M+H] + .

[0673] Preparation of 172 methyl (4,6-dichloropyrimidin-2-yl)acetate

[0674]

[0675] 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 rt for 1 h. The mixture was concentrated under vacuum, the residue was diluted with dioxane / H₂O (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 under vacuum, 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] + .

[0676] Preparation of 173 (4,6-bis((diphenylmethylene)amino)pyrimidin-2-yl)methanol

[0677]

[0678] A mixture of (4,6-dichloropyrimidin-2-yl)methyl acetate (preparation 172,700 mg, 3.16 mmol), diphenylmethaneimine (1.14 g, 6.32 mmol), Cs₂CO₃ (2.05 g, 6.32 mmol), Pd₂(dba)₃ (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 under vacuum, 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] + .

[0679] Preparation of 174 (4,6-Diaminopyrimidin-2-yl)methanol

[0680]

[0681] 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 rt for 4 h. The mixture was concentrated under vacuum, and the residue was treated with NH3 in MeOH to adjust the pH to approximately 10. The resulting mixture was evaporated to dryness under vacuum, 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] + .

[0682] Preparation of 175 6-Chloro-4-fluoronicotinic acid

[0683]

[0684] At 0 °C and under N2, i-PrMgCl (2.00 M, 136 mL) was added to a solution of 2-chloro-4-fluoro-5-iodopyridine (70.0 g, 272 mmol) in THF (700 mL). After 1 h at 0 °C, the reaction mixture was stirred at 0 °C under CO2 for 30 min. The reaction mixture was poured into H2O (1 L) and washed with EtOAc (2 x 500 mL). The combined aqueous phases were then adjusted to pH 1–2 with 1 N HCl (600 mL) and extracted with EtOAc (3 x 400 mL). The combined organic matter was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (25.5 g, 52%) as a yellow solid. LCMS m / z = 176 [M+H] + .

[0685] Preparation of 176 6-Chloro-4-fluoro-N-methylnicotinamide

[0686]

[0687] T3P (83.23 g, 130.79 mmol, 50% purity) and DIPEA (16.9 g, 130.79 mmol) were slowly added 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), and the mixture was stirred at 25 °C for 16 h. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic matter was washed with brine (100 mL), dried (MgSO4), and evaporated to dryness under vacuum to give the title compound (8.7 g, 71%) as a yellow solid, which was used without further purification. 1 H NMR(400MHz, DMSO-d6)δ:8.63(d,1H)8.54(br s,1H)7.77(d,1H)2.79(d,3H)

[0688] Preparation of 177 4,6-Dichloro-N-methylnicotinamide

[0689]

[0690] One drop of DMF was added to a mixture of 4,6-dichloronicotinic acid (10 g, 52 mmol) and SOCl2 (50 mL), and the mixture was stirred at 70 °C for 2 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was diluted with THF (50 mL) and added to a solution of MeNH2·HCl (4.21 g, 62.4 mmol) and DIPEA (20.1 g, 156 mmol) in THF (50 mL). The resulting mixture was stirred at rt for 16 h. The reaction was quenched with H2O and extracted with EtOAc. The combined organic matter was washed with H2O and brine, dried (Na2SO4), and evaporated to dryness under vacuum. 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] + .

[0691] Preparation of 178 4,6-Dichloro-N-cyclopropylnicotinamide

[0692]

[0693] A mixture of 4,6-dichloronicotinic acid (1 g, 5.2 mmol), cyclopropylamine (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 rt under N2 for 12 h. The mixture was concentrated under vacuum, 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] + .

[0694] Preparation of 179 6-(4,6-Dichloronicotinamide)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0695]

[0696] 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 rt under N2 for 12 h. The reaction mixture was evaporated to dryness under vacuum, 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] + .

[0697] Preparation of 180 6-Chloro-N-methyl-4-(methylamino)nicotinamide

[0698]

[0699] MeNH2 from 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 rt for 2 h. The mixture was evaporated to dryness under vacuum 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] + .

[0700] Preparation of 181 6-Chloro-4-(isopropylamino)-N-methylnicotinamide

[0701]

[0702] 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 overnight at 70 °C. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel chromatography to give the title compound (450 mg, 41%). LCMS m / z = 228 [M+H] + .

[0703] Preparation of 182 6-Chloro-N-cyclopropyl-4-(methylamino)nicotinamide

[0704]

[0705] A solution of 4,6-dichloro-N-cyclopropylnicotinamide (preparation 178, 800 mg, 3.5 mmol), methylamine (323 mg, 10.4 mmol), and DIPEA (1.3 g, 10.4 mmol) in MeCN (20 mL) was stirred at rt under N2 for 16 h. The reaction mixture was evaporated to dryness under vacuum, 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] + .

[0706] Preparation of 1836-(6-chloro-4-(ethylamino)nicotinamide)-2-azaspiro[3.3]heptane-2-carboxylic acid tert-butyl ester

[0707]

[0708] The title compound was prepared from tert-butyl 6-(4,6-dichloronicotinamide)-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] + .

[0709] Preparation of 184 6-Chloro-4-(ethylamino)-N-methylnicotinamide

[0710]

[0711] DIPEA (359 mg, 2.78 mmol) was added 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), and the mixture was heated at 100 °C for 1 h. The reaction mixture was evaporated to dryness, diluted with H₂O, and extracted with EtOAc (3 x 10 mL). The combined organic matter was dried (Na₂SO₄) and evaporated to dryness under vacuum to give the title compound (150 mg) as a yellow solid. LCMS m / z = 214 [M+H] + .

[0712] Preparation of 185 6-Chloro-N-cyclopropyl-4-(ethylamino)nicotinamide

[0713]

[0714] DIPEA (738 mg, 5.71 mmol) was added to a mixture of ethylamine hydrochloride (186 mg, 2.28 mmol) and 4,6-dichloro-N-cyclopropylnicotinamide (preparation 178 mg, 440 mg, 1.90 mmol) in n-BuOH (4 mL), 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, which was purified by preparative HPLC-6 to give the title compound (100 mg, 22%) as a gray gel. LCMS m / z = 240 [M+H] + .

[0715] Preparation of 186 (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)-N-methylnicotinamide

[0716]

[0717] A mixture of 4,6-dichloro-N-methylnicotinamide (preparation 177, 200 mg, 0.975 mmol), (2S)-1-fluoropropane-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 H₂O and extracted into EtOAc. The combined organic matter was washed (with H₂O and brine), dried (with Na₂SO₄), and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography (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] + .

[0718] Preparation of 187 6-Chloro-4-((1,3-difluoropropane-2-yl)amino)-N-methylnicotinamide

[0719]

[0720] The title compound was prepared from 4,6-dichloro-N-methylnicotinamide (Preparation 177) and 1,3-difluoropropane-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 as a white solid (60 mg, 18%). LCMS m / z = 264 [M+H] + .

[0721] Preparation of 188 (R)-6-chloro-4-((1,1-difluoropropane-2-yl)amino)-N-methylnicotinamide

[0722]

[0723] A mixture of (R)-1,1-difluoropropane-2-amine (120 mg, 1.26 mmol), 4,6-dichloro-N-methylnicotinamide (preparative 177, 258 mg, 1.26 mmol), and DIPEA (489 mg, 3.78 mmol) in dioxane (5 mL) was stirred at 140 °C for 16 h. The reaction mixture was evaporated to dryness under vacuum, 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] + .

[0724] Preparation of 189 to 198

[0725] The title compound was prepared from a suitable chloropyridine (RCl) and amine (RNH2) using a method similar to that described in Preparation 188.

[0726]

[0727]

[0728]

[0729]

[0730] Preparation of 199 (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)-N-(pyridin-2-ylmethyl)nicotinamide

[0731]

[0732] Part 1: A mixture of 4,6-dichloropyridin-3-carboxylic acid (500 mg, 2.60 mmol) and oxaloyl chloride (659 mg, 5.20 mmol) in THF (10 mL) was stirred at rt for 2 h. The mixture was concentrated under vacuum, and the residue was dissolved in THF (10 mL) with the addition of DIPEA (1006 mg, 7.80 mmol) and 1-(pyridin-2-yl)methylamine (421 mg, 3.90 mmol), and the resulting mixture was stirred at rt for 2 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by column chromatography (SiO2, 25% EtOAc / PE) to give 4,6-dichloro-N-(pyridin-2-ylmethyl)nicotinamide (470 mg, 63%) as a white solid.

[0733] Part 2: A mixture of 4,6-dichloro-N-(pyridin-2-ylmethyl)nicotinamide (200 mg, 0.708 mmol), (2S)-1-fluoropropane-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 h. The cooled mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 3) to give the title compound (180 mg, 79% yield) as a white solid. LCMS mz = 323 [M+H] + .

[0734] Preparation of 200 6-Chloro-4-(ethylamino)-N-(oxazol-4-ylmethyl)nicotinamide

[0735]

[0736] Using a method similar to that described in Part 199, 4,6-dichloro-N-(oxazol-4-yl)methylamine hydrochloride and 4,6-dichloropyridine-3-carboxylic acid, 300 mg of 4,6-dichloro-N-(oxazol-4-ylmethyl)nicotinamide, 67%, was prepared as a yellow solid.

[0737] A mixture of 4,6-dichloro-N-(oxazol-4-ylmethyl)nicotinamide (300 mg, 1.10 mmol), ethylamine (74.3 mg, 1.65 mmol), and DIPEA (650 mg, 3.3 mmol) in MeCN (10 mL) was stirred at rt for 16 h. The mixture was purified by silica gel column chromatography eluting with EtOAc / PE (1 / 3) to give the title compound (200 mg, 65%) as a white solid. LCMS m / z = 281 [M+H] + .

[0738] Preparation of 201 6-Chloro-4-(isopropylamino)nicotinic acid

[0739]

[0740] A mixture of 6-chloro-4-fluoronicotinic acid (preparation 175, 1 g, 5.70 mmol), propane-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 silica gel column chromatography (10:1 DCM / MeOH) to give the title compound (980 mg, 80%). LCMS m / z = 215 [M+H] + .

[0741] Preparation of 202 6-Chloro-4-(ethylamino)nicotinic acid

[0742]

[0743] A mixture of methyl 6-chloro-4-(ethylamino)nicotinic acid (600 mg, 2.79 mmol) and NaOH (6 mL, 2 M 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 off to give the title compound (500 mg, yield: 89%). LCMS m / z = 201 [M+H] + .

[0744] Preparation of 203 6-Chloro-4-(cyclopropylamino)nicotinic acid

[0745]

[0746] A solution of methyl 4,6-dichloronicotinic acid (3.0 g, 14.5 mmol), cyclopropylamine (1.65 g, 29.0 mmol), and DIPEA (5.61 g, 43.5 mmol) in dioxane (30 mL) was stirred at rt under N2 for 16 h. The mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give methyl 6-chloro-4-(cyclopropylamino)nicotinic acid (1.2 g, 36.5%) as a white solid.

[0747] A solution of methyl 6-chloro-4-(cyclopropylamino)nicotinic acid (1.2 g, 5.29 mmol) and LiOH (378 mg, 15.8 mmol) in MeOH (6 mL), H₂O (6 mL), and THF (6 mL) was stirred under nitrogen at rt for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (1.1 g, 98%) as a white solid. LCMS m / z = 213 [M+H] + .

[0748] Preparation of 204 6-Chloro-N-cyclopropyl-4-(cyclopropylamino)nicotinamide

[0749]

[0750] 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 cyclopropylamine (59.9 mg, 1.05 mmol) in DMF (8 mL), and the mixture was stirred at rt under N2 for 16 h. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was concentrated under vacuum, and the residue was purified by silica gel column chromatography (1:1 EtOAc / PE) to give the title compound (110 mg, 62%) as a white solid. LCMS m / z = 252 [M+H] + .

[0751] Preparation 205 to 220

[0752] The title compound is prepared from a suitable carboxylic acid and amine using a method similar to that described in Preparation 204.

[0753]

[0754]

[0755]

[0756]

[0757] A DCM is the reaction solvent.

[0758] B DIPEA is used to replace TEA.

[0759] Preparation of 222 (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)nicotinic acid methyl ester

[0760]

[0761] A mixture of methyl 4,6-dichloropyridine-3-carboxylate (300 mg, 1.45 mmol), (2S)-1-fluoropropane-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 Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 2) to obtain the title compound as a white solid (200 mg, 53% yield). LCMS m / z = 247 [M+H] + .

[0762] Preparation of 223 (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)nicotinic acid

[0763]

[0764] A mixture of (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)nicotinic acid methyl ester (preparation 222, 200 mg, 0.81 mmol), LiOH (57.9 mg, 2.42 mmol), and H₂O (1 mL) in THF (4 mL) was stirred at rt for 16 h. HCl (1 N) was added to adjust the pH to 3, the mixture was diluted with water, and extracted with EtOAc. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated to give the title compound as a white solid (200 mg, 100% yield). LCMS m / z = 233 [M+H] + .

[0765] Preparation of 224(S)-6-chloro-4-((1-fluoropropan-2-yl)amino)-N-(3-(hydroxymethyl)bicyclo[1.1.1]pentan-1-yl)nicotinamide

[0766]

[0767] A mixture of (S)-6-chloro-4-((1-fluoropropane-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 rt for 5 min. (3-Aminobicyclo[1.1.1]pentan-1-yl)methanol (87.3 mg, 0.772 mmol) was added, and the reaction was stirred at rt for 4 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluted with EtOAc / PE (1 / 1) to give the title compound as a white solid (150 mg, 71% yield). LCMS m / z = 328 [M+H] + .

[0768] Preparation of 225 5-Bromo-2-chloro-N-(oxetane-3-yl)pyridine-4-amine

[0769]

[0770] TEA (2.01 g, 19.83 mmol) was added to a mixture of 5-bromo-2,4-dichloropyridine and oxetine-3-amine (580 mg, 7.93 mmol) in DMF (5 mL), and the reaction was heated at 70 °C for 12 h. The mixture was diluted with water H₂O (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic matter was dried (Na₂SO₄) and evaporated to dryness under vacuum. The residue was purified by silica gel column chromatography (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] + .

[0771] Preparation of 226 5-Bromo-2-chloro-N-methylpyridin-4-amine

[0772]

[0773] 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] +

[0774] Preparation of 227 2-Chloro-5-(5-methyl-1,3,4-thiadiazol-2-yl)-N-(oxecyclobutane-3-yl)pyridine-4-amine

[0775]

[0776] Part 1. To a solution of bis(pinacolyl)diboron (925 mg, 3.64 mmol) and 5-bromo-2-chloro-N-(oxetane-3-yl)pyridine-4-amine (preparation 225, 800 mg, 3.04 mmol) in dioxane (5 mL), Pd(dppf)Cl2·DCM (248 mg, 0.304 mmol) and KOAc (596 mg, 6.07 mmol) were added and the reaction was heated at 90 °C under N2 for 2 h. The reaction mixture was evaporated to dryness under vacuum to give 2-chloro-N-(oxetane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)pyridine-4-amine (crude substance) as a yellow oil.

[0777] Part 2. To a solution of 2-chloro-N-(oxetane-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentane-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 H₂O (0.20 mL), Xphos Pd G₂ (207 mg, 0.263 mmol) and K₃PO₄ (1.12 g, 5.25 mmol) were added, and the resulting mixture was heated at 80 °C under N₂ 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] +

[0778] Preparation of 228 2-Chloro-N-methyl-5-(5-methyl-1,3,4-thiadiazol-2-yl)pyridine-4-amine

[0779]

[0780] In addition to using preparative HPLC-3, 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. LCMS m / z = 241 [M+H] +

[0781] Preparation 2292,4-Dichloro-5-((trimethylsilyl)ethynyl)pyridine

[0782]

[0783] 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 under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (800 mg, 90%) as a yellow solid. LCMS m / z = 244 [M+H] +

[0784] Preparation 230 2,4-Dichloro-5-ethynylpyridine

[0785]

[0786] TBAF (2 mL) was added to a solution of 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyridine (prepared at 229, 800 mg, 3.27 mmol) in THF, and the mixture was stirred at rt for 1 h. The solution was diluted with EtOAc (100 mL) and washed with water and brine. The combined organic matter was evaporated to dryness, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (380 mg, 68%) as a yellow solid. LCMS m / z = 172 [M+H] +

[0787] Preparation of 231 2,4-Dichloro-5-(1H-1,2,3-triazol-4-yl)pyridine

[0788]

[0789] CuI (83.8 mg, 0.44 mmol) and TMSN3 (380 mg, 3.3 mmol) were added 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), and the mixture was stirred at 40 °C for 16 h. The reaction was quenched with NH4OH and extracted with EtOAc. The combined organic compounds were concentrated and purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (200 mg, 42%) as a yellow solid. LCMS m / z = 215 [M+H] +

[0790] Preparation of 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

[0791]

[0792] At 0 °C, TBAF (243 mg, 0.93 mmol) and MeI (792 mg, 0.56 mmol) were added 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), and the mixture was stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine and water. The combined organic matter was concentrated and purified by silica gel column chromatography (50% EtOAc / PE) to give 2,4-dichloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (70 mg, 45%) as a yellow solid. LCMS m / z = 229 [M+H] + And 2,4-dichloro-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (40 mg, 28%), a yellow solid. LCMS m / z = 229 [M+H] +

[0793] Preparation of 234 2-Chloro-N-methyl-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-4-amine

[0794]

[0795] A mixture of 2,4-dichloro-5-(1-methyl-1H-1,2,3-triazol-4-yl)pyridine (preparation 232, 70 mg, 0.31 mmol), methylamine (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 silica gel column chromatography (5% MeOH / DCM) to give the title compound (50 mg, 73%) as a white solid. LCMS m / z = 224 [M+H] +

[0796] Preparation of 235 2-Chloro-N-methyl-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridin-4-amine

[0797]

[0798] Following the procedure described in Preparation 234, 30 mg of the title compound as a white solid was obtained from 2,4-dichloro-5-(2-methyl-2H-1,2,3-triazol-4-yl)pyridine (Preparation 233), in 77% yield. LCMS m / z = 224 [M+H] +

[0799] Preparation of 236 2-Chloro-5-iodo-N-methylpyridin-4-amine

[0800]

[0801] Methylamine (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 under rt at N2 for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (240 mg, 81%). LCMS m / z = 269 [M+H] +

[0802] Preparation of 237 2-Chloro-N-methyl-5-(5-methylthiazo-2-yl)pyridin-4-amine

[0803]

[0804] A solution of 2-chloro-5-iodo-N-methylpyridin-4-amine (preparation 236, 120 mg, 0.45 mmol), 5-methyl-2-(tributyltinyl)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 under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (100 mg, 93%). LCMS m / z = 240 [M+H] +

[0805] Preparation of 238 2-(6-chloro-4-fluoropyridin-3-yl)-5-methyl-1,3,4-thiadiazole

[0806]

[0807] Under an inert N2 atmosphere, 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-dioxoboronyl-2-yl)pyridine (340 g, 1.32 mol), Na2CO3 (285.8 g, 2.70 mol), Pd(dppf)Cl2.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 rt and diluted with EtOAc (2 L). The solids were removed by filtration and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography on silica gel (5-50% EtOAc / PE) and the resulting solid was recrystallized from toluene to give the title compound (45 g, 22%) as a yellow solid.

[0808] Preparation 239 2-(bromomethyl)-5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazole

[0809]

[0810] 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 under vacuum, and the residue was purified by silica gel column chromatography (10:1 PE / EtOAc) to give the title compound (50 mg, 18%). LCMS m / z = 308 [M+H] +

[0811] Preparation 240 methyl (5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate

[0812]

[0813] 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 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (10:1 PE / EtOAc) to give the title compound (20 mg, 43%). LCMS m / z = 288 [M+H] +

[0814] Preparation of 241 :(5-(6-chloro-4-(methylamino)pyridin-3-yl)-1,3,4-thiadiazol-2-yl)methanol

[0815]

[0816] A mixture of methyl (5-(6-chloro-4-fluoropyridin-3-yl)-1,3,4-thiadiazol-2-yl)acetate (preparation 240, 20 mg, 0.07 mmol), MeNH2 (0.5 mL, 2 M 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 under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (11 mg, 61%). LCMS m / z = 257 [M+H] +

[0817] 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

[0818]

[0819] 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)-N4-(2,4-dimethoxybenzyl)pyrimidin-4,6-diamine (preparation 5, 14 mg, 0.04 mmol), BrettPhos Pd G4 (2 mg), and Cs₂CO₃ (39 mg, 0.12 mmol) in dioxane (2 mL) was stirred at 100 °C under N₂ for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (1:20 MeOH / DCM) to give the title compound (12 mg, 56%). LCMS m / z = 531 [M+H] + .

[0820] Preparation of 243 to 246

[0821] Using a method similar to that described in Preparation 242, the title compound was prepared from 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) and a suitable chloropyridine (RCl).

[0822]

[0823]

[0824] Preparation of 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

[0825]

[0826] A solution of 6-chloro-N-(cyanomethyl)-4-(methylamino)nicotinamide (preparation 212,195 mg, 0.868 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (preparation 5,296 mg, 0.955 mmol), BrettPhos PdG4 (80 mg, 0.087 mmol), and Cs₂CO₃ (848 mg, 2.60 mmol) in dioxane (4.34 mL) was purged with N₂ for 5 min and then stirred overnight at 100 °C. The reaction mixture was filtered and the filtrate was washed with 10% MeOH in DCM. The combined organic compounds were concentrated and the residue was purified by silica gel reversed-phase chromatography (20–100% MeCN / H₂O (+0.1% TFA)) to give the title compound.

[0827] 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] + .

[0828] 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] + .

[0829] Preparation 249 (R)-6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-methylnicotinamide

[0830]

[0831] A mixture of 6-chloro-4-(isopropylamino)-N-methylnicotinamide (preparation 181, 50 mg, 0.22 mmol), (R)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine (preparation 14, 67.3 mg, 0.22 mmol), BrettPhosPd G4 (40.5 mg, 0.044 mmol), and Cs₂CO₃ (215 mg, 0.659 mmol) in dioxane (2 mL) was stirred at 100 °C under N₂ for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (50 mg, 45%). LCMS m / z = 498 [M+H] + .

[0832] Preparation 250 (R)-6-((6-((2,4-dimethoxybenzyl)amino)-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-(ethylamino)-N-methylnicotinamide

[0833]

[0834] A mixture of 6-chloro-4-(ethylamino)-N-methylnicotinamide (preparation 184, 60 mg, 0.280 mmol), (R)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)pyrimidin-4,6-diamine (preparation 14, 85.7 mg, 0.280 mmol), Cs₂CO₃ (182 mg, 0.560 mmol), and Pd(t-Bu₃P)₂ (71.5 mg, 0.140 mmol) in dioxane (2 mL) was stirred at 100 °C under N₂ for 16 h. The reaction mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography eluting with MeOH / DCM (1 / 20) to give the title compound (60 mg, 44%) as a white solid. LCMS m / z = 484 [M+H] + .

[0835] Preparation of 251 to 254

[0836] The title compound was prepared from a suitable chloropyridine (RCl) and a suitable amine (RNH2) using a method similar to that described in Preparation 250. The alternative catalyst systems used are indicated in the table.

[0837]

[0838]

[0839] Preparation of 255 N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine

[0840]

[0841] A solution of 6-dichloro-2-(difluoromethyl)pyrimidine (preparation 2,330 mg, 1.65 mmol), 2-methylpropane-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 H2O. The combined organic compounds were evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (50% EtOAc / PE) to give the title compound (300 mg, 77%) as a yellow solid. LCMS m / z = 236 [M+H] + .

[0842] Preparation 256 6-((diphenylmethylene)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide

[0843]

[0844] A mixture of 6-chloro-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide (preparation 220, 500 mg, 1.81 mmol), diphenylmethaneimine (360 mg, 1.99 mmol), Pd2(dba)3 (50 mg), XantPhos (50 mg), and Cs2CO3 (1.18 g, 3.62 mmol) in dioxane (100 mL) was stirred at 100 °C for 16 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (20:1 DCM / MeOH) to give the title product (398 mg, 50%). LCMS m / z = 440 [M+H] + .

[0845] Preparation 257 6-Amino-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide

[0846]

[0847] HCl / dioxane (2 mL, 4 M) was added to a solution of 6-((diphenylmethylene)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide (prepared as 256, 398 mg, 0.9 mmol) in DCM (2 mL), and the mixture was stirred at rt for 1 h. The mixture was concentrated under vacuum, and the residue was purified by silica gel column chromatography (10:1 DCM / MeOH) to give the title compound (198 mg, 80%). LCMS m / z = 440 [M+H] + .

[0848] Preparation 2586-((6-(tert-butylamino)-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide

[0849]

[0850] A mixture of 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), Pd2(dba)3 (93.2 mg, 0.102 mmol), XantPhos (58.9 mg, 0.102 mmol), and Cs2CO3 (498 mg, 1.5 mmol) in dioxane (2 mL) was stirred at 100 °C for 12 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (100 mg, 41%) as a yellow solid. LCMS m / z = 475 [M+H] + .

[0851] Preparation 259 6-((6-amino-2-(hydroxymethyl)pyrimidin-4-yl)amino)-4-(isopropylamino)-N-methylnicotinamide

[0852]

[0853] 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), Cs₂CO₃ (278 mg, 0.856 mmol), and BrettPhosPd G₄ (40 mg, 0.043 mmol) in NMP (3 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by preparative HPLC-3 to obtain the title compound (40 mg, 28%) as a white solid. LCMS m / z = 332 [M+H] + .

[0854] Preparation 260 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoro-N-methylnicotinamide

[0855]

[0856] A mixture of 6-chloro-4-fluoro-N-methylnicotinamide (preparation 176, 1.4 g, 7.45 mmol), 2-(difluoromethyl)pyrimidin-4,6-diamine (preparation 8, 4.77 g, 29.8 mmol), Cs₂CO₃ (7.26 g, 22.35 mmol), and BrettPhos Pd G₃ (337.49 mg, 0.373 mmol) in t-AmOH (60 mL) was degassed and purged with N₂ (x 3), and the mixture was stirred at 120 °C under N₂ for 2 h. The reaction mixture was concentrated under reduced pressure and H₂O (30 mL) was added. The mixture was extracted with EtOAc (3 x 30 mL). The resulting solids were removed by filtration, and the filtrate was evaporated to dryness under vacuum to give the title compound (1.5 g, 45%), which was used without further purification. LCMS m / z = 313 [M + H] + .

[0857] Preparation of 261 5-(4,6-dichloropyridin-3-yl)-3-methyl-1,2,4-oxadiazole

[0858]

[0859] Part 1. A mixture of compound 4,6-dichloronicotinamide (2 g, 10 mmol) and 1,1-dimethoxy-N,N-dimethylethane-1-amine (1.67 g, 12 mmol) in DMF (20 mL) was stirred at 70 °C for 2 h. The reaction mixture was diluted with EtOAc and washed with water and brine. The combined organic compounds were evaporated to dryness under vacuum to give (E)-4,6-dichloro-N-(1-(dimethylamino)ethylidene)nicotinamide (2 g), which was not further purified. LCMS m / z = 260 [M+H] + .

[0860] Part 2. A mixture of the compound from Part 1 (2 g, 7.7 mmol), NH₂OH (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 silica gel column chromatography (5:1 PE / EtOAc) to give the title compound (700 mg, 39%). LCMS m / z = 230 [M+H] + .

[0861] Preparation of 262 2-Chloro-N-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-4-amine

[0862]

[0863] A mixture of 5-(4,6-dichloropyridin-3-yl)-3-methyl-1,2,4-oxadiazole (700 mg, 3.0 mmol) and propane-2-amine (360 mg, 6.1 mmol) in EtOH (20 mL) was stirred at 80 °C for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (20:1 DCM / MeOH) to give the title compound (600 mg, 79%). LCMS m / z = 253 [M+H] + .

[0864] Preparation of 263 N2-Benzyl-N4-Isopropyl-5-(3-Methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine

[0865]

[0866] 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 under microwave irradiation for 1 h. The reaction mixture was diluted with EtOAc and washed with brine and water. The organic matter was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (230 mg, 82%) as a yellow solid. LCMS m / z = 324 [M+H] + .

[0867] Preparation of 264 N4-Isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine

[0868]

[0869] TfOH (534 mg, 3.6 mmol) was added 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), and the resulting mixture was stirred at rt for 3 h. The reaction mixture was treated with aqueous NaHCO3 solution to adjust the pH to approximately pH 10. The solution was evaporated under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (110 mg, 67%) as a white solid. LCMS m / z = 234 [M+H] + .

[0870] Preparation of 265N4-(tert-butyl)-2-(difluoromethyl)-N6-(4-(isopropylamino)-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[0871]

[0872] A mixture of N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine (preparation 255, 100 mg, 0.424 mmol), N4-isopropyl-5-(3-methyl-1,2,4-oxadiazol-5-yl)pyridine-2,4-diamine (preparation 264, 98.9 mg, 0.424 mmol), Pd(t-Bu3P)2 (43.3 mg, 0.085 mmol), and Cs2CO3 (414 mg, 1.3 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (5% MeOH / DCM) to give the title compound (80 mg, 44%) as a white solid. LCMS m / z = 433 [M+H] + .

[0873] Preparation of 266 6-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(ethylamino)nicotinamide)-2-azaspiro[3.3]heptan-2-carboxylic acid tert-butyl ester

[0874]

[0875] The title compound was prepared using a method similar to that described in Preparation 265, from tert-butyl 6-(6-chloro-4-(ethylamino)nicotinamide)-2-azaspiro[3.3]heptane-2-carboxylate (Preparation 183) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8). Yield: 120 mg, 45%; LCMS m / z = 519 [M+H] + .

[0876] Preparation of 267 6-Chloro-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinic acid methyl ester

[0877]

[0878] A mixture of methyl 6-chloro-4-fluoropyridine-3-carboxylate (300 mg, 1.58 mmol), (1R,2S)-2-fluorocyclopropane-1-amine hydrochloride (176 mg, 1.58 mmol), and DIPEA (611 mg, 4.74 mmol) in dioxane (10 mL) was stirred at rt for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (1:5 EtOAc / PE) to give the title compound (120 mg, 31%) as a white solid. LCMS m / z = 245 [M+H] + .

[0879] Preparation of 268 6-Chloro-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinic acid methyl ester

[0880]

[0881] The title compound (100 mg, 26%) was prepared as a white solid from methyl 6-chloro-4-fluoropyridine-3-carboxylate and (1S,2R)-2-fluorocyclopropane-1-amine-4-toluenesulfonate using a method similar to that described in preparation 267. LCMS m / z = 245 [M+H] + .

[0882] Preparation 269 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)methyl nicotinate

[0883]

[0884] The title compound (60 mg, 28%) was prepared as a white solid from methyl 6-chloro-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinic acid (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. LCMS m / z = 519 [M+H] + .

[0885] Preparation 270 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)methyl nicotinate

[0886]

[0887] The title compound (60 mg, 28%) was prepared as a white solid from methyl 6-chloro-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinic acid (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. LCMS m / z = 519 [M+H] + .

[0888] Preparation 271 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-N-methylnicotinamide

[0889]

[0890] Methyl 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1R,2S)-2-fluorocyclopropyl)amino)nicotinic acid (60 mg, 0.115 mmol) in MeNH2 (30% of MeOH, 5 mL) was stirred at 70 °C in a sealed container for 16 h. The mixture was concentrated under vacuum to give the title compound (60 mg, 100%) as a white solid. LCMS m / z = 518 [M+H] + .

[0891] Preparation 272 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-N-methylnicotinamide

[0892]

[0893] The title compound (60 mg, 100%) was prepared as a white solid from methyl 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4-(((1S,2R)-2-fluorocyclopropyl)amino)nicotinic acid (Preparation 270) using a method similar to that described in Preparation 271. LCMS m / z = 518 [M+H] + .

[0894] Preparation of 273 N-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoro-N-methylethane-1-amine

[0895]

[0896] A mixture of 2-(4-bromo-1H-pyrazol-1-yl)-N-methylethane-1-amine hydrochloride (1 g, 4.16 mmol), triethylamine (2.318 mL, 16.63 mmol), and 2,2,2-trifluoroethyltrifluoromethanesulfonate (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 and washed with water and brine, dried (Na₂SO₄), and concentrated under vacuum. The resulting residue was purified by silica gel chromatography (0–100% EtOAc / hexane) to give the title compound (888 mg, 74.7%) as a colorless oil. LCMS m / z = 286.0 [M+H] + .

[0897] Preparation of 274 2,2,2-Trifluoro-N-methyl-N-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)ethyl)ethane-1-amine

[0898]

[0899] A mixture of N-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-2,2,2-trifluoro-N-methylethane-1-amine (preparation 273, 445 mg, 1.555 mmol), bis(pinacol)diboron (474 ​​mg, 1.867 mmol), PdCl2 (dppf), DCM (191 mg, 0.233 mmol), and potassium acetate (458 mg, 4.67 mmol) in 1,4-dioxane (6 mL) was stirred overnight at 90 °C. The crude substance in the solution was used directly without further purification. LCMS m / z = 334.1 [M+H] + .

[0900] Preparation of 275 1-(3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxoboropentan-2-yl)-1H-pyrazole

[0901]

[0902] At 0 °C, a solution of 1.3 M 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 US 2016 / 0256448, 1.8 g, 5.08 mmol) in THF (20.33 mL). After 30 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxoboropentane (1.555 mL, 7.62 mmol) was added dropwise. The reaction mixture was then allowed to warm to rt. After 48 h, the reaction mixture was diluted with 50% saturated ammonium chloride solution (25 mL) and then extracted with EtOAc (50 mL x 2). The combined organic matter was washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0–100% EtOAc / hexane) to give the title compound (635 mg, 35.3%) as a colorless solid. LCMS m / z = 355.0 [M+H] + ; 1H NMR (500MHz, CDCl3) δppm 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).

[0903] Preparation 276 :(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazol-1-yl)propane-2-yl)tert-butyl carbamate

[0904]

[0905] A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxoboronyl-2-yl)-1H-pyrazole (358 mg, 1.845 mmol), 4,4-dimethyl-1,2,3-oxathiazolidin-3-carboxylic acid tert-butyl ester 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 filtrates were concentrated under reduced pressure and purified by silica gel column chromatography (0–100% EtOAc / hexane) to give the title compound (112 mg, 16.6%). LCMS m / z = 366.2 [M+H] + .

[0906] Preparation of the exemplified compounds

[0907] Example 1 :(S)-1-(4-(6-((6-amino-2-(1-fluoroethyl)pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol(167)

[0908]

[0909] TFA (10 mL) was added 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-methylpropane-2-ol (preparation 114,840 mg, 1.45 mmol) in DCM (5 mL), and the reaction was stirred at rt for 4 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC-3 to give the title compound as a white solid (421.1 mg, 67% yield). LCMS m / z = 430 [M+H] + . 1 H-NMR(400MHz,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).

[0910] Example 2 :(S)-2-(1-fluoroethyl)-N4-(4-isopropoxy-5-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine(129)

[0911]

[0912] TFA (5 equivalents) was added to a solution of (S)-N4-(2,4-dimethoxybenzyl)-2-(1-fluoroethyl)-N6-(4-isopropoxy-5-(1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (preparation 117, 80 mg, 0.141 mmol) in DCM (1 mL), and the reaction was stirred at rt for 4 h. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC-3 to give the title compound as a white solid (13.1 mg, 23% yield). LCMS m / z = 414 [M+H] + . 1H-NMR(400MHz,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).

[0913] Example 3 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol(120)

[0914]

[0915] 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-methylpropane-2-ol (preparation 146,480 mg, 0.86 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 2 h. The mixture was concentrated under vacuum and saturated NaHCO3 aqueous solution (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 a 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] + . 1HNMR(500MHz,DMSO-d6)δ9.79(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).

[0916] Example 4 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-cyclopropoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (173)

[0917]

[0918] 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-methylpropane-2-ol (preparation 147,800 mg, 1.37 mmol) in TFA (2 mL) and DCM (2 mL) was stirred at rt for 2 h. The mixture was concentrated under vacuum and saturated aqueous NaHCO3 solution (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 under vacuum. 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(500MHz,DMSO-d6)δ9.84(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).

[0919] Example 5 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(methoxy-d3)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol(126)

[0920]

[0921] 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-methylpropane-2-ol (preparation 139, 300 mg, 0.537 mmol) in DCM (10 mL) and TFA (2.5 mL) was stirred at rt for 16 h. The reaction mixture was concentrated under vacuum, and Na2CO3 (aqueous solution) was added to the residue to adjust the pH to 10. The mixture was filtered, the solid was washed with water and DCM, and dried to give the title compound as a white solid (147.4 mg, yield: 67%). LCMS m / z = 409 [M+H] + . 1 H-NMR(400MHz,DMSO-d6)δ:9.82(s,1H),8.38(s,1H),8.06(s,1H),7.91(s,1H),7.3 7(s,1H),6.96-6.92(m,3H),6.51(t,1H),4.74(br,s,1H),4.04(s,2H),1.08(s,6H).

[0922] Example 6 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (198)

[0923]

[0924] TFA (1 mL) was added 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-methylpropane-2-ol (preparation 108, 180 mg, 0.3 mmol) in DCM (2 mL), and the reaction was stirred at rt for 1 h. The mixture was concentrated under vacuum, and the crude material was purified by preparative HPLC-3 to give the title product (85 mg, 62%). LCMS m / z = 460 [M+H] + . 1 H-NMR(400MHz,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).

[0925] Example 7 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(difluoromethoxy)pyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (181)

[0926]

[0927] 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-methylpropane-2-ol (preparation 115, 50 mg, 0.08 mmol) and TFA (1 mL) in DCM (2 mL) was stirred at rt for 1 h. The mixture was concentrated under vacuum and purified by preparative HPLC-3 to give the title product (26.2 mg, 69%). LCMS m / z = 442 [M+H] + . 1H-NMR(400MHz,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).

[0928] Examples 8 to 38

[0929] Following a procedure similar to that described in Example 7, the following compounds were prepared from suitable protected starting materials (SM) and purified by HPLC-3.

[0930]

[0931]

[0932]

[0933]

[0934]

[0935]

[0936]

[0937]

[0938]

[0939]

[0940]

[0941] 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

[0942]

[0943] TFA (1 mL) was added 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), and the reaction was stirred at rt for 1 h. The mixture was concentrated under vacuum, 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, yield 61%).

[0944] The product was further purified by preparative SFC using an AD-H (250 x 4.6 mm 5 μm) column with a mobile phase of 1.0 mL / min: n-hexane (0.1% diethylamine): EtOH (0.1% diethylamine) = 70:30 to give the first elution (S)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine, (195) (12.8 mg, yield 25%).

[0945] Further elution yielded a second elution of (R)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine, (196) (12.1 mg, yield 24%).

[0946] LCMS m / z=459[M+H]+.

[0947] 1 H-NMR(400MHz,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).

[0948] Examples 41 and 42 (S)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[0949]

[0950] TFA (84 mg, 0.736 mmol) was added to a solution of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine (preparation 148, 80 mg, 0.147 mmol) in DCM, and the solution was stirred overnight at rt. The reaction was concentrated under vacuum, and the crude product was purified by preparative HPLC-3 to give the title product (40 mg) as a white solid. The product was further separated by SFC using an IG 20 x 250 mm, 10 μm (Daicel) column with a mobile phase of CO2 / MeOH (0.2% MeOH / NH3) = 50 / 50 at 100 g / min to obtain:

[0951] First eluted enantiomer 1,(S)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-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]+.

[0952] 1H-NMR(400MHz,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).

[0953] Second eluted enantiomeric form 2: (R)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4-(4-((1-fluoropropane-2-yl)oxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (88) (5.5 mg, 9% yield).

[0954] 1 H-NMR(400MHz,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).

[0955] Examples 43 and 44 (S)-N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidin-4,6-diamine and (R)-N4-(4-cyclopropoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidin-4,6-diamine

[0956]

[0957] 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 (preparative 137, 150 mg, 0.26 mmol) in DCM / TFA (8 mL / 2 mL) was stirred at rt for 4 h. The reaction mixture was concentrated under vacuum. 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] +

[0958] It was further purified by SFC using an OJ 20x 250 mm, 10 μm (Daicel) column, with a mobile phase of 100 g / min: CO2 / MEOH (1% MeOH / NH3) = 50 / 50 to obtain:

[0959] First eluted 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).

[0960] 1H-NMR(400MHz,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

[0961] Second eluted 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).

[0962] 1 H-NMR(400MHz,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).

[0963] Example 45 2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)ethane-1-ol trifluoroacetate (59)

[0964]

[0965] TFA (1 mL, 12.98 mmol) was added 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)pyrimidin-4,6-diamine (preparation 122.68 mg, 0.111 mmol) in DCM (2 mL), and the reaction was stirred at rt for 10 min. The reaction mixture was concentrated under reduced pressure, diluted with DMSO, and purified by reversed-phase chromatography (10-90% MeCN aqueous solution containing 0.01% TFA) to give the title compound as a white solid. LCMS m / z = 378 [M+H] + ;1H NMR (500MHz, DMSO-d6) δ8.44(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).

[0966] Example 46 :2-(difluoromethyl)-N4-(5-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidin-4,6-diamine (95)

[0967]

[0968] To a mixture of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(1-methyl-1H-pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidin-4,6-diamine (preparation 109, 50 mg, 0.09 mmol) in DCM (2 mL), HCl / dioxane (2 mL, 4 M) was added and the reaction was stirred at rt for 1 h. The mixture was concentrated under vacuum and the residue was purified by silica gel column chromatography. 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(400MHz,DMSO-d6)δppm 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).

[0969] Example 47 2-(difluoromethyl)-N4-(4-methoxy-5-(1-(pyrrolidone-3-yl)-1H-pyrazole-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (97)

[0970]

[0971] Following a procedure similar to that described in Example 46, tert-butyl pyrrolidine-1-carboxylate (Preparation 123) of 3-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazole-1-yl)pyrrolidine-1-carboxylate was used to obtain 5.1 mg of the title compound as a white solid in 7% yield. LCMS m / z = 403 [M+H] + .

[0972] 1H-NMR(400MHz,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).

[0973] Example 48:2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-1-ol (122)

[0974]

[0975] Following a procedure similar to that described in Example 46, 41.2 mg of the title compound as a white solid was obtained from 2-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-1-ol (Preparation 124), in 48% yield. LCMS m / z = 406 [M+H] +。

[0976] 1 H-NMR(500MHz,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).

[0977] Example 49 :N4-(5-(1-cyclopropyl-1H-pyrazole-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (154)

[0978]

[0979] Following the procedure described in Example 46, 25.4 mg of the title compound, 54%, was obtained from 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). LCMS m / z = 428 [M+H] +

[0980] 1 H-NMR(400MHz,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).

[0981] Example 50 :N4-(5-(1-(azacyclobutane-3-yl)-1H-pyrazol-4-yl)-4-methoxypyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diaminocarbamate (76)

[0982]

[0983] TFA (1 mL, 13.51 mmol) was added 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)azacyclobutane-1-carboxylate (preparation 156, 50 mg, 0.102 mmol) in DCM (2 mL), 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] +

[0984] 1 H-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).

[0985] Examples 51 to 53

[0986] The compounds in the table below were prepared from suitable Boc-protected compounds following a procedure similar to that described in Example 50.

[0987]

[0988]

[0989] Example 54 2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (80)

[0990]

[0991] TFA (1 mL, 13.51 mmol) was added to a solution of (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), and the reaction 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 5-6 with NH3·H2O to give the title compound (9.80 mg, 24.6%) as a pale yellow solid.

[0992] 1 H-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).

[0993] Example 55 :N4-(5-(1-(azacyclobutane-3-yl)-1H-pyrazol-4-yl)-4-(oxacyclobutane-3-yloxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diaminocarbamate (168)

[0994]

[0995] TFA (0.50 mL, 6.75 mmol) was added to a solution of tert-butyl 3-(4-(6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(oxetane-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)azacyclobutane-1-carboxylate (preparation 159, 62 mg, 0.117 mmol) in DCM (1.0 mL), 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 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] +

[0996] 1H-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).

[0997] Example 56 :2-(difluoromethyl)-N4-(5-(1-(2-(methylamino)ethyl)-1H-pyrazol-4-yl)-4-(oxecyclobutane-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (175)

[0998]

[0999] TFA (1.54 g, 13.51 mmol) was added to a solution of (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(oxetane-3-yloxy)pyridin-3-yl)-1H-pyrazol-1-yl)ethyl)(methyl)carbamate (preparation 160, 26 mg, 0.0488 mmol) in DCM (2 mL). The mixture was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain 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 gray oil. LCMS m / z = 433 [M+H] +

[1000] 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).

[1001] 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)

[1002]

[1003] Following the procedure described in Example 45, 20 mg of the title compound, 43.5%, was obtained from (1-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-yl)carbamate (Preparation 116).

[1004] LCMS m / z = 405.2[M+H] + ;1H NMR(500MHz,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).

[1005] Example 58 : 2-(difluoromethyl)-N4-(5-(1-(1-methylazacyclobutane-3-yl)-1H-pyrazol-4-yl)-4-(oxacyclobutane-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (183)

[1006]

[1007] A solution of N4-(5-(1-(azacyclobutan-3-yl)-1H-pyrazol-4-yl)-4-(oxacyclobutan-3-yloxy)pyridin-2-yl)-2-(difluoromethyl)pyrimidin-4,6-diaminocarbamate (Example 55, 15.0 mg, 0.0315 mmol) in MeOH (2.0 mL) was adjusted to pH 5-6 with AcOH (9.00 μL, 0.157 mmol). HCHO (3.07 mg, 0.0378 mmol) was added and the mixture was stirred at 25 °C for 1 h. Na(CN)BH3 (2.97 mg, 0.047 mmol) was added and the reaction was stirred at 25 °C for 1 h. 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 gray oil. LCMS m / z = 445 [M+H] +

[1008] 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).

[1009] Example 59 2-(difluoromethyl)-N4-(4-isopropoxy-5-(1-isopropyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (56)

[1010]

[1011] BrettPhos Pd, G4 (14.63 mg, 0.0159 mmol) and Cs₂CO₃ (103.55 mg, 0.318 mmol) were added to a solution of 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (preparation 7, 17.81 mg, 0.111 mmol) in dioxane (3 mL), and the reaction was stirred at 90 °C under N₂ 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] +

[1012] 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).

[1013] Example 60 :N4-(5-(1-cyclopropyl-1H-pyrazole-4-yl)-4-methoxypyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (52)

[1014]

[1015] Following a procedure similar to that described in Example 59, the title compound (10.50 mg, 19.2%) was obtained as a brown gel from 2-chloro-5-(1-cyclopropyl-1H-pyrazol-4-yl)-4-methoxypyridine (Preparation 81) and 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7). LCMS m / z = 373 [M+H] +

[1016] 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).

[1017] Example 61 2-(difluoromethyl)-N4-(4-methoxy-5-(1-(oxecyclobutane-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (78)

[1018]

[1019] Following a procedure similar to that described in Example 59, 4.3 mg of the title compound, 8.17%, was obtained from 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) and 2-chloro-4-methoxy-5-(1-(oxecyclobutan-3-yl)-1H-pyrazol-4-yl)pyridine (Preparation 82). LCMS m / z = 390 [M+H] +

[1020] 1 H-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(br d,3H),6.64-6.31(m,1H),5.59(quin,1H),4.90(d,4H),3.86(s,3H).

[1021] Examples 62 to 72

[1022] BrettPhos Pd, G4 (0.02-0.2 equivalents) and Cs₂CO₃ (2.0-3.0 equivalents) were added to a mixture of a suitable 2-chloropyridine starting material (SM) and 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (preparation 7, 1-1.5 equivalents) in dioxane, and the reaction was heated at 90-100 °C until the starting material was consumed under N₂. 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.

[1023]

[1024]

[1025]

[1026]

[1027] A - The crude residue was further purified by silica gel chromatography before HPLC.

[1028] B -K2CO3 is used to replace Cs2CO3

[1029] Examples 73 and 74 (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[1030]

[1031] A mixture of 2-chloro-4-methoxy-5-(1-(tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyridine (preparation dose 54, 160 mg, 0.572 mmol), 2-(difluoromethyl)pyrimidin-4,6-diamine (preparation dose 8, 91.5 mg, 0.572 mmol), BrettPhos-Pd G4 (20 mg, 0.0217 mmol), and Cs2CO3 (230 mg, 0.708 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated under vacuum, 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)pyrimidin-4,6-diamine (80 mg, 35%) as a white solid. LCMS m / z = 404[M+H] + .

[1032] It was further purified by SFC using an OZ 20*250mm, 10μm (Daicel) column and a mobile phase of 100g / min: CO2 / MeOH (0.2% MeOH / NH3) = 65 / 35 to obtain:

[1033] First eluted 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.

[1034] 1H-NMR(500MHz,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).

[1035] Second eluted 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.

[1036] 1H-NMR(500MHz,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).

[1037] Examples 75 and 76 (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine and (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(1-(2-(methylamino)propyl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine

[1038]

[1039] Following the procedures described in Examples 73 and 74, the title compound was obtained from 1-(4-(6-chloro-4-methoxypyridin-3-yl)-1H-pyrazol-1-yl)-N-methylpropane-2-amine (Preparation 90) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8).

[1040] LCMS m / z = 405[M+H] + .

[1041] The compound was further purified by SFC using an OZ 20 x 250 mm, 10 μm (Daicel) column and a mobile phase of 100 g / min: CO2 / MeOH (0.2% MeOH / NH3) = 65 / 35 to obtain:

[1042] First eluted 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.

[1043] 1H-NMR(500MHz,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,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).

[1044] Second eluted enantiomeric form 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

[1045] 1 H-NMR(500MHz,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).

[1046] Example 77 :N4-(4-(difluoromethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (69)

[1047]

[1048] A mixture of 2-chloro-4-(difluoromethoxy)-5-(1-methyl-1H-pyrazol-4-yl)pyridine (preparation 67, 50 mg, 0.218 mmol), 2-(difluoromethyl)pyrimidin-4,6-diamine (preparation 8), Pd(t-Bu3P)2 (20 mg, 0.050 mmol), and Cs2CO3 (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 the title compound as a white oil, 18.1 mg, 20.8%. LCMS m / z = 399 [M+H]+.

[1049] 1 H NMR(400MHz,DMSO-d6)δ10.06(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)

[1050] Examples 78 to 86

[1051] The compounds in the table below were prepared using a procedure similar to that described in Example 45, and using a procedure similar to that described in Preparations 122 and 75.

[1052]

[1053]

[1054]

[1055] Examples 87-89

[1056] The title compound was prepared using the following scheme and the two-part chemical schemes using appropriate fluoropyridine (RF) and EtOH as outlined in the table.

[1057]

[1058] Part 1. Add EtOH (0.33 mmol, 1.5 equivalent) and t-BuOK (73.9 mg, 0.66 mmol, 3 equivalent) to a mixture of appropriate fluoride (RF, 0.22 mmol, 1 equivalent) in THF (1 mL) and stir the mixture at 100 °C under microwave irradiation for 4 h. Quench the reaction with H2O (3.0 mL) and extract with EtOAc (3 x 10 mL). The combined organic matter was evaporated to dryness by Speedvac and the residue was used in Part 2 without further purification.

[1059] Part 2. The solution of the compound from Part 1 (crude substance, 0.22 mmol, 1 equivalent) in DCM (3 mL) and TFA (1 mL) was stirred at 30 °C for 2 h. Volatile substances were removed by Speedvac and the residue was purified by preparative HPLC-4 to obtain the title compound.

[1060]

[1061]

[1062] Examples 90-93

[1063] The title compound was prepared using a three-part chemical scheme as outlined below.

[1064]

[1065] 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)azacyclobutane-1-carboxylate (preparation 168, 283.3 mg, 0.5 mmol, 1 equivalent) in DCM (3 mL) and TFA (1 mL) was stirred at 30 °C for 2 h. The solvent was evaporated by Speedvac to give N4-(5-(1-(azacyclobutane-3-yl)-1H-pyrazol-4-yl)-4-fluoropyridin-2-yl)-2-(difluoromethyl)pyrimidin-4,6-diamine, which was used in Part 2 without further purification.

[1066] Part 2. A solution of N4-(5-(1-(azacyclobutan-3-yl)-1H-pyrazol-4-yl)-4-fluoropyridin-2-yl)-2-(difluoromethyl)pyrimidin-4,6-diamine (Part 1, 188 mg, 0.5 mmol, 1 equivalent) and CH3CO2H (150 mg, 2.5 mmol, 5 equivalents) and HCHO (48.6 mg, 0.6 mmol, 1.2 equivalents, 37% purity) in MeOH (5 mL) was stirred at 30 °C for 1 h. NaBH3CN (47.1 mg, 0.75 mmol, 1.5 equivalents) was added and the mixture was stirred at 30 °C for 1 h. The volatiles were removed in vacuum by Speedvac to obtain 2-(difluoromethyl)-N4-(4-fluoro-5-(1-(1-methylazacyclobutane-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine, which was used in part 3 without further purification.

[1067] Part 3. To a solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(1-(1-methylazacyclobutan-3-yl)-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine (Part 2, 85.9 mg, 0.22 mmol, 1 equivalent) in THF (1 mL), an appropriate alcohol (ROH, 0.33 mmol, 1.5 equivalent) and t-BuOK (73.9 mg, 0.66 mmol, 3 equivalent) were added, and the mixture was heated at 100 °C for 4 h under microwave irradiation. The reaction mixture was evaporated to dryness by Speedvac, and the residue was purified by preparative HPLC-4 to give the title compound.

[1068]

[1069]

[1070] Example 94 :1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-ethoxypyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (152)

[1071]

[1072] Part 1. Under a nitrogen atmosphere, Na₂CO₃ (2.6 mL, 15 mmol) and Pd(PPh₃)₄ (86.6 mg, 0.075 mmol) were added 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-dioxoboropentan-2-yl)-1H-pyrazol-1-yl)propane-2-ol (478 mg, 1.8 mmol) in dioxane (10 mL), and the mixture was stirred at 100 °C for 5.5 h. The reaction mixture was diluted with H₂O (5.0 mL) and extracted with EtOAc (3 x 10 mL). The combined organic compounds were evaporated to dryness by Speedvac to give 1-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol, which was used in part 2 without further purification.

[1073] Part 2. Under N2, Cs2CO3 (1.27 g, 3.9 mmol) and Brettphos Pd G3 (59 mg, 0.065 mmol) were added to a solution of 1-(4-(6-chloro-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-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), and the mixture was stirred at 120 °C for 2 h. The reaction mixture was diluted with H2O (5.0 mL) and extracted with EtOAc (3 x 10 mL). The combined organic compounds 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-methylpropane-2-ol, which was used in part 3 without further purification.

[1074] Part 3. EtOH (0.33 mmol) and t-BuOK (73.9 mg, 0.66 mmol) were added to a mixture of 1-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)-1H-pyrazol-1-yl)-2-methylpropane-2-ol (Part 2, 86.5 mg, 0.22 mmol) in THF (1 mL), 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] + .

[1075] Examples 95-96

[1076] The title compound was prepared using the 1-step protocol outlined below.

[1077]

[1078] NaH (61.6 mg, 1.54 mmol, 7 equivalents, 60%) was added to a mixture of a suitable alcohol (ROH, 0.33 mmol, 1.5 equivalents) in DMF (4 mL), 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)pyrimidin-4,6-diamine (Preparation 171, 73.7 mg, 0.22 mmol, 1 equivalent) was added to the mixture, and the reaction was stirred at 100 °C for 3 h. The reaction was quenched with H2O (1.0 mL) and evaporated to dryness using Speedvac. The residue was purified by preparative HPLC-4 to give the title compound.

[1079]

[1080] Example 97 2-(difluoromethyl)-N4-(5-(1-methyl-1H-pyrazol-4-yl)-4-((tetrahydro-2H-pyran-2-yl)methoxy)pyridin-2-yl)pyrimidin-4,6-diamine (172)

[1081]

[1082] A solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine (preparation 171, 73.7 mg, 0.22 mmol) in DMA (4 mL) was mixed with (tetrahydro-2H-pyran-2-yl)methanol (38.3 mg, 0.33 mmol) and t-BuOK (73.9 mg, 0.66 mmol) and stirred at 100 °C for 6 h. 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] + .

[1083] Examples 98-108

[1084] Using a method similar to that described in Example 97, employing the solvents and heating methods mentioned in the table, the title compound was prepared from 2-(difluoromethyl)-N4-(4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidin-4,6-diamine (Preparation 171) and a suitable alcohol (ROH). (Method A = DMA, 100°C, 6 h; Method B = THF, 100°C, microwave, 4 h; Method C = DMA, 100°C, microwave, 4 h). The crude product was purified by preparative HPLC-4.

[1085]

[1086]

[1087]

[1088] 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)cyclobutane-1-ol(107)

[1089]

[1090] Part 1. NaH (60%, 84.0 mg, 2.1 mmol) was added to a solution of (1s,3s)-cyclobutane-1,3-diol (39.6 mg, 0.45 mmol) in THF (4 mL), and the mixture was stirred at 30 °C for 1 h. 2-Chloro-4-fluoro-5-(1-methyl-1H-pyrazol-4-yl)pyridine (preparation 97, 73.7 mg, 0.3 mmol) was added, and the mixture was stirred at 30 °C for 2 h. The reaction was quenched with H₂O (3.0 mL) and extracted with EtOAc (3 x 10 mL). The combined organic compounds were concentrated by Speedvac to give (1s,3s)-3-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutane-1-ol, which was used in Part 2 without further purification.

[1091] Part 2. To a solution of (1s,3s)-3-((2-chloro-5-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutane-1-ol (Part 1, 0.27 mmol) and 2-(difluoromethyl)pyrimidin-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL), Cs₂CO₃ (263.9 g, 0.81 mmol) and Brettphos Pd G₃ (12.24 mg, 0.014 mmol) were added and the mixture was stirred at 120 °C under N₂ for 2 h. The reaction mixture was diluted with H₂O (3.0 mL) and extracted with EtOAc (3 x 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] + .

[1092] Example 110 2-(difluoromethyl)-N4-(4-methoxy-5-(1-methyl-1H-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (16)

[1093]

[1094] A mixture of 1,2-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 mixed with t-BuOK (101 mg, 0.9 mmol) and stirred at 100 °C for 3 h. 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.

[1095] 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)pyrimidin-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL), Cs₂CO₃ (263.9 g, 0.81 mmol) and Brettphos Pd G₃ (12.24 mg, 0.014 mmol) were added and the mixture was stirred at 120 °C under N₂ for 2 h. The reaction mixture was diluted with H₂O (3.0 mL) and extracted with EtOAc (3 x 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]). + .

[1096] Examples 112-123

[1097] The title compound was prepared from a suitable protected starting material (SM) using a method similar to that described in Example 111. Alternative conditions (Method B) used HCl (2N in EtOAc) as mentioned in the table.

[1098]

[1099]

[1100]

[1101]

[1102]

[1103] Example 124 : 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclopropyl-4-(cyclopropylamino)nicotinamide (57)

[1104]

[1105] 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), Pd2(dba)3 (47.2 mg, 0.052 mmol), Xantphos (29.8 mg, 0.52 mmol), and Cs2CO3 (251 mg, 0.774 mmol) in dioxane (10 mL) was stirred at 100 °C under N2 for 16 h. The reaction mixture was evaporated to dryness under vacuum, and the residue was purified by silica gel column chromatography (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(400MHz,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).

[1106] Example 125 :(S)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-((1-fluoropropane-2-yl)amino)-N-methylnicotinamide(48)

[1107]

[1108] (S)-6-chloro-4-((1-fluoropropane-2-yl)amino)-N-methylnicotinamide (prepared at 186, 150 mg, 0.610 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (prepared at 8, 117 mg, 0.731 mmol), Cs₂CO₃ (397 mg, 1.22 mmol), and Pd ( t A mixture of Bu3P)2 (155 mg, 0.305 mmol) in dioxane (4 mL) was stirred at 100 °C under N2 for 16 h. The reaction mixture was purified by silica gel column chromatography (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] + . 1H NMR(400MHz,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).

[1109] Example 126 :(R)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-((1-fluoropropane-2-yl)amino)-N-methylnicotinamide (49)

[1110]

[1111] The preparations included (R)-6-chloro-4-((1-fluoropropane-2-yl)amino)-N-methylnicotinamide (190, 75 mg, 0.305 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (8, 48.8 mg, 0.305 mmol), Cs₂CO₃ (298 mg, 0.92 mmol), and Pd ( t A mixture of Bu3P)2 (31.2 mg, 0.061 mmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 3 h. The reaction mixture was purified by silica gel column chromatography (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(400MHz,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).

[1112] Examples 127-146

[1113] The title compound was prepared from a suitable 2-chloropyridine (RCl) and pyrimidine-4,6-diamine (RNH2) using a method similar to that described in Example 126.

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121] A -0.2 equivalents of Pd₂(dba)₃ + 0.2 equivalents of XantPhos is a catalyst.

[1122] Example 147 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclopropyl-4-(isopropylamino)nicotinamide trifluoroacetate (60)

[1123]

[1124] To a mixture of compound 6-chloro-N-cyclopropyl-4-(isopropylamino)nicotinamide (preparation 217, 20 mg, 0.079 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (preparation 8, 15 mg, 0.094 mmol) in dioxane (1 mL), Cs₂CO₃ (51.4 mg, 0.158 mmol), Brettphos (4.23 mg, 7.88 μmol), and BrettPhos Pd G₄ (7.26 mg, 7.88 μmol) were added, and the mixture was stirred at 80 °C under N₂ for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic matter was dried (Na₂SO₄) and evaporated to dryness under vacuum. The residue was purified by preparative HPLC-10 to give the title compound (20 mg, 52%) as a white solid. LCMS m / z = 378[M+H] + . 1 H NMR(400MHz,MeOH-d4)δ:8.28(s,1H),6.67-6.38(m,1H),6.32(s,1H),6.06(s,1H),3.8 4-3.76(m,,1H),2.86-2.79(m,1H),1.34(d,6H),0.85-0.79(m,2H),0.65-0.60(m,2H).

[1125] Example 1486-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclopropyl-4-(ethylamino)nicotinamide (39)

[1126]

[1127] A mixture of 6-chloro-N-cyclopropyl-4-(ethyl...

Claims

1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein: 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 it is attached, it forms a cyclopropyl group; R 2 Selected from C 1-5 Alkyl, CD3, C 3-6 Cycloalkyl, bicyclo[1.1.1]pentane and 4 to 6 membered heterocycle containing O, wherein the alkyl, cycloalkyl or heterocycle is optionally substituted by 1 to 3 R 4 replace; Each R 4 independently selected from halogen, CH3, C 2-3 Alkenyl, OH, CH2OH, C 4-6 Cycloalkyl, 4 to 6 membered heterocycle containing O and phenyl, wherein the alkyl, cycloalkyl, heterocycle or phenyl is optionally substituted by OH or NH2, C 1-2 Alkyl, CH2NH2 or halogen substituted; R 3 C(O)NHR 5 , X1 is NH or O; X2 is N or CH; X3 is N or CH; R 5 Selected from 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 optionally substituted with 1-2 R 7 replace; Each R 7 independently selected from CN, NH2, OH, CH2OH, cyclopropyl, pyridyl and oxazolyl, or two R attached to the same carbon atom 7 Together they form a 4-membered heterocyclic ring containing N; R 6 Selected from C 1-5 Alkyl, CHF2, CF3, 4- or 5-membered heterocyclic ring containing N or O, and C 3-4 Cycloalkyl, wherein the alkyl or heterocyclic ring is optionally substituted by one R 8 replace; R 8 Selected from OH, NR 9 R 9 , OCH3, CH3 and a 4-membered heterocyclic ring containing N or O, wherein the alkyl or heterocyclic ring is optionally replaced by one R 10 replace; Each R 9 are independently selected from H, CH3 and CH2CF3; and R 10 Selected from CH3 and CF3.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1A Each independently selected from H, halogen and CH3; R 2 Selected from C 1-5 Alkyl, CD3, C 3-6 Cycloalkyl and 4 to 6 membered heterocyclic ring containing O, wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by 1-3 R 4 replace; Each R 4 independently selected from halogen, CH3, OH, C 4-6 Cycloalkyl, 4 to 6 membered heterocyclic ring containing O, and phenyl, wherein the cycloalkyl or phenyl is optionally substituted with OH or NH2; Each R 7 independently selected from CN, OH, CH2OH, cyclopropyl, pyridyl and oxazolyl, or two R attached to the same carbon atom 7 together form a 4-membered heterocyclic ring containing N; and R 10 For CH3.

3. The compound according to claim 1 or 2, wherein the compound is represented by formula (II): or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2, wherein the compound is represented by formula (III): or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3 or 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1A Each independently selected from H, halogen and CH3; R 2 Selected from C 1-5 Alkyl, CD3, C 3-4 Cycloalkyl and 4 to 6 membered heterocyclic ring containing O, wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by 1-3 R 4 replace; Each R 4 independently selected from halogen, CH3 and phenyl; R 5 Selected from 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 optionally substituted with 1-2 R 7 replace; and Each R 7 independently selected from CN, OH, CH2OH, cyclopropyl, pyridyl and oxazolyl, or two R attached to the same carbon atom 7 Together they form a 4-membered heterocyclic ring containing N.

6. The compound according to any one of claims 3 to 5, 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 optionally substituted by 1-3 R 4 replace.

7. The compound according to any one of claims 3 to 5, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 8. The compound of any one of claims 3 to 7, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from F, CH3, cyclobutyl and phenyl.

9. The compound according to any one of claims 3 to 8, 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]pentyl, wherein said CH3, CH2CH3, CH2CH2CH3, CH(CH3)2, cyclobutyl, cyclopropyl or bicyclo[1.1.1]pentyl is optionally substituted by 1-2 R 7 replace.

10. The compound according to any one of claims 3 to 9, or a pharmaceutically acceptable salt thereof, wherein R 5 Selected from 11. The compound according to any one of claims 3 to 10, or a pharmaceutically acceptable salt thereof, wherein each R 7 Independently selected from CN, CH2OH, cyclopropyl, or two R attached to the same carbon atom 7 Together we form 12. The compound according to any one of claims 3 to 11, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, F and CH3.

13. The compound of claim 1 or 2, wherein the compound is represented by formula (IV), (V) or (VI): or a pharmaceutically acceptable salt thereof.

14. The compound of claim 1 or 2, wherein the compound is represented by formula (VII), (VIII), (IX) or (X): or a pharmaceutically acceptable salt thereof.

15. The compound of claim 13 or 14, or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1A Each independently selected from H, halogen and CH3; R 2 Selected from C 1-3 Alkyl, CD3, C 3-4 Cycloalkyl and 4 to 6 membered heterocyclic ring containing one O, wherein the alkyl, cycloalkyl or heterocyclic ring is optionally substituted by 1 to 3 R 4 replace; Each R 4 is independently selected from halogen, OH, cyclopropyl, a 4- to 6-membered heterocycle containing one O, and phenyl, wherein the cyclopropyl or phenyl is optionally substituted with OH or NH2; R 6 Selected from C 1-4 Alkyl, CHF2, CF3, 4- or 5-membered heterocyclic ring containing N or O, and C 3-4 Cycloalkyl, wherein the alkyl, heterocyclic or cycloalkyl is optionally replaced by R 8 replace; R 8 Selected from OH, NR 9 R 9 , OCH3, CH3 and a 4-membered heterocycle containing N or O, wherein the heterocycle is optionally substituted with CH3; and Each R 9 Independently selected from H, CH3 and CH2CF3.

16. The compound of any one of claims 13 to 15, 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 optionally substituted by 1-3 R 4 replace.

17. The compound of any one of claims 13 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 Selected from 18. The compound of any one of claims 13 to 17, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from F, OH, cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranyl and tetrahydropyranyl, wherein the cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with OH or NH2.

19. The compound of any one of claims 13-17, or a pharmaceutically acceptable salt thereof, wherein each R 4 Independently selected from F, OH, Where *― represents OH or NH2.

20. The compound of any one of claims 13 to 19, 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 optionally replaced by R 8 replace.

21. The compound of any one of claims 13 to 19, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from 22. The compound of any one of claims 13 to 21, or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from OH, OCH3, CH3, NH2, NHCH3, N(CH3)2, NHCH2CF3, N(CH3)CH2CF3, azetidinyl, azetidinyl and oxetanyl.

23. The compound of any one of claims 13-21, or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from 24. The compound of any one of claims 13-23, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 1A Each is independently selected from H, F and CH3.

25. The compound of claim 1 or 2, wherein the compound is represented by formula (III) or (VII): or a pharmaceutically acceptable salt thereof, wherein: R 1 and R 1A Each independently selected from H, F and CH3; R 2 Selected from C 1-3 Alkyl, CD3, C 3-4 Cycloalkyl and a 4-membered heterocyclic ring containing O, wherein the alkyl is optionally substituted with 1-3 halo groups; R 5 is selected from CH3, CH2CH3 and cyclopropyl; R 6 Selected from C 1-5 alkyl, CHF2, CF3 and a 4- to 5-membered heterocyclic ring containing O or N, wherein the alkyl or heterocyclic ring is optionally replaced by R 8 replace; R 8 Selected from OH, NR 9 R 9 , OCH3, CH3 and a 4-membered heterocyclic ring containing O or N; and Each R 9 Independently selected from H and CH3.

26. The compound of claim 25, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from CH3, CHF2, CF3, CD3, CH2CH3, CH2CF3, CH2CH2CH3, CH(CH3)2, CH(CH3)CH2F, CH(CH3)CHF2, cyclobutyl, cyclopropyl and 27. The compound of claim 25 or 26, 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 optionally substituted by one R 8 replace.

28. The compound of claim 25 or 26, or a pharmaceutically acceptable salt thereof, wherein R 6 Selected from 29. The compound of at least one of claims 25 to 28, or a pharmaceutically acceptable salt thereof, wherein R 8 Selected from OH, OCH3, NH2, NHCH3, N(CH3)2, CH3, 30. A compound of Table 1, or a pharmaceutically acceptable salt thereof.

31. A pharmaceutical composition comprising a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient.

32. A method for treating a patient with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31.

33. The method of claim 32, wherein the patient has received one or more prior treatments for the GIST.

34. The method of claim 33, wherein the GIST has progressed following prior treatment.

35. The method of claim 34, wherein the prior treatment comprises administration of one or more agents.

36. The method of claim 35, wherein the prior treatment comprises administration of imatinib or a pharmaceutically acceptable salt thereof.

37. The method of claim 35, wherein the prior treatment comprises administration of afatinib or a pharmaceutically acceptable salt thereof.

38. The method of claim 34, wherein the prior treatment comprises administration of one or more agents, each independently selected from the group consisting of imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, flavopiridol, ribociclib, sorafenib, pegidatinib, oclatumomab, clelanib, afatinib, ripretinib, bezulatinib, AZD3229, BLU-263, everolimus, and larotrectinib, and pharmaceutically acceptable salts thereof.

39. The method of any one of claims 32-38, wherein the GIST is characterized by tumors having one or more KIT mutations.

40. The method of claim 39, wherein the tumor has a primary activating KIT mutation.

41. The method of claim 39 or 40, wherein the GIST is characterized by a tumor having one or more KIT mutations, each of which is independently selected from the group consisting of exon 9 KIT mutations, exon 11 KIT mutations, exon 13 KIT mutations, and exon 17 KIT mutations, and combinations thereof.

42. The method of claim 41, wherein 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.

43. The method of claim 41, wherein 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.

44. The method of claim 41, wherein the tumor has an exon 9 KIT mutation.

45. The method of claim 41, wherein the tumor has an exon 11 KIT mutation.

46. ​​The method of claim 41, wherein the tumor has an exon 17 KIT mutation.

47. The method of claim 46, wherein the exon 17 KIT mutation is selected from the group consisting of N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P.

48. The method of claim 46, wherein the exon 17 KIT mutation is selected from the group consisting of N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

49. The method of claim 47 or 48, wherein the exon 17 KIT mutation is D816V.

50. The method of claim 41, wherein the tumor has an exon 13 KIT mutation.

51. The method of claim 50, wherein the exon 13 KIT mutation is selected from K642E, V654A and N655K, and combinations thereof.

52. The method of claim 50, wherein the exon 13 KIT mutation is K642E.

53. The method of claim 46, wherein the exon 17 mutation is A829P.

54. The method of any one of claims 33-53, wherein the tumor has a mutational resistance to the one or more prior treatments.

55. The method of claim 54, wherein the tumor has an imatinib resistance mutation.

56. The method of claim 55, wherein the imatinib resistance mutation is selected from the group consisting of exon 13 KIT mutations, exon 17 KIT mutations, and exon 14 KIT mutations, and combinations thereof.

57. The method of claim 56, wherein the imatinib resistance mutation is an exon 13 KIT mutation.

58. The method of claim 57, wherein the exon 13 KIT mutation is V654A or N655K.

59. The method of claim 56, wherein the imatinib resistance mutation is an exon 17 KIT mutation.

60. The method of claim 59, wherein the exon 17 KIT mutation is selected from the group consisting of N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P.

61. The method of claim 59, wherein the exon 17 KIT mutation is selected from the group consisting of N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, and D823D.

62. The method of claim 60 or 61, wherein the exon 17 KIT mutation is D816V.

63. The method of claim 60 or 61, wherein the exon 17 KIT mutation is D816E.

64. The method of claim 60, wherein the exon 17 KIT mutation is A829P.

65. The method of claim 56, wherein the imatinib resistance mutation is an exon 14 KIT mutation.

66. The method of claim 65, wherein the exon 14 KIT mutation is N680K.

67. The method of claim 54, wherein the tumor has an exon 17 inhibitor resistance mutation.

68. The method of claim 67, wherein the exon 17 inhibitor is selected from afatinib, BLU-263, ripretinib, AZD3229 and bezulatinib and pharmaceutically acceptable salts thereof.

69. The method of claim 68, wherein the exon 17 inhibitor is afatinib or a pharmaceutically acceptable salt thereof.

70. The method of claim 67 or 68, wherein the exon 17 inhibitor resistance mutation is N655K.

71. The method of claim 67 or 68, wherein the exon 17 inhibitor resistance mutation is N680K.

72. A method for 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, comprising administering to the patient an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31.

73. The method of claim 72, wherein the 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, intracranial germ cell tumor, pancreatic cancer and mediastinal B-cell lymphoma.

74. A method of treating a patient suffering from gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective combination comprising: A compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, and At least one additional agent.

75. The method of claim 74, wherein the additional agent is an exon 9 KIT inhibitor or an exon 11 KIT inhibitor.

76. The method of claim 74 or 75, wherein the additional agent is imatinib or a pharmaceutically acceptable salt thereof.

77. The method of claim 74, wherein the additional agent is an exon 17 KIT inhibitor.

78. The method of claim 77, wherein the additional agent is selected from afatinib, BLU-263, ripretinib, AZD3229, and bezulatinib, and pharmaceutically acceptable salts thereof.

79. A method of treating a patient having 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: (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 the mutation is detected, administering to the patient an effective amount of the compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 31.

80. The method of claim 79, comprising (b) detecting the presence or absence of an exon 13 KIT mutation.

81. The method of claim 80, wherein the exon 13 KIT mutation is V654A or N655K.

82. The method of claim 79, comprising (b) detecting the presence or absence of an exon 14 KIT mutation.

83. The method of claim 82, wherein the exon 14 KIT mutation is N680K.

84. 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 administering to the patient an effective amount of a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 31, if an exon 13 KIT mutation or an exon 14 KIT mutation is present.

85. The method of claim 84, wherein the exon 13 KIT mutation is V654A or N655K.

86. The method of claim 84, wherein the exon 14 KIT mutation is N680K.

87. A method of treating a patient with gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound as described in any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 31, wherein the GIST has a mutation that is resistant to a KIT inhibitor administered to treat GIST having a primary activating mutation in exon 9 or exon 11.

88. The method of claim 87, wherein the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flavopiridol, ribociclib, sorafenib, pegidatinib, oclatumomab, clelanib, afatinib, ripretinib, bezulatinib, AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof.

89. The method of claim 87 or 88, wherein the KIT inhibitor is imatinib or a pharmaceutically acceptable salt thereof.

90. The method of any one of claims 87-89, wherein the mutation is an exon 13 KIT mutation.

91. The method of claim 90, wherein the exon 13 KIT mutation is V654A or N655K.

92. A method for treating a patient having a primary gastrointestinal stromal tumor (GIST) characterized by a primary activating mutation in exon 9 or exon 11 KIT, comprising administering to the patient: (i) an effective amount of a compound as described in any one of claims 1-30 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 31; and ii) an effective amount of a KIT inhibitor effective against GIST having a primary activating mutation in exon 9 or exon 11.

93. The method of claim 92, wherein the KIT inhibitor is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, bimetinib, vandetanib, famitinib, anlotinib, axitinib, flavopiridol, ribociclib, sorafenib, pegidatinib, oclatumomab, clelanib, afatinib, ripretinib, bezulatinib, AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof.

94. The method of claim 92 or 93, wherein the KIT inhibitor is imatinib.

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