KIT INHIBITORS

CROSS-REFERENCE TO RELATED APPLICATIONS

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

FIELD

[002] This application is directed to KIT inhibitors and methods for their use, such as to control the activity of mutated forms of the enzyme KIT (also referred to as “CD117”) in a subject.

BACKGROUND

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

[004] The enzyme KIT (also called CD117) is a receptor tyrosine kinase expressed on a wide variety of cell types. The KIT molecule contains a long extracellular domain, a transmembrane segment, and an intracellular portion. The ligand for KIT is stem cell factor (SCF), whose binding to the extracellular domain of KIT induces receptor dimerization, kinase domain activation and activation of downstream signaling pathways. Mutations in KIT are found in over 80% of primary GIST patients, most commonly KIT mutations are found in exon 11 and less commonly in exon 9; these mutations make the KIT enzyme function independent of activation by its ligand, SCF, leading to a high cell division rate and possibly genomic instability (C. R. Antonescu, 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.

[005] GIST patients with primary mutations in exon 9 or 11 of KIT respond well to frontline therapy of imatinib, with an overall response rate of 60%; but after patients progress (or fail after imatinib), the subsequent therapies, including sunitinib, regorafenib and ripretinib, show less robust efficacy and the overall response rate remains below 10% for each of these therapies (Ther. Adv. Med. Oncol. 2021; 13: 1758835920986498).

[006] It has been observed that patients who develop resistance to imatinib often display on- target mutations in KIT, most frequently in exon 17 (at several different amino acids including D816) or in exon 13 (including V654A and N655K). These resistance mutations occur in addition to the primary exon 9 or 11 mutation (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 with small molecules designed to target the exon 17 resistant mutations in KIT, it has been observed that the patients with KIT exon 13, specifically KIT exon 13 V654A, mutations are unlikely to respond to treatment (George, S., Abstract #11511, American Society of Clinical Oncology, June 2018, Chicago, Illinois; Heinrich, M., Abstract #3027631, Connective Tissue Oncology Society, November 2018, Rome, Italy). For transformative therapy for GIST patients, the resistant mutations such as exon 13 mutations within the KIT enzyme must be inhibited.

[007] Current KIT inhibitors are inadequate for treatment of GIST that has become resistant to inhibitors of the primary activating KIT mutations. For example, the current KIT inhibitors fail to sufficiently inhibit the mutation exon 13, e.g., V654A and N655K. As such, there is a need for a small molecule treatment targeting resistant KIT mutations, e.g., exon 13 V654A and/or exon 13 N655K resistant mutations.

SUMMARY

[008] Provided herein are compounds, or pharmaceutically acceptable salts thereof, and compositions which are useful for inhibiting mutant KIT proteins and for treating gastrointestinal stromal tumors (GISTs). For example, the IC50 values for inhibition of autophosphorylation of KIT in Table 1 demonstrate that these compounds are potent inhibitors of mutant KIT.

[009] A first embodiment of the disclosure is a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[010] R ¹ and R ^1A are each independently selected from H, halogen, and CH ₃ , or R ¹ and R ^1A taken together with the carbon to which they are attached form cyclopropyl; [OH] R ² is selected from C _1-5 alkyl, CD ₃ , C _3-6 cycloalkyl, bicyclo[l. l.l]pentane, and 4- to 6- membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R ⁴ ;

[012] each R ⁴ is independently selected from halogen, CH ₃ , C _2-3 alkenyl, OH, CH ₂ OH, C4- ecycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said alkyl, cycloalkyl, heterocycle or phenyl is optionally substituted with OH or NH ₂ , C _1-2 alkyl, CH ₂ NH ₂ , or halogen;

[014] X ₁ is NH or O;

[015] X ₂ is N or CH;

[016] X ₃ is N or CH;

[017] R ⁵ is selected from H, C _1-3 alkyl, CD ₃ , C _3-4 cycloalkyl and bicyclofl.1.1] pentane, wherein said alkyl, cycloalkyl or bicyclo[l. l.l.]pentane is optionally substituted with 1-2 R ⁷ ;

[018] each R ⁷ is independently selected from CN, NH ₂ , OH, CH ₂ OH, cyclopropyl, pyridinyl, and oxazolyl, or taken together two R ⁷ attached to the same carbon atom form 4-membered heterocycle containing N;

[019] R ⁶ is independently selected from C _1-3 alkyl, CHF ₂ , CF ₃ , 4- or 5-membered heterocycle containing N or O, and C _3-4 cycloalkyl, wherein said alkyl or heterocycle is optionally substituted with one R ⁸ ;

[020] R ⁸ is independently selected from OH, NR ⁹ R ⁹ , OCH ₃ , CH ₃ and 4-membered heterocycle containing N or O, wherein said alkyl or heterocycle is optionally substituted with one R ¹⁰ ;

[021] each R ⁹ is independently selected from H, CH ₃ and CH ₂ CF ₃ ; and

[022] R ¹⁰ is selected from CH ₃ and CF ₃ .

[023] Another embodiment of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing). [024] Another embodiment of the disclosure is a method of treating a patient suffering from gastrointestinal stromal tumor (GIST) with an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or with an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing).

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

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

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

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

[029] Another embodiment of the disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor with 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 exon 14 KIT mutation; and (c) administering 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 of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), to the patient, if the mutation is detected.

[030] Another embodiment of the disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor with 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 exon 14 KIT mutation; and (c) administering 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 of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), to the patient, if the mutation is present.

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

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

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

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

DETAILED DESCRIPTION

[035] The disclosed compounds or pharmaceutically acceptable salts thereof are inhibitors of KIT enzymes and are useful for treating a KIT-dependent disorder or disease.

Definitions

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

[037] The term “alkyl” used alone or as part of a larger moiety, such as “alkoxy”, “hydroxyalkyl” and the like, means a saturated aliphatic straight-chain or branched monovalent hydrocarbon radical. Unless otherwise specified, an alkyl group typically has 1 to 6 carbon atoms (Ci-6 alkyl), (i.e., 1, 2, 3, 4, 5 or 6) alternatively, 1 to 3 carbon atoms (C _1-3 alkyl) (i.e., 1, 2 or 3). Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like.

[038] The term “alkenyl” means an aliphatic straight-chain or branched monovalent hydrocarbon radical with one double bond. Unless otherwise specified, an alkenyl group typically has 1 to 6 carbon atoms (C _1-3 alkenyl), alternatively, 1 to 3 carbon atoms (C _1-3 alkenyl). [039] “Cycloalkyl” means a saturated aliphatic cyclic hydrocarbon ring radical. Unless otherwise specified, a cycloalkyl has 3 to 8 ring carbon atoms (C _3-8 cycloalkyl), alternatively, 3 to 6 ring carbon atoms (C _3-6 cycloalkyl), alternatively, 3 to 5 carbon atoms (C _3-5 cycloalkyl). Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

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

[041] The term “heterocycle” refers to a monocyclic non-aromatic ring radical containing unless otherwise specified, 3 to 8 ring atoms (i.e., “3, 4, 5, 6, 7, or 8 membered”) selected from carbon atoms and 1 or 2 heteroatoms. Each heteroatom is independently selected from nitrogen, quaternary nitrogen, oxidized nitrogen (e.g., NO); oxygen; and sulfur, including sulfoxide and sulfone. Representative heterocycles include azetidinyl, morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and the like.

[042] The term “hydroxyl” or “hydroxy” refers to the group OH.

[043] The term “substituted”, whether preceded by the term “optionally” or not, refers to the replacement of a hydrogen substituent in a given structure with a non-hydrogen substituent. Thus, for example, a substituted alkyl is an alkyl wherein at least one non-hydrogen substituent is in the place of a hydrogen substituent on the alkyl group. To illustrate, monofluoroalkyl is an alkyl substituted with a fluoro substituent, and difluoroalkyl is an alkyl substituted with two fluoro substituents. It should be recognized that if there is more than one substitution on a substituent, each non-hydrogen substituent can be identical or different (unless otherwise stated).

[044] If a group is described as “optionally substituted”, the group can be either (1) not substituted or (2) substituted. If a group is described as optionally substituted with up to a particular number of non-hydrogen substituents, that group can be either (1) not substituted; or (2) substituted by up to that particular number of non-hydrogen substituents or by up to the maximum number of substitutable positions on the substituent, whichever is less. Thus, for example, if a group is described as a cycloalkyl optionally substituted with up to 3 non-hydrogen substituents, then any cycloalkyl with less than 3 substitutable positions would be optionally substituted by up to only as many non-hydrogen substituents as the cycloalkyl has substitutable positions.

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

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

[047] “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[048] When two or more stereoisomers are depicted by their chemical names or structures, and the names or structures are connected by an “or”, one or the other of the two or more stereoisomers is intended, but not both. The enrichment of one stereoisomer relative to the other is as indicated above.

[049] When a disclosed compound having a chiral center is depicted by a structure without showing a configuration at that chiral center, the structure is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center, or the compound with a mixture of the R and S configuration at that chiral center. When a disclosed compound having a chiral center is depicted by its chemical name without indicating a configuration at that chiral center with “S” or “R”, the name is meant to encompass the compound with the S configuration at that chiral center, the compound with the R configuration at that chiral center or the compound with a mixture of the R and S configuration at that chiral center.

[050] A racemic mixture means a mixture of 50% of one enantiomer and 50% of its corresponding enantiomer. The present teachings encompass all enantiomerically-pure, enantiomerically-enriched, diastereomerically pure, diastereomerically enriched, and racemic mixtures, and diastereomeric mixtures of the compounds described herein.

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

[052] “Peak 1” or “first eluting isomer” in the Experimental section refers to an intended reaction product compound obtained from a chromatography separation/purification that elutes earlier than a second intended reaction product compound from the same preceding reaction. The second intended product compound is referred to as “peak 2” or “second eluting isomer”.

[053] When a compound is designated by a name or structure that indicates a single enantiomer, unless indicated otherwise, the compound is at least 60%, 70%, 80%, 90%, 99% or 99.9% optically pure (also referred to as “enantiomerically pure”). Optical purity is the weight in the mixture of the named or depicted enantiomer divided by the total weight in the mixture of both enantiomers.

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

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

[056] Pharmaceutically acceptable salts are known in the art. For example, S. M. Berge et al. describes pharmacologically acceptable salts in J. Pharm. Sci. (1977) 66: 1-19. Compounds of this disclosure with basic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable acid(s). Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of this disclosure with acidic groups can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). 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).

[057] A “subject” or “patient” is a mammal in need of medical treatment, preferably a human, but can also be an animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like) and laboratory animals (e.g., rats, mice, guinea pigs, and the like). In one aspect, the patient is a human. In one aspect, the patient is an adult human.

[058] The term “effective amount” means an amount when administered to the subject or patient which results in beneficial or desired results, including clinical results, e.g., inhibits, suppresses or reduces the symptoms of the condition being treated in the subject as compared to a control. For example, a therapeutically effective amount can be given in unit dosage form (e.g., 0.1 mg to about 50 g per day, alternatively from 1 mg to about 5 grams per day. The precise amount of compound or pharmaceutically acceptable salt thereof administered to provide an “effective amount” to the subject will depend on the mode of administration, the type, and severity of the disease or condition, and on the characteristics of the subject, such as general health, age, sex, body weight, and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. When administered in combination with other therapeutic agents, e.g., when administered in combination with an anti -cancer or antiviral agent, an “effective amount” of any additional therapeutic agent(s) will depend on the type of drug used. Suitable dosages are known for approved therapeutic agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the disclosure or a pharmaceutically acceptable salt thereof being used by following, for example, dosages reported in the literature and recommended in the Physician’s Desk Reference (57 ^th ed., 2003).

[059] As used herein, a “malignant disease” refers to a disease in which abnormal cells divide without control and can invade nearby tissues. Malignant cells can also spread to other parts of the body through the blood or lymph system. Examples of malignant diseases are carcinoma, sarcoma, leukemia, and lymphoma. Cancer is a malignant disease. Systemic mastocytosis is a malignant disease. Indolent systemic mastocytosis is a malignant disease.

[060] Examples of cancer include, but are not limited to, gastrointestinal stomal tumor (GIST), AML (acute myeloid leukemia), melanoma, lung cancer, uterine cancer, astrocytoma, liver cancer, seminoma, renal cell carcinoma, intercranial germ cell tumors, pancreatic cancer and mediastinal B-cell lymphoma. [061] As used herein, an “inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that inhibits a protein e.g., an enzyme such that a reduction in activity of the protein can be observed e.g., by biochemical assay. In certain embodiments, an inhibitor has an IC50 of less than ImM, 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.

[062] The term “KIT” refers to a human tyrosine kinase that may be referred to as mast/ stem cell growth factor receptor (SCFR), proto-oncogene c-KIT, tyrosine-protein kinase Kit or CD117.

[063] The term “KIT mutation”, as used herein, refers to a KIT gene, cDNA, mRNA, or protein whose sequence differs from the KIT gene sequence of human reference genome hgl9, or the corresponding cDNA, mRNA, or protein. In some embodiments, when discussing KIT mutations in a nucleotide sequence that encodes a KIT polypeptide, mutations are described in terms of the change that is produced in the sequence of the polypeptide that is encoded by the nucleotide. In some embodiments the KIT mutation is V654A, N655K or K642E in exon 13. As used herein, the term “an exon 9 KIT mutation” refers to a mutation in exon 9 of KIT. As used herein, the term “an exon 11 KIT mutation” refers to a mutation in exon 11 of KIT. As used herein, the term “an exon 13 KIT mutation” refers to a mutation in exon 13 of KIT. As used herein, the term “an exon 17 KIT mutation” refers to a mutation in exon 17 of KIT. As used herein, the term “an exon 18 KIT mutation” refers to a mutation in exon 18 of KIT. A829P is a mutation at the very start of exon 18 KIT but, in some embodiments, A829P is referred to as an “exon 17” KIT mutation. In some embodiments, the KIT mutation isN822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D in exon 17. In some embodiments, the KIT mutation is A829P in exon 18 or in exon 17.

[064] As used herein, a “selective KIT inhibitor” refers to a compound or a pharmaceutically acceptable salt thereof that selectively inhibits KIT protein kinase over another protein kinase and exhibits at least a 2-fold selectivity for a KIT protein kinase over another kinase. For example, a selective KIT inhibitor inhibitor exhibits at least a 10-fold selectivity; at least a 15 -fold selectivity; at least a 20-fold selectivity; at least a 30-fold selectivity; at least a 40-fold selectivity; at least a 50-fold selectivity; at least a 60-fold selectivity; at least a 70-fold selectivity; at least a 80-fold selectivity; at least a 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 a KIT kinase over another kinase. In some embodiments, a selective KIT inhibitor exhibits at least 150-fold selectivity over another kinase, e.g., 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 a KIT kinase over another kinase is measured in a cellular assay (e.g., a cellular assay as provided herein). In other embodiments, selectivity for a KIT kinase or over another kinase is measured in a biochemical assay (e.g., a biochemical assay provided in Evans, et al. (2017)). In some embodiments, a KIT inhibitor is a selective KIT inhibitor. In some embodiments, the selective KIT inhibitor is a compound disclosed herein, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing. In some embodiments, the selective KIT inhibitor is avapritinib. In some embodiments, the selective KIT inhibitor is bezuclastinib. In some embodiments, the selective KIT inhibitor is BLU-263. In some embodiments, a KIT inhibitor is a pan-KIT inhibitor. In one embodiment, a pan-KIT inhibitor is AZD3229.

Compound Embodiments

[065] Example embodiments include:

[066] First embodiment: a compound represented by Formula (I): or a pharmaceutically acceptable salt thereof. The variables in Formula (I) are described in the summary above.

[067] Second embodiment: a compound represented by Formula (I), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ^1A are each independently selected from H, halogen and CEE; R ² is selected from C _1-5 alkyl, CD ₃ , C3-6cycloalkyl and 4- to 6-membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R ⁴ ; each R ⁴ is independently selected from halogen, CEE, OH, NH ₂ , C _4-6 cycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH ₂ ; each R ⁷ is independently selected from CN, OH, CH ₂ OH, cyclopropyl, pyridinyl, and oxazolyl, or taken together two R ⁷ attached to the same carbon atom form 4-membered heterocycle containing N; and R ¹⁰ is CH ₃ . The remainder of the variables in Formula (I) are described above in the first embodiment. In some second embodiments, each R ⁴ is independently selected from halogen, CH ₃ , OH, C _4-6 cycloalkyl, 4- to 6-membered heterocycle containing O, and phenyl, wherein said cycloalkyl or phenyl is optionally substituted with OH or NH ₂ .

[068] Third embodiment: a compound represented by Formula (II): or a pharmaceutically acceptable salt thereof. The variables in Formula (II) are described in the first and/or second embodiment.

[069] Fourth embodiment: a compound represented by Formula (III): or a pharmaceutically acceptable salt thereof. The variables in Formula (III) are described in the first and/or second embodiment.

[070] Fifth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ^1A are each independently selected from H, halogen and CH ₃ ; R ² is selected from C _1-5 alkyl, CD ₃ , C _3-4 cycloalkyl and 4- to 6-membered heterocycle containing O, wherein said alkyl, cycloalkyl or heterocycle is optionally substituted with 1-3 R ⁴ ; each R ⁴ is independently selected from halogen, CH ₃ and phenyl; R ⁵ is selected from H, Ci-3alkyl, CD ₃ , C _3-4 cycloalkyl and bicyclofl.1.1] pentane, wherein said alkyl, cycloalkyl or bicyclofl .1.1 ,]pentane is optionally substituted with 1-2 R ⁷ ; and each R ⁷ is independently selected from CN, OH, CH ₂ OH, cyclopropyl, pyridinyl and oxazolyl, or taken together two R ⁷ attached to the same carbon atom form 4-membered heterocycle containing N. The remainder of the variables in Formula (I) are described above in the first or second embodiment. [071] Sixth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from CH ,, CD ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ )2, CH(CH ₃ )CH ₂ CH ₃ , cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-3 R ⁴ . The remainder of the variables in Formula (I), (II) and (III) are described above in the first, second and/or fifth embodiment.

[072] Seventh embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from:

(III) are described above in the first, second and/or fifth embodiment.

[073] Eighth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R ⁴ is independently selected from F, CH ₃ , cyclobutyl and phenyl. The remainder of the variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth and/or seventh embodiment.

[074] Ninth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from H, CH ₃ , CD ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , cyclobutyl, cyclopropyl and bicylo[l. l.l]pentanyl, wherein said CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , cyclobutyl, cyclopropyl orbicylo[l.l. l]pentanyl are optionally substituted with 1-2 R ⁷ . The remainder of the variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth, seventh and/or eighth embodiment.

[075] Tenth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ⁵ is selected from: variables in Formula (I), (II) and (III) are described above in the first, second, fifth, sixth, seventh and/or eighth embodiment. [076] Eleventh embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein each R ⁷ is independently selected from CN,

R ⁷ attached to the same carbon atom form . The remainder of the variables in

Formula (I), (II) and (II) are described above in the first, second, fifth, sixth, seventh, eighth, ninth and/or tenth embodiment.

[077] Twelfth embodiment: a compound represented by Formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ^1A are each independently selected from H, F and CEE. The remainder of the variables in Formula (I), (II) and (II) are described above in the first, second, fifth, sixth, seventh, eighth, ninth, tenth and/or eleventh embodiment. [078] Thirteenth embodiment: a compound represented by Formula (IV), (V) or (VI): or a pharmaceutically acceptable salt thereof. The variables in Formula (IV), (V) and (VI) are described above in the first and/or second embodiment. [079] Fourteenth embodiment: a compound represented by Formula (VII), (VII), (IX) or (X): or a pharmaceutically acceptable salt thereof. The variables in Formula (VII), (VIII), (IX) and

(X) are described above in the first and/or second embodiment.

[080] 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 are each independently selected from H, halogen, and CFF; R ² is selected from C _1-3 alkyl, CD ₃ , C3- 4cycloalkyl and 4- to 6-membered heterocycle containing one O, wherein said alkyl, cycloalkyl, or heterocycle is optionally substituted with 1-3 R ⁴ ; each R ⁴ is independently selected from halogen, OH, cyclopropyl, 4- to 6-membered heterocycle containing one O, and phenyl, wherein said cyclopropyl or phenyl is optionally substituted with OH or NH ₂ ; R ⁶ is selected from Ci-4alkyl, CHF ₂ , CF ₃ , 4- or 5 -membered heterocycle containing N or O, and C _3-4 cycloalkyl, wherein said alkyl, heterocycle or cycloalkyl is optionally substituted with R ⁸ ; R ⁸ is selected from OH, NR ⁹ R ⁹ , OCH ₃ , CH ₃ and 4-membered heterocycle containing N or O, wherein said heterocycle is optionally substituted with CH ₃ ; and each R ⁹ is independently selected from H, CH ₃ , and CH ₂ CF ₃ . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first and/or second embodiment.

[081] Sixteenth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from CH ₃ , CD ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , cyclobutyl, cyclopropyl, oxetanyl, tetrahydrofuranyl, tetrahydrofuranyl and tetrahydropyranyl, each of which is optionally substituted with 1-3 R ⁴ . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second and/or fifteenth embodiment.

[082] 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 is selected from: variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second and/or fifteenth embodiment.

[083] 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 is independently selected from F, OH, cyclobutyl, oxetanyl, phenyl, tetrahydrofuranyl and tetrahydropyranyl, wherein said cyclobutyl, oxetanyl, oxetanyl, phenyl, tetrahydrofuranyl or tetrahydropyranyl is optionally substituted with OH or NH ₂ . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth and/or seventeenth embodiment.

[084] 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 is independently selected from F, OH, wherein * — represents OH or NH ₂ . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth and/or seventeenth embodiment.

[085] Twentieth embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from CH ,, CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH ₂ CH(CH ₃ )2, C(CH ₃ )3, CH ₂ CH ₂ CH(CH ₃ ) ₂ , CHF ₂ , CF ₃ , cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, each of which is optionally substituted with R ⁸ . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth and/or nineteenth embodiment.

[086] Twenty -first embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from: . The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth and/or nineteenth embodiment.

[087] Twenty-second embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from OH, OCH ₃ , CH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , NHCH ₂ CF ₃ , N(CH ₃ )CH ₂ CF ₃ , azetidinyl, azetidinyl and oxetanyl. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and/or twenty-first embodiment.

[088] Twenty -third embodiment: a compound represented by Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from: in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth and/or twenty-first embodiment.

[089] 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 are each independently selected from H, F and CHa. The remainder of the variables in Formula (I), (IV), (V), (VI), (VII), (VIII), (IX) or (X) are described above in the first, second, fifteenth, sixteenth, seventeenth, eighteenth, nineteenth, twentieth, twenty-first, twenty-second and/or twenty-third embodiment.

[090] Twenty -fifth embodiment: a compound represented by Formula (III) or (VII): or a pharmaceutically acceptable salt thereof, wherein R ¹ and R ^1A are each independently selected from H, F and CH ₃ ; R ² is selected from C _1-3 alkyl, CD ₃ , C _3-4 cycloalkyl and 4-membered heterocycle containing one O, wherein said alkyl is optionally substituted with 1-3 halo; R ⁵ is selected from CH ₃ , CH ₂ CH ₃ and cyclopropyl; R ⁶ is selected from C _1-5 alkyl, CHF ₂ , CF ₃ and 4- to 5-membered heterocycle containing O or N, wherein said alkyl or heterocycle is optionally substituted with R ⁸ ; R ⁸ is selected from OH, NR ⁹ R ⁹ , OCH ₃ , CH ₃ and 4-membered heterocycle containing O or N; and each R ⁹ is independently selected from H and CH ₃ .

[091] Twenty-sixth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ² is selected from CH ₃ , CHF ₂ , CF ₃ , CD ₃ , CH ₂ CH ₃ , CH ₂ CF ₃ , CH ₂ CH ₂ CH ₃ , CH(CH ₃ ) ₂ , CH(CH ₃ )CH ₂ F, CH(CH ₃ )CHF ₂ , cyclobutyl, cyclopropyl and . The remainder of the variables in Formula (III) or (VII) are described above in the twenty -fifth embodiment.

[092] Twenty-seventh embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ )2, CH ₂ CH ₂ CH(CH ₃ ) ₂ , CHF ₂ , azetidinyl, oxetanyl, tetrahydrofuranyl and pyrrolidinyl, each of which is optionally substituted with one R ⁸ . The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth and/or twenty-sixth embodiment.

[093] Twenty-eighth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from:

The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth and/or twenty-sixth embodiment.

[094] Twenty -ninth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from OH, OCH ₃ , NH ₂ , NHCH ₃ ,

N(CH ₃ )2, CH ₃ , . The remainder of the variables in Formula (III) or (VII) are described above in the twenty -fifth, twenty-sixth, twenty-seventh and/or twenty-eighth embodiment.

[095] Thirtieth embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from OH, OCH ₃ , NH ₂ , NHCH ₃ , N(CH ₃ )2, and CH ₃ . The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth and/or twenty-ninth embodiment.

[096] Thirty-first embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ )2, CH ₂ CH ₂ CH(CH ₃ ) ₂ and CHF ₂ , each of which is optionally substituted with one R ⁸ . The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty -ninth and/or thirtieth embodiment. In some thirty-first embodiments, R ⁶ is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ )2, CH ₂ CH ₂ CH(CH ₃ ) ₂ and CHF ₂ , each of which is optionally substituted with one R ⁸ . In some thirty- first embodiments, R ⁶ is selected from CH ₃ , CH ₂ CH ₃ , CH ₂ CH ₂ CH ₃ , CH ₂ CH(CH ₃ ) ₂ , and CH ₂ CH ₂ CH(CH ₃ ) ₂ , each of which is substituted with one R ⁸ .

[097] Thirty-second embodiment: a compound represented by Formula (III) or (VII), or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from CH ₃ , CH ₂ CH ₂ OH, CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ NHCH ₃ , CH ₂ CH ₂ NH ₂ , CH ₂ CH(N(CH ₃ ) ₂ )CH ₃ , CH ₂ CH(NHCH ₃ )CH ₃ , CH ₂ C(NHCH ₃ )(CH ₃ ) ₂ , CH ₂ C(NH ₂ )(CH ₃ ) ₂ , CH ₂ CH ₂ OCH ₃ , CH ₂ CH(OH)(CH ₃ ), CH ₂ C(OH)(CH ₃ ) ₂ , CH ₂ CH ₂ C(OH)(CH ₃ ) ₂ , and C(CH ₃ ) ₂ CH ₂ OH. The remainder of the variables in Formula (III) or (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty -ninth, thirtieth and/or thirty-first embodiment.

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

[099] Thirty-fourth embodiment: a compound represented by Formula (VII), or a pharmaceutically acceptable salt thereof. The variables in Formula (VII) are described above in the twenty-fifth, twenty-sixth, twenty-seventh, twenty-eighth, twenty-ninth, thirtieth, thirty-first and/or thirty-second embodiment.

[100] The disclosure also includes the compounds depicted in Table 1 and prepared in the Exemplification, both the neutral form and pharmaceutically acceptable salts thereof.

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

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

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

Use Embodiments

[104] Compounds of the disclosure (e.g., compounds of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or compounds in Table 1, or pharmaceutically acceptable salts of any of the foregoing) are useful as KIT inhibitors. For example, KIT inhibitors of this disclosure inhibit mutant KIT protein kinases where the mutation is in exon 13, such as K642E, V654A or N655K KIT mutation, or in exon 14, such as T680K KIT mutation. K642E is an exon 13 KIT mutation that can be a primary activating mutation. It is less common than the exon 9 and exon 11 primary activating KIT mutations. The KIT inhibitors of the disclosure can therefore treat conditions associated with aberrant KIT activity in humans or non-human patients. KIT inhibitors of the disclosure (also referred to as compounds of the disclosure) include compounds of Formula (I),

(II), (III), (IV), (V), (VI), (VII), (VIII), (IX) and/or (X), and pharmaceutically acceptable satis thereof, and compounds depicted in Table 1. The compounds of the disclosure are selective for exon 13 KIT over KIT and PDGFR wild type and therefore are expected to show minimal side effects resulting from wild type inhibition (such as anemia, thrombocytopenia and edema). The compounds of the disclosure also exhibit decreased brain penetration. Decreased or lack of brain penetration is anticipated to provide safety benefits and minimize unwanted cognitive effects. The method comprises administering to the patient an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II),

(III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or administering to the patient an effective amount of a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and a pharmaceutically acceptable carrier or excipient.

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

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

[107] In one aspect, the malignant disease (or cancer) treatable by the disclosed methods (e.g., GIST) is characterized by a primary activating KIT mutation. A “primary activating mutation” is an initial mutation that converts or contributes to the conversion of a normal cell to a cancer cell i.e., a primary activating mutation is responsible for initiating tumorigenesis and/or driving the cancer. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation or an exon 11 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation or an exon 17 KIT mutation, or a combination thereof. In some embodiments, the primary activating KIT mutation is selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation and an exon 17 KIT mutation. For some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In one embodiment, the exon 17 KIT mutation is D816V. In some embodiments, the primary activating mutation is A829P. A829P is a mutation at the very start of exon 18 KIT but is commonly referred to as an ’’exon 17” mutation. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P. In some embodiments, the primary activating KIT mutation is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In some embodiments the primary activating KIT mutation is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation such as 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 another aspect, the cancer is GIST and the primary activating mutation is selected from an exon 9 and/or an exon 11 mutation. In another aspect, the cancer is GIST and the primary activating mutation is an exon 9 KIT mutation or an exon 11 KIT mutation, or a combination thereof. In another aspect, the cancer is GIST and the primary activating mutation is an exon 13 KIT mutation. In another aspect, the cancer is GIST and the primary activating mutation is an exon 17 KIT mutation.

[108] For patients with Primary GIST, complete surgical resection is the initial treatment of choice for patients, with surgery being effective in approximately 50% of GIST patients. As used herein, the term “Primary GIST” is GIST with only primary activating mutations (e.g., without secondary resistance conferring mutations). Of the remaining patients, tumor recurrence is frequent. For patients with reoccurrence of GIST after surgical resection, patients are administered one or more anti-cancer agents for the treatment of GIST. In one aspect, the one or more anticancer agents are administered prior to treatment with the KIT inhibitors of the disclosure. For example, the KIT inhibitors of the disclosure are administered after the GIST progressed after the prior treatment. For example, the patient’ s tumor, was or upon treatment became resistant (or refactory) to the prior agent, the patient was intolerant to the treatment with the prior agent or the GIST reoccurred after the prior treatment. Examples of agents studied and used in the prior treatment of GIST are selected from: imatinib (e.g., the methanesulfonic acid salt), sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, agents studied and used in the prior treatment of GIST are selected from: imatinib (e.g., the methanesulfonic acid salt), sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, and bezuclastinib, and pharmaceutically acceptable salts thereof (Vallilas, C., et al. International Journal of Molecular Sciences. 2021; 22, 493). Further examples of agents studied and used in the prior treatment of GIST are selected from: AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof. (S)-2-(4-(4-(4-(5-(l- Amino- 1 -(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin- 1 -yl)pyrrolo[2, 1 -f] [ 1 ,2,4]triazin-6-yl)- lH-pyrazol-l-yl)ethanol (also known as BLU-263 and elenestinib) is another KIT inhibitor for use in the treatment of GIST. N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phe nyl)- 2-[4-(propan-2-yl)-lH-l,2,3-triazol-l-yl]acetamide (also known as AZD3229 and NB003) is another KIT inhibitor for use in the treatment of GIST. In some embodiments, agents studied and used in the prior treatment of GIST are selected from: AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof.

[109] In some aspects, patients with GIST are administered “Primary KIT Inhibitors.” 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 exon 9 and/or exon 11. Treatment with Primary KIT Inhibitors, such as imatinib, has also been shown to be sufficient for initial treatment, i.e., for treating of patients with Primary GIST, e.g., patients with exon 9 and/or exon 11 activating KIT mutations. However, despite the beneficial effect of a targeted therapy such as imatinib, eventually 50% of patients develop primary or secondary resistance to imatinib after 2 years. These secondary imatinib-resistant mutations are most frequently located on KIT exon 11, 13, 14, 17, 18 or combinations thereof.

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

[111] Regorafenib has shown promising results in a phase 3 clinical trial of imatinib-resistant and sunitinib-resistant GISTs with activity against several, but not all, exon 17 and 18 mutations, of which D816 is one. Regorafenib has been approved for third line GIST treatment.

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

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

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

[115] Bezuclastinib, also known as CGT9486 and PLX9486, has the following structure: [117] 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 KIT inhibitor of the disclosure or a pharmaceutically acceptable salt thereof (e.g, a compound of the disclosure, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or prior to treatment with a pharmaceutical composition containing a KIT inhibitor of the disclosure or a pharmaceutically acceptable salt thereof (e.g., a compound of the disclosure, including a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In one embodiment, the prior treatment comprises administering one or more agents selected from: imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, everolimus, larotrectinib, bezuclastinib, AZD3229 and BLU- 263, and pharmaceutically acceptable salts thereof. In one embodiment, prior treatment comprises administering a Primary KIT Inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof; imatinib mesylate is a pharmaceutically acceptable salt of imatinib). The prior treatment is continued until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the Primary KIT Inhibitor (e.g., imatinib or pharmaceutically acceptable salt thereof). In another embodiment, the prior treatment comprises administering an exon 17 KIT inhibitor. Examples of exon 17 inhibitors are avapritinib, BLU-263, ripretinib, and AZD3229. Examples of selective exon 17 inhibitors are avapritinib, BLU-263, and bezuclastinib. In one embodiment, the prior treatment comprises administering an exon 13 KIT inhibitor. An example of an exon 13 KIT inhibitor is sunitinib. In some embodiments, the exon 17 KIT inhibitor is selected from avapritinib, BLU-263, ripretinib, bezuclastinib, and AZD3229. In some embodiments, the exon 17 KIT inhibitor is avapritinib. In some embodiments, the exon 17 KIT inhibitor is BLU-263. In some embodiments, the exon 17 KIT inhibitor is ripretinib. In some embodiments, the exon 17 KIT inhibitor is bezuclastinib. In some embodiments, the exon 17 KIT inhibitor is AZD3229. Examples of selective exon 17 inhibitors are avapritinib, BLU-263, and bezuclastinib. In some embodiments, the exon 17 KIT inhibitor is a selective exon 17 KIT inhibitor. In some embodiments, the selective exon 17 KIT inhibitor is selected from avapritinib, BLU-263, and bezuclastinib. In some embodiments, the selective exon 17 KIT inhibitor is avapritinib. In some embodiments, the selective exon 17 KIT inhibitor is BLU-263. In some embodiments, the selective exon 17 KIT inhibitor is bezuclastinib. In another embodiment, the prior treatment comprises administering one or more agents selected from: imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, everolimus, larotrectinib, bezuclastinib, AZD3229 and BLU-263, and pharmaceutically acceptable salts thereof. In another embodiment, the prior treatment comprises administering one or more agents selected from: regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof.

[118] In another embodiment, prior treatment comprises administering a Primary KIT Inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the Primary KIT Inhibitor (e.g., imatinib or pharmaceutically acceptable salt thereof); after which prior treatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the sunitinib or pharmaceutically acceptable salt thereof).

[119] In another embodiment, prior treatment comprises administering a Primary KIT Inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the Primary KIT Inhibitor (e.g., imatinib or pharmaceutically acceptable salt thereof); after which prior treatment further comprises administering an exon 17 KIT inhibitor or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the exon 17 inhibitor or pharmaceutically acceptable salt thereof).

[120] In another embodiment, prior treatment comprises administering a Primary KIT Inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the Primary KIT Inhibitor (e.g., imatinib or pharmaceutically acceptable salt thereof), after which prior treatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified progressed or becomes resistant, refractory or intolerant to the sunitinib or pharmaceutically acceptable salt thereof); after which prior treatment further comprises administering regorafenib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the regorafenib or pharmaceutically acceptable salt thereof). [121] In another embodiment, prior treatment comprises administering a Primary KIT Inhibitor (e.g., imatinib or a pharmaceutically acceptable salt thereof). The prior treatment is continued until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the Primary KIT Inhibitor (e.g., imatinib or pharmaceutically acceptable salt thereof), after which prior treatment further comprises administering sunitinib or a pharmaceutically acceptable salt thereof (e.g., until the GIST is identified progressed or becomes resistant, refractory or intolerant to the sunitinib or pharmaceutically acceptable salt thereof); after which prior treatment further comprises administering regorafenib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the regorafenib or pharmaceutically acceptable salt thereof); after which prior treatment further comprises administering repretinib or a pharmaceutically acceptable amount thereof (e.g., until the GIST is identified as progressed or becomes resistant, refractory or intolerant to the ripretinib or pharmaceutically acceptable salt thereof).

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

[123] The tumor is or has become mutation resistant to the agent used in the prior treatment because a mutation is present in the tumor that renders the tumor resistant or refractory to the prior agent, i.e., a “resistant mutation”. For example, the tumor may have become mutation resistance to a Primary KIT Inhibitor. In some embodiments, the tumor has a mutation that is 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 is 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 -resistant mutation. In one embodiment, the tumor has a mutation that is resistant to a prior agent. In one embodiment, the mutation that is resistant to the prior agent is selected from an exon 13 KIT mutation, an exon 17 KIT mutation, an exon 18 KIT mutation, and an exon 14 KIT mutation, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K and K642E, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 13 KIT mutation, e.g., an exon 13 KIT mutation selected from V654A, N655K, and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D, and combinations thereof. In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, and a combination thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 17 KIT mutation, e.g., an exon 17 KIT mutation selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D and A829P, and combinations thereof. In some embodiments, the mutation that is resistant to the prior agent is an exon 14 KIT mutation, e.g., an exon 14 KIT mutation such as N680K. In some embodiments, the tumor is or has become resistant to the prior agent has one or more mutations.

[124] In some embodiments, the tumor is mutation resistant to the prior treatment as a consequence of one or more exon 17 mutation(s). Examples of exon 17 inhibitors that can inhibit such exon 17 mutation(s), which is causing the tumor to be resistant to the prior treatment, and thereby treat the tumor are selected from avapritinib, BLU-263, ripretinib, AZD3229 and bezuclastinib. Other mutations that may be inhibited by the exon 17 inhibitors described above include N655K, N680K, or a combination thereof.

[125] In some embodiments, the tumor after prior treatment (e.g., with Primary KIT Inhibitor such as imatinib) has one or more exon 13 mutation(s), such as exon 13 KIT mutations selected from V654A, N655K and K642E, and combinations thereof. In some embodiments, the tumor after prior treatment (e.g., with Primary KIT Inhibitor such as imatinib) has one or more exon 13 mutation(s), such as exon 13 KIT mutations selected from V654A, N655K, and a combination thereof. [126] In one embodiment, the disclosure provides a method of treating a patient suffering from gastrointestinal stromal tumor (GIST), comprising administering to the patient an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), 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., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing). In some embodiments, the patient received one or more prior treatments for the GIST. In some embodiments, the GIST progressed after the prior treatment. In some embodiments, the prior treatment comprises administering one or more agents. In some embodiments, the one or more agents comprises imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the one or more agents comprises avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering one or more agents, each independently selected from: imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, BLU-263, everolimus or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the prior treatment comprises administering imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, BLU-263, everolimus or larotrectinib, or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering sunitinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering regorafenib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering ripretinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering bezuclastinib or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering AZD3229 or a pharmaceutically acceptable salt thereof. In some embodiments, the prior treatment comprises administering BLU- 263 or a pharmaceutically acceptable salt thereof. In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations. In some embodiments, the tumor has a primary activating KIT mutation. In some embodiments, the GIST is characterized by a tumor with one or more KIT mutations, each independently selected from an exon 9 KIT mutation, an exon 11 KIT mutation, an exon 13 KIT mutation and an exon 17 KIT mutation, and combinations thereof. In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P, K642E, V654A and N655K, and combinations thereof. In some embodiments, each of the one or more KIT mutations is independently selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, A829P and K642E, and combinations thereof. In some embodiments, the tumor has an exon 9 KIT mutation. In some embodiments, the tumor has an exon 11 KIT mutation. In some embodiments, the tumor has an exon 17 KIT mutation. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In some embodiments, the exon 17 KIT mutation is D816V. In some embodiments, the tumor has an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is selected from K642E, V654A and N655K, and combinations thereof. In some embodiments, the exon 13 KIT mutation is K642E. In some embodiments, the exon 17 mutation is A829P. In some embodiments, the exon 18 mutation is A829P. In some embodiments, the tumor is mutation resistant to the one or more prior treatments. In some embodiments, the tumor is mutation resistant to imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, B LU-263, everolimus or larotrectinib, or a pharmaceutically acceptable salt thereof, or a combination thereof. In some embodiments, the tumor is mutation resistant to imatinib. In some embodiments, the tumor has an imatinib-resistant mutation. In some embodiments, the tumor has an exon 13 inhibitor-resistant mutation. In some embodiments, the tumor has an exon 14 inhibitorresistant mutation. In some embodiments, the tumor has an exon 17 inhibitor-resistant mutation. In some embodiments, the exon 17 inhibitor is selected from avapritinib, BLU-263, ripretinib, AZD3229 and bezuclastinib, and pharmaceutically acceptable salts thereof. In some embodiments, the exon 17 inhibitor is avapritinib or a pharmaceutically acceptable salt thereof. In some embodiments, the exon 17 inhibitor-resistant mutation is N655K. In some embodiments, the exon 17 inhibitor-resistant mutation is N680K. In some embodiments, the imatinib -resistant mutation is selected from an exon 13 KIT mutation, an exon 17 KIT mutation and an exon 14 KIT mutation, and combinations thereof. In some embodiments, the imatinib-resistant mutation is an exon 13 KIT mutation. In some embodiments, the exon 13 KIT mutation is V654A or N655K. In some embodiments, the imatinib-resistant mutation is an exon 17 KIT mutation. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y, D823D, and A829P. In some embodiments, the exon 17 KIT mutation is selected from N822K, D816V, D816E, D816F, D816H, D816I, D816Y, D820E, D820Y and D823D. In some embodiments, the exon 17 KIT mutation is D816V. In some embodiments, the exon 17 KIT mutation is D816E. In some embodiments, the exon 17 KIT mutation is A829P. In some embodiments, the exon 18 KIT mutation is A829P. In some embodiments, the imatinib-resistant mutation is an exon 14 KIT mutation. In some embodiments, the exon 14 KIT mutation is N680K.

[127] Another embodiment of the disclosure is a method of treating a patient suffering from gastrointestinal stromal tumor (GIST), comprising administering to the patient 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 of any of the foregoing), or a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and (ii) one or more agents (e.g., 1, 2, 3, or 4 additional agents).

[128] In one embodiment the patient suffering from GIST is administered a combination comprising (i) an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or 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 of any of the foregoing) and (ii) a Primary Kit Inhibitor (e.g., imatinib) as the additional agent. In one embodiment, the patient suffering from GIST is administered a combination comprising (i) a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or 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 of any of the foregoing) and (ii) an exon 9 or exon 11 inhibitor as the additional agent. In one embodiment, the patient suffering from GIST is administered a combination comprising (i) an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or 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 of any of the foregoing) and (ii) an exon 17 inhibitor as the additional agent.

[129] In another embodiment the patient suffering from GIST is administered a combination comprising (i) an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or 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 of any of the foregoing), and as additional agents: (ii) a Primary Kit Inhibitor (e.g., imatinib), or a pharmaceutically acceptable salt thereof, and (iii) at least one agent selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, sunitinib, avapritinib, BLU-263, ripretinib, AZD3229, bezuclastinib, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is selected from regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, sunitinib, avapritinib, BLU-263, ripretinib, AZD3229 and bezuclastinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is an exon 17 inhibitor. In one embodiment, the additional agent (iii) is selected from avapritinib, BLU- 263, ripertinib, AZD3229, and bezuclastinib, and pharmaceutically acceptable salts thereof. In one embodiment, the additional agent (iii) is avapritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is BLU-263 or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is ripertinib or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is AZD3229 or a pharmaceutically acceptable salt thereof. In one embodiment, the additional agent (iii) is bezuclastinib or a pharmaceutically acceptable salt thereof.

[130] In another embodiment the patient suffering from GIST is administered a combination (e.g., an effective combination) comprising (i) a compound disclosed herein or the pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition disclosed herein (e.g., a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof, e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), and as additional agents: (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, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib and sunitinib, and pharmaceutically acceptable salts thereof. In any of the foregoing embodiments, the exon 17 inhibitor is selected from avapritinib, BLU-263, ripertinib, AZD3229, and bezuclastinib. In one embodiment, the exon 17 inhibitor is selected from avapritinib, BLU-263, ripertinib, AZD3229, and bezuclastinib. In one embodiment, the exon 17 inhibitor is avapritinib or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is BLU-263 or a pharmaceutically acceptable salt thereof. In one embodiment, the exon 17 inhibitor is ripertinib 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 bezuclastinib or a pharmaceutically acceptable salt thereof. [131] In one aspect the combination therapy described in this paragraph can be administered as a first line therapy, i.e., before resistant mutations have been identified, or as second, third, or fourth line therapy, i.e., after one or more resistance conferring mutations have emerged. When a combination of agents is administered, the agents in the combination can be administered simultaneously (in the same or different formulations) or concurrently in any order.

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

[133] Another embodiment of the disclosure is a method of treating a patient suffering from gastrointestinal stromal tumor (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., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), or 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 of any of the foregoing), and one or more agents. In some embodiments, the agent is an exon 9 KIT inhibitor or exon 11 KIT inhibitor. In some embodiments, the agent is selected from imatinib, sunitinib, regorafenib, nilotinib, cabozantinib, pazopanib, ponatinib, dasatinib, binimetinib, vandetanib, famitinib, anlotinib, axitinib, alvocidib, ribocliclib, sorafenib, pexidartinib, olaratumab, crenolanib, avapritinib, ripretinib, bezuclastinib, AZD3229, BLU-263, everolimus and larotrectinib, and pharmaceutically acceptable salts thereof. In some embodiments, the agent is imatinib or a pharmaceutically acceptable salt thereof. In some embodiments, the additional agent is an exon 17 KIT inhibitor. In some embodiments, the agent is selected from avapritinib, BLU-263, ripretinib, AZD3229, and bezuclastinib.

[134] Another embodiment of the disclosure is a method of treating a patient suffering from a malignant disease (e.g., GIST) characterized by a tumor with an exon 9 KIT mutation, an exon 11 KIT mutation, or an exon 17 KIT mutation, or a combination thereof. The method comprises: (a) obtaining a biological sample from the patient; (b) detecting the presence or absence of an exon 13 KIT mutation or exon 14 KIT mutation; and (c) administering an effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition disclosed herein, to the patient, if the mutation is detected. In one aspect, the presence of absence of an exon 13 KIT mutation is detected in step b), for example, wherein the exon 13 KIT mutation is V654A or N655K. In another aspect, the presence or absence of an exon 14 KIT mutation is detected in step (b), for example, wherein the exon 14 KIT mutation is N680K. The presence of absence of exon 13 mutations V654A or N655K or exon 14 mutation N680K is detected according to methods disclosed in WO 2020/102095, the entire teachings of which are incorporated herein by reference.

[135] Another embodiment of the disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor with 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 exon 14 KIT mutation; and (c) administering 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 of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), to the patient, if the mutation is present. In one aspect, the presence of absence of an exon 13 KIT mutation is detected in step (b), for example, wherein the exon 13 KIT mutation is V654A or N655K. In another aspect, the presence or absence of an exon 14 KIT mutation is detected in step (b), for example, wherein the exon 14 KIT mutation is N680K. The presence of absence of exon 13 mutations V654A or N655K or exon 14 mutation N680K is detected according to methods disclosed in WO 2020/102095, the entire teachings of which are incorporated herein by reference.

[136] Another embodiment of the disclosure is a method of treating a patient suffering from a malignant disease characterized by a tumor with an exon 9 KIT mutation, an exon 11 KIT mutation or an exon 17 KIT mutation, or a combination thereof, comprising administering 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 of any of the foregoing), or administering an effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and a compound disclosed herein or a pharmaceutically acceptable salt thereof (e.g., a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX) or (X), or a compound of Table 1, or a pharmaceutically acceptable salt of any of the foregoing), to the patient, if an exon 13 KIT mutation or exon 14 KIT mutation is detected. In some embodiments, the exon 13 KIT mutation is V654A orN655K. In some embodiments, the exon 14 KIT mutation isN680K.

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

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

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

Pharmaceutical Compositions

[140] While it is possible for a compound of the disclosure to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation, where the compound is combined with one or more pharmaceutically acceptable excipients or carriers. The compounds of the disclosure or pharmaceutically acceptable salts thereof may be formulated for administration in any convenient way for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation may be active itself, or may be a prodrug, e.g., capable of being converted to an active compound in a physiological setting.

[141] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

[142] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (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, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) cyclodextrins; and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

[143] Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha- tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

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

[145] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, com, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

[146] Suspensions, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

[147] Ointments, pastes, creams and gels may contain, in addition to compounds of the disclosure or pharmaceutically acceptable salts thereof, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

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

[149] The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of compound of the disclosure or pharmaceutically acceptable salt thereof that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect.

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

[151] When the compounds of the disclosure or pharmaceutically acceptable salths thereof are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

[152] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subcuticularly, or by inhalation.

Dosages

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

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

[155] A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the compounds of the disclosure employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

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

[157] The terms “administer”, “administering”, “administration”, and the like, as used herein, refer to methods that may be used to enable delivery of compositions to the desired site of biological action. These methods include, but are not limited to, intraarticular (in the joints), intravenous, intramuscular, intratumoral, intradermal, intraperitoneal, subcutaneous, orally, topically, intrathecally, inhalationally, transdermally, rectally, and the like. Administration techniques that can be employed with the agents and methods described herein are found in e.g., Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergam on; and Remington’s, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa.

[158] The particular mode of administration and the dosage regimen will be selected by the attending clinician, taking into account the particulars of the case (e.g. the subject, the disease, the disease state involved, the particular treatment, and whether the treatment is prophylactic). Treatment can involve daily or multi-daily or less than daily (such as weekly or monthly etc.) doses over a period of a few days to months, or even years.

[159] The pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. In an embodiment, the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous, subcutaneous, intramuscular, oral, intranasal, or topical administration to human beings. In preferred embodiments, the pharmaceutical composition is formulated for intravenous administration.

[160] “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the formulation and/or administration of an active agent to and/or absorption by a subject and can be included in the compositions of the present disclosure without causing a significant adverse toxicological effect on the subject. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with or interfere with the activity of the compounds provided herein. One of ordinary skill in the art will recognize that other pharmaceutical excipients are suitable for use with disclosed compounds.

EXEMPLIFICATION

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

Abbreviations

[162] Abbreviations and acronyms used herein include the following:

AcOH means acetic acid;

AIBN means 2,2’-azobis(2-methylpropionitrile); t-AmOH means tert-amyl alcohol;

Aq. means aqueous;

Boc means tert-butoxy carbonyl;

(BPin)2 means 4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-l,3,2-dioxaborolane; br means broad;

Brettphos means 2-(Dicyclohexylphosphino)3,6-dimethoxy-2',4',6'-triisopropyl -l, 1 biphenyl;

BrettPhos Pd G3 means [(2-Di-cyclohexylphosphino-3,6-dimethoxy-2',4',6'- triisopropyl- 1,1 '-biphenyl)-2-(2'-amino-l, 1 ' -biphenyl)]palladium(II) methanesulfonate;

BrettPhos Pd G4 means dicyclohexyl-[3,6-dimethoxy-2-[2,4,6-tri(propan-2-yl)phenyl] phenyl]phosphane;methanesulfonic acid;7V-methyl-2-phenylaniline;palladium n-BuOH means butan-l-ol; t-BuOK means potassium tert-butoxide; d means doublet; dd means doublet of doublets;

DAST means Diethylaminosulfur trifluoride;

DCM means dichloromethane;

DIAD means diisopropyl azodicarboxylate;

DIPEA means N-ethyldiisopropylamine or N,N-diisopropylethylamine;

DMA means N,N-Dimethylacetamide;

DMF means N,N-dimethylformamide;

DMSO means Dimethylsulfoxide;

EtOAc means ethyl acetate;

EtOH means ethanol;

EtONa means sodium ethoxide;

Eq. means equivalent;

FA means formic acid;

HATU means l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyri dinium 3- oxid hexafluorophosphate;

IPA means 2-propanol;

[Ir(OMe)(l,5-cod)]2 means Bis(l,5-cyclooctadiene)di-p-methoxydiiridium(I);

KO Ac means potassium acetate;

LCMS means liquid chromatography mass spectrometry; m means multiplet;

MeCN means acetonitrile;

Mel means iodomethane;

MeNFE means methylamine;

MeOH means methanol;

MeOH-d4 means deutero-methanol;

MPLC means medium pressure liquid chromatography;

MS m/z means mass spectrum peak;

NBS means N-bromosuccinimide;

NMP means N-methyl pyrrolidine;

PE means petroleum ether;

Pd(amphos)C12 means Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloro palladium(II);

Pd(t-Bu ₃ P) ₂ means Bis(tri-tert-butylphosphine)palladium(0);

Pd2(dba) ₃ means tris(dibenzylideneacetone)dipalladium (0); Pd(dppf)C12 means [1 J’-bis(diphenylphosphino)ferrocene]dichloropalladium(II);

PG means protecting group; i-PrMgCl means isopropyl magnesium chloride; q means quartet; rt means room temperature;

RT means retention time; s means singlet; sat. means saturated;

SFC means supercritical fluid chromatography; t means triplet;

T3P means 2,4,6-Tripropyl-l,3,5,2,4,6-trioxatriphosphorinane-2,4,6-tri oxide;

TBAF means Tetrabutylammonium fluoride;

TBDMS means tert-Butyldimethylsilane;

TBDMSC1 means tert-Butyl(chloro)dimethylsilane;

TEA means triethylamine;

TFA means trifluoroacetic acid;

TfOH means trifluoroethanesulfonic acid;

THF means tetrahydrofuran;

TLC means thin layer chromatography;

TMSN3 means trimethyl silyl azide;

Xantphos means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; and

XPhos Pd G2 means Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-l,l'- biphenyl)[2-(2'-amino-l, 1 '-biphenyl)]palladium(II).

General Synthetic Methods and Intermediates

[163] According to a first process, compounds of Formula (I) may be prepared from the compounds of Formulae (ii) and (iii), as illustrated by Scheme 1.

Scheme 1

[164] The compound of Formula (I) may be prepared from the compounds of Formulae (ii) and (iii) according to process step (a) a Buchwald-Hartwig cross-coupling. Typical conditions comprise, reaction of the amine of Formula (iii) with the chloride of Formula (ii) in the presence of a suitable inorganic base, a suitable catalyst in a suitable solvent at elevated temperature. Preferred conditions comprise, reaction of the compounds of Formulae (ii) and (iii) in the presence of, BrettPhos Pd G3, BrettPhos Pd G4, Pd(t-Bu3P)2 or Xantphos, optionally in conjunction with Pd2(dba)3 or BrettPhos in the presence of a suitable base such as CS ₂ CO ₃ , K ₂ CO ₃ , or KO Ac in a suitable solvent such as dioxane, toluene, t-AmOH, NMP or DMF, at between 90°C and 130°C.

[165] According to a second process, the compound of Formula (I) may be prepared from the compounds of Formulae (ii), (iv) and (v), as illustrated in Scheme 2. PG is a suitable amine protecting group, preferably 2,4-dimethoxybenzyl or tButyl. [166] The compound of Formula (v) may be prepared from the compounds of Formulae (ii) and (iv) according to process step (a) a Buchwald-Hartwig cross-coupling reaction as previously described in Scheme 1.

[167] The compound of Formula (I) may be prepared from the protected compound of Formula (v) by process step (b), a de-protection reaction. Typical conditions comprise reaction of the compound of Formula (v) with a suitable acid, such as HC1, or TFA in a suitable solvent such as dioxane, THF or DCM at about rt.

[168] According to a third process, the compound of Formula (v) may be prepared from the compounds of Formulae (vi), and (vii) as illustrated in Scheme 3.

(vi) (vii)

Scheme 3

[169] The compound of Formula (v) may be prepared from the compounds of Formulae (vi) and (vii) by process step (a), a Buchwald-Hartwig cross-coupling reaction, as previously described in Scheme 1.

[170] According to a fourth process, the compound of Formula (vi) may be prepared from the compounds of Formulae (ii) and (viii), as illustrated in Scheme 4.

Scheme 4

PG ² is a suitable nitrogen protecting group, preferably benzyl or diphenylmethylene

[171] The compound of Formula (viii) may be prepared from the compound of Formula (ii) and PG ² NH ₂ by process Step (c), an amination reaction, wherein PG ² is a benzyl group. Typical conditions comprise reaction of the compound of Formula (ii), with PG ² NH ₂ at elevated temperature, such as 200°C and under microwave irradition. [172] Alternatively, wherein PG ² is a diphenylmethylene group, the compound of Formula (viii) may be prepared from the compound of Formula (ii) and PG ² NH ₂ by process Step (a), a cross coupling reaction, as previously described in Scheme 1.

[173] The compound of Formula (vi) may be prepared from the compound of Formula (viii) by process Step (d) a deprotection reaction. Typical conditions comprise reaction of the compound of

Formula (viii) with a suitable acid such as triflic acid or HC1 in a suitable solvent, such as DCM at about rt.

[174] According to a fifth process, the compound of Formula (ii) may be prepared from the compounds of Formula (ix), (x), (xi), (xii), (xiii), (xiv), (xv) and (xvi) as illustrated in Scheme 5.

Scheme 5

Hal ¹ is a halogen, preferably Br or I

Hal ² is a halogen, preferably Cl or F

W is Sn(n-Bu)3 or B(Pin) Aik is a C1-C4 alkyl group [175] Wherein X ₁ is O, the compound of Formula (xi) may be prepared from the compound of Formula (ix) by process step (e). Typical conditions comprise reaction of the compound of Formula (ix) with a suitable alkyl fluorinating agent such as ethyl 2-bromo-2,2-difluoroacetate, in the presence of a suitable base such as K ₂ CO ₃ , in a suitable solvent such as DMF, at elevated temperature, typically at about 60°C.

[176] The compound of Formula (xi) may be prepared from the compound of Formula (x) by process step Step (f). Typical conditions comprise reaction of the compound of Formula (x) with R ² XIH, in the presence of a suitable organic or inorganic base such as DIPEA or TEA, CS ₂ CO ₃ , t- BuOK, NaH or KF, optionally in a suitable solvent such as THF, DMF, DMA, DMSO, dioxane, n-BuOH or MeCN at between 0°C and 140°C, optionally under microwave irradiation.

[177] The compound of Formula (xii) may be prepared from the compound of Formula (xi), according to process step (g), a boronate ester formation achieved by treatment with a suitable boronate such as (BPin)2, in the presence of a suitable inorganic base, such as K ₂ CO ₃ or KO Ac and a suitable catalyst, such as, Pd(dppf)C12 in a suitable non-polar solvent at between rt and elevated temperature. Preferred conditions comprise, treatment of the compound of Formula (xi) with (BPin)2 in the presence of Pd(dppf)C12 and KO Ac in dioxane, at 90°C.

[178] Wherein, R ³ is a 5 membered aromatic heterocycle, as defined previously, the compound of Formula (ii) may be prepared from the compound of Formula (xi) by process step (h), a palladium catalysed cross-coupling reaction. Such cross-coupling reactions may include a Suzuki type reaction, wherein W is a boronic acid or ester, or a Stille type cross coupling reaction, when W is an alkyl stannane.

[179] Typical cross-coupling conditions comprise a palladium catalyst containing suitable phosphine ligands, such as Pd(amphos)C12, Pd(dppf)C12, Pd(PPh3)C12 or Xphos Pd G2, in the presence of the compound of Formula (xvi), in the presence of an inorganic or organic base, such as CS ₂ CO ₃ , K ₂ CO ₃ , Na2CC>3, K3PO4, TEA or KO Ac in a suitable solvent, such as, EtOH, dioxane, aqueous dioxane or DMF at between rt and elevated temperature.

[180] Wherein, R ³ is a 5 membered aromatic heterocycle, as defined previously, the compound of Formula (ii) may be prepared from the compound of Formula (xii) and R ³ -Hal ¹ , according to process step (h), as previously described.

[181] Wherein R ³ is C(O)NHR ⁵ , the compound of Formula (ii) may be prepared from the compounds of Formulae (xiii), (xiv) and (xv). [182] The compound of Formula (xiv) may be prepared from the compound of Formula (xiii) and R ² XIH according to process step (f), as previously described.

[183] The compound of Formula (xv) may be prepared from the compound of Formula (xiv) by process step (i), a hydrolysis reaction. Typical conditions comprise reaction of the compound of Formula (xiv) with an alkali metal hydroxide, such as LiOH or NaOH, in aqueous solvent such as MeOH, EtOH or THF at between rt and about 80 °C.

[184] The compound of Formula (ii) may be prepared by from the compound of Formula (xv) and R ⁵ NH ₂ according to process step (j), an amide bond formation. Typical conditions comprise reaction of the acid of Formula (xv) with R ⁵ NH ₂ , in the presence of a suitable coupling agent and organic base in a suitable polar aprotic solvent. Preferred conditions, comprise the reaction of the acid of Formula (xv) with R ⁵ NH ₂ , in the presence of HATU or T3P, in the presence of a suitable organic base, typically DIPEA or TEA, in a suitable solvent, such as DMF or DCM, at room temperature.

[185] Alternatively, the compound of Formula (ii) may be prepared by the in-situ formation of the acid chloride of the acid of Formula (xv), typically using oxalyl chloride or thionyl chloride in a suitable solvent such as THF or DCM at rt and the subsequent amide bond formation of the acid chloride and the amine R ⁵ NH ₂ in the presence of a suitable organic base, typically DIPEA at 0°C.

[186] According to a sixth process, the compound of Formula (ii) may be prepared from the compounds of Formula (x), (xvi), (xvii), (xviii), (xix) and (xx) as illustrated in Scheme 6.

Scheme 6

[187] Wherein, R ³ is a 5 membered aromatic heterocycle, as defined previously, the compound of Formula (xviii) may be prepared from the compounds of Formulae (x) and (xvi), according to process step (h), as previously described in Scheme 5.

[188] Wherein, R ³ is a 5 membered aromatic heterocycle, as defined previously, the compound of Formula (xviii) may be prepared from the compound of Formulae (xvii) and R ³ -Hal ¹ , according to process step (h), as previously described in Scheme 5.

[189] Wherein, R ³ is C(O)NHR ⁵ , the compound of Formula (xviii) may be prepared from the compound of Formulae (xix) and R ⁵ NH ₂ , according to process step (j), as previously described in

Scheme 5.

[190] Wherein, R ³ is C(O)NHR ⁵ , the compound of Formula (xviii) may be prepared from the compound of Formulae (xx) and R ⁵ NH ₂ , according to process step (k), an aminolysis reaction. Typical conditions comprise reaction of the compound of Formula (xx) with R ⁵ NH ₂ at elevated temperature such as 70°C in a sealed vessel.

[191] The compound of Formula (ii) may be prepared from the compound of Formulae (xviii) and R ² XIH, according to process step (f), as previously described in Scheme 5.

[192] According to a seventh process, compounds of Formula (vi), may be prepared from compounds of the Formulae (xxi) and (xxii), as illustrated by Scheme 7.

[193] The compound of Formula (xxii) may be prepared from the compound of Formula (xxi) according to process step (1) a halogenation reaction, preferably a bromination reaction. Typical conditions comprise, reaction of the compound of Formula (xxi) with NBS in DMF at rt.

[194] The compound of Formula (vi) may be prepared from the compounds of Formulae (xxii) and (xvi) according to process step (h), as previously described in Scheme 5.

[195] According to an eighth process, compounds of Formula (I) may be prepared from the compounds of Formulae (iii), (xviii) and (xxiii) as illustrated in Scheme 8.

(iii) (xxiii) (I)

Scheme 8

[196] The compound of Formula (xxiii) may be prepared from the compounds of Formulae (iii) and (xviiii) by process step (a), a Buchwald-Hartwig coupling as previously described in Scheme 1. [197] The compound of Formula (I) may be prepared from the compound of Formula (xxiii) and

R ² XIH by process step (f) as previously described in Scheme 5.

[198] According to a ninth process, compounds of Formula (v), wherein R ³ is C(O)NHR ⁵ , may be prepared from the compounds of Formulae (iv), (xiv) and (xxiv) as illustrated in Scheme 9.

Scheme 9

[199] The compound of Formula (xxiv) may be prepared from the compounds of Formulae (xiv) and (iv) according to process step (a), as previously described in Scheme 1.

[200] The compound of Formula (v) may be prepared from the compound of Formula (xxiv) according to process step (k), an aminolysis reaction, as previously described in Scheme 6.

[201] The compounds of Formulae (iii), (iv), (vii), (ix), (x), (xiii), (xvi), (xvii), (xix), (xx) and (xxi) are either commercially available or may be prepared by analogy to methods known in the literature, or the methods described in the experimental sections below.

[202] Compounds of Formulae (I), (ii), (v), (vi) (viii), (xviii) and (xxiii) may be converted to alternative compounds of Formulae (I), (ii), (v), (vi) (viii), (xviii) and (xxiii) by standard chemical transformations, known to those skilled in the art. Examples of these transformations include, but are not limited to reductive amination reaction, reduction of ester to a secondary alcohol using NaBH ₄ , fluorination, using DAST, bromination using AIBN and NBS, and methods for the synthesis of 5 membered heterocycles from functional groups such as a nitrile, as described in Comprehensive Heterocyclic Chemistry or in the literature.

[203] It will be appreciated by those skilled in the art, that it may be necessary to utilise a suitable protecting group strategy for the preparation of compounds of Formula (I). Typical protecting groups may comprise, carbamate and preferably Boc for the protection of aliphatic amines, or a TBDMS group for the protection of a primary alcohol. [204] It will be further appreciated that it may be necessary or desirable to carry out the transformations in a different order from that described in the schemes, or to modify one or more of the transformations, to provide the desired compound disclosed herein.

[205] Methods for preparing compounds of the disclosure can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent’s freezing temperature to the solvent’s boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.

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

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

[208] One of ordinary skill in the art will recognize that modifications of 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 species being analyzed.

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

Preparation of Intermediates

[210] Preparation 1: 2-(difluoromethyl)pyrimidine-4,6-diol

To a solution of malonamide (600 g, 5.88 mol) in EtOH (12 L), was added EtONa (799. g, 11.75 mol) and the solution 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 washed with EtOHZEtOAc (1 : 1) and dried in vacuo to give the title compound, (800 g, 71.4%) as a yellow solid.

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

[212] Preparation 3: 6-chloro-2-(difluoromethyl)-N-(2,4-dimethoxybenzyl)pyrimidin -4- amine

To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 50.0 g, 251 mmol) and 2,4-dimethoxybenzylamine (46.2 g, 276 mmol) in NMP (250 mL) was added DIPEA (64.9 g, 502 mmol) and the reaction stirred at 140 °C for 2 h. The cooled reaction mixture was poured into water (500 mL) and extracted with EtOAc (400 mL x 3), the combined organic layers were washed with brine (500 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (PE/EtOAc =50/1 to 10/1) to give the title compound (60.0 g, 70.3% yield) as a yellow solid. LCMS m/z = 330 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[213] Preparation 4: 6-chloro-2-(difluoromethyl)pyrimidin-4-amine

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

[214] Preparation 5: 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-di amine

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

[215] Preparation 6: N,N'-(2-(difluoromethyl)pyrimidine-4,6-diyl)bis(l,l-diphenyl methanimine)

To a solution of 4,6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 145 g, 721.41 mmol) in dioxane (2 L), was added diphenylmethanimine (326.86 g, 1.80 mol), CS ₂ CO ₃ (705.15 g, 2.16 mol), Xantphos (41.74 g, 72.14 mmol) and Pd2(dba)3 (33.03 g, 36.07 mmol) under N2 and the reaction was heated at 100 °C for 8 h. The cooled reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ISCO, 0~10 % EtOAc/PE) to give the title compound (250 g, 67%) as a yellow oil. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 6.39-6.57 (m, 2H) 7.27-7.60 (m, 20H)

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

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

[217] Preparation 8: 2-(difluoromethyl)pyrimidine-4,6-diamine

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

[218] Preparation 9: 2-(l-fluoroethyl)pyrimidine-4,6-diol

To a solution of malonamide (30 g, 294 mmol) in EtOH (300 mL) was added EtONa (40.0 g, 588 mmol) and the solution stirred at 20 °C for 1 h. Ethyl 2-fluoropropanoate (38.7 g, 323 mmol) was added drop-wise and the reaction stirred at 100 °C for 2 h. The pH of the mixture was adjusted to pH = 6 with 1 N HC1, and then concentrated in vacuo. The residue was adjusted to pH = 2 with 1 N HC1 and filtered to provide 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] ⁺ .

[219] Preparation 10: 4,6-dichloro-2-(l-fluoroethyl)pyrimidine

To a stirred solution of 2-(l-fluoroethyl)pyrimidine-4,6-diol (Preparation 9, 31 g, 196 mmol) in toluene (300 mL) was added POCI ₃ (72.8 mL, 784 mmol) at 25 °C. TEA (54.4 mL, 392 mmol) was added drop-wise and the reaction 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 Na ₂ SO ₄ , filtered and the filtrate was evaporated under reduced pressure to give the title compound, 40 g.

[220] Preparation 11: 6-chloro-N-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidin- 4- amine

A solution of 4,6-dichloro-2-(l-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 organics were washed with brine (300 mL x 3), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title compound (22 g, crude) as a yellow solid, which was used in the next step directly. LCMS m/z = 326 [M+H] ⁺ .

[221] Preparation 12: 6-chloro-2-(l-fluoroethyl)pyrimidin-4-amine

A solution of 6-chloro-N-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidin- 4-amine (Preparation 11, 22 g, 67.6 mmol) in HC1/EtOAc (4.0 M, 85 mL) was stirred at 20 °C for 12 h. The mixture was concentrated in vacuo, the pH of the residue adjusted to pH = 8 with saturated NaHCO ₃ solution, and the mixture extracted with DCM (300 mL x 3). The combined organics were washed with brine (300 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was triturated with PE/EtOAc = 1/1 and filtered to give the title compound (10 g, 84% yield) as a gray solid. LCMS m/z = 176 [M+H] ⁺ . [222] Preparation 13 and Preparation 14: (S)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl) pyrimidine-4,6-diamine and (R)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidine-4,6 - diamine

A solution of 6-chloro-2-(l-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 organics were washed with brine (300 mL x 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified by silica gel chromatography to provide N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidine-4,6-dia mine (6.6 g, 37%) as a yellow solid.

This product was further purified by SFC, using an OZ 20 x 250mm, 10pm (Daicel) column, eluting with 35% MeOH (0.2% MeOH/NH ₃ ) at 100 g/min, to obtain the first eluting enantiomer: (S)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidine-4,6 -diamine (2.1 g) as a yellow solid. LCMS m/z = 307 [M+H] ⁺ . (Preparation 13)

Further elution provided the second eluting enantiomer, (R)-N4-(2,4-dimethoxybenzyl)- 2-(l-fluoroethyl)pyrimidine-4,6-diamine. (Preparation 14)

The stereochemistry of Preparation 13 was confirmed by X-ray.

[223] Preparation 15: 2-(fluoromethyl)pyrimidine-4,6-diol

To a solution of malonamide (60.0 g, 588 mmol) in EtOH (600 mL) was added EtONa (80.0 g, 1.18 mol) and the solution stirred for 1 h. Ethyl 2-fluoroacetate (68.6 g, 646 mmol) was added dropwise the reaction stirred at 100°C for 2 h. The pH of the reaction mixture was adjusted to 6 using IN HC1 and concentrated under reduced pressure. The pH of the residue was adjusted to 2 using IM HC1 and the mixture filtered to provide the title compound as a yellow solid, 32.0 g 37.8% yield. ¹ H NMR: (400 MHz, DMSO-d ₆ ) δ 11.91 (brs, 2H), 5.26 (d, 2H), 5.14 (s, 1H). [224] Preparation 16: 4,6-dichloro-2-(fluoromethyl)pyrimidine

To a solution of 2-(fluoromethyl)pyrimidine-4,6-diol (Preparation 15, 32.0 g, 222 mmol) in toluene (300 mL) was added POCI ₃ (82.8 mL, 891 mmol) dropwise at 25°C. TEA (61.8 mL, 444 mmol) was added dropwise and the reaction was stirred at 100°C for 2 h. The reaction mixture was poured into warm water (500 mL) and extracted with EtOAc (300 mL x 3). The combined organic layer was washed with brine (300 mL), dried over Na ₂ SO ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by MPLC (silica gel, PEZEtOAc = 100/1-10/1) to give the title compound (30.0 g, 74.6% yield) as a white solid. NMR: (400 MHz, CDCL) 8: 5.43 (s, 1H), 5.54 (s, 1H), 7.40 (s, 1H).

[225] Preparation 17: N4,N6-bis(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4, 6- diamine

To a solution of 4,6-dichloro-2-(fluoromethyl)pyrimidine (Preparation 16, 1.10 g, 6.08 mmol) in DMSO (15 mL) was added 2,4-dimethoxybenzylamine (5.08 g, 30.39 mmol) and the reaction stirred at 100°C for 24 h. The cooled reaction was quenched with H ₂ O (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 Na ₂ SO ₄ , 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 yellow solid.

[226] Preparation 18: 2-(fluoromethyl)pyrimidine-4,6-diamine

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

[227] Preparation 19: N4-(2,4-dimethoxybenzyl)-2-(fluoromethyl)pyrimidine-4,6-diam ine

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 organics were washed with brine (300 mL x 3), dried over Na ₂ SO ₄ and evaporated under reduced pressure to give the title compound (50.0 g, crude) as a yellow solid. LCMS m/z = 312 [M+H] ⁺

[228] Preparation 20: 5-bromo-2-chloro-4-methoxypyridine

To a solution of MeOH (704 mg, 22.0 mmol) in THF (30 mL) at 0 °C was added NaH (60% dispersion, 1.76 g, 44.0 mmol), the mixture stirred at 0 °C for 30 mins, 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 H ₂ O, extracted with EtOAc and the combined organic layers were concentrated in vacuo. The residue was purified by silica gel chromatography to give the title compound as a white solid (3.5 g, 72%). LCMS m/z = 222 [M+H] ⁺ .

[229] Preparation 21: 5-bromo-2-chloro-4-isopropoxypyridine

To a solution of IP A (1.32 g, 22.0 mmol) in THF (30 mL) was added NaH (1.76 g, 44.0 mmol) at 0 °C, the solution 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) then washed with water (80 mL) and brine (80 mL). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (PEZEtOAc = 10/1 to 2/1) to afford the title compound (4.0 g, 73%) as a white solid. LCMS m/z = 250 [M+H] ⁺ .

[230] Preparation 22: 2-chloro-5-iodo-4-methoxypyridine

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

[231] Preparation 23: 2-chloro-5-iodo-4-(methoxy-d3)pyridine

A mixture of methanol-ds (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 stirred for 4 h at rt. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with EtOAc/PE (1/4) to afford the title compound (1.8 g, 90%) as a white solid. LCMS m/z = 273 [M+H] ⁺ .

[232] Preparation 24: 2-chloro-4-cyclopropoxy-5-iodopyridine

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

[233] Preparation 25: 2-chloro-4-((l-fluoropropan-2-yl)oxy)-5-iodopyridine

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

[234] Preparation 26: 2-chloro-5-iodo-4-isopropoxypyridine

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

[235] Preparation 27: 5-bromo-2-chloro-4-cyclopropoxypyridine

To a solution of cyclopropanol (8.70 g, 150 mmol) in THF (200 mL) was added NaH (5.99 g, 150 mmol, 60% in mineral oil) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. 5- Bromo-2,4-di chloropyridine (34.0 g, 150 mmol) was added and the reaction stirred at 60 °C for 3 h. The reaction mixture was cooled to 0 °C and quenched by addition of saturated aq. NH4CI solution (100 mL) and then extracted with EtOAc (100 mL x 3). The combined organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with PEZEtOAc = 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] ⁺

[236] Preparation 28: 5-bromo-2-chloro-4-(oxetan-3-yloxy)pyridine

The title compound was obtained as a white solid, 1.97 g, 67.6%, from oxetan-3-ol and 5- bromo-2,4-dichloropyridine following the procedure described in Preparation 27.

[237] Preparation 29: 2-chloro-4-(difluoromethoxy)-5-iodopyridine

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 K ₂ CO ₃ (1.62 g, 11.76 mmol) in DMF (20 mL) was stirred at 60 °C under N2 for 16 h. The cooled mixture was diluted with EtOAc, washed with water, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give the title product (500 mg, 42%). LCMS m/z = 306 [M+H] ⁺ .

[238] Preparation 30: l,l-diphenyl-N-(4-(trifluoromethoxy)pyridin-2-yl)methanimine

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 CS ₂ CO ₃ (6.93 g, 21.3 mmol) in dry dioxane (400 mL) was added diphenylmethanimine (2.83 g, 15.6 mmol) and the reaction stirred at 100 °C under N2 for 16 h. The cooled mixture was concentrated in vacuo and purified by silica gel chromatography to give the title product (2.6 g, 53%). LCMS m/z = 343 [M+H] ⁺ . [239] Preparation 31: 4-(trifluoromethoxy)pyridin-2-amine

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

[240] Preparation 32: 5-bromo-4-(trifluoromethoxy)pyridin-2-amine

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

[241] Preparation 33: l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-4-(4,4,5,5-tetrame thyl- l,3,2-dioxaborolan-2-yl)-lH-pyrazole

A mixture of 2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazo l-l-yl)ethan- l-ol (1 g, 4.2 mmol), IH-imidazole (571 mg, 8.4 mmol) and TBDMSC1 (945 mg, 6.3 mmol) in DCM (20 mL) was stirred at rt for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/5) to afford the title compound (1 g, yield: 63%) as a white solid. LCMS m/z = 353 [M+H] ⁺ . [242] Preparation 34: l-(oxetan-2-ylmethyl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaboro lan-2- yl)-lH-pyrazole

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

[243] Preparation 35: 2-methyl-4-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH- pyrazol-l-yl)butan-2-ol

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

[244] Preparation 36: l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazo l-l- yl)propan-2-one

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

[245] Preparation 37: tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazol-l-yl)ethyl)carbamate To a solution of 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (4.50 g, 23.19 mmol) and tert-butyl N-(2-hydroxyethyl)-N-methyl-carbamate (4.06 g, 23.19 mmol) in THF (30 mL) was added DIAD (5.16 g, 25.51 mmol) and PPhs (6.69 g, 25.51 mmol) and the reaction stirred at 25°C for 12 h under N2. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep-HPLC-2 to give the title compound (2.11 g, 25.9%) as a yellow oil.

[246] Preparation 38: tert-butyl 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)methyl)azetidine-l-carboxylate

A mixture of 2 tert-butyl 2-(hydroxymethyl)azetidine-l -carboxylate (300 mg, 1.6 mmol) and 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (315 mg, 1.6 mmol) in THF (20 mL) was added PPI13 (630 mg, 2.4 mmol), the mixture stirred at 0°C and DIAD added (0.3 mL). The reaction was stirred at rt overnight and was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/3) to give the title compound (300 mg, yield 52%). LCMS m/z = 364 [M+H] ⁺ .

[247] Preparation 39: tert-butyl (l-(4-bromo-lH-pyrazol-l-yl)-2-methylpropan-2- yl)carbamate

A mixture of 4-bromo-U/-pyrazole (2.5 g, 17.0 mmol), tert-butyl 4,4-dimethyl-l,2,3- oxathiazolidine-3 -carboxylate 2,2-dioxide (4.69 g, 18.7 mmol) and CS ₂ CO ₃ (8.35 g, 25.5 mmol) in anhydrous DMF (50 mL) was stirred at 80°C overnight. The cooled mixture was partitioned between water and EtOAc, the layers separated and the organic phase concentrated in vacuo. The residue was purified by silica gel chromatography EtOAc/PE (1/5) to give the title compound (4.4 g, 81 % yield) as a colorless oil. LCMS m/z = 318, 320 [M+H] ⁺ [248] Preparation 40: tert-butyl (l-(4-bromo-lH-pyrazol-l-yl)-2-methylpropan-2- yl)(methyl)carbamate

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

[249] Preparation 41: tert-butyl methyl(2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-yl)carbamate

A mixture of tert-butyl (l-(4-bromo-lH-pyrazol-l-yl)-2-methylpropan-2-yl)(methyl) carbamate (Preparation 40, 1.7 g, 5.14 mmol), bis(pinacolato)diboron (1.96 g, 7.71 mmol), KOAc (1.51 g, 15.4 mmol) and Pd(dppf)C12 (200 mg, 2.6 mmol) in dioxane (20 mL) was stirred at 100°C under N2 for 16 h. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/10) to give the title compound (600 mg, yield 30%). LCMS m/z = 380 [M+H] ⁺ .

[250] Preparation 42: l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol A mixture of 2-chloro-5-iodo-4-methoxypyridine (Preparation 22, 750 mg, 2.79 mmol), 2-methyl- 1 -(4-(4,4,5, 5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazol- 1 -yl)propan-2-ol (891 mg, 3.35 mmol), Pd(dppf)C12 (204 mg, 0.279 mmol) and K ₂ CO ₃ (770 mg, 5.58 mmol) in dioxane (12 mL) and H ₂ O (3 mL) was stirred at 90°C for 4 h under N2. The cooled mixture was concentrated in vacuo to give the crude product which was purified by silica gel chromatography (PE: EtOAc =1 :2) to give the title compound (560 mg, 71.5%) as a yellow oil. LCMS m/z = 282 [M+H] ⁺

[251] Preparation 43: l-(4-(6-chloro-4-(methoxy-d3)pyridin-3-yl)-lH-pyrazol-l-yl)- 2- methylpropan-2-ol

A mixture of 2-chloro-5-iodo-4-(methoxy-d3)pyridine (Preparation 23, 2 g, 7.33 mmol), 2-methyl- 1-(4-(4, 4, 5, 5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)propan-2-ol (2.14 g, 8.06 mmol), K ₂ CO ₃ (2.01 g, 14.6 mmol) and Pd(dppf)C12 (536 mg, 0.733 mmol) in dioxane/water (40 mL/8 mL) was stirred at 80 °C for 6 h under N2. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE= 2/1 to afford the title compound (1.2 g, yield: 57%) as a white solid. LCMS m/z = 285 [M+H] ⁺ .

[252] Preparation 44: 2-chloro-4-isopropoxy-5-(l-methyl-lH-pyrazol-4-yl)pyridine

A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 120 mg, 0.479 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazole (79.73 mg, 0.383 mmol), Pd(dppf)C12 (35.05 mg, 0.048 mmol) and K ₂ CO ₃ (132.40 mg, 0.958 mmol) in dioxane (2 mL) and H ₂ O (0.10 mL) was degassed and purged with N2 and the reaction stirred at 90°C for 2 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (PE: EtOAc = 1 : 1) to give the title compound (50 mg, 41.5%) as a yellow solid.

Alternative synthesis: A mixture of NaH (60%, 53 mg, 1.32 mmol) in IPA (5 mL) was stirred at 0 °C for 2 h, then 2-chloro-4-fluoro-5-(l-methyl-lH-pyrazol-4-yl)pyridine (Preparation 97, 70 mg, 0.33 mmol) was added. The mixture was stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE =1/2 to afford the title compound (60 mg, 72% yield) as a white solid. LCMS m/z = 252 [M+H] ⁺ .

[253] Preparation 45: l-(4-(6-chloro-4-isopropoxypyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol

A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 2.0g, 8.06 mmol), 2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)propan-2-ol (2.15 g, 8.06 mmol), K ₂ CO ₃ (3.34 g, 24.2 mmol) and Pd(dppf)C12 (592 mg, 0.81 mmol) in dioxane/water (20 mL/ 4 mL) was stirred at 80 °C for 3 h. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (PEZEtOAc = 10/1 to 2/1) to afford the title compound (2.2 g, 88% yield) as a yellow solid. LCMS m/z = 310 [M+H] ⁺ .

[254] Preparation 46: l-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-lH-pyrazol-l-yl)- 2- methylpropan-2-ol

A mixture of 2-chloro-4-cyclopropoxy-5-iodopyridine (Preparation 24, 1.18 g, 4 mmol), 2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)propan-2-ol (1.28 g, 4.8 mmol), Pd(dppf)C12 (150 mg, 0.2 mmol) and K ₂ CO ₃ (1.1 g, 8 mmol) in dioxane (20 mL) and H ₂ O (3 mL) was stirred at 90°C for 4 h under N2. The cooled mixture was concentrated to give the crude product which was purified by silica gel chromatography (PE: EtOAc =1 :2) to give the title compound (900 mg, 73.3 %) as a beige solid. LCMS m/z =308 [M+H] ⁺ . [255] Preparation 47: l-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH-pyrazol-l -yl)-2- methylpropan-2-ol

A mixture of 2-chloro-4-(difluoromethoxy)-5-iodopyridine (Preparation 29, 100 mg, 0.33 mmol), 2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l-yl)propan-2- ol (105 mg, 0.39 mmol), Pd(dppf)C12 (20 mg, 0.027 mmol) and K ₂ CO ₃ (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 in vacuo and the residue purified by silica gel chromatography to give the title compound (50 mg, 47%). LCMS m/z = 318 [M+H] ⁺ .

[256] Preparation 48: 2-chloro-4-isopropoxy-5-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyr idine

A mixture of 5-bromo-2-chloro-4-isopropoxypyridine (Preparation 21, 300 mg, 1.19 mmol), l-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)-lH-pyrazole (355 mg, 1.42 mmol), Pd(dppf)C12 (174 mg, 0.238 mmol) and K ₂ CO ₃ (492 mg, 3.56 mmol) in dioxane/FLO (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 Na ₂ SO ₄ , and concentrated in vacuo. The crude product was purified by column chromatography on silica gel (PE/EtOAc= 2/1) to give the title compound (140 mg, 40.1 %) as white solid. LCMS m/z = 294 [M+H] ⁺ .

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

[258] Preparation 50: tert-butyl 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH- pyrazol-l-yl)pyrrolidine-l-carboxylate

The title compound was obtained, 210 mg, 77% yield, from 2-chloro-4-(difluoro methoxy)-5-iodopyridine (Preparation 29) and tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate , following the procedure described in Preparation 48. LCMS m/z = 415 [M+H] ⁺ .

[259] Preparations 51 to 74

A mixture of the appropriate chloropyridine (1.0 equiv.) and alkylated (4-(4, 4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1 equiv. to 1.2 equiv.), K ₂ CO ₃ (2.0 to 3.0 equiv.) and Pd(dppf)C12 (0.03 to 0.2 equiv.) in dioxane/water (10/1 to 3/1 V/V) was stirred at between 70°C and 100 °C until the starting materials had been consumed. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with PE/EtOAc or MeOH/DCM) to provide the desired compound.

^A CS ₂ CO ₃ was used instead of K ₂ CO ₃ [260] Preparation 75: 2-chloro-4-methoxy-5-(l-(2-((tetrahydro-2H-pyran-2-yl)oxy)et hyl)- lH-pyrazol-4-yl)pyridine

A mixture of l-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-4-(4,4,5,5-tetram ethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (348 mg, 1.079 mmol), 5-bromo-2-chloro-4-methoxypyridine (Preparation 20, 200 mg, 0.899 mmol), PdC12(dppf):DCM (73.4 mg, 0.090 mmol) was purged with N2. 2M aq. Na ₂ CO ₃ (1.349 mL, 2.70 mmol) and dioxane (3.60 mL) were added and the reaction stirred at 90 °C overnight under N2. The cooled mixture was concentrated in vacuo and the residue purified by silica gel chromatography (0-70% EtOAc in hexanes) to give the title compound (256 mg, 84.2%) as a light brown glass. LCMS m/z = 338 [M+H] ⁺

[261] Preparation 76: tert-butyl 2-((4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l- yl)methyl)azetidine-l-carboxylate

A mixture of tert-butyl 2-((4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyraz ol-l- yl)methyl)azetidine-l -carboxylate (Preparation 38, 400 mg, 1.10 mmol), 5-bromo-2-chloro-4- methoxypyridine (Preparation 20, 244 mg, 1.10 mmol), Pd(dppf)C12 (34 mg, 0.0465 mmol), and TEA (260 mg, 2.57 mmol) in dioxane (6 mL) and H ₂ O (1.5 mL) was stirred at 80°C for 2 h. The cooled mixture was concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound as a yellow solid (150 mg, 36%). LCMS m/z = 379 [M+H] ⁺ .

[262] Preparation 77: tert-butyl (2-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l- yl)ethyl)carbamate

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

[263] Preparation 78: tert-butyl 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-lH-pyrazol- l-yl)methyl)azetidine-l-carboxylate

The title compound was obtained as a white solid, 120 mg, 43% yield, from 5-bromo-2- chloro-4-cyclopropoxypyridine (Preparation 27) and tert-butyl 2-((4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)methyl)azetidine-l-carbox ylate (Preparation 38), following the procedure described in Preparation 76. LCMS m/z = 405 [M+H] ⁺

[264] Preparation 79: tert-butyl (2-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l- yl)ethyl)(methyl)carbamate

To a solution of 5-bromo-2-chloro-4-methoxypyridine (Preparation 20, 46 mg, 0.207 mmol), tert-butyl methyl(2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH -pyrazol-l- yl)ethyl)carbamate (Preparation 37, 79.89 mg, 0.227 mmol) in EtOH (3 mL) and H ₂ O (0.20 mL) was added Pd(amphos)C12 (14.64 mg, 0.0207 mmol) and KOAc (40.59 mg, 0.413 mmol) and the reaction stirred at 80°C for 2 h under N2. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by prep-TLC (PE: EtOAc = 0: 1) to give the title compound (50 mg, 65.9%) as a yellow oil.

[265] Preparations 80 to 86

The compounds in the following table were prepared from the appropriate pyrazole pinacol ester and bromopyridine, following a similar procedure to that described in Preparation 79.

[266] Preparation 87: tert-butyl 3-(4-(6-chloro-4-(oxetan-3-yloxy)pyridin-3-yl)-lH- pyrazol-l-yl)azetidine-l-carboxylate To a solution of 5-bromo-2-chloro-4-(oxetan-3-yloxy)pyridine (Preparation 28, 500 mg,

1.89 mmol), and tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazo l-l- yl)azeti dine- 1 -carboxylate (990.25 mg, 2.84 mmol) in dioxane (5 mL) and H ₂ O (0.50 mL) was added Xphos Pd G2 (148.73 mg, 0.189 mmol) and K3PO4 (802.51 mg, 3.78 mmol) and the reaction stirred at 80 °C for 3 h under N2. The cooled reaction mixture was concentrated under reduced pressure. The residue was purified by prep HPLC-6 to give the title compound (120 mg, 15.6 %) as a white solid.

[267] Preparation 88: tert-butyl (l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-

2-methylpropan-2-yl)carbamate

A mixture of tert-butyl (l-(4-bromo-lH-pyrazol-l-yl)-2-methylpropan-2-yl)carbamate (Preparation 39, 543 mg, 1.706 mmol), bis(pinacolato)diboron (520 mg, 2.048 mmol), Pd(dppf)C12:DCM (209 mg, 0.256 mmol) and KO Ac (502 mg, 5.12 mmol) in dioxane (6.83 mL) was stirred at 90°C for 9 h. The reaction was cooled to rt then more bis(pinacolato)diboron (200 mg, 0.787 mmol) was added. The reaction mixture was stirred for a further 2 h at 90°C. 5- Bromo-2-chloro-4-methoxypyridine (Preparation 20, 380 mg, 1.706 mmol) and 2M aq. Na2CO3 (2.56 mL, 5.12 mmol) were added. The reaction mixture was stirred overnight at 90°C then concentrated in vacuo onto silica and purified by silica gel chromatography (0-100% EtAOc in hexanes) to give the title compound (135 mg, 20.8 % yield). LCMS m/z = 381 [M+H] ⁺

[268] Preparation 89: N-(2-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)eth yl)-

2,2,2-trifluoroethan-l-amine

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

[269] Preparation 90: l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-N- methylpropan-2-amine

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

[270] Preparation 91: 2-chloro-4-(difluoromethoxy)-5-(l-(l-methylpyrrolidin-3-yl)- lH- pyrazol-4-yl)pyridine

To a solution of tert-butyl 3-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH-pyrazol- l-yl)py ^rr °lidine-l -carboxylate (Preparation 50, 200 mg, 0.482 mmol) in DCM was added TFA (274 mg, 2.4 mmol) and the reaction stirred at rt for 16 h. The reaction mixture was concentrated in vacuo and purified by column chromatography on silica gel (PE/ EtOAc= 1/1) to give 2- chloro-4-(difluoromethoxy)-5-(l-(pyrrolidin-3-yl)-lH-pyrazol -4-yl)pyridine trifluoroacetate.

To a solution of 2-chloro-4-(difluoromethoxy)-5-(l-(pyrrolidin-3-yl)-lH-pyraz ol-4- yl)pyridine trifluoroacetate (200 mg) in MeOH (4 mL) was added formaldehyde (95 mg, 3.2 mmol) and AcOH (2 drops) and the solution stirred for 10 mins. Na(CN)BH3 (201 mg, 3.2 mmol) was added and the reaction stirred at rt for 16 h. The reaction was quenched with 1 M HC1, concentrated in vacuo and the residue purified by column chromatography on silica gel (MeOH/ DCM= 5%) to give the title compound (130 mg, 62%). LCMS m/z = 329 [M+H] ⁺ . [271] Preparation 92: 2-chloro-4-methoxy-5-(l-(l-methylpyrrolidin-3-yl)-lH-pyrazol -4- yl)pyridine

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

[272] Preparation 93: 5-(l-(azetidin-2-ylmethyl)-lH-pyrazol-4-yl)-2-chloro-4- methoxypyridine

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

[273] Preparations 94 and 95: (R)-2-chloro-4-methoxy-5-(l-((l-methylazetidin-2-yl) methyl)-lH-pyrazol-4-yl)pyridine and (S)-2-chloro-4-methoxy-5-(l-((l-methylazetidin-2- yl)methyl)-lH-pyrazol-4-yl)pyridine

To a solution of 5-(l-(azetidin-2-ylmethyl)-lH-pyrazol-4-yl)-2-chloro-4-metho xy pyridine (Preparation 93, 160 mg, 0.574 mmol) in MeOH (5 mL) and DCM (5 mL) at rt was added HCHO (5.0 eq) and AcOH (0.2 mL) and the solution stirred for 5 min. Na(CN)BHa (5.0 eq) was added and the reaction stirred at rt for 16 h. The solution was quenched with H ₂ O, the mixture extracted with DCM and the combined organic layers were concentrated in vacuo. The residue was purified by Prep HPLC-3 to provide 2-chloro-4-methoxy-5-(l-((l-methylazetidin-2- yl)methyl)-lH-pyrazol-4-yl)pyridine as a colorless oil (80 mg, 48%). LCMS m/z = 293[M+H] ⁺ .

The compound was further purified by SFC using an IG 20 x 250mm, 10pm (Daicel) column, mobile phase: CO ₂ /MeOH (0.2% MeOH/NFE) = 50/50, at a flow rate of 100 g/min, to give

First eluting Enantiomer 1 (Preparation 94): (S)-2-chloro-4-methoxy-5-(l-((l-methy lazetidin-2-yl)methyl)-lH-pyrazol-4-yl)pyridine or (R)-2-chloro-4-methoxy-5-(l-((l -methyl azetidin-2-yl)methyl)-lH-pyrazol-4-yl)pyridine, 30 mg

Second eluting Enantiomer 2 (Preparation 95): (R)-2-chloro-4-methoxy-5-(l-((l-methyl azetidin-2-yl)methyl)-lH-pyrazol-4-yl)pyridine or (S)-2-chloro-4-methoxy-5-(l-((l -methyl azetidin-2-yl)methyl)-lH-pyrazol-4-yl)pyridine, 30 mg.

[274] Preparation 96: 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2- yl)pyridine

A mixture of 2-chloro-4-fluoropyridine (10 g, 76.0 mmol), bis(pinacolato)diboron (9.64 g, 38.0 mmol), [Ir(OMe)(l,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 in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/10) to afford the title compound (15 g, 77% yield) as colorless oil. LCMS m/z = 258 [M+H] ⁺ .

[275] Preparation 97: 2-chloro-4-fluoro-5-(l-methyl-lH-pyrazol-4-yl)pyridine

A mixture of 2-chloro-4-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan- 2-yl)pyridine (Preparation 96, 15 g, 58.36 mmol), 4-bromo-l -methyl- IH-pyrazole (9.4 g, 58.36 mmol), K ₂ CO ₃ (16.1 g, 116.73 mmol) and Pd(dppf)C12 (4.27 g, 5.83 mmol) in dioxane/water (80 mL/ 20 mL) was stirred at 80 °C for 6 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/2) to afford the title compound (5 g, 41% yield) as a brown solid. ¹ H NMR (400 MHz, DMSO-de) S ppm 8.83-8.80 (m, 1H), 8.27-8.26 (m, 1H), 8.00 (s, 1H), 7.69-7.67 (m, 1H), 3.90 (s, 3H).

[276] Preparation 98: 2-chloro-4-ethoxy-5-(l-methyl-lH-pyrazol-4-yl)pyridine

A mixture of 2-chloro-4-fluoro-5-(l-methyl-lH-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 in vacuo and purified by silica gel column chromatography to give the title compound (900 mg, 80%). LCMS m/z = 238 [M+H] ⁺

[277] Preparation 99: 2-chloro-4-cyclopropoxy-5-(l-methyl-lH-pyrazol-4-yl)pyridine

A mixture of 2-chloro-4-fluoro-5-(l-methyl-lH-pyrazol-4-yl)pyridine (Preparation 97, 100 mg, 0.47 mmol), cyclopropanol (54 mg, 0.94 mmol) and CS ₂ CO ₃ (308 mg, 0.95 mmol) in MeCN (15 mL) was stirred at 80 °C for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/2) to give the title compound (70 mg, yield 59%). LCMS m/z = 250 [M+H] ⁺ .

[278] Preparation 100: l-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-lH-pyrazol-l -yl)- 2-methylpropan-2-ol

A mixture of 5-bromo-4-(trifluoromethoxy)pyridin-2-amine (Preparation 32, 100 mg, 0.39 mmol), 2-methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)- lH-pyrazol-l- yl)propan-2-ol (155 mg, 0.58 mmol), Pd(dppf)Cl ₂ (20 mg, 0.027 mmol) and K ₂ CO ₃ (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 in vacuo and the residue was purified by silica gel chromatography eluting with MeOH/DCM (1/20) to give the title compound (110 mg, 89%). LCMS m/z = 317 [M+H] ⁺ .

[279] Preparations 101 to 105

The compounds in the following table were prepared from 5 -bromo-4-(trifluorom ethoxy) pyridin-2-amine (Preparation 32) and the appropriate pyrazole pinacol ester, following a similar procedure to that described in Preparation 100.

[280] Preparation 106: 5-(l-(2-(methylamino)propyl)-lH-pyrazol-4-yl)-4-

(trifluoromethoxy)pyridin-2-amine A mixture of l-(4-(6-amino-4-(trifluoromethoxy)pyridin-3-yl)-lH-pyrazol-l -yl)propan-

2-one (Preparation 105, 140 mg, 0.46 mmol) and MeNH ₂ (1 mL, 2 M in THF) in DCM (10 mL) was stirred at rt for 0.5 h. Na(CN)BH ₃ (58 mg, 0.92 mmol) was added and the reaction stirred at rt for 16 h. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel eluting with MeOH/DCM (1/10) to give the title compound (110 mg, yield 75%). LCMS m/z = 316 [M+H] ⁺ .

[281] Preparation 107: l-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH-pyrazol-l - yl)propan-2-ol To a solution of l-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH-pyrazol-l -yl) propan-2-one (Preparation 72, 140 mg, 0.464 mmol) in THF was added NaBJL (69.9 mg, 1.85 mmol) at 0 °C and the reaction 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 Na ₂ SO ₄ , concentrated in vacuo and purified by column chromatography on silica gel (DCM/ MeOH= 5%) to give the title compound (45 mg, 32%) as white solid. LCMS m/z = 304 [M+H] ⁺ .

[282] Preparation 108: l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino) pyrimidin-4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-lH-p yrazol-l-yl)-2-methyl propan-2-ol

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

[283] Preparations 109 to 113

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

[284] Preparation 114: (S)-l-(4-(6-((6-((2,4-dimethoxybenzyl)amino)-2-(l-fluoroethy l) pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-lH-pyrazol-l -yl)-2-methylpropan-2-ol A mixture of l-(4-(6-chloro-4-isopropoxypyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol (Preparation 45, 800 mg, 2.59 mmol), (S)-N4-(2,4-dimethoxybenzyl)-2-(l- fluoroethyl)pyrimidine-4,6-diamine (Preparation 13, 800 mg, 2.59 mmol), BrettPhos Pd G4 (397 mg, 0.26 mmol) and CS ₂ CO ₃ (2.54 g, 7.77 mmol) in dioxane (20 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (EtOAc/MeOH = 10/1 to 3/1) to afford the title compound (840 mg, 56% yield) as a yellow solid. LCMS m/z = 580 [M+H] ⁺ . [285] Preparation 115: l-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4- dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH- pyrazol-l-yl)-2-methyl propan-2-ol

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

[286] Preparation 116: tert-butyl (l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl) amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazo l-l-yl)-2-methylpropan-2- yl)carbamate

A mixture of tert-butyl (l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-yl)carbamate (Preparation 88, 135 mg, 0.354 mmol), 2-(difluoromethyl)-7V4- (2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 110 mg, 0.354 mmol), BrettPhos Pd G4 (32.7 mg, 0.035 mmol) and CS ₂ CO ₃ (346 mg, 1.063 mmol) in dioxane (2 mL) was purged with N2 and the reaction stirred at 80 °C overnight. Additional BrettPhosPd G4 (12 mg, 0.013 mmol) and CS ₂ CO ₃ (115 mg, 0.353 mmol) were added and the reaction stirred at 100 °C for a further 10 h. The cooled mixture was concentrated onto silica gel and purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound (178 mg, 77 %). LCMS m/z = 655 [M+H] ⁺

[287] Preparation 117: (S)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)-N6-(4-isoprop oxy- 5-(l-(oxetan-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4 ,6-diamine

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

[288] Preparations 118 to 137 A mixture of the appropriate chloro pyridine (1 equiv.), the appropriate protected pyrimidine-4,6-diamine (1.2 equiv.), BrettPhos Pd G4 (0.03 equiv. to 0.2 equiv.) and CS ₂ CO ₃ (2- 3 equiv.) in dioxane was stirred at between 70-100 °C until the starting materials had been consumed. The cooled mixture was concentrated in vacuo. The crude product was purified by silica gel column chromatography using an appropriate solvent system (eg MeOH/DCM or PE/EtOAc) to provide the desired compound.

^A -K ₂ CO ₃ was used in place of CS ₂ CO ₃

[289] Preparation 138: l-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4- dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH- pyrazol-l-yl)propan-2-one A mixture of l-(4-(6-chloro-4-(difluoromethoxy)pyridin-3-yl)-lH-pyrazol-l -yl)propan-2- one (Preparation 72, 140 mg, 0.46 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl) pyrimidine-4,6-diamine (Preparation 5, 143 mg, 0.28 mmol), BrettPhos Pd G4 (10 mg, 0.011 mmol) and CS ₂ CO ₃ (300 mg, 0.92 mmol) in dioxane (5 mL) was stirred at 100°C under N2 for 16 h. The cooled mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with MeOH/DCM (100%~10%) to give title compound (110 mg, yield 41%). LCMS m/z = 576 [M+H] ⁺ .

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

[291] Preparations 140 and 141: tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)pyrrolidine-l-carboxylate and tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)pyrrolidine-l-carboxylate

A mixture of tert-butyl 3-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-lH-pyrazol-l- yl)pyrrolidine-l -carboxylate (Preparation 66, 180 mg, 0.44 mmol), 2-(difluoromethyl)-N4-(2,4- dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 137 mg, 0.44 mmol), CS ₂ CO ₃ (290 mg, 0.89 mmol) and Brettphos Pd G4 (40 mg, 0.043 mmol) in dioxane (4 mL) was stirred at 100 °C for 16 h under N2. The cooled reaction mixture was concentrated in vacuo and the residue was purified by Prep HPLC-3. The product was further purified by SFC using an AD 20x250mm, 10pm (Daicel) column, mobile phase: CO2/MEOH (1% MeOH/NFE) = 50/50 at 100 g/min to afford:

First eluting Enantiomer 1: tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6- ((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-y l)-lH-pyrazol-l-yl)pyrrolidine- 1 -carboxylate or tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dime thoxy benzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH-pyrazol-l -yl)pyrrolidine-l -carboxylate (Preparation 140), (20 mg, 7% yield) as a white solid. LCMS m/z = 679 [M+H] ⁺ and

Second eluting Enantiomer 2: tert-butyl (R)-3-(4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)pyrrolidine-l -carboxylate or tert-butyl (S)-3-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6- ((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-y l)-lH-pyrazol-l-yl)pyrrolidine- 1-carboxylate (Preparation 141), (20 mg, 7% yield) as a white solid. LCMS m/z = 679 [M+H] ⁺ . [292] Preparations 142 and 143: tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)methyl)azetidine-l-carboxylate and tert-butyl (S)-2-((4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)methyl)azetidine-l-carboxylate

A mixture of tert-butyl 2-((4-(6-chloro-4-cyclopropoxypyridin-3-yl)-lH-pyrazol-l- yl)methyl)azetidine-l -carboxylate (Preparation 78, 100 mg, 0.246 mmol), 2-(difluoromethyl)- N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5, 76.0 mg, 0.245 mmol), K ₂ CO ₃ (67.7 mg, 0.491 mmol) and Brettphos Pd G4 (20 mg) in dioxane (4 mL) was stirred at 100 °C for 16 h under N2. The cooled reaction mixture was concentrated in vacuo. The residue was purified by Prep-HPLC-3. The product was further purified by chiral-SFC using an AD 20 x 250mm, 10pm (Daicel) column, mobile phase: CCh/EtOH (1% MeOH/NFE) = 50/50 at 100 g/min, to afford:

First eluting Enantiomer 1 : tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2-(difluoromethyl)- 6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3 -yl)-lH-pyrazol-l- yl)methyl)azetidine-l -carboxylate or tert-butyl (S)-2-((4-(4-cyclopropoxy-6-((2- (difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-y l)amino)pyridin-3-yl)-lH- pyrazol-l-yl)methyl)azetidine-l -carboxylate (Preparation 142) (12 mg, 7% yield) as a white solid. LCMS m/z = 679 [M+H] ⁺ and

Second eluting Enantiomer 2: tert-butyl (S)-2-((4-(4-cyclopropoxy-6-((2-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-yl)amino)p yridin-3-yl)-lH-pyrazol-l- yl)methyl)azetidine-l -carboxylate or tert-butyl (R)-2-((4-(4-cyclopropoxy-6-((2- (difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-y l)amino)pyridin-3-yl)-lH- pyrazol-l-yl)methyl)azetidine-l -carboxylate (Preparation 143) (12 mg, 7% yield) as a white solid. LCMS m/z = 679 [M+H] ⁺ . [293] Preparations 144 and 145: N4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6-(4- isopropoxy-5-(l-((R)-tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)p yridin-2-yl)pyrimidine-4,6- diamine and N4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6-(4-isoprop oxy-5-(l-((S)- tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidin e-4,6-diamine

A mixture of 2-chloro-4-isopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol -4-yl) pyridine (Preparation 49, 100 mg, 0.325 mmol), (S)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoro ethyl)pyrimidine-4,6-diamine (Preparation 13, 120 mg, 0.390 mmol), BrettPhos Pd G4 (0.2 equiv.) and CS ₂ CO ₃ (212 mg, 0.650 mmol) in dioxane was stirred at 100 °C overnight. The cooled solution was concentrated in vacuo and the residue was purified by column chromatography on silica gel (DCM/ MeOH= 10%) to give N4-(2,4-dimethoxybenzyl)-2-((S)-l- fhioroethyl)-N6-(4-isopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH -pyrazol-4-yl)pyridin-2- yl)pyrimidine-4,6-diamine. (50 mg, 27 %). LCMS m/z = 578 [M+H] ⁺

This was further separated by prep-SFC using an AD 20 x 250mm, 10pm (Daicel) column, mobile phase: CO ₂ /EtOH (0.2% MeOH/NFF) = 55/45, at 100 g/min to give:

First eluting Diastereoisomer 1: N4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6-(4- isopropoxy-5-(l-((R)-tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)p yridin-2-yl)pyrimidine-4,6- diamine or N4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6-(4-isoprop oxy-5-(l-((S)- tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidin e-4,6-diamine (Preparation 144), 16 mg and

Second eluting Diastereoisomer 2: N4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6- (4-isopropoxy-5-(l-((S)-tetrahydrofuran-3-yl)-lH-pyrazol-4-y l)pyridin-2-yl)pyrimidine-4,6- diamine orN4-(2,4-dimethoxybenzyl)-2-((S)-l-fluoroethyl)-N6-(4-isopr opoxy-5-(l-((R)- tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidin e-4,6-diamine (Preparation 145), 12 mg. [294] Preparation 146: l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino) pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl )-2-methylpropan-2-ol

A mixture of l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-2-met hylpropan- 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 CS ₂ CO ₃ (1.29 g, 3.98 mmol) in dioxane (12 mL) was stirred at 100°C for 16 h under N2. The mixture was poured into water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was concentrated in vacuo and the crude product was purified by silica gel chromatography (PE: EtOAc =1 : 10) to give the title compound (480 mg, 43.6%) as a yellow oil. LCMS m/z = 556 [M+H] ⁺ .

[295] Preparation 147: l-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4- dimethoxybenzyl)amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH- pyrazol-l-yl)-2- methylpropan-2-ol

A mixture of l-(4-(6-chloro-4-cyclopropoxypyridin-3-yl)-lH-pyrazol-l-yl)- 2-methyl propan-2-ol (Preparation 46, 900 mg, 2.93 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxy benzyl)pyrimidine-4,6-diamine (Preparation 5, 1 g, 3.22 mmol), Pd(t-Bu3P)2 (300 mg, 0.586 mmol) and CS ₂ CO ₃ (1.9 g, 5.86 mmol) in dioxane (20 mL) was stirred at 100°C for 16 h under N2. The cooled mixture was poured into water (80 mL) and extracted with EtOAc (100 mL x 3). The combined organic layer was concentrated in vacuo and the crude product was purified by silica gel chromatography (PE: EtOAc =1 : 10) to give the title compound (800 mg, 47.1%) as a beige solid. LCMS m/z = 582 [M+H] ⁺ . [296] Preparation 148: 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((l-fluoro propan-2-yl)oxy)-5-(l-methyl-lH-pyrazol-4-yl)pyridin-2-yl)py rimidine-4,6-diamine

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

[297] Preparation 149: N4-(5-(l-(2-((tert-butyldimethylsilyl)oxy)ethyl)-lH-pyrazol- 4-yl)- 4-cyclopropoxypyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimet hoxybenzyl)pyrimidine-4,6- diamine

The title compound was obtained, 80 mg, 29% yield, from 5-(l-(2-((tert-butyldimethyl silyl)oxy)ethyl)-lH-pyrazol-4-yl)-2-chloro-4-cyclopropoxypyr idine (Preparation 57) and 2- (difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine-4,6-diam ine (Preparation 5), following a similar procedure to that described in Preparation 147. LCMS m/z = 668 [M+H] ⁺

[298] Preparation 150: N4-(4-(difluoromethoxy)-5-(l-(2-(methylamino)propyl)-lH- pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimeth oxybenzyl)pyrimidine-4,6- diamine

The title compound was obtained, 80 mg, 71% yield, from l-(4-(4-(difluoromethoxy)-6- ((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin -4-yl)amino)pyridin-3-yl)-lH- pyrazol-l-yl)propan-2-one (Preparation 138) and MeNH ₂ , following a similar procedure to that described in Preparation 106. LCMS m/z = 591 [M+H] ⁺ .

[299] Preparation 151: l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl) amino)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazo l-l-yl)propan-2-ol

To a solution of l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)p yrimidin- 4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)propan-2- one (Preparation 121, 100 mg, 0.185 mmol) in MeOH (5 mL) was added NaBPL (21.0 mg, 0.56 mmol) and the reaction stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound as a white solid (50 mg, 50%). LCMS m/z = 542 [M+H] ⁺ .

[300] Preparation 152: 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(l-(2-

(dimethylamino)propyl)-lH-pyrazol-4-yl)-4-methoxypyridin- 2-yl)pyrimidine-4,6-diamine

To a solution of l-(4-(6-((2-(difluorornethyl)-6-((2,4-dimethoxybenzyl)amino) pyrimidin- 4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)propan-2- one (Preparation 121, 100 mg, 0.185 mmol) in DCM/MeOH (1/1, 5 mL) was added dimethylamine in THF (2 mL, 2 N) and AcOH (5 drops) and the solution stirred for 5 mins. Na(CN)BFL, (34.85 mg, 0.56 mmol) was added and the reaction stirred at rt for 16 h. The solution was concentrated in vacuo and the residue purified by silica gel chromatography to give the title compound as a yellow solid (65 mg, 62%) LCMS m/z = 569 [M+H] ⁺ .

[301] Preparation 153: N4-(4-cyclopropoxy-5-(l-(2-(methylamino)propyl)-lH-pyrazol-4 - yl)pyridin-2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl) pyrimidine-4,6-diamine

I l l

The title compound was obtained, 50 mg, 61% yield, from l-(4-(4-cyclopropoxy-6-((2- (difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-y l)amino)pyridin-3-yl)-lH- pyrazol-l-yl)propan-2-one (Preparation 130) and MeNTB following a similar procedure to that described in Preparation 106. LCMS m/z = 581 [M+H] ⁺ .

[302] Preparation 154: tert-butyl 3-(4-(6-((6-amino-2-(fluoromethyl)pyrimidin-4- yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)azetidine-l -carboxylate

To a solution of 2-(fluoromethyl)pyrimidine-4,6-diamine (Preparation 18, 15.58 mg, 0.11 mmol), tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)azetid ine-l- carboxylate (Preparation 83, 50 mg, 0.137 mmol) in dioxane (2 mL) was added BrettPhos Pd, G4 (12.62 mg, 0.0137 mmol) and CS ₂ CO ₃ (89.31 mg, 0.274 mmol) and the reaction stirred at 90°C for 2 h under N2. The cooled reaction mixture was concentrated under reduced pressure and the residue purified by prep-TLC (EtOAc: MeOH = 10: 1) to give the title compound (15 mg, 23.26%) as a yellow oil.

[303] Preparations 155 to 160

The compounds in the following table were prepared from 2-(difluoromethyl)pyrimidine- 4,6-diamine hydrochloride (Preparation 7) and the appropriate chloro-pyridine, following a similar procedure to that described in Preparation 154. [304] Preparations 161 and 162: tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl) pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl )pyrrolidine-l-carboxylate and tert-butyl (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino )-4-methoxy pyridin-3-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxylate

A mixture of tert-butyl 3-(4-(6-chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l- yl)pyrrolidine-l -carboxylate (Preparation 55, 160 mg, 0.422 mmol), 2-(difluoromethyl) pyrimidine-4,6-diamine (Preparation 8, 67.5 mg, 0.422 mmol), BrettPhos Pd G4 (77.65 mg, 0.084 mmol) and CS ₂ CO ₃ (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 Prep HPLC-3 to provide tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- methoxypyridin-3-yl)- lH-pyrazol-l-yl)pyrrolidine-l -carboxylate as a white solid (100 mg, 47%). LCMS m/z = 503 [M+H] ⁺

This was further purified by chiral SFC using an AD 20 x 250mm, 10pm (Daicel) column, mobile phase: CO2 MeOH (0.2% MeOH/NFE) = 60/40, at 80 g/min to give:

First eluting Enantiomer 1: tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin- 4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)pyrrolidi ne-l-carboxylate or tert-butyl (R)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino )-4-methoxypyridin-3-yl)-lH- pyrazol-l-yl)pyrrolidine-l-carboxylate (Preparation 161) and

Second eluting Enantiomer 2: tert-butyl (R)-3-(4-(6-((6-amino-2- (difluoromethyl)pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl) -lH-pyrazol-l-yl)pyrrolidine-l- carboxylate or tert-butyl (S)-3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino )-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxyla te (Preparation 162). [305] Preparations 163 and 164: tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl) pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl )methyl)azetidine-l- carboxylate and tert-butyl (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amin o)-

4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)methyl)azetidine-l -carboxylate tert-Butyl 2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4 -methoxy pyridin-3-yl)-lH-pyrazol-l-yl)methyl)azetidine-l-carboxylate was obtained as a white solid, 80 mg, 40% from 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) and tert-butyl 2-((4-(6- chloro-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)methyl)azetidi ne-l-carboxylate (Preparation 76), following the procedure described in Preparation 161 and 162. This was further purified by SFC using an AY 20 x 250mm, 10pm (Daicel) column, mobile phase: CCh/EtOH (0.5% MeOH/NFE) =65/35 Flow rate: 80 g/min to give:

First eluting Enantiomer 1 : tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl) pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl )methyl)azetidine-l -carboxylate or tert-butyl (S)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amin o)-4-methoxypyridin- 3 -yl)- IH-pyrazol- 1 -yl)methyl)azetidine- 1 -carboxylate (Preparation 163).

Second eluting Enantiomer 2: tert-butyl (S)-2-((4-(6-((6-amino-2-(difluorom ethyl) pyrimidin-4-yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl )methyl)azetidine-l -carboxylate or tert-butyl (R)-2-((4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amin o)-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)methyl)azetidine-l-carb oxylate (Preparation 164).

[306] Preparation 165: tert-butyl 3-(4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l- yl)azetidine-l-carboxylate

To tert-butyl 3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazo l-l-yl) azeti dine- 1 -carboxylate (1.5 g, 7.13 mmol) and 5-bromo-2-chloro-4-fluoropyridine (4.32 g, 12.8 mmol) in dioxane (30 mL) was added NaaCCE (3.78 g, 35.64 mmol), H ₂ O (5 mL) and Pd(PPh3)4 (4.12 g, 3.56 mmol) under N2 and the mixture stirred at 100 °C for 16 h. The reaction was diluted with EtOAc (50 mL) and extracted with H ₂ O (3x 20 mL). The combined organics were washed with H ₂ O (3x 10 mL), dried (ISfeSCU) and concentrated under reduced pressure. The residue was purified by column chromatography (ISCO®; 0-25% EtOAc/PE) to afford the title compound as a yellow oil (1.6 g, 57%).

[307] Preparation 166: tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l- yl)ethyl)carbamate

The title compound was prepared from tert-butyl (2-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethyl)carbamate and 5-bromo-2-chloro-4-fluoropyridine using an analogous method to that described for Preparation 165. (400 MHz, DMSO- d ₆ ) 8: 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)

[308] Preparation 167: tert-butyl (2-(4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l- yl)ethyl)(methyl)carbamate tert-Butyl (2-(4-(6-chloro-4-fluoropyri din-3 -yl)- IH-pyrazol- 1 -yl)ethyl)carbamate (Preparation 166, 1.0 g, 2.93 mmol) was dissolved in THF (10.0 mL), then NaH (176.0 mg, 4.40 mmol, 60.0% purity) and Mel (625.0 mg, 4.40 mmol) were added at 0 °C under N2 and the reaction stirred at 25 °C for 2 h. The reaction mixture was washed with H ₂ O (5 mL), dried over MgSCL, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ISCO®; 0-20% EtOAc/PE) to give the title compound (0.86 g, 74.3% yield) as a white solid. [309] Preparation 168: tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4- yl)amino)-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)azetidine-l- carboxylate

To a solution of tert-butyl 3-(4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l- yl)azeti dine- 1 -carboxylate (Preparation 165, 1.6 g, 4.08 mmol) and 2-(difluoromethyl) pyrimidine-4,6-diamine (Preparation 8, 726 mg, 4.08 mmol) in t-AmOH (30 mL) was added BrettPhos Pd G3 (370 mg, 0.408 mmol) and CS ₂ CO ₃ (2.66 g, 8.16 mmol) under N2 and the mixture stirred at 120 °C for 2 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with H ₂ O 30 mL (10 mL x 3). The combined organics were dried (ISfeSCU) and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography ((ISCO®; 0-75% EtOAc/PE) to afford the title compound as a yellow solid (800 mg, 41%).

[310] Preparation 169: tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4- yl)amino)-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)ethyl)carbam ate

The title compound was prepared as a white solid (380 mg, 40%) from tert-butyl (2-(4- (6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)ethyl)carbam ate (Preparation 166) and 2- (difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) using an analogous method to that described for Preparation 168. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ : 10.09 (s, 1 H) 8.59 (d, 1H), 8.14-8.04 (m, 1H), 7.95 (s, 1H), 7.57-7.48 (m, 1H), 7.02-6.96 (m, 2H), 6.68-6.64 (m, 1H), 6.54 (s, 1H), 6.45 (s, 1H), 4.19 (br t, 2H), 3.41 (br d, 2H), 1.36 (s, 10H). [311] Preparation 170: tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4- yl)amino)-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)ethyl)(methy l)carbamate

The title compound was prepared as a yellow solid (860 mg, 42.7%) from tert-butyl (2- (4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)ethyl)(me thyl)carbamate (Preparation 167) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8) using an analogous method to that described for Preparation 168.

1H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.09 (s, 1H) 8.58 (d, 1H) 8.10 (d, 1H) 7.95 (s, 1H) 7.52 (d, 1H) 6.99 (br s, 1H) 6.64 (s, 1H) 6.54 (s, 1H) 4.35-4.23 (m, 3H) 3.63-3.54 (m, 3H) 2.75-2.64 (m, 4H) 1.36 (s, 9H)

[312] Preparation 171: 2-(difluoromethyl)-N4-(4-fluoro-5-(l-methyl-lH-pyrazol-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine

To a solution of 2-chloro-4-fluoro-5-(l -methyl- lH-pyrazol-4-yl)pyri dine (Preparation 97, 1.9 g, 8.98 mmol) and 2-(difhioromethyl)pyrimidine-4,6-diamine (Preparation 8, 1.73 g, 10.77 mmol) in t-AmOH (40 mL) was added CS ₂ CO ₃ (8.78 g, 26.93 mmol) and BrettPhos Pd G3 (407 mg, 0.449 mmol,) under N2 and the mixture stirred at 120 °C for 2 h. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with H ₂ O (30 mL) and extracted with EtOAc (3x 20 mL). The combined organics were washed with H ₂ O (3x 20 mL), dried ( Na ₂ SO ₄ ) and evaporated to dryness in vacuo to give the title compound as a brown solid (1.7 g, 54%). LCMS m/z = 336 [M+H] ⁺ . [313] Preparation 172: (4,6-dichloropyrimidin-2-yl)methyl acetate

A mixture of 4,6-dichloro-2-(chloromethyl)pyrimidine (1.5 g, 7.59 mmol) and Nal (1.69 g, 11.3 mmol) in acetone (50 mL) was stirred at rt for 1 h. The mixture was concentrated in vacuo, the residue was diluted with dioxane/LLO (1 : 1, 50 mL), KOAc (1.48 g, 15.1 mmol) added and the reaction was stirred at 60 °C for 16 h. The mixture was concentrated in vacuo and the residue purified by column chromatography (1 : 10 EtOAc/PE) to afford the title compound as a colourless oil (1.5 g, 89%). LCMS m/z = 221 [M+H] ⁺ .

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

A mixture of (4,6-dichloropyrimidin-2-yl)methyl acetate (Preparation 172, 700 mg, 3.16 mmol), diphenylmethanimine (1.14 g, 6.32 mmol), CS ₂ CO ₃ (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 in vacuo and the residue purified by column chromatography (1 : 10 MeOH/DCM) to afford the title compound as a yellow solid (500 mg, 33%). LCMS m/z = 469 [M+H] ⁺ .

[315] Preparation 174: (4,6-diaminopyrimidin-2-yl)methanol

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 in vacuo and the residue treated with NH3 in MeOH to adjust the pH to ~10. The resulting mixture was evaporated to dryness in vacuo and the residue purified by column chromatography (1 : 10 MeOH/DCM) to afford the title compound as a white solid (120 mg, 81%). LCMS m/z = 141 [M+H] ⁺ . [316] Preparation 175: 6-chloro-4-fluoronicotinic acid

To a solution of 2-chloro-4-fluoro-5-iodopyridine (70.0 g, 272 mmol) in THF (700 mL) was added i-PrMgCl (2.00 M, 136 mL) at 0 °C under N2. After 1 h at 0 °C the reaction mixture was stirred at 0 °C under CO2 for 30 mins. The reaction mixture was poured into H ₂ O (1 L) and washed with EtOAc (2x 500 mL). Then combined aqueous phase was adjusted pH = 1 ~ 2 with IN HC1 (600 mL) and extracted with EtOAc (3x 400 mL). The combined organics were dried (Na ₂ SO ₄ ) and concentrated under reduced pressure to afford the title compound as a yellow solid (25.5 g, 52 %). LCMS m/z = 176 [M+H] ⁺ .

[317] Preparation 176: 6-chloro-4-fluoro-N-methylnicotinamide

To a solution of 6-chloro-4-fluoronicotinic acid (Preparation 175, 11.48 g, 65.40 mmol) and methylamine hydrochloride (4.42 g, 65.40 mmol) in MeCN (120 mL) was slowly added T3P (83.23 g, 130.79 mmol, 50% purity) and DIPEA (16.9 g, 130.79 mmol) and the mixture stirred at 25 °C for 16 h. The reaction mixture was diluted with H ₂ O (50 mL) and extracted with EtOAc (3x 100 mL). The combined organics were washed with brine (100 mL), dried (MgSO4) and evaporated to dryness in vacuo to afford the title compound as a yellow solid (8.7 g, 71%) which was used without further purifcation. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ : 8.63 (d, 1H) 8.54 (br s, 1H) 7.77 (d, 1H) 2.79 (d, 3H)

[318] Preparation 177: 4,6-dichloro-N-methylnicotinamide

A drop of DMF was added to a mixture of 4, 6-di chloronicotinic acid (10 g, 52 mmol) in SOCh (50 mL) and the mixture stirred at 70 °C for 2 h. The reaction mixture was evaporated to dryness in vacuo and the residue diluted with THF (50 mL) and added to a solution of MeNH ₂ .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 H ₂ O and extracted with EtOAc. The combined organics were washed with H ₂ O and brine, dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo. The residue was purified by column chromatography (10: 1 to 5: 1 PEZEtOAc) to afford the title compound as a yellow solid (8 g, 75%). LCMS m/z = 205 [M+H] ⁺ .

[319] Preparation 178: 4,6-dichloro-N-cyclopropylnicotinamide

A mixture of 4,6-dichloronicotinic acid (1 g, 5.2 mmol), cyclopropanamine (297 mg, 5.2 mmol), HATU (3 g, 7.8 mmol) and TEA (1.6 g, 15.6 mmol) in DMF (20 mL) was stirred at rt for 12 h under N2. The mixture concentrated in vacuo and the residue purified by column chromatography (50% EtOAc/PE) to afford the title compound (800 mg, 66%). LCMS m/z = 231 [M+H] ⁺ .

[320] Preparation 179: tert-butyl 6-(4,6-dichloronicotinamido)-2-azaspiro[3.3]heptane-2- carboxylate

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 for 12 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue was purified by column chromatography (50% EtOAc/PE) to afford the title compound (900 mg, 74%). LCMS m/z = 386 [M+H] ⁺ .

[321] Preparation 180: 6-chloro-N-methyl-4-(methylamino)nicotinamide

MeNH ₂ in THF (20 mL, 2N) was added to a mixture of 4,6-dichloro-N-methyl nicotinamide (Preparation 177, 300 mg, 1.46 mmol) in DCM (20 mL) and the mixture stirred at rt for 2 h. The mixture was evaporated to dryness in vacuo and purified by column chromatography (1 :5 EtOAc /PE) to give the title compound as a colourless oil (300 mg, 100%).

LCMS m/z = 200 [M+H] ⁺ .

[322] Preparation 181: 6-chloro-4-(isopropylamino)-N-methylnicotinamide

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

[323] Preparation 182: 6-chloro-N-cyclopropyl-4-(methylamino)nicotinamide

A solution of 4,6-dichloro-N-cyclopropylnicotinamide (Preparation 178, 800 mg, 3.5 mmol), methanamine (323 mg, 10.4 mmol) and DIPEA (1.3 g, 10.4 mmol) in MeCN (20 mL) was stirred at rt for 16 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography (50% EtOAc/PE) to afford the title compound (500 mg, 64%). LCMS m/z = 226 [M+H] ⁺ .

[324] Preparation 183: tert-butyl 6-(6-chloro-4-(ethylamino)nicotinamido)-2-azaspiro

[3.3] heptane-2-carboxylate

The title compound was prepared from tert-butyl 6-(4,6-dichloronicotinamido)-2- azaspiro[3.3]heptane-2-carboxylate (Preparation 179) and ethylamine using an analogous method to that described for Preparation 182. Yield: 600 mg, 65%; LCMS m/z = 395 [M+H] ⁺ . [325] Preparation 184: 6-chloro-4-(ethylamino)-N-methylnicotinamide

To a solution of 4,6-dichloro-N-methylnicotinamide (Preparation 177, 190 mg, 0.927 mol) and ethylamine hydrochloride (90.7 mg, 1.11 mmol) in n-BuOH (5 mL) was added DIPEA (359 mg, 2.78 mmol) and the mixture heated at 100 °C for 1 h. The reaction mixture was evaporated to dryness, diluted with H ₂ O and extracted with EtOAc (3x 10 mL). The combined organics were dried (Na ₂ SO ₄ ) and evaporated to dryness in vacuo to afford the title compound as a yellow solid (150 mg). LCMS m/z = 214 [M+H] ⁺ .

[326] Preparation 185: 6-chloro-N-cyclopropyl-4-(ethylamino)nicotinamide

To a mixture of ethanamine hydrochloride (186 mg, 2.28 mmol) and 4,6-dichloro-N- cyclopropylnicotinamide (Preparation 178, 440 mg, 1.90 mmol) in n-BuOH (4 mL) was added DIPEA (738 mg, 5.71 mmol) and the resulting mixture 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 prep-HPLC-6, to give the title compound as a gray gum (100 mg, 22%). LCMS m/z = 240 [M+H] ⁺ .

[327] Preparation 186: (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)-N-methyl nicotinamide

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

[328] Preparation 187: 6-chloro-4-((l,3-difluoropropan-2-yl)amino)-N-methyl nicotinamide

The title compound was prepared from 4,6-dichloro-N-methylnicotinamide (Preparation 177) and l,3-difluoropropan-2-amine using an analogous method to that described for Preparation 186. The compound was additionally purified by Prep HPLC-3 to afford the title compound as a white solid (60 mg, 18%). LCMS m/z = 264 [M+H] ⁺ .

[329] Preparation 188: (R)-6-chloro-4-((l,l-difluoropropan-2-yl)amino)-N-methyl nicotinamide

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

[330] Preparation 189 to 198

The title compounds were prepared from the appropriate chloropyridine (RC1) and amine (RNH ₂ ) using an analogous method to that described for Preparation 188.

[331] Preparation 199: (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)-N-(pyridin-2-yl methyl)nicotinamide

Part 1: A mixture of 4,6-dichloropyridine-3-carboxylic acid (500 mg, 2.60 mmol) and oxalyl chloride (659 mg, 5.20 mmol) in THF (10 mL) was stirred at rt for 2 h. The mixture was concentrated in vacuo and the residue and dissolved in THF (10 mL) and DIPEA (1006 mg, 7.80 mmol) and l-(pyri din-2 -yl)methanamine (421 mg, 3.90 mmol) added and the resulting mixture stirred at rt for 2 h. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography (SiO ₂ , 25% EtOAc/PE) to afford 4,6-dichloro-N-(pyridin-2- ylmethyl)nicotinamide as a white solid (470 mg, 63%).

Part 2: A mixture of 4,6-dichloro-N-(pyridin-2-ylmethyl)nicotinamide (200 mg, 0.708 mmol), (2S)-l-fluoropropan-2-amine hydrochloride (96.4 mg, 0.849 mmol) and DIPEA (273 mg, 2.12 mmol) in dioxane (4 mL) and stirred at 140 °C for 16 h. The cooled mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with EtOAc/PE (1/3) to give the title compound (180 mg, 79% yield) as a white solid. LCMS mz = 323 [M+H] ⁺ . [332] Preparation 200: 6-chloro-4-(ethylamino)-N-(oxazol-4-ylmethyl)nicotinamide

4,6-Dichloro-N-(oxazol-4-ylmethyl)nicotinamide was prepared as a yellow solid, 300 mg, 67%, from l-(l,3-oxazol-4-yl)methanamine hydrochloride and 4,6-dichloropyridine-3- carboxylic acid using s similar method to that described for Preparation 199, Part 1.

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

[333] Preparation 201: 6-chloro-4-(isopropylamino)nicotinic acid

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

[334] Preparation 202: 6-chloro-4-(ethylamino)nicotinic acid

A mixture of methyl 6-chloro-4-(ethylamino)nicotinate (600 mg, 2.79 mmol) and NaOH (6 mL, 2M in water) in EtOH (6 mL) was stirred at 80 °C for 1 h. The mixture was cooled to 0 °C, the pH adjusted to 4-5 with HC1 (2M) and the solid filtered off to give the title compound (500 mg, yield: 89%). LCMS m/z = 201 [M+H] ⁺ . [335] Preparation 203: 6-chloro-4-(cyclopropylamino)nicotinic acid

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

A solution of methyl 6-chloro-4-(cyclopropylamino)nicotinate (1.2 g,5.29 mmol) and LiOH (378 mg, 15.8 mmol) in MeOH (6 mL), H ₂ O (6 mL) and THF (6 mL) was stirred at rt for 16 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (50% EtOAc/PE) to afford the title compound as a white solid (1.1g, 98%). LCMS m/z = 213 [M+H] ⁺ .

[336] Preparation 204: 6-chloro-N-cyclopropyl-4-(cyclopropylamino)nicotinamide

HATU (535 mg, 1.41 mmol) and TEA (213 mg, 2.11 mmol) were added to a mixture of 6-chloro-4-(cyclopropylamino)nicotinic acid (Preparation 203, 150 mg, 0.705 mmol) and cyclopropanamine (59.9 mg, 1.05 mmol) in DMF (8 mL) and the mixture stirred at rt for 16 h under N2. The reaction mixture was diluted with EtOAc and washed with water. The organic layer was concentrated in vacuo and the residue purified by column chromatography on silica gel (1 : 1 EtOAc/PE) to afford the title compound as a white solid (1 lOmg, 62%). LCMS m/z = 252 [M+H] ⁺ .

[337] Preparation 205 to 220

The title compounds were prepared from the appropriate carboxylic acid and amine using an analogous method to that described for Preparation 204.

^A DCM was reaction solvent

^B DIPEA was used instead of TEA [338] Preparation 222: methyl (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)nicotinate

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

[339] Preparation 223: (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)nicotinic acid

A mixture of methyl (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)ni cotinate (Preparation 222, 200 mg, 0.81 mmol), LiOH (57.9 mg, 2.42 mmol) and H ₂ O (1 mL) in THF (4 mL) was stirred at rt for 16 h. HC1 (IN) was added to adjust the pH = 3, the mixture was diluted with water and extracted with EtOAc. The combined organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give the title compound (200 mg, 100% yield) as a white solid. LCMS m/z = 233 [M+H] ⁺ .

[340] Preparation 224: (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)-N-(3-(hydroxy methyl)bicyclo[l.l.l]pentan-l-yl)nicotinamide

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

[341] Preparation 225: 5-bromo-2-chloro-N-(oxetan-3-yl)pyridin-4-amine

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

[342] Preparation 226: 5-bromo-2-chloro-N-methylpyridin-4-amine

N Cl

..v NHMe

The title compound was prepared from 5-bromo-2,4-dichloropyridine and methylamine using an analogous method to that described for Preparation 225. LCMS m/z = 221 [M+H] ⁺

[343] Preparation 227: 2-chloro-5-(5-methyl-l,3,4-thiadiazol-2-yl)-N-(oxetan-3-yl)p yridin- 4-amine

Part 1. To a solution of bis(pinacolato)diboron (925 mg, 3.64 mmol) and 5-bromo-2- chloro-N-(oxetan-3-yl)pyridin-4-amine (Preparation 225, 800 mg, 3.04 mmol) in dioxane (5 mL) was added Pd(dppf)C12.DCM (248 mg, 0.304 mmol) and KOAc (596 mg, 6.07 mmol) and the reaction was heated at 90 °C for 2 h under N2. The reaction mixture was evaporated to dryness in vacuo to afford 2-chloro-N-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2-dioxab orolan-2- yl)pyridin-4-amine as a yellow oil (crude).

Part 2. To a solution of 2-chloro-N-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyridin-4-amine (Part 1) and 2-bromo-5-methyl-l,3,4-thiadiazole (470 mg, 2.63 mmol) in dioxane (5 mL) and H ₂ O (0.20 mL) was added XPhos Pd G2 (207 mg, 0.263 mmol) and K3PO4 (1.12 g, 5.25 mmol) and the resulting mixture heated at 80 °C for 2 h under N2. The reaction mixture was evaporated to dryness and the residue purified by prep-HPLC-9, to give the title compound as a yellow oil (60 mg, 8%). LCMS m/z = 283 [M+H] ⁺

[344] [001] Preparation 228: 2-chloro-N-methyl-5-(5-methyl-l,3,4-thiadiazol-2- yl)pyridin-4-amine

The title compound was prepared from 5-bromo-2-chloro-N-methylpyridin-4-amine and

2-bromo-5-methyl-l,3,4-thiadiazole using an analogous method to that described for Preparation

227, except Prep HPLC-3 was used. LCMS m/z = 241 [M+H] ⁺

[345] Preparation 229: 2,4-dichloro-5-((trimethylsilyl)ethynyl)pyridine

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

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

[347] Preparation 231: 2,4-dichloro-5-(lH-l,2,3-triazol-4-yl)pyridine

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

[348] Preparation 232 and 233: 2,4-dichloro-5-(l-methyl-lH-l,2,3-triazol-4-yl)pyridine and 2,4-dichloro-5-(2-methyl-2H-l,2,3-triazol-4-yl)pyridine

To a solution of 2,4-dichloro-5-(lH-l,2,3-triazol-4-yl)pyridine (Preparation 231, 100 mg, 0.47 mmol) in THF (5 mL) was added TBAF (243 mg, 0.93 mmol) and Mel (792 mg, 0.56 mmol) at 0 °C and the mixture stirred at rt for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine and water. The combined organics were concentrated and purified by column chromatography on silica gel (50% EtOAc/PE) to afford 2,4-dichloro-5-(l- methyl-lH-l,2,3-triazol-4-yl)pyridine as a yellow solid (70 mg, 45%). LCMS m/z = 229 [M+H] ⁺ and 2,4-dichloro-5-(2-methyl-2H-l,2,3-triazol-4-yl)pyridine as a yellow solid (40 mg, 28%). LCMS m/z = 229 [M+H] ⁺ [349] Preparation 234: 2-chloro-N-methyl-5-(l-methyl-lH-l,2,3-triazol-4-yl)pyridin- 4- amine

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

[350] Preparation 235: 2-chloro-N-methyl-5-(2-methyl-2H-l,2,3-triazol-4-yl)pyridin- 4- amine

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

[351] Preparation 236: 2-chloro-5-iodo-N-methylpyridin-4-amine

Methanamine (34 mg, 1.1 mmol) was added to a solution of 2, 4-di chi oro-5 -iodopyridine (300 mg, 1.1 mmol) and DIPEA (426 mg, 3.3 mmol) in MeCN (5 mL) and the resulting mixture stirred at rt for 16 h under N2. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel (50% EtOAc/PE) to afford the title compound (240 mg, 81%). LCMS m/z = 269 [M+H] ⁺ [352] Preparation 237: 2-chloro-N-methyl-5-(5-methylthiazol-2-yl)pyridin-4-amine

A solution of 2-chloro-5-iodo-N-methylpyridin-4-amine (Preparation 236, 120 mg, 0.45 mmol), 5-methyl-2-(tributylstannyl)thiazole (173.5 mg, 0.447 mmol), Pd(PPh3)Ch (470.3 mg, 0.67 mmol) and K ₂ CO ₃ (180 mg, 1.3 mmol) in DMF (4 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (5% MeOH/DCM) to afford the title compound (100 mg, 93%). LCMS m/z = 240 [M+H] ⁺

[353] Preparation 238: 2-(6-chloro-4-fluoropyridin-3-yl)-5-methyl-l,3,4-thiadiazole

Under an inert atmosphere of N2 were combined 2-bromo-5-methyl-l,3,4-thiadiazole (160 g, 894 mmol), dioxane (2.4 L), DMF (0.48 L), 2-chloro-4-fluoro-5-(tetramethyl-l,3,2- dioxaborolan-2-yl)pyridine (340 g, 1.32 mol), Na ₂ CO ₃ (285.8 g, 2.70 mol), Pd(dppf)C12.DCM (36.6 g, 44.91 mmol) and CuCl (89 g, 899 mmol) and the resulting mixture stirred for 4 h at 80 °C. The reaction mixture was cooled to rt and diluted with EtOAc (2 L). The solids were removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography on silica gel (5-50% EtOAc/PE) and the resulting solid recrystallised from toluene to afford the title compound as a yellow solid (45g, 22%).

[354] Preparation 239: 2-(bromomethyl)-5-(6-chloro-4-fluoropyridin-3-yl)-l,3,4- thiadiazole

A mixture of 2-(6-chloro-4-fluoropyridin-3-yl)-5-methyl-l,3,4-thiadiazole (Preparation

238, 200 mg, 0.87 mmol), NBS (195 mg, 0.87 mmol) and AIBN (14 mg, 0.08 mmol) in CCI4 (10 mL) was stirred at 90 °C for 16 h. The mixture was evaporated in vacuo and the residue purified by column chromatography on silica gel (10: 1 PEZEtOAc) to give the title compound (50 mg, 18%). LCMS m/z = 308 [M+H] ⁺

[355] Preparation 240: (5-(6-chloro-4-fluoropyridin-3-yl)-l,3,4-thiadiazol-2-yl)met hyl acetate

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

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

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

[357] Preparation 242: (5-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino) pyrimidin-4-yl)amino)-4-(methylamino)pyridin-3-yl)-l,3,4-thi adiazol-2-yl)methanol

A mixture of (5-(6-chloro-4-(methylamino)pyridin-3-yl)-l,3,4-thiadiazol-2 -yl)methanol (Preparation 241, 11 mg, 0.04 mmol), 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)pyrimidine- 4,6-diamine (Preparation 5, 14 mg, 0.04 mmol), BrettPhos Pd G4 (2 mg) and CS ₂ CO ₃ (39 mg, 0.12 mmol) in dioxane (2 mL) was stirred at 100 °C under N2 for 16 h. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel (1 :20 MeOH/DCM) to afford the title compound (12 mg, 56%). LCMS m/z = 531 [M+H] ⁺ .

[358] Preparation 243 to 246 The title compounds were prepared from 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl) pyrimidine-4,6-diamine (Preparation 5) and the appropriate chloropyridine (RC1) using an analogous method to that described for Preparation 242.

[359] Preparation 247 and 248: N-(cyanomethyl)-6-((2-(difluoromethyl)-6-((2,4- dimethoxybenzyl)amino)pyrimidin-4-yl)amino)-4-(methylamino)n icotinamide and 6-((2-

(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin- 4-yl)amino)-4- (methylamino)nicotinamide

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-di amine (Preparation 5, 296 mg, 0.955 mmol), BrettPhos Pd G4 (80 mg, 0.087 mmol) and CS ₂ CO ₃ (848 mg, 2.60 mmol) in dioxane (4.34 mL) was purged with N2 for 5 min before stirring at 100 °C overnight. The reaction mixture was filtered and the filtrate washed with 10% MeOH in DCM. The combined organics were concentrated and the residue purified by reverse-phase chromatography on silica gel (20-100% MeCN/LBO (+0.1% TFA) to afford the title compounds.

N-(cyanomethyl)-6-((2-(difluoromethyl)-6-((2,4-dimethoxyb enzyl)amino)pyrimidin-4- yl)amino)-4-(methylamino)nicotinamide (Preparation 247, 29 mg, 6.7%); LCMS m/z = 499 [M+H] ⁺ .

6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyri midin-4-yl)amino)-4- (methylamino)nicotinamide (Preparation 248, 47 mg, 11.8%); LCMS m/z = 460 [M+H] ⁺ .

[360] Preparation 249: (R)-6-((6-((2,4-dimethoxybenzyl)amino)-2-(l-fluoroethyl) pyrimidin-4-yl)amino)-4-(isopopylamino)-N-methylnicotinamide

A mixture of 6-chloro-4-(isopropylamino)-N-methylnicotinamide (Preparation 181, 50 mg, 0.22 mmol), (R)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidine-4,6 -diamine (Preparation 14, 67.3 mg, 0.22 mmol), BrettPhos Pd G4 (40.5 mg, 0.044 mmol) and CS ₂ CO ₃ (215 mg, 0.659 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 h under N2. The mixture was concentrated in vacuo and the residue was purified column chromatography on silica gel (5% MeOH/DCM) to afford the title compound (50 mg, 45%). LCMS m/z = 498 [M+H] ⁺ .

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

A mixture of 6-chloro-4-(ethylamino)-N-m ethylnicotinamide (Preparation 184, 60 mg, 0.280 mmol), (R)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)pyrimidine-4,6 -diamine (Preparation 14, 85.7 mg, 0.280 mmol), CS ₂ CO ₃ (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 for 16 h under N2. The reaction mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel eluting with MeOH/DCM (1/20) to afford the title compound as a white solid (60 mg, 44%).

LCMS m/z = 484 [M+H] ⁺ .

[362] Preparations 251 to 254

The title compounds were prepared from the appropriate chloropyridine (RC1) and the appropriate amine (RNH ₂ ) using an analogous method to that described for Preparation 250. Alternative catalyst systems used are noted in the table.

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

A solution of 6-dichloro-2-(difluoromethyl)pyrimidine (Preparation 2, 330 mg, 1.65 mmol), 2-methylpropan-2-amine (361 mg, 4.94 mmol) and DIPEA (252 mg, 4.95 mmol) in NMP was stirred at 100 °C for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with brine and H ₂ O. The combined organics were evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (50% EtOAc/PE) to afford the title compound as a yellow solid (300 mg, 77%). LCMS m/z = 236 [M+H] ⁺ . [364] Preparation 256: 6-((diphenylmethylene)amino)-4-(isopropylamino)-N-(oxazol-4- ylmethyl)nicotinamide

A mixture of 6-chloro-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamid e (Preparation 220, 500 mg, 1.81 mmol), diphenylmethanimine (360 mg, 1.99 mmol), Pd2(dba)3 (50 mg), XantPhos (50 mg) and CS ₂ CO ₃ (1.18 g, 3.62 mmol) in dioxane (100 mL) was stirred at 100 °C for 16 h. The mixture was concentrated in vacuo and the residue purified by column chromatography on silica gel (20: 1 DCM/MeOH) to afford the title product (398 mg, 50%). LCMS m/z = 440 [M+H] ⁺ .

[365] Preparation 257: 6-amino-4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide

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

[366] Preparation 258: 6-((6-(tert-butylamino)-2-(difluoromethyl)pyrimidin-4-yl)ami no)- 4-(isopropylamino)-N-(oxazol-4-ylmethyl)nicotinamide

A mixture of compound N-(tert-butyl)-6-chloro-2-(difluoromethyl)pyrimidin-4-amine (Preparation 255, 120 mg, 0.509 mmol), 6-amino-4-(isopropylamino)-N-(oxazol-4-ylmethyl) nicotinamide (Preparation 257, 150 mg, 0.509 mmol), Pd2(dba)3 (93.2 mg, 0.102 mmol), XantPhos (58.9 mg, 0.102 mmol) and CS ₂ CO ₃ (498 mg, 1.5 mmol) in dioxane ( 2 mL) was stirred at 100 °C for 12 h. The reaction mixture was evaporated to dryness in vacuo and the residue and purified by column chromatography on silica gel (5% MeOH/DCM) to afford the title compound as a yellow solid (100 mg, 41%). LCMS m/z = 475 [M+H] ⁺ .

[367] Preparation 259: 6-((6-amino-2-(hydroxymethyl)pyrimidin-4-yl)amino)-4-

(isopropylamino)-N-methylnicotinamide

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), CS ₂ CO ₃ (278 mg, 0.856 mmol) and Brettphos Pd 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 in vacuo and the residue purified by Prep-HPLC-3 to get the title compound as a white solid (40 mg, 28%). LCMS m/z = 332 [M+H] ⁺ .

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

To a mixture of 6-chloro-4-fluoro-N-methylnicotinamide (Preparation 176, 1.4 g, 7.45 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 4.77 g, 29.8 mmol) and CS ₂ CO ₃ (7.26 g, 22.35 mmol), BrettPhos Pd G3 (337.49 mg, 0.373 mmol) in t-AmOH (60 mL) was degassed and purged (x3) with N2 and the mixture stirred at 120 °C for 2 h under N2. The reaction mixture was concentrated under reduced pressure and H ₂ O (30 mL) added. The mixture was extracted with EtOAc (3x 30 mL). The resulting solids were removed by filtration and the filtrate evaporated to dryness in vacuo to afford the title compound (1.5 g, 45%) which was used without further purification. LCMS m/z = 313 [M+H] ⁺ . [369] Preparation 261: 5-(4,6-dichloropyridin-3-yl)-3-methyl-l,2,4-oxadiazole

N Cl

O f J y i M/

Part 1. A mixture of compound 4, 6-di chloronicotinamide (2 g, 10 mmol) and 1,1- dimethoxy-N,N-dimethylethan-l -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 organics were evaporated to dryness in vacuo to afford (E)-4, 6-di chi oro-N-(l- (dimethylamino)ethylidene)nicotinamide (2 g) which was without further purification. LCMS m/z = 260 [M+H] ⁺ .

Part 2. A mixture of the compound of Part 1 (2 g, 7.7 mmol), NH ₂ OH (492 mg, 15.4 mmol) and AcOH (1 mL) in dioxane/water (20 mL/1 mL) was stirred at 70 °C for 1 h. The reaction mixture was concentrated and purified by column chromatography on silica gel (5: 1 PE/ EtOAc) to give the title compound (700 mg, 39%). LCMS m/z = 230 [M+H] ⁺ .

[370] Preparation 262: 2-chloro-N-isopropyl-5-(3-methyl-l,2,4-oxadiazol-5-yl)pyridi n-4- amine

A mixture of 5-(4,6-dichloropyridin-3-yl)-3-methyl-l,2,4-oxadiazole (700 mg, 3.0 mmol) and propan-2-amine (360 mg, 6.1 mmol) in EtOH (20 mL) was stirred at 80 °C for 16 h. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (20: 1 DCM/MeOH) to afford the title compound (600 mg, 79%). LCMS m/z = 253 [M+H] ⁺ . [371] Preparation 263: N2-benzyl-N4-isopropyl-5-(3-methyl-l,2,4-oxadiazol-5-yl) pyridine-2,4-diamine

A mixture of 2-chloro-N-isopropyl-5-(3-methyl-l,2,4-oxadiazol-5-yl)pyridi n-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 was diluted with EtOAc and washed with brine and water. The organics were evaporated to dryness in vacuo and the residue was purified by column chromatography on silica gel (5% MeOH/DCM) to afford the title compound as a yellow solid (230 mg, 82%). LCMS m/z = 324 [M+H] ⁺ .

[372] Preparation 264: N4-isopropyl-5-(3-methyl-l,2,4-oxadiazol-5-yl)pyridine-2,4- diamine

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

[373] Preparation 265: N4-(tert-butyl)-2-(difluoromethyl)-N6-(4-(isopropylamino)-5- (3- methyl-l,2,4-oxadiazol-5-yl)pyridin-2-yl)pyrimidine-4,6-diam ine 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-l,2,4-oxadiazol-5-yl)pyridine-2,4-d iamine (Preparation 264, 98.9 mg, 0.424 mmol), Pd(t-Bu3P)2 (43.3 mg, 0.085 mmol) and CS ₂ CO ₃ (414 mg, 1.3 mmol) in dioxane (2 mL) was stirred at 100 °C for 16 h. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (5% MeOH/DCM) to afford the title compound as a white solid (80 mg, 44%). LCMS m/z = 433 [M+H] ⁺ .

[374] Preparation 266: tert-butyl 6-(6-((6-amino-2-(difluoromethyl)pyrimidin-4- yl)amino)-4-(ethylamino)nicotinamido)-2-azaspiro[3.3]heptane -2-carboxylate

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

[375] Preparation 267: methyl 6-chloro-4-(((lR,2S)-2-fluorocyclopropyl)amino)nicotinate

A mixture of methyl 6-chloro-4-fluoropyridine-3-carboxylate (300 mg, 1.58 mmol), (lR,2S)-2-fhiorocyclopropan-l-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 in vacuo and the residue was purified by column chromatography on silica gel (1 :5 EtOAc/PE) to afford the title compound as a white solid (120 mg, 31%). LCMS m/z = 245 [M+H] ⁺ . [376] Preparation 268: methyl 6-chloro-4-(((lS,2R)-2-fluorocyclopropyl)amino)nicotinate

The title compound we prepared as a white solid (100 mg, 26%) from methyl 6-chloro-4- fluoropyridine-3 -carboxylate and (lS,2R)-2-fluorocyclopropan-l-amine 4-methylbenzene sulfonate using an analogous method to that described for Preparation 267. LCMS m/z = 245 [M+H] ⁺ .

[377] Preparation 269: methyl 6-((4-(difluoromethyl)-6-((3,5-dimethoxybenzyl) amino)pyridin-2-yl)amino)-4-(((lR,2S)-2-fluorocyclopropyl)am ino)nicotinate The title compound was prepared as a white solid (60 mg, 28%) from methyl 6-chloro-4-

(((lR,2S)-2-fluorocyclopropyl)amino)nicotinate (Preparation 267) and 2-(difluoromethyl)-N4- (2,4-dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 5) using a similar method to that described for Preparation 242. LCMS m/z = 519 [M+H] ⁺ .

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

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

[379] Preparation 271: 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin- 2- yl)amino)-4-(((lR,2S)-2-fluorocyclopropyl)amino)-N-methylnic otinamide

Methyl 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin- 2-yl)amino)-4- (((lR,2S)-2-fluorocyclopropyl)amino)nicotinate (60 mg, 0.115 mmol) in MeNH ₂ (30% in MeOH, 5 mL) was stirred at 70 °C for 16 h in a sealed vessel. The mixture was concentrated in vacuo to afford the title compound as a white solid (60 mg, 100%). LCMS m/z = 518 [M+H] ⁺ .

[380] Preparation 272: 6-((4-(difluoromethyl)-6-((3,4-dimethylbenzyl)amino)pyridin- 2- yl)amino)-4-(((lS,2R)-2-fluorocyclopropyl)amino)-N-methylnic otinamide

The title compound was prepared as a white solid (60 mg, 100%) from methyl 6-((4- (difluoromethyl)-6-((3,5-dimethoxybenzyl)amino)pyridin-2-yl) amino)-4-(((lS,2R)-2-fluoro cyclopropyl)amino)nicotinate (Preparation 270) using an analogous method to that described for Preparation 271. LCMS m/z = 518 [M+H] ⁺ .

[381] Preparation 273: N-(2-(4-bromo-lH-pyrazol-l-yl)ethyl)-2,2,2-trifluoro-N- methylethan-l-amine

A mixture of 2-(4-bromo-17/-pyrazol-l-yl)-A-methylethan-l -amine hydrochloride (1 g, 4.16 mmol), triethylamine (2.318 ml, 16.63 mmol) and 2,2,2-trifluoroethyltrifluoromethane sulfonate (3.59 ml, 24.95 mmol) in DMF (8 ml) was stirred overnight under microwave irradiation at 80 °C. The cooled mixture was diluted with EtOAc and washed with water and brine, dried ( Na ₂ SO ₄ ) and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (0-100% EtOAc/hexanes) to give the title compound as a colorless oil (888 mg, 74.7%). LCMS m/z = 286.0 [M+H] ⁺ .

[382] Preparation 274: 2,2,2-trifluoro-N-methyl-N-(2-(4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazol-l-yl)ethyl)ethan-l-amine

A mixture of N-(2-(4-bromo- IH-pyrazol- 1 -yl)ethyl)-2,2,2-trifluoro-N-methylethan- 1 - amine (Preparation 273, 445 mg, 1.555 mmol), bis(pinacolato)diboron (474 mg, 1.867 mmol), PdC12(dppf). DCM (191 mg, 0.233 mmol) and potassium acetate (458 mg, 4.67 mmol) in 1,4- dioxane (6 ml) was stirred at 90 °C overnight. Crude material in solution was used directly without further purification. LCMS m/z = 334.1 [M+H] ⁺ .

[383] Preparation 275: l-(3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole

A solution of iPrMgCl.LiCl 1.3M in THF (4.89 ml, 6.35 mmol) was added dropwise to a solution of I -(3-(benzyloxy)cyclobutyl)-4-iodo- l //-pyrazole (prepared according to US 2016/0256448,1.8 g, 5.08 mmol) in THF (20.33 ml) at 0 °C. After 30 min, 2-i sopropoxy-4, 4,5,5 - tetramethyl-l,3,2-dioxaborolane (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 organics were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% EtOAc/hexanes) to give the title compound as a colorless solid (635 mg, 35.3 %). LCMS m/z = 355.0 [M+H] ⁺ ; 1H NMR (500 MHz, CDCh) 8 ppm 7.85 (d, 1H), 7.74 (d, 1H), 7.38 (t, 5H), 4.97 (t, 1H), 4.49 (d, 2H), 4.47 - 4.41 (m, 1H), 2.90 - 2.73 (m, 2H), 2.65 (m, 2H), 1.34 (d, 12H). [384] Preparation 276: tert-butyl (2-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)propan-2-yl)carbamate

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

Preparation of Exemplified Compounds

[385] Example 1: (S)-l-(4-(6-((6-amino-2-(l-fluoroethyl)pyrimidin-4-yl)amino) -4- isopropoxypyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (167)

To a solution of (S)-l-(4-(6-((6-((2,4-dimethoxybenzyl)amino)-2-(l-fluoroethy l) pyrimidin-4-yl)amino)-4-isopropoxypyridin-3-yl)-lH-pyrazol-l -yl)-2-methylpropan-2-ol (Preparation 114, 840 mg, 1.45 mmol) in DCM (5 mL) was added TFA (10 mL) and the reaction stirred at rt for 4 h. The mixture was concentrated in vacuo and the residue was purified by prep HPLC-3 to afford the title compound (421.1 mg, 67% yield) as a white solid. LCMS m/z = 430 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). [386] Example 2: (S)-2-(l-fluoroethyl)-N4-(4-isopropoxy-5-(l-(oxetan-3-yl)-lH -pyrazol-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine (129)

To a solution of (S)-N4-(2,4-dimethoxybenzyl)-2-(l-fluoroethyl)-N6-(4-isoprop oxy-5-(l- (oxetan-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-di amine (Preparation 117, 80 mg, 0.141 mmol) in DCM (1 mL) was added TFA (5 equiv.) and the reaction stirred at rt for 4 h. The mixture was concentrated in vacuo and the residue was purified by prep HPLC-3 to afford the title compound (13.1 mg, 23% yield) as a white solid. LCMS m/z = 414 [M+H] ⁺ . 1H-NMR (400 MHz, DMSO-d ₆ ) 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).

[387] Example 3: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (120)

A solution of l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)p yrimidin-4- yl)amino)-4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpr opan-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 in vacuo and sat. aq. NaHCO ₃ , 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 the crude product which was washed with DCM. The precipitate was filtered to provide the title compound (294 mg, 84%) as a light yellow solid. LCMS m/z = 406 [M+H] ⁺ . ¹ HNMR (500 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.37 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 7.38 (s, 1H), 6.95-6.90 (m, 3H), 6.64-6.37 (m, 1H), 4.70 (s, 1H), 4.03 (s, 2H), 3.89 (s, 3H), 1.08 (s, 6H). [388] Example 4: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- cyclopropoxypyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2- ol (173)

A mixture of l-(4-(4-cyclopropoxy-6-((2-(difluoromethyl)-6-((2,4-dimethox ybenzyl) amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-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 in vacuo and saturated aq. NaHCO ₃ solution (20 mL) was added. The precipitate was filtered and the solid dissolved in MeOH (30 mL). The mixture was filtered, and the filtrate concentrated in vacuo. The crude product was washed with DCM and the precipitate was filtered to give the title compound (440 mg, 74.6 %) as a beige solid. LCMS m/z = 432 [M+H] ⁺ . 1H NMR (500 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.37 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 6.89 (s, 3H), 6.50 (t, 1H), 4.70 (s, 1H), 4.03 (s, 2H), 3.96 - 3.86 (m, 1H), 1.08 (s, 6H), 0.93 - 0.75 (m, 4H).

[389] Example 5: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- (methoxy- d3)pyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (126)

A mixture of l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)p yrimidin-4- yl)amino)-4-(methoxy-d3)pyridin-3-yl)-lH-pyrazol-l-yl)-2-met hylpropan-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 in vacuo, and Na ₂ CO ₃ , (aq.) 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 afford the title compound (147.4 mg, yield: 67%) as a white solid. LCMS m/z = 409 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) δ : 9.82 (s, 1H), 8.38 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 7.37 (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). [390] Example 6: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-

(trifluoromethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)-2-methyl propan-2-ol (198)

To a mixture of l-(4-(6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)p yrimidin- 4-yl)amino)-4-(trifluoromethoxy)pyridin-3-yl)-lH-pyrazol-l-y l)-2-methylpropan-2-ol (Preparation 108, 180 mg, 0.3 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction stirred at rt for 1 h. The mixture was concentrated in vacuo and the crude purified by prep HPLC-3 to give the title product (85 mg, 62%). LCMS m/z = 460 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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).

[391] Example 7: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-

(difluoromethoxy)pyridin-3-yl)-lH-pyrazol-l-yl)-2-methylp ropan-2-ol (181)

A mixture of l-(4-(4-(difluoromethoxy)-6-((2-(difluoromethyl)-6-((2,4- dimethoxybenzyl) amino)pyrimidin-4-yl)amino)pyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan- 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 in vacuo and purified by prep HPLC-3 to give the title product (26.2 mg, 69%). LCMS m/z = 442 [M+H] ⁺ . 1H-NMR (400 MHz, DMSO-d ₆ ) 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).

[392] Examples 8 to 38

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

[393] Examples 39 and 40: (S)-2-(difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH- pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4, 6-diamine and (R)-2- (difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH-pyrazol -4-yl)-4-(trifluoro methoxy)pyridin-2-yl)pyrimidine-4,6-diamine

To a mixture of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(5-(l-(2-(met hyl amino)propyl)-lH-pyrazol-4-yl)-4-(tri fluoromethoxy )pyri din-2 -yl)pyrimidine-4,6-diamine (Preparation 112, 100 mg, 0.16 mmol) in DCM (2 mL) was added TFA (1 mL) and the reaction stirred at rt for 1 h. The mixture was concentrated in vacuo and the residue was purified by HPLC-3, to afford 2-(difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH-pyraz ol-4-yl)-4- (trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine (50.0 mg, yield 61%).

The product was further purified by Prep-SFC using an AD-H (250 x 4.6mm 5pm) column, mobile Phase :n-Hexane (0.1% diethylamine):EtOH(0.1% diethylamine)=70:30 at 1.0 mL/min to give first eluting (S)-2-(difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH- pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)pyrimidine-4, 6-diamine or (R)-2- (difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH-pyrazol -4-yl)-4- (trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine, (195)(12.8 mg, yield 25%).

Further elution provided second eluting (R)-2-(difluoromethyl)-N4-(5-(l-(2- (methylamino)propyl)-lH-pyrazol-4-yl)-4-(tri fluoromethoxy )pyri din-2 -yl)pyrimidine-4, 6- diamine or (S)-2-(difluoromethyl)-N4-(5-(l-(2-(methylamino)propyl)-lH-p yrazol-4-yl)-4- (trifluoromethoxy)pyridin-2-yl)pyrimidine-4,6-diamine, (196) (12.1 mg, yield 24%).

LCMS m/z = 459 [M+H]+. 1H NMR (400 MHz, DMSO-d ₆ ) 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).

[394] Examples 41 and 42: (S)-2-(difluoromethyl)-N4-(4-((l-fluoropropan-2-yl)oxy)-5-(l - methyl-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)- N4-(4-((l-fluoropropan-2-yl)oxy)-5-(l-methyl-lH-pyrazol-4-yl )pyridin-2-yl)pyrimidine-4,6- diamine

To a solution of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-((l-fluoro propan- 2 -yl)oxy)-5-(l -methyl- lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 148, 80 mg, 0.147 mmol) in DCM was added TFA (84 mg, 0.736 mmol) and the solution was stirred at rt overnight. The reaction was concentrated in vacuo and the crude product was purified by prep HPLC-3 to afford the title product (40 mg) as white solid which was further separated by SFC using an IG 20 x 250 mm, 10pm (Daicel) column, mobile phase CCh/MeOH (0.2% MeOH/NHs) = 50/50 at 100 g/min to obtain:

First Eluting Enantiomer 1, (S)-2-(difluoromethyl)-N4-(4-((l-fluoropropan-2-yl)oxy)-5- (l-methyl-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamin e or (R)-2-(difluoromethyl)-N4- (4-((l-fluoropropan-2-yl)oxy)-5-(l-methyl-lH-pyrazol-4-yl)py ridin-2-yl)pyrimidine-4,6-di amine (87) (3.0 mg, 5% yield) LCMS m/z = 394 [M+H]+.

1H-NMR (400 MHz, DMSO-d ₆ ) δ : 9.74 (s, 1H), 8.37 (s, 1H), 8.03 (s, 1H), 7.89 (s, 1H), 7.44 (s, 1H), 6.89 (d, 3H), 6.50 (t, 1H), 4.77-4.75 (m, 3H), 3.87 (s, 3H), 1.37 (d, 3H). Second Eluting Enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-((l-fluoropropan-2-yl)oxy)- 5-(l -methyl- lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (S)-2-(difluoromethyl)-N4- (4-((l-fluoropropan-2-yl)oxy)-5-(l-methyl-lH-pyrazol-4-yl)py ridin-2-yl)pyrimidine-4,6-di amine (88) (5.5 mg, 9% yield). 1H NMR (400 MHz, DMSO-d ₆ ) 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).

[395] Examples 43 and 44: (S)-N4-(4-cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6- diamine and (R)-N4-(4- cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyr idin-2-yl)-2-(difluoro methyl)pyrimidine-4,6-diamine

A mixture of N4-(4-cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4- yl)pyridin- 2-yl)-2-(difluoromethyl)-N6-(2,4-dimethoxybenzyl)pyrimidine- 4,6-diamine (Preparation 137, 150 mg, 0.26 mmol) in DCM/TFA (8 mL/2 mL) was stirred at rt for 4 h. The reaction mixture was concentrated in vacuo. The residue was purified by prep HPLC-3 to afford N4-(4-cyclo propoxy-5-(l -(tetrahydrofuran-3 -yl)- lH-pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl) pyrimidine-4,6-diamine (50 mg, 44% yield) as a white solid. LCMS m/z = 430 [M+H] ⁺

This was further purified by SFC using an OJ 20 x 250mm, 10pm (Daicel) column, mobile phase: CO2/MEOH(1% MeOH/NHs) = 50/50 at 100 g/min; to afford:

First eluting Enantiomer 1: (S)-N4-(4-cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH- pyrazol-4-yl)pyri din-2 -yl)-2-(difluoromethyl)pyrimidine-4,6-diamine or (R)-N4-(4- cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyr idin-2-yl)-2- (difhioromethyl)pyrimidine-4,6-diamine (164) as a white solid (16.5 mg).

1H-NMR (400 MHz, DMSO-d ₆ ) δ : 9.85 (s, 1H), 8.37 (m, 1H), 8.06 (s, 1H), 7.88 (s, 1H), 7.80 (s, 1H), 6.89-6.87 (m, 3H), 6.50 (t, 1H), 5.06-5.04 (m, 1H), 4.01-3.97 (m, 2H), 3.91-3.89 (m, 3H), 2.35-2.26 (m, 2H), 0.89-0.82 (m, 4H) and

Second eluting Enantiomer 2: (R)-N4-(4-cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH- pyrazol-4-yl)pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6- diamine or (S)-N4-(4- cyclopropoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyr idin-2-yl)-2- (difluoromethyl)pyrimidine-4,6-diamine (165) as a white solid (22.5 mg). 1H NMR (400 MHz, DMSO-d ₆ ) 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).

[396] Example 45: 2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)ethan-l-ol trifluoroacetate (59)

To a solution of 2-(difluoromethyl)-N4-(2,4-dimethoxybenzyl)-N6-(4-methoxy-5- (l-(2- ((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-lH-pyrazol-4-yl)pyridi n-2-yl)pyrimidine-4,6-di amine (Preparation 122, 68 mg, 0.111 mmol) in DCM (2 mL) was added TFA (1 mL, 12.98 mmol) and the reaction stirred at rt for 10 mins. The reaction mixture was concentrated under reduced pressure, diluted with DMSO and purified by reverse phase chromatography (10-90% MeCN in water with 0.01% TFA) to afford the title compound as a white solid. LCMS m/z = 378 [M+H] ⁺ ; 1H NMR (500 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 8.14 (s, 1H), 7.93 (s, 1H), 7.23 (s, 1H), 7.16 (s, 3H), 6.64 (t, 2H), 4.18 (t, 2H), 3.99 (s, 3H), 3.77 (t, 2H).

[397] Example 46: 2-(difluoromethyl)-N4-(5-(l-methyl-lH-pyrazol-4-yl)-4-(trifl uoro methoxy)pyridin-2-yl)pyrimidine-4,6-diamine (95)

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

[398] Example 47: 2-(difluoromethyl)-N4-(4-methoxy-5-(l-(pyrrolidin-3-yl)-lH-p yrazol-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine

The title compound was obtained as a white solid, 5.1 mg, 7% yield, from tert-butyl 3-(4- (6-((2-(difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimi din-4-yl)amino)-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)pyrrolidine-l-carboxyla te (Preparation 123), following a similar procedure to that described in Example 46. LCMS m/z = 403 [M+H] ⁺ .

1H-NMR (400 MHz, DMSO-d ₆ ) 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).

[399] Example 48: 2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- methoxy pyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-l-ol (122)

The title compound was obtained as a white solid, 41.2 mg, 48% yield, from 2-(4-(6-((2- (difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-y l)amino)-4-methoxypyri din-3- yl)-lH-pyrazol-l-yl)-2-methylpropan-l-ol (Preparation 124), following a similar procedure to that described in Example 46. LCMS m/z = 406 [M+H] ^{+ 1} H NMR (500 MHz, DMSO-d ₆ ) 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). [400] Example 49: N4-(5-(l-cyclopropyl-lH-pyrazol-4-yl)-4-(trifluoromethoxy)py ridin-2- yl)-2-(difluoromethyl)pyrimidine-4,6-diamine (154)

The title compound was obtained, 25.4 mg, 54%, from N4-(5-(l-cyclopropyl-lH- pyrazol-4-yl)-4-(trifluoromethoxy)pyridin-2-yl)-2-(difluorom ethyl)-N6-(2,4- dimethoxybenzyl)pyrimidine-4,6-diamine (Preparation 110), following the procedure described in Example 46. LCMS m/z = 428 [M+H] ^{+ 1} H NMR (400 MHz, DMSO-d ₆ ) 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).

[401] Example 50: N4-(5-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-methoxypyridin-2 -yl)-2-

(difluoromethyl)pyrimidine-4,6-diamine formate (76)

To a solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- methoxypyridin-3-yl)-lH-pyrazol-l-yl)azetidine-l -carboxylate (Preparation 156, 50 mg, 0.102 mmol) in DCM (2 mL) was added TFA (1 mL, 13.51 mmol) and the reaction stirred at 25°C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC-8, to give the title compound (13.40 mg, 27%) as yellow oil. LCMS m/z = 389 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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).

[402] Examples 51 to 53

The compounds in the following table were prepared from the appropriate Boc protected compound, following a similar procedure to that described in Example 50.

[403] Example 54: 2-(difluoromethyl)-N4-(4-methoxy-5-(l-(2-(methylamino)ethyl) -lH- pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (80)

To a solution of tert-butyl (2-(4-(6-((6-arnino-2-(difluoromethyl)pyrimidin-4-yl)amino)- 4-methoxypyridin-3-yl)-lH-pyrazol-l-yl)ethyl)(methyl)carbama te (Preparation 155, 50 mg, 0.102 mmol) in DCM (2 mL) was added TFA (1 mL, 13.51 mmol) and the reaction was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue and then adjusted with NH ₃ .H ₂ O to pH 5-6 to give the title compound (9.80 mg, 24.6%) as a pale-yellow solid. 1H NMR (400MHz, DMSO-d ₆ ) 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). [404] Example 55: N4-(5-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-(oxetan-3-yloxy) pyridin-2- yl)-2-(difluoromethyl)pyrimidine-4,6-diamine formate (168)

To a solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- (oxetan-3-yloxy)pyridin-3-yl)-lH-pyrazol-l-yl)azetidine-l-ca rboxylate (Preparation 159, 62 mg, 0.117 mmol) in DCM (1.0 mL) was added TFA (0.50 mL, 6.75 mmol) and the reaction stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a residue and the pH adjusted with NH3.H ₂ O to pH 5-6. The residue was purified by prep HPLC-8, to give the title compound (25.0 mg, 42.9%) as colorless oil. LCMS m/z = 431 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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).

[405] Example 56: 2-(difluoromethyl)-N4-(5-(l-(2-(methylamino)ethyl)-lH-pyrazo l-4-yl)-

4-(oxetan-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (175)

To a solution of tert-butyl (2-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)- 4-(oxetan-3-yloxy)pyridin-3-yl)-lH-pyrazol-l-yl)ethyl)(methy l)carbamate (Preparation 160, 26 mg, 0.0488 mmol) in DCM (2 mL) was added TFA (1.54 g, 13.51 mmol). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue and then adjusted with NH4OH to pH 7-8. The residue was purified by prep HPLC-11 to give the title compound (5.0 mg, 23.7%) as a gray oil. LCMS m/z = 433 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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). [406] Example 57: N4-(5-(l-(2-amino-2-methylpropyl)-lH-pyrazol-4-yl)-4-methoxy pyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine trifluoroacetate (116)

The title compound was obtained, 20 mg, 43.5%, from tert-butyl (l-(4-(6-((2- (difluoromethyl)-6-((2,4-dimethoxybenzyl)amino)pyrimidin-4-y l)amino)-4-methoxypyri din-3- yl)-lH-pyrazol-l-yl)-2-methylpropan-2-yl)carbamate (Preparation 116), following the procedure described in Example 45.

LCMS m/z = 405.2 [M+H] ⁺ ; 1H NMR (500 MHz, DMSO-d ₆ ) 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).

[407] Example 58: 2-(difluoromethyl)-N4-(5-(l-(l-methylazetidin-3-yl)-lH-pyraz ol-4-yl)- 4-(oxetan-3-yloxy)pyridin-2-yl)pyrimidine-4,6-diamine (183)

To a solution of N4-(5-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-(oxetan-3-yloxy) pyridin-2- yl)-2-(difhioromethyl)pyrimidine-4,6-diamine formate (Example 55, 15.0 mg, 0.0315 mmol) in MeOH (2.0 mL) and adjusted with AcOH (9.00 uL, 0.157 mmol) to pH 5-6. HCHO (3.07 mg, 0.0378 mmol) was added and the mixture stirred at 25°C for 1 h. Na(CN)BH3 (2.97 mg, 0.047 mmol) was added and the reaction 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 prep-HPLC-11, to give the title compound (9.30 mg, yield: 64.3%) as a gray oil. LCMS m/z = 445 [M+H] ⁺

1H-NMR (400MHz, DMSO-d ₆ ) 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). [408] Example 59: 2-(difluoromethyl)-N4-(4-isopropoxy-5-(l-isopropyl-lH-pyrazo l-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine (56)

To a solution of 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7, 17.81 mg, 0.111 mmol) and 2-chloro-5-(l-isopropyl-lH-pyrazol-4-yl)-4-methoxypyridine (Preparation 80, 40.0 mg, 0.159 mmol) in dioxane (3 mL) was added BrettPhos Pd, G4 (14.63 mg, 0.0159 mmol) and CS ₂ CO ₃ (103.55 mg, 0.318 mmol) and the reaction stirred at 90 °C for 2 h under N2. The cooled reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC-11 to give the title compound (12.50 mg, 21.0%) as brown oil. LCMS m/z = 375 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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).

[409] Example 60: N4-(5-(l-cyclopropyl-lH-pyrazol-4-yl)-4-methoxypyridin-2-yl) -2-

(difluoromethyl)pyrimidine-4,6-diamine (52)

The title compound was obtained as a brown gum (10.50 mg, 19.2%) from 2-chloro-5-(l- cyclopropyl-lH-pyrazol-4-yl)-4-methoxypyridine (Preparation 81) and 2- (difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) following a similar procedure to that described in Example 59. LCMS m/z = 373 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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). [410] Example 61: 2-(difluoromethyl)-N4-(4-methoxy-5-(l-(oxetan-3-yl)-lH-pyraz ol-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine (78)

The title compound was obtained, 4.3 mg, 8.17%, from 2-(difluoromethyl)pyrimidine- 4,6-diamine hydrochloride (Preparation 7) and 2-chloro-4-methoxy-5-(l-(oxetan-3-yl)-lH- pyrazol-4-yl)pyridine (Preparation 82), following a similar procedure to that described in Example 59. LCMS m/z = 390 [M+H] ^{+ 1} H NMR (400MHz, DMSO-d ₆ ) 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). [411] Examples 62 to 72

To a mixture of the appropriate 2-chloropyridine starting material (SM) and 2-(difluoro methyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7, 1-1.5 equiv.), in dioxane was added BrettPhos Pd, G4 (0.02-0.2 equiv.) and CS ₂ CO ₃ (2.0-3.0 equiv.) and the reaction was heated at 90°C-100°C until the starting materials had been consumed under N2. The cooled reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC to afford the desired compound.

^A -the crude residue was additionally purified by silica gel chromatography before HPLC.

^B -K ₂ CO ₃ was used instead of CS ₂ CO ₃

[412] Examples 73 and 74: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(l-(tetrahydrofuran-

3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)-N4- (4-methoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyrid in-2-yl)pyrimidine-4,6- diamine

A mixture of 2-chloro-4-methoxy-5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4- yl)pyridine (Preparation 54, 160 mg, 0.572 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 91.5 mg, 0.572 mmol), BrettPhos-Pd G4 (20 mg, 0.0217 mmol) and CS ₂ CO ₃ (230 mg, 0.708 mmol) in dioxane (3 mL) was stirred at 100 °C for 16 h. The cooled mixture was concentrated in vacuo and the residue purified by prep HPLC-3 to provide N4-(4-cyclopropoxy-5-(l- (tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)-2-(difl uoromethyl)pyrimidine-4,6-di amine as a white solid (80 mg, 35%). LCMS m/z = 404 [M+H] ⁺ . This was further purified by SFC using an OZ 20*250mm, 10pm (Daicel) column, mobile phase: CO2/MeOH(0.2% MeOH/bflL) = 65/35, at 100 g/min to provide: First eluting Enantiomer 1: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(l-(tetrahydrofuran-3 -yl)- lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine or (R)-2-(difluoromethyl)-N4-(4-methoxy- 5-(l-(tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyr imidine-4,6-diamine (109), 22 mg.

1H-NMR (500 MHz, DMSO-d ₆ ) δ : 9.79 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.39 (s, 1H), 6.95-6.90 (m, 3H), 6.51 (t, 1H), 5.06-5.04 (m, 1H), 4.02-3.82 (m, 7H), 2.36-2.29 (m, 2H).

Second eluting Enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(l- (tetrahydrofuran-3-yl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidi ne-4,6-diamine or (S)-2- (difluoromethyl)-N4-(4-methoxy-5-(l-(tetrahydrofuran-3-yl)-l H-pyrazol-4-yl)pyridin-2- yl)pyrimidine-4,6-diamine (HO), 29 mg.

1H-NMR (500 MHz, DMSO-d ₆ ) 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).

[413] Examples 75 and 76: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(l-(2-(methylamino) propyl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine and (R)-2-(difluoromethyl)- N4-(4-methoxy-5-(l-(2-(methylamino)propyl)-lH-pyrazol-4-yl)p yridin-2-yl)pyrimidine-4,6- diamine

The title compounds were obtained from l-(4-(6-chloro-4-methoxypyridin-3-yl)-lH- pyrazol-l-yl)-N-methylpropan-2-amine (Preparation 90) and 2-(difluoromethyl)pyrimidine-4,6- diamine (Preparation 8) following the procedure described in Examples 73 and 74.

LCMS m/z = 405 [M+H] ⁺ .

The compound was further purified by SFC using OZ 20 x 250mm, 10pm (Daicel) column, mobile phase: CCh/MeOH (0.2%MeOH/NH3) = 65/35, at 100 g/min to provide:

First eluting Enantiomer 1: (S)-2-(difluoromethyl)-N4-(4-methoxy-5-(l-(2- (methylamino)propyl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine -4,6-diamine or (R)-2- (difluoromethyl)-N4-(4-methoxy-5-(l-(2-(methylamino)propyl)- lH-pyrazol-4-yl)pyri din-2- yl)pyrimidine-4,6-diamine (117), 16 mg. ¹ H NMR (500 MHz, DMSO-d ₆ ) 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, 3 H), 0.93 (d, 3H).

Second eluting Enantiomer 2: (R)-2-(difluoromethyl)-N4-(4-methoxy-5-(l-(2- (methylamino)propyl)-lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine -4,6-diamine or (S)-2- (difluorornethyl)-N4-(4-methoxy-5-(l-(2-(methylamino)propyl) -lH-pyrazol-4-yl)pyri din-2- yl)pyrimidine-4,6-diamine (118), 12 mg 1H NMR (500 MHz, DMSO-d ₆ ) 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, 3 H), 0.93 (d, 3H).

[414] Example 77: N4-(4-(difluoromethoxy)-5-(l-methyl-lH-pyrazol-4-yl)pyridin- 2-yl)-2- (difluoromethyl)pyrimidine-4,6-diamine (69)

A mixture of 2-chloro-4-(difluoromethoxy)-5-(l-methyl-lH-pyrazol-4-yl)pyr idine (Preparation 67, 50 mg, 0.218 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8), Pd(t-Bu ₃ P) ₂ (20 mg, 0.050 mmol) and CS ₂ CO ₃ (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 prep HPLC-3 to give 18.1 mg, 20.8%, of the title compound as a white oil. LCMS m/z = 399 [M+H]+.

^X H NMR (400 MHz, DMSO-d ₆ ) δ 10.06 (s, 1H), 8.51 (s, 1H), 8.05 (s, 1H), 7.86 (s, 1H), 7.61(s, 1H), 7.37 (t, 1H), 7.19 (s, 2H), 6.86 (s, 1H), 6.50 (t, 1H), 3.89 (s, 3H)

[415] Examples 78 to 86

The compounds in the following table were prepared following a similar procedure to that described in Example 45 using similar procedures described in preparations 122 and 75 [416] Example 87-89

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

[417] Example 90-93

The title compounds were prepared using a 3 -part chemistry protocol as outlined below.

Part 1. A solution of tert-butyl 3-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4- yl)amino)-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)azetidine-l- carboxylate (Preparation 168,

283.3 mg, 0.5 mmol, 1 eq.) in DCM (3 mL) and TFA (1 mL) was stirred at 30 °C for 2 h. The solvents were evaporated by Speedvac to afford N4-(5-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4- fluoropyridin-2-yl)-2-(difluoromethyl)pyrimidine-4,6-diamine which was used in Part 2 without further purification.

Part 2. A solution of N4-(5-(l-(azetidin-3-yl)-lH-pyrazol-4-yl)-4-fluoropyridin-2- yl)-2- (difluoromethyl)pyrimidine-4,6-diamine (Part 1, 188mg, 0.5 mmol, 1 eq) and CH ₃ CO2H (150 mg, 2.5 mmol, 5 eq.) and HCHO (48.6 mg, 0.6 mmol, 1.2 eq., 37% purity) in MeOH (5 mL) was stirred at 30 °C for 1 h. To this was added NaBHsCN (47.1 mg, 0.75 mmol, 1.5 eq.) and the mixture stirred at 30 °C for 1 h. The volatiles were removed in vacuo by Speedvac to give 2- (difluoromethyl)-N4-(4-fluoro-5-(l-(l-methylazetidin-3-yl)-l H-pyrazol-4-yl)pyri din-2- yl)pyrimidine-4,6-diamine which was used in Part 3 without further purification. Part 3. To a solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(l-(l-methylazetidin-3-yl) - lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Part 2, 85.9 mg, 0.22 mmol, 1 eq.) in THF (1 mL) was added the appropriate alcohol (ROH, 0.33 mmol, 1.5 eq.) and t-BuOK (73.9 mg, 0.66 mmol, 3 eq.) and the mixture heated under microwave irradiation at 100 °C for 4 h. The reaction mixtures were evaporated to dryness by Speedvac and the residues purified by prep HPLC-4 to give the title compounds.

[418] Example 94: l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- ethoxy pyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (152)

Part 1. To a solution of 5-bromo-2-chloro-4-fluoropyridine (315 mg, 1.5 mmol) and 2- methyl-l-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH -pyrazol-l-yl)propan-2-ol (478 mg, 1.8 mmol) in dioxane (10 mL) was added Na ₂ CO ₃ (2.6 mL, 15 mmol, 2M) and Pd(PPh3)4 (86.6 mg, 0.075 mmol) under N2 atmosphere and the mixture stirred at 100 °C for 5.5 h. The reaction was diluted with H ₂ O (5.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were evaporated to dryness by Speedvac to afford l-(4-(6-chloro-4-fluoropyri din-3 -yl)- lH-pyrazol-l-yl)-2-methylpropan-2-ol which was used in Part 2 without further purification.

Part 2. To a solution of l-(4-(6-chloro-4-fluoropyridin-3-yl)-lH-pyrazol-l-yl)-2- methylpropan-2-ol (Part 1, 351 mg, 1.3 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 416 mg, 2.6 mmol) in t-AmOH (10 mL) was added CS ₂ CO ₃ (1.27 g, 3.9 mmol) and Brettphos Pd G3 (59 mg, 0.065 mmol) under N2 and the mixture stirred at 120 °C for 2 h. The reaction mixture was diluted with H ₂ O (5.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were evaporated to dryness by Speedvac to afford l-(4-(6-((6-amino-2- (difluoromethyl)pyrimidin-4-yl)amino)-4-fluoropyridin-3-yl)- lH-pyrazol-l-yl)-2-methylpropan- 2-ol which was used in Part 3 without further purification.

Part 3. To a mixture of l-(4-(6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4- fluoropyridin-3-yl)-lH-pyrazol-l-yl)-2-methylpropan-2-ol (Part 2, 86.5 mg, 0.22 mmol) in THF (1 mL) was added EtOH (0.33 mmol), t-BuOK (73.9 mg, 0.66 mmol) and the mixture heated at 100 °C for 4 h under microwave irradiation. The reaction was evaporated to dryness by Speedvac and the residue purified by prep HPLC-4 to afford the title compound (23.7 mg, 26%). LCMS m/z = 420 [M+H] ⁺ .

[419] Example 95-96

The title compounds were prepared using a l-step protocol outlined below.

To a mixture of the appropriate alcohol (ROH, 0.33 mmol, 1.5 eq.) in DMF (4 mL) was added NaH (61.6 mg, 1.54 mmol, 7 eq., 60%) and the mixture was stirred at 30 °C for 2 h. 2- (Difluoromethyl)-N4-(4-fluoro-5-(l -methyl- lH-pyrazol-4-yl)pyri din-2 -yl)pyrimidine-4, 6- diamine (Preparation 171, 73.7 mg, 0.22 mmol, 1 eq.) was added to the mixture and the reaction stirred at 100 °C for 3 h. The reaction was quenched with H ₂ O (1.0 mL) and evaporated to dryness using a Speedvac. The residues were purified by prep HPLC-4 to give the title compounds.

[420] Example 97: 2-(difluoromethyl)-N4-(5-(l-methyl-lH-pyrazol-4-yl)-4-((tetr ahydro-

2H-pyran-2-yl)methoxy)pyridin-2-yl)pyrimidine-4,6-diamine (172)

To a solution of 2-(difluoromethyl)-N4-(4-fluoro-5-(l-methyl-lH-pyrazol-4-yl) pyridin-2- yl)pyrimidine-4,6-diamine (Preparation 171, 73.7 mg, 0.22 mmol) in DMA (4 mL) was added (tetrahydro-2H-pyran-2-yl)methanol (38.3 mg, 0.33 mmol) and t-BuOK (73.9 mg, 0.66 mmol) and the mixture stirred at 100 °C for 6 h. The volatiles were removed by Speedvac and the residue purified by prep-HPLC-4 to afford the title compound. Yield: l l%; LCMS m/z = 432 [M+H] ⁺ . [421] Example 98-108

The title compounds were prepared from 2-(difluoromethyl)-N4-(4-fluoro-5-(l-methyl- lH-pyrazol-4-yl)pyridin-2-yl)pyrimidine-4,6-diamine (Preparation 171) and the appropriate alcohol (ROH) using a similar method to that described for Example 97 using the solvent and heating method noted in the table. (Method A = DMA, 100 °C, 6 h; Method B = THF, 100 °C, microwave, 4 h; C = DMA, 100 °C, microwave, 4 h.). The crude products were purified by prep HPLC-4.

[422] Example 109: (ls,3s)-3-((2-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)ami no)-5-(l- methyl-lH-pyrazol-4-yl)pyridin-4-yl)oxy)cyclobutan-l-ol (107)

Part 1. To a solution of (ls,3s)-cyclobutane-l,3-diol (39.6 mg, 0.45 mmol) in THF (4 mL) was added NaH (60%, 84.0 mg, 2.1 mmol) and the mixture was stirred at 30 °C for 1 h. To this was added 2-chloro-4-fluoro-5-(l-methyl-lH-pyrazol-4-yl)pyridine (Preparation 97, 73.7 mg, 0.3 mmol) and the mixture stirred at 30 °C for 2 h. The reaction was quenched with H ₂ O (3.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were concentrated by Speedvac to afford (ls,3s)-3-((2-chloro-5-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)cyclobutan-l-ol which was used in Part 2 without further purification.

Part 2. To a solution (ls,3s)-3-((2-chloro-5-(l-methyl-lH-pyrazol-4-yl)pyridin-4- yl)oxy)cyclobutan-l-ol (Part 1, 0.27 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL) was added CS ₂ CO ₃ (263.9 g, 0.81 mmol) and Brettphos Pd G3 (12.24 mg, 0.014 mmol) and the mixture stirred at 120 °C for 2 h under N2. The reaction was diluted with H ₂ O (3.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were evaporated to dryness by Speedvac and the residue purified by prep- HPLC-4 to give the title compound. Yield: 22%; LCMS m/z = 404 [M+H] ⁺ .

[423] Example 110: 2-(difluoromethyl)-N4-(4-methoxy-5-(l-methyl-lH-pyrazol-4- yl)pyridin-2-yl)pyrimidine-4,6-diamine (16) Part 1. A mixture of 2-chloro-4-fluoro-5-(l-methyl-lH-pyrazol-4-yl)pyridine (Preparation 97, 73.7 mg, 0.3 mmol), MeOH (14.4 mg, 0.45 mmol) in THF (4 mL) was added t- BuOK (101 mg, 0.9 mmol) and the mixture was stirred at 100 °C for 3 h. The reaction mixture were concentrated by Speedvac to afford 2-chloro-4-methoxy-5-(l-methyl-lH-pyrazol-4- yl)pyridine which was used in Part 2 without further purification.

Part 2. To a solution 2-chloro-4-methoxy-5-(l-methyl-lH-pyrazol-4-yl)pyridine (Part 1, 0.27 mmol) and 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 51.8 g, 0.32 mmol) in t-AmOH (3 mL) was added CS ₂ CO ₃ (263.9 g, 0.81 mmol) and Brettphos Pd G3 (12.24 mg, 0.014 mmol) and the mixture was stirred at 120 °C for 2 h under N2. The reaction was diluted with H ₂ O (3.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were evaporated to dryness by Speedvac and the residue purified by prep-HPLC-4 to give the title compound (14 mg, 9%; LCMS m/z = 348 [M+H] ⁺ .

[424] Example 112-123

The title compounds were prepared from the appropriate protected starting material (SM) using a similar method to that described for Example 111. Alternative conditions (Method B) using HC1 (2N in EtOAc) as noted in the table.

[425] Example 124: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclop ropyl- 4-(cyclopropylamino)nicotinamide (57)

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 CS ₂ CO ₃ (251, mg, 0.774 mmol) in dioxane (10 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was evaporated to dryness in vacuo and the residue purified by column chromatography on silica gel (1 : 1 EtOAc/PE) to afford the title compound as a white solid (15 mg, 15%). LCMS m/z = 376 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). [426] Example 125: (S)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(( l-fluoro propan-2-yl)amino)-N-methylnicotinamide (48)

A mixture of (S)-6-chloro-4-((l-fluoropropan-2-yl)amino)-N-methylnicotina mide (Preparation 186, 150 mg, 0.610 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 117 mg, 0.731 mmol), CS ₂ CO ₃ (397 mg, 1.22 mmol) and Pd( ^l Bu3P)2 (155 mg, 0.305 mmol) in dioxane (4 mL) was stirred at 100 °C for 16 h under N2. The reaction mixture was purified by column chromatography on silica gel (10: 1 DCM/MeOH) followed by Prep HPLC-3 to afford the title compound as a white solid (41 mg, 18%). LCMS m/z = 370 [M+H] ⁺ . ^NMR (400 MHz, DMSO-d ₆ ) 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).

[427] Example 126: (R)-6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(( l- fluoropropan-2-yl)amino)-N-methylnicotinamide (49)

A mixture of (R)-6-chloro-4-((l-fluoropropan-2-yl)amino)-N-methylnicotina mide (Preparation 190, 75 mg, 0.305 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 48.8 mg, 0.305 mmol), CS ₂ CO ₃ (298 mg, 0.92 mmol) and Pd(*Bu3P)2 (31.2 mg, 0.061 mmol) in dioxane (2 mL) was stirred at 100 °C for 3 h under N2. The reaction mixture was purified by column chromatography on silica gel (10: 1 DCM/MeOH) followed by Prep HPLC-3, to afford the title compound as a white solid (22.6 mg, 20%). LCMS m/z = 370 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) 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). [428] Example 127-146

The title compounds were prepared from the appropriate 2-chloropyridine (RC1) and pyrimidine-4,6-diamine (RNH ₂ ) using a similar method to that described for Example 126.

^A - 0.2 eq. Pd2(dba)3 + 0.2 eq. XantPhos was the catalyst

[429] Example 147: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclop ropyl- 4-(isopropylamino)nicotinamide trifluoroacetate (60) 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) was added CS ₂ CO ₃ (51.4 mg, 0.158 mmol), Brettphos (4.23 mg, 7.88 pmol) and BrettPhos Pd G4 (7.26 mg, 7.88 pmol) and the mixture was stirred at 80 °C for 1 h under N2. The reaction was quenched with water (10 mL) and extracted with EtOAc (3x 15 mL). The combined organics were dried (TsfeSCU) and evaporated to dryness in vacuo. The residue was purified by prep HPLC-10 to afford the title compound as a white solid (20 mg, 52%). LCMS m/z = 378 [M+H] ⁺ . ¹ H NMR (400 MHz, MeOH-d ₄ ) 8: 8.28 (s, 1H), 6.67-6.38 (m, 1H), 6.32 (s, 1H), 6.06 (s, 1H), 3.84-3.76 (m„ 1H), 2.86-2.79 (m, 1H), 1.34 (d, 6H), 0.85-0.79 (m, 2H), 0.65-0.60 (m, 2H). [430] Example 148: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-N-cyclop ropyl- 4-(ethylamino)nicotinamide (39)

A mixture of 6-chloro-N-cyclopropyl-4-(ethylamino)nicotinamide (Preparation 185, 10 mg, 0.042 mmol), 2-(difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 6.68 mg, 0.042 mmol), CS ₂ CO ₃ (27.2 mg, 0.083 mmol) and BrettPhos Pd G4 (3.84 mg, 4.17 Dmol) in dioxane (2 mL) was stirred at 90 °C for 1 h under N2. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by prep HPLC-3 to give the title compound as a pale yellow solid. LCMS m/z = 364 [M+H]+. ^T H NMR (400 MHz, DMSO-d ₆ ) δ : 9.65 (s, 1H), 8.28 (d, 1H), 8.25 (s, 1H), 8.23 (t, 1H), 6.99 (s, 1H), 6.85 (s, 2H), 6.79 (s, 1H), 6.46 (t, 1H), 3.14-3.09 (m, 2H), 2.79-2.72 (m, 1H), 1.19 (t, 3H), 0.67-0.63 (m, 2H), 0.54-0.51 (m, 2H).

[431] Example 149-162

The title compounds were prepared from the appropriate 2-chloropyridine (RC1) and pyrimidine-4,6-diamine (RNH ₂ ) using a similar method to that described for Example 148.

^A - Pd(t-Bu ₃ P) ₂ was used as the reaction catalyst [432] Example 165: 6-((6-amino-2-(fluoromethyl)pyrimidin-4-yl)amino)-4-(isoprop yl amino)-N-methylnicotinamide

A mixture of 6-((6-amino-2-(hydroxymethyl)pyrimidin-4-yl)amino)-4-(isopro pylamino)- N-methylnicotinamide (Preparation 259, 30 mg, 0.091 mmol) and DAST (72.7 mg, 0.452 mmol) in DCM (5 mL) was stirred at 0 °C for 4 h. The reaction was quenched with NaHCO ₃ , (aq.) and concentrated to dryness in vacuo. The residue was purified by Prep HPLC-3 to afford the title compound as a white solid (11.2 mg, 37%). LCMS m/z = 333 NMR (400 MHz, DMSO-de) 6: 9.50 (s, 1H), 8.31-8.27 (m, 3H), 7.10 (s, 1H), 6.65-6.63 (m, 3H), 5.13 (d, 2H), 3.58-3.53 (m, 1H), 2.71 (d, 3H), 1.19 (d, 6H).

[433] Example 168-181

The title compounds were prepared using a single step protocol using 6-((6-amino-2- (difluoromethyl)pyrimidin-4-yl)amino)-4-fluoro-N-methylnicot inamide (Preparation 260) and the appropriate primary amine (RNH ₂ ) as shown in the scheme below.

To a mixture of 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-fluoro -N- methylnicotinamide (Preparation 260, 46.8 mg, 0.15 mmol, 1 eq.) and TEA (0.45 mmol, 3 eq.) in MeCN (3 mL) was added the appropriate amine (RNH ₂ , 0.30 mmol, 2 eq.) and the resulting mixture shaken at 100 °C for 3 h. The solids were removed by filtration and the filtrate evaporated to dryness using a Speedvac. The residue was purified prep-HPLC-4 to afford the title compound. [434] Example 182-194

The title compounds were prepared using a 3 -step chemistry protocol using 6-chloro-4- fluoronicotinic acid, R ¹ NH ₂ , 2-(difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7) and R ² NH ₂ as outlined in the scheme and table below.

Part 1. To a solution of 6-chloro-4-fluoronicotinic acid (87.5 mg, 0.5 mmol, 1 eq) and the appropriate amine (R ¹ NH ₂ , 0.5 mmol, 1 eq) in MeCN (4 mL) was added DIPEA (0.702 mL, 4 mmol, 8 eq.) and T3P (0.5 mL) and the mixture stirred at 30 °C for 16 hrs. The reaction was quenched with 5 M ISfeCCL (4 mL) and extracted with EtOAc (3x 10 mL). The combined organics were evaporated to dryness in a Speedvac to afford a residue that was used in Part 2 without further purification.

Part 2. CS ₂ CO ₃ (440 mg, 1.35 mmol, 3 eq) and Brettphos Pd G3 (20.41 mg, 22.5 Dmol, 0.05 eq.) were added to a solution of the compound of Part 1 (0.45 mmol, 1 eq.) and 2- (difluoromethyl)pyrimidine-4,6-diamine hydrochloride (Preparation 7, 144 mg, 0.9 mmol, 2 eq.) under a N2 atmosphere and the mixture stirred at 120 °C for 2 h. The reactions were diluted with H ₂ O (3 mL) and extracted with EtOAc (3x 10 mL). The organic layer was collected and evaporated to dryness by Speedvac to afford a residue that was used in Part 3 without further purification.

Part 3. The second amine displacement was carried out using 2 alternative conditions (Method A or Method B) as described below and noted in the following table.

Method A: TEA (0.26 mL, 1.8 mmol, 6 eq.) was added to a solution of the compound of Part 2 (0.3 mmol, 1 eq) and the appropriate amine (R ² NH ₂ , 0.6 mmol, 2 eq.) in MeCN (4 mL) and the resulting mixture stirred at 100 °C for 36 h. The reaction mixture was evaporated to dryness by Speedvac and the residue purified by prep-HPLC-4 to afford the title compound.

Method B: KF (53.2 mg, 0.9 mmol, 3 eq.) was added to a solution of the compound of Part 2 (0.3 mmol, 1 eq.) and the appropriate amine (R ² NH ₂ , 0.6 mmol, 2 eq.) in DMSO (2 mL) and the mixture stirred at 100 °C for 16 h. The reaction was evaporated to dryness by Speedvac and the residue purified by prep-HPLC-4 to give to afford the title compound.

[435] Example 195-198

The title compounds were prepared from 6-chloro-4-fluoronicotinic acid using a 3 -step chemistry protocol as shown in Scheme below.

Part 1. To a solution of 6-chloro-4-fluoronicotinic acid (87.5 mg, 0.5 mmol, 1 eq.) and the appropriate amine (R ¹ NH ₂ , 0.45 mmol, 0.9 eq.) in MeCN (4 mL) was added TEA (0.580 mL, 4 mmol, 8 eq) and the mixture stirred at 100 °C for 16 h. The solvent was removed by Speedvac to give Compound A which was used in Part 2 without further purification.

Part 2. To a solution of the appropriate Compound A (Part 1, 0.45 mmol, 1 eq.) and the appropriate amine (R ² NH ₂ , 0.675 mmol, 1.5 eq.) in DMF (4 mL) was added TEA (0.391 mL, 2.7 mmol, 6 eq.) and HATU (855 mg, 2.25 mmol, 5 eq.) and the mixture stirred at 30 °C for 2 h. The reaction was quenched with 5N ISfeCCL (4.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were concentrated by Speedvac to afford crude Compound B which was used in Part 3 without further purification.

Part 3. To a solution of the appropriate Compound B (Part 2, 0.3 mmol, 1 eq.) and 2- (difluoromethyl)pyrimidine-4,6-diamine (Preparation 8, 96 mg, 0.6 mmol, 2 eq.) in t-AmOH (4 mL) was added CS ₂ CO ₃ (293.4 mg, 0.9 mmol, 3 eq.) and Brettphos Pd G3 (13.6 mg, 15 Dmol, 0.05 eq.) under N2 and the mixture stirred at 120 °C for 2 h. The reaction mixture was diluted with H ₂ O (3.0 mL) and extracted with EtOAc (3x 10 mL). The combined organics were concentrated by Speedvac and the residue purified by prep-HPLC-4 to give the title compounds.

[436] Example 199: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(isopr opyl amino)-N-(oxazol-4-ylmethyl)nicotinamide (147)

TFA (2 mL) was added to a solution of 6-((6-(tert-butylamino)-2-(difluoromethyl) pyrimidin-4-yl)amino)-4-(isopropylamino)-N-(oxazol-4-ylmethy l)nicotinamide (Preparation 258, 100 mg, 0.210 mmol) in THF and the mixture stirred at 70 °C for 12 h. The reaction was concentrated in vacuo and the residue purified by prep-HPLC-3, to afford the title compound as a white solid (45.6 mg, 52%). LCMS m/z = 419 [M+H] ⁺ . ¹ H NMR (500 MHz, DMSO-d ₆ ) δ : 9.70 (s, 1H), 8.79 (t, 1H), 8.40 (s, 1H), 8.32 (s, 1H), 8.29 (d, 1H), 7.70 (s, 1H), 7.11 (s, 1H), 6.89 (s, 2H), 6.76 (s, 1H), 6.48 (t, 1H), 4.31 (d, 2H), 3.59-3.55 (m, 1H), 1.20 (d, 6H).

[437] Example 200: 2-(difluoromethyl)-N4-(4-(isopropylamino)-5-(3-methyl-l,2,4- oxadiazol-5-yl)pyridin-2-yl)pyrimidine-4,6-diamine (58)

The title compound was prepared as a white solid (33.6 mg, 49%), from N4-(tert-butyl)- 2-(difluoromethyl)-N6-(4-(isopropylamino)-5-(3-methyl-l,2,4- oxadiazol-5-yl)pyridin-2- yl)pyrimidine-4,6-diamine (Preparation 265) using a similar method to that described for Example 199. LCMS m/z = 377 [M+H] ⁺ ; ¹ H NMR (500 MHz, DMSO-d ₆ ) δ : 9.96 (s, 1H), 8.61 (s, 1H), 7.73 (d, 1H), 7.36 (s, 1H), 6.97 (s, 2H), 6.74 (s, 1H), 6.51 (t, 1H), 3.76-3.70 (m, 1H), 2.42 (s, 1H), 1.29 (d, 6H).

[438] Example 201: 6-((6-amino-2-(difluoromethyl)pyrimidin-4-yl)amino)-4-(ethyl amino)-N-(2-azaspiro[3.3]heptan-6-yl)nicotinamide (149) TFA (137 mg, 1.2 mmol) was added to a solution of tert-butyl 6-(6-((6-amino-2-(difluoro methyl)pyrimidin-4-yl)amino)-4-(ethylamino)nicotinamido)-2-a zaspiro[3.3]heptane-2- carboxylate (Preparation 266, 120 mg, 0.231 mmol) in DCM and the mixture stirred at rt for 12 h. The mixture was concentrated in vacuo and the residue was purified by Prep HPLC-3 to afford the title compound as a white solid (45.7 mg, 47%). LCMS m/z = 419 [M+H] ⁺ ; ^T H NMR (400 MHz, DMSO-d ₆ ) δ : 9.69 (s, 1H), 8.43 (s, 1H), 8.33 (s, 1H), 8.21-8.19 (m, 1H), 7.02 (s, 1H), 6.88 (s, 2H), 6.80 (s, 1H), 6.48 (t, 1H), 4.18 (s, 1H), 3.83-3.10 (m, 7H), 2.43-2.05 (m, 4H), 1.18 (t, 3H).

[439] Example 202: 6-((6-amino-4-(difluoromethyl)pyridin-2-yl)amino)-4-(((lR,2S )-2- fluorocyclopropyl)amino)-N-methylnicotinamide (44)

TFA (1 mL) was added to a solution of 6-((4-(difluoromethyl)-6-((2,4-dimethoxy benzyl)amino)pyridin-2-yl)amino)-4-(((lR,2S)-2-fluorocyclopr opyl)amino)-N-methyl nicotinamide (Preparation 271, 60 mg, 0.115 mmol) in DCM (4 mL) was stirred at rt for 16 h. The reaction mixture was evaporated to dryness in vacuo and the residue purified by prep HPLC- 3 to afford the title compound as a white solid (9.3 mg, 22%). LCMS m/z = 368 [M+H] ⁺ ; 'H NMR (400 MHz, DMSO-d ₆ ) δ : 9.77 (s, 1H), 8.56 (s, 1H), 8.34-8.33 (m, 2H), 7.37 (s, 1H), 6.90- 6.89 (m, 2H), 6.79 (s, 1H), 6.49 (t, 1H), 4.88 (d, 1H), 3.77 (s, 1H), 2.72 (d, 3H), 1.21-1.14 (m, 1H), 0.89-0.81 (m, 1H).

[440] Example 203: 6-((6-amino-4-(difluoromethyl)pyridin-2-yl)amino)-4-(((lS,2R )-2- fluorocyclopropyl)amino)-N-methylnicotinamide (45)

The title compound was prepared as a white solid (9.1 mg, 21%) from 6-((4-(difluoro methyl)-6-((2,4-dimethoxybenzyl)amino)pyridin-2-yl)amino)-4- (((lS,2R)-2-fluorocyclopropyl) amino)-N-methylnicotinamide (Preparation 272) using a similar method to that described for Example 202. LCMS m/z = 368 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ : 9.77 (s, 1H), 8.56 (s, 1H), 8.36-8.35 (m, 2H), 7.38 (s, 1H), 6.91 (s, 2H), 6.79 (s, 1H), 6.49 (t, 1H), 4.98-4.81 (m, 1H), 3.85-3.78 (m, 1H), 2.73-2.66 (m, 3H), 1.22-1.17 (m, 1H), 0.90-0.84 (m, 1H).

[441] Examples 111, 146, 166 and 167 were intentionally omitted from the Preparation of Exemplified Compounds.

Inhibition of autophosphorylation of KIT

[442] The results obtained in these experiments for compounds prepared according to the examples are summarized in Table 1 below. Table 1 shows the activity of the exemplified compounds in the pKIT assay according to the Meso Scale Discovery (MSD) assay described herein.

[443] In this MSD assay, specific capture antibodies for the analytes were coated in arrays in each well of a 96-well carbon electrode plate surface. The detection system used SULFO-TAG™ labels that emit light upon electrochemical stimulation initiated at the electrode surfaces of the MULTIARRAY and MULTI-SPOT® plates. The electrical stimulation was decoupled from the output signal, which was light and generated assays with minimal background. The goal of this assay was to assess the percent inhibition of autophosphorylation of c-kit in cells when treated with compounds of the disclosure in a dose-dependent manner.

[444] Materials included:

HMC 1.1 (exon 11)

HMC 1.1 (exon 11/13)

IMDM medium (Gibco: 12440053)

IMDM medium (phenol red free) (Gibco: 21056023)

Penicillin-Steptomycin (Gibco: 15140122)

HyClone™ Calf Serum, supplemented with Iron (GE Healthcare Life Sciences: SH3007203.03) Screen Matrix 384-well cone-bottom plate (Thermo: 4309)

96-well clear U-bottom plates (individually wrapped, sterile) (Falcon: 353077)

96-well clear V-bottom plate (sterile) (Grenier: 651161)

AlphaLISA 5X Lysis buffer (PerkinElmer: AL003F)

Halt™ Protease Inhibitor Cocktail, EDTA-Free (100X) (ThermoFisher: 87785) Phospho c-Kit (Tyr721) Assay Whole Cell Lysate Kit (MSD: 515DPD)* [445] HMC1.2 cells were maintained in IMDM media supplemented with 10% Calf Serum with Iron and 100 units/mL Penicillin-Streptomycin and grown in a 37°C humidified tissue culture incubator. HMC1.2 cells were passaged by 1 : 10 dilution into fresh IMDM media supplemented with 10% Calf Serum with Iron and 100 units/mL Penicillin-Streptomycin every 2-3 days and were discarded after 20 passages.

[446] HMC1.1 cells were maintained in IMDM media supplemented with 20% Calf Serum with Iron and 100 units/mL Penicillin-Streptomycin and grown in a 37°C humidified tissue culture incubator. HMC1.1 cells were passaged by 1 :5 dilution into fresh IMDM media supplemented with 20% Calf Serum with Iron and 100 units/mL Penicillin-Streptomycin every 5-7 days and were discarded after 20 passages.

[447] Seeding was performed as follows: HMC cells were brought to IxlO ⁶ cells/mL in fresh phenol red free, serum-free, iron-free IMDM media with Pen/Strep; cells were seeded/plated into respective U-bottom plate by dispensing 50μL/well (50,000 cells) using the Multidrop, and covered and incubated cells at 37°C in a humidified tissue culture incubator for 4 hours (starvation).

[448] Dosing was performed as follows: The compound mother plate was prepared by adding 16μL of compound to 24μL of DMSO to row A, odd-numbered columns of screen matrix plate. The Bravo protocol 5 cpds 8-point 4-fold serial dilution vertical for 96-well was used to: add 30μL DMSO to all other columns and serially dilute compounds 1 :4 from 4mM to 244nM. Intermediate plates were prepared in V-bottom plates by dispensing 98μL of phenol red free, serum free IMDM media with Pen/Strep into all wells. 2μL DMSO or 2μL lOmM staurosporine was added to appropriate control wells. At the end of four hours, the Bravo protocol 10 cpds vertical dose MSD 2 U-plates 96-well was used to: add 2μL from the compound plate to the intermediate plate and dose cells with 7μL from the intermediate plate. The cells were covered and incubated at 37°C in a humidified tissue culture incubator for 90 min. The complete lysis buffer was prepared with AlphaLISA 5X Lysis Buffer supplemented with IX protease inhibitor cocktail and kept on ice. The cells were pelleted by centrifuging plate at 2500 xg for 5min, 4°C and media removed. Complete lysis buffer was added (14μL/well). The cells were covered and shaken at 4°C on a plate shaker at 600rpm for 30min and kept cold

[449] The MSD protocol was preformed as follows: Tris Wash Buffer (2L) was prepared by diluting 10X stock of Tris Wash Buffer to IX in water. Blocking Solution was prepared by dissolving 600mg Blocker A in 20mL IX Trish Wash Buffer (per plate). The Antibody Dilution Buffer was prepared by mixing ImL Blocking solution and 2mL IX Trish Wash Buffer (per plate) and kept on ice. Blocking Solution was added (150μL/well) to each MSD plate using a multichannel repeater pipette. The plate was covered and incubated at room temperature on a plate shaker at 700rpm for Ihr. The Bio Tek protocol RL-96w-wash-MSD_stacker_fromC was used to wash plates 3X with 150μL/well. Cells were pelleted by centrifuging lysate plates at 2500 xg for 5 mins. The Bravo protocol was used (transfer 25 ul supernatants from V-96 to assay plate) to transfer 25μL sample lysate per well to each MSD plate. The plates were covered and incubated at room temperature on a plate shaker at 700rpm for Ihr. The Bio Tek protocol RL-96w-wash- MSD stacker fromC was used to wash plates 3X with 150μL/well. The Detection Antibody Solution was prepared by diluting the 60μL of the 50X antibody stock in 2.94mL of the Antibody Dilution Buffer (per plate) and kept on ice. 25μL/well of detection antibody solution was added to each MSD plate. The plates were covered and incubated at room temperature on a plate shaker at 700rpm for Ihr. The Read Buffer was prepared by diluting 5mL of 4X stock of Read Buffer to IX in 15mL water (per plate). The Bio Tek protocol RL-96w-wash-MSD_stacker_fromC was used to wash plates 3X with 150μL/well. Read Buffer was added 150μL/well to each MSD plate. The plate was read on an MSD Sector Imager within 5 minutes of adding read buffer.

[450] Table 1 shows the activity of the exemplified compounds in the pKIT assay according to the Meso Scale Discovery (MSD) assay described herein. “A” represents IC50 of less than or equal to 10.0 nM (IC50 < 10.0 nm), “B” represents IC50 of greater than 10.0 nM and equal to or less than 40.0 nM (10.0 nM < IC50 < 40.0 nM), and “C” represents IC50 of greater than 40.0 nM (IC50 > 40.0).

Table 1 osz

[451] Compounds 40, 41, 68 and 124 were intentionally omitted from Table 1.

[452] Additional Compounds 204-211 fall within the scope of Formula (I), see Table 2 below, were also tested in the pKIT assay (pKIT HMC1.1 V654A) and all of these compounds had inhibitory activities of greater than 625 nM.

Table 2

EQUIVALENTS

[453] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.

[454] Furthermore, the disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims are introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the disclosure, or aspects of the disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the disclosure or aspects of the disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [455] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the disclosure described and claimed herein. Such equivalents are intended to be encompassed by the following claims.