Compositions and methods for treating KIT- and PDGFRA-mediated diseases

Abstract

The present disclosure provides a compound of formula (I-0): The present disclosure provides compounds of formula (I) and (II), pharmaceutically acceptable salts thereof, and / or solvates of any of the foregoing, which are useful for treating diseases and conditions associated with mutant KIT and PDGFRα, and which exhibit a non-brain penetration profile advantageous for treating diseases and conditions associated with mutant KIT and PDGFRα. The present disclosure also provides methods for treating gastrointestinal stromal tumors and systemic mastocytosis.

Description

[Technical Field]

[0001]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 091,486, filed October 14, 2020. The entire contents of the aforementioned application are incorporated herein by reference.

[0002] This disclosure relates to novel compounds and their use as selective inhibitors of activated KIT and PDGFRα mutant protein kinases. The compounds disclosed herein are useful, for example, in pharmaceutical compositions for the treatment of chronic disorders. The KIT receptor belongs to the class III receptor tyrosine kinase family, which also includes the structurally related protein PDGFRα. Normally, stem cell factor binds to KIT and activates it by inducing dimerization and autophosphorylation, thereby initiating downstream signaling. However, in several tumor types, somatic activating mutations in KIT promote ligand-independent constitutive oncogenic activity, including acute myeloid leukemia, melanoma, intracranial germ cell tumors, mediastinal B-cell lymphoma, seminoma, and gastrointestinal stromal tumors. Mutant KIT is also known to play a role in mast cell activation, which is common and likely necessary for its maintenance. Impaired mast cell activation occurs when mast cells are pathologically overproduced or when their activation is disproportionate to a perceived threat to homeostasis. Mast cell activation syndrome refers to a group of disorders with diverse causes that present with episodic multisystem symptoms as a result of the release of mast cell mediators. Mastocytosis is a type of mast cell activation syndrome. The World Health Organization (WHO) classifies mastocytosis into seven different categories: cutaneous mastocytosis, indolent systemic mastocytosis (ISM), smoldering systemic mastocytosis (SSM), mastocytosis with associated hematologic neoplasia (SM-AHN), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and mast cell sarcoma. [Background technology]

[0003] Systemic mastocytosis (SM) is a clonal disorder of mast cells characterized by increased mast cell burden with focal and / or diffuse infiltration of neoplastic mast cells in the skin, bone marrow, spleen, liver, gastrointestinal tract, and other organs, and increased release of mast cell mediators. SM includes five subtypes of mastocytosis: indolent SM (ISM), smoldering SM (SSM), SM with associated hematologic neoplasms of non-MC lineage (SM-AHN), aggressive SM (ASM), and MC leukemia (MCL). The latter three subtypes are associated with shorter overall survival and are grouped as progressive SM (AdvSM). ISM is a chronic disorder associated with normal or near-normal life expectancy, while SSM has an intermediate prognosis. ISM and SSM are grouped as non-advSM.

[0004] In all subtypes of SM and in the majority of patients with this disease, neoplastic mast cells exhibit mutations at the D816 position in exon 17 of KIT, resulting in ligand-independent activation of KIT kinase activity. Because wild-type mast cells require KIT activity for their differentiation and survival, constitutive activation of KIT by the D816V mutation is thought to be the pathogenic driver of SM. Specifically, the KIT D816V mutation is found in 90% to 98% of SM patients, and rare KIT D816Y, D816F, and D816H variants have been identified. Based on these findings, KIT D816V is considered a primary therapeutic target for SM.

[0005]

[0005] The chronic disorders of indolent SM and SSM are characterized by severe symptoms, such as itching, flushing, gastrointestinal cramps, diarrhea, anaphylaxis, bone pain, and osteoporosis. These symptoms can be severely debilitating and negatively impact quality of life. There are currently no approved treatments for ISM or SSM. Therefore, it would be beneficial to discover new therapies that target ISM or SSM.

[0006]

[0006] Compounds having mutant KIT and PDGFRα inhibitory activity are described in WO2015 / 057873, CN108191874, and WO2019 / 034128. The chemical structures of the compounds known in the art differ from the chemical structures of the compounds disclosed herein.

[0007]

[0007] Furthermore, compounds having mutant KIT and PDGFRα inhibitory activity have been disclosed in the art, but the properties of these known compounds are significantly different from those of the compounds of the present disclosure. Summary of the Invention

[0008]

[0008] The object of the present disclosure is to provide novel compounds with highly selective and potent activity against mutant KIT and PDGFRα kinases for the safe and effective treatment of chronic disorders such as ISM and SSM and other diseases mediated by mutant KIT or PDGFRA. In treating these disorders, particularly chronic disorders such as ISM and SSM, new therapies need to be well tolerated. In particular, there is a need for new compounds that target mutant KIT and PDGFRα kinases with reduced levels of undesirable CNS side effects associated with other known KIT and PDGFRα inhibitors.

[0009] The present inventors have discovered novel compounds that possess high selectivity and potency against mutant KIT and PDGFRα kinases, while at the same time possessing additional desirable properties, such as little or no penetration into the CNS, low unbound concentrations in the brain, and high or active transport out of the brain, i.e., high efflux rates from the CNS. Given this balance of desirable properties, the compounds of the present disclosure are particularly well suited for peripheral treatments, especially chronic peripheral treatments, while reducing or minimizing side effects in the CNS.

[0010]

[0010] Thus, the compounds of the present disclosure are intended to provide treatments with desirable efficacy, safety, and pharmaceutical properties for the treatment of KIT- and PDGFRA-mediated diseases. More specifically, the compounds of the present disclosure exhibit a series of beneficial properties, including reduced levels of brain penetration, while maintaining efficacy and other desirable pharmaceutical properties, compared to compounds known in the art that have mutant KIT and PDGFRA inhibitory activity. DETAILED DESCRIPTION OF THE INVENTION

[0011] Abbreviations and Definitions The following abbreviations and terms have the indicated meanings throughout:

[0012] The term "KIT" refers to a human tyrosine kinase sometimes referred to as the mast / stem cell growth factor receptor (SCFR), the proto-oncogene c-KIT, the tyrosine protein kinase Kit, or CD117. As used herein, the term "KIT nucleotide" encompasses the KIT gene, KIT mRNA, KIT cDNA, and their amplification products, mutations, variants, and fragments. The term "KIT gene" refers to a gene encoding a polypeptide with KIT kinase activity, e.g., the sequence of which is located between nucleotides 55,524,085 and 55,606,881 on chromosome 4 of the human genome reference hg19. The term "KIT transcript" refers to a transcription product of the KIT gene, an example of which has the sequence of NCBI reference sequence NM_000222.2. The term "KIT protein" refers to a polypeptide sequence produced by translation of a KIT nucleotide or a portion thereof.

[0012]

[0013] The term "PDGFRA" refers to a human tyrosine kinase sometimes called platelet-derived growth factor alpha. As used herein, the term "PDGFRA nucleotide" encompasses the PDGFRA gene, PDGFRA mRNA, KIT cDNA, and their amplification products, mutations, variants, and fragments. The term "PDGFRA gene" refers to a gene encoding a polypeptide with PDGFRA kinase activity, e.g., the sequence of which is located between nucleotides 54,229,089 and 54,298,247 on chromosome 4, GRCh38.p12, in Reference Homo sapiens Annotation Release 109. The term "PDGFRA transcript" refers to a transcription product of the PDGFRA gene, an example of which has the sequence of NCBI Reference Sequence NM_006206.6. The term "PDGFRA protein" or "PDGFRα" refers to a polypeptide sequence produced by translation of a PDGFRA nucleotide or a portion thereof.

[0013]

[0014] As used herein, "malignant disease" refers to a disease in which abnormal cells divide uncontrollably and may invade nearby tissues. Malignant cells may also spread to other parts of the body via the blood or lymphatic system. Non-limiting examples of malignant diseases are carcinoma, sarcoma, leukemia, and lymphoma. Cancer is a non-limiting example of a malignant disease. In some embodiments, systemic mastocytosis is a non-limiting example of a malignant disease.

[0014]

[0015] Non-limiting examples of cancer include gastrointestinal stromal tumor (GIST), AML (acute myeloid leukemia), melanoma, seminoma, intracranial germ cell tumor, and mediastinal B-cell lymphoma.

[0015]

[0016] As used herein, "eosinophilic disorder" refers to a disorder in which eosinophils are found in greater than normal amounts in various parts of the body and / or the ratio of low to normal eosinophil concentrations is higher than normal (e.g., greater than 30%). The eosinophilic disorders described herein are characterized by an excess of eosinophils (eosinophilia). The increased number of eosinophils leads to tissue inflammation and organ damage. The heart, lungs, skin, and nervous system are most frequently affected, but any organ can be damaged.

[0016]

[0017] Eosinophilic disorders are diagnosed depending on the area where eosinophil levels are elevated: Eosinophilic pneumonia (lungs) Eosinophilic cardiomyopathy (heart) Eosinophilic esophagitis (EoE) Eosinophilic gastritis (gastric-EG) Eosinophilic gastroenteritis (stomach and small intestine - EGE) Eosinophilic enteritis (small intestine) Eosinophilic colitis (colon-EC) Hypereosinophilic syndrome (blood and any organ - HES)

[0018] As used herein, the term "subject" or "patient" refers to an organism treated by the methods of the present disclosure. Such organisms include, but are not limited to, mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, etc.), and in some embodiments, humans.

[0017]

[0019] As used herein, the phrase "therapeutically effective amount" refers to an amount of an active agent sufficient to produce a beneficial or desired result. A therapeutically effective amount can be administered in one or more administrations, applications, or doses, and is not intended to be limited to a particular formulation or route of administration.

[0018]

[0020] As used herein, the phrase "the weight equivalent of a pharmaceutically acceptable salt thereof" with respect to a particular compound includes the weight of both the compound and the associated salt.

[0021] As used herein, the phrase "a pharmaceutically acceptable salt thereof," when used in reference to an active agent that is distributed in salt form, refers to any pharmaceutically acceptable salt form of the active agent.

[0019]

[0022] As used herein, the term "treating" includes any effect that results in improvement of a condition, disease, disorder, etc., or the amelioration of a symptom thereof, such as alleviating, reducing, modulating, ameliorating, or eliminating.

[0020]

[0023] Although it is possible for the active agent to be administered alone, in some embodiments, the active agent can be administered as a formulation, in which the active agent is combined with one or more pharmaceutically acceptable excipients or carriers.For example, the active agent can be formulated for administration in any convenient way for use in human or veterinary medicine.In certain embodiments, the compound contained in pharmaceutical preparations can be active itself, or for example, can be a prodrug that can be converted into active compound in physiological environment.

[0021]

[0024] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0022]

[0025] As used herein, the definition of each expression, e.g., m, n, etc., when it occurs more than once in any construct, is intended to be independent of its definition elsewhere in the same construct.

[0023]

[0026] Certain compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents. All such isomers, and mixtures thereof, are intended to be included in the present disclosure.

[0024]

[0027] For example, if a particular enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, in which case the resulting diastereomeric mixture is separated and the auxiliary cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group, e.g., amino, or an acidic functional group, e.g., carboxyl, formation of a diastereomeric salt with an appropriate optically active acid or base, followed by resolution of the diastereomers by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0025]

[0028] Unless otherwise specified, when a disclosed compound is named or depicted by structure without specifying stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound, as well as enantiomeric mixtures thereof.

[0026]

[0029] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the equation shown below: In the example shown below, the composition contains 90% of one enantiomer, e.g., the S enantiomer, and 10% of the other enantiomer, i.e., the R enantiomer. ee=(90-10) / 100=80%.

[0027]

[0030] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0031] The compounds or compositions described herein can contain at least 50%, 75%, 90%, 95%, or 99% enantiomeric excess of one form of the compound, e.g., the S-enantiomer. In other words, such compounds or compositions contain an enantiomeric excess of the S enantiomer over the R enantiomer.

[0028]

[0032] In one embodiment, the compounds described herein may also contain unnatural proportions of deuterium at one or more of the atoms that constitute such compounds. Additionally, all tautomeric forms of the compounds described herein are intended to be within the scope of the present disclosure.

[0029]

[0033] The compounds disclosed herein can be useful in the form of free base or as salt.Representative salts include hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate etc. (See, for example, Berge et al. (1977) "Pharmaceutical Salts", J. Pharm. Sci. 66:1-19).

[0030]

[0034] Certain compounds disclosed herein can exist in unsolvated forms as well as solvated forms, including hydrated forms. As used herein, the term "hydrate" or "hydrated" refers to a compound formed by the combination of water with the parent compound.

[0031]

[0035] In general, solvated forms are equivalent to unsolvated forms and are within the scope of the present disclosure. Certain compounds disclosed herein may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure.

[0032]

[0036] The present disclosure provides a compound of formula (I-0):

[0033] [ka]

[0034] a pharmaceutically acceptable salt or stereoisomer thereof, and / or a solvate of any of the foregoing. (In the formula,

[0035] [ka]

[0036] is selected from a single bond and a double bond;

[0037] [ka]

[0038] is selected from a single bond and a double bond; Z is selected from CH and NH; Y is selected from C and N; X1 is selected from CH, C, and N; X2 is selected from CH, C, and N; However, if X1 and X2 are both N, then Y is not N and Z is not CH; A is,

[0039] [ka]

[0040] and; R1 is selected from hydrogen and methyl; R2 is selected from hydrogen and methyl, or R1 and R2 together form a cyclopropyl; R3 is selected from hydrogen and methyl; R4 is selected from hydrogen and methyl, or R3 and R4 together form a cyclopropyl; R5 is selected from hydrogen and methyl; R6 is selected from hydrogen and methyl, or R5 and R6 together form a cyclopropyl; or one of R2 or R4 together with R6 forms a cyclobutyl; R7 is hydrogen, or one of R2, R4, or R6 together with R7 forms a ring selected from oxetane, tetrahydrofuran, and tetrahydropyran, wherein said tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl; m is 0 or 1; n is 0 or 1; B is the compound

[0041] [ka]

[0042] is selected from OH and NH2 unless Alternatively, R7 is hydrogen, or one of R2, R4, or R6 together with R7 forms a ring selected from tetrahydrofuran and tetrahydropyran, wherein the tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl. Non-limiting embodiments of the present disclosure include: Embodiment 1. Formula (I):

[0043] [ka]

[0044] a compound of the formula (I), a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. (In the formula,

[0045] [ka]

[0046] is selected from a single bond and a double bond;

[0047] [ka]

[0048] is selected from a single bond and a double bond; Z is selected from CH and NH; Y is selected from C and N; X1 is selected from CH, C, and N; X2 is selected from CH, C, and N; However, if X1 and X2 are both N, then Y is not N and Z is not CH; A is,

[0049] [ka]

[0050] and; R1 is selected from hydrogen and methyl; R2 is selected from hydrogen and methyl, or R1 and R2 together form a cyclopropyl; R3 is selected from hydrogen and methyl; R4 is selected from hydrogen and methyl, or R3 and R4 together form a cyclopropyl; R5 is selected from hydrogen and methyl; R6 is selected from hydrogen and methyl, or R5 and R6 together form a cyclopropyl; or one of R2 or R4 together with R6 forms a cyclobutyl; R7 is hydrogen, or one of R2, R4, or R6 together with R7 forms a ring selected from oxetane, tetrahydrofuran, and tetrahydropyran, wherein said tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl; m is 0 or 1; n is 0 or 1; B is selected from OH and NH2 Alternatively, R7 is hydrogen, or one of R2, R4, or R6 together with R7 forms a ring selected from tetrahydrofuran and tetrahydropyran, wherein the tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl. In one embodiment, the compound of formula (I) is

[0051] [ka]

[0052] It is not the S isomer. In some embodiments of Embodiment 1, when m is 0, R1 and R2 are not present. In some embodiments of Embodiment 1, when n is 0, R3 and R4 are not present. In some embodiments of Embodiment 1, m+n=1, or m and n cannot both be 0.

[0053]

[0039] It should be noted that in the present disclosure, when any two R groups (e.g., R1 and R2) together form a ring structure (e.g., cyclopropyl), it is intended that the intervening carbon and / or oxygen atoms be included in the same ring structure.

[0054] Embodiment 2. Formula (II):

[0055] [ka]

[0056] The compound of embodiment 1, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the definitions of variables A and B are provided in formula (I-0) or formula (I). Embodiment 3. Formula (III):

[0057] [ka]

[0058] The compound of embodiment 1, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. (In the formula, X1 is selected from CH, C, and N; X2 is selected from CH, C, and N; However, only one of X1 and X2 is N.) The definitions of the variables A and B are provided in Formula (I-0) or Formula (I). In one embodiment, the compound of formula (III) is

[0059] [ka]

[0060] It is not the S isomer. Embodiment 4. X1 is N;

[0061] [ka]

[0062] is a single bond, X2 is C,

[0063] [ka]

[0064] is a double bond, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. Embodiment 5. X1 is C,

[0065] [ka]

[0066] is a double bond and X2 is N;

[0067] [ka]

[0068] is a single bond, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0044] Embodiment 6.A is

[0069] [ka]

[0070] and; R3 is selected from hydrogen and methyl; R4 is selected from hydrogen and methyl, or R3 and R4 together form cyclopropyl; R5 is selected from hydrogen and methyl, or R5 and R6 together form a cyclopropyl; The compound of any one of embodiments 1-5, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein R7 is hydrogen.

[0071]

[0045] Embodiment 7.A is

[0072] [ka]

[0073] and; w is 1 or 2; t is 1 or 2; The compound of any one of embodiments 1-5, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein s is 0 or 1.

[0074] Embodiment 8. The compound of any one of embodiments 1-7, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein B is NH2. Embodiment 9. The compound of any one of embodiments 1-7, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein B is OH.

[0075]

[0048] Embodiment 10.K p <0.4. The compound of any one of embodiments 1-9, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. In some embodiments of embodiment 10, the compound has a K p <0.4. In some embodiments of embodiment 10, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0076] Embodiment 11. The compound of any one of embodiments 1-9, wherein K p≦0.30, the compound, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0077] In some embodiments of embodiment 11, the compound has a K p In some embodiments of embodiment 11, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0078] Embodiment 12. The compound of any one of embodiments 1-9, wherein K p ≦0.20, the compound, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0079] In some embodiments of embodiment 12, the compound has a K p In some embodiments of embodiment 12, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0080] Embodiment 13. The compound of any one of embodiments 1-9, wherein K p The compound, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β-amino acid value of ≦0.10.

[0081] In some embodiments of embodiment 13, the compound has a K p In some embodiments of embodiment 13, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof is selected from Compound 2.

[0082] Embodiment 14. A compound of any one of embodiments 1-13, which is capable of inhibiting K in homogenized rat brain. p,uu≦0.2, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0083] In some embodiments of embodiment 14, the compound exhibits a K p,uu In some embodiments of embodiment 14, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0084]

[0058] Embodiment 14-1. A compound of any one of embodiments 1 to 13, which is capable of inhibiting K in homogenized rat brain. p,uu <0.1, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0085] In some embodiments of embodiment 14-1, the compound exhibits a K p,uu <0.1. In some embodiments of embodiment 14-1, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0086]

[0060] Embodiment 14-2. A compound of any one of embodiments 1 to 13, which is capable of inhibiting K in homogenized rat brain. p,uu ≦0.05, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0087] In some embodiments of embodiment 14-2, the compound exhibits a K p,uu In some embodiments of embodiment 14-2, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0088]

[0062] Embodiment 14-3. K in rat brain slices p,uu The compound of any one of embodiments 1-13, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β- or β-blocking ability of ≦0.02.

[0089] In some embodiments of embodiment 14-3, the compound exhibits a K p,uu In some embodiments of embodiment 14-3, any of the aforementioned compounds, pharmaceutically acceptable salts, and / or solvates thereof are selected from compounds 1 and 2.

[0090] Embodiment 15. Unbound clearance (Cl) in rats u 15. The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the blood flow rate is <900 mL / min / kg.

[0091] Embodiment 16. Unbound clearance (Cl) in rats u 15. The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the blood flow rate is <750 mL / min / kg.

[0092]

[0066] Embodiment 17. IC against CYP3A4 50 The compound of any one of embodiments 1-14, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein

[0093]

[0067] Embodiment 18.A is

[0094] [ka]

[0095] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0068] Embodiment 19.A is

[0096] [ka]

[0097] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0069] Embodiment 20.A is

[0098] [ka]

[0099] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0070] Embodiment 21.A is

[0100] [ka]

[0101] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0071] Embodiment 22.A is

[0102] [ka]

[0103] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0072] Embodiment 23.A is

[0104] [ka]

[0105] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0073] Embodiment 24.A

[0106] [ka]

[0107] The compound of any one of embodiments 1-5, 8 and 9 selected from: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0074] Embodiment 25. A compound of any one of embodiments 1 to 5, 8 and 9, which is any one of the compounds listed in Table 1 below, its pharmaceutically acceptable salt, and / or any solvate of the foregoing.

[0108] In some embodiments of Embodiment 25, the compound is any one of Compounds 1-7, 13, 14, 14-A, 28, 33, and 38. In some embodiments of Embodiment 25, the compound is any one of Compounds 1-7, 13, 14, 28, 33, and 38. In some embodiments of Embodiment 25, the compound is any one of Compounds 1-6. In some embodiments of Embodiment 25, the compound is any one of Compounds 1 and 2.

[0109] Embodiment 26. A compound of any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing; and a pharmaceutically acceptable excipient.

[0110]

[0077] Embodiment 27. A method for treating a disease or condition in a patient in need thereof, comprising administering to the patient any one of the compounds of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or any of the foregoing solvates, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor.

[0111]

[0078] Embodiment 28. A method for treating a disease or condition mediated by mutant KIT or PDGFRα in a patient in need of treatment for said disease or condition, comprising administering to the patient a compound of any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0112]

[0079] Embodiment 29. The method of embodiment 28, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor.

[0113]

[0080] Embodiment 30. A compound described in any one of embodiments 1 to 25, for use as a pharmaceutical for treating a disease or condition in a patient in need thereof, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor, a compound, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0114]

[0081] Embodiment 31. A compound described in any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, for use as a pharmaceutical for treating a disease or condition mediated by mutant KIT or PDGFRA in a patient in need of treatment for said disease or condition.

[0115]

[0082] Embodiment 32. The compound of embodiment 31, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor.

[0116]

[0083] Embodiment 33. A method for treating an eosinophilic disorder, comprising administering a therapeutically effective amount of a compound described in any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing to a subject in need of treatment for an eosinophilic disorder.

[0117]

[0084] Embodiment 34. The method of embodiment 33, wherein the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0118]

[0085] Embodiment 35. The method of embodiment 33, wherein the eosinophilic disorder is hypereosinophilic syndrome.

[0086] Embodiment 36. The method of embodiment 33, wherein the eosinophilic disorder is eosinophilic leukemia.

[0119]

[0087] Embodiment 37. The method of embodiment 36, wherein the eosinophilic leukemia is chronic eosinophilic leukemia.

[0088] Embodiment 38. The method of any one of embodiments 33 to 37, wherein the eosinophilic disorder is refractory to treatment with imatinib, sunitinib, and / or regorafenib.

[0120]

[0089] Embodiment 39. A compound of any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, for use as a medicament for treating an eosinophilic disorder.

[0121] Embodiment 40. The compound of embodiment 39, wherein the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0122] Embodiment 41. The compound of embodiment 39, wherein the eosinophilic disorder is hypereosinophilic syndrome. Embodiment 42 The compound of embodiment 39, wherein the eosinophilic disorder is eosinophilic leukemia.

[0123] Embodiment 43. The compound of embodiment 42, wherein the eosinophilic leukemia is chronic eosinophilic leukemia.

[0094] Embodiment 44. The method of any one of embodiments 39 to 43, wherein the eosinophilic disorder is refractory to treatment with imatinib, sunitinib, and / or regorafenib.

[0124]

[0095] Embodiment 45. A method for treating a mast cell disorder, comprising administering a therapeutically effective amount of a compound described in any one of embodiments 1 to 25, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing to a subject in need of treatment for a mast cell disorder.

[0125]

[0096] Embodiment 46. The method of embodiment 45, wherein the mast cell disorder is mediated by mutant KIT or PDGFRα.

[0097] Embodiment 46-1. The method of embodiment 45, wherein the mast cell disorder is mediated by wild-type KIT or PDGFRα.

[0126]

[0098] Embodiment 47. The method of any one of embodiments 46, wherein the mast cell disorder is selected from mast cell activation syndrome (MCAS) and hereditary alpha tryptasia (HAT).

[0127]

[0099] Embodiment 48. The method of embodiment 47, wherein the MCAS is selected from monoclonal mast cell activation syndrome (MMAS), secondary MCAS, and idiopathic MCAS.

[0100] Embodiment 48-1. The method of embodiment 27, wherein the disease or condition is systemic mastocytosis.

[0128]

[0101] Embodiment 49. The method of any one of embodiments 48, wherein the systemic mastocytosis is selected from indolent systemic mastocytosis and smoldering systemic mastocytosis.

[0102] Please note that in the present disclosure, any one of the above-identified embodiments is intended to include the corresponding subembodiments. For example, when reference is made to embodiment 14, this is intended to include embodiment 14, embodiment 14-1, embodiment 14-2, embodiment 14-3, and the specific embodiments recited therein.

[0129] [Table 1-1]

[0130] [Table 1-2]

[0131] [Table 1-3]

[0132] [Table 1-4]

[0133] [Table 1-5]

[0134] Table 1-6

[0135] Table 1-7

[0136] Table 1-8

[0137] Table 1-9

[0138] Table 1-10

[0139] Table 1-11

[0140] Table 1-12

[0141] Table 1-13

[0142] Table 1-14

[0143] Table 1-15

[0144] Table 1-16

[0145] Table 1-17

[0146] Table 1-18

[0147] Table 1-19

[0148] Table 1-20

[0149] Table 1-21

[0150] Table 1-22

[0151] Table 1-23

[0152] Table 1-24

[0153] Table 1-25

[0154] Table 1-26

[0155] Table 1-27

[0156] Table 1-28

[0157] Table 1-29

[0158] Table 1-30

[0159] Table 1-31

[0160] Table 1-32

[0161] Table 1-33

[0162] Table 1-34

[0163] Table 1-35

[0164] Table 1-36

[0165] Table 1-37

[0166] Table 1-38

[0167] Table 1-39

[0168] Table 1-40

[0169] Table 1-41

[0170] Table 1-42

[0171] Table 1-43

[0172]

[0103] The compounds of the present disclosure are selective KIT inhibitors. In some embodiments, the compounds of the present disclosure are selective D816V KIT inhibitors. The compounds of the present disclosure are selective PDGFRα inhibitors. In some embodiments, the compounds of the present disclosure are selective PDGFRα exon 18 inhibitors. In some embodiments, the compounds of the present disclosure are selective PDGFRα D842V inhibitors. As used herein, "selective KIT inhibitor" or "selective PDGFRα inhibitor" refers to a compound, or a pharmaceutically acceptable salt or solvate of either of the foregoing, that selectively inhibits KIT protein kinase or PDGFRα protein kinase over another protein kinase, and exhibits at least 2-fold selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase. For example, a selective KIT inhibitor or a selective PDGFRA inhibitor exhibits at least 9-fold selectivity, 10-fold selectivity, at least 15-fold selectivity, at least 20-fold selectivity, at least 30-fold selectivity, at least 40-fold selectivity, at least 50-fold selectivity, at least 60-fold selectivity, at least 70-fold selectivity, at least 80-fold selectivity, at least 90-fold selectivity, at least 100-fold, at least 125-fold, at least 150-fold, at least 175-fold, or at least 200-fold selectivity for KIT protein kinase or PDGFRA kinase over another kinase. In some embodiments, a selective KIT inhibitor or a selective PDGFRA 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). In some embodiments, the selective KIT inhibitor or selective PDGFRα inhibitor exhibits greater selectivity over PDGRFβ, CSF1R (colony stimulating factor receptor 1), and FLT3.In some embodiments, the selective KIT inhibitor or selective PDGFRα inhibitor exhibits selectivity over LCK (lymphocyte-specific protein kinase), ABL (nuclear protein tyrosine kinase), never-in-mitosis gene A (NIMA)-associated kinase 5 (NEK5), and ROCK1 (rho-associated coil-coil-continuing protein kinase-1). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a cellular assay (e.g., a cellular assay). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over another kinase is measured in a biochemical assay (e.g., a biochemical assay).

[0173]

[0104] The compounds of the present disclosure are selective over ion channels. In some embodiments, selective KIT or selective PDGFRα inhibitors have limited potency in inhibiting the human voltage-gated sodium channel (hNav1.2).

[0174] Compounds of the present disclosure are selective for mutant KIT over wild-type KIT. In some embodiments, compounds of the present disclosure are selective for exon 17 mutant KIT over wild-type KIT.

[0175] The compounds of the present disclosure may be useful for treating diseases or conditions associated with mutant KIT or mutant PDGFRA activity in humans or non-humans. In some embodiments, the compounds of the present disclosure are for use as pharmaceuticals. In some embodiments, the compounds of the present disclosure are for use in therapy. In some embodiments, the compounds of the present disclosure are for use in the manufacture of a medicament. In some embodiments, the present disclosure provides methods for treating KIT-driven malignancies, including mastocytosis (SM), GIST (gastrointestinal stromal tumor), AML (acute myeloid leukemia), melanoma, seminoma, intracranial germ cell tumor, and / or mediastinal B-cell lymphoma. In addition, KIT mutations have been associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), dysgerminoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK / T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain tumors. In some embodiments, the present disclosure provides methods for treating Ewing's sarcoma, DLBCL, dysgerminoma, MDS, NKTCL, CMML, and / or brain tumors. KIT mutations have also been found in thyroid cancer, colorectal cancer, endometrial cancer, bladder cancer, NSCLC, and breast cancer (AACR Project GENIE). In some embodiments, compounds of the present disclosure may be useful for treating mast cell activation syndrome (MCAS). Compounds of the present disclosure may be useful for treating systemic mastocytosis. Compounds of the present disclosure may be useful for treating progressive systemic mastocytosis. Compounds of the present disclosure may be useful for treating indolent SM and smoldering SM. Compounds of the present disclosure may be useful for treating GIST.

[0176] The compounds of the present disclosure may be useful for treating diseases or conditions associated with KIT mutations in exon 9, exon 11, exon 14, exon 17, and / or exon 18 of the KIT gene sequence. The compounds of the present disclosure may be useful for treating diseases or conditions associated with PDGFRA mutations in exon 12, exon 14, and / or exon 18 of the PDGFRA gene sequence. In some embodiments, provided herein are methods for treating diseases or conditions associated with at least one KIT mutation in exon 9, exon 11, exon 14, exon 17, and / or exon 18 of the KIT gene sequence. In some embodiments, provided herein are methods for treating diseases or conditions associated with at least one PDGFRA mutation in exon 12, exon 14, and / or exon 18 of the PDGFRA gene sequence.

[0177] The compounds of the present disclosure may be active against one or more KIT protein kinases having mutations in exon 17 of the KIT gene sequence (e.g., KIT protein mutations D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P), and are much less active than wild-type KIT protein kinase. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation, such as those selected from D816V, D816Y, D816F, D816K, D816H, D816A, D816G, D816E, D816I, D816F, D820A, D820E, D820G, D820Y, N822K, N822H, V560G, Y823D, and A829P. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation, such as those selected from C809, C809G, D816H, D820A, D820G, N822H, N822K, and Y823D.

[0178]

[0109] Compounds of the present disclosure may be active against one or more KIT protein kinases that have a mutation in exon 11 of the KIT gene sequence (eg, the KIT protein mutation del557-559insF, V559G / D). In some embodiments, the present invention relates to a KIT mutation, including at least one KIT mutation, such as L576P, V559D, V560D, V560G, W557G, Del 554-558EVQWK, del557-559insF, Del EVQWK554-558, Del EVQWKVVEEINGNNYVYI554-571, Del KPMYEVQWK550-558, Del KPMYEVQW550-557FL, Del KV558-559, Del KV558-559N, Del MYEVQW552-557, Del PMYE551-554, Del VV559-560, Del WKVVE557-561, Del WK557-558, Del The present invention provides a method for treating a disease or condition associated with a gene selected from the group consisting of WKVV557-560C, Del WKVV557-560F, DelYEVQWK553-558, and insertion K558NP.

[0179] The compounds of the present disclosure may be active against one or more KIT protein kinases having mutations in exons 11 / 13 of the KIT gene sequence (e.g., KIT protein mutations V559D / V654A, V560G / D816V, and V560G / 822K). In some embodiments, provided herein are methods for treating diseases or conditions associated with one or more KIT mutations in exons 11 / 13.

[0180]

[0111] Compounds of the present disclosure may be active against one or more KIT protein kinases having a mutation in exon 9 of the KIT gene sequence. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one KIT mutation in exon 9.

[0181] In some embodiments, compounds of the present disclosure are not active against KIT protein kinases having mutations V654A, N655T, T670I, and / or N680.

[0182] The compounds of the present disclosure may be active against one or more PDGFRα protein kinases harboring mutations. In some embodiments, provided herein are methods for treating diseases or conditions associated with at least one PDGFRA mutation in exon 12 of the PDGFRA gene sequence, such as the PDGFRα protein mutations V561D, Del RV560-561, Del RVIES560-564, Ins ER561-562, SPDGHE566-571R, SPDGHE566-571K, or Ins YDSRW582-586. In some embodiments, provided herein are methods for treating diseases or conditions associated with at least one PDGFRA mutation in exon 14 of the PDGFRA gene sequence, such as the PDGFRα protein mutation N659K. In some embodiments, the present invention encompasses, for example, PDGFRα protein mutations D842V, D842Y, D842I, DI842-843IM, D846Y, Y849C, Del D842, Del I843, Del RD841-842, Del DIM842-845, Del DIMH842-845, Del IMHD843-846, Del Methods are provided for treating a disease or condition associated with at least one PDGFRA mutation in exon 18 of the PDGFRA gene sequence, such as MHDS844-847, RD841-842KI, DIMH842-845A, DIMH842-845V, DIMHD842-846E, DIMHD842-846S, DIMHD842-846N, DIMHD842-846G, IMHDS843-847T, IMHDS8843-847M, or HDSN845-848P.

[0183] The compounds of the present disclosure may be active against one or more PDGFRα protein kinases having a mutation in exon 18 of the PDGFRA gene sequence (e.g., the protein mutations PDGFRα D842V, PDGFRα D842I, or PDGFRα D842Y). In some embodiments, provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 18, such as, for example, the protein mutation PDGFRα D842V.

[0184]

[0115] Compounds of the present disclosure may be useful for treating eosinophilic disorders. In some embodiments, the eosinophilic disorder is mediated by mutant KIT or PDGFRα. In some embodiments, the eosinophilic disorder is mediated by wild-type KIT or PDGFRα. In some embodiments, provided herein is a method of treating an eosinophilic disorder, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. In one embodiment, the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0185] In some embodiments, the eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastritis, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease. Other eosinophilic disorders include eosinophilic esophagitis, eosinophilic gastroenteritis, eosinophilic fasciitis, and Churg-Strauss syndrome.

[0186] In one embodiment, the eosinophilic disorder is hypereosinophilic syndrome. In a specific embodiment, the hypereosinophilic syndrome is idiopathic hypereosinophilic syndrome. In one embodiment, the eosinophilic disorder is eosinophilic leukemia. In a specific embodiment, the eosinophilic leukemia is chronic eosinophilic leukemia. In another embodiment, the eosinophilic disorder is refractory to treatment with imatinib, sunitinib, and / or regorafenib. In a specific embodiment, the eosinophilic disorder is refractory to treatment with imatinib.

[0187]

[0118] Compounds of the present disclosure can be useful for reducing the number of eosinophils in a subject in need thereof. In some embodiments, provided herein is a method for reducing the number of eosinophils in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0188] In one embodiment, the disclosed methods reduce the number of eosinophils in the blood, bone marrow, gastrointestinal tract (e.g., esophagus, stomach, small intestine and colon), or lungs. In another embodiment, the methods disclosed herein reduce the number of blood eosinophils. In a further embodiment, the methods disclosed herein reduce the number of eosinophils in the lungs. In yet another embodiment, the methods disclosed herein reduce the number of eosinophil progenitor cells.

[0189] In another embodiment, the disclosed methods reduce the number of eosinophils (after administration) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In certain embodiments, the methods disclosed herein reduce the number of eosinophils below the limit of detection.

[0190] In another embodiment, the disclosed methods reduce the number of eosinophil precursors (after administration) by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, or at least about 99%. In a specific embodiment, the methods disclosed herein reduce the number of eosinophil precursors below the limit of detection.

[0191] The compounds of the present disclosure may be useful for treating mast cell disorders. The compounds of the present disclosure may be useful for treating mastocytosis. Mastocytosis is subdivided into two groups of disorders: (1) cutaneous mastocytosis (CM), which refers to a form limited to the skin, and (2) systemic mastocytosis (SM), which refers to a form in which mast cells infiltrate extracutaneous organs, with or without skin involvement. SM is further subdivided into five forms: indolent (ISM); smoldering SM (SSM); aggressive (ASM); SM with associated hematologic non-mast cell-based disease (SM-AHNMD); and mast cell leukemia (MCL).

[0192]

[0123] The diagnosis of SM is based in part on histologic and cytologic studies of bone marrow demonstrating infiltration by mast cells, often of atypical morphology, which frequently abnormally express non-mast cell markers (CD25 and / or CD2). The diagnosis of SM is confirmed when bone marrow mast cell infiltration occurs in association with one of the following: (1) abnormal mast cell morphology (spindle-shaped cells); (2) elevated serum tryptase levels greater than 20 ng / mL; or (3) the presence of an activating KIT protein mutation, e.g., an exon 17 mutation, e.g., a D816 mutation such as D816V.

[0193] Activating mutations at the D816 position are found in the majority (90-98%) of mastocytosis cases, with the most common mutations being D816V, D816H, and D816Y. The D816V mutation is found in the activation loop of the protein kinase domain and results in constitutive activation of the KIT kinase.

[0194]

[0125] No medications are approved for the non-progressive forms of systemic mastocytosis, ISM, or SSM. Current approaches to managing these chronic diseases include nonspecific symptom-directed therapy, which has varying degrees of effectiveness and does not affect MC burden. Cytoreductive therapy, such as cladribine and interferon alpha, may be used for refractory symptoms. Based on the current treatment status, there remains an unmet medical need for patients with ISM and SSM with moderate to severe symptoms that cannot be adequately managed with available symptom-directed therapy.

[0195] Compounds of the present disclosure may be useful for treating ISM or SSM. In some embodiments, patients with ISM or SSM have at least one, at least two, or at least three symptoms that cannot be adequately controlled by symptomatic treatment. Symptoms can be assessed using a patient-reported outcome (PRO) tool, such as the Indolent Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (ISPOR Europe 2019, Copenhagen, Denmark, November 2-6, 2019). Compounds of the present disclosure may be useful for improving symptoms associated with ISM or SSM, such as reducing or eliminating itching, flushing, headache, and / or GI events such as vomiting, diarrhea, and abdominal pain. Symptom improvement can be assessed using the ISM-SAF.

[0196] Compounds of the present disclosure may be useful for treating other mast cell disorders, such as mast cell activation syndrome (MCAS) and hereditary alpha tryptassemia (HAT) (Picard Clin. Ther. 2013 May 35(5)548; Akin J. Allergy Clin. Immuno. 140(2)34962.). Compounds of the present disclosure may be useful for treating mast cell disorders associated with KIT and PDGFRα mutations. Compounds of the present disclosure may be useful for treating mast cell diseases associated with wild-type KIT and PDGFRα.

[0197] The compounds of the present disclosure may be useful for treating mast cell activation syndrome (MCAS), an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a range of chronic symptoms, including anaphylactic or near-anaphylactic attacks. Unlike mastocytosis, in which a patient's mast cell numbers abnormally increase, patients with MCAS have a normal number of mast cells that do not function properly and are defined as "hyperresponsive." Types of MCAS include primary MCAS (monoclonal mast cell activation syndrome (MMAS)), secondary MCAS (MCAS resulting from another disease), and idiopathic MCAS (MCAS excluding primary or secondary MCAS).

[0198]

[0129] Compounds of the present disclosure may be useful for treating hereditary alpha tryptasia (HAT) (overexpression of TPSAB1 causing elevated tryptase). Other mast cell disorders include mast cell-mediated asthma, anaphylaxis (including idiopathic, Ig-E and non-Ig-E mediated), urticaria (including idiopathic and chronic), atopic dermatitis, swelling (angioedema), irritable bowel syndrome, mastocytosis, mastocytosis, pruritus, chronic pruritus, pruritus secondary to chronic renal failure, and mast cell-related conditions of the heart, blood vessels, intestine, brain, kidney, liver, pancreas, muscle, bone, and skin. In some embodiments, the mastocytosis is not associated with mutant KIT or mutant PDGFRα.

[0199] KIT and PDGFRA mutations are widely observed in GISTs. The compounds of the present disclosure may be useful for treating GISTs associated with KIT mutations. The compounds of the present disclosure may be useful for treating unresectable or metastatic GISTs. Approximately 80% of metastatic GISTs have primary activating mutations in either the extracellular region (exon 9) or the juxtamembrane (JM) domain (exon 11) of the KIT gene sequence. Many mutant KIT tumors respond to treatment with targeted therapies such as imatinib, a selective tyrosine kinase inhibitor that specifically inhibits BCR-ABL, KIT, and PDGFRA proteins. However, most GIST patients ultimately relapse due to secondary mutations in KIT that significantly reduce the binding affinity of imatinib. These resistance mutations always occur within the adenosine 5-triphosphate (ATP)-binding pocket (exons 13 and 14) or the activation loop (exons 17 and 18) of the kinase gene. Currently, no selective targeted agents are approved for GISTs. Imatinib is currently approved as a treatment for GIST, and multikinase inhibitors are used after imatinib. In many cases, these multikinase inhibitors, such as sunitinib, regorafenib, and midostaurin, only weakly inhibit imatinib-resistant mutants, and / or multikinase inhibitors are limited by more complicated safety profiles and narrow therapeutic windows. In some embodiments, compounds of the present disclosure may be useful for treating GIST in patients treated with imatinib. Compounds of the present disclosure may be useful for treating GIST as first-line (1L), second-line (2L), third-line (3L), or fourth-line (4L) therapy.

[0200] The compounds of the present disclosure may be useful for treating GIST when certain mutations in KIT are absent or present. In some embodiments, the compounds of the present disclosure can treat GIST when certain mutations in KIT are absent. In certain embodiments, the compounds of the present disclosure cannot treat GIST when certain mutations in KIT are present. In some embodiments, the compounds of the present disclosure do not provide clinical benefit in patients with KIT ATP-binding pocket mutations (KIT protein mutations V654A, N655T, and / or T670I).

[0201] The compounds of the present disclosure may be useful for treating GIST associated with PDGFRA mutations. In 5-6% of patients with unresectable metastatic GIST, the primary mutation occurs in exon 18 of the PDGFRA gene sequence at amino acid 842 of the protein.

[0202]

[0134] Compounds of the present disclosure may also be useful in the treatment of AML. AML patients also carry KIT mutations, with the majority of these mutations at the D816 position of the KIT protein.

[0203] In some embodiments, the compounds of the present disclosure are administered to a subject in need thereof. In some embodiments, the compounds of the present disclosure are administered as pharmaceutical formulations, wherein the compounds are combined with one or more pharmaceutically acceptable excipients or carriers. Thus, in some embodiments, disclosed herein are compositions comprising at least one entity selected from a compound of Formula I, and a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, optionally further comprising at least one pharmaceutically acceptable excipient.

[0204] The compounds of the present disclosure can be formulated for administration in any convenient manner for use in human or veterinary medicine. In some embodiments, the compounds included in the pharmaceutical composition may be active themselves or may be, for example, prodrugs that can be converted to active compounds in a physiological environment.

[0205]

[0137] The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0206]

[0138] Examples of pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) celluloses, such as sodium carboxymethylcellulose, ethyl cellulose, and cellulose acetate, and derivatives thereof; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository wax; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as cellulose acetate, ... (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer; (21) cyclodextrins, such as Captisol®, and (22) other non-toxic compatible substances used in pharmaceutical formulations.

[0207]

[0139] Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents, such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc.

[0208]

[0140] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) may contain one or more pharmaceutically acceptable carriers, such as, for example, sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or extenders, such as, for example, starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; (3) humectants, such as, for example, glycerol; (4) disintegrants, such as, for example, agar, calcium carbonate, (5) solution retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (11) coloring agents.

[0209]

[0141] Liquid dosage forms can include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to active ingredients, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, and mixtures thereof.

[0210]

[0142] Suspensions may contain, in addition to the active compounds, suspending agents such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0211]

[0143] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc and zinc oxide, or mixtures thereof.

[0212] Powders and sprays can contain, in addition to the active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0213]

[0145] Non-limiting examples of dosage forms for topical or transdermal administration of the compounds of the present disclosure 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.

[0214]

[0146] When the compounds of the present disclosure are administered to humans and animals as pharmaceuticals, the compounds can be given by themselves or in combination with a pharmaceutically acceptable carrier as a pharmaceutical composition containing, for example, 0.1 to 99.5% (such as 0.5 to 90%) of the active ingredient.

[0215]

[0147] The formulations can be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intravesically, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0216] In addition, the compounds of the present disclosure can be administered alone or in combination with other compounds, including other KIT or PDGFRα modulating compounds, or other therapeutic agents. In some embodiments, the compounds of the present disclosure can be administered in combination with ripretinib. In some embodiments, the compounds of the present disclosure can be administered in combination with one or more compounds selected from imatinib, sunitinib, regorafenib, cabozantinib, crenolanib, midostaurin, brentuximab vedotin, and mastitinib to treat the diseases or conditions disclosed herein.

[0217] The compounds of the present disclosure can be administered to patients who have previously been treated with another compound or compounds. The compounds of the present disclosure can be useful as first line (1L), second line (2L), third line (3L), or fourth line (4L) therapy.

[0218]

[0150] In some embodiments, a compound of the present disclosure is administered after prior treatment with imatinib.

[0151] Compounds of the present disclosure can be administered to patients who have not previously been treated with midostaurin. In some embodiments, compounds of the present disclosure can be administered to patients who have previously been treated with midostaurin. [Example]

[0219] definition C Celsius Cs2CO3 Cesium Carbonate DCM dichloromethane DIPEA Diisopropylamine DMF Dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide h time H2 Hydrogen Gas H2O Water HCl Hydrochloric acid HOAc acetic acid HOBT Hydroxybenzotriazole HPLC High-Performance Liquid Chromatography IC50 Inhibitory concentration 50% IPA Isopropyl Alcohol K2CO3 Potassium Carbonate KOAc Potassium Acetate LCMS Liquid Chromatography Mass Spectrometry LiAlH4 Lithium Aluminum Hydride min MsCl Mesyl chloride MTBE Methyl tert-butyl ether MeOH Methanol N2 nitrogen gas NaOH Sodium hydroxide Na2SO4 Sodium Sulfate NH4HCO3 Ammonium Formate NMP N-methylpyrrolidone Pd / C Palladium Carbon Pd(dppf)Cl2 [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) PE Petroleum Ether RT room temperature TEA Triethylamine THF tetrahydrofuran TsCl Tosyl chloride The methods for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by one skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting materials (reactants), intermediates, or products at the temperature at which the reaction is carried out, which can range, for example, from the freezing temperature of the solvent to the boiling temperature of the solvent. A given reaction can be carried out in one solvent or a mixture of two or more solvents. Depending on the specific reaction step, a suitable solvent for a particular reaction step can be selected by one skilled in the art.

[0220]

[0153] Preparation of the compounds of the present 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 of ordinary skill in the art. Protecting group chemistry can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), the entire contents of which are incorporated herein by reference.

[0221]

[0154] The reaction can be monitored according to any suitable method known in the art. For example, product formation can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13C), can be monitored by spectroscopic means such as infrared (IR) spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry (MS), or chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC). Analytical Instruments and Methods for Compound Characterization: LC-MS: Unless otherwise specified, all liquid chromatography-mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were acquired at 22.4°C using an Agilent Model 6120 mass spectrometer equipped with an Agilent Poroshel 120 (EC-C18, 2.7 μm particle size, 3.0 × 50 mm dimensions) reverse-phase column at 22.4°C. The mobile phase consisted of a mixture of 0.1% formic acid solvent in HO and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over 4 minutes was used. The flow rate was constant at 1 mL / min.

[0222] Silica Gel Chromatography: Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit.

[0223] Proton NMR: Unless otherwise specified, all H NMR spectra were obtained using a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 seconds, 1 second delay; 16-64 scans). When characterized, all protons are reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0224]

[0158] Those skilled in the art will understand that variations in gradient, column length, and flow rate are possible and that, depending on the chemical species being analyzed, some conditions may be more suitable for compound characterization than others. Example synthetic preparations Preparation of intermediates Preparation 1: N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (I-1)

[0225] [ka]

[0226] Step 1: Synthesis of ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (iii): Ethyl 2-chloropyrimidine-5-carboxylate (5.00 g, 26.8 mmol, 1.00 equiv.), tert-butyl 4-(4,4,5,5-tetramethyl-1,3 A mixture of (2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (9.11 g, 29.5 mmol, 1.10 equiv.), Pd(dppf)Cl.CHCl (2.63 g, 3.22 mmol, 0.12 equiv.), and CsCO (17.5 g, 53.6 mmol, 2.00 equiv.) was degassed and purged with N(g) three times, then the mixture was stirred at 60 °C under N(g) for 12 h. The reaction mixture was filtered, then diluted with HO (300 mL), and extracted with EtOAc (400 mL × 3). The combined organic layers were washed with brine (500 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc = 50:1 to 10:1, plate 1, Rf = 0.71) to give the title compound (4.90 g, 54.9% yield) as a pale yellow solid. LCMS: RT = 0.977 min, m / z = 278.2 (M-56 + H) + .

[0227] Step 2: Synthesis of 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (iv): A solution of ethyl 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate (3.00 g, 9.00 mmol, 1.00 equiv) in THF (30.0 mL) was added to a mixture of NaOH (803 mg, 20.1 mmol, 2.23 equiv) in HO (20.1 mL). The mixture was then stirred at 25° C. for 2 h. The mixture was concentrated in vacuo to remove THF, then the pH was adjusted to 2-3 with 1 M HCl and filtered. The filter cake was concentrated in vacuo to give the title compound (2.49 g, 90.6% yield) as a pale yellow solid, which was used in the next step without further purification. 1H NMR (400 MHz, d6-DMSO) δ 9.11 (s, 2H), 7.28 (br s, 1H), 4.12 (br s, 3H), 3.52–3.55 (br t, J = 5.2 Hz, 2H), 2.63 (s, 2H), 1.43 (s, 9H). Step 3: Synthesis of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (v): To a solution of 2-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid (2.49 g, 8.16 mmol, 1.00 equiv) in DMF (50.0 mL) was added HATU (6.20 g, 16.3 mmol, 2.00 equiv), DIPEA (5.27 g, 40.8 mmol, 7.10 mL, 5.00 equiv), N,O-dimethylhydroxylamine hydrochloride (1.19 g, 12.2 mmol, 1.50 equiv). The mixture was then stirred at 25° C. for 9 h. The mixture was diluted with EtOAc (50.0 mL) and washed with water (100 mL × 2). The aqueous layer was extracted with EtOAc (50.0 mL × 2). The combined organic layers were then washed sequentially with 1 M HCl (40.0 mL), saturated NaHCO (40.0 mL), and brine (50.0 mL). The organic layers were dried over Na SO , filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether: EtOAc = 5:1 to 10:3, petroleum ether: EtOAc = 1:1, Rf = 0.60) to give the title compound (1.89 g, 66.5% yield) as a pale yellow solid: LCMS: RT = 0.888 min, m / z = 293.3 (M-56 + H) + . 1H NMR: (400 MHz, d6-DMSO) δ 9.00 (s, 2H), 7.30 (br s, 1H), 4.13 (br s, 2H), 3.60 (s, 3H), 3.54 (br t, J = 5.6 Hz, 2H). 3.31 (s, 3H), 2.69 (s, 1H), 2.63 (br d, J = 1.6 Hz, 2H), 1.43 (s, 9H). Step 4: Synthesis of N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide trifluoroacetate (vi): To a solution of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.89 g, 5.42 mmol, 1.00 equiv) in DCM (18.9 mL) was added TFA (7.48 g, 65.6 mmol, 4.86 mL, 12.1 equiv). The mixture was stirred at 25° C. for 0.5 h and then concentrated in vacuo to give the title compound (1.97 g, crude) as a yellow oil, which was used in the next step without further purification.

[0228]

[0164] Step 5: Synthesis of 2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide (viii): To a solution of N-methoxy-N-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxamide trifluoroacetate (1.97 g, 5.44 mmol, 1.00 equiv) in DCM (20.0 mL) was added DIPEA (4.22 g, 32.6 mmol, 5.68 mL, 6.00 equiv), and the resulting mixture was stirred at 25°C for 5 minutes. 6-Bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (1.33 g, 5.71 mmol, 1.05 equiv) was added, and the mixture was stirred at 25 °C for an additional 2 hours. The reaction mixture was concentrated in vacuo, diluted with isopropanol (20 mL) and water (5 mL), stirred for 16 hours, and filtered. The filter cake was washed with isopropanol (10 mL × 3), petroleum ether (20 mL × 2), and concentrated in vacuo to give the title compound (1.99 g, 82.4% yield) as a yellow solid, which was used in the next step without further purification: LCMS: RT = 0.897 min, m / z = 446.2 (M + H) + . 1H NMR: (400 MHz, d6-DMSO) δ 9.03 (s, 2H), 7.96 (d, J = 1.6 Hz, 1H), 7.93 (s, 1H), 7.40 (br s, 1H), 7.24 (d, J = 1.6 Hz, 1H), 4.75 (br s, 2H), 4.14 (t, J = 5.6 Hz, 2H), 3.61 (s, 3H), 3.32 (s, 3H), 2.83 (br s, 2H). Step 6: Synthesis of (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone (ix): To a cooled (0° C.) solution of 2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)-N-methoxy-N-methylpyrimidine-5-carboxamide (1.78 g, 4.01 mmol, 1.00 equiv) in THF (110 mL) was added (4-fluorophenyl)magnesium bromide (1.00 M solution in THF, 28.1 mL, 7.00 equiv) dropwise under N2 (g). The resulting mixture was stirred at 25° C. for 4 hours. The mixture was slowly poured into saturated aqueous NH4Cl (50.0 mL) and then diluted with EtOAc (50.0 mL). The aqueous layer was extracted with EtOAc (30.0 mL × 3), and the combined organic layers were washed with brine (50.0 mL), dried over Na2SO4, and concentrated. The crude product was triturated with isopropanol (30.0 mL) for 3 hours at 25° C. and stirred for 12 hours. The mixture was filtered with isopropanol (3.00 mL × 3), and the filter cake was washed with petroleum ether (3.00 mL) and dried under vacuum to give the title compound (1.36 g, 69.6% yield, 98.3% purity) as a pale yellow solid: LCMS: RT = 1.024 min, m / z = 479.2 (M + H) + 1H NMR (400 MHz, d6-DMSO) δ 9.09 (s, 2H), 7.92 - 7.98 (m, 4H), 7.49 (br s, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.25 (d, J= 1.6 Hz, 1H), 4.78 (br s, 2H), 4.16 (t, J = 5.6 Hz, 2H), 2.87 (br s, 2H). Step 7: Synthesis of (S,E)—N-((2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (x): Synthesis of (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (x) To a solution of (S)-2-methylpropane-2-sulfinamide (1.05 g, 8.70 mmol, 4.00 equiv.) and Ti(OEt) (22.0 g, 96.5 mmol, 20.0 mL, 44.4 equiv.) was added Ti(OEt) (1.06 g, 2.17 mmol, 1.00 equiv.). The mixture was then stirred at 90° C. for 14 hours. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and filtered. The filter cake was washed with EtOAc (30.0 mL × 3), and the filtrate was then washed with brine (50.0 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, petroleum ether: EtOAc = 3:1 to 0:1) to give the title compound (1.07 g, yield 82.1%) as a pale yellow solid: LCMS: RT = 2.749 min, m / z = 584.3 (M + H) + . 1H NMR: (400 MHz, d6-DMSO) δ 8.23 ​​(s, 2H), 7.97 (d, J = 1.6 Hz, 1H), 7.95 (s, 1H), 7.58 - 7.82 (m, 2H), 7.43 (br s, 1H), 7.37 (br t, J = 8.8 Hz, 2H), 7.26 (d, J = 1.2 Hz, 1H), 4.78 (br s, 2H), 4.17 (br t, J = 5.6 Hz, 2H), 2.86 (br s, 2H), 1.26 (s, 9H). Step 8: Synthesis of N-((S)-1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (I-1): Synthesis of (S,E)-N-((2-(1-(6-bromopyridin-4-yl)pyrimidin-5-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethyl)-2-methylpropane-2-sulfinamide (I-1) To a cooled (0 °C) solution of (4-fluorophenyl)methylene)-2-methylpropane-2-sulfinamide (600 mg, 1.00 mmol, 1.00 equiv.) under N2 (g), MeMgBr (3.00 M solution in ether, 3.34 mL, 10.0 equiv.) was added. The mixture was then stirred at 25 °C for 1 h. The mixture was carefully quenched with saturated aqueous NH4Cl (30.0 mL) and extracted with EtOAc (20.0 mL × 3). The organic extract was washed with brine (20.0 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (SiO2, petroleum ether: EtOAc = 1:1, Rf = 0.35, 0.30) to give the title compound I-1 (632 mg, 89.3% yield, 84.7% purity) as a yellow solid: LCMS: RT = 1.024 min, m / z = 598.2 (M + H) +.

[0229] In some preparations, I-1 is mixed with MeOH (7 volumes) and 4 M HCl in dioxane (6.0 equivalents) and heated to 40° C. After completion of the reaction, the mixture is cooled to room temperature and charged with MTBE (10 volumes). The mixture is filtered, washed with MTBE, and dried under vacuum to give the amine (I-1a):

[0230] [ka]

[0231] get. Amine I-1a (2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.1 mmol), Pd(dppf)Cl (200 μmol), dppf (300 μmol), and KOAc (4.0 mmol) in 1,4-dioxane (30 mL) are purged with N (g) for 10 min and stirred at 80° C. for 16 h. The solution is then diluted with EA, washed with H O and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH=15 / 1) to give compound (I-1A):

[0232] [ka]

[0233] get. In several preparations in DMF / HO (40 mL / 10 mL), I-1A is mixed with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.0 mmol), Pd(dppf)Cl (605 μmol), and KCO (18.2 mmol), purged with N(g) for 10 minutes, and stirred under N at 70° C. for 16 hours. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give compound (I-1B):

[0234] [ka]

[0235] get. The corresponding (S)-hydroxy intermediates: (I-8), (I-8A), and (I-8B):

[0236] [ka]

[0237] is prepared by treating intermediate ix (obtained from Step 6 above) with methylmagnesium Grignard in THF at 0 °C to room temperature. After completion of the reaction, the mixture is quenched with NH4Cl solution and extracted with EA. The combined organic layers are washed with HO and brine, dried over sodium sulfate, filtered, and concentrated. The residue is purified by column chromatography to give the racemate. The enantiomers are separated by chiral HPLC to give (R)-I-8 and (S)-I-8. (S)-Hydroxy compounds I-8A and I-8B are prepared by replacing I-1a with I-8 in the method of Preparation 1.

[0238] Preparation 2: (S)-1-(4-Fluorophenyl)-1-(2-(4-(6-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (I-2).

[0239] [ka]

[0240] To a suspension of compound I-5 (see Preparation 6) (1.32 g, 3.22 mmol, 1.00 equiv., 3HCl) in DMF (23.2 mL) was added DIEA (1.66 g, 12.9 mmol, 2.24 mL, 4.00 equiv.) and 4-chloro-6-iodo-7H-pyrrolo[2,3-d]pyrimidine (900 mg, 3.22 mmol, 1.00 equiv.). The mixture was stirred at 40° C. for 60 h. The mixture was added dropwise to HO (150 mL), and the resulting suspension was filtered. The filter cake was washed with HO (20.0 mL × 3). The crude product was purified by preparative HPLC (column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 mm; mobile phase: [water (0.05% HCl) to CHCN]; B%: 10% to 35%, 20 min) to give the title compound (1.20 g, yield 64.0%, purity 99.8%) as a yellow solid: LCMS: RT = 0.882 min, m / z = 528.3 (M-16) +.

[0241] In some preparations, a mixture of I-2 (2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.1 mmol), Pd(dppf)Cl2 (200 μmol), dppf (300 μmol), and KOAc (4.0 mmol) in 1,4-dioxane (30 mL) was purged with N2(g) for 10 min and stirred at 80 °C for 16 h. The solution was then diluted with EA, washed with H2O and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 15 / 1) to give compound (I-2A):

[0242] [ka]

[0243] get. In several preparations in DMF / HO (40 mL / 10 mL), I-2 was mixed with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.0 mmol), Pd(dppf)Cl (605 μmol), and KCO (18.2 mmol), purged with N(g) for 10 min, and stirred at 70° C. under N for 16 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1) to give compound (I-2B):

[0244] [ka]

[0245] get. The corresponding (S)-hydroxy intermediates: (I-7), (I-7A), and (I-7B):

[0246] [ka]

[0247] is prepared by substituting intermediate I-6 (see Preparation 6) for intermediate I-5 in the method of Preparation 2. Preparation 3: 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol (1k):

[0248] [ka]

[0249] Step 1: 6-Bromopyrrolo[2,1-f][1,2,4]triazin-4(3H)-one 1a (22 mmol) is dissolved in phosphorus oxychloride (100 mL) and reacted at 130 °C for 3 hours. The reaction solution is concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate (100 mL) is added to the resulting residue, and the mixture is extracted with DCM. The combined organic phase is washed with saturated aqueous NaCl (100 mL). The organic phase is dried over anhydrous NaSO and concentrated under reduced pressure to give 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b.

[0250] Step 2: Under an argon atmosphere, ethyl 2-chloropyrimidine-5-carboxylate 1c (10 mmol), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1d (11 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (1.2 mmol), and cesium carbonate (20 mmol) were dissolved in 1,4-dioxane / HO (66 mL, V / V = 10 / 1) and reacted at 60 °C for 5 h. The reaction solution was diluted with EA (150 mL) and washed with water (30 mL × 2) and saturated aqueous NaCl solution (30 mL), successively. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give ethyl 2-(1-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e.

[0251] Step 3: Ethyl 2-(1-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylate 1e (5.4 mmol) is dissolved in THF (15 mL), and aqueous NaOH (10 mL, 1 M) is added dropwise, followed by reaction at room temperature for 5 hours. The reaction solution is concentrated under reduced pressure to remove THF, and HO (20 mL) is added, and the solution is adjusted to approximately pH 2-3 with 1 M aqueous HCl. A large amount of white solid product precipitates, which is filtered and dried to give crude 2-(1-(t-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f.

[0252] Step 4: 2-(1-(t-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidine-5-carboxylic acid 1f (4.86 mmol) is dissolved in DCM (50 mL). N,N-Diisopropylethylamine (24 mmol), 2-(7-azabenzotriazole)tetramethyluronium hexafluorophosphate (9.7 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.3 mmol) are added in that order, and the reaction is allowed to proceed at room temperature for 6 hours. The reaction solution is diluted with DCM (150 mL) and washed successively with HO (20 mL × 2), 1 M aqueous HCl (20 mL), saturated aqueous sodium bicarbonate (20 mL), and saturated aqueous NaCl (20 mL). The organic phase is dried over anhydrous NaSO and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to obtain 1 g of t-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate.

[0253] Step 5: Under an argon atmosphere, 1 g (3.4 mmol) of t-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate is dissolved in 15 mL of THF. The reaction solution is cooled to 0° C. in an ice-water bath, and 14 mL of 4-fluorophenylmagnesium bromide (1M / THF) is added dropwise. The reaction is allowed to proceed at room temperature for 4 hours. The reaction is quenched by adding saturated aqueous ammonium chloride solution. The reaction solution is diluted with EA (100 mL) and washed successively with HO (20 mL×2) and saturated aqueous NaCl solution (20 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give t-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1h.

[0254] Step 6: t-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate 1h (2.4 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (2 mL) was added, and the mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to give crude (4-fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i, which was used directly in the next step.

[0255] Step 7: (4-Fluorophenyl)(2-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)methanone 1i (2.4 mmol) is dissolved in DCM (15 mL). DIPEA (9.5 mmol) is added dropwise and stirred at room temperature for 5 minutes. Next, 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine 1b (2.8 mmol) is added and the reaction is allowed to proceed at room temperature for 12 hours. The reaction solution is concentrated under reduced pressure to remove DCM. The residue is diluted with EA (70 mL) and washed successively with HO (10 mL), 1 M aqueous HCl (10 mL), and saturated aqueous NaCl (20 mL). The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j.

[0256] Step 8: Under an argon atmosphere, (2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)(4-fluorophenyl)methanone 1j (0.4 mmol) was dissolved in THF (10 mL). The reaction solution was cooled to 0° C. in an ice-water bath, and methylmagnesium bromide (4.2 mL, 1 M / THF) was added dropwise, followed by reaction at room temperature for 3 hours. At 0° C., the reaction was quenched by adding saturated aqueous ammonium chloride solution (10 mL). The reaction solution was distilled under reduced pressure to remove THF. The reaction solution was diluted by adding EA (50 mL) to the residue. The aqueous layer was separated, and the organic phase was washed successively with water (10 mL×2) and saturated aqueous NaCl solution (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography to give 1-(2-(1-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-ol (1k).

[0257] In some preparations, a mixture of 1k (2.0 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (3.1 mmol), Pd(dppf)Cl2 (200 μmol), dppf (300 μmol), and KOAc (4.0 mmol) in 1,4-dioxane (30 mL) is purged with N2(g) for 10 min and stirred at 80 °C for 16 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH) to give compound (1k-A):

[0258] [ka]

[0259] get. In several preparations in DMF / HO (40 mL / 10 mL), 1k-A was mixed with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (6.0 mmol), Pd(dppf)Cl (605 μmol), and KCO (18.2 mmol), purged with N(g) for 10 min, and stirred at 70° C. under N for 16 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH) to give compound (1k-B):

[0260] [ka]

[0261] get. The corresponding (S)-hydroxy intermediates: (I-9), (I-9A), and (I-9B):

[0262] [ka]

[0263] is prepared by treating intermediate 1j (obtained from step 7 above) with (S)-2-methylpropane-2-sulfinamide (0.908 mmol) and ethyl orthotitanate (0.715 mmol) and stirring in THF (3.2 mL) at 70 °C until the reaction is complete by tlc. After reaching room temperature, water is added and the product is extracted with EA. The combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo onto Celite. The residue is purified by MPLC (0-10% MeOH-EtOAc) to give the sulfonamide. The resulting sulfonamide is dissolved in THF and cooled to 0 °C. Methylmagnesium bromide (3 M solution in diethyl ether, 1.5 mmol) is added and the resulting mixture is stirred at 0 °C until complete. If necessary, add more methylmagnesium bromide. Saturated ammonium chloride is added and the product is extracted into EA. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo while loading onto Celite. The residue was purified by MPLC (0-10% MeOH-EtOAc) with methylsulfinamide and deprotected by stirring at room temperature in 4 M HCl in 1,4-dioxane (1.5 mL) / MeOH (1.5 mL). The solvent was removed in vacuo, and the residue was triturated in EAc to give the racemate. The enantiomers were separated by chiral HPLC to give (R)-I-9 and (S)-I-9.

[0264] Preparation 4: (R)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (I-3)

[0265] [ka]

[0266] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 10.3 mmol, 1.00 equiv) and (R)-2-methyloxirane (1.50 g, 25.8 mmol, 1.81 mL, 2.50 equiv) in acetonitrile (6.70 mL) was added triethylamine (4.38 g, 43.3 mmol, 6.03 mL, 4.20 equiv). The mixture was stirred at 100° C. for 12 h, then cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether:EA=2:1) ​​to give the title compound (2.05 g, 78.9% yield) as a white oil. LCMS: RT=0.759 min, m / z=253.2 (M+H)+. 1H NMR: (400 MHz, d6-DMSO) δ 7.85 (s 1H), 7.56 (s, 1H), 7.88 (d, J = 4.8 Hz 1H), 4.00 - 4.02 (m, 2H), 3.93 - 3.96 (m, 1H), 1.24 (s, 12H), 1.00 - 1.01 (m, 3H). Preparation 5: (S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (I-4).

[0267] [ka]

[0268] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.00 g, 10.3 mmol, 1.00 equiv) and (S)-2-methyloxirane (1.80 g, 30.9 mmol, 2.17 mL, 3.00 equiv) in acetonitrile (6.70 mL) was added triethylamine (4.38 g, 43.3 mmol, 6.03 mL, 4.20 equiv). The mixture was stirred at 100° C. for 12 h, then cooled and concentrated in vacuo. The residue was purified by column chromatography (SiO, petroleum ether: EtOAc = 2:1) to give the title compound (2.13 g, 72.4% yield, 88.4% purity) as a white oil: LCMS: RT = 0.767 min, m / z = 253.2 (M+H). 1H NMR (400 MHz, d6-DMSO) δ 7.85 (s 1H), 7.56 (s, 1H), 7.88 (d, J = 4.8 Hz 1H), 4.00 - 4.02 (m, 2H), 3.93 - 3.96 (m, 1H), 1.24 (s, 12H), 1.01 (d, J = 6.0 Hz, 3H). Preparation 6: (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (I-5A)

[0269] [ka]

[0270] Step 1: Synthesis of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (20.0 g, 1.0 equiv.), (S)-(-)-2-methyl-2-propanesulfinamide (9.43 g, 1.5 equiv.), and LiOH (0.64 g, 0.5 equiv.) were added to a reaction vessel along with toluene (160 mL). To this mixture, titanium(IV) isopropoxide (18.42 g, 1.25 equiv.) was added, and the reaction was stirred at 50-60 °C for 1 h. The reaction was then distilled while additional toluene (80 mL) was charged at 40-60 °C until 80 mL was removed. The reaction mixture was cooled to 20-30 °C and then added to monosodium citrate solution (80 mL, 30% w / w citric acid, pH 3-4). The mixture was stirred at 45-55°C for 1.5 hours, and then the phases were separated. The organic phase was washed with potassium bicarbonate (40 mL, 25% w / w aqueous solution), and 40 mL was removed by distillation. The product solution was diluted with tetrahydrofuran (30 mL) and then used directly in the next step as a solution (approximately 15% w / w tert-butyl (S,Z)-4-(5-((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate).

[0271] Step 2: Synthesis of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate with isolation Methylmagnesium chloride (27.8 g, 22% w / w in THF, 2.0 equiv.) was added to a reaction solution of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate in toluene / THF (120 g, corresponding to 20 g of input material) at 10 °C over 2–3 h. The reaction mixture was stirred for 1.5 h to allow the reaction to reach completion. The reaction mixture was quenched by adding methanol (40 mL), followed by water (10 mL). The mixture was distilled to remove 100–110 mL of distillate and then washed with ammonium chloride (80 mL, 20% w / w in water). The organic phase was washed with water (80 mL), diluted with toluene (60 mL), and distilled to remove 60–80 mL of distillate. To a solution of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate at 50-60°C, n-heptane (80 mL) was added and then cooled to 42°C, at which point seed crystals were added (25-50 mg). The solution was held for 30 minutes and then cooled to 0-10°C for 30 minutes. The solid was isolated by filtration and washed with a mixture of n-heptane and toluene (1:1, 30 mL), followed by n-heptane (30 mL). The product was dried to give 9 g (40–45%) of crude tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (96.4–97.2%).

[0272] Step 3: Recrystallization of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (10.0 g) was dissolved in isopropanol (100 mL), heated to 40-60°C, and then passed through a clarifying filter, washing / rinsing with isopropanol (20 mL). The resulting solution was vacuum distilled at 40-60°C, and 60-70 mL of distillate was removed. The mixture was diluted with water (45 mL) at 50-60°C and then cooled to 40°C, at which point 25-50 mg of seed crystals were added. The mixture was further cooled to 20-25°C, and water (20 mL) was added. The solid was isolated by filtration and washed with an isopropanol / water mixture (1:1, 20 mL), and then the slurry was washed with isopropanol / water (1:2, 30 mL). Drying afforded 8.5 g (85%) of the product: tert-butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (>99.8%).

[0273] Step 4: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (I-5A) tert-Butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (7) (9.0 g) was heated in acetonitrile (40 mL) with hydrochloric acid (33%, 8.14 g, 4.1 equivalents) at 45-55 °C for 1 hour to give (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (I-5A). Preparation of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanol (I-6):

[0274] [ka]

[0275] (I-6) and its R-enantiomer are described in WO2015 / 057873. Preparation of compounds Example 1 Synthesis of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol (1)

[0276] [ka]

[0277] Step 1: Synthesis of N-((S)-1-(4-fluorophenyl)-1-(2-(1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (i): I in DMF (5.00 mL) and HO (1.00 mL) To a solution of HCl (300 mg, 424 μmol, 1.00 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (142 mg, 594 mmol, 1.40 equiv.), and KCO (117 mg, 849 μmol, 2.00 equiv.) under N (g), Pd(dppf)Cl·CHCl (52.0 mg, 63.7 μmol, 0.15 equiv.) was added. The mixture was then stirred at 90 °C for 2 h. The mixture was diluted with EtOAc (50.0 mL) and then washed sequentially with water (10.0 mL) and brine (35.0 mL × 3). The aqueous layer was extracted with EtOAc (20.0 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)-CH3CN]; B%: 29%-49%, 6.5 min). The product-containing fractions were combined, adjusted to pH 9 with saturated aqueous NaHCO3, extracted with EtOAc (20.0 mL × 3), and concentrated in vacuo to give the title compound (66.0 mg, 105 μmol, 24.7% yield) as a pale yellow solid: LCMS: RT = 0.877 min, m / z = 630.3 (M+H)+.

[0278] Step 2: Synthesis of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)-3,6-dihydropyridin-1(2H)-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol (1): N-((S)-1-(4-fluorophenyl)-1-(2 To a solution of -(1-(6-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-5-yl)ethyl)-2-methylpropane-2-sulfinamide (66.0 mg, 105 mmol, 1.00 equiv.) was added HCl / MeOH (4.00 M, 0.50 mL, 19.1 equiv.). The mixture was then stirred at 25° C. for 2 hours. The pH of the mixture was adjusted to 5 and concentrated in vacuo. The residue was diluted with DMF (1.00 mL) and purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)-CH3CN]; B%: 14% to 34%, 6.5 min). The product-containing fractions were combined, adjusted to pH 8 with saturated aqueous NaHCO3, extracted with EtOAc (20.0 mL × 3), and the combined organic layers were washed with brine (20.0 mL), dried over Na2SO4, and concentrated to give the title compound (18.0 mg, 31.7% yield) as a yellow gum: LCMS: RT = 2.178 min, m / z = 526.5 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 8.79 (s, 2H), 8.08 (s, 1H), 7.99 (d, J = 1.6 Hz, 1H), 7.87 (s, 1H), 7.85 (s, 1H), 7.44 - 7.51 (m, 2H), 7.23 - 7.30 (m, 2H), 7.08 - 7.16 (m, 2H), 4.94 (t, J = 5.6 Hz, 1H), 4.74 (br s, 2H), 4.12 - 4.19 (m, 4H), 3.72 - 3.79 (m, 2H), 2.82 (br s, 2H), 1.80 (s, 3H). Example 2 Synthesis of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)ethan-1-ol hydrochloride (2)

[0279] [ka]

[0280] To a solution of I-2 (90.0 mg, 152 mmol, 98.3% purity, 1.00 equiv.), 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol (43.5 mg, 183 mmol, 1.20 equiv.) in DMF (2.00 mL) was added Pd(dppf)Cl 2·CHCl (45.0 mg, 55.1 mmol) and KCO (63.1 mg, 457 mmol, 3.00 equiv.) were added, followed by HO (0.50 mL). The mixture was degassed with Ng (g) three times and then stirred at 95 °C for 5 h. The mixture was diluted with EtOAc (20.0 mL), washed with water (10.0 mL × 3), and washed with brine (10.0 mL). The aqueous layer was extracted with EtOAc (20 mL). The combined organic layers were dried over NaSO and concentrated in vacuo. The residue was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)-CHCN]; B%: 9%-29%, 7 min). The fractions containing the product were lyophilized to give the title compound (30.3 mg, 34.4% yield) as a pale yellow solid: LCMS: RT=0.711 min, m / z=512.4 (M-16)+. 1H NMR (400 MHz, d6-DMSO) δ13.21 - 12.41 (m, 1H), 9.63 - 8.94 (m, 3H), 8.42 (s, 2H), 8.30 (s, 1H), 8.22 (s, 1H), 8.00 (s, 1H), 7.53 - 7.42 (m, 2H), 7.31 (t, J = 8.8 Hz, 2H), 7.12 (br d, J = 1.2 Hz, 1H), 4.19 (br t, J = 5.2 Hz, 2H), 4.13 - 4.06 (m, 4H), 4.03 - 3.97 (m, 4H), 3.76 (t, J = 5.2 Hz, 2H), 2.02 (s, 3H). Compounds 12, 13, 14, 14A, and 15 are prepared using the same procedure, replacing I-2 with the appropriate intermediate.

[0281] Example 3 Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (3)

[0282] [ka]

[0283] The title compound was prepared as described in Example 2, except that 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)—CH3CN]; B%: 11%–31%, 6.5 min). The product-containing fractions were combined, the pH adjusted to 8–9 with solid sodium carbonate, and extracted with EtOAc (20.0 mL × 3). The organic layer was washed with brine (10.0 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound (97.5 mg, 50.8% yield) as an off-white solid: LCMS: EW25770-9-P1C, product: RT=0.876 min, m / z=524.4 (M-16)+. 1H NMR: EW25770-9-P1A 400 MHz, d6-DMSO) δ12.0 (s, 1H), 8.40 (s, 2H), 8.34 (s, 1H), 8.15 (s, 1H), 8.09 (s, 1H), 7.41 - 7.51 (m, 2H), 7.05 - 7.15 (m, 2H), 6.92 (d, J = 1.2 Hz, 1H), 5.61 (q, J = 6.4 Hz, 1H), 4.93 - 5.00 (m, 2H), 4.84 - 4.92 (m, 2H), 3.95 - 3.98 (m, 4H), 3.87 - 3.88 (m, 4H), 1.73 (s, 3H). Compounds 28, 29, 30, 31, and 32 are prepared using the same procedure, replacing I-2 with the appropriate intermediate.

[0284] Example 4 Synthesis of (R)-1-(4-(4-(4-(5-((S)-1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)propan-2-ol (4)

[0285] [ka]

[0286] The title compound was prepared as described in Example 3, except that I-3 was used instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)-CH3CN]; B%: 11%-31%, 6.5 min). The pH of the product-containing fractions was adjusted to 8 and extracted with EtOAc (20.0 mL × 3). The combined organic extracts were washed with brine (20.0 mL), dried over Na2SO4, and concentrated to give the title compound (51.3 mg, 17.0% yield) as an off-white solid: LCMS: RT=0.858 min, m / z=526.4 (M-16)+. 1H NMR (400 MHz, d6-DMSO) δ 12.0 (s, 1H), 8.39 (s, 2H), 8.05 - 8.20 (m, 2H), 7.94 (s, 1H), 7.41 - 7.53 (m, 2H), 7.01 - 7.18 (m, 2H), 6.86 (d, J = 2.0 Hz, 1H), 4.97 (d, J = 4.8 Hz, 1H), 4.01 - 4.05 (m, 2H), 3.92 - 3.98 (m, 4H), 3.81 - 3.91 (m, 4H), 1.73 (s, 3H), 1.06 (d, J = 6.0 Hz, 3H). Compounds 7, 8, 9, 10, and 11 are prepared using the same procedure, replacing I-2 with the appropriate intermediate.

[0287] Example 5 Synthesis of (S)-1-(4-(4-(4-(5-((S)-1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-1H-pyrazol-1-yl)propan-2-ol hydrochloride (5)

[0288] [ka]

[0289] The title compound was prepared as described in Example 2, except that I-4 was used instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 mm; mobile phase: [water (0.05% HCl)—CHCN]; B%: 10% to 30%, 7 min). Fractions containing the desired product were combined and lyophilized to give the title compound (128.5 mg, 57.8% yield) as a yellow solid: LCMS: RT=0.850 min, m / z=526.5 (M-16)+. 1H NMR: (400 MHz, d6-DMSO) δ 13.3 (br s, 1H), 9.55 (br s, 3H), 8.47 (s, 2H), 8.35 (s, 1H), 8.28 (s, 1H), 8.04 (s, 1H), 7.51 - 7.55 (m, 2H), 7.26 - 7.34 (m, 2H), 7.26 (s, 1H), 4.15 - 4.17 (m, 4H), 4.10 - 4.11 (m, 2H), 4.02 - 4.04 (m, 4H), 3.96 - 4.00 (m, 2H), 2.03 (s, 3H), 1.07 (d, J = 6.0 Hz, 3H). Compounds 38, 39, 40, 41, and 42 are prepared using the same procedure, replacing I-2 with the appropriate intermediate.

[0290] Example 6 Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride

[0291] [ka]

[0292] The title compound was prepared as described in Example 3, except that 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used instead of 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethan-1-ol. The crude product was purified by preparative HPLC (column: 3_Phenomenex Luna C18 75 × 30 mm × 3 um; mobile phase: [water (0.05% HCl)-CH3CN]; B%: 10%-30%, 7 min). Fractions containing the desired product were combined and lyophilized to give the title compound (66.4 mg, 29.4% yield) as a pale yellow solid: LCMS: RT=0.776 min, m / z=555.5 (M+H)+. 1H NMR: (400 MHz, d6-DMSO) δ 13.3 (s, 1H), 9.44 (br s, 3H), 8.95 (s, 2H), 8.44 (s, 2H), 8.35 (s, 1H), 7.43 - 7.55 (m, 3H), 7.27 - 7.32 (m, 2H), 4.72 (dd, J = 8.0, 12.0 Hz, 2H), 4.49 (dd, J = 4.8, 11.6 Hz, 2H), 4.09 - 4.19 (m, 4H), 3.95 - 4.07 (m, 4H), 2.02 (s, 3H). Compounds 33, 34, 35, 36, and 37 are prepared using the same procedure, replacing I-2 with the appropriate intermediate.

[0293] Example 7

[0209]

[0294] [ka]

[0295] A mixture of 1k-B (prepared according to Preparation 3) (0.4 mmol), CsCO (0.8 mmol), and 2,2-dimethyloxirane (1.2 mmol) in NMP (5 mL) is stirred at 120° C. for 10 h. The reaction mixture is diluted with EA, washed with HO and brine, and dried over NaSO. The organic layer is concentrated in vacuo, and the residue is purified by preparative HPLC followed by lyophilization to give compound 69. Compounds 70, 71, 72, 73, and 74 are prepared using the same procedure, replacing 1kB with the appropriate intermediate.

[0296] Example 8

[0211]

[0297] [ka]

[0298] Step 1: To a solution of methyl 2-bromo-2-methylpropanate (x) (16 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (16 mmol) in NMP (20 mL) is added cesium carbonate (50 mmol) and sodium iodide (16 mmol) at room temperature. The resulting mixture is stirred at 120° C. for 8 hours. The reaction mixture is diluted with DCM and washed successively with HO and brine. The organic layer is concentrated in vacuo, and the residue is purified by flash column chromatography on silica gel (petroleum ether:ethyl acetate) to give compound (xii).

[0299] Step 2: A mixture of methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanate (xii) (0.6 mmol), I-7 (0.6 mmol), Pd(dppf)Cl (0.12 mmol), and KCO (1.8 mmol) in DMF / HO (8 mL / 2 mL) is stirred at 70 °C under N (g) for 4 h. The solution is then diluted with DCM, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH) to give compound (xiii).

[0300] Step 3: To a solution of (S)-methyl 2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)-2-methylpropanate (xiii) (0.34 mmol) in THF (20 mL) is added LiAlH (13.4 mmol) at 0 °C, and the resulting mixture is stirred at room temperature for 6 h. The reaction mixture is quenched with HO (100 mL) and 10% NaOH·HO (300 mL) and then extracted with EA. The organic layer is concentrated in vacuo, and the residue is purified by preparative HPLC followed by lyophilization to give compound 79. Compounds 75, 76, 77, 78 and 80 are prepared using the same procedure, substituting the appropriate intermediate for I-7.

[0301] Example 9

[0215]

[0302] [ka]

[0303] Step 1: To a solution of (S)-1-(benzyloxy)propan-2-ol (xvi) (30 mmol) and TEA (90 mmol) in DCM (80 mL) is added TsCl (33 mmol). The mixture is stirred at room temperature for 24 h. The solution is diluted with DCM, washed with HO, and washed with brine. The organic layer is concentrated, and the residue is purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give compound (xvii).

[0304] Step 2: A mixture of (S)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xvii) (6.2 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (6.2 mmol), and CsCO (13 mmol) in NMP (12 mL) is irradiated in a microwave at 110 °C for 0.5 h. The solution is then diluted with EA, washed with HO, and washed with brine. The organic layer is concentrated, and the residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (xviii).

[0305] Step 3: To a solution of (R)-1-(1-(benzyloxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xviii) (2.3 mmol) in MeOH (20 mL) is added Pd / C (800 mg) and HOAc (0.2 mL), the solution is purged with H2(g) for 5 minutes, and then stirred under H2(g) at room temperature for 16 hours. The mixture is then filtered, and the filtrate is concentrated to give compound (xix).

[0306] Step 4: A mixture of ((R)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xix) (595 μmol), I-1a (595 μmol), Pd(dppf)Cl (60 μmol), and KCO (1.8 mmol) in DMF / HO (4 mL / 1 mL) was purged with N(g) for 10 min and stirred at 70° C. under N(g) for 16 h. The mixture was extracted with EA, and the combined organic extracts were concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH). Compounds 16, 17, 19, 20, and 21 were prepared using the same procedure, replacing I-1a with the appropriate intermediate.

[0307] Example 10

[0220]

[0308] [ka]

[0309] Step 1: To a solution of (R)-1-(benzyloxy)propan-2-ol (xxii) (18 mmol) and TEA (54 mmol) in DCM (30 mL) is added TsCl (22 mmol). The resulting mixture is stirred at 25° C. for 16 h. The mixture is then concentrated in vacuo, and the residue is purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give compound (xxiii).

[0310] Step 2: A mixture of (R)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xxiii) (6.9 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (10 mmol) and CsCO (6.9 mmol) in NMP (50 mL) is stirred in a microwave at 110 °C for 16 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (xxiv).

[0311] Step 3: To a mixture of (S)-1-(1-(benzyloxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxiv) (2.6 mmol) in MeOH (20 mL) is added Pd / C (800 mg) and HOAc (0.2 mL). The resulting mixture is purged with H2(g) for 5 minutes and then stirred under H2(g) at room temperature for 16 hours. The mixture is then filtered and concentrated to give compound (xxv).

[0312] Step 4: A mixture of (S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xxv) (392 μmol), I-1 (261 μmol), KCO (227 μmol), and Pd(dppf)Cl (7 μmol) in DMF / HO (5 mL / 1 ml) is stirred at 70° C. under N (g) for 4 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by preparative HPLC followed by lyophilization to give compound (24). Compounds 22, 23, 25, 26, and 27 are prepared using the same procedure, replacing I-1a in step 4 with the appropriate intermediate.

[0313] Example 11

[0225]

[0314] [ka]

[0315] To a solution of trans-3-(benzyloxy)cyclobutanol (xxxi) (1.7 mmol) in DCM (20 mL) is added TsCl (2.0 mmol) and TEA (3.4 mmol). The mixture is stirred at room temperature for 16 h. The solution is diluted with DCM, washed with HO and brine, and then concentrated. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (xxxii).

[0316] Step 2: A mixture of trans-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (xxxii) (0.95 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (0.95 mmol), and CsCO (1.9 mmol) in NMP (5 mL) is irradiated in a microwave at 110 °C for 0.5 h. The solution is then diluted with EA and washed with HO and brine. The organic layer is concentrated in vacuo, and the residue is purified by flash column chromatography on silica gel (PE / EA) to give the title compound (xxxiii).

[0317] Step 3: To a solution of cis-3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxxiii) (0.54 mmol) in MeOH (5 mL) is added Pd / C (200 mg) and HOAc (5 drops), the solution is purged with H2(g) for 5 minutes, and stirred under H2(g) at room temperature for 16 hours. The mixture is filtered, and the filtrate is evaporated to dryness in vacuo to give compound (xxxiv).

[0318] Step 4: A mixture of cis-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutanol (xxxiv) (0.21 mmol), I-1a (0.21 mmol), Pd(dppf)Cl (0.021 μmol), and KCO (0.63 mmol) in DMF / HO (4 mL / 1 mL) was purged with N for 10 min and stirred at 70 °C under N(g) for 16 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was directly purified by flash column chromatography (DCM / MeOH). The resulting material was further purified by preparative HPLC followed by lyophilization to give compound (46). Compounds 44, 45, 47, 48, and 49 are prepared using the same procedure, substituting the appropriate intermediate for I-1a in step 4.

[0319] Example 12

[0230]

[0320] [ka]

[0321] Step 1: To a solution of cis-3-benzyloxy-cyclobutanol (xxxv) (2.8 mmol) and TEA (8.4 mmol) in DCM (10 mL) is added 4-methyl-benzenesulfonyl chloride (3.4 mmol), and the resulting mixture is stirred at room temperature for 16 hours. The mixture is diluted with brine and extracted with DCM. The organic extract is concentrated. The residue is directly purified by flash column chromatography on silica gel (PE / EA) to give compound (xxxvi).

[0322] Step 2: A mixture of cis-toluene-4-sulfonic acid 3-benzyloxy-cyclobutyl ester (xxxvi) (1.5 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xi) (2.2 mmol), and CsCO (4.5 mmol) in NMP (15 mL) is irradiated in a microwave at 120 °C for 2 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (xxxvii).

[0323] Step 3: To a solution of trans-1-(3-benzyloxy-cyclobutyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xxxvii) (1.2 mmol) in MeOH (10 mL) is added Pd / C (200 mg) and concentrated HCl (0.5 mL). The reaction mixture is stirred under H2(g) at room temperature for 16 h. The mixture is filtered and the filtrate is concentrated to give compound (xxxviii).

[0324] Step 4: A mixture of trans-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-cyclobutanol (xxxviii) (0.8 mmol), I-1a (0.8 mmol), Pd(dppf)Cl (0.08 mmol), and KCO (2.3 mmol) in dioxane / HO (4 mL / 1 mL) was purged with N(g) for 10 min and stirred at 70 °C under N(g) for 4 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was purified by flash chromatography on silica gel. The resulting material was further purified by preparative HPLC followed by lyophilization to give compound (52). Compounds 50, 51, 53, 54, and 55 are prepared using the same procedure, substituting the appropriate intermediate for I-1a in step 4.

[0325] Example 13

[0235]

[0326] [ka]

[0327] Step 1: A mixture of 4-bromo-1H-pyrazole (xxxix) (55 mmol) and K2CO3 (110 mmol) in ethyl 2-chloroacetate (25 mL) is stirred at 80 °C for 15 h. The reaction mixture is cooled, diluted with EA, and washed with HO. The organic layer is evaporated and the residue is purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound (xl).

[0328] Step 2: To a solution of ethyl 2-(4-bromo-1H-pyrazol-1-yl)acetate (xl) (30 mmol) and titanium tetraisopropanolate (15 mmol) in anhydrous THF (60 mL) was added a solution of ethylmagnesium bromide (3 M in hexane, 30 mL, 90 mmol) dropwise over 2 h at 60 °C. After stirring at the same temperature for 2 h, the reaction mixture was diluted with EA and washed successively with 1 N aqueous HCl and HO. The organic layer was evaporated and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate) to give compound (xli).

[0329] Step 3: To a solution of 1-[(4-bromo-1H-pyrazol-1-yl)methyl]cyclopropan-1-ol (xli) (1.4 mmol) and 3,4-dihydro-2H-pyran (4.1 mmol) in DCM (8 mL) is added pyridinium paratoluenesulfonate (1.4 mmol) at room temperature. The mixture is stirred for 4 hours, then diluted with brine and washed with DCM. The organic layer is concentrated, and the residue is purified by silica gel chromatography (PE / EA) to give compound (xlii).

[0330] Step 4: 4-Bromo-1-{[1-(oxan-2-yloxy)cyclopropyl]methyl}-1H-pyrazole (xlii) (0.5 mmol), I-1A (1.1 mmol), Pd(dppf)Cl (106 μmol), and NaCO (1.6 mmol) in a mixture of 1,4-dioxane (3 mL), HO (1 mL), and DMF (0.5 mL) is stirred under N (g) at 80 °C for 3 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by silica gel chromatography (ethyl acetate / methanol) to give compound (xlii).

[0331] Step 5: To a solution of 1-(4-fluoro-phenyl)-1-{2-[4-(6-{1-[1-(tetrahydro-pyran-2-yloxy)-cyclopropylmethyl]-1H-pyrazol-4-yl}-pyrrolo[2,1-f][1,2,4]triazin-4-yl)-piperazin-1-yl]-pyrimidin-5-yl}-ethylamine (xliii) (0.32 mmol) in MeOH (4 mL) is added p-toluenesulfonic acid (1.0 mmol) at room temperature, and the resulting mixture is stirred for 2 hours. The reaction mixture is concentrated, and the residue is purified by preparative HPLC, followed by lyophilization to give compound (58). Compounds 56, 57, 60, 61, and 62 are prepared using the same procedure, replacing I-1a in Step 4 with the appropriate intermediate.

[0332] Example 14

[0241]

[0333] [ka]

[0334] Step 1: To a solution of 4-bromo-1H-pyrazole (xxxix) (14 mmol) in THF (50 mL) is added NaH (30 mmol) at 0° C. The solution is stirred at room temperature for 1 h, and then methyl 2,4-dibromobutanoate (xliv) (14 mmol) is added to the solution. The mixture is stirred for 16 h and then diluted with EA. The organic layer is washed with HO, washed with brine, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give compound (xiv).

[0335] Step 2: To a solution of methyl 1-(4-bromo-1H-pyrazol-1-yl)cyclopropanecarboxylate (xiv) (2.3 mmol) in MeOH (15 mL) is added NaBH (6.8 mmol), and the resulting mixture is stirred at 50 °C until completion. The reaction mixture is diluted with DCM, washed successively with HO and brine, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (xlvii).

[0336] Step 3: A mixture of (1-(4-bromo-1H-pyrazol-1-yl)cyclopropyl)methanol (xlvii) (463 μmol), I-1A (prepared as described in Preparation 1) (695 μmol), Pd(t-BuP) (93 μmol), and CsCO (1.4 mmol) in THF / HO (8 mL / 2 mL) was purged with N(g) for 10 min and stirred at 80° C. under N(g) for 12 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was purified by flash column chromatography (DCM / MeOH). The resulting material was further purified by preparative HPLC followed by lyophilization to give compound (65). Compounds 63, 64, 66, 67, and 68 were prepared using the same procedure, substituting the appropriate intermediate for I-1A in Step 3.

[0337] Example 15

[0245]

[0338] [ka]

[0339] Step 1: To a solution of tetrahydro-furan-3-ol (xlviii) (23 mmol) and TEA (45 mmol) in DCM (20 mL) is added MsCl (25 mmol) at room temperature. The mixture is stirred at room temperature for 16 hours. The reaction mixture is then diluted with DCM, washed successively with HO and brine, dried over anhydrous NaSO, and concentrated to dryness to give compound (xlix).

[0340] Step 2: To a solution of (S)-tetrahydrofuran-3-yl methanesulfonate (xlviii) (11 mmol) in NMP (50 mL) is added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xi) (17 mmol) and CsCO (34 mmol) at room temperature. The mixture is stirred at 120 °C for 2 h. The solution is diluted with EA, washed successively with HO and brine, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (l).

[0341] Step 3: A mixture of (R)-1-(tetrahydro-furan-3-yl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole 1 (0.3 mmol), I-1a (0.3 mmol), Pd(dppf)Cl (0.06 mmol), and KCO (0.9 mmol) in DMF (2 mL) and HO (0.5 mL) is stirred at 80 °C under N (g) until reaction completion. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH). The resulting material is sequentially purified by preparative HPLC followed by lyophilization to give compound 83. Compounds 81, 82, 84, 85, and 86 are prepared using the same procedure, substituting the appropriate intermediate for I-1a in step 3.

[0342] Example 16

[0249]

[0343] [ka]

[0344] Step 1: To a solution of (R)-tetrahydrofuran-3-ol (li) (11 mmol) and TEA (23 mmol) in DCM (20 mL) was added MsCl (12.5 mmol) at room temperature, and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with DCM, washed successively with HO and brine, and concentrated to give compound (lii).

[0345] Step 2: A mixture of I-1B (0.6 mmol), (R)-tetrahydrofuran-3-yl methanesulfonate (lii) (0.9 mmol), and Cs2CO3 (1.9 mmol) in NMP (10 mL) is stirred at 120 °C until reaction completion by tlc. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is directly purified by preparative HPLC, followed by lyophilization to give compound (89). Compounds 87, 88, 90, 91, and 92 are prepared using the same procedure, replacing I-1B in Step 2 with the appropriate intermediate.

[0346] Example 17

[0252]

[0347] [ka]

[0348] Step 1: To a solution of tetrahydro-2H-pyran-4-ol (liii) (31 mmol) and TEA (94 mmol) in DCM (100 mL) is added MsCl (47 mmol) at 0 °C. The reaction is stirred at room temperature for 3 h, then diluted with DCM, washed with saturated aqueous Na2CO3, and dried over anhydrous Na2SO4. The solvent is removed to give compound (liv).

[0349] Step 2: A mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (liv) (18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (21 mmol) and Cs2CO3 (27 mmol) in NMP (50 mL) is stirred at 80°C for 4 hours. The reaction mixture is diluted with DCM and washed with brine. The organic layer is evaporated in vacuo. The residue is purified by flash column chromatography on silica gel (PE / EA) to give compound (lv).

[0350] Step 3: A mixture of I-1a (603 μmol), 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (lv) (754 μmol), KCO (754 μmol), and Pd(dppf)Cl (41 μmol) in DMF / HO (10 mL / 2 mL) is stirred at 70° C. under N (g) for 4 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by preparative HPLC followed by lyophilization to give compound (95). Compounds 93, 94, 96, 97, and 98 are prepared using the same procedure, substituting the appropriate intermediate for I-1a in Step 3.

[0351] Example 18

[0256]

[0352] [ka]

[0353] Step 1: A solution of 3,6-dioxabicyclo[3.1.0]hexane (lvi) (61 mmol), 4-bromo-1H-pyrazole (xxxix) (61 mmol), and CsCO (121 mmol) in NMP (100 mL) is stirred at 120° C. for 16 h. The solution is cooled, diluted with DCM, and then washed with HO and brine. The organic layer is concentrated and purified by flash column chromatography on silica gel (PE / EA) to give compound (lvii).

[0354] Step 2: A mixture of rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lvii) (12 mmol), 4-nitrobenzoic acid (12 mmol), diisopropyl azodicarboxylate (17 mmol), and triphenylphosphine (17 mmol) in THF (50 mL) is stirred at room temperature for 16 hours. The solution is diluted with EA and washed with HO and brine. The organic layer is concentrated and purified by flash column chromatography on silica gel (PE / EA) to give compound (lviii).

[0355] Step 3: A mixture of rac-cis-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-yl 4-nitrobenzoate (lvii) (11 mmol) and lithium hydroxide (53 mmol) in MeOH / THF / HO (30 mL / 30 mL / 30 mL) is stirred at room temperature for 4 hours. The resulting mixture is diluted with EA, washed with HO and brine, and concentrated in vacuo. The residue is purified by flash column chromatography on silica gel (PE / EA) to give rac-cis-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol. This material was subjected to chiral separation by SFC (column: AD20 × 250 mm, 10 μm (Daicel); mobile phase: CO / MeOH (0.2% ammonia in methanol) = 60 / 40; flow rate: 80 g / min) to give peak 1 (lx) and peak 2 (lxi). Peak 1 is appropriately assigned as (3S,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol, and peak 2 is appropriately assigned as (3R,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol.

[0356] Step 4: A mixture of (3R,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lxi) (70 mg, 0.3 mmol) (peak 2 from Step 3), I-1A (0.6 mmol), Pd[(t-Bu)P] (0.06 mmol), and NaCO (0.9 mmol) in dioxane / HO (8 mL / 2 mL) is stirred at 90 °C for 4 h. After cooling, the solution is diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give compound (101). Compounds 99, 100, 102, 103, and 104 are prepared using the same procedure, replacing I-1A in Step 4 with the appropriate intermediate.

[0357] Example 19

[0261]

[0358] [ka]

[0359]

[0262] rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1.1 g) (from Step 1 of Example 18) is subjected to chiral separation by SFC (column: AD20 × 250 mm, 10 μm (Daicel); mobile phase: CO2 / MeOH (0.2% ammonia in MeOH) = 80 / 20; flow rate: 80 g / min) to give peak 1 (lxiii) and peak 2 (lxiv). Peak 1 is appropriately assigned as (3R,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol, and peak 2 is appropriately assigned as (3S,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol.

[0360] Step 2: A mixture of (3R,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (0.3 mmol) (lxiii) (peak 1 from Step 1), I-1A (0.6 mmol), Pd[(t-Bu)P] (0.06 mmol), and NaCO (0.9 mmol) in dioxane / HO (8 mL / 2 mL) is degassed with N and stirred at 90 °C for 4 h. The solution is then diluted with DCM, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH) to give the title compound (107). Compounds 105, 106, 108, 109, and 110 are prepared using the same procedure, substituting the appropriate intermediate for I-1a in Step 2.

[0361] Example 20

[0264]

[0362] [ka]

[0363] A mixture of (3S,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (70 mg, 0.3 mmol) (1xiv) (peak 2 from Step 1 of Example 19), I-1A (0.6 mmol), Pd[(t-Bu)P] (0.06 mmol), and NaCO (0.9 mmol) in dioxane / HO (8 mL / 2 mL) is degassed with N and stirred at 90 °C for 4 h. The solution is then diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH) to give compound 113. Compounds 111, 112, 114, 115, and 116 are prepared using the same procedure, replacing I-1A with the appropriate intermediate.

[0364] Example 21

[0266]

[0365] [ka]

[0366] A mixture of (3S,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lxiii) (0.22 mmol) (peak 1 from Step 3 of Example 18), I-1A (0.44 mmol), Pd[(t-Bu)P] (0.044 mmol), and NaCO (0.66 mmol) in dioxane / HO (8 mL / 2 mL) is stirred at 90 °C for 4 h. After cooling, the solution is diluted with EA, washed with HO and brine, and concentrated. The residue is purified by flash column chromatography on silica gel (DCM / MeOH) to give the title compound (119). Compounds 117, 118, 120, 121, and 122 are prepared using the same procedure, substituting the appropriate intermediate for I-1A.

[0367] Example 22

[0268]

[0368] [ka]

[0369] Step 1: To a solution of 2-(benzyloxy)cyclobutanone (5.7 mmol) in MeOH (20 mL) is added NaBH (11.4 mmol) at 0° C. The solution is then stirred at room temperature for 3 h. The mixture is diluted with EA and washed with water and brine, and the organic layer is then concentrated and purified by flash column chromatography on silica gel (PE / EA) to give peak 1 (appropriately assigned as cis-2-(benzyloxy)cyclobutanol) as a colorless oil and peak 2 (appropriately assigned as trans-2-(benzyloxy)cyclobutanol).

[0370] Step 2: To a solution of cis-2-(benzyloxy)cyclobutanol (1.5 mmol) in DCM (10 mL) is added mesyl chloride (2.3 mmol) and triethylamine (4.6 mmol) at 0° C. The mixture is stirred at room temperature for 3 h. The solution is then diluted with DCM, washed with water and brine, dried over anhydrous NaSO, and concentrated to give the desired compound.

[0371] Step 3: A mixture of cis-2-(benzyloxy)cyclobutyl methanesulfonate (1.2 mmol), 4-bromo-1H-pyrazole (1.2 mmol), and Cs2CO3 (3.5 mmol) in DMF (8 mL) is stirred for 16 h at 100° C. The solution is then diluted with EA, washed with water and brine, dried over anhydrous Na2SO4, concentrated, and purified by flash column chromatography (PE / EA) to give the desired compound. Chiral separation of trans-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole: trans-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole was subjected to chiral separation by SFC (column: IG20 x 250 mm, 10 μm (Daicel); mobile phase: CO2 / MeOH (0.2% ammonia in methanol) = 75 / 25; flow rate: 4 g / min) to obtain peak 1 (250 mg) and peak 2 (250 mg). Peak 1 is appropriately assigned as 1-((1S,2S)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole, and peak 2 is appropriately assigned as 1-((1R,2R)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole.

[0372] Step 4: A solution of 1-((1S,2S)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole (820 μmol) in TFA (2 mL) is stirred at 80° C. for 16 h. The solution is then concentrated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give the desired compound.

[0373] Step 5: A mixture of (1S,2S)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol (556 μmol), I-1A (667 μmol), Pd(t-BuP) (99 μmol), and CsCO (1.1 mmol) in dioxane / HO (8 mL / 2 mL) was purged with N for 10 minutes and stirred at 90 °C under N for 4 hours. The solution was then diluted with DCM, washed with HO and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH). The resulting material was further purified by preparative HPLC followed by lyophilization to give compound (125). Compounds 123, 124, 126, 127, and 128 were prepared using the same procedure, replacing I-1A in Step 5 with the appropriate intermediate.

[0374] Example 23

[0274]

[0375] [ka]

[0376] Step 1: A solution of 1-((1R,2R)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole (820 μmol) (from peak 2 of Step 3 of Example 22) in TFA (2 mL) is stirred at 80° C. for 16 h. The solution is then concentrated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate) to give the desired compound. Step 2: A mixture of (1R,2R)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol (556 μmol), I-1A (667 μmol), Pd(t-BuP) (99 μmol), and CsCO (1.1 mmol) in dioxane / HO (8 mL / 2 mL) was purged with N(g) for 10 min and stirred at 90 °C under N(g) for 4 h. The solution was then diluted with EA, washed with HO and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH). The resulting material was further purified by preparative HPLC followed by lyophilization to give compound 131. Compounds 129, 130, 132, 133, and 134 were prepared using the same procedure, replacing I-1A with the appropriate intermediate. Biological Example 1: Biochemical Enzyme Activity Inhibition Assay PDGFRα and KIT enzyme activity was monitored using a Perkin Elmer electrophoretic mobility shift technology platform, EZReader 2. Fluorescently labeled substrate peptides were incubated in the presence of kinase and ATP, and in the presence of test compound, such that each dose of test compound resulted in a reflectance ratio of the peptide being phosphorylated.

[0377] During the linear steady-state phase of a kinase enzyme reaction, a mixed pool of phosphorylated (product) and non-phosphorylated (substrate) peptides was passed through a PerkinElmer EZ Reader 2 microfluidic system under an applied potential difference. The presence of phosphate groups on the product peptides resulted in mass and charge differences between them and those of the substrate peptides, resulting in separation of the substrate and product pools in the sample (Perrin et al., Expert Opin Drug Discovery 2010, Jan 5(1):51-63).

[0378]

[0278] When the mixture of product and substrate peptide passes through the laser in the instrument, these pools are detected (λex = 488 nm, λem = 568 nm) and resolved as separate peaks. The ratio between these peaks reflects the activity of the compound at that concentration in that well under those conditions. Inhibition of KIT(D816V) mutant biochemical enzyme activity All test articles were dissolved in 100% DMSO at a stock concentration of 10 mM. 100x, 10-point, 4-fold serial dilutions of all test compounds were made in 100% DMSO, starting at the appropriate concentration, usually 1 mM. A 0.130 nL volume of each concentration was transferred to the appropriate wells of a 384-well assay plate (Greiner 781 201) using a TTPLabtech Mosquito nanoliter dispenser. The remaining components of the reaction were then added to the 130 nL of compound using a Multidrop as follows: KITD816V assay for ATP in APPKM: In each well of a 384-well assay plate, 0.3 nM intact enzyme was incubated in a total of 13 μL of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl, 1 mM DTT) containing 1 μM Src tide (5-FAM-GEEPLYWSFPAKKK-NH) and 20 μM ATP in the presence or absence of a range of compound concentrations (final concentration 1% DMSO) at 25°C for 60 minutes. The reaction was stopped by adding 70 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA, and 0.2% Coating Reagent 3, Caliper Lifesciences). Plates were read on a Caliper EZReader2. The results obtained in these experiments for the compounds prepared according to the Examples are summarized below in Table 2. For biochemical D816V and D842V activity, the following designations are used: ≦0.30 nM=A; ≧0.31 and <1.4 nM=B; ≧1.4 nM=C; and ND=not determinable.

[0379] [Table 2]

[0380] For reference, the chemical structure of Comparative A is as follows:

[0381] [ka]

[0382] Inhibition of PDGFRA mutant biochemical enzyme activity All test articles are dissolved in 100% DMSO at a stock concentration of 10 mM. 100X, 10-point, 4-fold serial dilutions of all test compounds are made in 100% DMSO, starting at the appropriate concentration, usually 1 mM. Using a TTPLabtech Mosquito nanoliter dispenser, a volume of 0.130 μL of each concentration is transferred to the appropriate wells of a 384-well assay plate (Greiner 781 201). The remaining components of the reaction are then added to 130 nL of compound using a Multidrop as follows: PDGFRα D842V assay for apparent Michaelis-Menten constant (APPKM) with respect to ATP: In each well of a 384-well assay plate, 7 nM of intact enzyme was incubated in a total of 13 μL of buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 10 mM MgCl, 1 mM DTT) containing 1 μM CSKtide (5-FAM-AHA-KKKKDDIYFFFG-NH) and 25 μM ATP in the presence or absence of a range of compound concentrations (final concentration 1% DMSO) for 90 min at 25°C. The reaction was stopped by adding 70 μL of stop buffer (100 mM HEPES pH 7.5, 0.015% Brij 35, 35 mM EDTA, and 0.2% Coating Reagent 3, Caliper Lifesciences). Plates are read on a Caliper EZReader2. Biological Example 2: UT-7 Cell Proliferation by SCF Stimulation Assay as a Measure of Wild-Type KIT Activity UT-7 cells are a human megakaryoblastic leukemia cell line that can grow in culture depending on granulocyte-macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). UT-7 cells respond to SCF stimulation by activating the KIT receptor tyrosine kinase and subsequent downstream signal transduction that can support cell growth and proliferation (Kuriu et al., 1999; Komatsu et al., 1991; Sasaki et al., 1995). Test compounds were assayed for their ability to inhibit SCF-stimulated proliferation of UT-7 cells.

[0383] Inhibition of SCF-stimulated UT-7 cell proliferation is assessed using the CellTiter-Glo assay, which quantifies the amount of adenosine triphosphate (ATP) present, a readout of metabolically active cells that is directly proportional to the number of viable cells in culture. The ability of test compounds to inhibit SCF-stimulated UT-7 cell proliferation is determined using a 10-point dose curve ranging from 25 μM to 95.4 pM of test compound.

[0384] UT-7 cells were maintained in IMDM supplemented with 10% FBS, 5 ng / mL GM-CSF, and 100 units / mL penicillin-streptomycin and grown in a humidified tissue culture incubator at 37°C. UT-7 cells were washed once with serum-free, GM-CSF-free IMDM. The cells were then resuspended in IMDM containing 4% FBS and 50 ng / mL SCF and seeded at 2500 cells per well in a 22 μL volume into a 384-well microplate. A 10-point dose concentration series of test compound (25.0 μM to 95.4 pM) was then added to the cells in a volume of 3.1 μL per well (final concentration: 0.25% DMSO) and placed in a tissue culture incubator (5% CO2, 37°C) for 72 hours. After 3 days with the test compound, freshly prepare CellTiter-Glo reagent and add 25 μL of the reagent to each well. Plates are mixed by shaking at 300 rpm on a plate shaker at room temperature for 10 minutes. Plates are read on an EnVision plate reader using the ultra-sensitive luminescence protocol for 384-well plates. Data are normalized to 0% and 100% inhibition controls, and IC50s are calculated using a four-parameter logistic IC50 curve fit. Biological Example 3: Evaluation of Brain Permeability in the Rat Brain-to-Plasma Ratio (Kp, Brain) To understand brain permeability, the brain-to-plasma ratio of a compound was obtained in Sprague-Dawley (SD) rats. The bioequilibrium distribution between blood and brain in preclinical species such as rats is a commonly used parameter to assess brain permeability. p , the brain has a higher concentration ratio between brain and blood (C 脳 / C 血漿 The passive diffusion properties of a compound, its affinity for membrane transporters in the blood-brain barrier (BBB), and differences in relative drug binding affinity between plasma proteins and brain tissue affect the K p ,affects the brain. p ,Compounds with brain sizes smaller than 0.1 have limited access to the CNS, but K p Compounds with a brain K greater than 0.3-0.5 are considered to have good brain permeability. pCompounds with a brain activity greater than 1 freely cross the BBB (Expert Opin. Drug Delivery (2016) 13 (01): pp. 85-92).

[0385] The brain permeability of the compounds disclosed herein was measured in Sprague-Dawley rats (3 / compound). Animals received an IV infusion of 1 mg / kg / hr of compound via jugular vein cannulation for 8 hours. At 24 hours, blood was collected by tail vein bleeding or cardiac puncture (under anesthesia) and centrifuged to obtain plasma samples. Brain tissue was collected and homogenized in phosphate-buffered saline (PBS). Compound concentrations were obtained in plasma and brain homogenates by LC-MS / MS analysis. Table 3 below shows the K values ​​of Compounds 1 and 2 and Comparative A prepared according to the examples described herein. p ,The brain results are shown.

[0386] Compounds 1 and 2 have significantly lower K p ,brain (mean = 0.133 and 0.045). Rat plasma protein binding of test compounds was evaluated in vitro using equilibrium dialysis. Test compounds were evaluated in 100% plasma in a 5-hour dialysis block at 37°C. Samples from the donor and receiver sides were analyzed by LC-MS / MS. The bound and unbound fractions of plasma proteins were calculated using the following equation: Bound fraction (fb) * (%) = 100 × ([donor] 5h -[receiver] 5h ) / [donor] 5h (Equation 1) Unbound fraction (fu), p * (%)=100-% join * (Equation 2) Where: [donor] 5h is the donor concentration measured at 5 h, and [receiver] 5h is the receiver concentration measured at 5 hours, and fb * is the bound fraction determined from plasma, and fu,p *is calculated as the unbound fraction of plasma. Warfarin and quinidine were used as positive controls. Similarly, rat brain protein binding of test compounds was also assessed in vitro using equilibrium dialysis. 1 μM of compound was assessed in brain homogenates in a 5-hour dialysis block at 37°C. Samples from the donor and receiver sides were analyzed by LC-MS / MS. The bound and unbound fractions of brain protein were calculated using the equations above (Equations 1 and 2). Unbound brain-to-plasma ratio (Kpuu, brain) Based on the brain and plasma concentrations obtained above, and the fu, brain values ​​obtained above, the unbound brain-to-plasma ratio (K puu , brain) were calculated as shown in Table 3.

[0387] Compounds 1 and 2 exhibited significantly lower K values ​​compared to Comparative A (average = 0.84). p,uu , brain (mean = 0.017 and 0.01). The unbound drug concentration in tissue is the free drug available to exert a pharmacological effect in the tissue compartment. 1 and 2 show K p,uu , because the brain is very low, this means that the amount of 1 or 2 available in the brain to exert a pharmacological effect is very low compared to comparison A.

[0388] [Table 3]

Claims

1. Formula (I): 【Chemistry 1】 a compound of the formula (I), a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing. (In the formula, 【Chemistry 2】 is selected from a single bond and a double bond; 【Transformation 3】 is selected from a single bond and a double bond; Z is selected from CH and NH; Y is selected from C and N; X １ is selected from CH, C, and N; X ２ is selected from CH, C, and N; However, X １ and X ２ are both N, then Y is not N and Z is not CH; A is, 【Chemistry 4】 and R １ is selected from hydrogen and methyl; R ２ is selected from hydrogen and methyl, or R １ and R ２ together form a cyclopropyl; R ３ is selected from hydrogen and methyl; R ４ is selected from hydrogen and methyl, or R ３ and R ４ together form a cyclopropyl; R ５ is selected from hydrogen and methyl; R ６ is selected from hydrogen and methyl, or R ５ and R ６ together form a cyclopropyl, or R ２ Or R ４ One of them is R ６ together with R ７ is hydrogen or R ２ , R ４ , or R ６ One of them is R ７ together form a ring selected from tetrahydrofuran, and tetrahydropyran, wherein said tetrahydrofuran or tetrahydropyran is optionally substituted with hydroxyl; m is 0 or 1; n is 0 or 1; B is OH and NH ２ (selected from

2. Formula (II): 【Transformation 5】 2. The compound of claim 1, which is a compound of the formula:

3. Formula (III): 【Transformation 6】 2. The compound of claim 1, which is a compound of the formula:

4. X １ is N, 【Transformation 7】 is a single bond, and X ２ is C, 【Transformation 8】 is a double bond, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

5. X １ is C, 【Chemistry 9】 is a double bond, and X ２ is N, 【Chemistry 10】 is a single bond, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

6. A is, 【Chemistry 11】 and R ３ is selected from hydrogen and methyl; R ４ is selected from hydrogen and methyl, or R ３ and R ４ together form a cyclopropyl; R ５ is selected from hydrogen and methyl; R 6 is selected from hydrogen and methyl; or R ５ and R ６ together to form a cyclopropyl; R ７ is hydrogen, A compound according to any one of claims 1 to 5, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

7. B is NH ２ The compound according to any one of claims 1 to 6, wherein:

8. 7. The compound of any one of claims 1 to 6, wherein B is OH, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

9. A is, 【Chemistry 12】 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

10. A is, 【Chemistry 13】 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

11. A is, 【Chemistry 14】 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

12. A is, 【Chemistry 15】 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

13. A is, 【Chemistry 16】 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

14. A is 【Chemistry 17】 The compound according to any one of claims 1 to 5, 7 and 8, wherein:

15. The following Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 A compound according to any one of claims 1 to 5, 7 and 8, selected from the group consisting of: a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

16. A compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing; and a pharmaceutically acceptable excipient.

17. 19. A pharmaceutical composition for treating a disease or condition in a patient in need thereof, comprising a compound according to any one of claims 1 to 15, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor.

18. 18. The pharmaceutical composition of claim 17, wherein the disease or condition is systemic mastocytosis.

19. 19. The pharmaceutical composition of claim 18, wherein the systemic mastocytosis is selected from indolent systemic mastocytosis and smoldering systemic mastocytosis.

20. 16. The compound of any one of claims 1 to 15, for use as a medicament for treating a disease or condition in a patient in need thereof, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intracranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, dysgerminoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain tumor, a compound, a pharmaceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

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