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

Abstract

The present disclosure provides a compound of formula I: and pharmaceutical 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 an advantageous non-brain penetrance profile 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] This application claims priority from U.S. Provisional Application No. 62 / 833,529, filed April 12, 2019, U.S. Provisional Application No. 62 / 911,016, filed October 4, 2019, and U.S. Provisional Application No. 62 / 930,240, filed November 4, 2019. The entire contents of each of the foregoing applications are incorporated herein by reference.

[0002] The present disclosure relates to novel pyrrolotriazine compounds and their use as selective inhibitors of activated KIT and PDGFRα mutant protein kinases. The compounds disclosed herein are useful in pharmaceutical compositions, for example, 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 and activates KIT by inducing dimerization and autophosphorylation. This initiates downstream signaling. However, in several tumor types, somatic activating mutations in KIT promote ligand-independent constitutive oncogenic activity, including tumor types such as acute myeloid leukemia, melanoma, intercranial germ cell tumor, mediastinal B-cell lymphoma, seminoma, and gastrointestinal stromal tumor. Mutant KIT is also known to play a role in mast cell activation, which is common and likely necessary for maintenance. Impaired mast cell activation occurs when mast cells are pathologically overproduced or when their activation is out of proportion 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 neoplasms (SM-AHN), aggressive systemic mastocytosis (ASM), mast cell leukemia (MCL), and mast cell sarcoma.

[0003] Systemic mastocytosis is a clonal disorder of mast cells characterized by an 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 an 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 subclassifications are associated with reduced overall survival and are grouped as advanced 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-advanced SM (non-Adv SM).

[0004] In all subtypes of SM and in the majority of patients with this disease, neoplastic mast cells display 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 own differentiation and survival, constitutive activation of KIT by the D816V mutation is considered to be the pathogenic driver of SM. Specifically, the KIT D816V mutation is found in 90% to 98% of SM patients, and rare KITD816Y, D816F, and D816H mutations have been identified. Based on these findings, KIT D816V is considered the primary therapeutic target for SM.

[0005] 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 is still no approved treatment for ISM or SSM. Therefore, it would be beneficial to discover new treatments that target ISM or SSM.

[0006] Pyrrolotriazine compounds with mutant KIT and PDGFRα inhibitory activity are reported in WO 2015 / 057873. Specifically, certain compounds with N-alkylpyrazole are exemplified in WO 2015 / 057873 and have mutant KIT and PDGFRα inhibitory activity, for example, compound 63 with N-ethylpyrazole. The chemical structures of these N-alkylpyrazole compounds exemplified in WO 2015 / 057873 are different from the chemical structures of the compounds disclosed herein.

[0007] Furthermore, pyrrolotriazine compounds having mutant KIT and PDGFRα inhibitory activity are disclosed in WO 2015 / 057873, however, the properties of these compounds are significantly different from those of the compounds of the present disclosure. Summary of the Invention

[0008] The objective 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 diseases such as ISM and SSM and other diseases mediated by mutant KIT and PDGFRA. In the treatment of 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 low levels of undesirable CNS side effects associated with other known pyrrolotriazine compounds.

[0009] The present inventors have discovered novel compounds that have high selectivity and potency against mutant KIT and PDGFRα kinases while at the same time having 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 ratios from the CNS. Given this balance of desirable properties, the compounds of the present disclosure are particularly suitable for peripheral treatments, especially chronic peripheral treatments, while also causing reduced or minimized side effects in the CNS.

[0010] Thus, the compounds of the present disclosure are intended to provide a treatment 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 known pyrrolotriazine compounds with mutant KIT and PDGFRα inhibitory activity.

[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 mast / stem cell growth factor receptor (SCFR), proto-oncogene c-KIT, 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 thereof. "KIT gene" is used to refer to a gene encoding a polypeptide having KIT kinase activity, e.g., the sequence of which is located between nucleotides 55,524,085 and 55,606,881 of chromosome 4 of the reference human genome hg19. "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.

[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, mutants, variants, and fragments thereof. "PDGFRA gene" is used to refer to a gene encoding a polypeptide having PDGFRA kinase activity, for example, the sequence of which is located between nucleotides 54,229,089 and 54,298,247 of chromosome 4 of reference Homo sapiens annotation release 109, GRCh38.p12. "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.

[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 and 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.

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

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

[0017] Eosinophilic disorders are diagnosed depending on where the levels of eosinophils 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 that is treated by the methods of the present disclosure. Such organisms include, but are not limited to, mammals (e.g., murine, simian, equine, bovine, feline, canine, feline, etc.), and in some embodiments, humans.

[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 dosages, and is not intended to be limited to a particular formulation or route of administration.

[0020] As used herein, the phrase "the equivalent weight amount of a pharma- ceutically 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 pharma- ceutically acceptable salt thereof," when used in reference to an active agent that is distributed in salt form, refers to any pharma- ceutically acceptable salt form of the active agent.

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

[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 pharma- ceutically acceptable excipients or carriers.For example, the active agent can be formulated for administration in any convenient manner for use as a human or veterinary medicine.In certain embodiments, the compound contained in the pharmaceutical preparation can be active per se, or can be, for example, a prodrug that can be converted into an active compound in a physiological situation.

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

[0025] As used herein, "alkyl" refers to a saturated linear or branched hydrocarbon monovalent radical, e.g., as used herein, C1 to C6, respectively. 12 Alkyl, C1-C 10 Alkyl, also referred to as C1-C6 alkyl, refers to straight or branched groups of 1 to 12, 1 to 10, or 1 to 6 carbon atoms. For example, a C1 alkyl is methyl.

[0026] As used herein, "halo" refers to any halogen radical, e.g., -F, -Cl, -Br, or -I.

[0027] As used herein, "haloalkyl" and "haloalkoxy" refer to alkyl and alkoxy structures substituted with one or more halo groups or combinations thereof. For example, the terms "fluoroalkyl" and "fluoroalkoxy" include haloalkyl and haloalkoxy groups, respectively, where halo is fluorine. "Haloalkylene" refers to divalent alkyl, e.g., -CH2-, -CH2CH2-, and -CH2CH2CH2-, in which one or more hydrogen atoms are replaced by halo, including alkyl moieties in which all hydrogens are replaced by halo.

[0028] As used herein, "cycloalkyl" refers to a cyclic, bicyclic, tricyclic, or polycyclic non-aromatic hydrocarbon group having 3 to 12 carbons. Any substitutable ring atom can be substituted (e.g., by one or more substituents). Cycloalkyl groups can include fused or spiro rings. Fused rings are rings that share a common carbon atom. Examples of cycloalkyl moieties include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0029] As used herein, "heterocyclyl" refers to a monovalent radical of a heterocyclic ring system. Examples of heterocyclyl include ring systems in which all rings are non-aromatic and at least one ring contains a heteroatom, such as, but not limited to, oxetanyl, tetrahydrofuranyl, and tetrahydropyranyl.

[0030] As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than one time in any construct, is intended to be independent of its definition elsewhere in the same construct.

[0031] Certain compounds of the present disclosure may exist as specific geometric forms or stereoisomers. 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 a substituent, such as, for example, an alkyl group. All such isomers, and mixtures thereof, are intended to be included in the present disclosure.

[0032] 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 group is 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, a diastereomeric salt is formed with an appropriate optically active acid or base, and the diastereomers are then resolved by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0033] 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.

[0034] The "enantiomeric excess" or "% enantiomeric excess" of a composition can be calculated using the formula 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%.

[0035] Thus, a composition containing 90% of one enantiomer and 10% of the other is said to have an enantiomeric excess of 80%.

[0036] The compounds or compositions described herein may 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.

[0037] The compounds described herein may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds may contain, for example, deuterium ( 2 H), tritium ( 3 H), Carbon 13 ( 13 C), or carbon 14 ( 14 C). All isotopic variations of the compounds disclosed herein, whether radioactive or not, are intended to be included within the scope of the disclosure. Additionally, all tautomers of the compounds described herein are intended to be within the scope of the disclosure.

[0038] 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 (see, for example, Berge et al., (1977) "Pharmaceutical Salts", J.Pharm.Sci.66:1-19.).

[0039] 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.

[0040] In general, solvated forms are equivalent to unsolvated forms and are included 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.

[0041] The present disclosure provides compounds of Formula I and pharma- ceutically acceptable salts and / or solvates of any of the foregoing.Non-limiting embodiments of the present disclosure include the following:

[0042] Embodiment 1 A compound of formula I: [ka] A pharma- ceutically acceptable salt, and / or solvate of any of the foregoing, wherein: A is, [ka] 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 or R2 or R4 together with R6 form a cyclobutyl; R7 is hydrogen, or one of R2, R4, or R6 together with R7 forms a ring selected from oxetane, tetrahydrofuran, and tetrahydropyran, said tetrahydrofuran or said tetrahydropyran being optionally substituted with hydroxyl; m is 0 or 1; A compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein n is 0 or 1.

[0043] In some embodiments of embodiment 1, R1 and R2 are not present when m is 0. In some embodiments of embodiment 1, R3 and R4 are not present when n is 0. In some embodiments of embodiment 1, m+n=1 or m and n cannot both be 0.

[0044] 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.

[0045] Embodiment 2 A compound of embodiment 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein: A is, [ka] 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 R4 and R6 together form a cyclobutyl; or R5 and R6 together form a cyclopropyl; R7 is hydrogen, a compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0046] Embodiment 3 A compound of embodiment 2, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein A is [ka] 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; R7 is hydrogen, a compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0047] Embodiment 4 A compound of embodiment 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein: A is, [ka] and w is 1 or 2; t is 1 or 2; and s is 0 or 1. The compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0048] Embodiment 5: The compound is selected from the group consisting of K p <0.39, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0049] In some embodiments of embodiment 5, the compound has a K p<0.39. In some embodiments of embodiment 5, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 2, 3, 4, 5, 6, 7, 9, 10, 11, 12, 13, 14, 17, 18, 19, 20, 21, and 22.

[0050] Embodiment 6 The compound is selected from the group consisting of K p The compound of any one of embodiments 1-4, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β-

[0051] In some embodiments of embodiment 6, the compound is 、 K p In some embodiments of embodiment 6, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 3, 4, 5, 6, 9, 11, 13, 17, 18, 19, 20, 21, and 22.

[0052] Embodiment 7: The compound is capable of inhibiting K in homogenized rat brain. p,uu The compound of any one of embodiments 1-6, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β-

[0053] In some embodiments of embodiment 7, the compound has a K p,uu In some embodiments of embodiment 7, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 17, 18, 19, 20, and 22.

[0054] Embodiment 8: The compound is shown to inhibit K p,uu <0.1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0055] In some embodiments of embodiment 8, the compound has a K p,uu <0.1. In some embodiments of embodiment 8, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 2, 3, 4, 5, 6, 7, 9, 11, 12, 17, 18, 19, 20, and 22.

[0056] Embodiment 9: The compound is capable of inhibiting K in homogenized rat brain. p,uu <0.05, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0057] In some embodiments of embodiment 9, the compound has a K p,uu In some embodiments of embodiment 9, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 3, 4, 5, 6, 9, 17, 19, 20, and 22.

[0058] Embodiment 10: The compound is shown to inhibit K p,uu The compound of any one of embodiments 1-9, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β-

[0059] In some embodiments of embodiment 10, the compound exhibits a K p,uu In some embodiments of embodiment 10, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 20, 21, and 22.

[0060] Embodiment 11 The compound is shown to inhibit K p,uu The compound of any one of embodiments 1-10, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having a β-

[0061] In some embodiments of embodiment 11, the compound has a K p,uu In some embodiments of embodiment 11, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 17, 18, 20, and 22.

[0062] Embodiment 12: The compound has an unbound clearance (Cl) of <900 mL / min / kg in rats. u 12. The compound of any one of embodiments 1-11, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein

[0063] In some embodiments of embodiment 12, the compound has a Cl concentration of <900 mL / min / kg in rats as measured according to the procedures described in Example 4. u In some embodiments of embodiment 12, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 3, 4, 7, and 9.

[0064] Embodiment 13: The compound has an unbound clearance (Cl) of <750 mL / min / kg in rats. u 13. The compound of any one of embodiments 1-12, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein

[0065] In some embodiments of embodiment 13, the compound has a Cl concentration of <750 mL / min / kg in rats as measured according to the procedures described in Example 4. uIn some embodiments of embodiment 13, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is selected from compounds 4, 7, and 9.

[0066] Embodiment 14 The compound has an IC for CYP3A4 of <10 μM 50 The compound of any one of embodiments 1-12, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, having the formula:

[0067] In some embodiments of embodiment 14, the compound has an IC for CYP3A4 of <10 μM, as measured according to the procedures described in Example 5. 50 In some embodiments of embodiment 14, the compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing is compound 4.

[0068] In the above formula, A is [ka] A compound of embodiment 1 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0069] In the above formula, A is [ka] A compound of embodiment 1 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0070] Embodiment 16 In the above formula, A is [ka] A compound of embodiment 1 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0071] In the above formula, A is [ka] A compound of embodiment 1 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0072] In the above formula, A is [ka] The compound of any one of embodiments 1-3 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0073] In the above formula, A is [ka] The compound of any one of embodiments 1-3 or 5 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0074] In the above formula, A is [ka] A compound according to any one of embodiments 1-3 or 5-6 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0075] Embodiment 20 In the above formula, A is [ka] A compound according to any one of embodiments 1-3 or 5-7 selected from: a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0076] Embodiment 21 The compound of any one of embodiments 1-13, wherein said compound is selected from 4, 7, and 9, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0077] Embodiment 22 The compound of any of embodiments 1-13, wherein said compound is selected from 4 and 9, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0078] Embodiment 23: wherein the compound is [ka] The compound of any one of embodiments 1-13, wherein:

[0079] Embodiment 24. The compound is [ka] The compound of any one of embodiments 1-13, wherein:

[0080] Embodiment 25: wherein the compound is [ka] The compound of any one of embodiments 1-13, wherein:

[0081] EMBODIMENT 26 A compound according to any one of embodiments 1 to 25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing; and a pharma- ceutically acceptable excipient.

[0082] Embodiment 27 A method of treating a disease or condition in a patient in need thereof, comprising administering to the patient a compound of any one of embodiments 1-25, a pharmacologic 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, intercranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, embryonal tumor, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0083] Embodiment 28. A method of treating a disease or condition mediated by mutant KIT or PDGFRα in a patient in need thereof, comprising administering to said patient a compound of any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0084] 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, intercranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, embryonal tumor, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0085] Embodiment 30. The compound according to any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, 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, intercranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, embryonal tumor, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0086] Embodiment 31. A compound according to any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, for use as a medicament for treating a disease or condition mediated by mutant KIT or PDGFRA in a patient in need thereof.

[0087] 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, intercranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, embryonal tumor, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

[0088] Embodiment 33. A method of treating an eosinophilic disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0089] Embodiment 34. The method of embodiment 33, wherein said eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastropathy, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0090] Embodiment 35. The method of embodiment 33, wherein said eosinophilic disorder is hypereosinophilic syndrome.

[0091] Embodiment 36. The method of embodiment 33, wherein said eosinophilic disorder is eosinophilic leukemia.

[0092] Embodiment 37. The method of embodiment 36, wherein said eosinophilic leukemia is chronic eosinophilic leukemia.

[0093] Embodiment 38. The method of any one of embodiments 33-37, wherein said eosinophilic disorder is resistant to treatment with imatinib, sunitinib, and / or regorafenib.

[0094] Embodiment 39. A compound of any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, for use as a medicament for treating an eosinophilic disorder.

[0095] Embodiment 40. A compound of embodiment 39, wherein said eosinophilic disorder is selected from hypereosinophilic syndrome, eosinophilia, eosinophilic enterogastropathy, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0096] Embodiment 41 The compound of embodiment 39, wherein the eosinophilic disorder is hypereosinophilic syndrome.

[0097] Embodiment 42. The compound of embodiment 39, wherein the eosinophilic disorder is eosinophilic leukemia.

[0098] Embodiment 43. The compound of embodiment 42, wherein said eosinophilic leukemia is chronic eosinophilic leukemia.

[0099] Embodiment 44 The method of any one of embodiments 39-43, wherein said eosinophilic disorder is resistant to treatment with imatinib, sunitinib, and / or regorafenib.

[0100] Embodiment 45 A method of treating a mast cell disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-25, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

[0101] Embodiment 46. The method of embodiment 45, wherein said mast cell disorder is mediated by mutant KIT or PDGFRα.

[0102] Embodiment 46-1 The method of embodiment 45, wherein said mast cell disorder is mediated by wild-type KIT or PDGFRα.

[0103] Embodiment 47. The method of embodiment 46, wherein said mast cell disorder is selected from mast cell activation syndrome (MCAS) and hereditary alpha tryptassemia (HAT).

[0104] Embodiment 48. The method of embodiment 47, wherein said MCAS is selected from monoclonal mast cell activation syndrome (MMAS), secondary MCAS, and idiopathic MCAS.

[0105] Embodiment 48-1 The method of embodiment 27, wherein the disease or condition is systemic mastocytosis.

[0106] Embodiment 49. The method of any one of embodiments 48, wherein said systemic mastocytosis is selected from indolent systemic mastocytosis and smoldering systemic mastocytosis. Table 1 lists compounds that were prepared by the synthetic methods described herein. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0107] 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, a "selective KIT inhibitor" or a "selective PDGFRα inhibitor" refers to a compound or a pharma- ceutically acceptable salt or solvate of any of the foregoing that selectively inhibits KIT protein kinase or PDGFRα protein kinase over other protein kinases, and exhibits at least 2-fold selectivity for KIT protein kinase or PDGFRα protein kinase over other kinases. For example, a selective KIT inhibitor or 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 PDGFRα kinase over other kinases. In some embodiments, a selective KIT inhibitor or selective PDGFRα inhibitor exhibits at least 150-fold selectivity over other kinases, such as 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 or selective PDGFRα inhibitor exhibits selectivity over PDGRFβ, CSF1R (colony stimulating factor receptor 1), and FLT3.In some embodiments, the selective KIT or selective PDGFRα inhibitors exhibit 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 coiled-coil continued protein kinase-1). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over other kinases is measured in a cellular assay (e.g., a cellular assay). In some embodiments, selectivity for KIT protein kinase or PDGFRα protein kinase over other kinases is measured in a biochemical assay (e.g., a biochemical assay).

[0108] The compounds of the present disclosure are selective over ion channels, in some embodiments, selective KIT or selective PDGFRα inhibitors have limited potential to inhibit the human voltage-gated sodium channel (hNav1.2).

[0109] The compounds of the present disclosure are selective for mutant KIT over wild-type KIT. In some embodiments, the compounds of the present disclosure are selective for exon 17 mutant KIT over wild-type KIT.

[0110] 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 medicaments. 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 medicines. 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, intercranial germ cell tumor, and / or mediastinal B-cell lymphoma. Additionally, mutations in KIT are associated with Ewing's sarcoma, DLBCL (diffuse large B-cell lymphoma), germinoma, MDS (myelodysplastic syndrome), NKTCL (nasal NK / T-cell lymphoma), CMML (chronic myelomonocytic leukemia), and brain cancer. In some embodiments, the present disclosure provides methods for treating Ewing's sarcoma, DLBCL, dysplasia, MDS, NKTCL, CMML, and / or brain cancer. 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, the compounds of the present disclosure may be useful for treating mast cell activation syndrome (MCAS). The compounds of the present disclosure may be useful for treating systemic mastocytosis. The compounds of the present disclosure may be useful for treating advanced systemic mastocytosis. The compounds of the present disclosure may be useful for treating indolent SM and smoldering SM. The compounds of the present disclosure may be useful for treating GIST.

[0111] The compounds of the present disclosure may be useful for treating a disease or condition associated with a KIT mutation 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 a disease or condition associated with a PDGFRA mutation in exon 12, exon 14, and / or exon 18 of the PDGFRA 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, exon 11, exon 14, exon 17, and / or exon 18 of the KIT gene sequence. In some embodiments, provided herein are methods for treating a disease or condition associated with at least one PDGFRA mutation in exon 12, exon 14, and / or exon 18 of the PDGFRA gene sequence.

[0112] The compounds of the present disclosure may be active against one or more KIT protein kinases having a mutation 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) that are much less active than the 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.

[0113] 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 at least one KIT mutation, e.g., L576P, V559D, V560D, V560G, W557G, Del554-558EVQWK, 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 Methods are provided for treating a disease or condition associated with, for example, one selected from among WKVV557-560C, Del WKVV557-560F, DelYEVQWK553-558, and insertion K558NP.

[0114] 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 a disease or condition associated with one or more KIT mutations in exons 11 / 13.

[0115] 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.

[0116] In some embodiments, compounds of the disclosure are not active against KIT protein kinases having the mutations V654A, N655T, T670I, and / or N680.

[0117] The compounds of the present disclosure may be active against one or more PDGFRα protein kinases with mutations. In some embodiments, provided herein is a method for treating a disease or condition associated with at least one PDGFRA mutation in exon 12 of the PDGFRA gene sequence, such as PDGFRα protein mutation V561D, Del RV560-561, Del RVIES560-564, Ins ER561-562, SPDGHE566-571R, SPDGHE566-571K, or Ins YDSRW582-586. In some embodiments, provided herein is a method for treating a disease or condition associated with at least one PDGFRA mutation in exon 14 of the PDGFRA gene sequence, such as PDGFRα protein mutation N659K. In some embodiments, the present disclosure relates to at least one PDGFRA mutation in exon 18 of the PDGFRA gene sequence, such as the 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 diseases or conditions associated with MHDS844-847, RD841-842KI, DIMH842-845A, DIMH842-845V, DIMHD842-846E, DIMHD842-846S, DIMHD842-846N, DIMHD842-846G, IMHDS843-847T, IMHDS8843-847M, or HDSN845-848P, etc.

[0118] The compounds of the disclosure may be active against one or more PDGFRA protein kinases that have a mutation in exon 18 of the PDGFRA gene sequence (e.g., 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, protein mutation PDGFRα D842V.

[0119] The 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, the eosinophilic disorder is mediated by wild-type KIT or PDGFRα. In some embodiments, the present disclosure provides a method for treating eosinophilic disorders, comprising administering to a subject a therapeutically effective amount of a compound of the present disclosure, or a pharma- ceutically 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 enterogastropathy, eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0120] 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.

[0121] In one embodiment, the eosinophilic disorder is hypereosinophilic syndrome. In a particular embodiment, the hypereosinophilic syndrome is idiopathic hypereosinophilic syndrome. In one embodiment, the eosinophilic disorder is eosinophilic leukemia. In a particular embodiment, the eosinophilic leukemia is chronic eosinophilic leukemia. In another embodiment, the eosinophilic disorder is resistant to treatment with imatinib, sunitinib, and / or regorafenib. In a particular embodiment, the eosinophilic disorder is resistant to treatment with imatinib.

[0122] The 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, or its pharma- ceutically acceptable salt, and / or any of the solvates described above.

[0123] 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.

[0124] In another embodiment, the disclosed methods reduce the number of eosinophils (following 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.

[0125] In another embodiment, the disclosed methods reduce the number of eosinophil precursors (following 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 eosinophil precursors below the limit of detection.

[0126] 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 restricted 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 (SSM), aggressive (ASM), SM with associated hematological non-mast cell lineage disease (SM-AHNMD), and mast cell leukemia (MCL).

[0127] The diagnosis of SM is based in part on histologic and cytologic observations of bone marrow showing infiltration by mast cells, often of atypical morphology, that frequently express non-mast cell markers (CD25 and / or CD2). The diagnosis of SM is confirmed when bone marrow mast cell infiltration occurs in the context of any 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., D816V.

[0128] 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.

[0129] No medications are approved for non-advanced forms of systemic mastocytosis, ISM, or SSM. Current approaches to the management of these chronic diseases include non-specific symptom-directed therapies that have varying degrees of effectiveness and do not affect the burden of MC. Cytoreductive therapies, 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 treated with available symptom-directed therapies.

[0130] The 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, at least three symptoms that cannot be adequately controlled by symptomatic treatments. Symptoms can be assessed using a patient-reported outcome (PRO) tool, such as the Painless Systemic Mastocytosis Symptom Assessment Form (ISM-SAF) (ISPOR Europe 2019, Copenhagen Denmark, November 2-6, 2019). The compounds of the present disclosure may be useful for improving symptoms associated with ISM or SSM, such as reducing or eliminating pruritus, flushing, headache, and / or GI events such as vomiting, diarrhea, and abdominal pain. Symptom improvement can be assessed using the ISM-SAF.

[0131] 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. May 2013 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 disorders associated with wild-type KIT and PDGFRα.

[0132] The compounds of the present disclosure may be useful in treating Mast Cell Activation Syndrome (MCAS), an immunological condition in which mast cells inappropriately and excessively release chemical mediators, resulting in a variety of chronic symptoms, including, in some cases, anaphylactic or near-anaphylactic attacks. Unlike mastocytosis, in which the patient's mast cell numbers increase abnormally, MCAS patients 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).

[0133] Compounds of the present disclosure may be useful for treating hereditary alpha tryptasia (HAT) (overexpression of TPSAB1 causing elevated tryptase).

[0134] 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, mast cell gastroenteritis, mast cell colitis, pruritus, chronic pruritus, pruritus secondary to chronic renal failure, and mast cell associated heart, vascular, intestine, brain, kidney, liver, pancreas, muscle, bone and skin conditions. In some embodiments, the mastocytosis is not associated with mutant KIT or mutant PDGFRα.

[0135] KIT and PDGFRA mutations are widely observed in GIST. Compounds of the present disclosure may be useful for treating GIST associated with KIT mutations. Compounds of the present disclosure may be useful for treating unresectable or metastatic GIST. Nearly 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 eventually 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. There are no selective targeted agents among the currently approved drugs for GIST. 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 small therapeutic windows. In some embodiments, the compounds of the present disclosure may be useful for treating GIST in patients treated with imatinib. The 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) treatment.

[0136] 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).

[0137] The compounds of the present disclosure may be useful for treating GIST associated with PDGFRA mutations. In 5 to 6% of patients with unresectable metastatic GIST, the primary mutation occurs in exon 18 of the gene sequence of PDGFRA at protein amino acid 842.

[0138] The compounds of the present disclosure may also be useful in the treatment of AML. AML patients also harbor KIT mutations, with the majority of these mutations at the D816 position of the KIT protein.

[0139] In some embodiments, the compound of the present disclosure is administered to a subject in need thereof.In some embodiments, the compound of the present disclosure is administered as a formulation, where the compound is combined with one or more pharma- ceutically acceptable excipients or carriers.Thus, in some embodiments, disclosed herein is a composition comprising at least one selected from the compound of formula I, and its pharma- ceutically acceptable salts, and / or any of the above solvates, and optionally further comprising at least one pharma- ceutically acceptable excipient.

[0140] 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 can be active themselves or can be, for example, prodrugs that can be converted to active compounds in physiological situations.

[0141] The phrase "pharmacologically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0142] Examples of pharma- ceutically acceptable carriers include: (1) sugars, such as, for example, lactose, glucose, and sucrose; (2) starches, such as, for example, corn starch and potato starch; (3) cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as, for example, cocoa butter and suppository wax; (9) oils, such as, for example, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like; and (10) propylene glycol. (11) polyols, such as, for example, glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as, for example, ethyl oleate and ethyl laurate; (13) agar; (14) buffers, such as, for example, 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, for example, Captisol®; and (22) other non-toxic compatible substances used in the formulation of pharmaceutical agents.

[0143] Examples of pharma- ceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as, for example, ascorbic acid, cysteine ​​hydrochloride, sodium bisulfite, sodium metabisulfite, and sodium sulfite; (2) oil-soluble antioxidants, such as, for example, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and alpha-tocopherol; and (3) metal chelating agents, such as, for example, citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0144] Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) may contain one or more pharma- ceutically 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) sorbitol, sorbitol, sorbitol-containing salts, such as, for example, agar-agar, calcium carbonate, dibasic salts, and / or sorbitol-containing salts; (5) sorbitol-containing salts, such as, for example, sorbitol-containing salts, and / or sorbitol-containing salts; Disintegrating agents such as potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) absorbents such as kaolin and bentonite clay; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents.

[0145] Liquid dosage forms may include pharma- ceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active ingredient, liquid dosage forms may include 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, sesame oil, etc.), glycerol, tetrahydrofuryl alcohol, glycols and fatty acid esters of polyethylene sorbitan, and mixtures thereof.

[0146] Suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxylate, bentonite, agar-agar, tragacanth, and mixtures thereof.

[0147] The ointments, pastes, creams and gels may contain, in addition to the active compound, excipients such as animal or vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, zinc oxide, or mixtures thereof.

[0148] 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 can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

[0149] Non-limiting examples of dosage forms for topical or transdermal administration of a compound 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 pharma- ceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.

[0150] When the compounds of the present disclosure are administered as pharmaceuticals to humans and animals, the compounds can be administered per se or as a pharmaceutical composition comprising, for example, 0.1 to 99.5% (such as 0.5 to 90%) of the active ingredient together with a pharma- ceutically acceptable carrier.

[0151] Formulations may be administered topically, orally, transdermally, rectally, vaginally, parentally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0152] 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.

[0153] 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.

[0154] In some embodiments, a compound of the disclosure is administered following pretreatment with imatinib.

[0155] The compounds of the present disclosure can be administered to patients who have not been previously treated with midostaurin. In some embodiments, the compounds of the present disclosure can be administered to patients who have been previously treated with midostaurin. EXAMPLES

[0156] General synthesis methods and intermediates definition C Celsius Cs2CO3 Cesium carbonate DCM Dichloromethane DIPEA Diisopropylamine DMF Dimethylformamide DMSO Dimethyl sulfoxide EA 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-Methylpyrrolidinone 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

[0157] The method for preparing the compounds of the present disclosure can be carried out in a suitable solvent that can be easily selected by those skilled in the art of organic synthesis. A suitable solvent can be substantially non-reactive with the starting material (reactant), intermediate, or product at the temperature at which the reaction is carried out, for example, at a temperature ranging 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 those skilled in the art.

[0158] The preparation of the compounds of the present disclosure may include the protection and deprotection of various chemical groups. The necessity of protection and deprotection, and the selection of suitable protecting groups can be easily determined by those skilled in the art. The chemical nature of protecting groups can be found, for example, in Wuts and Greene, Protective Groups in Organic Synthesis, 5th Edition, John Wiley & Sons: New Jersey, (2014), which is incorporated herein by reference in its entirety.

[0159] The reaction can be monitored according to any suitable method known in the art. For example, the composition of the product can be monitored by nuclear magnetic resonance (NMR) spectroscopy (e.g., 1 H or 13C), 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:

[0160] LC-MS: Unless otherwise stated, all liquid chromatography mass spectrometry (LC-MS) data (samples analyzed for purity and identity) were acquired at 22.4 degrees Celsius using an Agilent model 6120 mass spectrometer utilizing ES-API ionization and an Agilent model 1260 LC system equipped with an Agilent Poroshel 120 (EC-C18, 2.7um particle size, 3.0x50mm dimensions) reversed-phase column. The mobile phase consisted of a mixture of 0.1% formic acid solvent in H2O 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 utilized. The flow rate was constant at 1mL / min.

[0161] Preparative LC-MS: Preparative HPLC was performed on a Shimadzu Discovery VP® Preparative System equipped with a Luna 5u C18(2)100A, AXIA pack, 250x21.2mm reversed phase column at 22.4 degrees Celsius. The mobile phase consisted of a mixture of 0.1% formic acid solvent in H2O and 0.1% formic acid in acetonitrile. A constant gradient of 95% aqueous / 5% organic to 5% aqueous / 95% organic mobile phase over 25 minutes was used. The flow rate was constant at 20mL / min. Reactions performed in the microwave were performed in a Biotage Initiator microwave unit.

[0162] Silica gel chromatography: Silica gel chromatography was performed on either a Teledyne Isco CombiFlash® Rf unit or a Biotage® Isolera Four unit.

[0163] Proton NMR: Unless otherwise stated, all 1 H NMR spectra were acquired using a Varian 400 MHz Unity Inova 400 MHz NMR instrument (acquisition time = 3.5 s, 1 s delay; 16 to 64 scans). When characterized, all protons are reported in parts per million (ppm) relative to residual DMSO (2.50 ppm) in DMSO-d6 solvent.

[0164] One of skill in the art will appreciate that variations in gradients, column lengths, and flow rates are possible and that, depending on the chemical species being analyzed, some conditions may be more suitable for compound characterization than others.

[0165] Example 1: Synthetic Formulation Preparation of intermediates Preparation 1: (S)-1-(2-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethan-1-amine (I-1) [ka]

[0166] Step 1: Synthesis of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (ii): To a solution of tert-butyl piperazine-1-carboxylate (i) (10.0 g, 53.7 mmol) and diisopropylethylamine (23.4 mL, 134.25 mmol) in dioxane (80 mL), ethyl 2-chloropyrimidine-5-carboxylate (10 g, 53.7 mmol) was added and the reaction mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was concentrated to give the title compound (ii) (17 g, crude), which was used directly in the next step without further purification. MS (ES+) C 16 H 24 N4O4requires:336,found:237,281[M-56+H] +

[0167] Step 2: Synthesis of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (iii): To a solution of ethyl 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylate (ii) (17 g, crude) in THF / MeOH / HO (300 mL) was added sodium hydroxide (4.3 g, 107.5 mmol) and the reaction was stirred at 70 °C for 2 h. LCMS showed the reaction was complete. The reaction mixture was cooled to room temperature, acidified with 1 M HCl to pH 5-6 and filtered. The solid was collected and dried to afford the title compound (iii) (16 g, 96%) as a white solid which was used directly in the next step without further purification. MS (ES+) C 14 H 20 N4O4requires:308,found:253[M-56+H] +

[0168] Step 3: Synthesis of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (iv): To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (iii) (13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7 mmol) in DCM (200 mL) was added TEA (25 mL, 179.2 mmol) and the mixture was stirred at room temperature for 1 h followed by addition of N,O-dimethylhydroxylamine (5 g, 53.7 mmol). The reaction mixture was stirred for an additional 3 h. LCMS showed the reaction was complete. The reaction mixture was washed with HO (100 mL) and the organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (iv) (11.2 g, 67%) as a white solid. MS(ES+)C 16 H 25 N5O4requires:351,found:296[M-56+H] +.found:296[M-56+H] +

[0169] Step 4: Synthesis of tert-butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (v): To a solution of tert-butyl 4-(5-(methoxy(methyl)carbamoyl)pyrimidin-2-yl)piperazine-1-carboxylate (iv) (7.8 g, 22.22 mmol) in dry THF (50 mL) under nitrogen at 0° C., C6H5MgFBr (1 M in THF, 50 mL) was added and the mixture was stirred at room temperature for 3 h. LCMS showed the reaction was complete. The reaction mixture was quenched with 1M HCl and extracted with EA. The combined organic layers were washed with H2O and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:EA=5:1) to give the title compound (v) (7.2 g, 84%) as a yellow solid. MS(ES+)C 20 H 23 FN4O3requires:386,found:331[M-56+H] +

[0170] Step 5: Synthesis of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate (vi): tert-Butyl 4-(5-(4-fluorobenzoyl)pyrimidin-2-yl)piperazine-1-carboxylate (v) (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 mixture was stirred at 50-60 °C for 1 h. The reaction mixture was then distilled to remove 80 mL while charging additional toluene (80 mL) at 40-60 °C. The reaction mixture was cooled to 20-30 °C and added to monosodium citrate solution (80 mL, citric acid 30 wt%, pH 3-4). The mixture was stirred at 45-55 °C for 1.5 h and then the phases were separated. The organic phase was washed with potassium bicarbonate (40 mL, 25 wt% in water) and the organic phase was distilled to remove 40 mL. The product solution of (vi) was diluted with THF (30 mL) before being used directly as a solution in the next step (approximately 15 wt%).

[0171] Step 6: Synthesis of tert-butyl 4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (vii): To a solution of tert-butyl (S,Z)-4-(5-(((tert-butylsulfinyl)imino)(4-fluorophenyl)methyl)-pyrimidin-2-yl)piperazine-1-carboxylate (vi) in toluene / THF (120 g, prepared in step 5) was added methylmagnesium chloride (27.8 g, 22 wt% in THF, 2.0 equiv.) over 2-3 h at 10 °C. The reaction mixture was stirred for 1.5 h to reach completion. The reaction mixture was quenched by adding methanol (40 mL) followed by HO (10 mL). The mixture was distilled to remove 100-110 mL and then washed with ammonium chloride (80 mL, 20 wt % in HO). The organic phase was washed with HO (80 mL), diluted with toluene (60 mL) and distilled to remove 60-80 mL of distillate. The solution at 50-60 °C was charged with n-heptane (80 mL) and then cooled to 42 °C, at which point seeds were added (25-50 mg). The solution was held for 30 min and then cooled to 0-10 °C in 30 min. 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 of crude product of (vii), 96.4-97.2%.

[0172] Step 6a: Recrystallization of crude 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) and heated to 40-60 °C before being passed through a clarifying filter and washed / rinsed with isopropanol (20 mL). The resulting solution was vacuum distilled at 40-60 °C to remove 60-70 mL. 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 seeds were added. The mixture was further cooled to 20-25°C and water (20 mL) was added. The solid was isolated by filtration, washed with an isopropanol / water mixture (1:1, 20 mL), and then slurry washed with isopropanol / water (1:2, 30 mL). Drying gave 8.5 g of product (vii) >99.8%.

[0173] Step 7: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine hydrochloride (viii): tert-Butyl-4-(5-((S)-1-(((S)-tert-butylsulfinyl)amino)-1-(4-fluorophenyl)-ethyl)pyrimidin-2-yl)piperazine-1-carboxylate (vii) (50 g, 1 eq) was mixed with ethanol (7.5 vol) and concentrated hydrochloric acid (11.2 M, 5.6 eq). The reaction mixture was heated to reflux. After the reaction was complete by LCMS, the mixture was concentrated to 5 volumes at atmospheric pressure. Ethanol was added to continue concentration, maintaining 5 volumes until the H2O content was 3% or less. Concentration was finally stopped at 2 volumes and then cooled to 0-5 °C over 30 min. Filtration and drying under vacuum gave the title product (viii) (92% yield).

[0174] Step 8: Synthesis of (S)-1-(2-(4-(6-bromopyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanamine (I-1): A mixture of commercially available 6-bromo-4-chloropyrrolo[2,1-f][1,2,4]triazine (4.00 g, 17.2 mmol) (ex. Sigma Aldrich), (S)-1-(4-fluorophenyl)-1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanamine hydrochloride (viii) (5.81 g, 17.2 mmol) and triethylamine (7.20 mL, 51.6 mmol) in dioxane (50 mL) was stirred at room temperature overnight. The mixture was concentrated and then purified by flash column chromatography (DCM / MeOH=20 / 1) to give the title compound (I-1) (8.0 g, 94% yield) as a white solid. MS(ES+)C 22 H 22 BrFN8requires:496,found:497,499[M+H] +

[0175] Preparation 2: (S)-1-(2-(4-(6-(1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)-1-(4-fluorophenyl)ethanamine (I-2) [ka]

[0176] A mixture of I-1 (3.0 g, 6.05 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.17 g, 6.05 mmol), Pd(dppf)Cl2 (494 mg, 605 μmol) and K2CO3 (2.50 g, 18.2 mmol) in DMF / H2O (40 mL / 10 mL) was purged with N2(g) for 10 min and stirred at 70 °C under N2 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=10 / 1) to give the title compound (I-2) (2.0 g, 68% yield) as a yellow solid. MS(ES+)C 25 H 25 FN 10 requires:484,found:485[M+H] +

[0177] Preparation 3: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (I-3) [ka]

[0178] A mixture of I-1 (1.0 g, 2.02 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaneborolane) (768 mg, 3.12 mmol), Pd(dppf)Cl2 (165 mg, 202 μmol), dppf (167 mg, 303 μmol) and KOAc (395 mg, 4.04 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 the title compound (I-3) (700 mg) as a grey solid. MS(ES+)C28H34BFN8O2 requires:544,found:545[M+H] +

[0179] Preparation of compounds

[0180] Example 1: (S)-1-(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-methylpropan-2-ol (1) [ka]

[0181] A mixture of I-2 (prepared according to Preparation 2) (200 mg, 0.412 mmol), Cs2CO3 (269 mg, 0.83 mmol) and 2,2-dimethyloxirane (89.3 mg, 1.24 mmol) in NMP (5 mL) was stirred at 120 °C for 10 h. The reaction mixture was diluted with EtOAc, washed with H2O and brine, and dried over Na2SO4. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (1) (74.5 mg, 32% yield) as a white solid. MS (ES+) C 29 H 33 FN 10 O requires:556, found:557[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.03(s,1H),8.02(s,1H),7.87(s,1H),7.84(s,1H),7.49-7.45(m,2H),7.25(s,1H) ),7.13-7.08(m,2H),4.76(s,1H),4.12-4.07(m,4H),4.02(s,2H),3.93-3.90(m,4H),2.44(s,2H),1.73(s,3H),1.10(s,6H).

[0182] Example 2: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (2) [ka]

[0183] Step 1: Synthesis of methyl 2-methyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (xii) To a solution of methyl 2-bromo-2-methylpropanoate (x) (3.0 g, 16.7 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (3.23 g, 16.7 mmol) in NMP (20 mL) was added cesium carbonate (16.2 g, 50 mmol) and sodium iodide (3.1 g, 16.7 mmol) at room temperature. The resulting mixture was stirred at 120° C. for 8 h. The reaction mixture was diluted with DCM and washed successively with H2O and brine. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (petroleum ether:ethyl acetate=5 / 1) to give the title compound (xii) (1.5 g, 30% yield) as a colorless oil.

[0184] Step 2: Methyl (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (xiii): In DMF / HO (8 mL / 2 mL) was added 2-methyl-2-(4-(4,4 A mixture of 1,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propanoate (xii) (178 mg, 0.6 mmol), I-1 (300 mg, 0.6 mmol), Pd(dppf)Cl2 (99 mg, 0.12 mmol) and K2CO3 (251 mg, 1.8 mmol) was stirred at 70 °C under N2(g) for 4 h. The solution was then diluted with DCM, washed with H2O and brine and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the title compound (xiii) (240 mg, 68% yield) as a white solid. MS (ES+) C 30 H 33 FN 10 O2requires:584,found:585[M+H]+

[0185] Step 3: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)-2-methylpropan-1-ol (2): Into (S)-methyl 2-(4-(4-(4-(5-(1-amino-1 To a solution of -(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)-2-methylpropanoate (xiii) (200 mg, 0.34 mmol) was added LiAlH4 (100 mg, 3.4 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 6 h. The reaction mixture was quenched with H2O (100 mL) and 10% NaOH H2O (300 mL), then extracted with EA. The organic layer was concentrated in vacuo and the residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (2) (90.5 mg, 47% yield) as a white solid. MS (ES+) C 29 H 33 FN 10 O requires:556, found:557[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.18(s,1H),8.01(d,1H,J=1.6Hz),7.87(s,1H),7.84(s,1H),7.52-7.43(m,2H),7.26(d,1H,J=1.6Hz ),7.16-7.07(m,2H),4.99(t,1H,J=5.6Hz),4.17-4.04(m,4H),3.98-3. 87(m,4H),3.60(d,2H,J=5.6Hz),2.47(s,2H),1.74(s,3H),1.50(s,6H).

[0186] Example 3: (R) 1-{4-[4-(4-{5-[(S)-1-amino-1-(4-fluoro-phenyl)-ethyl]-pyrimidin-2-yl}-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-pyrazol-1-yl}-propan-2-ol (3) [ka]

[0187] To a solution of I-2 (prepared according to Preparation 2) (200 mg, 412 μmol) and (2R)-2-methyloxirane (XIV) (71.4 mg, 1.23 mmol) in NMP (3.0 mL) was added Cs2CO3 (400 mg, 1.23 mmol) at room temperature. The mixture was stirred at 120 °C for 2 h. The solution was then diluted with EA, washed with H2O and brine, and concentrated. The residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (3) (90.0 mg, 40% yield) as a white solid. MS (ES+) C 28 H 31 FN 10 O requires:542, found:543[M+H] +1 H-NMR(400MHz,DMSO-d6)δppm8.40(s,2H),8.05(s,1H),7.80(d,1H,J=1.6Hz),7.87(s,1H),7.83(s,1H),7.46(dd,2H,J=8.8,5.6Hz),7.24(s,1H),7. 10(t,2H,J=8.8Hz),4.96(d,1H,J=4.8Hz),4.11-4.08(m,4H),4.02-3.95( m,3H),3.92-3.89(m,4H),2.45(s,2H),1.73(s,3H),1.05(d,3H,J=5.6Hz).

[0188] Example 4: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol (4) [ka]

[0189] A mixture of I-1 (prepared according to Preparation 1) (500 mg, 1.00 mmol), commercially available 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)ethanol (xv) (285 mg, 1.20 mmol) (ex. AstraTech), Pd(dppf)Cl2 (219 mg, 300 μmol) and Na2CO3 (317 mg, 3.00 mmol) in dioxane / HO (20 mL / 2 mL) was stirred overnight at 100 °C under N2(g). The layers were separated and the organic layer was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=15 / 1). The resulting material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 μm 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (4) (154.0 mg, 29% yield) as a white solid. MS (ES+) C 27 H 29 FN 10 O requires:528, found:529[M+H] +1H-NMR(400MHz,6d-DMSO)δppm8.40(s,1H),8.07(s,1H),7.99(s,1H),7.87(s,1H),7.84(s,1H),7.49-7.44(m,2H),7.24(s,1H),7.14-7.06 (m,2H),4.93(t,1H,J=5.2Hz),4.17-4.13(m,2H),4.12-4.07(m,4H),3.94-3.88(m,4H),3.89-3.71(m,2H),2.45(br.S.,2H),1.73(s,3H).

[0190] Example 4A: (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol hydrochloride

[0191] To a solution of (S)-2-(4-(4-(4-(5-(1-amino-1-(4-fluorophenyl)ethyl)pyrimidin-2-yl)piperazin-1-yl)pyrrolo[2,1-f][1,2,4]triazin-6-yl)-1H-pyrazol-1-yl)ethanol (30 mg, 0.057 mmol) in MeOH (5 mL) was added HCl / dioxane (0.05 mL, 4.0 M) at room temperature. The solution was stirred at room temperature for 16 h. The solvent was removed under reduced pressure and the product was lyophilized to give the title compound (36.0 mg, 100% yield) as a moisture sensitive white solid. MS(ES+)C29H31FN10O requires:528,found:529[M+H]+1H-NMR(400MHz,6d-DMSO)δppm9.47(s,3H,br),8.45(s,2H),8.14(s,1H),8.11(s,1H),7.97(s,1H), 7.87(s,1H),7.53-7.50(m,2H),7.44(s,1H),7.31-7.28(m,2H),4.16-4.14(m,6H),4.00-3.89(m,4H),3.76-3.74(m,2H),2.03(s,3H).

[0192] Example 5: (R)-2-(4-(4-(4-(5-((S)-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)propan-1-ol (5) [ka]

[0193] Step 1: Synthesis of (S)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xvii): To a solution of (S)-1-(benzyloxy)propan-2-ol (xvi) (5.0 g, 30.12 mmol) and TEA (9.17 g, 90.36 mmol) in DCM (80 mL) was added TsCl (6.30 g, 33.13 mmol). The mixture was stirred at room temperature for 24 h. The solution was diluted with DCM, washed with H2O, and washed with brine. The organic layer was concentrated and the residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (xvii) (4.0 g, 42% yield) as a colorless oil. MS (ES+) C 17 H 20 O4S requires:320,found:338[M+18] +

[0194] Step 2: Synthesis of (R)-1-(1-(benzyloxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xviii): A mixture of (S)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xvii) (2.0 g, 6.25 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (1.22 g, 6.25 mmol) and Cs2CO3 (4.08 mg, 12.5 mmol) in NMP (12 mL) was irradiated in a microwave at 110° C. for 0.5 h. The solution was then diluted with EA, washed with HO and washed with brine. The organic layer was concentrated, and the residue was purified by flash column chromatography on silica gel (PE / EA=4 / 1) to give the title compound (xviii) (1.6 g, 75% yield) as a colorless oil. MS(ES+)C 19 H 27 BN2O3requires:342,found:343[M+H] +

[0195] Step 3: (R)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xix): 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) (800 mg, 2.34 mmol) in MeOH (20 mL) was added Pd / C (800 mg) and HOAc (0.2 mL), the solution was purged with H2(g) for 5 min and then stirred at room temperature under H2(g) for 16 h. The mixture was then filtered and the filtrate was concentrated to give the title compound (xix) (300 mg, 51% yield) as a colorless oil. MS(ES+)C 12 H 21 BN2O3requires:252,found:253[M+H] +

[0196] Step 4: Synthesis of (R)-2-(4-(4-(4-(5-((S)-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)propan-1-ol (5): In DMF / HO (4 mL / 1 mL), ((R)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xix) (1 A mixture of I-1 (50 mg, 595 μmol), I-2 (295 mg, 595 μmol), Pd(dppf)Cl2 (49 mg, 60 μmol) and K2CO3 (250 mg, 1.79 mmol) was purged with N2(g) for 10 min and stirred at 70 °C under N2(g) for 16 h. The mixture was extracted with EtOAc and the combined organic extracts were concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1). The obtained material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2×250 mm) followed by lyophilization afforded the title compound (5) (148.1 mg, 46% yield) as a white solid. MS(ES+)C 28 H 31 FN 10 O requires:542, found:543[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.11(s,1H),8.00(s,1H),7.8 7(s,1H),7.83(s,1H),7.48-7.44(m,2H),7.25(s,1H),7.14-7.08(m,2H), 4.98(t,1H,J=5.2Hz),4.36-4.32(m,1H),4.10-4.08(m,4H),3.92-3.90(m ,4H),3.69-3.61(m,2H),2.45(s,2H),1.73(s,3H),1.41(d,3H,J=6.8Hz).

[0197] Example 6: (S)-2-(4-(4-(4-(5-((S)-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)propan-1-ol (6) [ka]

[0198] Step 1: Synthesis of (R)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xxiii): To a solution of (R)-1-(benzyloxy)propan-2-ol (xxii) (3.0 g, 18 mmol) and TEA (5.48 g, 54.2 mmol) in DCM (30 mL) was added TsCl (4.13 g, 21.7 mmol). The resulting mixture was stirred at 25° C. for 16 h. The mixture was then concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=10 / 1) to give the title compound (xxiii) (2.30 g, 39% yield) as a yellow oil. MS(ES+)C 17 H 20 O4S requires:320,found:338[M+18] +

[0199] Step 2: Synthesis of (S)-1-(1-(benzyloxy)propan-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxiv): A mixture of (R)-1-(benzyloxy)propan-2-yl 4-methylbenzenesulfonate (xxiii) (2.20 g, 6.87 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (2.00 g, 10.3 mmol) and Cs2CO3 (2.24 g, 6.87 mmol) in NMP (50 mL) was stirred at 110° C. in a microwave 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 (petroleum ether / ethyl acetate=5 / 1 to 4 / 1) to give the title compound (xxiv) (1.80 g, 39% yield) as a yellow oil. MS(ES+)C 19 H 27 BN2O3requires:342,found:343[M+H] +

[0200] Step 3: Synthesis of (S)-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xxv): 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) (0.90 g, 2.6 mmol) in MeOH (20 mL) was added Pd / C (800 mg) and HOAc (0.2 mL). The resulting mixture was purged with H2(g) for 5 min and then stirred at room temperature under H2(g) for 16 h. The mixture was then filtered and concentrated to give the title compound (xxv) as a yellow oil (500 mg, 75% yield). MS(ES+)C 12 H 21 BN2O3requires:252,found:253[M+H] +

[0201] Step 4: Synthesis of (S)-2-(4-(4-(4-(5-((S)-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)propan-1-ol (6): In DMF / HO (5 mL / 1 ml), add (S)-2-(4-(4,4,5, A mixture of 5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-1-ol (xxv) (98 mg, 392 μmol), I-1 (130 mg, 261 μmol), K2CO3 (200 mg, 227 μmol) and Pd(dppf)Cl2 (20 mg, 27 μmol) was stirred at 70 °C under N2(g) for 4 h. The solution was then diluted with EA, washed with H2O and brine and concentrated. The residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (6) (40.7 mg, 28% yield) as a white solid. MS(ES+)C 28 H 31 FN 10 O requires:542, found:543[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.10(s,1H),7.99(s,1H),7.87(s ,1H),7.83(s,1H),7.47(dd,2H,J=8.8,5.6Hz),7.24(s,1H),7.11(t,2H,J=8. 8Hz),4.96(t,1H,J=5.6Hz),4.38-4.35(m,1H),4.11-4.08(m,4H),3.92-3.9 0(m,4H),3.70-3.60(m,2H),2.43(s,1H),1.73(s,3H),1.41(d,3H,J=6.8Hz).

[0202] Example 7: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(oxetan-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (7) [ka]

[0203] A mixture of 1-(oxetan-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxvi) (600 mg, 2.4 mol), I-1 (1.19 g, 2.4 mmol), Pd(dppf)Cl2 (391 mg, 0.48 mmol) and K2CO3 (994 mg, 7.2 mmol) in DMF / HO (16 mL / 4 mL) was purged with N2 for 10 min and stirred at 70 °C under N2(g) for 3 h. The solution was then diluted with EA, washed with HO and brine and concentrated. The mixture was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1). The resulting material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 μm 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (7) (236.3 mg, 18% yield) as a white solid. MS(ES+)C 28 H 29 FN 10 O requires:540, found:541 [M+H] +1H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.32(s,1H),8.03(d,1H,J=1.6Hz),7.99(s,1H),7.88(s,1H),7.52-7.44(m,2H),7.29(d,1H,J=1.6Hz) ,7.16-7.07(m,2H),5.64-5.52(m,1H),4.99-4.94(m,2H),4.93-4.89(m, 2H),4.12-4.06(m,4H),3.97-3.87(m,4H),2.50(br.s.,2H),1.74(s,3H).

[0204] Example 8: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (8) [ka]

[0205] Step 1: Synthesis of oxetan-3-ylmethyl methanesulfonate (xxviii): To a solution of oxetan-3-ylmethanol (xxvii) (300 mg, 3.40 mmol) and TEA (1.03 g, 10.2 mmol) in DCM (10 mL) was added MsCl (429 mg, 3.75 mmol) at 0 °C. The reaction was stirred at room temperature for 3 h, then diluted with DCM, washed with saturated Na2CO3 solution, and dried over anhydrous Na2SO4. The solvent was evaporated in vacuum to give the title compound (xxviii) (280 mg, 49% yield) as a yellow oil.

[0206] Step 2: Synthesis of 1-(oxetan-3-ylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxix): A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (280 mg, 1.44 mmol), oxetan-3-ylmethyl methanesulfonate (xxviii) (275 mg, 1.66 mmol) and Cs2CO3 (1.41 g, 4.33 mmol) in DMF (20 mL) was stirred at 70° C. for 4 h, then diluted with DCM and washed with brine. The organic layer was evaporated in vacuum. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=10 / 1) to give the title compound (xxix) (320 mg, 71% yield). MS(ES+)C 13 H 21 BN2O3requires:264,found:265[M+H] +

[0207] Step 3: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (8): In DMF / HO (10 mL / 2 ml), add I-1 (300 mg, 392 μm A mixture of (xxix) (239 mg, 904 μmol), K2CO3 (250 mg, 1.81 mmol) and Pd(dppf)Cl2 (30 mg, 41 μmol)) was stirred at 70 °C under N2(g) for 4 h. The solution was then diluted with EA, washed with H2O and brine and concentrated. The residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (8) (40.2 mg, 12% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.09(s,1H),7.98(s,1H),7.87(s,1H),7.84(s,1H),7.47(dd,2H,J=8.8,5.6Hz),7.22(s,1H),7.1 1(t,2H,J=8.8Hz),4.69-4.65(m,2H),4.45-4.41(m,4H),4.10-4.08(m ,4H),3.92-3.89(m,4H),3.46-3.41(m,1H),2.45(s,2H),1.73(s,3H).

[0208] Example 9: (S)-1-(4-(4-(4-(5-((S)-1-amino-1-(4-fluorophenyl)ethyl-pyrimidin-2-yl}-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-pyrazol-1-yl}-propan-2-ol (9) [ka]

[0209] A mixture of I-2 (220 mg, 455 μmol), (S)-2-methyloxirane (xxx) (79 mg, 1.37 mmol) and Cs2CO3 (445 mg, 1.37 mmol) was mixed in NMP (2 mL). The mixture was irradiated in a microwave at 120 °C for 1 h. The solution was then diluted with EA, washed with H2O and brine, and concentrated. The residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (9) (108 mg, 44% yield) as a white solid. MS (ES+) C 28 H 31 FN 10 O requires:542, found:543[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.05(s,1H),8.00(s,1H),7.87(s,1H),7.83(s,1H),7.48-7.44(m,2H),7.25(s,1H),7.14-7.0 8(m,2H),4.96(d,1H,J=4.4Hz),4.10-4.08(m,4H),4.02-3.98(m,3H),3.92-3.90(m,4H),2.44(s,2H),1.73(s,3H),1.06(d,3H,J=5.6Hz).

[0210] Example 10: cis-3-(4-(4-(4-(5-((S)-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)cyclobutanol (10) [ka]

[0211] Step 1: Synthesis of trans-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (xxxii): To a solution of trans-3-(benzyloxy)cyclobutanol (xxxi) (300 mg, 1.7 mmol) in DCM (20 mL) was added TsCl (389 mg, 2.0 mmol) and TEA (343 mg, 3.4 mmol). The mixture was stirred at room temperature for 16 h. The solution was diluted with DCM, washed with H2O and brine, and then concentrated. The residue was purified by flash column chromatography on silica gel (PE / EA=5 / 1) to give the title compound (xxxii) (315 mg, 56% yield) as a colorless oil. MS(ES+)C 18 H 20 O4S requires:332,found:350[M+18] +

[0212] Step 2: Synthesis of cis-3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxxiii): A mixture of trans-3-(benzyloxy)cyclobutyl 4-methylbenzenesulfonate (xxxii) (315 mg, 0.95 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xi) (185 mg, 0.95 mmol), and Cs2CO3 (619 mg, 1.9 mmol) in NMP (5 mL) was irradiated in a microwave at 110° C. for 0.5 h. The solution was then diluted with EA and washed with H2O and brine. The organic layer was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel (PE / EA=4 / 1) to give the title compound (xxxiii) (190 mg, 56% yield) as a colorless oil. MS(ES+)C 20 H 27 BN2O3requires:354,found:355[M+H] +

[0213] Step 3: Synthesis of cis-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutanol (xxxiv): To a solution of cis-3-(benzyloxy)cyclobutyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (xxxiii) (190 mg, 0.54 mmol) in MeOH (5 mL) was added Pd / C (200 mg) and HOAc (5 drops), the solution was purged with H2(g) for 5 min and stirred at room temperature under H2(g) for 16 h. The mixture was filtered and the filtrate was evaporated to dryness in vacuo to give the title compound (xxxiv) as a colorless oil (85 mg, 60% yield). MS(ES+)C 13 H 21 BN2O3requires:264,found:265[M+H] +

[0214] Step 4: Synthesis of (cis-3-(4-(4-(4-(5-((S)-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)cyclobutanol (10): In DMF / HO (4 mL / 1 mL), add cis-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)cyclobutanol (xxxiv) (5 A mixture of I-1 (104 mg, 0.21 mmol), I-2 (104 mg, 0.21 mmol), Pd(dppf)Cl2 (18 mg, 0.021 μmol) and K2CO3 (87 mg, 0.63) was purged with N2 for 10 min and stirred at 70 °C under N2(g) for 16 h. The solution was then diluted with EA, washed with H2O and brine and concentrated. The residue was directly purified by flash column chromatography (DCM / MeOH = 8 / 1). The obtained material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B=acetonitrile; gradient: B=15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2×250 mm) followed by lyophilization afforded the title compound (10) (14.6 mg, 13% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.17(s,1H),8.00(s,1H),7.87-7.86(m,2H),7.49-7.45(m,2H),7.26(s,1H),7.19-7.13(m,2H),5.33 (d,1H,J=6.4Hz),4.38-4.31(m,1H),4.13-4.06(m,4H),3.99-3.96(m,1H ),3.94-3.88(m,4H),2.79-2.71(m,2H),2.34-2.31(m,2H),1.73(s,3H).

[0215] Example 11: trans-3-{4-[4-(4-{5-[1-amino-1-(4-fluoro-phenyl)-ethyl]-pyrimidin-2-yl}-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-pyrazol-1-yl}-cyclobutanol (11) [ka]

[0216] Step 1: Synthesis of cis-toluene-4-sulfonic acid 3-benzyloxy-cyclobutyl ester (xxxvi): 4-Methyl-benzenesulfonyl chloride (640 mg, 3.37 mmol) was added to a solution of cis-3-benzyloxy-cyclobutanol (xxxv) (500 mg, 2.81 mmol) and TEA (851 mg, 8.43 mmol) in DCM (10 mL), and the resulting mixture was stirred at room temperature for 16 h. The mixture was diluted with brine and extracted with DCM. The organic extract was concentrated. The residue was directly purified by flash column chromatography on silica gel (PE / EA=11 / 1) to give the title compound (xxxvi) (490 mg, 53% yield) as a yellow solid. MS(ES+)C 18 H 20 O4S requires:332,found:350[M+18] +

[0217] Step 2: Synthesis of trans-1-(3-benzyloxy-cyclobutyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xxxvii): A mixture of cis-toluene-4-sulfonic acid 3-benzyloxy-cyclobutyl ester (xxxvi) (500 mg, 1.51 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xi) (430 mg, 2.22 mmol) and Cs2CO3 (1.47 g, 4.51 mmol) was added to NMP (15 mL) for 120 min. °C for 2 h in a microwave. 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 (PE / EA=1 / 1) to give the title compound (xxxvii) (227 mg, 42% yield) as a yellow solid. MS(ES+)C 20 H 27 BN2O3requires:354,found:355[M+H] +

[0218] Step 3: Synthesis of trans-3-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-cyclobutanol (xxxviii): To a solution of trans-1-(3-benzyloxy-cyclobutyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xxxvii) (420 mg, 1.18 mmol) in MeOH (10 mL) was added Pd / C (200 mg) and concentrated HCl (0.5 mL). The reaction mixture was stirred at room temperature under H2(g) for 16 h. The mixture was filtered and the filtrate was concentrated to give the title compound (xxxviii) (250 mg, 80% yield) as a solid. MS(ES+)C 13 H 21 BN2O3requires:264,found:265[M+H] +

[0219] Step 4: Synthesis of trans-3-{4-[4-(4-{5-[1-amino-1-(4-fluoro-phenyl)-ethyl]-pyrimidin-2-yl}-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-pyrazol-1-yl}-cyclobutanol (11): In dioxane / HO (4 mL / 1 mL), add trans-3-[4-(4,4,5,5-tetramethyl-[1 A mixture of [,3,2]dioxaborolan-2-yl)-pyrazol-1-yl]-cyclobutanol (xxxviii) (200 mg, 0.76 mmol), I-1 (376 mg, 0.76 mmol), Pd(dppf)Cl2 (61.8 mg, 0.076 mmol) and K2CO3 (313 mg, 2.27 mmol) was purged with N2(g) for 10 min and stirred at 70 °C under N2(g) for 4 h. The solution was then diluted with EA, washed with H2O and brine and concentrated. The residue was purified by flash chromatography on silica gel. The resulting material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 μm 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (11) (27.2 mg, 6% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.18(s,1H),7.99(d,1H,J=1.2Hz) ,7.87-7.85(m,2H),7.49-7.45(m,2H),7.24(s,1H),7.15-7.08(m,2H),5.24(d ,1H,J=5.2Hz),4.92-4.89(m,1H,),4.50-4.43(m,1H),4.17-4.10(m,4H),3.96 -3.90(m,4H),2.67-2.61(m,2H),2.44(s,2H),2.42-2.37(m,2H),1.73(s,3H).

[0220] Example 12: (S)-1-((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)methyl)cyclopropan-1-ol (12) [ka]

[0221] Step 1: Synthesis of ethyl 2-(4-bromo-1H-pyrazol-1-yl)acetate (xl): A mixture of 4-bromo-1H-pyrazole (xxxix) (8.0 g, 55 mmol) and K2CO3 (15.2 g, 110 mmol) in ethyl 2-chloroacetate (25 mL) was stirred at 80 °C for 15 h. The reaction mixture was cooled, diluted with EA and washed with H2O. The organic layer was evaporated and the residue was purified by chromatography on silica gel (petroleum ether / ethyl acetate = 5:1) to give the title compound (xl) (8.5 g, 66% yield) as a pale yellow oil. MS (ES+) C7H9BrN2O2requires: 232, found: 233 [M+H] +

[0222] Step 2: Synthesis of ethyl 1-((4-bromo-1H-pyrazol-1-yl)methyl)cyclopropan-1-ol (xli): To a solution of ethyl 2-(4-bromo-1H-pyrazol-1-yl)acetate (xl) (7.0 g, 30 mmol) and titanium tetraisopropanolate (4.26 g, 15 mmol) in anhydrous THF (60 mL) was added dropwise a solution of ethylmagnesium bromide (3 M in hexane, 30 mL, 90 mmol) at 60 °C over 2 h. After stirring at the same temperature for 2 h, the reaction mixture was diluted with EA and washed successively with 1N aqueous HCl and H2O. The organic layer was evaporated and the residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20:1 to 3:1) to give the title compound (xli) (1.3 g, 20% yield) as a yellow solid. MS(ES+)C7H9BrN2O requires:216,found:217[M+H] +

[0223] Step 3: Synthesis of 4-bromo-1-[1-(tetrahydro-pyran-2-yloxy)-cyclopropylmethyl]-1H-pyrazole (xlii): To a solution of 1-[(4-bromo-1H-pyrazol-1-yl)methyl]cyclopropan-1-ol (xli) (300 mg, 1.38 mmol) and 3,4-dihydro-2H-pyran (348 mg, 4.14 mmol) in DCM (8 mL) was added pyridinium paratoluenesulfonate (346 mg, 1.38 mmol) at room temperature. The mixture was stirred for 4 h, then diluted with brine and washed with DCM. The organic layer was concentrated and the residue was purified by silica gel chromatography (PE / EA=10:1) to give the title compound (xlii) (200 mg, 48% yield) as a white solid. MS(ES+)C 12 H 17 BrN2O2requires:300,found:217[M-THP+H] +

[0224] Step 4: Synthesis 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): 1,4-dioxane (3 ml), HO (1 mL) and DMSO (1 mL). A mixture of F (0.5 mL) with 4-bromo-1-{[1-(oxan-2-yloxy)cyclopropyl]methyl}-1H-pyrazole (xlii) (160 mg, 0.531 mmol), I-3 (577 mg, 1.06 mmol), Pd(DPPF)Cl2 (77.5 mg, 106 μmol) and Na2CO3 (168 mg, 1.59 mmol) was stirred at 80 °C under N2(g) for 3 h. The solution was then diluted with EA, washed with H2O and brine, and concentrated. The residue was purified by silica gel chromatography (ethyl acetate / methanol = 4:1) to give the title compound (270 mg, 50% yield) as a brown solid. MS (ES+) C 34 H 39FN 10 O2requires:621,found:622[M+H] +

[0225] Step 5: Synthesis of 1-{4-[4-(4-{5-[1-amino-1-(4-fluoro-phenyl)-ethyl]-pyrimidin-2-yl}-piperazin-1-yl)-pyrrolo[2,1-f][1,2,4]triazin-6-yl]-pyrazol-1-ylmethyl}-cyclopropanol (12): Synthesis of 1-(4-fluoro-phenyl)-1-{2-[4-(6-{1-[1-(tetrahydro- To a solution of]-1H-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) (200 mg, 0.32 mmol) was added p-toluenesulfonic acid (180 mg, 1.04 mmol) at room temperature, and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (mobile phase: A = HO (10 mM NH4HCO3 & 0.025% NH3 HO), B = acetonitrile; gradient: 51-56% B in 7 min, stop at 15 min; column: Agera du Lashell C18 (L) 21.2*250 mm, 10 μm, 150 Å) followed by lyophilization to give the title compound (12) (56 mg, 31% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,DMSO-d6)δppm8.40(s,2H),8.10(s,1H),8.02(s,1H),7.87(s,1H),7.82(s,1H),7.48-7.44(m,2H),7.25(s ,1H),7.13-7.08(m,2H),5.57(s,1H),4.17(s,2H),4.13-4.05(m,4H),3.95-3.85(m,4H),1.73(s,3H),0.69-0.66(m,4H).

[0226] Example 13: (S)-(1-(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)cyclopropyl)methanol (13) [ka]

[0227] Step 1: Synthesis of methyl 1-(4-bromo-1H-pyrazol-1-yl)cyclopropanecarboxylate (xiv): To a solution of 4-bromo-1H-pyrazole (xxxix) (2.0 g, 13.70 mmol) in THF (50 mL) was added NaH (1.20 g, 30.14 mmol) at 0° C. The solution was stirred at room temperature for 1 h, then methyl 2,4-dibromobutanoate (xliv) (3.53 g, 13.70 mmol) was added to the solution. The mixture was stirred for 16 h, then diluted with EA. The organic layer was washed with H2O, washed with brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=2 / 1) to give the title compound (xiv) (570 mg, 17% yield) as a white solid. MS(ES+)C8H9BrN2O2requires:244,found:245[M+H] +

[0228] Step 2: Synthesis of (1-(4-bromo-1H-pyrazol-1-yl)cyclopropyl)methanol (xlvii): To a solution of methyl 1-(4-bromo-1H-pyrazol-1-yl)cyclopropanecarboxylate (xiv) (550 mg, 2.25 mmol) in MeOH (15 mL) was added NaBH4 (257 mg, 6.75 mmol) and the resulting mixture was stirred at 50 °C for 36 h. The reaction mixture was diluted with DCM, washed successively with H2O and brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EA=1 / 1) to give the title compound (xlvii) (300 mg, 62% yield) as a white solid. MS (ES+) C7H9BrN2O requires: 216, found: 217 [M+H] +

[0229] Step 3: Synthesis of (S)-(1-(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)cyclopropyl)methanol (13): In THF / HO (8 mL / 2 mL) was added (1-(4-bromo-1H-pyrazo A mixture of (1-yl)cyclopropyl)methanol (xlvii) (100 mg, 463 μmol), (I-3 prepared as described in Preparation 3) (380 mg, 695 μmol), Pd(t-Bu3P)2 (47 mg, 93 μmol) and Cs2CO3 (452 ​​mg, 1.39 mmol) was purged with N2(g) for 10 min and stirred at 80 °C under N2(g) for 12 h. The solution was then diluted with EA, washed with H2O and brine and concentrated. The residue was purified by flash column chromatography (DCM / MeOH = 10 / 1). The resulting material was further purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 μm 150A 21.2 × 250 mm) followed by lyophilization to give the title compound (13) (57.3 mg, 22% yield) as a white solid. MS (ES+) C 29 H 31FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.15(s,1H),8.00(d,1H,J=1.6Hz) ,7.87(s,1H),7.83(s,1H),7.48-7.44(m,2H),7.27(d,1H,J=1.6Hz),7.14-7.0 8(m,2H),5.00(t,1H,J=5.6Hz),4.10-4.08(m,4H),3.92-3.90(m,4H),3.66(d, 2H,J=5.6Hz),2.43(s,2H),1.73(s,3H),1.13-1.11(m,2H),1.05-1.02(m,2H).

[0230] Example 14: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (14) [ka]

[0231] Step 1: Synthesis of (S)-tetrahydrofuran-3-yl methanesulfonic acid (xlix): To a solution of tetrahydrofuran-3-ol (xlviii) (2.0 g, 22.7 mmol) and TEA (4.6 g, 45.4 mmol) in DCM (20 mL) was added MsCl (4.7 g, 25.0 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was then diluted with DCM, washed successively with H2O and brine, dried over anhydrous Na2SO4, and concentrated to dryness to give the title compound (xlix) (2.0 g, crude) as a yellow oil.

[0232] Step 2: Synthesis of (R)-1-(tetrahydrofuran-3-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (l): To a solution of (S)-tetrahydrofuran-3-ylmethanesulfonic acid (xlviii) (1.9 g, 11.4 mmol) in NMP (50 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (xi) (3.3 g, 17.2 mmol) and Cs2CO3 (11.2 g, 34.3 mmol) at room temperature. The mixture was stirred at 120° C. for 2 h. The solution was diluted with EA, washed successively with H2O and brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EA=4 / 1) to give the title compound (1) (2.3 g, 76% yield) as a colorless oil. MS(ES+)C 13 H 21 BN2O3requires:264,found:265[M+H] +

[0233] Step 3: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-((R)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (14): In DMF (2 mL) and HO (0.5 mL), (R)-1-(tetrahydro A mixture of (4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (I) (80 mg, 0.3 mmol), I-1 (150 mg, 0.3 mmol), Pd(dppf)Cl2 (50 mg, 0.06 mmol) and K2CO3 (125 mg, 0.9 mmol) was stirred at 80 °C for 16 h under N2(g). 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 = 16 / 1). The resulting material was then purified by preparative HPLC (Mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; Gradient: B = 15% to 95% in 18 min; Column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (14) (65 mg, 38% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.16(s,1H),8.01(s,1H),7.87(s,2H),7.49-7.45(m,2H),7.26(s,1H),7.14- 7.08(m,2H),5.05-4.99(m,1H),4.10-4.04(m,4H),4.02-3.98(m,2H),3.94-3.82(m,6H),2.44-2.28(m,4H),1.73(s,3H).

[0234] Example 15: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (15) [ka]

[0235] Step 1: Synthesis of (R)-tetrahydrofuran-3-yl methanesulfonic acid (lii): To a solution of (R)-tetrahydrofuran-3-ol (li) (1.0 g, 11.4 mmol) and TEA (2.3 g, 23 mmol) in DCM (20 mL) was added MsCl (1.43 g, 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 H2O and brine, and concentrated to give the title compound (lii) (1.4 g, crude) as a colorless oil.

[0236] Step 2: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-((S)-tetrahydrofuran-3-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (15): A mixture of I-2 (300 mg, 0.62 mmol), (R)-tetrahydrofuran-3-yl methanesulfonate (LII) (155 mg, 0.93 mmol) and CsCO (600 mg, 1.89 mmol) in NMP (10 mL) was stirred at 120 °C for 16 h. The solution was then diluted with EA, washed with HO and brine and concentrated. The residue was directly purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (15) (133.5 mg, 39% yield) as a white solid. MS(ES+)C 29 H 31 FN10 O requires:554, found:555[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.17(s,1H),8.02(d,1H,J=0.8Hz) ,7.88(s,2H),7.52-7.44(m,2H),7.26(s,1H),7.11(t,2H,J=17.6Hz),5.08-4. 99(m,1H),4.16-4.05(m,4H),4.04-3.97(m,2H),3.96-3.88(m,5H),3.87-3.80 (m,1H),2.48-2.43(m,2H),2.43-2.36(m,1H),2.32-2.25(m,1H),1.74(s,3H).

[0237] Example 16: (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (16) [ka]

[0238] Step 1: Synthesis of tetrahydro-2H-pyran-4-yl methanesulfonic acid (liv): To a solution of tetrahydro-2H-pyran-4-ol (liii) (3.20 g, 31.3 mmol) and TEA (9.51 g, 94.0 mmol) in DCM (100 mL) was added MsCl (5.38 g, 47.0 mmol) at 0° C. The reaction was stirred at room temperature for 3 h, then diluted with DCM, washed with saturated aqueous Na2CO3, and dried over anhydrous Na2SO4. The solvent was removed to give the title compound (liv) (3.2 g, crude) as a yellow oil.

[0239] Step 2: Synthesis of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (lv): A mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (liv) (3.20 g, 17.7 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4.13 g, 21.3 mmol) and Cs2CO3 (8.68 g, 26.6 mmol) in NMP (50 mL) was stirred at 80° C. for 4 h. The reaction mixture was diluted with DCM and washed with brine. The organic layer was evaporated in vacuum. The residue was purified by flash column chromatography on silica gel (PE / EA=5 / 1) to give the title compound (lv) (1.2 g, 24% yield). MS(ES+)C 14 H 23 BN2O3requires:278,found:279[M+H] +

[0240] Step 3: Synthesis of (S)-1-(4-fluorophenyl)-1-(2-(4-(6-(1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-4-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethan-1-amine (16): In DMF / HO (10 mL / 2 ml), I-1 (300 mg, 60 A mixture of 1-(tetrahydro-2H-pyran-4-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (lv) (210 mg, 754 μmol), K2CO3 (104 mg, 754 μmol) and Pd(dppf)Cl2 (30 mg, 41 μmol) was stirred at 70 °C under N2(g) for 4 h. The solution was then diluted with EA, washed with HO and brine and concentrated. The residue was purified by preparative HPLC (mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; gradient: B = 15% to 95% in 18 min; column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (16) (40.2 mg, 6% yield) as a white solid. MS(ES+)C 30 H 33 FN 10 O requires:568, found:569[M+H] +1 H NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.19(s,1H),7.99(s,1H),7.88(s,1H),7.86(s,1H),7.48-7.45(m,2H,),7.24(s,1H),7.13-7.09(m,2H) ),4.42-4.37(m,1H),4.12-4.40(m,4H),3.99-3.96(m,2H),3.92-3.90( m,4H),3.52-3.46(m,2H),2.43(s,2H),2.05-1.92(m,4H),1.73(s,3H).

[0241] Example 17: (3R,4R)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (17) [ka]

[0242] Step 1: Synthesis of rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lvii): A solution of 3,6-dioxabicyclo[3.1.0]hexane (lvi) (5.2 g, 60.5 mmol), 4-bromo-1H-pyrazole (xxxix) (8.8 g, 60.5 mmol) and Cs2CO3 (39.3 g, 121 mmol) in NMP (100 mL) was stirred at 120 °C for 16 h. The solution was cooled and diluted with DCM, then washed with H2O and brine. The organic layer was concentrated and purified by flash column chromatography on silica gel (PE / EA = 3 / 1) to give the title compound (lvii) (10 g, 71% yield) as a colorless solid. MS (ES+) C7H9BrN2O2requires: 232, found: 233 [M+18] +

[0243] Step 2: Synthesis of rac-cis-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-yl 4-nitrobenzoate (lviii): A mixture of rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lvii) (2.7 g, 11.6 mmol), 4-nitrobenzoic acid (1.95 g, 11.6 mmol), diisopropyl azodicarboxylate (3.53 mg, 17.4 mmol) and triphenylphosphine (4.57 g, 17.4 mmol) in THF (50 mL) was stirred at room temperature for 16 h. The solution was diluted with EA and washed with H2O and brine. The organic layer was concentrated and purified by flash column chromatography on silica gel (PE / EA=3 / 1) to give the title compound (lviii) (4 g, 90% yield) as a colorless solid. MS(ES+)C 14 H 12 BrN3O5requires:381,found:382[M+H] +

[0244] Step 3: Synthesis of (3S,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1x) (peak 1) and (3R,4R)-4-(4-bromo-1H)-pyrazol-1-yl)tetrahydrofuran-3-ol (lxi) (peak 2): A mixture of rac-cis-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-yl 4-nitrobenzoic acid (lvii) (4 g, 10.5 mmol) and lithium hydroxide (2.2 g, 52.5 mmol) in MeOH / THF / HO (30 mL / 30 mL / 30 mL) was stirred at room temperature for 4 h. The resulting mixture was diluted with EA, washed with HO and brine, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (PE / EA=3 / 1=3 / 1) to give rac-cis-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1.3 g, 53% yield) as a colorless solid. MS (ES+) C7H9BrN2O2requires: 232, found: 233 [M+H] +This material was subjected to chiral separation by SFC (column: AD20*250mm, 10μm (Daicel); mobile phase: CO2 / MeOH (0.2% ammonia in methanol)=60 / 40; flow rate: 80g / min) to obtain peak 1 (lx) (500mg) and peak 2 (lxi) (500mg). Peak 1 was arbitrarily assigned as (3S,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol, and peak 2 was arbitrarily assigned as (3R,4R)-4-(4-)bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol.

[0245] Step 4: Synthesis of (3R,4R)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (17): In dioxane / HO (8 mL / 2 mL), (3R A mixture of I-3 (328.3 mg, 0.6 mmol), Pd[(t-Bu)P] (31 mg, 0.06 mmol) and NaCO (96 mg, 0.9 mmol) was stirred at 90 °C for 4 h. After cooling, the solution was diluted with EA, washed with H0 and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the title compound (17) (106.3 mg, 62% yield) as a white solid. MS (ES+) C 29 H 31 FN 10 O2requires:570,found:571,554[M+H] +1H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.15(s,1H),8.03(s,1H),7.88 (s,1H),7.87(s,1H),7.52-7.42(m,2H),7.28(s,1H),7.17-7.10(m,2H),5. 33(d,1H,J=4.8Hz),4.92-4.83(m,1H),4.46-4.38(m,1H),4.21-4.05(m,6 H),4.01(m,1H),3.95-3.85(m,4H),3.73(m,1H),2.45(s,2H),1.73(s,3H).

[0246] Example 18: (3R,4S)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (18) [ka]

[0247] Step 1: Chiral separation of rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lvii): rac-trans-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (1.1 g) (from step 1 of Example 17) was subjected to chiral separation by SFC (column: AD20*250 mm, 10 μm (Daicel); mobile phase: CO2 / MeOH (0.2% ammonia in methanol) = 80 / 40; flow rate: 80 g / min) to give peak 1 (lxiii) (400 mg) and peak 2 (lxiv) (500 mg). Peak 1 was arbitrarily assigned as (3R,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol and peak 2 was arbitrarily assigned as (3S,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol.

[0248] Step 2: Synthesis of (3R,4S)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (18): In dioxane / HO (8 mL / 2 mL), (3R,4S)-4- A mixture of (4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (70 mg, 0.3 mmol) (lxiii) (peak 1 from step 1), a mixture of I-3 (328.3 mg, 0.6 mmol), Pd[(t-Bu)3P]2 (31 mg, 0.06 mmol) and Na2CO3 (96 mg, 0.9 mmol) was degassed with N2 and stirred at 90 °C for 4 h. The solution was then diluted with DCM, washed with H2O and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH = 10 / 1) to give the title compound (18) (55.6 mg, 33% yield) as a white solid. MS (ES+) C 29 H 31 FN 10 O2requires:570,found:571,554[M+H] + , [M+H-NH3] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.15(s,1H),8.03(s,1H),7.91 (s,1H),7.88(s,1H),7.51-7.43(m,2H),7.28(s,1H),7.16-7.07(m,2H),5 .66(d,1H,J=4Hz),4.75-4.67(m,1H),4.51-4.42(m,1H),4.20(m,1H),4.1 5-3.99(m,6H),3.96-3.85(m,4H),3.63(m,1H),2.47(s,2H),1.73(s,3H).

[0249] Example 19: (3S,4R)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (19) [ka]

[0250] A mixture of (3S,4R)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (70 mg, 0.3 mmol) (lxiv) (peak 2 from step 1 of Example 22), I-3 (328.3 mg, 0.6 mmol), Pd[(T-BU)3P]2 (31 mg, 0.06 mmol) and Na2CO3 (96 mg, 0.9 mmol) in dioxane / HO (8 mL / 2 mL) was degassed with N2 and stirred at 90 °C 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=10 / 1) to give the title compound (19) (51.9 mg, 31% yield) as a white solid. MS (ES+) C 29 H 31 FN 10 O2requires:570,found:571,554[M+H] + and [M+H-NH3] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.15(s,1H),8.03(s,1H),7.91(s,1 H),7.88(s,1H),7.52-7.43(m,2H),7.28(s,1H),7.19-7.06(m,2H),5.66(d,1H, J=4.4Hz),4.75-4.66(m,1H),4.51-4.41(m,1H),4.20(m,1H),4.16-3.99(m,6H) ,3.97-3.83(m,4H),3.63(dd,1H,J=9.6Hz,J=2.8Hz),2.54(s,2H),1.73(s,3H).

[0251] Example 20: (3S,4S)-4-(4-(4-(4-(5-((S)-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)tetrahydrofuran-3-ol (20) [ka]

[0252] A mixture of (3S,4S)-4-(4-bromo-1H-pyrazol-1-yl)tetrahydrofuran-3-ol (lxiii) (50 mg, 0.22 mmol) (peak 1 from step 3 of example 21), I-3 (234.5 mg, 0.44 mmol), Pd[(t-Bu)3P]2 (22 mg, 0.044 mmol) and Na2CO3 (68 mg, 0.66 mmol) in dioxane / HO (8 mL / 2 mL) was stirred at 90 °C for 4 h. After cooling, the solution was 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 the title compound (20) (74.6 mg, 61% yield) as a white solid. MS (ES+) C 29 H 31 FN 10 O2requires:570,found:571,554[M+H] +1 H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.15(s,1H),8.03(d,1H,J=1.6Hz), 7.88(s,1H),7.87(s,1H),7.51-7.44(m,2H),7.28(d,1H,J=1.2Hz),7.17-7.10( m,2H),5.33(d,1H,J=5.6Hz),4.93-4.83(m,1H),4.47-4.38(m,1H),4.20-4.06 (m,6H),4.01(m,1H),3.95-3.88(m,4H),2.45(s,2H),3.73(m,1H),1.76(s,3H).

[0253] Example 21: (1S,2S)-2-(4-(4-(4-(5-((S)-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)cyclobutanol (21) [ka]

[0254] Step 1: Synthesis of trans-2-(benzyloxy)cyclobutanol and cis-2-(benzyloxy)cyclobutanol: To a solution of 2-(benzyloxy)cyclobutanone (1.0 g, 5.7 mmol) in MeOH (20 mL), 、 At 0° C., NaBH4 (432 mg, 11.4 mmol) was added. The solution was then stirred at room temperature for 3 h. The mixture was diluted with EA and washed with water and brine, then the organic layer was concentrated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=5 / 1) to give 400 mg of peak 1 (arbitrarily assigned to cis-2-(benzyloxy)cyclobutanol) as a colorless oil and 400 mg of peak 2 (arbitrarily assigned to trans-2-(benzyloxy)cyclobutanol) as a colorless oil. MS(ES+)C 11 H 14 O2requires:178,found:179[M+H] +

[0255] Step 2: Synthesis of cis-2-(benzyloxy)cyclobutyl methanesulfonate: To a solution of cis-2-(benzyloxy)cyclobutanol (270 mg, 1.52 mmol) in DCM (10 mL) was added mesyl chloride (259 mg, 2.28 mmol) and triethylamine (459 mg, 4.56 mmol) at 0° C. The mixture was stirred at room temperature for 3 h. The solution was then diluted with DCM, washed with water and brine, dried over anhydrous Na2SO4, and concentrated to give the title compound (300 mg, 77% yield) as a colorless oil. MS(ES+)C 12 H 16O4S requires:256,found:274[M+18] +

[0256] Step 3: Synthesis of trans-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole: A mixture of cis-2-(benzyloxy)cyclobutyl methanesulfonate (300 mg, 1.17 mmol), 4-bromo-1H-pyrazole (171 mg, 1.17 mmol) and Cs2CO3 (1.15 g, 3.51 mmol) in DMF (8 mL) was stirred at 100 °C for 16 h. The solution was then diluted with EA, washed with water and brine, dried over anhydrous Na2SO4, concentrated and purified by flash column chromatography (PE / EA=5 / 1) to give the title compound (170 mg, 47% yield) as a colorless oil. MS (ES+) C 14 H 15 BrN2O requires:306,found:307[M+H] + Chiral separation of trans-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole: trans-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole (600 mg) was chiral separated by SFC (column: IG20*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 was arbitrarily assigned to 1-((1S,2S)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole, and peak 2 was arbitrarily assigned to 1-((1R,2R)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole.

[0257] Step 4: Synthesis of (1S,2S)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol: A solution of 1-((1S,2S)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole (250 mg, 820 μmol) in TFA (2 mL) was stirred at 80 °C for 16 h. The solution was then concentrated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give the title compound (120 mg, 68% yield) as a white solid. MS (ES+) C7H9BrN2O requires: 216, found: 217 [M+H] +

[0258] Step 5: Synthesis of (1S,2S)-2-(4-(4-(4-(5-((S)-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)cyclobutanol: A mixture of (1S,2S)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol (120 mg, 556 μmol), I-3 (362 mg, 667 μmol), Pd(t-BuP) (50 mg, 99 μmol) and CsCO (362 mg, 1.12 mmol) in dioxane / HO (8 mL / 2 mL) was purged with N for 10 min and stirred at 90 °C under N for 4 h. The solution was then diluted with DCM, washed with H2O and brine, and concentrated. The residue was purified by flash column chromatography on silica gel (DCM / MeOH=10 / 1). The resulting material was further purified by preparative HPLC (mobile phase: A=H2O (0.1% NH4HCO3), B=acetonitrile; gradient: B=32% to 62% in 18 min; column: Xtimate™ 10um 150A 21.2×250mm) followed by lyophilization to give the title compound (52.6 mg, 17% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.19(s,1H),8.00(d,1H,J=1.6Hz),7.88 (s,2H),7.48-7.44(m,2H),7.26(d,1H,J=1.6Hz),7.14-7.08(m,2H),5.67(d,1H,J= 7.2Hz),4.46-4.39(m,1H),4.34-4.26(m,1H),4.10-4.06(m,4H),3.92-3.90(m,4H) ,2.44(s,2H),2.16-2.10(m,2H),1.89-1.79(m,1H),1.73(s,3H),1.62-1.52(m,1H).

[0259] Example 22: (1R,2R)-2-(4-(4-(4-(5-((S)-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)cyclobutanol (22) [ka]

[0260] Step 1: Synthesis of (1R,2R)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol: A solution of 1-((1R,2R)-2-(benzyloxy)cyclobutyl)-4-bromo-1H-pyrazole (250 mg, 820 μmol) (from peak 2 of step 3 of Example 21) in TFA (2 mL) was stirred at 80° C. for 16 h. The solution was then concentrated and purified by flash column chromatography on silica gel (petroleum ether / ethyl acetate=3 / 1) to give the title compound (120 mg, 68% yield) as a white solid. MS (ES+) C7H9BrN2O requires: 216, found: 217 [M+H] +

[0261] Step 2: Synthesis of (1R,2R)-2-(4-(4-(4-(5-((S)-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)cyclobutanol: In dioxane / HO (8 mL / 2 mL), (1R,2R)-2-(4-bromo-1H-pyrazol-1-yl)cyclobutanol (120 mg, 556 μmol), (S)-1-(4- A mixture of (fluorophenyl)-1-(2-(4-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,1-f][1,2,4]triazin-4-yl)piperazin-1-yl)pyrimidin-5-yl)ethanamine (362 mg, 667 μmol), Pd(t-Bu3P)2 (50 mg, 99 μmol) and Cs2CO3 (362 mg, 1.12 mmol) was purged with N2(g) for 10 min and stirred at 90 °C under N2 for 4 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=10 / 1). The resulting material was further purified by preparative HPLC (Mobile phase: A = H2O (0.1% NH4HCO3), B = acetonitrile; Gradient: B = 30% to 60% in 18 min; Column: Xtimate™ 10 um 150A 21.2 x 250 mm) followed by lyophilization to give the title compound (51.5 mg, 17% yield) as a white solid. MS(ES+)C 29 H 31 FN 10 O requires:554, found:555[M+H] +1H-NMR(400MHz,6d-DMSO)δppm8.41(s,2H),8.19(s,1H),8.00(d,1H,J=1.6Hz),7.88 (s,2H),7.48-7.44(m,2H),7.26(d,1H,J=1.6Hz),7.14-7.08(m,2H),5.67(d,1H,J= 7.2Hz),4.46-4.39(m,1H),4.34-4.26(m,1H),4.10-4.06(m,4H),3.92-3.90(m,4H) ,2.44(s,2H),2.16-2.10(m,2H),1.89-1.79(m,1H),1.73(s,3H),1.62-1.52(m,1H).

[0262] Example 2: Biochemical enzyme activity assays The enzymatic activity of PDGFRα and KIT 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 that was phosphorylated.

[0263] During the linear steady-state phase of the kinase enzymatic reaction, a mixed pool of phosphorylated (product) and non-phosphorylated (substrate) peptides was passed through a microfluidic system in a PerkinElmer EZ Reader 2 under an applied potential difference. The presence of a phosphate group on the product peptide resulted in a mass and charge difference between it and that of the substrate peptide, 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).

[0264] As the mixture of product and substrate peptides passes through the laser in the instrument, these pools are detected (λ ex = 488 nm, λ em = 568 nm), resolved as separate peaks. The ratio between these peaks reflects the activity of the compound at that concentration in that well under those conditions.

[0265] Inhibition of biochemical enzyme activity of KIT(D816V)PDGFRα(D842V) mutants All test articles were dissolved in 100% DMSO at a stock concentration of 10 mM. 100-fold, 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 μL 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 0.130 μL of compound using a Multidrop as follows:

[0266] PDGFRαD842V assay with apparent Michaelis-Menten constant of ATP (APPKM): 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 MgCl2, 1 mM DTT) containing 1 μM CSKtide (5-FAM-AHA-KKKKDDIYFFFG-NH2) and 25 μM ATP in the presence or absence of a range of compound dose concentrations (1% DMSO final concentration) 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 were read on a Caliper EZReader2.

[0267] KIT D816V assay for ATP in APPKM: In each well of a 384-well assay plate, 0.3 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 MgCl2, 1 mM DTT) containing 1 μM SRCtide (5-FAM-GEEPLYWSFPAKKK-NH2) and 20 μM ATP in the presence or absence of a range of compound dose concentrations (1% DMSO final concentration) at 25 ο C for 60 min. 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 in Table 2 below. For biochemical D816V and D842V activity the following designations are used: ≦0.30 nM=A; ≧0.31 and <1 nM=B; ND=undetermined. For cellular activity in HMC1.2 cell line the following designations are used: A means less than 4.5 nM; B means ≧4.6 and <10 nM; ND=undetermined. [Table 2]

[0268] For reference, the chemical structure of the compound of Example 63 in WO 2015 / 057873 is as follows: [ka]

[0269] Example 3: HMC1.2 autophosphorylation assay 10,000 HMC1.2 cells were incubated overnight in 22 μL of culture medium (IMDM without phenol red, serum-free) in each well of a 384-well plate under serum-starved conditions in a tissue culture incubator (5% CO2, 37 °C). A 10-point dose concentration series of compounds (2.5 μM to 9.54 pM) was then added to the cells in a volume of 3.1 μL per well (DMSO final concentration 0.25%). After 90 min, 6 μL of 5X AlphaLISA lysis buffer (Perkin Elmer) supplemented with protease and phosphatase inhibitor cocktail (Cell Signaling Technologies) was added to each well and shaken at 450 rpm for 15 min at 4 °C. 10 μL of phospho-Y719c-KIT and total c-KIT antibodies (final concentration 15 nM, Cell Signaling Technologies) and 50 μg / mL AlphaLISA rabbit acceptor beads (Perkin Elmer) were added to each well and shaken at 300 rpm at room temperature for 2 h. 10 μL of 100 μg / mL streptavidin donor beads (Perkin Elmer) were added to each well and shaken at 300 rpm at room temperature for 2 h, protected from light with solid black adhesive. Fluorescent signals were acquired on an Envision (Perkin Elmer) using the AlphaScreen 384-well HTS protocol. Data were normalized to 0% and 100% inhibition controls and IC 50 is a four-parameter logistic IC 50 Calculated using curve fitting.

[0270] This table shows the activity of the compounds in the mast cell leukemia cell line HMC1.2. This cell line contains KIT mutated at positions V560G and D816V, which results in constitutive activation of the kinase. The following compounds were tested in the assay to measure direct inhibition of KIT D816V kinase activity by assaying KIT autophosphorylation at tyrosine 719 on the KIT protein. The results of these experiments for the compounds prepared according to the examples are summarized in Table 2.

[0271] Example 4: Evaluation of brain permeability in rat brain-to-plasma ratio (Kp, brain) To understand the brain permeability, the brain-to-plasma ratio of the compound was obtained in Sprague-Dawley (SD) rats. The in vivo equilibrium distribution between blood and brain in preclinical species such as rats is a commonly used parameter to evaluate brain permeability. p , and the brain is the ratio of brain to blood concentrations (C 脳 / C 血漿 The passive diffusion properties of a compound, its affinity for membrane transporters at the blood-brain barrier (BBB), and differences in the relative drug binding affinities between plasma proteins and brain tissue affect Kp, the brain. p Compounds with brain sizes smaller than 0.1 have limited access to the CNS, but the K p Compounds with a brain K greater than 0.3-0.5 are considered to have good brain permeability. p , compounds with a brain concentration greater than 1 freely cross the BBB (Expert Opin. Drug Delivery (2016) 13(01):85-92).

[0272] Brain permeability of 4 and 63 was measured in Sprague-Dawley rats (3 / compound). Animals received an intravenous infusion of 1 mg / kg / hr of compound via the jugular cannula for 24 hours. After 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 3A below shows the plasma and brain concentrations and K for compound 4 and compound 63 of WO2015 / 057873 prepared according to the examples described herein. p , Results for the brain are shown. [Table 3]

[0273] Compound 4 has a very low K compared to 63 (average = 1.8). p , indicating the brain (mean = 0.17).

[0274] Rat plasma protein binding of 4 and 63 was evaluated in vitro using equilibrium dialysis. Compound 4 (10 μM) was evaluated in 100% plasma in a dialysis block at 37 °C for 5 h. Donor and receiver samples were analyzed by LC-MS / MS. The bound and unbound fractions of plasma proteins were calculated using the following equation - Fraction bound (fb)*(%)=100x([donor] 5h -[receiver] 5h ) / [donor] 5h (Formula 1) Fraction unbound (fu), p*(%)=100-% bound*(Equation 2) In the formula, [donor] 5h is the donor concentration measured at 5 h, and [receiver] 5H is the concentration of receiver measured at 5 h, 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.

[0275] The fb of 4 and 63 were 97.92% and 99.8%, respectively. Therefore, the fu,p of 4 and 63 were 2.08% and 0.2%, respectively.

[0276] Similarly, rat brain protein binding of 4 and 63 was also evaluated in vitro using equilibrium dialysis. 1 μM of compound was evaluated in brain homogenates in dialysis blocks at 37° C. for 5 hours. Donor and receiver samples were analyzed by LC-MS / MS. Bound and unbound fractions of brain protein were calculated using the formulas above (Equations 1 and 2). Due to extensive protein binding, 4 was further diluted 4-fold for measurements in brain homogenates. The fu, brain of 4 and 63 was 0.29% and 0.1%, respectively.

[0277] Unbound brain to plasma ratio (Kpuu, brain) Based on the brain and plasma concentrations obtained above (Table 3A) and the fu, brain values ​​obtained above, the unbound brain to plasma ratio (Kpuu , brain) was calculated for 4 and 63 as follows: [Table 4]

[0278] Compound 4 has a significantly better low K value compared to 63 (average = 0.84). p,uu , brain (mean = 0.024). The unbound drug concentration in tissue is the free drug available to exert its pharmacological effect in the tissue compartment. 4 has a very low K compared to 63. p,uu、 Having a brain saturation means that the amount of 4 available in the brain to exert its pharmacological effects is very low compared to 63.

[0279] Alternatively, rat brain protein binding of compounds 4 and 63 was evaluated in vitro by using 300 um thick rat brain slices (striatal region) in incubation trays. The fu, brain of compounds 4 and 63 by this method was 0.329% and 0.057%, respectively. In that case, the K p,uu , and the brain are 0.028 and 0.044, respectively.

[0280] For additional compounds of the disclosure prepared according to the Examples, the Kp, Kp,uu (brain homogenate) and Kp,uu (brain slice) results are listed in Table 3B. The results in Table 3B were obtained by the methods described above. [Table 5]

[0281] Evaluation of compounds as potential substrates of P-glycoprotein The possibility that the compounds prepared according to the examples are substrates of human P-glycoprotein (P-gp) was evaluated in vitro in multidrug resistance mutant 1-Mardin-Darby Canine Kidney (MDR1-MDCK) (Mardin-Darby Canine Kidney) cell monolayers overexpressing P-gp grown on permeable supports. Elacridar was used as a positive control inhibitor of quinidine transport via P-gp. The higher efflux ratio of P-gp means that the compounds are expelled from brain tissue by the transporter.

[0282] Evaluation of pharmacokinetics after single intravenous and oral administration in rats: 3 Sprague-Dawley rats were used for each compound for each route of administration (intravenous or oral). For intravenous administration, 1 mg / kg (dose=5 mL / kg) of each compound was administered via intravenous route by dorsal vein injection, while for oral route, 2.5 mg / kg (dose=5 mL / kg) was administered by oral gavage. Blood samples were taken from the tail vein before administration and 0.083, 0.25, 0.5, 1, 2, 4, and 8 hours after administration. In addition, blood samples were taken 24 hours later by cardiac puncture (under anesthesia with isoflurane) for terminal voiding hematuria. All blood samples were analyzed for drug concentration by LC / MS-MS. C max , T max , AUC last , AUC inf , MRT last , MRT inf , T 1 / 2 , V ss Pharmacokinetic parameters such as , CL were obtained by noncompartmental analysis (NCA). In addition, unbound clearance (CLu) was obtained as follows: Cl u =Cl / f u,plasma . %F was calculated as follows: %F=[AUC inf (oral) / dose] / [AUC inf (intravenous) / dose]*100 (Zhivkova & Doytchinova, Molecular Pharmaceuticals 10:3758-68(2013)). [Table 6]

[0283] Example 5: CYP Inhibition Data In vitro observations in human liver microsomes were performed according to standard methods. In summary, seven different concentrations of test articles, or a single concentration of positive control, were co-incubated with a single concentration of probe substrate for each of the CYP450 enzymes in pooled human liver microsomes for 5–10 min, after which the reaction was terminated by the addition of 0.1% formic acid in acetonitrile. Samples were then analyzed by LC-MS / MS for quantification of the probe substrate remaining after the reaction, and IC values ​​were calculated by nonlinear regression. 50 The IC values ​​were determined for CYP2C9, CYP2D6, and CYP3A4. The substrates for CYP2C9, CYP2D6, and CYP3A4 were diclofenac, dextromethorphan, and midazolam / testosterone, respectively. The data in Table 4 show the IC values ​​for CYP inhibition of the compounds prepared according to the examples for CYP2C9, CYP2D6, and CYP3A4. 50 This shows that. [Table 7]

[0284] Example 6: Monkey Plasma Protein Binding Using Intravenous Infusion, Monkey K p , Monkey K p,uu (Homogenate / brain slices) The compounds were administered to monkeys as a single intravenous bolus followed by a 2-hour intravenous infusion (3 monkeys / compound). Blood was collected from the femoral vein pre-dose immediately after the bolus and at the end of the infusion. After the infusion, the monkeys were euthanized and brain tissue was collected. Toxicokinetic evaluation of plasma (obtained by centrifugation of blood) and brain (homogenized in buffer) was performed to obtain the brain-to-plasma ratio (Kp) of the compounds. Kpuu was calculated considering fu, plasma and fu, brain as previously described. [Table 8]

[0285] Example 7: Biochemical activity assay of wild-type KIT 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 dependent on granulocyte-macrophage colony-stimulating factor (GM-CSF) or stem cell factor (SCF). UT-7 cells respond to SCF stimulation by activation of 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.

[0286] Inhibition of SCF-stimulated UT-7 cell proliferation was assessed using the CellTiter-Glo assay, which quantifies the amount of adenosine triphosphate (ATP) present, which is a readout for metabolically active cells and is directly proportional to the number of viable cells in culture. The ability of test compounds to inhibit SCF-stimulated UT-7 cell proliferation was determined using a 10-point dose curve ranging from 25 μM to 95.4 pM of test compound.

[0287] UT-7 cells were maintained in IMDM supplemented with 10% FBS, 5ng / mL GM-CSF, and 100 units / mL penicillin-streptomycin and cultured in a humidified tissue culture incubator at 37°C. UT-7 cells were washed once with serum-free GM-CSF-free IMDM. Cells were then resuspended in IMDM containing 4% FBS and 50ng / mL SCF and seeded at 2500 cells per well in a volume of 22μL in a 384-well microplate. A 10-point dose concentration series of test compounds (25.0μM to 95.4pM) was then added to the cells in a volume of 3.1μL to each well (0.25% DMSO final concentration) and placed in a tissue culture incubator (5% CO2, 37°C) for 72 hours. After 3 days with test compounds, CellTiter-Glo reagent was freshly prepared and 25μL of reagent was added to each well. Plates were mixed by shaking at 300 rpm for 10 minutes at room temperature on a plate shaker. Plates were read on an EnVision plate reader using the ultrasensitive luminescence protocol for 384-well plates. Data were normalized to 0% and 100% inhibition controls, and IC50s were calculated using a 4-parameter logistic IC50 curve fit.

[0288] Wild-type KIT assay Kd determination. For most assays involving wt KIT kinase, kinase-tagged T7 phage stocks were prepared in E. coli host derived from the BL21 strain. E. coli were grown to logarithmic phase, infected with T7 phage, and incubated with shaking at 32°C until lysis. Streptavidin-coated magnetic beads were treated with biotinylated small molecule ligands for 30 min at room temperature to generate affinity resins for kinase assays. Ligand-bound beads were blocked with excess biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% Tween 20, 1 mM DTT) to remove unbound ligand and reduce nonspecific binding. Binding reactions were constructed by combining kinase, ligand-bound affinity beads, and test compounds in 1x binding buffer (20% SeaBlock, 0.17xPBS, 0.05% Tween 20, 6 mM DTT). Test compounds were prepared as 111X stocks in 100% DMSO. Kds were determined using an 11-point 3-fold compound dilution series with three DMSO control points. All compounds for Kd measurements were dispensed by acoustic transfer (non-contact dispensing) in 100% DMSO. The compounds were then diluted directly into the assay to a final concentration of 0.9% DMSO. All reactions were performed in polypropylene 384-well plates. The final volume of each was 0.02 ml. The assay plate was incubated at room temperature for 1 hour with shaking and the affinity beads were washed with wash buffer (1xPBS, 0.05% Tween 20). The beads were then resuspended in elution buffer (1xPBS, 0.05% Tween 20, 0.5 μM non-biotinylated affinity ligand) and incubated at room temperature for 30 minutes with shaking. Kinase concentrations in the eluates were measured by qPCR.

[0289] Binding constant (Kds). Binding constants (Kds) were calculated using standard dose-response curves using the Hill equation: Response = Background + Signal - Background 1 + (Kd Hill slope / Dose Hill slope). The Hill slope was set to -1. Curves were fitted using a nonlinear least squares approximation using the Levenberg-Marquardt algorithm.

[0290] The results obtained in these WT KIT experiments for the compounds prepared according to the Examples are summarized below in Table 7. For wild type KIT binding, the following designations are used: <10.0 nM = A; ≥10.1 nM and <15 nM = B; ≥15.1 nM and <20 nM = C. For growth inhibition, the following designations are used: <90.0 nM = A; ≥90.1 nM and <150 nM = B; ≥150.1 nM and <200 nM = C. [Table 9]

Claims

1. Compounds of Formula I: [Formula 1] Pharmaceutically acceptable salts and / or solvates of any of the foregoing, wherein: A is, [chemical 2] and R １ is selected from hydrogen and methyl; R ２ is selected from hydrogen and methyl; or R １ and R ２ together to 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 to 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 taken together to form a cyclopropyl, or R ２ Or R ４ One of them is R ６ together to form cyclobutyl R ７ is hydrogen or R ２ , R ４ , or R ６ One of them is R ７ together with forming a ring selected from oxetane, tetrahydrofuran, and tetrahydropyran, said tetrahydrofuran or said tetrahydropyran being optionally substituted with hydroxyl; m is 0 or 1; n is 0 or 1, a compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

2. In the above formula, A is, [C3] and R ３ is selected from hydrogen and methyl; R ４ is selected from hydrogen and methyl, or R ３ and R ４ together to form a cyclopropyl R ５ is selected from hydrogen and methyl; or R ４ and R ６ together to form a cyclobutyl, or R ５ and R ６ together to form a cyclopropyl R 6 is selected from hydrogen and methyl; R ７ is hydrogen, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

3. In the above formula, A is, [C4] and R ３ is selected from hydrogen and methyl; R ４ is selected from hydrogen and methyl, or R ３ and R ４ together to 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 ７is hydrogen, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

4. In the above formula, A is, [C5] and w is 1 or 2; t is 1 or 2; 2. The compound of claim 1, wherein s is 0 or 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing.

5. In the formula, A is [C6] 2. The compound of claim 1 selected from:

6. In the formula, A is [C7] 2. The compound of claim 1 selected from:

7. In the formula, A is [C8] 2. The compound of claim 1 selected from:

8. In the formula, A is [C9] 2. The compound of claim 1 selected from:

9. In the formula, A is [C10] 2. The compound of claim 1 selected from:

10. 2. A compound according to claim 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the compound is [C11] The compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing,

11. The compound according to claim 10 [C12]

12. 2. A compound according to claim 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the compound is [C13] The compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing,

13. The compound according to claim 12 [C14]

14. 2. A compound according to claim 1, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, wherein the compound is [C15] The compound, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing,

15. The compound according to claim 14 [C16]

16. A compound according to any one of claims 1 to 10, 12 and 14, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, or a compound according to any one of claims 11, 13 and 15; and a pharma- ceutically acceptable excipient.

17. 15. 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 10, 12 and 14, a pharma- ceutically acceptable salt thereof, and / or a solvate of any of the foregoing, or a compound according to any one of claims 11, 13 and 15, wherein the disease or condition is selected from systemic mastocytosis, gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, seminoma, intercranial germ cell tumor, mediastinal B-cell lymphoma, Ewing's sarcoma, diffuse large B-cell lymphoma, germinoma, myelodysplastic syndrome, nasal NK / T-cell lymphoma, chronic myelomonocytic leukemia, and brain cancer.

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

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

20. The pharmaceutical composition according to claim 18, wherein the systemic mastocytosis is indolent systemic mastocytosis.

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