Small molecule inhibitors of TEA domain family members

Abstract

The present disclosure relates to a compound represented by formula (I), 1 and R 2 or a tautomer or pharma- ceutically acceptable salt thereof, pharmaceutical compositions thereof, and methods of use for treating diseases susceptible to inhibition of TEAD family transcription factors and / or inhibition of the growth-promoting activity of the transcriptional coactivator YAP. [Formula 1] TIFF2025509895000417.tif47128

Description

[Technical Field]

[0001] cross reference This application claims the benefit of U.S. Provisional Application No. 63 / 269,733, filed March 22, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Originally identified in a screen for organ hyperplasia in flies, the conserved Hippo pathway regulates cell proliferation, organ size, and stemness in most mammalian tissues. 1 At its core, the Hippo pathway consists of a linear kinase cascade in which extracellular signals such as cell density and substrate stiffness activate the kinases MST1 / 2 (serine / threonine-protein kinase 4 (STK4, also called MST1) and serine / threonine-protein kinase 3 (STK3, also called MST2)) and LATS1 / 2 (large tumor suppressor kinase 1 and large tumor suppressor kinase 2). 2 Phosphoryl relay via MST1 / 2 and LATS1 / 2 leads to the phosphorylation and cytoplasmic sequestration of Yes-associated protein 1 (YAP1, hereafter referred to as YAP). YAP is a transcriptional coactivator that promotes growth-promoting transcriptional programs through interaction with TEA domain family proteins (TEADs: genes TEAD1, TEAD2, TEAD3, and TEAD4), resulting in cell proliferation. 3 .

[0003] YAP is central to proliferation control, and in some types of cancer, mutations that inactivate components of the Hippo pathway result in constitutive activation of YAP and uncontrolled cell proliferation. 4 For example, YAP-activating mutations are present in over 70% of malignant pleural mesothelioma (MPM) cases. 5YAP also promotes immune evasion in solid tumors by directly regulating the transcription of PD-L1, TNF-α, CXCL6, CCL2, and CSF1, which promotes M2 macrophage polarization and the accumulation of tumor-resident myeloid-derived suppressor cells (MDSCs). 6-8 In addition to controlling "tumor-intrinsic" processes, YAP also regulates intratumoral regulatory T cells (T regs ) and suppress the activation of CD4- and CD8-positive tumor-reactive T cells. 9、10 These data indicate that inhibition of YAP has high therapeutic utility in oncology and immuno-oncology indications, although YAP does not possess a druggable protein domain. Summary of the Invention [Problem to be solved by the invention]

[0004] To address these and other shortcomings, the present disclosure provides potent small molecule inhibitors of the TEA domain family of proteins (TEADs), DNA-binding transcription factors, that enable site-specific localization of YAP at TEAD-binding elements in the genome. 11 . [Means for solving the problem]

[0005] The inhibitors each have the formula (I): [ka] or a tautomer thereof or a pharmaceutically acceptable salt thereof.

[0006] Ring A is a 6-membered aryl or a 6-membered heteroaryl having 1, 2, or 3 nitrogen ring members.

[0007] Ring B is C6-C 12 -aryl, C4-C7-cycloalkyl or a 6-membered heteroaryl having 1 or 2 nitrogen ring members.

[0008] Ring C is a 4- to 10-membered heterocycle containing 1 or 2 N ring members, where the heterocycle may be fused and may have 1 to 3 unsaturated bonds.

[0009] L is selected from the group consisting of -NH-, -O-, -CH2-, -S-, -C(O)-, -CHOH-, and a bond.

[0010] In various embodiments, R 1 is attached to a carbon ring member, and R 1 CN, halo, -[CH2] 0、1 NHC(O)(C1-C6-alkyl), -[CH2] 0、1 NHC(O)(C2-C6-alkenyl) and -[CH2] 0、1 NHC(O)(C2-C6-alkynyl), -[CH2] 0、1 NHC(O)(C3-C 10 -cycloalkyl), -[CH2] 0、1 NHC(O)(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S), —[CH] 0、1 NHSO2(C1-C6-alkyl), -[CH2] 0、1 NHSO2(C2-C6-alkenyl) and -[CH2] 0、1 NHSO2(C2-C6-alkynyl), -[CH2] 0、1 NHSO2(C3-C 10 -cycloalkyl) and -[CH2] 0、1 NHSO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S).

[0011] In other embodiments, R 1 is attached to the nitrogen ring member, and R 1 is CN, -C(O)(C1-C6-alkyl), -C(O)(C2-C6-alkenyl), -C(O)(C2-C6-alkynyl), -C(O)(C3-C 10-cycloalkyl), -C(O)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S)), -C1-C6-alkyl (C3-C 10 -cycloalkyl), -SO2(C1-C6-alkyl), -SO2(C2-C6-alkenyl), -SO2(C2-C6-alkynyl), -SO2(C3-C 10 -cycloalkyl) and -SO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S).

[0012] R 2 is selected from the group consisting of halo, C1-C6-haloalkyl, C1-C6-haloalkoxy and -SF5.

[0013] Ring A, ring B and ring C may be independently substituted with 1 to 3 substituents independently selected from halo and C1-C6-alkyl.

[0014] In formula (I), any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be selected from halo, OH, CN, C-C-alkoxy, C-C-alkyl, C-C-haloalkyl, C-C-hydroxyalkyl, (C-C-alkyl)NRR', -(C-C-alkyl)-OC(O)R, -(C-C-alkyl)-C(O)OR, C-C 10 Optionally substituted with 1 to 3 substituents independently selected from the group consisting of -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), -(C1-C6-alkyl)(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)).

[0015] R and R' are independently selected from H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl.

[0016] The present disclosure further provides, in embodiments, a pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION OF THE INVENTION

[0017] The compounds of the present disclosure are potent inhibitors of TEAD and, therefore, are useful in various embodiments as therapeutic agents for treating oncology and immuno-oncology indications. There is a need in the art for the development of therapeutics that affect the intrinsic growth processes of tumors while simultaneously activating adaptive immune responses against those tumors. The compounds of the present disclosure fulfill both desired activities by targeting TEAD family transcription factors, thereby inhibiting the growth-promoting activity of the transcriptional coactivator YAP and by promoting the activation of various tumor-reactive T cell populations. Thus, these compounds have proven utility in the treatment of various types of tumors.

[0018] The present compounds offer numerous advantages. First, in contrast to known TEAD inhibitors, the compounds of formula (I) of the present disclosure have a lower molecular weight and are less hydrophobic. In this regard, some known covalent inhibitors feature an electrophilic targeting group (e.g., acrylamide) directly attached to an aromatic moiety, increasing the electrophilicity of the covalent targeting group. This structural combination reduces the selectivity of the inhibitor for TEADs. In contrast, the compounds of the present disclosure that conform to formula (I) have low electrophilicity. A second advantage lies in the surprising discovery that the compounds of the present disclosure selectively inhibit TEADs, thereby halting cancer cell growth, as exemplified in the Examples below. The use of covalent agents that target TEADs increases the tolerability and safety of the compounds, as a lower dose of the compound is required to inactivate TEADs, especially considering the long intracellular half-life of the compounds (e.g., greater than 24 hours).

[0019] Embodiment Embodiment 1: Formula (I): [ka] [During the ceremony, Ring A is a 6-membered aryl or a 6-membered heteroaryl having 1, 2, or 3 nitrogen ring members; Ring B is C6-C 12 -aryl, C4-C7-cycloalkyl or 6-membered heteroaryl having 1 or 2 nitrogen ring members; Ring C is a 4-10 membered heterocycle containing 1 or 2 N ring members, wherein the heterocycle may be fused and may have 1 to 3 unsaturated bonds; L is selected from the group consisting of -NH-, -O-, -CH2-, -S-, -C(O)-, -CHOH-, and a bond; where: R 1 When is attached to a carbon ring member, R 1 CN, halo, -[CH2] 0、1 NHC(O)(C1-C6-alkyl), -[CH2] 0、1 NHC(O)(C2-C6-alkenyl) and -[CH2] 0、1 NHC(O)(C2-C6-alkynyl), -[CH2] 0、1 NHC(O)(C3-C 10 -cycloalkyl), -[CH2] 0、1 NHC(O)(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S), —[CH] 0、1 NHSO2(C1-C6-alkyl), -[CH2] 0、1 NHSO2(C2-C6-alkenyl) and -[CH2] 0、1 NHSO2(C2-C6-alkynyl), -[CH2] 0、1 NHSO2(C3-C 10 -cycloalkyl) and -[CH2] 0、1 NHSO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S); R 1When is attached to a nitrogen ring member, R 1 is CN, -C(O)(C1-C6-alkyl), -C(O)(C2-C6-alkenyl), -C(O)(C2-C6-alkynyl), -C(O)(C3-C 10 -cycloalkyl), -C(O)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S)), -C1-C6-alkyl (C3-C 10 -cycloalkyl), -SO2(C1-C6-alkyl), -SO2(C2-C6-alkenyl), -SO2(C2-C6-alkynyl), -SO2(C3-C 10 -cycloalkyl) and -SO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S); R 2 is selected from the group consisting of halo, C1-C6-haloalkyl, C1-C6-haloalkoxy and -SF5; Ring A, ring B and ring C may be independently substituted with 1 to 3 substituents independently selected from halo and C1-C6-alkyl; and Any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be selected from the group consisting of halo, OH, CN, C-C-alkoxy, C-C-alkyl, C-C-haloalkyl, C-C-hydroxyalkyl, (C-C-alkyl)NRR', -(C-C-alkyl)-OC(O)R, -(C-C-alkyl)-C(O)OR, C-C 10 optionally substituted with 1 to 3 substituents independently selected from the group consisting of -cycloalkyl, 3-6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), -(C1-C6-alkyl)(3-6 membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S); wherein R and R' are independently selected from H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl. or a pharmaceutically acceptable salt thereof.

[0020] Embodiment 2: The compound of embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl having 2 or 3 nitrogen ring members.

[0021] Embodiment 3: Ring A is optionally substituted: [ka] or a pharmaceutically acceptable salt thereof.

[0022] Embodiment 4: Ring A is optionally substituted: [ka] or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 5: Ring A is optionally substituted: [ka] or a pharmaceutically acceptable salt thereof.

[0024] Embodiment 6: Ring B is an optionally substituted C6-C 12 6. The compound of any one of embodiments 1-5, or a pharmaceutically acceptable salt thereof, wherein -aryl.

[0025] Embodiment 7: The compound according to any one of embodiments 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Ring B is optionally substituted phenyl.

[0026] Embodiment 8: The compound of any one of embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted 6-membered heteroaryl having 1 or 2 nitrogen ring members.

[0027] Embodiment 9: Ring B is optionally substituted [ka] or a pharmaceutically acceptable salt thereof.

[0028] Embodiment 10: The compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt thereof, wherein ring C is an optionally substituted 4- to 8-membered heterocycle.

[0029] Embodiment 11: The compound of any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring C contains one N ring member.

[0030] Embodiment 12: The compound according to any one of embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring C contains two N ring members.

[0031] Embodiment 13: Ring C is optionally substituted [ka] 11. The compound according to any one of embodiments 1 to 10, selected from the group consisting of:

[0032] Embodiment 14: Ring C is optionally substituted: [ka] 12. The compound of any one of embodiments 1 to 11, wherein:

[0033] Embodiment 15: 15. The compound of any one of embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

[0034] Embodiment 16: R 2 or a pharmaceutically acceptable salt thereof.

[0035] Embodiment 17: R 2 17. The compound of any one of embodiments 1-16, or a pharmaceutically acceptable salt thereof, wherein is -CF3.

[0036] Embodiment 18: R 1 is attached to the nitrogen ring member; or a pharmaceutically acceptable salt thereof.

[0037] Embodiment 19: R 1 But the expression: [ka] [In the formula, R 3 , R 4 and R 4a are independently selected from the group consisting of H, halo, CN, —C(O)OR and optionally substituted C1-C6-alkyl. or a pharmaceutically acceptable salt thereof.

[0038] Embodiment 20: R 1 But the expression: [ka] or a pharmaceutically acceptable salt thereof.

[0039] Embodiment 21: R 3 is selected from the group consisting of H, F, Cl, CHF, CF, CN, CHOH, CHOC(O)R, and CHNRR′; and R 4 and R 4a are independently selected from the group consisting of H, CHF, CHF, CHOH, CHNRR′, and CH—(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S); 21. A compound according to embodiment 19 or 20, or a pharmaceutically acceptable salt thereof.

[0040] Embodiment 22: R 1 But the expression: [ka] [In the formula, R 5 is selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-hydroxyalkyl. or a pharmaceutically acceptable salt thereof.

[0041] Embodiment 23: R 1 But the expression: [ka] [In the formula, R 6 and R 6a are independently selected from the group consisting of H, halo, CN and C1-C6-alkyl. or a pharmaceutically acceptable salt thereof.

[0042] Embodiment 24: R 6 and R 6aor a pharmaceutically acceptable salt thereof.

[0043] Embodiment 25: R 6 and R 6a or a pharmaceutically acceptable salt thereof.

[0044] Embodiment 26: R 6 and R 6a or a pharmaceutically acceptable salt thereof.

[0045] Embodiment 27: R 1 But the expression: [ka] [In the formula, R 7 and R 7a are independently selected from the group consisting of H, optionally substituted alkyl, and —C(O)OR. or a pharmaceutically acceptable salt thereof.

[0046] Embodiment 28: R 1 But -CN, [ka] or a pharmaceutically acceptable salt thereof.

[0047] Embodiment 29: R 1 but, [ka] or a pharmaceutically acceptable salt thereof.

[0048] Embodiment 30: The compound has the formula (IA): [ka] or a pharmaceutically acceptable salt thereof.

[0049] Embodiment 31: The compound of embodiment 30, or a pharmaceutically acceptable salt thereof, wherein L is —NH—.

[0050] Embodiment 32: R 2 32. The compound according to embodiment 30 or 31, or a pharmaceutically acceptable salt thereof, wherein is -CF3 or -SF5.

[0051] Embodiment 33: R 2 The compound of any one of embodiments 30-32, or a pharmaceutically acceptable salt thereof, wherein is in the para position.

[0052] Embodiment 34: The compound of any one of embodiments 30-33, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4-6 membered heterocycle containing two N ring members.

[0053] Embodiment 35: Ring C is [ka] 35. The compound of any one of embodiments 30 to 34, wherein:

[0054] Embodiment 36: The compound is selected from the group consisting of: 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonitrile; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide; N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide; N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide; N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]heptan-6-yl)acrylamide; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide; 1-(3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide; N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide; 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one; 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide; (S)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide; 2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide; (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile; (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile; 1-(2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(pentafluoro-16-sulfanayl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 4-((3-(4-acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-{4-[3-(4-tert-butylphenoxy)pyrazin-2-yl]piperazin-1-yl}prop-2-en-1-one; 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-(trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid; 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 3-(4-Acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide; 3-(4-Acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide; 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 3-(4-Acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide; 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one; 2-fluoro-1-(4-(6-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 3-(1-acryloylpiperidin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrazin-2(1H)-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one; 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one; 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one; 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-(5-(trifluoromethyl)picolinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 4-(dimethylamino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 2-chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 2-chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 3-oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile; Oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one; 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile; 2-methyl-2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile; 2-methyl-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (E)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; (E)-4-(methyl(prop-2-yn-1-yl)amino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; 2,3-dihydroxy-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propan-1-one; (E)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (Z)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (E)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (Z)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide; N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide; 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonyl)allyl acetate; 2-(Fluoromethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-(pyrrolidin-1-ylmethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-(trifluoromethoxy)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; N-methyl-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; N-(prop-2-yn-1-yl)-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; and N-((4-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazin-2-yl)methyl)acrylamide; or a pharmaceutically acceptable salt thereof.

[0055] Embodiment 37: A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 36 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0056] Embodiment 38: 36. A method of treating a disease in a subject suffering from the disease, comprising administering to the subject a compound of any one of embodiments 1-36 or a pharmaceutically acceptable salt thereof, wherein the disease is selected from the group consisting of diabetic foot ulcers (DFUs), venous ulcers (stasis ulcers), pressure ulcers, full or partial thickness burns, eczema, psoriasis, cellulitis, impetigo contagiousis, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acroexfoliating skin syndrome, Blau's syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, seborrheic dermatitis, capillaritis, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, lichen simplex chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, emphysema, silicosis, asbestos disease, pneumoconiosis, aluminumosis, bauxite fibrosis, beryllium disease, siderosis, stannosis, talc disease, Labrador lung (mixed dust pneumoconiosis), sarcoidosis, hypersensitivity pneumonitis (HP) / extrinsic allergic alveolitis (EAA), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), Idiopathic interstitial pneumonia: not otherwise specified, eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), e-cigarette or vaping use-associated lung injury (EVALI), hantavirus pulmonary syndrome (HPS), histoplasmosis, legionellosis, MAC pulmonary disease, alpha-1 antitrypsin deficiency, aspergillosis, lymphangioleiomyoma (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacteriosis (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderin deposition diseases, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (with or without situs inversus), rare causes of hypersensitivity pneumonitis (all causes except farmer's lung disease and pigeon breeder's lung disease), pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT), interstitial lung disease in systemic sclerosis, interstitial lung disease in rheumatoid arthritis, interstitial lung disease in idiopathic inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome), interstitial lung disease in Sjogren's syndrome,Interstitial lung disease in mixed connective tissue disease (MCTD), interstitial lung disease in overlap syndrome, interstitial lung disease in undifferentiated connective tissue disease, obliterative bronchiolitis (non-transplant patients), infectious colitis, ulcerative colitis, Crohn's disease, ischemic colitis, radiation colitis, peptic ulcer, intestinal cancer, intestinal obstruction, rheumatoid arthritis, psoriatic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, Graves' disease, type 1 diabetes, psoriasis, ankylosing spondylitis, scleroderma, myositis, gout, antiphospholipid syndrome (APS), vasculitis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, dilated cardiomyopathy Diastolic heart failure (heart failure with preserved ejection fraction), atrial septal defect, atrioventricular septal defect, coarctation of the aorta, double outlet right ventricle, D-transposition of the great arteries, Epstein's anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, tetralogy of Fallot, total anomalous pulmonary venous return, tricuspid atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, adult nephrotic syndrome, pediatric nephrotic syndrome, hemolytic uremic syndrome, medullary sponge kidney, renal hypoplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, alopecia Bart syndrome, Wenger's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schönlein purpura, IgA nephropathy (Berger's disease), interstitial nephritis, minimal change disease, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult Still's disease, agammaglobulinemia, alopecia areata, autoimmune angioedema, autoimmune dysautonomia, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune Myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Barrow's disease, bullous pemphigoid, celiac disease, chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, Coxsackie myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum,Essential mixed cryoglobulinemia, giant cell arteritis (temporal arteritis), giant cell myocarditis, granulomatosis with polyangiitis, Guillain-Barré syndrome, Hashimoto's thyroiditis, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis (PG), hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), Lambert-Eaton syndrome, leukocytoclastic vasculitis, linear IgA disease (LAD), microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease , multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paris-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, II Type I, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO) , Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcoholic liver disease, autoimmune hepatitis, biliary atresia, cirrhosis, lysosomal acid lipase deficiency (LAL-D), neonatal jaundice, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis (PBC), progressive familial intrahepatic cholestasis (PFIC), surgical scars, hypertrophic scars, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma),Primary central nervous system lymphoma (lymphoma), anal cancer, childhood astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor (gastrointestinal tract), cardiac tumor, childhood, medulloblastoma, germ cell tumor, primary central nervous system lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, olfactory neuroblastoma (head and neck cancer), retinoblastoma, fallopian tube carcinoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, cardiac tumors, hepatocellular carcinoma, histiocytosis, Langerhans cell, Hodgkin's lymphoma, hypopharyngeal cancer (head and neck cancer), intraocular melanoma, islet cell tumor, kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), lip and oral cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and bronchial tumors), male breast cancer, melanoma, intraocular melanoma, meningioma, melanocytoma Kell cell carcinoma (skin cancer), mesothelioma, malignant, squamous cell carcinoma of occult primary cervical cancer (head and neck cancer), midline carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone (undifferentiated pleomorphic sarcoma of bone). Pleomorphic Sarcoma of Bone Treatment), ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, Ewing's sarcoma (osteosarcoma), soft tissue sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the neck of unknown primary, metastatic (head and neck cancer), gastric cancer, T-cell lymphoma, cutaneous lymphoma (mycosis fungoides and Sézary syndrome), testicular cancer,Nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, thymoma and thymic carcinoma, thyroid carcinoma, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter, urethral carcinoma, uterine carcinoma, endometrial carcinoma, uterine sarcoma, vaginal carcinoma, vulvar carcinoma, and Wilms' tumor.

[0057] Embodiment 39: 39. The method of embodiment 38, wherein the disease is selected from the group consisting of brain tumor, gastric cancer, colon cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer, and soft tissue sarcoma.

[0058] Embodiment 40: 40. The method of embodiment 38 or 39, further comprising administering at least one additional chemotherapeutic agent.

[0059] Embodiment 41: 41. The method of embodiment 40, wherein said additional chemotherapeutic agent is selected from a B-RAF inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a MEK inhibitor, and an immune checkpoint inhibitor.

[0060] Embodiment 42: The method of embodiment 41, wherein said B-RAF inhibitor is selected from the group consisting of vemurafenib, dabrafenib, and encorafenib.

[0061] Embodiment 43: The method of embodiment 41, wherein said MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, selumetinib, and binimetinib.

[0062] Embodiment 44: 42. The method of embodiment 41, wherein said EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib.

[0063] Embodiment 45: 42. The method of embodiment 41, wherein said immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor and a PD-L1 inhibitor.

[0064] Embodiment 46: 46. ​​The method of embodiment 45, wherein the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and cemiplimab.

[0065] Embodiment 47: 46. ​​The method of embodiment 45, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

[0066] definition "Alkyl" refers to a straight or branched chain hydrocarbyl containing from 1 to about 20 carbon atoms. For example, an alkyl can have from 1 to 10 carbon atoms or from 1 to 6 carbon atoms. Representative alkyls include straight chain alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, and the like, and also branched chain isomers of straight chain alkyl groups, such as, but not limited to, CH(CH3)2, CH(CH3)(CH2CH3), CH(CH2CH3)2, C(CH3)3, C(CH2CH3)3, CH2CH(CH3)2, CH2CH(CH3)(CH 2CH3), CH2CH(CH2CH3)2, CH2C(CH3)3, CH2C(CH2CH3)3, CH(CH3)CH(CH3)(CH2CH3), CH2CH2CH(CH3)2, CH2CH2CH(CH3)(CH2CH3), CH2CH2CH(CH2CH3)2, CH2CH2C(CH3)3, CH2CH2C(CH2CH3)3, CH(CH3)CH2CH(CH3)2, CH(CH3)CH(CH3)CH(CH3)2, and the like. Thus, alkyl groups include primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Alkyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0067] The terms "halogen," "halide," and "halo" refer to -F or fluoro, -Cl or chloro, -Br or bromo, or -I or iodo, respectively.

[0068] The term "alkenyl" refers to a straight or branched chain hydrocarbyl group containing 2 to about 20 carbon atoms and having 1 to 3, 1 to 2, or at least one carbon-carbon double bond. Alkenyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0069] "Alkyne" or "alkynyl" refers to a straight- or branched-chain unsaturated hydrocarbon having the indicated number of carbon atoms and at least one triple bond. Examples of (C2-C8)alkynyl groups include, but are not limited to, acetylene, propyne, 1-butyne, 2-butyne, 1-pentyne, 2-pentyne, 1-hexyne, 2-hexyne, 3-hexyne, 1-heptyne, 2-heptyne, 3-heptyne, 1-octyne, 2-octyne, 3-octyne, and 4-octyne. Alkynyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0070] The term "alkoxy" or "alkoxyl" refers to an O-alkyl group having the indicated number of carbon atoms, for example, (C1-C6)-alkoxy groups include -O-methyl, -O-ethyl, -O-propyl, -O-isopropyl, -O-butyl, -O-sec-butyl, -O-tert-butyl, -O-pentyl, -O-isopentyl, -O-neopentyl, O-hexyl, -O-isohexyl, and dO-neohexyl.

[0071] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic, or polycyclic 3- to 14-membered ring system, e.g., C3-C8-cycloalkyl. Cycloalkyl may be attached via any atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Polycyclic cycloalkyls contain rings that may be fused, bridged, and / or spiro-fused. Cycloalkyl groups can be unsubstituted or substituted with one or more substituents described herein.

[0072] "Aryl", when used alone or as part of another term, means a carbocyclic aromatic group, whether fused or unfused, having the stated number of carbon atoms, or up to 14 carbon atoms if no number is stated, e.g., C-C 10 -aryl or C6-C 14 -aryl, etc. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthalenyl, etc. (See, for example, Lang's Handbook of Chemistry (Dean, JA, ed) 13th ed. Table 7-2

[1985] ). "Aryl" also contemplates an aryl ring that is part of a fused polycyclic ring system, such as an aryl fused to a cycloalkyl, as defined herein. An exemplary aryl is phenyl. An aryl group can be unsubstituted or substituted with one or more substituents described herein.

[0073] The term "heteroatom" refers to N, O, and S. Compounds of the present disclosure containing N or S atoms can be optionally oxidized to the corresponding N-oxide, sulfoxide, or sulfone compounds.

[0074] "Heteroaryl," alone or in combination with any other moiety described herein, refers to a monocyclic aromatic ring system containing 5 to 10 (e.g., 5 or 6) ring atoms, or a bicyclic aromatic group containing 8 to 10 atoms, containing one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) heteroatoms independently selected from the group consisting of O, S, and N. Heteroaryl is also intended to include oxidized S or N, e.g., sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon atom or heteroatom is the point of attachment of the heteroaryl ring system such that a stable compound is produced. Examples of heteroaryl groups include, but are not limited to, pyridinyl, pyridazinyl, pyrazinyl, quinoxalyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, and indolyl. Heteroaryl groups can be unsubstituted or substituted with one or more substituents described herein.

[0075] "Heterocycloalkyl" refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, tricyclic, or polycyclic ring system having 3 to 14 (e.g., 3 to 6) atoms, in which 1 to 3 carbon atoms in the ring are replaced by an O, S, or N heteroatom. Polycyclic heterocycloalkyls include rings that can be fused, bridged, and / or spirofused. Furthermore, heterocycloalkyls can be optionally fused to a 5- or 6-membered aryl or heteroaryl ring and also include oxidized S or N, e.g., sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. The point of attachment of the heterocycloalkyl ring is at a carbon atom or heteroatom such that a stable ring is maintained. Examples of heterocycloalkyl groups include, but are not limited to, morpholino, tetrahydrofuranyl, dihydropyridinyl, piperidinyl, pyrrolidinyl, piperazinyl, dihydrobenzofuryl, and dihydroindolyl. A heterocycloalkyl group can be unsubstituted or optionally substituted with one or more substituents described herein.

[0076] The terms "nitrile" or "cyano" can be used interchangeably and refer to the -CN group.

[0077] "Hydroxyl" or "hydroxy" refers to an --OH group.

[0078] The compounds described herein can exist in various isomeric forms, including configurational, geometric, and conformational isomers, including, for example, cis- or trans-conformations. The compounds may also exist in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the disclosed compounds, including tautomers of the disclosed compounds. The disclosed compounds may also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may result from loss of water. The specific composition of the open-chain and cyclized forms may depend on how the compound is isolated, stored, or administered. For example, a compound may exist primarily in an open-chain form under acidic conditions, but may cyclize under neutral conditions. All forms are encompassed by the present disclosure.

[0079] Some compounds described herein may have asymmetric centers and therefore may exist in different enantiomeric and diastereomeric forms. The compounds described herein may be in the form of optical isomers or diastereomers. Thus, the present disclosure encompasses the compounds described herein in the form of optical isomers, diastereoisomers, and mixtures thereof, including racemic mixtures, and their uses. Optical isomers of the compounds of the present disclosure can be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or by chemical separation of stereoisomers using optically active resolving agents.

[0080] Unless otherwise indicated, the term "stereoisomer" refers to one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of the other stereoisomers of the compound, e.g., more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of the other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of the other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of the other stereoisomers of the compound, or more than about 99% by weight of one stereoisomer of the compound and less than about 1% by weight of the other stereoisomers of the compound. The stereoisomers described above can be viewed as compositions containing two stereoisomers present in the respective weight percentages described herein.

[0081] In the event of a discrepancy between a drawn structure and the name given to that structure, the drawn structure shall prevail. Furthermore, if the stereochemistry of a structure or portion of a structure is not depicted, for example, with bold or dashed lines, the structure or portion of a structure shall be interpreted as encompassing all stereoisomers thereof. However, in some cases, when more than one chiral center is present, the structure and name may be depicted as a single enantiomer to aid in describing the relative stereochemistry. Those skilled in the art of organic synthesis will know whether a compound is prepared as a single enantiomer from the method used to prepare the compound.

[0082] As used herein, unless indicated to the contrary, the term "compound" is inclusive in that it includes a compound or a pharmaceutically acceptable salt, stereoisomer, and / or tautomer thereof. Thus, for example, a compound of Formula (I) includes pharmaceutically acceptable salts of tautomers of the compound.

[0083] In the present disclosure, a "pharmaceutically acceptable salt" is a pharmaceutically acceptable organic or inorganic acid or base salt of a compound described herein. Representative pharmaceutically acceptable salts include, for example, alkali metal salts, alkaline earth salts, ammonium salts, water soluble and water insoluble salts, such as acetate, amsonate (4,4-diaminostilbene-2,2-disulfonate), benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, calcium, calcium edetate, camsylate, carbonate, chloride, citrate, clavulanate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolyl arsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, lanthanide ... Pharmaceutically acceptable salts include phosphate, malate, maleate, mandelate, mesylate, methyl bromide, methyl nitrate, methyl sulfate, mucate, napsylate, nitrate, N-methylglucamine ammonium salt, 3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate (1,1-methene-bis-2-hydroxy-3-naphthoate, ainbonate), pantothenate, phosphate / diphosphate, picrate, polygalacturonate, propionate, p-toluenesulfonate, salicylate, stearate, diacetate, succinate, sulfate, sulfosalicylate, suramate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate. Pharmaceutically acceptable salts can have more than one charged atom in their structure. In this case, a pharmaceutically acceptable salt can have multiple counter ions, hence, a pharmaceutically acceptable salt can have one or more charged atoms and / or one or more counter ion.

[0084] The terms "treat," "treating," and "treatment" refer to the amelioration or eradication of a disease or symptoms associated with a disease. In various embodiments, the terms refer to minimizing or slowing the spread, progression, or worsening of the disease resulting from the administration of one or more prophylactic or therapeutic compounds described herein to a patient with such a disease.

[0085] The terms "prevent," "preventing," and "prevention" refer to the prevention of the onset, recurrence, or spread of disease in a patient resulting from the administration of a compound described herein.

[0086] The term "effective amount" refers to an amount of a compound or other active ingredient described herein sufficient to provide a therapeutic or prophylactic benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with a disease. Furthermore, a therapeutically effective amount with respect to a compound described herein means an amount of a therapeutic agent, alone or in combination with other therapies, that provides a therapeutic benefit in the treatment or prevention of a disease. When used in connection with a compound described herein, the term can encompass an amount that improves overall treatment, an amount that reduces or avoids symptoms or causes of a disease, or an amount that enhances the therapeutic effectiveness of or is synergistic with another therapeutic agent.

[0087] A "patient" or "subject" includes animals such as humans, cows, horses, sheep, lambs, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. In some embodiments, the animals are mammals, such as non-primates and primates (e.g., monkeys and humans). In one embodiment, the patient is a human, such as a human infant, child, adolescent, or adult. In this disclosure, the terms "patient" and "subject" are used interchangeably.

[0088] compound In various embodiments, the present disclosure provides a compound of formula (I): [ka] The present invention provides a compound represented by the formula:

[0089] Ring A is a 6-membered aryl or a 6-membered heteroaryl having 1, 2, or 3 nitrogen ring members.

[0090] Ring B is C6-C 12 -aryl, C4-C7-cycloalkyl or a 6-membered heteroaryl having 1 or 2 nitrogen ring members.

[0091] Ring C is a 4- to 10-membered heterocycle containing 1 or 2 N ring members, where the heterocycle may be fused and may have 1 to 3 unsaturated bonds.

[0092] L is selected from the group consisting of -NH-, -O-, -CH2-, -S-, -C(O)-, -CHOH-, and a bond.

[0093] In various embodiments, R 1 is attached to a carbon ring member, and R 1 CN, halo, -[CH2] 0、1 NHC(O)(C1-C6-alkyl), -[CH2] 0、1 NHC(O)(C2-C6-alkenyl) and -[CH2] 0、1 NHC(O)(C2-C6-alkynyl), -[CH2] 0、1 NHC(O)(C3-C 10 -cycloalkyl), -[CH2] 0、1 NHC(O)(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S), —[CH] 0、1 NHSO2(C1-C6-alkyl), -[CH2] 0、1 NHSO2(C2-C6-alkenyl) and -[CH2] 0、1 NHSO2(C2-C6-alkynyl), -[CH2] 0、1 NHSO2(C3-C 10-cycloalkyl) and -[CH2] 0、1 NHSO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S).

[0094] In other embodiments, R 1 is attached to the nitrogen ring member, and R 1 is CN, -C(O)(C1-C6-alkyl), -C(O)(C2-C6-alkenyl), -C(O)(C2-C6-alkynyl), -C(O)(C3-C 10 -cycloalkyl), -C(O)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S)), -C1-C6-alkyl (C3-C 10 -cycloalkyl), -SO2(C1-C6-alkyl), -SO2(C2-C6-alkenyl), -SO2(C2-C6-alkynyl), -SO2(C3-C 10 -cycloalkyl) and -SO2 (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S).

[0095] R 2 is selected from the group consisting of halo, C1-C6-haloalkyl, C1-C6-haloalkoxy and -SF5.

[0096] Ring A, ring B and ring C may be independently substituted with 1 to 3 substituents independently selected from halo and C1-C6-alkyl.

[0097] In formula (I), any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be selected from halo, OH, CN, C-C-alkoxy, C-C-alkyl, C-C-haloalkyl, C-C-hydroxyalkyl, (C-C-alkyl)NRR', -(C-C-alkyl)-OC(O)R, -(C-C-alkyl)-C(O)OR, C-C 10Optionally substituted with 1 to 3 substituents independently selected from the group consisting of -cycloalkyl, 3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S), -(C1-C6-alkyl)(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O, and S)).

[0098] R and R' are independently selected from H, C1-C6-alkyl, C2-C6-alkenyl and C2-C6-alkynyl.

[0099] In some embodiments, Ring A is a 6-membered heteroaryl having 2 or 3 nitrogen ring members. Illustrative examples of Ring A are optionally substituted: [ka] is selected from the group consisting of:

[0100] Thus, in one embodiment, ring A is optionally substituted: [ka] In another embodiment, ring A is optionally substituted: [ka] is.

[0101] In a further embodiment, optionally in combination with any other embodiment described herein, ring B is an optionally substituted C-C 12 -aryl. In an exemplary embodiment, Ring B is an optionally substituted phenyl.

[0102] In another embodiment, Ring B is an optionally substituted 6-membered heteroaryl having 1 or 2 nitrogen ring members. Examples of Ring B are optionally substituted: [ka] is selected from the group consisting of:

[0103] The present disclosure further provides, in some embodiments, compounds of formula (I) in which ring C is an optionally substituted 4- to 8-membered heterocycle. In one embodiment, ring C contains one N ring member. In another embodiment, ring C contains two N ring members. Examples of ring C include optionally substituted: [ka] and a ring selected from the group consisting of:

[0104] In illustrative examples, Ring C is optionally substituted: [ka] is.

[0105] According to various embodiments, optionally in combination with any other embodiments described herein, L is -NH-.

[0106] Further embodiments of the present disclosure include R 2 In an exemplary embodiment, R 2 is -CF3.

[0107] In some embodiments, R 1 is attached to the nitrogen ring member. For example, R 1 is the expression: [ka] [In the formula, R 3 , R 4 and R 4a are independently selected from the group consisting of H, halo, CN, —C(O)OR and optionally substituted C1-C6-alkyl. In an alternative embodiment, R 1 is the expression: [ka] It is expressed as:

[0108] In some embodiments, R 3 is selected from the group consisting of H, F, Cl, CHF, CF, CN, CHOH, CHOC(O)R, and CHNRR′; and R 4 and R 4a are independently selected from the group consisting of H, CHF, CHF, CHOH, CHNRR′, and CH—(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S), where R and R′ are as defined herein.

[0109] In another embodiment, R 1 When is attached to a nitrogen ring member, R 1 is the expression: [ka] [In the formula, R 5 is selected from the group consisting of H, C1-C6-alkyl, C1-C6-haloalkyl and C1-C6-hydroxyalkyl. It is expressed as:

[0110] In yet another embodiment, R 1 When is attached to a nitrogen ring member, R 1 is the expression: [ka] [In the formula, R 6 and R 6a are independently selected from the group consisting of H, halo, CN and C1-C6-alkyl. In some embodiments, R 6 and R 6a In another embodiment, at least one of R 6 and R 6a Each of R is halo. 6 and R6a At least one of is CN. All combinations of these are contemplated.

[0111] In a further embodiment, R 1 When is attached to a nitrogen ring member, R 1 is the expression: [ka] [In the formula, R 7 and R 7a are independently selected from the group consisting of H, optionally substituted alkyl, and —C(O)OR, where R is as defined herein. It is expressed as:

[0112] The present disclosure provides, in various embodiments, a compound of formula (I), wherein R 1 teeth, [ka] selected from the group consisting of The present invention provides a compound represented by the formula:

[0113] According to some embodiments, and optionally in combination with any other embodiment described herein, R 1 Specific examples of the formula: [ka] is.

[0114] Some compounds of formula (I) described herein may be represented by the formula (IA): [ka] Also suitable for.

[0115] In Formula (IA), in some embodiments, L is -NH-. In further embodiments, R 2 is CF3 or -SF5. 2can be attached to any position of the phenyl ring in formula (IA). In an exemplary embodiment, R 2 is in the para position relative to L, i.e., [ka] is.

[0116] In further embodiments of formula (IA), ring C is a 4-6 membered heterocycle containing two N ring members. Examples of ring C, according to exemplary embodiments, are: [ka] is.

[0117] The present disclosure also provides, in various embodiments, the compounds set forth in Table 1, or tautomers or pharmaceutically acceptable salts thereof. [Table 1] TIFF2025509895000037.tif175170TIFF2025509895000038.tif213170TIFF2025509895000039.tif174170TIFF2025509895000040.tif177170TIFF2025509895000041.tif186170TIFF2025509895000042.tif224170TIFF2025509895000043.tif166170TIFF2025509895000044.tif214170TIFF2025509895000045.tif215170TIFF2025509895000046.tif199170TIFF2025509895000047.tif205170TIFF2025509895000048.tif196170TIFF2025509895000049.tif210170TIFF2025509895000050.tif184170TIFF2025509895000051.tif199170TIFF2025509895000052.tif210170TIFF2025509895000053.tif186170TIFF2025509895000054.tif187170TIFF2025509895000055.tif194170TIFF2025509895000056.tif212170TIFF2025509895000057.tif189170TIFF2025509895000058.tif223170TIFF2025509895000059.tif219170TIFF2025509895000060.tif187170TIFF2025509895000061.tif210170TIFF2025509895000062.tif168170TIFF2025509895000063.tif207170TIFF2025509895000064.tif164170TIFF2025509895000065.tif182170TIFF2025509895000066.tif174170TIFF2025509895000067.tif202170TIFF2025509895000068.tif210170TIFF2025509895000069.tif218170TIFF2025509895000070.tif214170TIFF2025509895000071.tif211170TIFF202 5509895000072.tif220170TIFF2025509895000073.tif224170TIFF2025509895000074.ti f181170TIFF2025509895000075.tif184170TIFF2025509895000076.tif216170TIFF20255 09895000077.tif212170TIFF2025509895000078.tif194170TIFF2025509895000079.tif18 9170TIFF2025509895000080.tif221170TIFF2025509895000081.tif203170TIFF20255098 95000082.tif214170TIFF2025509895000083.tif196170TIFF2025509895000084.tif1941 70TIFF2025509895000085.tif187170TIFF2025509895000086.tif188170TIFF2025509895 000087.tif193170TIFF2025509895000088.tif187170TIFF2025509895000089.tif216170. Pharmaceutical Composition The present disclosure also provides pharmaceutical compositions comprising a therapeutically effective amount of one or more compounds described herein, or pharmaceutically acceptable salts, stereoisomers, and / or tautomers thereof, in admixture with a pharmaceutically acceptable carrier. In some embodiments, the compositions further contain one or more additional therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavoring agents, in accordance with accepted practices of pharmaceutical compounding.

[0118] In one embodiment, the pharmaceutical composition comprises a compound selected from those shown in Table 1, or a pharmaceutically acceptable salt, stereoisomer and / or tautomer thereof, and a pharmaceutically acceptable carrier.

[0119] The pharmaceutical compositions of the present disclosure are formulated, dosed, and administered in a manner consistent with good medical practice. Factors to consider in this regard include the particular disorder being treated, the particular subject being treated, the clinical condition of the subject, the cause of the disorder, the site of delivery of the agent, the method of administration, the schedule of administration, and other factors known to medical practitioners.

[0120] The "therapeutically effective amount" of the administered compound or its pharmaceutically acceptable salt, stereoisomer, and / or tautomer is determined by these considerations and is the minimum amount necessary to inhibit YAP transcriptional activity, inhibit one or more TEA domain family proteins (TEADs), exert therapeutic activity in oncology and / or immuno-oncology, and combinations thereof. Such amounts may be below amounts that are toxic to normal cells or to the subject as a whole. Generally, the initial therapeutically effective amount of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer) administered is in the range of about 0.01 to about 200 mg / kg, or in the range of about 0.1 to about 20 mg / kg, of patient body weight per day, with a typical initial range being about 0.3 to about 15 mg / kg / day. Oral unit dosage forms, such as tablets and capsules, can contain from about 0.1 mg to about 1000 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such dosage forms contain from about 50 mg to about 500 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain from about 25 mg to about 200 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In yet another embodiment, such dosage forms contain from about 10 mg to about 100 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In a further embodiment, such dosage forms contain from about 5 mg to about 50 mg of a compound of the present disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form may be administered once daily or twice daily.

[0121] The compositions of the present disclosure may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. As used herein, the term "parenteral" includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0122] Suitable oral compositions described herein include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs.

[0123] In another embodiment, also encompassed is a pharmaceutical composition suitable for single unit administration comprising a compound of the present disclosure or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof and a pharmaceutically acceptable carrier.

[0124] The composition of the present disclosure suitable for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.For example, the liquid formulation of the compound of the present disclosure contains one or more agents selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, in order to provide the compound of the present disclosure in a pharmaceutically palatable form.

[0125] For tablet compositions, the compound of the present disclosure mixed with non-toxic pharmaceutically acceptable excipients is used for tablet manufacture.Examples of such excipients include, but are not limited to, inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents such as corn starch or alginic acid; binders such as starch, gelatin or acacia, and lubricants such as magnesium stearate, stearic acid or talc.Tablets may be uncoated or may be coated by known coating techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained therapeutic effect over a desired period of time.For example, time-delay materials such as glyceryl monostearate or glyceryl distearate may be used.

[0126] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate, or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin, or olive oil.

[0127] In aqueous suspensions, the compounds of the present disclosure are mixed with suitable excipients to maintain a stable suspension, including, but not limited to, sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia.

[0128] Oral suspensions may also contain dispersing or wetting agents such as natural phosphatides, for example, lecithin, or condensation products of alkylene oxides with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain aliphatic alcohols, for example, heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols, for example, polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example, polyethylene sorbitan monooleate. Aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, for example, sucrose or saccharin.

[0129] Oily suspensions may be formulated by suspending the compounds of the present disclosure in a vegetable oil, for example, arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example, beeswax, hard paraffin or cetyl alcohol.

[0130] Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

[0131] Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water provide the compound of the present disclosure mixed with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, such as sweeteners, flavorings, and coloring agents, may also be present.

[0132] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oily phase can be vegetable oil, such as olive oil or peanut oil, or mineral oil, such as liquid paraffin, or a mixture thereof. Suitable emulsifiers can be naturally occurring gums, such as gum arabic or gum tragacanth, naturally occurring phosphatides, such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides, such as sorbitan monooleate, and the condensation reaction products of the partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion can also contain sweeteners and flavoring agents.

[0133] Syrups and elixirs may be formulated with sweetening agents, such as glycerol, propylene glycol, sorbitol, or sucrose. Such formulations may also contain demulcents, preservatives, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable, aqueous, or oily suspension. These suspensions may be formulated according to known techniques using suitable dispersing or wetting agents and suspending agents, as described above. Sterile injectable preparations may also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Acceptable vehicles and solvents that may be used include water, Ringer's solution, and isotonic sodium chloride solution. Additionally, sterile, fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil may be used, including synthetic mono- or diglycerides. Additionally, fatty acids, such as oleic acid, are used in the preparation of injectable solutions.

[0134] The compounds described herein can also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the compound with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, and therefore melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycol.

[0135] The composition for parenteral administration is administered in a sterile medium.Depending on the vehicle used and the concentration of the drug in the preparation, the parenteral preparation can be either a suspension or a solution containing the dissolved drug.Additives such as local anesthetics, preservatives and buffers can also be added to the parenteral composition.

[0136] How to use In further embodiments, the present disclosure provides a method of treating a disease in a subject suffering from the disease. The method comprises administering to the subject a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the disease is caused by abnormal activity of the TEA domain family proteins TEAD1, TEAD2, TEAD3 and / or TEAD4. In further embodiments, the disease is associated with constitutive activation of YAP. Specific examples of the disease include the following: Diabetic foot ulcers (DFU), venous ulcers (stasis ulcers), pressure ulcers, full or partial thickness burns, eczema, psoriasis, cellulitis, contagious impetigo, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acroexfoliating skin syndrome, Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, seborrheic dermatitis, capillaritis, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, lichen simplex chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome Distress syndrome (ARDS), chronic obstructive pulmonary disease, emphysema, silicosis, asbestosis, pneumoconiosis, aluminosis, bauxite fibrosis, beryllium disease, siderosis, stannosis, talcosis, Labrador lung (mixed dust pneumoconiosis), sarcoidosis, hypersensitivity pneumonitis (HP) / extrinsic allergic alveolitis (EAA), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia Non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), idiopathic interstitial pneumonia: not specified, eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), e-cigarette or vaping use-associated lung injury (EVALI), hantavirus pulmonary syndrome (HPS), histoplasmosis, legionellosis, MAC Pulmonary disease, alpha-1 antitrypsin deficiency, aspergillosis, lymphangioleiomyoma (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacteriosis (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (with or without situs inversus), rare causes of hypersensitivity pneumonitis (all causes except farmer's lung disease and pigeon breeder's lung disease),Pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT), interstitial lung disease in systemic sclerosis, interstitial lung disease in rheumatoid arthritis, interstitial lung disease in idiopathic inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome), interstitial lung disease in Sjögren's syndrome, interstitial lung disease in mixed connective tissue disease (MCTD), interstitial lung disease in overlap syndrome, interstitial lung disease in undifferentiated connective tissue disease, bronchiolitis obliterans (non-transplant patients), infectious colitis, ulcerative colitis, Crohn's disease, ischemic colitis, radiation colitis, peptic ulcer Cancer, intestinal cancer, intestinal obstruction, rheumatoid arthritis, psoriatic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, Graves' disease, type 1 diabetes, psoriasis, ankylosing spondylitis, scleroderma, myositis, gout, antiphospholipid syndrome (APS), vasculitis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, diastolic heart failure (heart failure with preserved ejection fraction), atrial septal defect, atrioventricular septal defect, coarctation of the aorta, double outlet right ventricle, D-transposition of the aorta, Epstein's anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, tetralogy of Fallot, total anomalous pulmonary venous return, triple Cuspinodullary atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, adult nephrotic syndrome, childhood nephrotic syndrome, hemolytic uremic syndrome, medullary sponge kidney, renal hypoplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, Alport syndrome, Wenger's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schönlein purpura, IgA nephropathy (Berger's disease), interstitial nephritis, minimal change syndrome, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult Still's disease, agammaglobulinemia, alopecia areata, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Barrow's disease, bullous pemphigoid, celiac disease, chronic relapsing multiple myelitis (CRMO),Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, Coxsackie myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devick's disease (neuromyelitis optica), discoid lupus erythematosus, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, giant cell arteritis (temporal arteritis), giant cell myocarditis, granulomatosis with polyangiitis, Guillain-Barré syndrome, Hashimoto's thyroiditis, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestationis ( PG), hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), Lambert-Eaton syndrome, leukocytoclastic vasculitis, linear IgA disease (LAD), microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatoid arthritis (PR), PANDAS, tumors Paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paris-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, Restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff-person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO), Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcoholic liver disease, autoimmune hepatitis, biliary atresia, liver cirrhosis, lysosomal acid lipase deficiency (LAL-D), neonatal jaundice,Non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis (PBC), progressive familial intrahepatic cholestasis (PFIC), surgical scars, hypertrophic scars, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma), primary central nervous system lymphoma (lymphoma), anal cancer, childhood astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, Ewing's sarcoma, osteosarcoma, Malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor (gastrointestinal tract), cardiac tumor, childhood, medulloblastoma, germ cell tumor, primary central nervous system lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, olfactory neuroblastoma (head and neck cancer), retinoblastoma, fallopian tube Cancer, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, cardiac tumor, hepatocellular carcinoma, histiocytosis, Langerhans cell, Hodgkin's lymphoma, hypopharyngeal cancer (head and neck cancer), intraocular melanoma, islet cell tumor, kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), lip and oral cancer, lung cancer (non-small cell, small cell, pleuropulmonary) Blastocystic and bronchial tumors), male breast cancer, melanoma, intraocular melanoma, meningioma, Merkel cell carcinoma (skin cancer), mesothelioma, malignant cervical squamous cell carcinoma of unknown primary (head and neck cancer), midline carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasm, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cancer, lip and oral cavity cancer, oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone Pleomorphic Sarcoma of Bone Treatment), ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, plasma cell neoplasm / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer,Renal cell (kidney) carcinoma, retinoblastoma, Ewing's sarcoma (osteosarcoma), soft tissue sarcoma, Sézary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous cell carcinoma of the neck of unknown primary, metastatic (head and neck cancer), gastric cancer, T-cell lymphoma, skin - see lymphoma (mycosis fungoides and Sézary syndrome), testicular cancer, nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, thymoma and thymic carcinoma, thyroid carcinoma, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer, endometrial cancer, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor.

[0137] In exemplary embodiments, the disease is selected from the group consisting of brain cancer, gastric cancer, colon cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer, and soft tissue sarcoma.

[0138] The compounds of the present disclosure are effective as single therapeutic agents for treating YAP-dependent cancers, including, for example, glioblastoma, head and neck squamous cell carcinoma, breast cancer, non-small cell lung cancer, melanoma, hepatocellular carcinoma, pancreatic adenocarcinoma, colorectal cancer, and prostate adenocarcinoma. According to the methods described herein, the compounds of the present disclosure can be administered with at least one additional chemotherapeutic agent. The additional chemotherapeutic agent can be administered prior to, simultaneously with, or after administration of the compounds of the present disclosure. Thus, the compounds are useful as combination therapeutic agents, and TEAD inhibition has been shown to provide synergistic efficacy when combined with other targeted therapies (e.g., EGFR inhibitors, MEK inhibitors, and ERK1 / 2 inhibitors). 15 Because YAP regulates PD-L1 levels and reprograms the tumor microenvironment, TEAD inhibitors are useful in combination with checkpoint inhibitors, such as antibodies targeting PD-L1, PD1, and CTLA4.

[0139] In various embodiments, the additional chemotherapeutic agent is selected from a B-RAF inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a MEK inhibitor, and an immune checkpoint inhibitor. Examples of B-RAF inhibitors include vemurafenib, dabrafenib, and encorafenib. Examples of MEK inhibitors include trametinib, cobimetinib, selumetinib, and binimetinib. Furthermore, examples of EGFR inhibitors include erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib.

[0140] In various embodiments, the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor and a PD-L1 inhibitor. Examples of PD-1 inhibitors include pembrolizumab, nivolumab, and cemiplimab. Examples of PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab. [Example]

[0141] Example Further embodiments of the present disclosure reside in the specific examples and data described in more detail herein.

[0142] Compound synthesis: The compounds of the present disclosure are prepared according to and by adapting the following exemplary procedures.

[0143] Example 1: Synthesis of 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonitrile Scheme 1 [ka] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate [ka] To a stirred mixture of 2,3-dichloropyrazine (1.00 g, 6.71 mmol, 1.00 equiv) and tert-butyl piperazine-1-carboxylate (1.00 g, 5.37 mmol, 0.80 equiv) in DMF (10.00 mL) was added CsCO (4.37 g, 13.43 mmol, 2.00 equiv) in portions at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The reaction was monitored by LCMS. The mixture was quenched with 20.00 mL of HO and extracted with ethyl acetate (20.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to give tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (1.00 g, yield 49.86%) as a yellow solid.

[0144] LCMS: (positive, ES, m / z): 299.2 Step 2: Synthesis of tert-butyl 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (0.90 g, 3.01 mmol, 1.00 equiv.), p-trifluoromethylaniline (0.58 g, 3.61 mmol, 1.20 equiv.), Xantphos (0.14 g, 0.24 mmol, 0.08 equiv.), and CS2CO3 (1.96 g, 6.02 mmol, 2 equiv.) in toluene (10.00 mL) was added Pd2(dba)3 (0.11 g, 0.12 mmol, 0.04 equiv.) in portions at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (4:1)) to give tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (0.8 g, yield 62.72%) as a yellow oil.

[0145] LCMS: (positive, ES, m / z): 424.2 Step 3: Synthesis of 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine [ka] To a stirring mixture of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (0.50 g, 1.18 mmol, 1.00 equiv) in DCM (2.00 mL) was added HCl (gas) in 1,4-dioxane (1.48 mL, 5.91 mmol, 5.00 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (0.30 g, 78.58% yield) as a yellow oil.

[0146] LCMS: (negative, ES, m / z): 322.1 Step 4: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] In a 10 mL bottle, 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (0.30 g, 0.93 mmol, 1.00 equiv.) and TEA (0.28 g, 2.78 mmol, 3.00 equiv.) in DCM (5.00 mL) were added at 0 °C. To the above mixture, acryloyl chloride (0.08 g, 0.93 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. To the resulting mixture, 50.00 mL of HO was added and extracted with ethyl acetate (50.00 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 90 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Run number: 5) to give 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (0.06 g, 17.14% yield) as a white solid.

[0147] LCMS: (positive, ES, m / z): 349.2. 1 H NMR (400 MHz, DMSO-d6): δ 8.60 (s, 1H), 7.92 - 7.87 (m, 3H), 7.84 - 7.83 (m, 1H), 7.65 - 7.63 (m, 2H), 6.78 - 6.81 (m, 1H), 6.17 - 6.12 (m, 1H), 5.72 - 5.69 (m, 1H), 3.80 - 3.76 (m, 4H), 3.16 - 3.13 (m, 4H). Example 2: Synthesis of 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carbonitrile Scheme 2 [ka] In a 10 mL bottle, 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (0.20 g, 0.62 mmol, 1.00 equiv.) and DIEA (0.24 g, 1.86 mmol, 3.00 equiv.) in DCM (2.00 mL) were added at 0 °C. To the above mixture, BrCN (0.07 g, 0.62 mmol, 1.00 equiv.) was added. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. To the resulting mixture, 50.00 mL of HO was added and extracted with ethyl acetate (50.00 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 90 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Runs: 5) to give 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carbonitrile (65.00 mg, 30.17% yield) as a white solid.

[0148] LCMS: (positive, ES, m / z): 349.2. 1 H NMR (400 MHz, DMSO-d6): δ 8.55 (s, 1H), 7.92 - 7.89 (m, 3H), 7.86 - 7.85 (m, 1H), 7.66 - 7.63 (m, 2H), 3.47 - 3.40 (m, 4H), 3.22 - 3.19 (m, 4H). Example 3: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide Scheme 3 [ka] Step 1: Synthesis of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine [ka] To a solution of 3-chloropyrazin-2-amine (4.00 g, 30.88 mmol, 1.00 equiv.), 1-iodo-4-(trifluoromethyl)benzene (8.40 g, 30.88 mmol, 1.00 equiv.), Xtanphos (1.79 g, 3.09 mmol, 0.10 equiv.), and CsCO (25.15 g, 77.19 mmol, 2.00 equiv.) in toluene (20.00 mL) was added Pd(dba) (2.83 g, 3.09 mmol, 0.10 equiv.). The resulting mixture was stirred at 90 °C under a N atmosphere for 3 h. The mixture was diluted with EA (150.00 mL), washed with HO (3 × 50.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to give 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (3.50 g, 35.51%) as a yellow solid.

[0149] (ES, m / z): [M+H] + =274. 1 H NMR (400 MHz, DMSO-d6): δ 9.17(s, 1H), 8.22 (s, 1H), 7.95 - 7.93 (m, 3H), 7.68 - 7.66 (m, 2H). Step 2: Synthesis of tert-butyl (1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)carbamate [ka] To a stirred mixture of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (200 mg, 0.73 mmol, 1.00 equiv.) and tert-butyl azetidin-3-ylcarbamate (151 mg, 0.88 mmol, 1.2 equiv.) in DMF (10.00 mL) was added CsCO (476.3 mg, 1.46 mmol, 2.00 equiv.) in portions at room temperature. The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The mixture was quenched with 20.00 mL of HO and extracted with ethyl acetate (20.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting with DCM (100%)) to afford tert-butyl (1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)carbamate (250 mg, 83.55% yield) as a yellow solid.

[0150] Step 3: Synthesis of 3-(3-aminoazetidin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine [ka] To a stirring mixture of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate (250 mg, 0.0.61 mmol, 1.00 equiv) in dioxane (2.00 mL) was added HCl (gas) in 1,4-dioxane (3.05 mL, 12.21 mmol, 20.00 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 3-(3-aminoazetidin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine (170 mg, 90.01% yield) as a yellow oil.

[0151] Step 4: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide [ka] 3-(3-aminoazetidin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine (100 mg, 0.32 mmol, 1.00 equiv) and TEA (134 mmL, 0.81 mmol, 2.50 equiv) in DCM (2.00 mL) at 0 °C. To the above mixture, acryloyl chloride (32 mmL, 0.39 mmol, 1.20 equiv) was added. The resulting mixture was stirred at 0 °C for an additional 0.5 h. The reaction was monitored by LCMS. To the resulting mixture was added 50.00 mL of HO and extracted with ethyl acetate (50.00 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluted with DCM:EA (4:6)) to afford N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide (53 mg, yield 45.12%) as a white solid.

[0152] 1 H NMR (400 MHz, DMSO) δ 10.86-10.30 (m, 1H), 8.59 - 8.31 (m, 1H), 8.17 - 7.82 (m, 2H), 7.77 - 7.59 (m, 2H), 7.59 - 7.33 (m, 2H), 6.31 - 6.07 (m, 2H), 5.71 - 5.59 (m, 1H), 4.67 (s, 1H), 4.48 - 4.13 (m, 2H), 3.85 - 3.50 (m, 3H). Example 4: Synthesis of N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate was used in step 2. N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide was obtained as a white solid.

[0153] (positive, ES, m / z): 378.19. 1 H NMR (400 MHz, DMSO) δ 8.73 - 8.54 (m, 2H), 7.88 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 3.0 Hz, 1H), 7.43 (d, J = 3.0 Hz, 1H), 7.00 (d, J = 5.7 Hz, 1H), 6.24 (dd, J = 17.1, 10.1 Hz, 1H), 6.10 (dd, J = 17.0, 2.3 Hz, 1H), 5.61 (dd, J = 10.0, 2.3 Hz, 1H), 4.51 - 4.39 (m, 2H), 2.34 (ddt, J = 9.6, 5.5, 2.0 Hz, 4H). Example 5: Synthesis of N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate was used in step 2. N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide was obtained as a white solid.

[0154] (positive, ES, m / z): 378.24. 1H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 8.42 (d, J = 7.2 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 3.0 Hz, 1H), 7.42 (d, J = 3.0 Hz, 1H), 6.93 (s, 1H), 6.27 - 6.05 (m, 2H), 5.60 (dd, J = 9.9, 2.5 Hz, 1H), 4.06 (dd, J = 16.6, 8.7 Hz, 2H), 2.84 - 2.72 (m, 2H), 1.98 - 1.84 (m, 2H). Example 6: Synthesis of N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]heptan-6-yl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate was used in Step 2. N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]heptan-6-yl)acrylamide was obtained as a white solid.

[0155] (positive, ES, m / z): 404.27. 1 H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.36 (d, J = 7.4 Hz, 1H), 7.77 - 7.68 (m, 3H), 7.66 - 7.53 (m, 3H), 6.21 - 6.02 (m, 2H), 5.59 (dd, J = 9.7, 2.6 Hz, 1H), 4.16 (d, J = 17.6 Hz, 3H), 4.03 (s, 2H), 2.56 - 2.54 (m, 2H), 2.14 (td, J = 8.8, 2.9 Hz, 2H). Example 7: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl pyrrolidin-3-ylcarbamate was used in step 2. N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide was obtained as a white solid.

[0156] (positive, ES, m / z): 378.28. 1 H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.33 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.69 - 7.49 (m, 5H), 6.21 (dd, J = 17.1, 10.0 Hz, 1H), 6.08 (dd, J = 17.1, 2.3 Hz, 1H), 5.58 (dd, J = 10.0, 2.3 Hz, 1H), 4.35 (q, J = 6.1 Hz, 1H), 3.74 (dd, J = 10.7, 6.5 Hz, 1H), 3.56 (d, J = 6.9 Hz, 2H), 3.31 (dd, J = 10.7, 5.3 Hz, 1H), 2.16 (dd, J = 12.6, 6.4 Hz, 1H), 1.86 (dd, J = 12.5, 6.2 Hz, 1H). Example 8: Synthesis of 1-(3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl 3-aminopyrrolidine-1-carboxylate was used in step 2. N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide was obtained as a white solid.

[0157] (positive, ES, m / z): 378.28. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 8.33 (d, J = 6.5 Hz, 1H), 7.76 (d, J = 2.7 Hz, 1H), 7.69 - 7.49 (m, 5H), 6.21 (dd, J = 17.1, 10.0 Hz, 1H), 6.08 (dd, J = 17.1, 2.3 Hz, 1H), 5.58 (dd, J = 10.0, 2.3 Hz, 1H), 4.35 (q, J = 6.1 Hz, 1H), 3.74 (dd, J = 10.7, 6.5 Hz, 1H), 3.56 (d, J = 6.9 Hz, 2H), 3.31 (dd, J = 10.7, 5.3 Hz, 1H), 2.16 (dd, J = 12.6, 6.4 Hz, 1H), 1.86 (dd, J = 12.5, 6.2 Hz, 1H). Example 9: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl piperidin-4-ylcarbamate was used in step 2. N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide was obtained as a white solid.

[0158] (positive, ES, m / z): 392.26. 1H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.84 - 7.76 (m, 2H), 7.62 (d, J = 8.6 Hz, 2H), 6.26 (dd, J = 17.1, 10.1 Hz, 1H), 6.09 (dd, J = 17.1, 2.3 Hz, 1H), 5.57 (dd, J = 10.1, 2.3 Hz, 1H), 3.84 (d, J = 11.2 Hz, 1H), 3.51 (d, J = 13.0Hz, 2H), 3.00 - 2.84 (m, 2H), 1.88 (d, J = 12.3 Hz, 2H), 1.77 - 1.65 (m, 2H). Example 10: Synthesis of N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide [ka] Following the general procedure in Scheme 3, tert-butyl (piperidin-3-ylmethyl)carbamate was used in Step 2. N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide was obtained as a white solid.

[0159] (positive, ES, m / z): 406.32. 1 H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 8.18 (t, J = 5.9 Hz, 1H), 7.88 - 7.76 (m, 4H), 7.59 (d, J = 8.7 Hz, 2H), 6.13 (dd, J = 17.1, 10.0 Hz, 1H), 6.00 (dd, J = 17.1, 2.3 Hz, 1H), 5.49 (dd, J = 10.0, 2.3 Hz, 1H), 3.77 - 3.53 (m, 4H), 3.18 - 2.97 (m, 2H), 1.99 (s, 1H), 1.83 - 1.65 (m, 3H), 1.24 - 1.01 (m, 1H). Example 11: Synthesis of 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl 2,5-diazabicyclo[2.2.1]heptane-2-carboxylate was used in Step 2. 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one was obtained as a white solid.

[0160] (positive, ES, m / z): 390.24. 1 H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.75 (d, J = 2.8 Hz, 1H), 7.67 (dd, J = 3.8, 2.8 Hz, 1H), 7.61 - 7.53 (m, 4H), 6.75 - 6.31 (m, 1H), 6.10 (ddd, J = 16.8, 9.3, 2.4 Hz, 1H), 5.63 (ddd, J = 14.3, 10.2, 2.4 Hz, 1H), 4.91 - 4.67 (m, 2H), 4.04 - 3.61 (m, 4H), 1.98 - 1.85 (m, 2H). Example 12: Synthesis of 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate was used in Step 2. 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one was obtained as a white solid.

[0161] (positive, ES, m / z): 404.30. 1H NMR (400 MHz, DMSO) δ 8.33 (s, 1H), 7.87 (q, J = 2.7 Hz, 2H), 7.72 - 7.54 (m, 4H), 6.74 (dd, J = 16.7, 10.4 Hz, 1H), 6.19 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.3, 2.4 Hz, 1H), 4.61 (d, J = 7.6 Hz, 2H), 3.45 (d, J = 12.0 Hz, 2H), 2.97 (dd, J = 17.1, 11.9 Hz, 2H), 2.03 - 1.68 (m, 4H). Example 13: Synthesis of (R)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (R)-2-methylpiperazine-1-carboxylate was used in Step 2. (R)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0162] (positive, ES, m / z): 392.1. 1 H NMR (400 MHz, DMSO) δ 8.34 (s, 1H), 7.89 (d, J = 2.8 Hz, 1H), 7.87 - 7.79 (m, 3H), 7.65 (d, J = 8.6 Hz, 2H), 6.81 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.6, 2.4 Hz, 1H), 5.70 (dd, J = 10.5, 2.4 Hz, 1H), 3.56 (d, J = 12.3 Hz, 1H), 3.43 - 3.30 (m, 4H), 2.93 (s, 1H), 2.68 (d, J = 9.5 Hz, 1H), 1.42 - 1.22 (m, 3H). Example 14: Synthesis of (S)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (S)-2-methylpiperazine-1-carboxylate was used in Step 2. (S)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0163] (positive, ES, m / z): 392.26. 1 H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 7.95 - 7.81 (m, 4H), 7.66 (d, J = 8.6 Hz, 2H), 6.83 (dd, J = 16.6, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.5 Hz, 1H), 5.71 (dd, J = 10.5, 2.4 Hz, 1H), 3.58 (d, J = 12.5 Hz, 1H), 3.35 (s, 4H), 2.94 (s, 1H), 2.81 - 2.62 (m, 1H), 1.36 (d, J = 6.7Hz, 3H). Example 15: Synthesis of (R)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (R)-2-(hydroxymethyl)piperazine-1-carboxylate was used in Step 2. (R)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0164] (positive, ES, m / z): 408.38. 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 3.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 3.1 Hz, 1H), 6.85 (td, J = 16.0, 10.4 Hz, 1H), 6.12 (dd, J = 16.6, 2.4 Hz, 1H), 5.68 (t, J = 8.8 Hz, 1H), 4.48 - 3.87 (m, 4H), 3.26 - 2.94 (m, 4H), 2.90 - 2.57 (m, 2H). Example 16: Synthesis of (S)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (S)-2-(hydroxymethyl)piperazine-1-carboxylate was used in Step 2. (S)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0165] (positive, ES, m / z): 408.46. 1 H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.79 (d, J = 3.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 3.0 Hz, 1H), 6.85 (td, J = 16.0, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.68 (td, J = 9.9, 2.5 Hz, 1H), 4.48 - 3.89 (m, 4H), 3.21 - 2.94 (m, 4H), 2.90 - 2.59 (m, 2H). Example 17: Synthesis of (S)-1-(2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl (S)-2-(2-hydroxyethyl)piperazine-1-carboxylate was used in Step 2. (S)-1-(2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0166] (positive, ES, m / z): 422.29. 1 H NMR (400 MHz, DMSO) δ 8.97 (s, 1H), 8.10 (d, J = 8.4 Hz, 2H), 7.76 (d, J = 3.0 Hz, 1H), 7.71 - 7.51 (m, 3H), 6.80 (dd, J = 16.6, 10.4 Hz, 1H), 6.18 - 5.98 (m, 1H), 5.73 - 5.53 (m, 1H), 4.52 (dq, J = 11.0, 5.7 Hz, 2H), 4.33 - 4.08 (m, 1H), 4.06 - 3.80 (m, 1H), 3.19 - 2.78 (m, 2H), 2.78 - 2.54 (m, 3H), 2.03 - 1.74 (m, 2H). Example 18: Synthesis of (R)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide Scheme 4 [ka] Step 1: Synthesis of 1-(tert-butyl) 2-methyl (R)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1,2-dicarboxylate [ka] In a 40 mL vial, 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (800 mg, 2.92 mmol, 1 equiv.), 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (749.91 mg, 3.07 mmol, 1.05 equiv.), toluene (10 mL), Pad(dppf)Cl (80 mg), Xantphos (120 mg), and CsCO (2857.64 mg, 8.77 mmol, 3 equiv.) were added at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 3 hours. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to afford 1-tert-butyl 2-methyl (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1,2-dicarboxylate (754.9 mg, 53.63%) as an off-white solid.

[0167] Step 2: Synthesis of methyl (R)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxylate [ka] In a 40 mL vial, 1-tert-butyl 2-methyl (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1,2-dicarboxylate (600 mg, 1.246 mmol, 1 equiv.), DCM (9 mL), and HCl / dioxane (2 mL, 4 M) were added at °C. The resulting mixture was stirred at room temperature for 1 hour. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0168] Step 3: Synthesis of (R)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide [ka] In a 40 mL vial, methyl (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-2-carboxylate (400 mg, 0.787 mmol, 1 equiv.) in MeOH (10 mL) and NH (g) were added at room temperature. The resulting mixture was stirred at 100° C. for 8 h. The desired product could be detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0169] Step 4: Synthesis of (R)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide [ka] A solution of (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-2-carboxamide (250 mg, 0.68 mmol, 1 equiv.) in DCM (5 mL) was treated with TEA (207.17 mg, 2.046 mmol, 3 equiv.) under a nitrogen atmosphere at 0 °C for 30 min, followed by the dropwise addition of acryloyl chloride (61.77 mg, 0.68 mmol, 1 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 11 h. The desired product could be detected by LCMS. The resulting mixture was extracted with CHCl (2 × 25 mL). The combined organic layers were washed with H0 (2 × 25 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash using the following conditions (acetonitrile:water / 0.05% NaHCO3 aqueous 33%-70% in 18 min) to give (2R)-1-(prop-2-enoyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-2-carboxamide (60 mg, 20.91%) as a white solid.

[0170] LCMS (ES, m / z): [M+H] + =421. 1H NMR (400 MHz, chloroform-d) δ 9.83 (s, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.95 (d, J = 2.8 Hz, 1H), 7.74 (d, J = 2.8 Hz, 1H), 7.61 (d, J = 8.4 Hz, 2H), 6.72 (d, J = 16.8 Hz, 2H), 6.51 (d, J = 1.8 Hz, 1H), 5.94 (d, J = 10.4 Hz, 1H), 5.57 (s, 1H), 5.35 (s, 1H), 4.28 - 4.14 (m, 2H), 3.57 - 3.37 (m, 3H), 2.67 (d, J = 12.8 Hz, 1H). Example 19: Synthesis of (S)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide [ka] Following the general procedure in Scheme 4, 1-(tert-butyl) 2-methyl (S)-piperazine-1,2-dicarboxylate was used in Step 1. (S)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide was obtained as a white solid.

[0171] (positive, ES, m / z): 421.61. 1 H NMR (400 MHz, DMSO) δ 9.60 (d, J = 9.1 Hz, 1H), 8.23 ​​(d, J = 8.6 Hz, 2H), 8.10 - 7.89 (m, 2H), 7.86 - 7.70 (m, 2H), 7.68 (d, J = 8.6 Hz, 2H), 6.97 - 6.79 (m, 1H), 6.21 (dd, J = 16.8, 2.3 Hz, 1H), 5.83 - 5.71 (m, 1H), 5.38 - 5.00 (m, 1H), 4.38 - 4.11 (m, 2H), 3.10 - 2.87 (m, 2H), 2.49 - 2.30 (m, 2H). Example 20: Synthesis of 2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide [ka] Following the general procedure in Scheme 4, tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate was used in Step 1. 2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide was obtained as a white solid.

[0172] (positive, ES, m / z): 435.36. 1 H NMR (400 MHz, DMSO) δ 8.71 - 8.33 (m, 1H), 7.97 - 7.80 (m, 4H), 7.66 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.09 - 6.73 (m, 2H), 6.14 (d, J = 16.6 Hz, 1H), 5.72 (d, J = 10.4 Hz, 1H), 5.00 - 4.53 (m, 1H), 4.47 - 3.87 (m, 1H), 3.75 - 3.46 (m, 3H), 3.01 - 2.66 (m, 4H). Example 21: Synthesis of (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile [ka] Following the general procedure in Scheme 3, tert-butyl (R)-2-(cyanomethyl)piperazine-1-carboxylate was used in Step 2. (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile was obtained as a white solid.

[0173] (positive, ES, m / z): 417.26. 1H NMR (400 MHz, DMSO) δ 8.41 (s, 1H), 8.01 - 7.79 (m, 4H), 7.69 (d, J = 8.5 Hz, 2H), 6.25 - 6.13 (m, 1H), 5.78 (d, J = 10.4 Hz, 1H), 5.10 (s, 1H), 3.84 - 3.49 (m, 4H), 3.01 (s, 3H). Example 22: Synthesis of (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile [ka] Following the general procedure in Scheme 3, tert-butyl (S)-2-(cyanomethyl)piperazine-1-carboxylate was used in Step 2. (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile was obtained as a white solid.

[0174] (positive, ES, m / z): 417.26. 1 H NMR (400 MHz, CDCl3) δ 8.07 - 8.02 (m, 2H), 7.98 (d, J = 2.2 Hz, 1H), 7.56 - 7.44 (m, 3H), 6.55 (d, J = 2.3 Hz, 1H), 6.19 (s, 1H), 4.38 (d, J = 12.3 Hz, 1H), 4.26 (dd, J = 12.3, 4.3 Hz, 1H), 4.16 (dp, J = 4.2, 2.0 Hz, 1H), 4.11 - 3.99 (m, 2H), 3.42 (s, 3H), 2.28 (ddp, J = 5.5, 3.7, 1.9Hz, 1H), 2.21 - 2.08 (m, 1H). Example 23: Synthesis of 1-(2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 5 [ka] Step 1: Synthesis of 3-chloro-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine [ka] In a 500 mL round-bottom flask, 3-chloropyrazin-2-amine (20.0 g, 154.38 mmol, 1 equiv.), 1-iodo-4-(trifluoromethyl)benzene (46.19 g, 169.82 mmol, 1.1 equiv.), Pd(dba) (2.0 g, 2.18 mmol, 0.01 equiv.), Xantphos (3.0 g, 5.18 mmol, 0.03 equiv.), CsCO (150.90 g, 463.14 mmol, 3 equiv.), and DMF (200 mL) were added at room temperature. The mixture was stirred at 90 °C under a nitrogen atmosphere for 6 h. The mixture was diluted with water (300 mL). The mixture was extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with water (2 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (15 g, 35.51%).

[0175] Step 2: Synthesis of tert-butyl 2-(2-methoxy-2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate [ka] In a 100 mL round-bottom flask, 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (3.0 g, 10.96 mmol, 1 equiv.), tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (3.12 g, 12.06 mmol, 1.1 equiv.), Pd(dba) (0.3 g, 0.33 mmol, 0.03 equiv.), Xantphos (0.45 g, 0.78 mmol, 0.07 equiv.), CsCO (10.72 g, 32.89 mmol, 3 equiv.), and DMF (30 mL) were added at room temperature. The resulting mixture was stirred at 90 °C under a nitrogen atmosphere for 4 h. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with water (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (5:1)) to give tert-butyl 2-(2-methoxy-2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (2.9 g, 53.38%).

[0176] Step 3: Synthesis of tert-butyl 2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 2-(2-methoxy-2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (2.2 g, 4.44 mmol, 1 equiv) was treated with THF (30 mL) at 0 °C for 5 min, followed by the addition of LiAlH (0.84 g, 22.20 mmol, 5 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The reaction was quenched with water / ice at 0 °C. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with water (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0177] Step 4: Synthesis of tert-butyl 2-(2-oxoethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate [ka] In a 40 mL vial, tert-butyl 2-(2-hydroxyethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (600 mg, 1.28 mmol, 1 equiv.), Dess-Martin (1.09 g, 2.56 mmol, 2 equiv.), and DCM (10 mL) were added at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (20 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (1 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0178] Step 5: Synthesis of tert-butyl 2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate [ka] In a 40 mL vial, tert-butyl 2-(2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (158 mg, 0.34 mmol, 1 equiv.), Seyfarth-Gilbert carboxylation (97.81 mg, 0.51 mmol, 1.5 equiv.), K2CO3 (140.74 mg, 1.02 mmol, 3 equiv.), and MeOH (5 mL) were added at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was diluted with water (10 mL). The mixture was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0179] Step 6: Synthesis of 3-(3-(prop-2-yn-1-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine [ka] In a 40 mL vial, tert-butyl 2-(prop-2-yn-1-yl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (120 mg, 0.26 mmol, 1 equiv.), TFA (6 mL), and DCM (18 mL) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0180] Step 7: Synthesis of 1-(2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of 3-[3-(prop-2-yn-1-yl)piperazin-1-yl]-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (100 mg, 0.27 mmol, 1 equiv.) in DCM (10 mL) was treated with TEA (84.01 mg, 0.83 mmol, 3 equiv.) at 0 °C for 5 min, followed by the dropwise addition of acryloyl chloride (25.05 mg, 0.27 mmol, 1 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with DCM (2 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash using the following conditions: (acetonitrile:water / 0.05% aqueous ammonia 25%-80% in 19 min) to give 1-[2-(prop-2-yn-1-yl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (88.3 mg, 75.51%) as a yellow solid.

[0181] 1H NMR (400 MHz, chloroform-d) δ 7.96 (s, 1H), 7.88 - 7.75 (m, 3H), 7.61 (d, J = 8.5 Hz, 2H), 7.31 (m, 1H), 6.64 (d, J = 13.9 Hz, 1H), 6.39 (d, J = 16.7 Hz, 1H), 5.81 (m, 1H), 4.85 (m, 1H), 4.22 (m, 1H), 3.76 (m, 2H), 3.35 (d, J = 12.2 Hz, 1H), 3.09 (m, 2H), 2.88 (m, 1H), 2.70 (m, 1H), 2.02 (s, 1H). Example 24: Synthesis of 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl 3-methylpiperazine-1-carboxylate was used in Step 2. 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0182] (positive, ES, m / z): 392.26. 1 H NMR (400 MHz, DMSO) δ 8.69 - 8.61 (m, 1H), 7.97 (d, J = 9.4 Hz, 3H), 7.89 (d, J = 2.8 Hz, 1H), 7.66 (d, J = 8.5 Hz, 2H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.17 (d, J = 17.1 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.06 - 3.68 (m, 5H), 3.22 (d, J = 9.6 Hz, 2H), 2.86 (ddd, J = 11.8, 6.9, 3.4Hz, 2H), 0.92 (d, J = 6.0 Hz, 3H). Example 25: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one Scheme 6 [ka] Step 1: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka] A solution of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (1.00 g, 3.65 mmol, 1.00 equiv), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.24 g, 4.02 mmol, 1.10 equiv), KCO (1.01 g, 7.31 mmol, 2.00 equiv), and Pd(dppf)Cl (0.27 g, 0.37 mmol, 0.10 equiv) in HO (3.00 mL) and dioxane (9.00 mL) was stirred at 90 °C for 3 h under N. The mixture was cooled and extracted with EA (3 × 30.00 mL). The combined organic layers were washed with HO (3 × 30.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (3:1)) to give tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.00 g, 65.08%) as a yellow solid.

[0183] LCMS-PH-CAL-Y-V2454220-1:(ES, m / z): [M+H] + =421 Step 2: Synthesis of 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (TFA salt) [ka] A 40 mL vessel was charged with a solution of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (370.00 mg, 0.88 mmol, 1.00 equiv) in DCM (1.50 mL) and TFA (1.50 mL). The mixture was stirred at room temperature for 1 hour and then concentrated under reduced pressure to afford 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (230 mg, 81.59%) as a yellow oil.

[0184] LCMS: (ES, m / z): [M+H] + =321. Step 3: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one [ka] In a 40 mL vessel, a solution of 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (210.00 mg, 0.66 mmol, 1.00 equiv) and TEA (199.03 mg, 1.97 mmol, 3.00 equiv) in DCM (3.00 mL) was placed. Acryloyl chloride (59.34 mg, 0.66 mmol, 1.00 equiv) was then added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. After the reaction was complete, the mixture was diluted with EA (45.00 mL), washed with HO (3 × 15.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (300.00 mg) was purified by Prep-HPLC under the following conditions (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Run number: 5) to give 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one (70.00 mg, 28.52%) as a yellow solid.

[0185] LCMS: (ES, m / z): [M+H] + =375. 1 H NMR (400 MHz, DMSO-d6): δ 8.74 (s, 1H), 8.11 (s, 2H), 7.81 (d, J = 11.6 Hz, 2H), 7.61 (d, J = 12.0 Hz, 2H), 6.95 - 6.86 (m, 1H), 6.33 - 6.13 (m, 2H), 5.74 - 5.70 (m, 1H), 4.29 - 4.22 (m, 2H), 3.80 - 3.78 (m, 2H), 2.61 - 2.58 (m, 2H). Example 26: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one Scheme 7 [ka] Step 1: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (500.00 mg, 1.189 mmol, 1.00 equiv) and Pd / C (12.66 mg, 0.12 mmol, 0.10 equiv) in MeOH (5.00 mL) was stirred overnight at 50 °C under an atmosphere of H (50 Psi). The resulting mixture was filtered, and the filter cake was washed with MeOH (3 × 5.00 mL). The filtrate was concentrated under reduced pressure. This afforded tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidine-1-carboxylate (500.00 mg, 99.52%) as a yellow solid.

[0186] LCMS ES, m / z: [M+H] + =423. Step 2: Synthesis of 3-(piperidin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine [ka] A solution of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidine-1-carboxylate (500.00 mg, 1.18 mmol, 1.00 equiv) and HCl / dioxane solution (6.00 mL) in DCM (2.00 mL) was stirred from 0 °C to room temperature for 1 h. The resulting mixture was concentrated under reduced pressure to afford 3-(piperidin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (280.00 mg, 73.39%) as a yellow solid.

[0187] LCMS ES, m / z: [M+H] + =323. Step 3: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one [ka] A solution of 3-(piperidin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (260.00 mg, 0.81 mmol, 1.00 equiv) and TEA (244.87 mg, 2.42 mmol, 3.00 equiv) in DCM (3.00 mL) was stirred at 0 °C, and acryloyl chloride (73.01 mg, 0.81 mmol, 1.00 equiv) was added. The mixture was stirred at room temperature for 1 h. The mixture was extracted with EA (3 × 10.00 mL). The combined organic layers were washed with HO (3 × 10.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 33% B to 56% B, 56% B in 16 min; Wavelength: 254 nm; RT1 (min): 7; Runs: 5) to give 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one (45.00 mg, 14.82%) as a white solid.

[0188] LCMS ES, m / z: 377. 1 H NMR (400 MHz, DMSO-d6): δ 8.80 (s, 1H), 8.06 (s, 2H), 7.84 (d, J = 4.2 Hz, 2H), 7.64 (d, J = 4.4 Hz, 2H), 6.90 - 6.81 (m, 1H), 6.15 - 6.10 (m, 1H), 5.70 - 5.66 (m, 1H), 4.71 - 4.52 (m, 1H), 4.38 - 4.14 (m, 1H), 3.62 - 3.44 (m, 1H), 3.32 - 3.30 (m, 1H), 2.72 - 2.52 (m, 1H), 1.89 - 1.85(m, 2H), 1.72 - 1.58 (m, 2H). Example 27: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, tert-butyl 1,4-diazepane-1-carboxylate was used in step 2. 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one was obtained as a white solid.

[0189] (positive, ES, m / z): 392.26. 1 H NMR (400 MHz, DMSO) δ 8.64 - 8.44 (m, 1H), 7.86 - 7.68 (m, 4H), 7.60 (dd, J = 8.6, 6.1 Hz, 2H), 6.85 - 6.62 (m, 1H), 6.22 - 5.99 (m, 1H), 5.75 - 5.58 (m, 1H), 3.85 - 3.62 (m, 3H), 3.59 - 3.37 (m, 5H), 1.90 - 1.74 (m, 2H). Example 28: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 8 [ka] Step 1: Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (0.20 g, 0.67 mmol, 1.00 equiv.), (4-(trifluoromethyl)phenyl)boronic acid (0.153 g, 0.80 mmol, 1.20 equiv.), and KCO (0.32 g, 2.34 mmol, 3.5 equiv.) in dioxane (10.00 mL) was added Pd(PPh) (0.077 g, 0.067 mmol, 0.1 equiv.) in a nitrogen atmosphere at room temperature. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere. The mixture was cooled to room temperature and extracted with NaCl (sat. aq. slon.) and EA. The organic layer was dried over NaSO and concentrated under reduced pressure. Purification by silica gel column chromatography (eluting with DCM:EA (10:1)) afforded tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate (178.00 mg, yield 65.11%) as a yellow solid.

[0190] Step 2: Synthesis of 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)pyrazine [ka] To a stirring mixture of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate (178 mg, 0.44 mmol, 1.00 equiv) in dioxane (2.00 mL) was added HCl (gas) in 1,4-dioxane (2.18 mL, 8.72 mmol, 20.00 equiv) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to afford 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)pyrazine (130 mg, 96.75% yield) as a yellow oil.

[0191] Step 3: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)pyrazine (100 mg, 0.32 mmol, 1.00 equiv) and TEA (134 mmL, 0.81 mmol, 2.50 equiv) in DCM (2.00 mL) at 0 °C. To the above mixture, acryloyl chloride (31 mmL, 0.39 mmol, 1.20 equiv) was added. The resulting mixture was stirred at 0 °C for an additional 0.5 h. The reaction was monitored by LCMS. To the resulting mixture was added 50.00 mL of HO and extracted with ethyl acetate (50.00 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (eluting with DCM:EA (3:7)) to afford 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one (65 mg, 55.3% yield) as a white solid.

[0192] (positive, ES, m / z): 363.26. 1 H NMR (400 MHz, DMSO) δ 8.31 - 8.21 (m, 2H), 8.14 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.2 Hz, 2H), 6.77 (dd, J = 16.6, 10.4 Hz, 1H), 6.10 (dd, J = 16.7, 2.4 Hz, 1H), 5.66 (dd, J = 10.4, 2.4 Hz, 1H), 3.58 (s, 4H), 3.12 (d, J = 15.6 Hz, 4H). Example 29: Synthesis of 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 8, (3-(trifluoromethyl)phenyl)boronic acid was used in Step 1. 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0193] (positive, ES, m / z): 363.26. 1 H NMR (400 MHz, DMSO) δ 8.29 (d, J = 2.5 Hz, 1H), 8.27 - 8.23 ​​(m, 3H), 7.87 - 7.70 (m, 2H), 6.77 (dd, J = 16.6, 10.4 Hz, 1H), 6.10 (dd, J = 16.7, 2.4 Hz, 1H), 5.67 (dd, J = 10.4, 2.4 Hz, 1H), 3.56 (d, J = 12.8 Hz, 4H), 3.10 (d, J = 6.5 Hz, 4H). Example 30: Synthesis of 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 3-(trifluoromethyl)aniline was used in step 2. 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0194] (positive, ES, m / z): 378.58. 1 H NMR (400 MHz, DMSO) δ 8.54 (s, 1H), 8.11 (t, J = 2.0 Hz, 1H), 8.02 (d, J = 8.2 Hz, 1H), 7.90 - 7.75 (m, 2H), 7.52 (t, J = 8.0 Hz, 1H), 7.33 - 7.25 (m, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 3.78 (d, J = 13.6 Hz, 4H), 3.13 (s, 4H). Example 31: Synthesis of 1-(4-(3-((4-(pentafluoro-16-sulfanayl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(pentafluoro-16-sulfanayl)aniline was used in step 2. 1-(4-(3-((4-(pentafluoro-16-sulfanayl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0195] (positive, ES, m / z): 436.1. 1 H NMR (400 MHz, DMSO) δ 8.72 (s, 1H), 7.92 - 7.83 (m, 4H), 7.83 - 7.74 (m, 2H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 3.77 (d, J = 12.5 Hz, 4H), 3.15 (d, J = 6.1 Hz, 4H). Example 32: Synthesis of 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-chloroaniline was used in step 2. 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0196] (positive, ES, m / z): 344.1. 1 H NMR (400 MHz, DMSO) δ 8.31 (s, 1H), 7.81 (d, J = 2.8 Hz, 1H), 7.78 - 7.66 (m, 3H), 7.38 - 7.23 (m, 2H), 6.84 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 3.77 (d, J = 9.7 Hz, 4H), 3.10 (t, J = 4.6 Hz, 4H). Example 33: Synthesis of 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-fluoroaniline was used in step 2. 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0197] (positive, ES, m / z): 328.46. 1 H NMR (400 MHz, DMSO) δ 8.20 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.74 - 7.63 (m, 3H), 7.14 (t, J = 8.9 Hz, 2H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 3.78 (d, J = 11.7 Hz, 4H), 3.17 - 2.95 (m, 4H). Example 34: Synthesis of 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(trifluoromethoxy)aniline was used in step 2. 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0198] (positive, ES, m / z): 394.55. 1H NMR (400 MHz, DMSO) δ 8.39 (s, 1H), 7.87 - 7.69 (m, 4H), 7.35 - 7.26 (m, 2H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.80 (s, 4H), 3.13 (s, 4H). Example 35: Synthesis of 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(difluoromethoxy)aniline was used in step 2. 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0199] (positive, ES, m / z): 376.1. 1 H NMR (400 MHz, DMSO) δ 8.26 (s, 1H), 7.79 (d, J = 2.8 Hz, 1H), 7.72 (dd, J = 9.4, 2.5 Hz, 3H), 7.36 - 6.94 (m, 3H), 6.89 - 6.76 (m, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.5, 2.4 Hz, 1H), 3.87 - 3.70 (m, 4H), 3.12 (p, J = 4.0 Hz, 4H). Example 36: Synthesis of 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(fluoromethoxy)aniline was used in step 2. 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0200] (positive, ES, m / z): 358.3. 1 H NMR (400 MHz, DMSO) δ 8.15 (s, 1H), 7.77 (d, J = 2.8 Hz, 1H), 7.70 (d, J = 2.9 Hz, 1H), 7.68 - 7.58 (m, 2H), 7.14 - 7.02 (m, 2H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.89 (s, 1H), 5.83 - 5.65 (m, 2H), 3.79 (d, J = 12.2 Hz, 4H), 3.11 (d, J = 6.5Hz, 4H). Example 37: Synthesis of 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 3-methoxy-4-(trifluoromethyl)aniline was used in step 2. 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0201] (positive, ES, m / z): 408.34. 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 7.94 - 7.82 (m, 2H), 7.65 (s, 1H), 7.55 - 7.46 (m, 2H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.6, 2.4 Hz, 1H), 5.73 (dd, J = 10.3, 2.4 Hz, 1H), 3.97 - 3.67 (m, 7H), 3.16 (d, J = 5.9 Hz, 4H). Example 38: Synthesis of 4-((3-(4-acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile [ka] Following the general procedure in Scheme 1, 4-aminobenzonitrile was used in step 2. 4-((3-(4-acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile was obtained as a white solid.

[0202] (positive, ES, m / z): 335.24. 1 H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.02 - 7.85 (m, 4H), 7.82 - 7.66 (m, 2H), 6.92 - 6.76 (m, 1H), 6.16 (dt, J = 16.7, 1.9 Hz, 1H), 5.72 (dt, J = 10.6, 1.8 Hz, 1H), 3.78 (d, J = 12.8 Hz, 4H), 3.16 (s, 4H). Example 39: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 5-(trifluoromethyl)pyridin-2-amine was used in step 2. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0203] (positive, ES, m / z): 379.27. 1 H NMR (400 MHz, DMSO) δ 9.01 (s, 1H), 8.63 (dt, J = 2.1, 1.0 Hz, 1H), 8.15 - 8.04 (m, 2H), 7.99 (s, 2H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.74 (d, J = 14.9 Hz, 4H), 3.16 (s, 4H). Example 40: Synthesis of 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 5-(difluoromethyl)pyridin-2-amine was used in step 2. 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0204] (positive, ES, m / z): 361.2. 1 H NMR (400 MHz, DMSO) δ 8.74 (s, 1H), 8.48 (s, 1H), 8.11 (d, J = 8.7 Hz, 1H), 8.06 - 7.92 (m, 3H), 7.25 - 6.90 (m, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.75 (d, J = 15.6 Hz, 4H), 3.14 (s, 4H). Example 41: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 5-(trifluoromethyl)pyrimidin-2-amine was used in step 2. 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0205] (positive, ES, m / z): 380.22. 1H NMR (400 MHz, DMSO) δ 10.36 (s, 1H), 8.89 - 8.74 (m, 2H), 8.15 (d, J = 2.6 Hz, 1H), 7.99 (d, J = 2.6 Hz, 1H), 6.79 (dd, J = 16.7, 10.5 Hz, 1H), 6.11 (dd, J = 16.6, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 3.50 (s, 4H), 3.32 - 3.28 (m, 4H). Example 42: Synthesis of 1-(4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 9 [ka] Step 1: Synthesis of tert-butyl 4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}pyrazin-2-yl)piperazine-1-carboxylate (1 g, 2.356 mmol, 1 equiv.), MeI (0.33 g, 2.356 mmol, 1 equiv.), and KCO (0.65 g, 4.712 mmol, 2 equiv.) in DMF (10 mL) was stirred at room temperature for 2 h. The product was precipitated by the addition of water. The crude product was used directly in the next step without further purification.

[0206] Step 2: Synthesis of N-methyl-3-(piperazin-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazin-2-amine [ka] A solution of tert-butyl 4-(3-{methyl[5-(trifluoromethyl)pyridin-2-yl]amino}pyrazin-2-yl)piperazine-1-carboxylate (300 mg, 0.684 mmol, 1 equiv) and TFA (1 mL, 13.463 mmol, 19.68 equiv) in DCM (4 mL) was stirred at room temperature for 1 h. The resulting mixture was concentrated under reduced pressure. The residual product was purified by reverse-phase flash to give N-methyl-3-(piperazin-1-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]pyrazin-2-amine (200 mg, 86.39%) as a yellow solid.

[0207] Step 3: Synthesis of 1-(4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of N-methyl-3-(piperazin-1-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]pyrazin-2-amine (200 mg, 0.591 mmol, 1 equiv.) and acryloyl chloride (53.50 mg, 0.591 mmol, 1.00 equiv.) in DCM (2 mL) was stirred at room temperature for 1 h. The resulting mixture was extracted with EtOAc (2 × 2 mL). The combined organic layers were dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue / crude product was purified by reverse-phase flash (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH3.HO), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B to 90% B, 90% B in 10 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to give 1-[4-(3-{methyl[5-(trifluoromethyl)pyridin-2-yl]amino}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (70 mg, 30.18%) as a white solid.

[0208] 1H NMR (400 MHz, DMSO-d6): δ 8.60 - 8.54 (m, 1H), 8.21 (d, J = 2.5 Hz, 1H), 8.04 (d, J = 2.5 Hz, 1H), 7.86 (dd, J = 9.0, 2.6 Hz, 1H), 6.81 - 6.69 (m, 2H), 6.09 (dd, J = 16.7, 2.4 Hz, 1H), 5.67 (dd, J = 10.5, 2.4 Hz, 1H), 3.47 (s, 3H), 3.22 (dd, J = 6.4, 3.7 Hz, 4H). Example 43: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 5, 3-chloro-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazin-2-amine was used in Step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0209] (positive, ES, m / z): 376.22. 1 H NMR (400 MHz, DMSO) δ 9.56 (d, J = 12.2 Hz, 1H), 8.53 (s, 1H), 8.28 (dd, J = 11.1, 2.7 Hz, 2H), 8.03 (dd, J = 9.1, 2.6 Hz, 1H), 7.78 (dd, J = 15.9, 8.8 Hz, 1H), 6.98 - 6.61 (m, 1H), 6.29 - 6.08 (m, 2H), 5.71 (ddd, J = 10.3, 4.8, 2.4 Hz, 1H), 4.22 - 4.03 (m, 2H), 3.74 (dt, J = 16.6, 5.6 Hz, 2H), 2.66 - 2.53 (m, 2H). Example 44: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used in Step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0210] (positive, ES, m / z): 378.28. 1 H NMR (400 MHz, DMSO) δ 9.80 (s, 1H), 8.60 (dt, J = 2.0, 1.0 Hz, 1H), 8.33 - 8.15 (m, 2H), 8.04 (dd, J = 9.0, 2.6 Hz, 1H), 7.84 (d, J = 8.9 Hz, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.68 (dd, J = 10.4, 2.5 Hz, 1H), 4.56 (d, J = 12.9 Hz, 1H), 4.18 (d, J = 13.7 Hz, 1H), 3.63 - 3.47 (m, 1H), 3.25 - 3.11 (m, 1H), 2.77 (t, J = 12.5 Hz, 1H), 1.86 (d, J = 12.8 Hz, 2H), 1.75 - 1.48 (m, 2H). Example 45: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 6-(trifluoromethyl)pyridin-3-amine was used in step 2. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0211] (positive, ES, m / z): 379.19. 1 H NMR (400 MHz, DMSO) δ 9.03 (d, J = 2.5 Hz, 1H), 8.88 (s, 1H), 8.39 (dd, J = 8.7, 2.5 Hz, 1H), 7.99 - 7.86 (m, 2H), 7.83 (d, J = 8.7 Hz, 1H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.92 - 3.69 (m, 4H), 3.19 (d, J = 6.1 Hz, 4H). Example 46: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 10 [ka] A solution of 2-fluoroacrylic acid (0.032 g, 0.37 mmol, 1.2 equiv.) in DMF (2 mL) was stirred at 0 °C for 5 min. HATU (0.14 g, 0.37 mmol, 1.2 equiv.) and DIPEA (153 mmL, 0.93 mmol, 3 equiv.) were then added dropwise. After stirring for an additional 5 min, 3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine (0.1 g, 0.31 mmol, 1 equiv.) was added. The reaction was continued at 0 °C for 1 h, after which it was quenched with HO (50 mL), NaCl (sat. aq. soln., 20 mL), and EtOAc (20 mL). The aqueous layer was separated and extracted with EA (3 × 20 mL). The combined organic phases were dried over NaSO and concentrated under reduced pressure, and purified by flash column chromatography (eluting with EA:DCM (2:3)) to afford 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one (80 mg, 65.46% yield) as a white solid.

[0212] (positive, ES, m / z): 397.06. 1 H NMR (400 MHz, DMSO) δ 9.03 (d, J = 2.5 Hz, 1H), 8.88 (s, 1H), 8.39 (dd, J = 8.7, 2.5 Hz, 1H), 7.95 - 7.87 (m, 2H), 7.84 (d, J = 8.7 Hz, 1H), 5.41 - 5.13 (m, 2H), 3.78 (t, J = 4.8 Hz, 4H), 3.23 (t, J = 5.1 Hz, 4H). Example 47: Synthesis of 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 6-(difluoromethyl)pyridin-3-amine was used in step 2. 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0213] (positive, ES, m / z): 361.77. 1 H NMR (400 MHz, DMSO) δ 8.96 (d, J = 2.5 Hz, 1H), 8.70 (s, 1H), 8.32 (dd, J = 8.5, 2.6 Hz, 1H), 7.97 - 7.82 (m, 2H), 7.65 (d, J = 8.6 Hz, 1H), 7.05 - 6.72 (m, 2H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.80 (d, J = 13.1 Hz, 4H), 3.17 (s, 4H). Example 48: Synthesis of 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 6-(trifluoromethoxy)pyridin-3-amine was used in step 2. 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0214] (positive, ES, m / z): 395.01. 1 H NMR (400 MHz, DMSO) δ 8.65 (d, J = 2.8 Hz, 1H), 8.58 (s, 1H), 8.30 (dd, J = 8.8, 2.8 Hz, 1H), 7.82 (q, J = 2.8 Hz, 2H), 7.30 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.80 (s, 4H), 3.16 (s, 4H). Example 49: Synthesis of 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 6-(difluoromethoxy)pyridin-3-amine was used in step 2. 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0215] (positive, ES, m / z): 377.63. 1H NMR (400 MHz, DMSO) δ 8.53 (d, J = 2.7 Hz, 1H), 8.41 (s, 1H), 8.18 (dd, J = 8.8, 2.8 Hz, 1H), 7.87 - 7.43 (m, 3H), 7.09 (d, J = 8.8 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.80 (s, 4H), 3.15 (d, J = 6.1 Hz, 4H). Example 50: Synthesis of 1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 5-fluoro-6-(trifluoromethyl)pyridin-3-amine was used in step 2. 1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0216] (positive, ES, m / z): 397.37. 1 H NMR (400 MHz, DMSO) δ 9.20 (d, J = 7.4 Hz, 1H), 8.84 (d, J = 9.0 Hz, 1H), 8.42 (d, J = 13.3 Hz, 1H), 7.96 (d, J = 7.8 Hz, 2H), 6.85 (d, J = 14.0 Hz, 1H), 6.16 (d, J = 10.8 Hz, 1H), 5.73 (d, J = 11.4 Hz, 1H), 3.78 (s, 4H), 3.19 (s, 4H). Example 51: Synthesis of 2-fluoro-1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-3-(piperazin-1-yl)pyrazin-2-amine was used to give 2-fluoro-1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one as a white solid.

[0217] (positive, ES, m / z): 397.37. 1 H NMR (400 MHz, DMSO) δ 9.20 (s, 1H), 8.85 (s, 1H), 8.42 (d, J = 13.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 5.39 - 5.14 (m, 2H), 3.76 (s, 4H), 3.23 (s, 4H). Example 52: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 2-(trifluoromethyl)pyrimidin-5-amine was used in step 2. 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0218] (positive, ES, m / z): 380.18. 1 H NMR (400 MHz, DMSO) δ 9.34 (s, 2H), 9.10 (s, 1H), 7.99 - 7.87 (m, 2H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.80 - 5.65 (m, 1H), 3.79 (d, J = 11.8 Hz, 4H), 3.21 (d, J = 6.4 Hz, 4H). Example 53: Synthesis of (S)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, tert-butyl (S)-2-methylpiperazine-1-carboxylate was used in step 1 and 6-(trifluoromethyl)pyridin-3-amine was used in step 2. (S)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0219] (positive, ES, m / z): 393.26. 1 H NMR (400 MHz, DMSO) δ 8.96 (d, J = 2.5 Hz, 1H), 8.60 (s, 1H), 8.32 (dd, J = 8.7, 2.5 Hz, 1H), 7.91 (s, 2H), 7.85 (d, J = 8.6 Hz, 1H), 6.83 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.6, 2.4 Hz, 1H), 5.72 (dd, J = 10.5, 2.4 Hz, 1H), 4.88 - 3.97 (m, 2H), 3.76 - 3.60 (m, 1H), 3.62 - 3.35 (m, 2H), 3.01 (d, J = 12.8 Hz, 1H), 2.70 (s, 1H), 1.33 (d, J = 6.7 Hz, 3H). Example 54: Synthesis of (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, tert-butyl (R)-2-methylpiperazine-1-carboxylate was used in step 1 and 6-(trifluoromethyl)pyridin-3-amine was used in step 2. (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0220] (positive, ES, m / z): 393.29. 1 H NMR (400 MHz, DMSO) δ 8.96 (d, J = 2.5 Hz, 1H), 8.60 (s, 1H), 8.32 (dd, J = 8.7, 2.6 Hz, 1H), 7.91 (s, 2H), 7.85 (d, J = 8.7 Hz, 1H), 6.83 (dd, J = 16.7, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.5, 2.4 Hz, 1H), 3.66 (d, J = 12.1 Hz, 2H), 3.56 - 3.36 (m, 2H), 3.02 (s, 1H), 2.69 (s, 1H), 1.46 - 1.22 (m, 3H). Example 55: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 3-chloro-N-(6-(trifluoromethyl)pyridin-2-yl)pyrazin-2-amine was used in Step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0221] (positive, ES, m / z): 376.29. 1H NMR (400 MHz, DMSO) δ 9.08 - 8.89 (m, 2H), 8.30 (d, J = 8.7 Hz, 1H), 8.16 (dt, J = 14.0, 2.4 Hz, 2H), 7.82 (d, J = 8.6 Hz, 1H), 7.00 - 6.72 (m, 1H), 6.37 (d, J = 14.9 Hz, 1H), 6.19 (ddd, J = 16.7, 9.6, 2.4 Hz, 1H), 5.75 (td, J = 9.6, 2.4 Hz, 1H), 4.39 - 4.17 (m, 2H), 3.87 - 3.74 (m, 2H), 2.70 - 2.55 (m, 2H). Example 56: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine was used in Step 1. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0222] (positive, ES, m / z): 394.32. 1 H NMR (400 MHz, DMSO) δ 9.04 - 8.88 (m, 2H), 8.30 (d, J = 8.3 Hz, 1H), 8.22 - 7.99 (m, 2H), 7.82 (d, J = 8.7 Hz, 1H), 6.37 (s, 1H), 5.44 - 5.17 (m, 2H), 4.38 - 4.15 (m, 2H), 3.79 (t, J = 5.8 Hz, 2H), 2.67 (s, 2H). Example 57: Synthesis of 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 3-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)pyrazin-2-amine was used in Step 1. 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0223] (positive, ES, m / z): 392.76. 1 H NMR (400 MHz, DMSO) δ 8.70 (d, J = 4.0 Hz, 1H), 8.55 (s, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 12.2 Hz, 2H), 7.28 (d, J = 8.8 Hz, 1H), 6.99 - 6.75 (m, 1H), 6.35 (d, J = 14.0 Hz, 1H), 6.18 (dd, J = 17.1, 9.1 Hz, 1H), 5.75 (t, J = 9.4 Hz, 1H), 4.39 - 4.18 (m, 2H), 3.81 (d, J = 8.1 Hz, 2H), 2.62 (s, 2H). Example 58: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyrazin-2-amine was used in Step 1. 2-Fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0224] (positive, ES, m / z): 410.78. 1H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 8.56 (dd, J = 2.7, 1.3 Hz, 1H), 8.20 (dd, J = 8.8, 2.6 Hz, 1H), 8.11 - 7.98 (m, 2H), 7.28 (d, J = 8.8 Hz, 1H), 6.36 (s, 1H), 5.45 - 5.13 (m, 2H), 4.36 - 4.15 (m, 2H), 3.78 (t, J = 5.7 Hz, 2H), 2.65 (s, 2H). Example 59: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, N-(3-chloropyrazin-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine was used in Step 1. 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0225] (positive, ES, m / z): 410.78. 1 H NMR (400 MHz, DMSO) δ 9.41 - 9.10 (m, 3H), 8.29 - 8.01 (m, 2H), 7.01 - 6.78 (m, 1H), 6.41 (d, J = 12.7 Hz, 1H), 6.19 (dd, J = 16.5, 10.4 Hz, 1H), 5.75 (dd, J = 11.2, 8.8 Hz, 1H), 4.38 - 4.19 (m, 2H), 3.91 - 3.74 (m, 2H), 3.32 (s, 1H), 2.68 - 2.57 (m, 2H). Example 60: Synthesis of 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)-2-(trifluoromethyl)pyrimidin-5-amine was used in Step 1. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0226] (positive, ES, m / z): 395.08. 1 H NMR (400 MHz, DMSO) δ 9.40 - 9.10 (m, 3H), 8.33 - 8.09 (m, 2H), 6.42 (s, 1H), 5.44 - 5.13 (m, 2H), 4.40 - 4.17 (m, 2H), 3.80 (t, J = 5.6 Hz, 2H), 3.32 (s, 1H), 2.68 (s, 2H). Example 61: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(3-((6-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used in Step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0227] (positive, ES, m / z): 378.27. 1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 8.98 (d, J = 2.6 Hz, 1H), 8.33 (dd, J = 8.7, 2.5 Hz, 1H), 8.21 - 8.02 (m, 2H), 7.84 (d, J = 8.6 Hz, 1H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.69 (dd, J = 10.5, 2.5 Hz, 1H), 4.60 (d, J = 12.9 Hz, 1H), 4.22 (d, J = 13.5 Hz, 1H), 3.51 (dtd, J = 11.6, 7.7, 4.0 Hz, 1H), 3.26 (t, J = 13.2 Hz, 1H), 2.94 - 2.74 (m, 1H), 1.90 (d, J = 13.0 Hz, 2H), 1.76 - 1.50 (m, 2H). Example 62: Synthesis of 1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, tert-butyl 3-aminoazetidine-1-carboxylate was used in step 1 and 6-(trifluoromethyl)pyridin-3-amine was used in step 2. 1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0228] (positive, ES, m / z): 365.2. 1H NMR (400 MHz, DMSO) δ 8.87 (d, J = 8.4 Hz, 2H), 8.41 (d, J = 11.1 Hz, 1H), 7.82 (q, J = 6.3 Hz, 1H), 7.71 - 7.47 (m, 2H), 7.28 (s, 1H), 6.36 (d, J = 14.6 Hz, 1H), 6.14 (d, J = 14.0 Hz, 1H), 5.70 (d, J = 10.8 Hz, 1H), 4.62 (d, J = 9.9 Hz, 2H), 4.32 (s, 1H), 4.07 (s, 1H), 3.91 (s, 1H). Example 63: Synthesis of 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N 2 -(azetidin-3-yl)-N 3 -(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2,3-diamine was used. 2-Fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0229] (positive, ES, m / z): 383.31. 1 H NMR (400 MHz, DMSO) δ 8.97 - 8.80 (m, 2H), 8.40 (dd, J = 8.7, 2.6 Hz, 1H), 7.83 (d, J = 8.7 Hz, 1H), 7.66 (d, J = 2.9 Hz, 1H), 7.54 (d, J = 3.0 Hz, 1H), 7.29 (d, J = 5.5 Hz, 1H), 5.61 - 5.41 (m, 1H), 5.33 (dd, J = 16.6, 3.6 Hz, 1H), 4.88 - 4.61 (m, 2H), 4.46 - 4.33 (m, 1H), 4.29 - 4.17 (m, 1H), 3.95 (dd, J = 10.7, 4.8 Hz, 1H). Example 64: Synthesis of 2-fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N 2 -(azetidin-3-yl)-N 3 -(6-(trifluoromethoxy)pyridin-3-yl)pyrazine-2,3-diamine was used. 2-Fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0230] (positive, ES, m / z): 399.2. 1 H NMR (400 MHz, DMSO) δ 8.64 - 8.51 (m, 2H), 8.29 (dd, J = 8.9, 2.8 Hz, 1H), 7.58 (d, J = 3.0 Hz, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.29 (d, J = 8.8 Hz, 1H), 7.19 (d, J = 5.5 Hz, 1H), 5.57 - 5.41 (m, 1H), 5.32 (dd, J = 16.6, 3.6 Hz, 1H), 4.85 - 4.62 (m, 2H), 4.44 - 4.33 (m, 1H), 4.23 (s, 1H), 4.01 - 3.88 (m, 1H). Example 65: Synthesis of 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(azetidin-3-yloxy)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine was used. 2-Fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0231] (positive, ES, m / z): 384.41. 1 H NMR (400 MHz, DMSO) δ 9.33 (s, 1H), 9.17 (dd, J = 5.6, 2.5 Hz, 1H), 8.81 - 8.54 (m, 1H), 7.93 - 7.62 (m, 2H), 6.74 - 6.53 (m, 1H), 5.77 - 5.28 (m, 3H), 4.85 (s, 1H), 4.65 - 4.41 (m, 1H), 4.29 - 4.11 (m, 1H), 3.98 (d, J = 14.4 Hz, 1H), 3.77 (q, J = 17.3 Hz, 1H). Example 66: Synthesis of 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4,4-difluorocyclohexan-1-amine was used in step 2. 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0232] (positive, ES, m / z): 352.28. 1 H NMR (400 MHz, DMSO) δ 7.70 (d, J = 2.9 Hz, 1H), 7.47 (d, J = 2.9 Hz, 1H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.92 (d, J = 7.8 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 4.03 (s, 1H), 3.76 (d, J = 14.1 Hz, 4H), 3.02 (s, 4H), 2.16 - 1.84 (m, 6H), 1.74 (t, J = 11.3 Hz, 2H). Example 67: Synthesis of 1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-amine was used in step 2. 1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0233] (positive, ES, m / z): 368.02. 1 H NMR (400 MHz, DMSO) δ 7.76 (d, J = 2.9 Hz, 1H), 7.57 (d, J = 2.8 Hz, 1H), 7.05 (s, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.75 (d, J = 12.1 Hz, 4H), 3.00 (s, 4H), 2.37 (s, 6H). Example 68: Synthesis of 2-fluoro-1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)pyrazin-2-amine was used. 2-Fluoro-1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0234] (positive, ES, m / z): 386.66. 1H NMR (400 MHz, DMSO) δ 7.77 (d, J = 2.8 Hz, 1H), 7.57 (d, J = 2.9 Hz, 1H), 7.07 (s, 1H), 5.36 - 5.13 (m, 2H), 3.74 (t, J = 5.0 Hz, 4H), 3.04 (t, J = 5.1 Hz, 4H), 2.37 (s, 6H). Example 69: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 11 [ka] Step 1: Synthesis of tert-butyl 4-{3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl}piperazine-1-carboxylate [ka] In a 40 mL vial, tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (500 mg, 1.32 mmol, 1.00 equiv.), 4-(trifluoromethyl)phenol (1069.73 mg, 6.60 mmol, 5.00 equiv.), CuI (25 mg, 0.13 mmol, 0.10 equiv.), KPO (840.41 mg, 3.96 mmol, 3.00 equiv.), N,N-bis(2-thienylmethyl)-ethanediamide (25 mg, 0.08 mmol, 0.07 equiv.), and DMSO (10 mL) were added at room temperature. The resulting mixture was stirred at 110 °C under a nitrogen atmosphere for 8 hours. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (2:1)) to afford tert-butyl 4-{3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl}piperazine-1-carboxylate (250 mg, 18.4%) as a white solid.

[0235] LCMS ES, m / z: [M+H] + =425 Step 2: Synthesis of 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenoxy)pyrazine (HCl salt) [ka] A solution of tert-butyl 4-[3-(4-tert-butylphenoxy)pyrazin-2-yl]piperazine-1-carboxylate (230 mg, 0.55 mmol, 1.00 equiv) and HCl (4 M in dioxane) (1 mL, 32.91 mmol, 59.03 equiv) in CHCl (3.0 mL) was stirred under a nitrogen atmosphere at 0 °C for 2 h. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0236] LCMS ES, m / z: [M+H] + =325 Step 3: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of 2-(4-tert-butylphenoxy)-3-(piperazin-1-yl)pyrazine (226.5 mg, 0.725 mmol, 1.00 equiv) in DCM (4.0 mL) was treated with TEA (212.21 mg, 2.09 mmol, 2.89 equiv) under a nitrogen atmosphere at 0°C for 5 min, followed by the dropwise addition of acryloyl chloride (66.06 mg, 0.73 mmol, 1.01 equiv) at 0°C. The resulting mixture was concentrated and purified by reverse phase flash using the following conditions (acetonitrile:water / 0.05% ammonia in 18 min, 25%-67% water) to give 1-(4-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one (220 mg, 82.81%) as a white solid.

[0237] LCMS (ES, m / z: [M+H] + =379. 1H NMR (400 MHz, DMSO-d6): δ 8.02-7.98(m,1H), 7.85-7.78 (m, 2H), 7.63-7.58(m, 1H),7.48-7.40 (m, 2H),6.89-6.79 (m, 1H), 6.20-6.11 (m, 1H), 5.75-5.68 (m, 1H), 3.80-3.63 (m, 4H), 3.63-3.48(m, 4H). Example 70: Synthesis of 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 4-methoxyphenol was used in step 1. 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0238] (positive, ES, m / z): 341.23. 1 H NMR (400 MHz, DMSO) δ 7.90 (d, J = 2.8 Hz, 1H), 7.55 (d, J = 2.7 Hz, 1H), 7.18 - 7.05 (m, 2H), 7.04 - 6.92 (m, 2H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.3 Hz, 1H), 3.78 (s, 3H), 3.77 - 3.68 (m, 4H), 3.63 - 3.48 (m, 4H). Example 71: Synthesis of 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 4-(difluoromethoxy)phenol was used in step 1. 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0239] (positive, ES, m / z): 377.13. 1 H NMR (400 MHz, DMSO) δ 7.95 (d, J = 2.8 Hz, 1H), 7.58 (d, J = 2.8 Hz, 1H), 7.48 - 7.03 (m, 5H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.83 - 3.64 (m, 4H), 3.58 (t, J = 5.1 Hz, 4H). Example 72: Synthesis of 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 4-(trifluoromethoxy)phenol was used in step 1. 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0240] (positive, ES, m / z): 395.27. 1 H NMR (400 MHz, DMSO) δ 7.97 (d, J = 2.8 Hz, 1H), 7.59 (d, J = 2.8 Hz, 1H), 7.50 - 7.39 (m, 2H), 7.41 - 7.29 (m, 2H), 6.85 (dd, J = 16.8, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.72 (d, J = 17.7 Hz, 4H), 3.57 (d, J = 6.8 Hz, 4H). Example 73: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 5-(trifluoromethyl)pyridin-2-ol was used in step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0241] (positive, ES, m / z): 380.26. 1 H NMR (400 MHz, DMSO) δ 8.69 (d, J = 3.4 Hz, 1H), 8.36 (dd, J = 8.5, 3.1 Hz, 1H), 8.15 (q, J = 2.5 Hz, 1H), 7.77 (q, J = 2.5 Hz, 1H), 7.49 (dd, J = 9.0, 3.3 Hz, 1H), 6.81 (dd, J = 16.7, 10.6 Hz, 1H), 6.13 (dt, J = 16.7, 2.2 Hz, 1H), 5.70 (dt, J = 10.4, 2.3 Hz, 1H), 3.69 - 3.45 (m, 8H). Example 74: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 2-chloro-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazine was used in Step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0242] (positive, ES, m / z): 377.21. 1H NMR (400 MHz, DMSO) δ 8.68 (d, J = 2.6 Hz, 1H), 8.65 - 8.54 (m, 1H), 8.37 (dd, J = 8.7, 2.6 Hz, 1H), 8.33 - 8.21 (m, 1H), 7.51 (d, J = 8.6 Hz, 1H), 6.93 - 6.69 (m, 2H), 6.13 (dd, J = 16.8, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.4 Hz, 1H), 4.38 - 4.12 (m, 2H), 3.71 (dt, J = 16.3, 5.7 Hz, 2H), 2.77 - 2.54 (m, 2H). Example 75: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used in Step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0243] (positive, ES, m / z): 391.54. 1H NMR (400 MHz, DMSO) δ 8.84 (d, J = 2.4 Hz, 1H), 8.67 - 8.55 (m, 2H), 7.92 (dd, J = 9.7, 2.8 Hz, 1H), 6.84 (td, J = 10.7, 5.0 Hz, 1H), 6.75 (d, J = 9.7 Hz, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.68 (d, J = 10.6 Hz, 1H), 4.60 - 4.40 (m, 1H), 4.26 - 4.02 (m, 1H), 3.09 (t, J = 13.0 Hz, 1H), 2.93 - 2.79 (m, 1H), 2.76 - 2.61 (m, 1H), 1.89 (s, 1H), 1.74 (t, J = 14.4 Hz, 2H), 1.59 (d, J = 12.9 Hz, 1H). Example 76: Synthesis of 2-fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperidin-4-yl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0244] (positive, ES, m / z): 397.03. 1 H NMR (400 MHz, DMSO) δ 8.70 (s, 1H), 8.53 (d, J = 2.6 Hz, 1H), 8.38 (d, J = 8.9 Hz, 1H), 8.26 (d, J = 2.6 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H), 5.33 - 5.08 (m, 2H), 3.31 (s, 2H), 1.94 (d, J = 13.3 Hz, 2H), 1.75 (s, 2H). Example 77: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 6-(trifluoromethyl)pyridin-3-ol was used in step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0245] (positive, ES, m / z): 380.22. 1 H NMR (400 MHz, DMSO) δ 8.77 (t, J = 1.7 Hz, 1H), 8.04 (t, J = 2.3 Hz, 3H), 7.61 (d, J = 2.7 Hz, 1H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.73 (dd, J = 17.9, 5.7 Hz, 4H), 3.61 (d, J = 6.1 Hz, 4H). Example 78: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperazin-1-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0246] (positive, ES, m / z): 398.17. 1H NMR (400 MHz, DMSO) δ 8.77 (s, 1H), 8.04 (d, J = 2.1 Hz, 3H), 7.62 (t, J = 2.3 Hz, 1H), 5.39 - 5.15 (m, 2H), 3.77 - 3.63 (m, 8H). Example 79: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used in Step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0247] (positive, ES, m / z): 379.23. 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1.7 Hz, 1H), 8.41 (d, J = 2.6 Hz, 1H), 8.07 (dd, J = 9.7, 2.2 Hz, 3H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.13 (dd, J = 16.7, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.5 Hz, 1H), 4.58 (d, J = 13.0 Hz, 1H), 4.22 (d, J = 13.6 Hz, 1H), 3.51 (tt, J = 11.6, 3.7 Hz, 1H), 3.28 (t, J = 13.0 Hz, 1H), 2.86 (t, J = 12.5 Hz, 1H), 2.11 - 1.94 (m, 2H), 1.86 - 1.57 (m, 2H). Example 80: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0248] (positive, ES, m / z): 447.1. 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1.8 Hz, 1H), 8.42 (d, J = 2.7 Hz, 1H), 8.07 (dd, J = 13.1, 2.2 Hz, 3H), 6.24 (s, 1H), 6.02 (s, 1H), 4.53 (d, J = 13.0 Hz, 1H), 3.96 (d, J = 13.5 Hz, 1H), 3.54 (t, J = 11.6 Hz, 1H), 3.00 (d, J = 12.9 Hz, 1H), 2.17 - 1.97 (m, 2H), 1.90 - 1.53 (m, 2H). Example 81: Synthesis of 2-(trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine and 2-(trifluoromethyl)acrylic acid were used. 2-(trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0249] (positive, ES, m / z): 447.1. 1H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.42 (d, J = 2.6 Hz, 1H), 8.15 - 7.97 (m, 3H), 6.24 (s, 1H), 6.02 (s, 1H), 4.53 (d, J = 13.0 Hz, 1H), 3.95 (d, J = 13.6 Hz, 1H), 3.54 (t, J = 11.4 Hz, 1H), 3.33 (s, 1H), 2.98 (t, J = 13.1 Hz, 1H), 2.05 (t, J = 17.8 Hz, 2H), 1.88 - 1.65 (m, 2H). Example 82: Synthesis of 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid Scheme 12 [ka] Step 1: Synthesis of 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine [ka] To a solution of 2,3-dichloropyrazine (18 g, 120.830 mmol, 1 equiv.) and 6-(trifluoromethyl)pyridin-3-ol (15.77 g, 96.664 mmol, 0.8 equiv.) in DMSO (200 mL) was added CsCO (59.05 g, 181.245 mmol, 1.5 equiv.), followed by stirring at room temperature for 2 h. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3 × 300 mL). The combined organic layers were washed with saturated brine (2 × 300 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (3:1). This gave 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (21 g, 63.06%) as a yellow solid.

[0250] LCMS (positive, ES, m / z): 276.1 Step 2: Synthesis of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate [ka] To a solution of 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (1.1 g, 3.991 mmol, 1 equiv.) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.48 g, 4.789 mmol, 1.2 equiv.) in dioxane / HO (10 mL / 1 mL) was added KCO (1.65 g, 11.973 mmol, 3 equiv.) and Pd(dppf)Cl.CHCl (0.33 g, 0.399 mmol, 0.1 equiv.). After stirring at 100 °C under a nitrogen atmosphere for 5 h, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / THF (3:1)) to give tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (1.65 g, 97.87%) as a yellow solid.

[0251] LCMS (positive, ES, m / z): 423.2 Step 3: Synthesis of tert-butyl-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (800 mg, 1.894 mmol, 1 equiv.) and Rh(PPh3)3Cl2 (181.60 mg, 0.189 mmol, 0.1 equiv.) in MeOH (6 mL) and THF (3 mL) was stirred overnight at room temperature under a hydrogen atmosphere (10 atm). The mixture was concentrated under reduced pressure and purified by silica gel column chromatography (eluting with PE / EA (1:1)). This afforded tert-butyl-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate (720 mg, 89.44%) as a white solid.

[0252] LCMS (positive, ES, m / z): 425.0. Step 4: Synthesis of 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine [ka] A mixture of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate (5 g, 11.781 mmol, 1 equiv.) in DCM (40 mL) and TFA (10 mL) was stirred at room temperature for 2 h. The resulting mixture was concentrated under reduced pressure to afford 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine) (3.6 g, 94.03%) as a white solid. The crude material was used directly in the next step without further purification.

[0253] LCMS-PH (positive, ES, m / z): 325.3. Step 5: Synthesis of methyl 2-{[4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-1-yl]methyl}prop-2-enoate [ka] To a solution of 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (500 mg, 1.542 mmol, 1 equiv.) and methyl 2-(bromomethyl)prop-2-enoate (331.19 mg, 1.850 mmol, 1.2 equiv.) in MeCN (10 mL) was added NaI (277.32 mg, 1.850 mmol, 1.2 equiv.) and KCO (639.23 mg, 4.626 mmol, 3 equiv.) and stirred at 60 °C for 2 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 20 mL). The organic layers were combined, washed with saturated brine (2 × 20 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give methyl 2-{[4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-1-yl]methyl}prop-2-enoate (647 mg, 72.82%) as an orange oil. The crude product was used directly in the next step without further purification.

[0254] Step 6: Synthesis of 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid [ka] To a solution of methyl 2-{[4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-1-yl]methyl}prop-2-enoate (600 mg, 1.420 mmol, 1 equiv.) in THF / HO (8 mL, 3:1), LiOH·HO (238.40 mg, 5.680 mmol, 4 equiv.) was added and stirred at room temperature for 12 h. The mixture was acidified to pH 6 with 1 N HCl (aq.) and extracted with EtOAc (3 × 30 mL). The organic layers were combined, washed with saturated brine (2 × 30 mL), dried over anhydrous NaSO, and concentrated. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 90 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Runs: 5) to give 2-{[4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-1-yl]methyl}prop-2-enoic acid (330 mg, 56.89%) as a white solid.

[0255] LCMS (positive, ES, m / z): 409.2. 1 H NMR (300 MHz, DMSO-d6) δ 8.75 (d, J = 2.0 Hz, 1H), 8.41 (d, J = 2.7 Hz, 1H), 8.05 (d, J = 2.7 Hz, 1H), 8.03 (d, J = 1.7 Hz, 2H), 5.88 (d, J = 3.2 Hz, 1H), 5.38 (d, J = 2.9 Hz, 1H), 3.20 (s, 3H), 3.03 (d, J = 11.2 Hz, 2H), 2.18 (dd, J = 12.1, 8.5 Hz, 2H), 1.97 - 1.80 (m, 4H). Example 83: Synthesis of 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one Scheme 13 [ka] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate [ka] To a stirred solution of 2-bromo-3-chloropyrazine (1.6 g, 8.27 mmol, 1 equiv.) in THF (20 mL) was added n-BuLi (1.06 g, 16.54 mmol, 2 equiv.) dropwise at −78°C under a nitrogen atmosphere. The resulting mixture was stirred at −78°C for 1 h. To the above mixture was added a solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.81 g, 9.10 mmol, 1.1 equiv.) in THF (10 mL) dropwise over 10 min at −78°C. The resulting mixture was stirred at −78°C for an additional 1 h. After completion of the reaction, the reaction was quenched with HO (20 mL). The resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 50.09%) as a yellow oil.

[0256] LCMS: (ES, m / z): [M+H] + =314 Step 2: Synthesis of tert-butyl 4-hydroxy-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 4.14 mmol, 1 equiv.) and 6-(trifluoromethyl)pyridin-3-ol (743.30 mg, 4.56 mmol, 1.1 equiv.) in DMAc (15 mL, 161.32 mmol, 38.94 equiv.) was added K2CO3 (1145.17 mg, 8.29 mmol, 2.0 equiv.) at room temperature. The mixture was stirred at 110 °C overnight. The reaction was quenched by adding water (100 mL) at room temperature. The mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (2 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: ACN in water (0.1% FA), 10% to 40% gradient in 10 min; detection: UV 254 nm), which gave tert-butyl 4-hydroxy-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate (250 mg, 13.70%) as a white solid.

[0257] LCMS (ES, m / z): [M+H] + =441. Step 3: Synthesis of 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol [ka] To a stirred solution of tert-butyl 4-hydroxy-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate (250 mg, 0.568 mmol, 1 equiv.) in DCM (3 mL) was added dropwise HCl (gas) in 1,4-dioxane (0.50 mL, 16.46 mmol, 29.0 equiv.) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The resulting mixture was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography using the following conditions: column, C18 silica gel; mobile phase, ACN in water (10 mmol / L NH4HCO3), 5% to 25% gradient in 10 min; detection, UV at 254 nm. This gave 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol (120 mg, 62.12%) as a yellow solid.

[0258] LCMS (ES, m / z): [M+H] + =341. Step 4: Synthesis of 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] A solution of 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol (120 mg, 0.353 mmol, 1 equiv) and TEA (71.37 mg, 0.70 mmol, 2 equiv) in DCM (5 mL) was stirred at 0 °C, followed by the dropwise addition of acryloyl chloride (63.83 mg, 0.70 mmol, 2 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The reaction was quenched with water / ice (5 mL) at 0 °C. The resulting mixture was extracted with DCM (3 × 10 mL). The combined organic layers were washed with brine (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC under the following conditions (column: X-Bridge Prep OBD C18 column, 30 × 150 mm, 5 μm; mobile phase A: water (0.1% NH₃·HO), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B → 41% B, 41% B in 8 min; wavelength: 220 nm; RT (min): 7.56) to give 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one as a white solid (4 mg, 2.88%).

[0259] LCMS (ES, m / z): [M+H] + =395. 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.6 Hz, 1H), 8.43 (d, J = 2.6 Hz, 1H), 8.18 (d, J = 2.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.93 (dd, J = 8.5, 2.6 Hz, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.09 (dd, J = 16.7, 2.5 Hz, 1H), 5.66 (dd, J = 10.4, 2.5 Hz, 1H), 5.53 (s, 1H), 4.25 (m, 1H), 3.95 (m, 1H), 3.57 (m, 1H), 3.22 (m, 1H), 2.35-2.05 (m, 4H). Example 84: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 2-chloro-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used in Step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0260] (positive, ES, m / z): 377.21. 1 H NMR (400 MHz, DMSO) δ 8.78 (t, J = 1.6 Hz, 1H), 8.47 (t, J = 2.5 Hz, 1H), 8.13 - 7.97 (m, 3H), 7.06 - 6.76 (m, 2H), 6.17 (dt, J = 16.8, 3.3 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.47 - 4.25 (m, 2H), 3.80 (dt, J = 14.1, 5.6 Hz, 2H), 2.83 - 2.63 (m, 2H). Example 85: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(1,2,3,6-tetrahydropyridin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0261] (positive, ES, m / z): 395.31. 1 H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.47 (d, J = 2.5 Hz, 1H), 8.07 (d, J = 16.8 Hz, 3H), 7.02 (s, 1H), 5.42 - 5.15 (m, 2H), 4.44 - 4.17 (m, 2H), 3.78 (t, J = 5.6 Hz, 2H), 2.79 (s, 2H). Example 86: Synthesis of 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid [ka] Following the general procedure in Scheme 12, 2-(azetidin-3-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used in step 5. 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid was obtained as a white solid.

[0262] (positive, ES, m / z): 381.1. 1H NMR (400 MHz, DMSO) δ 8.74 (t, J = 1.7 Hz, 1H), 8.44 (d, J = 2.7 Hz, 1H), 8.11 - 7.95 (m, 3H), 5.70 (d, J = 3.7 Hz, 1H), 5.15 (d, J = 3.6 Hz, 1H), 4.10 (t, J = 7.8 Hz, 1H), 3.70 (t, J = 7.4 Hz, 2H), 3.21 (s, 2H). Example 87: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 11, 2-(trifluoromethyl)pyrimidin-5-ol was used in step 1. 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0263] (positive, ES, m / z): 381.02. 1 H NMR (400 MHz, DMSO) δ 9.18 (s, 2H), 8.08 (d, J = 2.7 Hz, 1H), 7.63 (d, J = 2.7 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.17 (dd, J = 16.7, 2.4 Hz, 1H), 5.74 (dd, J = 10.4, 2.4 Hz, 1H), 3.83 - 3.67 (m, 4H), 3.63 (dd, J = 6.7, 3.5 Hz, 4H). Example 88: Synthesis of 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-((3-(piperazin-1-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0264] (positive, ES, m / z): 399.08. 1 H NMR (400 MHz, DMSO) δ 9.17 (s, 2H), 8.08 (d, J = 2.3 Hz, 1H), 7.64 (d, J = 2.4 Hz, 1H), 5.40 - 5.16 (m, 2H), 3.77 - 3.65 (m, 8H). Example 89: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 5-((3-chloropyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used in Step 1. 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0265] (positive, ES, m / z): 378.3. 1 H NMR (400 MHz, DMSO) δ 9.19 (s, 2H), 8.52 (d, J = 2.5 Hz, 1H), 8.11 (s, 1H), 7.09 - 6.76 (m, 2H), 6.17 (d, J = 17.0 Hz, 1H), 5.74 (dd, J = 10.5, 2.4 Hz, 1H), 4.48 - 4.24 (m, 2H), 3.82 (dd, J = 13.7, 7.0 Hz, 2H), 2.79 - 2.70 (m, 2H). Example 90: Synthesis of 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-((3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0266] (positive, ES, m / z): 396.1. 1 H NMR (400 MHz, DMSO) δ 9.18 (d, J = 8.1 Hz, 2H), 8.52 (d, J = 7.9 Hz, 1H), 8.12 (d, J = 7.4 Hz, 1H), 7.03 (s, 1H), 5.42 - 5.14 (m, 2H), 4.47 - 4.18 (m, 2H), 3.78 (d, J = 7.7 Hz, 2H), 2.78 (s, 2H). Example 91: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used in Step 1. 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0267] (positive, ES, m / z): 380.59. 1H NMR (400 MHz, DMSO) δ 9.18 (s, 2H), 8.45 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 6.88 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.7, 2.4 Hz, 1H), 5.70 (dd, J = 10.4, 2.5 Hz, 1H), 4.59 (d, J = 13.1 Hz, 1H), 4.22 (d, J = 13.7 Hz, 1H), 3.60 - 3.46 (m, 1H), 3.23 (d, J = 10.9 Hz, 1H), 2.86 (t, J = 12.8 Hz, 1H), 2.03 (d, J = 13.6 Hz, 2H), 1.86 - 1.56 (m, 2H). Example 92: Synthesis of 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0268] (positive, ES, m / z): 398.05. 1 H NMR (400 MHz, DMSO) δ 9.18 (s, 2H), 8.46 (d, J = 2.7 Hz, 1H), 8.11 (d, J = 2.7 Hz, 1H), 5.39 - 5.08 (m, 2H), 4.43 (s, 1H), 4.06 (s, 1H), 3.56 (tt, J = 11.4, 3.6 Hz, 1H), 3.32 (s, 1H), 3.00 (s, 1H), 2.20 - 1.98 (m, 2H), 1.78 (s, 2H). Example 93: Synthesis of 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one Scheme 14 [ka] Step 1: Synthesis of tert-butyl 4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazine-1-carboxylate [ka] A solution of 4,4-difluorocyclohexan-1-ol (0.30 g, 2.20 mmol, 1.50 equiv) in DMF (1.00 mL) was treated with NaH (117.51 ​​mg, 2.94 mmol, 2.00 equiv, 60%) under a nitrogen atmosphere at 0 °C for 0.5 h, followed by the dropwise addition of tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (438.91 mg, 1.47 mmol, 1.00 equiv) at room temperature. The resulting mixture was stirred at room temperature for 3 h and then diluted with HO (50.00 mL). The aqueous layer was extracted with DCM (3 × 50.00 mL). The organic phase was washed with brine (4 × 50.00 mL) and dried over anhydrous NaSO. After removal of the solvent, the residue was purified by silica gel column chromatography (eluted with THF (1:10)) to give tert-butyl 4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazine-1-carboxylate (0.30 g, 45.56%) as a white solid.

[0269] LCMS ES, m / z: 399.2. Step 2: Synthesis of 2-((4,4-difluorocyclohexyl)oxy)-3-(piperazin-1-yl)pyrazine [ka] A solution of tert-butyl 4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazine-1-carboxylate (300.00 mg, 0.75 mmol, 1.00 equiv) and HCl (gas) in 1,4-dioxane (1.00 mL, 32.91 mmol, 43.71 equiv) in DCM (5.00 mL) was stirred at room temperature for 1 h. The mixture was concentrated under reduced pressure to afford 2-((4,4-difluorocyclohexyl)oxy)-3-(piperazin-1-yl)pyrazine (0.20 g, 89.29% yield) as a white solid, which was used directly in the next step without further purification.

[0270] LCMS ES, m / z: 299.2 Step 3: Synthesis of 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one [ka] To a stirred solution of 2-[(4,4-difluorocyclohexyl)oxy]-3-(piperazin-1-yl)pyrazine (200.00 mg, 0.75 mmol, 1.00 equiv) and TEA (228.55 mg, 2.26 mmol, 3.00 equiv) in DCM (5.00 mL) was added acryloyl chloride (68.14 mg, 0.75 mmol, 1.00 equiv) dropwise at 0 °C under a N atmosphere. After the reaction was complete, the mixture was extracted with EA (3 × 15.00 mL). The combined organic layers were washed with HO (3 × 15.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (270.05 mg) was purified by Prep-HPLC under the following conditions (column: XBridge C18, 19 × 150 mm, 5 μm; mobile phase A: 20 mM NH4HCO3 + 0.05% NH3H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 min) to give 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one.

[0271] LCMS ES, m / z: 353.2. 1H NMR (400 MHz, DMSO-d6): δ .7.78-7.77 (m, 1H), 7.62-7.61 (m, 1H), 6.87-6.80 (m, 1H), 6.15-6.11 (m, 1H), 5.71-5.68(m, 1H), 5.28-5.27(m, 1H),3.69-3.65(m, 4H),3.46(m, 4H),2.07-1.91(m, 8H). Example 94: Synthesis of 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 13, 4-(trifluoromethyl)cyclohexan-1-ol was used in step 1. 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0272] (positive, ES, m / z): 385.33. 1 H NMR (400 MHz, DMSO) δ 7.77 (d, J = 3.0 Hz, 1H), 7.62 (d, J = 2.9 Hz, 1H), 6.84 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (d, J = 16.7 Hz, 1H), 5.72 (d, J = 10.5 Hz, 1H), 5.00 (s, 1H), 3.67 (d, J = 18.0 Hz, 4H), 3.45 (s, 4H), 2.40 (s, 1H), 2.30 - 2.11 (m, 2H), 2.03 - 1.86 (m, 2H), 1.67 - 1.34 (m, 4H). Example 95: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 15 [ka] Step 1: Synthesis of (3-bromopyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol [ka] A solution of 2-bromopyrazine (4 g, 25.15 mmol, 1 equiv.) in THF was treated with LDA (27 mL, 199.10 mmol, 7.91 equiv.) under a nitrogen atmosphere at −78° C. for 20 minutes, followed by the dropwise addition of 4-(trifluoromethyl)benzaldehyde (6.57 g, 37.73 mmol, 1.5 equiv.) at −78° C. The resulting mixture was stirred at −40° C. under a nitrogen atmosphere for 30 minutes. The resulting mixture was quenched with 100.00 mL of HO at −40° C. and then extracted with ethyl acetate (100.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to give (3-bromopyrazin-2-yl)[4-(trifluoromethyl)phenyl]methanol (4.3 g, 51.31%) as a yellow solid.

[0273] Step 2: Synthesis of (3-bromopyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanone [ka] A solution of (3-bromopyrazin-2-yl)[4-(trifluoromethyl)phenyl]methanol (1 g, 3.00 mmol, 1 equiv.) and Dess-Martin periodinane (2.55 g, 6.00 mmol, 2 equiv.) in DCM was stirred at room temperature under a nitrogen atmosphere for 2 h. 100.00 mL of HO was added to the resulting mixture, which was then extracted with ethyl acetate (100.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to afford 2-bromo-3-[4-(trifluoromethyl)benzoyl]pyrazine (980 mg, 98.60%) as a white solid.

[0274] Step 3: Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazine-1-carboxylate [ka] In a 40 mL vial, 2-bromo-3-[4-(trifluoromethyl)benzoyl]pyrazine (3 g, 9.06 mmol, 1 equiv.), tert-butyl piperazine-1-carboxylate (2.53 g, 13.59 mmol, 1.5 equiv.), Xantphos (0.47 g, 0.81 mmol, 0.09 equiv.), CsCO (8.86 g, 27.18 mmol, 3 equiv.), Pd(dba) (0.33 g, 0.36 mmol, 0.04 equiv.), and 1,4-dioxane (30 mL) were added at room temperature. The resulting mixture was stirred at 80 °C under a nitrogen atmosphere for 3 h. 100 mL of HO was added to the resulting mixture, which was then extracted with ethyl acetate (100 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (3:1)) to afford tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazine-1-carboxylate (3.6 g, 91.04%) as a white solid.

[0275] Step 4: Synthesis of (3-(piperazin-1-yl)pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanone (HCl salt) [ka] In a 40 mL vial, tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazine-1-carboxylate (530 mg, 1.21 mmol, 1 equiv.), DCM (4 mL), and HCl (gas) in 1,4-dioxane (2 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure to give 2-(piperazin-1-yl)-3-[4-(trifluoromethyl)benzoyl]pyrazine (400 mg, 98%) as a white solid.

[0276] Step 5: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of 2-(piperazin-1-yl)-3-[4-(trifluoromethyl)benzoyl]pyrazine (400 mg, 1.18 mmol, 1 equiv.) in DCM was treated with TEA (361.06 mg, 3.56 mmol, 3 equiv.) under a nitrogen atmosphere at 0° C. for 3 minutes, followed by the dropwise addition of acryloyl chloride (113.03 mg, 1.24 mmol, 1.05 equiv.) at 0° C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product (200 mg) was purified by prep-HPLC under the following conditions (column: YMC-Actus Triart C18, 250 × 50 mm, 10 μm; mobile phase A: 0.1% NH₃·H₂O, mobile phase B: ACN; flow rate: 80 mL / min; gradient: 15% B to 50% B in 17 min) to give 1-(4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one (70 mg, 14.78%) as a yellow solid.

[0277] LCMS: (ES, m / z): [M+H] + =391. 1 H NMR (400 MHz, DMSO-d6) δ 8.37 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 2.4 Hz, 1H), 7.93 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 10.4 Hz, 1H), 6.13 (d, J = 2.4 Hz, 1H), 5.69 (d, J = 2.4 Hz, 1H), 3.66 (d, J = 27.8 Hz, 4H), 3.46 (d, J = 23.2 Hz, 4H). Example 96: Synthesis of 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 15, 6-(trifluoromethyl)nicotinaldehyde was used in step 1. 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0278] (positive, ES, m / z): 392.22. 1 H NMR (400 MHz, DMSO) δ 9.28 (d, J = 2.0 Hz, 1H), 8.65 - 8.53 (m, 1H), 8.42 (d, J = 2.1 Hz, 1H), 8.12 (dd, J = 8.2, 0.9 Hz, 1H), 8.05 (d, J = 2.2 Hz, 1H), 6.79 (dd, J = 16.6, 10.4 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.83 - 3.62 (m, 4H), 3.64 - 3.44 (m, 4H). Example 97: Synthesis of 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 16 [ka] Step 1: Synthesis of tert-butyl 4-(3-{hydroxyl[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazine-1-carboxylate [ka] In a 40 mL vial, tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazine-1-carboxylate (500 mg, 1.14 mmol, 1 equiv.), NaBH (43.34 mg, 1.14 mmol, 1 equiv.), and MeOH (5 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 30 minutes. The desired product could be detected by LCMS. 50 mL of HO was added to the resulting mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-{hydroxyl[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazine-1-carboxylate (450 mg, crude) as a white solid. The crude product was used directly in the next step without further purification.

[0279] Step 2: Synthesis of (3-(piperazin-1-yl)pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (HCl salt) [ka] In a 40 mL vial, tert-butyl 4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazine-1-carboxylate (400 mg, 0.91 mmol, 1 equiv.), DCM (3 mL), and HCl (gas) in 1,4-dioxane (4 M, 1.5 mL) were added at room temperature. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. The resulting mixture was concentrated under reduced pressure to give 1-[4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (450 mg, 97.00%) as a white solid.

[0280] Step 3: Synthesis of 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of [3-(piperazin-1-yl)pyrazin-2-yl][4-(trifluoromethyl)phenyl]methanol (200 mg, 0.59 mmol, 1 equiv.) in DMA was treated with NaHCO3 (148.98 mg, 1.77 mmol, 3 equiv.) under a nitrogen atmosphere at 0 °C for 3 min, followed by the dropwise addition of acryloyl chloride (56.18 mg, 0.62 mmol, 1.05 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. 20.00 mL of HO was added to the resulting mixture, which was then extracted with ethyl acetate (50.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 90 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Run number: 5) to give 1-[4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one as a yellow solid.

[0281] LCMS: (ES, m / z): [M+H] + =393. 1 H NMR (400 MHz, CDCL3) δ 8.42 - 8.29 (m, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 10.4 Hz, 1H), 6.34 (d, J = 16.8, Hz, 1H), 6.06 (s, 1H), 5.76 (d, J = 10.4 Hz, 1H), 3.72-3.58 (m, 4H), 3.22 (dt, J = 10.8 Hz, 2H), 3.01 (d, J = 5.2 Hz, 2H). Example 98: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 17 [ka] Step 1: Synthesis of 2-(piperazin-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine [ka] A solution of tert-butyl 4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazine-1-carboxylate (400 mg, 0.91 mmol, 1 equiv.) and triethylsilane (106.08 mg, 0.91 mmol, 1 equiv.) in TFA was stirred at room temperature under a nitrogen atmosphere for 2 hours. The resulting mixture was concentrated under reduced pressure to give 2-(piperazin-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine (360 mg, crude) as a white solid. The crude product was used directly in the next step without further purification.

[0282] Step 2: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] A solution of 2-(piperazin-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine (300 mg, 0.93 mmol, 1 equiv.) in DCM was treated with TEA (282.54 mg, 2.79 mmol, 3 equiv.) under a nitrogen atmosphere at 0 °C for 3 min, followed by the dropwise addition of acryloyl chloride (88.45 mg, 0.97 mmol, 1.05 equiv.) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 2 h. The desired product could be detected by LCMS. 50 mL of HO was added to the resulting mixture, which was then extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 60 mL / min; Gradient: 40% B → 60% B, 56% B in 16 min; Wavelength: 254 nm; RT1 (min): 7; Run number: 5) to give 1-[4-(3-{[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (70 mg, 19.98%) as a yellow oil.

[0283] LCMS: (ES, m / z): [M+H]+=377. 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (d, J = 2.8 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 10.4 Hz, 1H), 6.14 (d, J = 2.4 Hz, 1H), 5.71 (d, J = 2.4 Hz, 1H), 4.31 (s, 2H), 3.71 (s, 4H), 3.12 (t, J = 5.2 Hz, 4H). Example 99: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide Scheme 18 [ka] Step 1: Synthesis of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid [ka] To a stirred solution of 3-chloropyrazine-2-carboxylic acid (1580 mg, 10 mmol, 1 equiv) and tert-butyl piperazine-1-carboxylate (2790 mg, 15 mmol, 1.5 equiv) in CHCN (30 mL) was added t-BuONa (1920 mg, 20 mmol, 2.0 equiv) and stirred at room temperature for 2 h. The mixture was quenched with HO (30 mL), the pH was adjusted to 5–6 with 1 N HCl (aq.), and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine (1 × 100 mL), dried over anhydrous NaSO, concentrated under reduced pressure, and purified by C column chromatography (ACN / HO: 20%) to give 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid (2100 mg, 68.18%) as a white solid.

[0284] Step 2: Synthesis of tert-butyl 4-[3-(cyclobutylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate [ka] To a stirred solution of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid (802 mg, 2.60 mmol, 1 equiv.), cyclobutylamine (222 mg, 3.12 mmol, 1.2 equiv.), and DIEA (1008 mg, 7.80 mmol, 3 equiv.) in DCM (8 mL) was added HATU (1186 mg, 3.12 mmol, 1.2 equiv.) in portions and stirred at room temperature for 1 h. The mixture was quenched with HO (30 mL) and extracted with DCM (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, concentrated under reduced pressure, and purified by silica gel column chromatography (Combiflash, PE / THF=4:1) to give tert-butyl 4-[3-(cyclobutylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate (745 mg, 79.24%) as a white solid.

[0285] Step 3: Synthesis of N-cyclobutyl-3-(piperazin-1-yl)pyrazine-2-carboxamide [ka] To a stirred solution of tert-butyl 4-[3-(cyclobutylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate (342 mg, 0.94 mmol, 1 equiv.) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (1 mL, 4 mmol, 4.255 equiv.) at room temperature and stirred for 1 h. The resulting mixture was concentrated under reduced pressure to give N-cyclobutyl-3-(piperazin-1-yl)pyrazine-2-carboxamide (240 mg, 97.06%) as a white solid.

[0286] Step 4: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide [ka] Acryloyl chloride (142.14 mg, 1.571 mmol, 1.2 equiv) was added dropwise to a stirred solution of N-cyclobutyl-3-(piperazin-1-yl)pyrazine-2-carboxamide (342 mg, 1.309 mmol, 1.0 equiv) and TEA (397.29 mg, 3.927 mmol, 3 equiv) in DCM (4 mL) at 0 °C and stirred for 1 h. The reaction was quenched with water (20 mL) and extracted with DCM (3 × 30 mL). The combined organic phases were washed with brine (1 × 50 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The crude material was purified by Prep-HPLC under the following conditions (column: XBridge C18, 19 × 150 mm, 5 μm; mobile phase A: 20 mM NH4HCO3 + 0.05% NH3H2O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 min) to give N-cyclobutyl-3-[4-(prop-2-enoyl)piperazin-1-yl]pyrazine-2-carboxamide (63 mg, 15.26%) as a white solid.

[0287] LCMS (ES, m / z): [M+H] + =316. 1 H NMR (400 MHz, chloroform-d) δ 8.20 (d, J = 2.3 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 8.3 Hz, 1H), 6.59 (dd, J = 16.8, 10.5 Hz, 1H), 6.32 (dd, J = 16.8, 1.9 Hz, 1H), 5.73 (dd, J = 10.5, 1.9 Hz, 1H), 4.52 (m, 1H), 3.80 (d, J = 26.6 Hz, 4H), 3.57 - 3.50 (m, 4H), 2.48 - 2.36 (m, 2H), 2.08 - 1.93 (m, 2H), 1.84 - 1.75 (m, 2H). Example 100: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide [ka] Following the general procedure in Scheme 18, 3,3-difluorocyclobutan-1-amine was used in step 2. 3-(4-acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide was obtained as a white solid.

[0288] (positive, ES, m / z): 352.36. 1H NMR (400 MHz, DMSO) δ 9.19 (d, J = 6.8 Hz, 1H), 8.27 (d, J = 2.4 Hz, 1H), 8.00 (d, J = 2.3 Hz, 1H), 6.83 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.8, 2.3 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.31 - 4.13 (m, 1H), 3.72 - 3.58 (m, 4H), 3.45 - 3.43 (m, 4H), 3.32 (d, J = 3.2 Hz, 1H), 2.96 (t, J = 7.0 Hz, 2H), 2.87 - 2.67 (m, 2H). Example 101: Synthesis of 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 18, 6-(trifluoromethyl)-2-azaspiro[3.3]heptane was used in Step 2. 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0289] (positive, ES, m / z): 410.36. 1 H NMR (400 MHz, DMSO) δ 8.23 ​​(t, J = 2.6 Hz, 1H), 7.97 (t, J = 2.7 Hz, 1H), 6.83 (dd, J = 16.7, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 4.25 - 4.03 (m, 4H), 3.76 - 3.59 (m, 4H), 3.50 - 3.40 (m, 4H), 3.17 - 3.00 (m, 1H), 2.51 - 2.19 (m, 4H). Example 102: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide [ka] Cyclopentamine was used in step 2 according to the general procedure in Scheme 18. 3-(4-acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide was obtained as a white solid.

[0290] (positive, ES, m / z): 330.02. 1 H NMR (400 MHz, DMSO) δ 8.58 (s, 1H), 8.23 ​​(d, J = 8.3 Hz, 1H), 7.97 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.16 (d, J = 15.3 Hz, 1H), 5.71 (s, 1H), 4.16 (s, 1H), 3.74 - 3.54 (m, 8H), 1.88 (s, 2H), 1.67 (s, 2H), 1.53 (s, 4H). Example 103: Synthesis of 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 18, 4-(trifluoromethyl)piperidine was used in step 2. 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0291] (positive, ES, m / z): 398.32. 1H NMR (400 MHz, DMSO) δ 8.26 (d, J = 2.5 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 6.83 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.60 (d, J = 13.2 Hz, 1H), 3.71 - 3.61 (m, 4H), 3.46 (td, J = 12.8, 6.0 Hz, 4H), 3.22 - 3.11 (m, 1H), 2.87 (td, J = 13.1, 2.9 Hz, 1H), 2.69 (s, 1H), 1.97 (d, J = 12.7 Hz, 1H), 1.80 (d, J = 12.9 Hz, 1H), 1.43 (pd, J = 12.8, 4.5 Hz, 2H), 1.28 (t, J = 2.3 Hz, 1H). Example 104: Synthesis of 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 18, 4-(difluoromethyl)piperidine was used in step 2. 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0292] (positive, ES, m / z): 366.1. 1 H NMR (400 MHz, DMSO) δ 8.25 (s, 1H), 7.99 (s, 1H), 6.81 (d, J = 14.6 Hz, 1H), 6.16 (d, J = 14.8 Hz, 1H), 5.72 (s, 1H), 3.93 - 3.53 (m, 12H), 2.04 (s, 4H). Example 105: Synthesis of 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 4-(trifluoromethyl)piperidine was used in step 2. 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0293] (positive, ES, m / z): 370.35. 1 H NMR (400 MHz, DMSO) δ 7.85 - 7.73 (m, 2H), 6.87 (dd, J = 16.6, 10.4 Hz, 1H), 6.15 (dd, J = 16.6, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.17 (d, J = 12.8 Hz, 2H), 3.85 - 3.62 (m, 4H), 2.66 (t, J = 12.2 Hz, 2H), 1.95 (d, J = 12.6 Hz, 2H), 1.64 - 1.43 (m, 2H). Example 106: Synthesis of 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 3-phenylazetidine was used in step 2. 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0294] (positive, ES, m / z): 350.3. 1H NMR (400 MHz, DMSO) δ 7.81 (d, J = 2.8 Hz, 1H), 7.69 (t, J = 2.5 Hz, 1H), 7.47 - 7.21 (m, 6H), 6.90 - 6.77 (m, 1H), 6.14 (ddd, J = 16.9, 4.0, 2.5 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.43 (t, J = 8.2 Hz, 2H), 4.04 - 3.87 (m, 3H), 3.72 (d, J = 14.7 Hz, 4H), 3.63 (d, J = 6.7 Hz, 1H), 3.14 (s, 4H). Example 107: Synthesis of 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 3-(4-fluorophenyl)azetidine was used in step 2. 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0295] (positive, ES, m / z): 368.29. 1 H NMR (400 MHz, DMSO) δ 7.81 (d, J = 2.8 Hz, 1H), 7.69 (d, J = 2.8 Hz, 1H), 7.53 - 7.39 (m, 2H), 7.25 - 7.10 (m, 2H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.49 - 4.35 (m, 2H), 4.04 - 3.86 (m, 3H), 3.72 (d, J = 13.9 Hz, 4H), 3.14 (s, 4H). Example 108: Synthesis of 1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, tert-butyl 3-aminoazetidine-1-carboxylate was used in step 1 and 3-(4-fluorophenyl)azetidine was used in step 2. 1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0296] (positive, ES, m / z): 354.79. 1 H NMR (400 MHz, DMSO) δ 7.48 (q, J = 3.9 Hz, 4H), 7.19 (t, J = 8.8 Hz, 2H), 6.43 (d, J = 6.3 Hz, 1H), 6.37 - 6.26 (m, 1H), 6.10 (d, J = 17.2 Hz, 1H), 5.67 (dd, J = 10.0, 2.2 Hz, 1H), 4.67 - 4.42 (m, 4H), 4.27 - 4.16 (m, 1H), 4.10 - 3.98 (m, 3H), 3.93 - 3.83 (m, 2H). Example 109: Synthesis of 2-fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(azetidin-3-yl)-3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-amine was used. 2-Fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0297] (positive, ES, m / z): 372.71. 1H NMR (400 MHz, DMSO) δ 7.48 (q, J = 4.8 Hz, 4H), 7.19 (t, J = 8.7 Hz, 2H), 6.43 (d, J = 5.5 Hz, 1H), 5.56 - 5.23 (m, 2H), 4.63 (s, 2H), 4.47 (q, J = 8.8 Hz, 2H), 4.25 (d, J = 7.3 Hz, 2H), 4.04 (q, J = 8.0 Hz, 2H), 3.90 (q, J = 7.7 Hz, 2H). Example 110: Synthesis of 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 6-(trifluoromethyl)-2-azaspiro[3.3]heptane was used in step 2. 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0298] (positive, ES, m / z): 382.39. 1 H NMR (400 MHz, DMSO) δ 7.76 (d, J = 2.8 Hz, 1H), 7.64 (d, J = 2.8 Hz, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.5, 2.4 Hz, 1H), 4.04 (s, 2H), 3.96 (s, 2H), 3.72 (d, J = 13.5 Hz, 4H), 3.09 (s, 5H), 2.46 (dd, J = 13.1, 9.1 Hz, 2H), 2.30 (dd, J = 13.1, 7.4 Hz, 2H). Example 111: Synthesis of 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one Scheme 19 [ka] Step 1: Synthesis of 5-bromo-6-chloropyrazin-2-ol [ka] To a stirred solution of 5-bromo-6-chloropyrazin-2-amine (10 g, 48.5 mmol, 1.00 equiv) in HSO (60 mL) was added NaNO (3.68 g, 53.3 mmol, 1.10 equiv) in portions at 0 °C. The resulting mixture was stirred at 0 °C for 1 h. The reaction was quenched by adding ice-water (200 mL) at 0 °C. The precipitated solid was collected by filtration, washed with water (2 × 300 mL), and then dried to give 5-bromo-6-chloropyrazin-2-ol (5.5 g, 54.78%) as an off-white solid.

[0299] Step 2: Synthesis of 5-(benzyloxy)-2-bromo-3-chloropyrazine [ka] To a stirred solution of 5-bromo-6-chloropyrazin-2-ol (5.4 g, 25.784 mmol, 1 equiv.) and benzyl bromide (8.82 g, 51.568 mmol, 2 equiv.) in toluene (60 mL) was added AgCO (7.47 g, 27.073 mmol, 1.05 equiv.) at 0 °C. The mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure. The residue was dissolved in water (150 mL) and extracted with EtOAc (3 × 100 mL). The combined organic phases were washed with brine (1 × 100 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (THF / PE = 25%) to give 5-(benzyloxy)-2-bromo-3-chloropyrazine (6 g, 77.68%) as a white solid.

[0300] Step 3: Synthesis of 6-(benzyloxy)-3-bromo-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine [ka] p-Trifluoromethylaniline (1.62 g, 10.063 mmol, 1.2 equiv) was added to a stirred solution of 5-(benzyloxy)-2-bromo-3-chloropyrazine (2.512 g, 8.386 mmol, 1 equiv) and t-BuOK (1.88 g, 16.772 mmol, 2 equiv) in DMAc (50 mL) at room temperature. The mixture was stirred at 100 °C for 2 h. Water (200 mL) was added to the mixture, and the aqueous layer was extracted with EA (3 × 200 mL). The combined organic phases were washed with brine (1 × 100 mL) and concentrated. The residue was purified by silica gel column chromatography (eluted with PE / THF:20%) to give 6-(benzyloxy)-3-bromo-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (1.945 g, 54.67%) as a yellow solid.

[0301] LCMS-PH-CAL-Y-V2475860-3:(ES, m / z): [M+H] + =424 Step 4: Synthesis of tert-butyl 4-[5-(benzyloxy)-3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl]piperazine-1-carboxylate [ka] To a stirred solution of 6-(benzyloxy)-3-bromo-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (1.945 g, 4.585 mmol, 1 equiv.) and tert-butyl piperazine-1-carboxylate (1.02 g, 5.502 mmol, 1.2 equiv.) in DMF (20 mL) was added CsCO (2.99 g, 9.170 mmol, 2 equiv.), Pa(dba) (0.41 g, 0.45 mmol, 0.1 equiv.), and Xphos at room temperature. The resulting mixture was stirred at 100 °C for 3 h. Water (60 mL) was added to the mixture, which was extracted with EA (3 × 60 mL), washed with brine (2 × 60 mL), and dried over anhydrous NaSO. The organic phase was concentrated and purified by silica gel column chromatography (PE / THF: 25%) to give tert-butyl 4-[5-(benzyloxy)-3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl]piperazine-1-carboxylate (700 mg, 28.83%) as a yellow solid.

[0302] LCMS (ES,m / z): [M+H] + =530 Step 5: Synthesis of 5-(piperazin-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol [ka] To a solution of tert-butyl 4-[5-(benzyloxy)-3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl]piperazine-1-carboxylate (700 mg, 1.322 mmol, 1 equiv) in DCM (8 mL) was added TFA (2 mL) and stirred for 1 h at 80° C. The resulting mixture was concentrated under reduced pressure to afford 5-(piperazin-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol (440 mg, 98.10%) as a brown oil.

[0303] LCMS (ES, m / z): [M+H] + =340 Step 6: Synthesis of 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Acryloyl chloride (128.03 mg, 1.415 mmol, 1.2 equiv) and TEA (357.87 mg, 3.537 mmol, 3 equiv) were added dropwise to a stirred solution of 5-(piperazin-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol (400 mg, 1.179 mmol, 1 equiv) in DCM (10 mL) at 0° C. and then stirred at room temperature for 1 h. The resulting solution was stirred at 100° C. for 3 h. Water (20 mL) was added to the mixture, and the aqueous layer was extracted with DCM (3×30 mL). The combined organic phases were dried over NaSO, concentrated under reduced pressure, and then purified by prep-HPLC under the following conditions: column: XBridge C18, 19 × 150 mm, 5 μm; mobile phase A: 20 mM NHHCO + 0.05% NHHO, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 min. to give 1-[4-(5-hydroxy-3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one (2.5 mg, 0.54%) as a yellow solid.

[0304] LCMS (ES,m / z): [M+H] + =394. 1 H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 8.46 (s, 1H), 8.02 (d, J = 8.5 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 7.31 (s, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.14 (dd, J = 16.5, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 3.79 (s, 4H), 2.92 (s, 4H). Example 112: Synthesis of 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 3-chloro-5-methylpyrazin-2-amine was used in Step 1. 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0305] (positive, ES, m / z): 322.29. 1 H NMR (400 MHz, DMSO) δ 8.52 (s, 1H), 7.88 - 7.74 (m, 3H), 7.62 (d, J = 8.5 Hz, 2H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 3.77 (d, J = 13.6 Hz, 4H), 3.14 (s, 4H), 2.33 (s, 3H). Example 113: Synthesis of 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 1, 2,3-dichloro-5,6-dimethylpyrazine was used in Step 1. 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0306] (positive, ES, m / z): 407.58. 1H NMR (400 MHz, DMSO) δ 9.04 (d, J = 2.5 Hz, 1H), 8.71 (s, 1H), 8.40 - 8.26 (m, 1H), 7.79 (d, J = 8.7 Hz, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (dd, J = 16.8, 2.4 Hz, 1H), 5.72 (dd, J = 10.5, 2.4 Hz, 1H), 3.76 (d, J = 13.1 Hz, 4H), 3.08 (s, 4H), 2.35 (d, J = 5.2 Hz, 6H). Example 114: Synthesis of 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5,6-dimethyl-3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine was used. 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one was obtained as a white solid.

[0307] (positive, ES, m / z): 425.49. 1 H NMR (400 MHz, DMSO) δ 9.04 (s, 1H), 8.71 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.7 Hz, 1H), 5.38 - 5.12 (m, 2H), 3.74 (d, J = 5.7 Hz, 4H), 3.12 (s, 4H), 2.35 (d, J = 5.7 Hz, 6H). Example 115: Synthesis of 2-fluoro-1-(4-(6-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-methyl-3-(piperidin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(6-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0308] (positive, ES, m / z): 411.62. 1 H NMR (400 MHz, DMSO) δ 8.73 (d, J = 2.5 Hz, 1H), 8.09 - 7.90 (m, 3H), 5.33 - 5.10 (m, 2H), 4.41 (s, 1H), 4.04 (s, 1H), 3.52 - 3.46 (m, 2H), 2.97 (s, 1H), 2.46 (s, 3H), 2.01 (d, J = 13.2 Hz, 2H), 1.77 (s, 2H). Example 116: Synthesis of 1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidine-1-carboxylate was used in Step 1. 1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0309] (positive, ES, m / z): 393.79. 1H NMR (400 MHz, DMSO) δ 8.76 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 8.08 - 7.91 (m, 2H), 6.94 - 6.80 (m, 1H), 6.12 (ddd, J = 16.7, 2.4, 1.0 Hz, 1H), 5.69 (ddd, J = 10.4, 2.5, 1.0 Hz, 1H), 4.56 (d, J = 13.0 Hz, 1H), 4.20 (d, J = 13.7 Hz, 1H), 3.33 - 3.19 (m, 2H), 2.83 (t, J = 12.6 Hz, 1H), 2.31 (s, 3H), 1.97 (d, J = 13.1 Hz, 2H), 1.84 - 1.55 (m, 2H). Example 117: Synthesis of 2-fluoro-1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-methyl-2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine was used. 2-Fluoro-1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0310] (positive, ES, m / z): 411.81. 1 H NMR (400 MHz, DMSO) δ 8.76 (d, J = 2.3 Hz, 1H), 8.31 (s, 1H), 8.08 - 7.94 (m, 2H), 5.33 - 5.07 (m, 2H), 4.40 (s, 1H), 4.03 (s, 1H), 3.54 - 3.45 (m, 2H), 3.06 - 2.87 (m, 1H), 2.31 (s, 3H), 2.12 - 1.95 (m, 2H), 1.75 (s, 2H). Example 118: Synthesis of 3-(1-acryloylpiperidin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrazin-2(1H)-one Scheme 20 [ka] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-iodopiperidine-1-carboxylate (3.11 g, 9.98 mmol, 1.2 equiv.) and Zn (0.82 g, 12.47 mmol, 1.5 equiv.) in DMAc (15 mL) was stirred at 60 °C for 0.5 h under a nitrogen atmosphere. A solution of 2-chloro-3-iodopyrazine (2 g, 8.31 mmol, 1 equiv.), CuI (0.32 g, 1.66 mmol, 0.2 equiv.), and Pd(dppf)Cl (0.61 g, 0.83 mmol, 0.1 equiv.) in DMAC (15 mL) was stirred at 60 °C for 0.5 h. The Zn solution was then added to the CuI solution at 60 °C. The resulting mixture was stirred at 60 °C for 16 h. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / THF (4:1)) to afford tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (1.4 g, 56.52%) as a yellow solid.

[0311] LCMS (ES, m / z): [M+H] + =298 Step 2: Synthesis of tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate [ka] A solution of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (1.2 g, 4.03 mmol, 1 equiv.) and KOH (3.39 g, 60.45 mmol, 15 equiv.) in DMSO (20 mL) and HO (5 mL) was stirred at 80 °C for 2 h. The resulting mixture was diluted with water (60 mL). The mixture was acidified to pH = 3 with citric acid solution (4 M, 40 mL). The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This gave tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate (1 g, 88.83%) as a yellow solid.

[0312] LCMS (ES, m / z): [M+H] + =280. Step 3: Synthesis of tert-butyl 4-(3-oxo-4-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-ylpiperidine-1-carboxylate [ka] To a stirred solution of tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate (0.8 g, 2.86 mmol, 1 equiv.) in ACN (8 mL) was added K2CO3 (1.19 g, 8.59 mmol, 3 equiv.) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.63 g, 3.43 mmol, 1.2 equiv.) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. LCMS showed two peaks with the desired MS. The second peak was the desired product. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash chromatography using the following conditions: XBridge C18, 19 × 150 mm, 5 μm; mobile phase A: 20 mM + 0.05% NH₃H₂O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 min to afford tert-butyl 4-(3-oxo-4-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-ylpiperidine-1-carboxylate (700 mg, 57.46%) as a yellow solid.

[0313] LCMS (ES, m / z): [M+H] + =426. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 2H), 7.73 (d, J = 4.6 Hz, 1H), 7.39 (d, J = 4.6 Hz, 1H), 4.04 (m, 2H), 3.26 (m , 1H), 2.86 (m, 2H), 1.88-1.79 (m, 2H), 1.49 (m, 2H), 1.41 (s, 9H). Step 4: Synthesis of 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one [ka] To a stirred solution of tert-butyl 4-(3-oxo-4-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-ylpiperidine-1-carboxylate (700 mg, 1.645 mmol, 1 equiv) in DCM (2 mL) was added HCl / dioxane (2 mL, 8.00 mmol, 4.86 equiv) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete, the resulting mixture was concentrated under reduced pressure to afford 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one (500 mg, 93.41%) as a white solid.

[0314] LCMS (ES,m / z): [M+H] + =326 Step 5: Synthesis of 3-[1-(prop-2-enoyl)piperidin-4-yl]-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one [ka] To a stirred solution of 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one (300 mg, 0.92 mmol, 1 equiv.) in DCM (5 mL) was added DIEA (595.98 mg, 4.61 mmol, 5 equiv.) and acryloyl chloride (166.94 mg, 1.84 mmol, 2 equiv.) at 0° C. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (150 mL). The mixture was extracted with DCM (3 × 100 mL). The combined organic layers were washed with brine (3 × 200 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (XBridge C18, 19 × 150 mm, 5 μm; mobile phase A: 20 mM 0.05% NH3HO, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 min) to give 3-[1-(prop-2-enoyl)piperidin-4-yl]-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one (80 mg, 22.87%) as a white solid.

[0315] LCMS (ES,m / z): [M+H] + =380. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 2H), 7.73 (d, J = 4.6 Hz, 1H), 7.38 (d, J = 4.6 Hz, 1H), 6.83 (dd, J = 16.7, 10.5 Hz, 1H), 6.10 (dd, J = 16.7, 2.4 Hz, 1H), 5.67 (dd, J = 10.5, 2.5 Hz, 1H), 4.50 (d, J = 12.7 Hz, 1H), 4.15 (m, 1H), 3.40 (m, 1H), 3.19 (m, 1H), 2.79 (m, 1H), 1.91 (m, 2H), 1.52 (m, 2H). Example 119: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 4-chloropyridazin-3-amine was used in step 1. 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0316] (positive, ES, m / z): 378.28. 1 H NMR (400 MHz, DMSO) δ 8.68 (d, J = 5.2 Hz, 1H), 8.55 (s, 1H), 7.88 (d, J = 8.5 Hz, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.15 (d, J = 5.3 Hz, 1H), 6.85 (dd, J = 16.7, 10.5 Hz, 1H), 6.16 (dd, J = 16.7, 2.4 Hz, 1H), 5.73 (dd, J = 10.4, 2.4 Hz, 1H), 3.77 (d, J = 13.8 Hz, 4H), 3.04 (t, J = 4.9Hz, 4H). Example 120: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 4-chloropyridazin-3-amine and 2-iodo-5-(trifluoromethyl)pyridine were used in step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0317] (positive, ES, m / z): 379.65. 1 H NMR (400 MHz, DMSO) δ 9.12 (s, 1H), 8.78 (d, J = 5.4 Hz, 1H), 8.61 (s, 1H), 8.10 (d, J = 8.9 Hz, 1H), 7.96 (d, J = 8.9 Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 6.84 (dd, J = 16.7, 10.4 Hz, 1H), 6.15 (d, J = 17.0 Hz, 1H), 5.77 - 5.66 (m, 1H), 3.68 (d, J = 15.1 Hz, 4H), 3.09 (d, J = 5.6 Hz, 4H). Example 121: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 4-chloropyridazin-3-amine and 5-iodo-2-(trifluoromethyl)pyridine were used in step 1. 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0318] (positive, ES, m / z): 379.27. 1H NMR (400 MHz, DMSO) δ 8.99 (s, 1H), 8.79 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 8.42 - 8.32 (m, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.18 (d, J = 5.4 Hz, 1H), 6.86 (dd, J = 16.7, 10.4 Hz, 1H), 6.16 (d, J = 16.5 Hz, 1H), 5.73 (d, J = 10.5 Hz, 1H), 3.78 (s, 4H), 3.06 (s, 4H). Example 122: Synthesis of 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 5-chloropyridazin-4-amine was used in step 1. 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0319] (positive, ES, m / z): 378.28. 1 H NMR (400 MHz, DMSO) δ 8.85 (s, 1H), 8.79 (d, J = 2.6 Hz, 2H), 7.63 (d, J = 8.4 Hz, 2H), 7.11 (d, J = 8.4 Hz, 2H), 6.79 (dd, J = 16.6, 10.4 Hz, 1H), 6.12 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 3.44 (d, J = 14.7 Hz, 4H), 3.08 (t, J = 5.1 Hz, 4H). Example 123: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one Scheme 21 [ka] Step 1: Synthesis of tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(2-chloropyrimidin-4-yl)piperazine-1-carboxylate (800.00 mg, 2.68 mmol, 1.00 equiv.), p-trifluoromethylaniline (431.44 mg, 2.68 mmol, 1 equiv.), and CsCO (1744.86 mg, 5.36 mmol, 2 equiv.) in toluene (6.00 mL) was added Pd(dba) (245.20 mg, 0.27 mmol, 0.1 equiv.). The resulting mixture was stirred at 90 °C under a N atmosphere for 3 h. The reaction mixture was diluted with EA (90.00 mL). The organic layer was washed with HO (3 × 20.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (3:1)) to afford tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazine-1-carboxylate (650.00 mg, 57.33%) as a yellow solid.

[0320] LCMS (ES,m / z): [M+H] + =424 Step 2: Synthesis of 4-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine [ka] A 40 mL vessel was charged with a solution of tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazine-1-carboxylate (450.00 mg, 1.06 mmol, 1.00 equiv) in DCM (2.00 mL). HCl (gas) in 1,4-dioxane (2.6 mL, 10.6 mmol, 10.00 equiv) was added at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. This afforded 4-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine (300.00 mg, 87.31%) as a yellow solid.

[0321] LCMS (ES,m / z): [M+H] + =324 Step 3: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one [ka] A 40 mL vessel was charged with a solution of 4-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine (300.00 mg, 0.93 mmol, 1.00 equiv) and TEA (281.68 mg, 2.78 mmol, 3.00 equiv) in DCM (5.00 mL). Acryloyl chloride (83.98 mg, 0.93 mmol, 1.00 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with EA (45.00 mL), washed with HO (3 × 15.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (350.00 mg) was purified by Prep-HPLC under the following conditions (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH3.HO), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 60% B → 90% B, 90% B in 10 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to give 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one (70.00 mg, 19.99%) as a white solid.

[0322] LCMS (ES,m / z): [M+H] + =378. 1 H NMR (400 MHz, DMSO-d6): δ 9.56 (s, 1H), 8.07 (s, 1H), 8.05 (d, J=14.0 Hz, 2H), 7.93 (d, J=12.0Hz, 2H), 6.91-6.82 (m, 1H), 6.40 (s, 1H), 6.20 (s, 1H), 6.14 (s, 1H), 3.96-3.86 (m, 8H). Example 124: Synthesis of 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 21, tert-butyl 4-(methylamino)piperidine-1-carboxylate was used in Step 1. 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0323] (positive, ES, m / z): 406.32. 1 H NMR (400 MHz, DMSO) δ 10.21 (s, 1H), 8.14 - 7.92 (m, 1H), 7.94 - 7.32 (m, 4H), 6.93 - 6.70 (m, 1H), 6.25 - 6.02 (m, 1H), 5.68 (ddd, J = 10.5, 8.0, 2.5 Hz, 1H), 4.94 - 4.35 (m, 2H), 4.34 - 3.96 (m, 1H), 3.26 - 3.05 (m, 1H), 3.07 - 2.78 (m, 3H), 2.72 (t, J = 12.9 Hz, 1H), 1.71 (s, 4H). Scheme 22: Synthesis of 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one (Example 125) [ka] Step 1: Synthesis of tert-butyl 4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazine-1-carboxylate [ka] To a solution of tert-butyl 4-(4-chloropyrimidin-2-yl)piperazine-1-carboxylate (650.00 mg, 2.18 mmol, 1.00 equiv), p-trifluoromethylaniline (350.55 mg, 2.18 mmol, 1.00 equiv), and CsCO (1417.69 mg, 4.35 mmol, 2.00 equiv) in toluene (5.00 mL) was added Pd(dba) (199.22 mg, 0.22 mmol, 0.10 equiv). The resulting mixture was stirred at 90 °C under a N atmosphere for 3 h. The mixture was diluted with EA (75.00 mL), washed with HO (3 × 25.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (3:1)) to afford tert-butyl 4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazine-1-carboxylate (600.00 mg, 65.13%) as a yellow solid.

[0324] LCMS (ES,m / z): [M+H] + =424 Step 2: Synthesis of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine [ka] A 40 mL vessel was charged with a solution of tert-butyl 4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazine-1-carboxylate (450.00 mg, 1.06 mmol, 1.00 equiv) in DCM (2.00 mL). HCl (gas) in 1,4-dioxane (2.6 mL, 10.6 mmol, 10.00 equiv) was added at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure to afford 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine (300.00 mg, 87.31%) as a yellow solid.

[0325] LCMS (ES, m / z): [M+H] + =324. Step 3: Synthesis of 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one [ka] A 40 mL vessel was charged with a solution of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine (300.00 mg, 0.93 mmol, 1.00 equiv) and TEA (281.68 mg, 2.78 mmol, 3.00 equiv) in DCM (5.00 mL). Acryloyl chloride (83.98 mg, 0.93 mmol, 1.00 equiv) was added at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The mixture was diluted with EA (45.00 mL), washed with HO (3 × 15.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (350.00 mg) was purified by Prep-HPLC under the following conditions (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH3.HO), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B → 90% B, 90% B in 10 min; wavelength: 254 nm; RT1 (min): 7; run number: 5) to give 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one (70.00 mg, 19.99%) as a white solid.

[0326] LCMS (ES, m / z): [M+H] + =378 1 H NMR (300 MHz, DMSO-d6): δ 9.7 (s, 1H), 8.05 (s, 1H), 7.83(d, J=2.9 Hz, 2H), 7.69 (d, J=3.5 Hz, 2H), 6.90-6.80 (m, 1H), 6.40-6.38 (m, 1H), 6.19-6.13 (m, 1H), 5.75-5.70 (m, 1H), 3.75-3.65 (m, 8H). Example 126: Synthesis of 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidine-1-carboxylate was used in Step 1. 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0327] (positive, ES, m / z): 379.39. 1 H NMR (400 MHz, DMSO) δ 8.90 - 8.55 (m, 3H), 8.08 (d, J = 1.6 Hz, 2H), 6.87 (dd, J = 16.7, 10.5 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.70 (dd, J = 10.5, 2.5 Hz, 1H), 4.64 (d, J = 13.1 Hz, 1H), 4.24 (d, J = 13.8 Hz, 1H), 3.29 - 3.12 (m, 2H), 2.78 (t, J = 12.7 Hz, 1H), 2.01 (d, J = 12.8 Hz, 2H), 1.88 - 1.60 (m, 2H). Example 127: Synthesis of 2-fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-(piperidin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine was used. 2-Fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0328] (positive, ES, m / z): 397.79. 1H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.08 (d, J = 1.6 Hz, 2H), 5.36 - 5.10 (m, 2H), 4.47 (s, 1H), 4.07 (s, 1H), 3.29 (ddd, J = 12.6, 8.7, 3.6 Hz, 2H), 2.92 (s, 1H), 2.13 - 1.98 (m, 2H), 1.91 - 1.69 (m, 2H). Example 128: Synthesis of 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 4-chloro-2-methylpyrimidin-5-amine was used in Step 1. 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0329] (positive, ES, m / z): 392.19. 1 H NMR (400 MHz, DMSO) δ 8.30 (s, 1H), 8.08 (s, 1H), 7.48 (d, J = 8.5 Hz, 2H), 6.77 (dd, J = 16.7, 10.4 Hz, 1H), 6.69 (d, J = 8.5 Hz, 2H), 6.10 (dd, J = 16.7, 2.4 Hz, 1H), 5.67 (dd, J = 10.4, 2.4 Hz, 1H), 3.59 (t, J = 4.8 Hz, 4H), 3.52 - 3.39 (m, 4H), 2.46 (s, 3H). Example 129: Synthesis of 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 5-chloro-2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine was used in Step 1. 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0330] (positive, ES, m / z): 391.27. 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 1.6 Hz, 2H), 6.95 - 6.75 (m, 1H), 6.27 (s, 1H), 6.16 (d, J = 16.4 Hz, 1H), 5.72 (d, J = 10.5 Hz, 1H), 4.38 - 4.17 (m, 2H), 3.77 (dt, J = 12.0, 5.7 Hz, 2H), 2.71 - 2.55 (m, 2H), 2.42 (s, 3H). Example 130: Synthesis of 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine was used. 2-Fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one was obtained as a white solid.

[0331] (positive, ES, m / z): 409.19. 1H NMR (400 MHz, DMSO) δ 8.78 (t, J = 1.7 Hz, 1H), 8.61 (s, 1H), 8.06 (d, J = 1.6 Hz, 2H), 6.27 (s, 1H), 5.40 - 5.11 (m, 2H), 4.35 - 4.11 (m, 2H), 3.75 (t, J = 5.6 Hz, 2H), 2.66 (s, 2H), 2.43 (s, 3H). Example 131: Synthesis of 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidine-1-carboxylate was used in Step 1. 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0332] (positive, ES, m / z): 391.27. 1 H NMR (400 MHz, DMSO) δ 8.78 (d, J = 1.7 Hz, 1H), 8.60 (d, J = 2.2 Hz, 1H), 8.06 (d, J = 1.6 Hz, 2H), 6.95 - 6.75 (m, 1H), 6.27 (s, 1H), 6.16 (d, J = 16.4 Hz, 1H), 5.72 (d, J = 10.5 Hz, 1H), 4.38 - 4.17 (m, 2H), 3.77 (dt, J = 12.0, 5.7 Hz, 2H), 2.71 - 2.55 (m, 2H), 2.42 (s, 3H). Example 132: Synthesis of 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-methyl-5-(piperidin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine was used. 2-Fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0333] (positive, ES, m / z): 411.2. 1 H NMR (400 MHz, DMSO) δ 8.82 - 8.58 (m, 1H), 8.32 - 7.99 (m, 2H), 7.81 - 7.34 (m, 1H), 5.35 - 5.08 (m, 2H), 4.45 (s, 1H), 3.23 (t, J = 12.3 Hz, 2H), 2.88 (s, 1H), 2.43 - 2.31 (m, 3H), 2.01 (d, J = 12.8 Hz, 2H), 1.86 - 1.66 (m, 2H). Example 133: Synthesis of 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 4-chloro-2-methoxypyrimidin-5-amine was used in Step 1. 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0334] (positive, ES, m / z): 393.2. 1H NMR (400 MHz, DMSO) δ 8.80 - 8.56 (m, 1H), 8.35 - 8.04 (m, 2H), 7.82 - 7.68 (m, 2H), 7.36 (dd, J = 8.5, 2.8 Hz, 1H), 6.91 - 6.74 (m, 1H), 6.12 (ddd, J = 16.7, 5.3, 2.5 Hz, 1H), 5.69 (ddd, J = 10.4, 4.4, 2.4 Hz, 1H), 4.57 (d, J = 13.1 Hz, 1H), 4.27 - 4.16 (m, 1H), 3.22 - 3.06 (m, 2H), 2.84 (t, J = 12.4 Hz, 1H), 2.42 - 2.31 (m, 4H), 1.96 (s, 2H), 1.49 (d, J = 14.0 Hz, 2H). Example 134: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one Scheme 23 [ka] Step 1: Synthesis of tert-butyl 4-(3-bromopyridin-2-yl)piperazine-1-carboxylate [ka] A 40 mL vessel was charged with a solution of 3-bromo-2-fluoropyridine (1.00 g, 5.68 mmol, 1.00 equiv), tert-butyl piperazine-1-carboxylate (1.06 g, 5.68 mmol, 1.00 equiv), and CsCO (3.70 g, 11.36 mmol, 2.00 equiv) in DMF (6.00 mL). The mixture was stirred at 80 °C overnight. The mixture was diluted with EA (60.00 mL). The organic layer was washed with HO (3 × 20.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (2:1)) to afford tert-butyl 4-(3-bromopyridin-2-yl)piperazine-1-carboxylate (850.00 mg, 43.71%) as a yellow solid.

[0335] LCMS (ES, m / z): [M+H] + =342 Step 2: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazine-1-carboxylate [ka] A solution of tert-butyl 4-(3-bromopyridin-2-yl)piperazine-1-carboxylate (830.00 mg, 2.43 mmol, 1.00 equiv), p-trifluoromethylaniline (390.77 mg, 2.43 mmol, 1.00 equiv), CsCO (1850.37 mg, 4.85 mmol, 2.00 equiv), and Pd(dba) (222.08 mg, 0.24 mmol, 0.1 equiv) in toluene (5.00 mL) was stirred at 90 °C under a N atmosphere for 3 h. The mixture was diluted with toluene (75.00 mL), washed with EA and HO (3 × 25.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE:EA (2:1)) to afford tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazine-1-carboxylate (640.00 mg, 62.47%) as a yellow solid.

[0336] LCMS (ES,m / z): [M+H] + =423 Step 3: Synthesis of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine [ka] A 40 mL vessel was charged with a solution of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazine-1-carboxylate (450.00 mg, 1.07 mmol, 1.00 equiv) in DCM (2.00 mL). HCl (gas) in 1,4-dioxane (2.6 mL, 10.6 mmol, 10.00 equiv) was added at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure. This afforded 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine (300.00 mg, 87.37%) as a yellow solid.

[0337] LCMS (ES, m / z): [M+H] + =323 Step 4: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one [ka] A solution of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine (350.00 mg, 1.09 mmol, 1.00 equiv) and TEA (329.63 mg, 3.26 mmol, 3.00 equiv) in DCM (5.00 mL) was placed in a 40 mL vial. Acryloyl chloride (98.28 mg, 1.09 mmol, 1.00 equiv) was added at 0 °C. The mixture was stirred at room temperature for 1 h. After completion of the reaction, it was diluted with EA (45.00 mL), washed with HO (3 × 15.00 mL), and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product (200.00 mg) was purified by Prep-HPLC under the following conditions (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH3.HO), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B → 90% B, 90% B in 10 min; wavelength: 254 nm; RT1 (min): 7; run number: 5) to give 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one (110 mg, 26.92%) as a white solid.

[0338] LCMS (ES,m / z): [M+H] + =377. 1 H NMR (400 MHz, DMSO-d6): δ 8.15 (s, 1H), 8.04 - 8.02 (m, 1H), 7.59 - 7.58 (m, 1H), 7.56 - 7.52 (m, 2H), 7.01 - 6.97 (m, 3H), 6.84 - 6.75 (m, 1H), 6.13 - 6.07 (m, 1H), 6.19 - 6.15 (m, 1H), 5.69 - 5.65 (m, 1H), 3.57 - 3.51 (m, 4H), 3.17 - 3.13 (m, 4H). Example 135: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine was used. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0339] (positive, ES, m / z): 396.1. 1 H NMR (400 MHz, DMSO) δ 8.53 (s, 1H), 8.31 (d, J = 2.7 Hz, 1H), 8.09 (dd, J = 4.8, 1.6 Hz, 1H), 7.71 - 7.56 (m, 2H), 7.24 (dd, J = 8.6, 2.7 Hz, 1H), 7.04 (dd, J = 7.8, 4.7 Hz, 1H), 5.31 - 5.05 (m, 2H), 3.47 (t, J = 5.0 Hz, 4H), 3.19 (d, J = 5.3 Hz, 4H). Example 136: Synthesis of 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 2-chloro-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine was used in Step 1. 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0340] (positive, ES, m / z): 409.1. 1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.8 Hz, 1H), 8.26 - 8.16 (m, 2H), 8.09 (dd, J = 4.9, 1.8 Hz, 1H), 7.50 (dd, J = 7.4, 1.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 7.4, 4.9 Hz, 1H), 5.91 (s, 1H), 5.41 - 5.13 (m, 2H), 4.31 - 4.08 (m, 2H), 3.76 (d, J = 5.7 Hz, 2H), 3.41 (d, J = 1.0 Hz, 2H), 2.47 (s, 2H). Example 137: Synthesis of 2-fluoro-1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1',2',3',6'-tetrahydro-2,4'-bipyridine was used. 2-Fluoro-1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0341] (positive, ES, m / z): 394.1. 1 H NMR (400 MHz, DMSO) δ 8.54 (dd, J = 13.7, 3.8 Hz, 2H), 7.89 (d, J = 8.8 Hz, 1H), 7.71 (dd, J = 15.8, 8.3 Hz, 1H), 7.53 (s, 1H), 7.43 (dd, J = 8.3, 4.5 Hz, 1H), 6.46 (s, 1H), 5.36 - 5.06 (m, 2H), 4.10 (s, 2H), 3.63 (t, J = 5.7 Hz, 2H), 2.68 (s, 2H). Example 138: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-carboxylate was used in Step 1. 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0342] (positive, ES, m / z): 378.1. 1 H NMR (400 MHz, DMSO) δ 8.63 (d, J = 2.8 Hz, 1H), 8.47 (dd, J = 4.6, 1.4 Hz, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.58 (td, J = 9.1, 2.1 Hz, 2H), 7.37 (dd, J = 8.2, 4.6 Hz, 1H), 6.84 (dd, J = 16.7, 10.4 Hz, 1H), 6.11 (dd, J = 16.7, 2.5 Hz, 1H), 5.67 (dd, J = 10.5, 2.4 Hz, 1H), 4.52 (d, J = 13.2 Hz, 1H), 4.14 (d, J = 13.7 Hz, 1H), 3.32 - 3.27 (m, 1H), 3.13 (d, J = 15.4 Hz, 1H), 2.78 - 2.68 (m, 1H), 1.86 - 1.64 (m, 4H). Example 139: Synthesis of 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine was used. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0343] (positive, ES, m / z): 396.1. 1 H NMR (400 MHz, DMSO) δ 8.63 (d, J = 2.8 Hz, 1H), 8.55 - 8.40 (m, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.62 - 7.49 (m, 2H), 7.37 (dd, J = 8.2, 4.6 Hz, 1H), 5.33 - 5.09 (m, 2H), 4.36 (s, 1H), 3.97 (s, 1H), 3.27 (s, 1H), 3.10 - 2.78 (m, 2H), 1.92 - 1.67 (m, 4H). Example 140: Synthesis of 1-(4-(3-(5-(trifluoromethyl)picolinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 15, 2-bromopyridine and 5-(trifluoromethyl)nicotinaldehyde were used in step 1. 1-(4-(3-(5-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0344] (positive, ES, m / z): 391.27. 1 H NMR (400 MHz, DMSO) δ 9.08 (d, J = 2.2 Hz, 1H), 8.51 (dd, J = 8.3, 2.3 Hz, 1H), 8.40 (dd, J = 4.7, 1.9 Hz, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.85 (dd, J = 7.6, 1.9 Hz, 1H), 6.99 (dd, J = 7.6, 4.7 Hz, 1H), 6.72 (dd, J = 16.7, 10.4 Hz, 1H), 6.09 (dd, J = 16.7, 2.4 Hz, 1H), 5.67 (dd, J = 10.4, 2.4 Hz, 1H), 3.39 (s, 4H), 3.22 - 3.15 (m, 4H). Example 141: Synthesis of 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 15, 2-bromopyridine and 6-(trifluoromethyl)nicotinaldehyde were used in step 1. 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0345] (positive, ES, m / z): 391.00. 1 H NMR (400 MHz, DMSO) δ 9.06 (d, J = 2.1 Hz, 1H), 8.46 (dd, J = 4.7, 1.9 Hz, 1H), 8.39 (dd, J = 8.2, 2.1 Hz, 1H), 8.10 (d, J = 8.1 Hz, 1H), 7.88 (dd, J = 7.6, 1.9 Hz, 1H), 7.05 (dd, J = 7.6, 4.7 Hz, 1H), 6.72 (dd, J = 16.7, 10.5 Hz, 1H), 6.09 (dd, J = 16.7, 2.3 Hz, 1H), 5.67 (dd, J = 10.4, 2.4 Hz, 1H), 3.34 - 3.26 (m, 4H), 3.21 (s, 4H). Example 142: Synthesis of 1-(4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 16, tert-butyl 4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazine-1-carboxylate was used in Step 1. 1-(4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0346] (positive, ES, m / z): 393.29. 11H NMR (400 MHz, DMSO) δ 8.78 (s, 1H), 8.28 (dd, J = 4.8, 1.9 Hz, 1H), 7.98 (d, J = 8.1 Hz, 1H), 7.91 - 7.78 (m, 2H), 7.19 (dd, J = 7.6, 4.7 Hz, 1H), 6.85 (dd, J = 16.7, 10.4 Hz, 1H), 6.38 (s, 1H), 6.27 - 6.09 (m, 2H), 5.71 (dd, J = 10.5, 2.4 Hz, 1H), 3.86 - 3.54 (m, 4H), 3.20 - 3.06 (m, 2H), 2.80 (s, 2H). Example 143. Scheme 24: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one Scheme 24

Chem.

Chem.

[0347] LCMS (positive, ES, m / z): 279.2 Step 2: Synthesis of tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazine-1-carboxylate [ka] To a stirred mixture of tert-butyl 4-(2-aminopyridin-3-yl)piperazine-1-carboxylate (0.71 g, 2.55 mmol, 1.00 equiv.), 1-iodo-4-(trifluoromethyl)benzene (0.83 g, 3.06 mmol, 1.20 equiv.), CsCO (1.66 g, 5.10 mmol, 2.00 equiv.), and Xantphos (0.03 g, 0.05 mmol, 0.02 equiv.) in toluene (30.00 mL) was added Pd(dba) (0.02 g, 0.025 mmol, 0.01 equiv.). The reaction mixture was stirred at 90 °C under a nitrogen atmosphere for 12 h. The desired product was detected by LCMS. The mixture was quenched with HO (50.00 mL) and then extracted with EA (3 × 50.00 mL). The combined organic layers were washed with brine (2 × 80.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluted with PE:EA (5:1)) to give tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazine-1-carboxylate (0.60 g, 55.68%) as a yellow solid.

[0348] LCMS (negative, ES, m / z): 421.2 Step 3: Synthesis of 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine [ka] To a stirred mixture of 2-[4-(2-oxo-1H-pyridine-3-amido)piperidin-1-yl]ethyl 7-[(3R)-3-[(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5H,6H,8H-imidazo[1,5-a]pyrazine-1-carboxylate (0.45 g, 0.56 mmol, 1.00 equiv.) in DCM (1.00 mL) was added HCl (gas) in 1,4-dioxane (1.41 mL, 5.64 mmol, 10.00 equiv.) at 0° C. The resulting mixture was stirred at room temperature for 2 hours. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure to afford 2-[4-(2-oxo-1H-pyridine-3-amido)piperidin-1-yl]ethyl 7-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5H,6H,8H-imidazo[1,5-a]pyrazine-1-carboxylate (0.35 g, 88.94%) as a yellow solid.

[0349] LCMS: (negative, ES, m / z): 321.1. Step 4: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one [ka] In a 10 mL bottle, 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-2-amine (0.30 g, 0.93 mmol, 1.00 equiv.) and TEA (0.28 g, 2.79 mmol, 3.00 equiv.) in DCM (1.00 mL) were added at 0 °C. To the above mixture, acryloyl chloride (0.09 g, 1.02 mmol, 1.10 equiv.) was added. The resulting mixture was stirred at room temperature for an additional 2 h. The reaction was monitored by LCMS. The resulting mixture was quenched with 50.00 mL of HO and extracted with ethyl acetate (50 mL × 3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified (Column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; Mobile phase A: water (0.05% NH3.HO), Mobile phase B: ACN; Flow rate: 90 mL / min; Gradient: 90% B → 90% B, 90% B in 10 min; Wavelength: 254 nm; RT1 (min): 7; Runs: 5) to give 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one (70.00 mg, 19.98%) as a white solid.

[0350] LCMS (positive, ES, m / z): 377.2. 1 H NMR (400 MHz, DMSO-d6): δ 8.43 (s, 1H), 8.03 - 7.99 (m, 3H), 7.62 (d, J = 8.8 Hz, 2H), 7.50 (d, J = 7.6 Hz, 1H), 6.92 - 6.83 (m, 2H), 6.19 - 6.15 (m, 1H), 5.74 - 5.71 (m, 1H), 3.85 - 3.71 (m, 4H), 2.87 - 2.84 (m, 4H). Example 144: Synthesis of 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine was used. 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0351] (positive, ES, m / z): 396.42. 1 H NMR (400 MHz, DMSO) δ 9.07 (d, J = 8.1 Hz, 1H), 8.69 - 8.45 (m, 2H), 8.02 (d, J = 8.5 Hz, 1H), 7.80 (s, 1H), 7.55 (s, 1H), 6.96 (d, J = 8.6 Hz, 1H), 5.40 - 5.12 (m, 2H), 3.80 (s, 4H), 2.91 (d, J = 9.4 Hz, 4H). Example 145: Synthesis of 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 3-chloro-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine was used in Step 1. 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0352] (positive, ES, m / z): 375.1. 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 2.5 Hz, 1H), 8.55 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 8.9 Hz, 1H), 8.19 (dd, J = 4.9, 1.8 Hz, 1H), 7.76 (d, J = 8.7 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.01 (dd, J = 7.5, 4.9 Hz, 1H), 6.94 - 6.77 (m, 1H), 6.24 - 6.11 (m, 1H), 5.95 (d, J = 10.5 Hz, 1H), 5.82 - 5.69 (m, 1H), 4.38 - 4.10 (m, 2H), 3.80 (d, J = 6.1 Hz, 2H), 2.46 - 2.33 (m, 2H). Example 146: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(6-(trifluoromethyl)pyridin-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2-amine was used. 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0353] (positive, ES, m / z): 393.1. 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 2.6 Hz, 1H), 8.56 (s, 1H), 8.32 - 8.13 (m, 2H), 7.76 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 7.5, 1.9 Hz, 1H), 7.01 (dd, J = 7.5, 4.9 Hz, 1H), 5.95 (s, 1H), 5.43 - 5.12 (m, 2H), 4.34 - 4.13 (m, 2H), 3.78 (s, 2H), 3.30 - 3.17 (m, 2H). Example 147: Synthesis of 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 3-chloro-N-(6-(trifluoromethoxy)pyridin-3-yl)pyridin-2-amine was used in Step 1. 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridin]-1′(2′H)-yl)prop-2-en-1-one was obtained as a white solid.

[0354] (positive, ES, m / z): 391.2. 1 H NMR (400 MHz, DMSO) δ 8.55 (d, J = 2.8 Hz, 1H), 8.21 (dd, J = 9.3, 3.7 Hz, 2H), 8.10 (dd, J = 4.8, 1.9 Hz, 1H), 7.57 - 7.43 (m, 1H), 7.23 (d, J = 8.8 Hz, 1H), 7.00 - 6.75 (m, 2H), 6.24 - 6.08 (m, 1H), 5.93 (d, J = 9.4 Hz, 1H), 5.81 - 5.67 (m, 1H), 4.44 - 4.12 (m, 2H), 3.81 (d, J = 6.0 Hz, 2H), 2.47 - 2.30 (m, 2H). Example 148: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(6-(trifluoromethoxy)pyridin-3-yl)-1',2',3',6'-tetrahydro-[3,4'-bipyridine]-2-amine was used. 2-Fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0355] (positive, ES, m / z): 409.1. 1 H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.8 Hz, 1H), 8.26 - 8.16 (m, 2H), 8.09 (dd, J = 4.9, 1.8 Hz, 1H), 7.50 (dd, J = 7.4, 1.9 Hz, 1H), 7.22 (d, J = 8.8 Hz, 1H), 6.91 (dd, J = 7.4, 4.9 Hz, 1H), 5.91 (s, 1H), 5.41 - 5.13 (m, 2H), 4.31 - 4.08 (m, 2H), 3.76 (d, J = 5.7 Hz, 2H), 3.41 (d, J = 1.0 Hz, 2H), 2.47 (s, 2H). Example 149: Synthesis of 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate was used in Step 1. 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0356] (positive, ES, m / z): 377.44. 1H NMR (400 MHz, DMSO) δ 8.91 (d, J = 2.5 Hz, 1H), 8.72 (s, 1H), 8.26 (dd, J = 8.9, 2.5 Hz, 1H), 8.11 (dd, J = 4.8, 1.7 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.65 (dd, J = 7.7, 1.8 Hz, 1H), 6.98 (dd, J = 7.6, 4.8 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.70 (dd, J = 10.4, 2.5 Hz, 1H), 4.64 (d, J = 13.0 Hz, 1H), 4.23 (d, J = 13.6 Hz, 1H), 3.25 (q, J = 12.7 Hz, 2H), 2.79 (t, J = 12.7 Hz, 1H), 1.87 (d, J = 12.9 Hz, 2H), 1.64 - 1.40 (m, 2H). Example 150: Synthesis of 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine was used. 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0357] (positive, ES, m / z): 395.44. 1H NMR (400 MHz, DMSO) δ 8.90 (d, J = 2.5 Hz, 1H), 8.73 (s, 1H), 8.25 (dd, J = 8.5, 2.5 Hz, 1H), 8.12 (dd, J = 4.8, 1.8 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.68 (dd, J = 7.7, 1.8 Hz, 1H), 6.99 (dd, J = 7.6, 4.8 Hz, 1H), 5.35 - 5.12 (m, 2H), 4.48 (s, 1H), 4.07 (s, 1H), 3.28 (d, J = 12.0 Hz, 2H), 3.01 - 2.82 (m, 1H), 1.90 (d, J = 13.0 Hz, 2H), 1.58 (s, 2H). Example 151: Synthesis of 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridine]-1′(2′H)-carboxylate was used in Step 1. 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0358] (positive, ES, m / z): 393.1. 1 H NMR (400 MHz, DMSO) δ 8.59 - 8.35 (m, 2H), 8.19 (s, 1H), 8.02 (d, J = 9.5 Hz, 1H), 7.57 (d, J = 6.9 Hz, 1H), 7.24 (s, 1H), 6.96 - 6.78 (m, 2H), 6.12 (s, 1H), 5.69 (s, 1H), 4.63 (s, 1H), 4.22 (s, 1H), 3.21 (s, 2H), 2.79 (d, J = 12.3 Hz, 1H), 1.87 (s, 2H), 1.49 (s, 2H). Example 152: Synthesis of 2-fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, N-(piperidin-4-yl)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyridin-2-amine was used. 2-Fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0359] (positive, ES, m / z): 411.1. 1 H NMR (400 MHz, DMSO) δ 8.54 (d, J = 2.8 Hz, 1H), 8.43 (s, 1H), 8.19 (dd, J = 8.9, 2.8 Hz, 1H), 8.03 (dd, J = 4.8, 1.7 Hz, 1H), 7.60 (dd, J = 7.5, 1.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 1H), 6.89 (dd, J = 7.6, 4.8 Hz, 1H), 5.32 - 5.11 (m, 2H), 4.47 (s, 1H), 4.06 (s, 1H), 3.22 (d, J = 11.9 Hz, 1H), 2.91 (s, 1H), 2.72 - 2.57 (m, 1H), 1.91 (d, J = 12.9 Hz, 2H), 1.57 (s, 2H). Example 153: Synthesis of 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 3-chloro-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine was used in Step 1. 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0360] (positive, ES, m / z): 376.2. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 2.6 Hz, 1H), 8.08 (dd, J = 4.8, 1.8 Hz, 1H), 7.99 (d, J = 8.6 Hz, 1H), 7.89 (dd, J = 15.5, 8.0 Hz, 2H), 7.27 (dd, J = 7.5, 4.8 Hz, 1H), 6.95 - 6.76 (m, 1H), 6.21 - 6.07 (m, 2H), 5.71 (d, J = 8.1 Hz, 1H), 4.35 - 4.15 (m, 2H), 3.75 (dt, J = 11.5, 5.9Hz, 2H), 2.62 (s, 2H). Example 154: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-1',2',3',6'-tetrahydro-3,4'-bipyridine was used. 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0361] (positive, ES, m / z): 394.2. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 2.6 Hz, 1H), 8.09 (dd, J = 4.8, 1.8 Hz, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.89 (ddd, J = 14.4, 8.1, 2.3 Hz, 2H), 7.27 (dd, J = 7.5, 4.8 Hz, 1H), 6.18 (s, 1H), 5.33 (d, J = 16.9 Hz, 2H), 4.34 - 4.13 (m, 2H), 3.73 (t, J = 5.6 Hz, 2H), 2.65 (s, 2H). Example 155: Synthesis of 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate was used in Step 1. 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0362] (positive, ES, m / z): 378.1. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 2.6 Hz, 1H), 8.01 (dd, J = 6.5, 4.2 Hz, 2H), 7.93 - 7.79 (m, 2H), 7.21 (dd, J = 7.5, 4.8 Hz, 1H), 6.86 (dd, J = 16.7, 10.5 Hz, 1H), 6.12 (dd, J = 16.7, 2.5 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 4.63 (d, J = 13.1 Hz, 1H), 4.22 (d, J = 13.7 Hz, 1H), 3.24 (d, J = 15.0 Hz, 2H), 2.77 (t, J = 12.8 Hz, 1H), 1.95 (d, J = 12.9 Hz, 2H), 1.63 (t, J = 14.4 Hz, 2H). Example 156: Synthesis of 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 3-(piperidin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine was used. 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0363] (positive, ES, m / z): 396.2. 1 H NMR (400 MHz, DMSO) δ 8.67 (d, J = 2.6 Hz, 1H), 8.08 - 7.97 (m, 2H), 7.89 (ddd, J = 9.6, 8.0, 2.3 Hz, 2H), 7.22 (dd, J = 7.5, 4.9 Hz, 1H), 5.33 - 5.10 (m, 2H), 4.46 (s, 1H), 4.05 (s, 1H), 3.32 - 3.22 (m, 2H), 2.91 (s, 1H), 1.99 (d, J = 13.0 Hz, 2H), 1.69 (s, 2H). Example 157: Synthesis of 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 6, 5-((3-chloropyridin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used in Step 1. 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0364] (positive, ES, m / z): 377.36. 1H NMR (400 MHz, DMSO) δ 9.09 (s, 2H), 8.09 (dd, J = 4.9, 1.8 Hz, 1H), 7.90 (d, J = 7.4 Hz, 1H), 7.30 (dd, J = 7.5, 4.8 Hz, 1H), 6.95 - 6.74 (m, 1H), 6.26 - 6.11 (m, 2H), 5.72 (d, J = 10.2 Hz, 1H), 4.39 - 4.14 (m, 2H), 3.77 (dt, J = 11.1, 5.7 Hz, 2H), 2.66 (d, J = 15.4 Hz, 2H). Example 158: Synthesis of 2-fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-1',2',3',6'-tetrahydro-3,4'-bipyridine was used. 2-Fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one was obtained as a white solid.

[0365] (positive, ES, m / z): 395.36. 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 2H), 8.10 (dd, J = 4.9, 1.8 Hz, 1H), 7.91 (dd, J = 7.5, 1.9 Hz, 1H), 7.31 (dd, J = 7.5, 4.9 Hz, 1H), 6.22 (s, 1H), 5.42 - 5.14 (m, 2H), 4.37 - 4.11 (m, 2H), 3.75 (t, J = 5.7 Hz, 2H), 2.68 (s, 2H). Example 159: Synthesis of 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 7, tert-butyl 2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-carboxylate was used in Step 1. 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0366] (positive, ES, m / z): 379.39. 1 H NMR (400 MHz, DMSO) δ 9.09 (s, 2H), 8.03 (dd, J = 4.8, 1.8 Hz, 1H), 7.89 (dd, J = 7.5, 1.8 Hz, 1H), 7.25 (dd, J = 7.5, 4.8 Hz, 1H), 6.87 (dd, J = 16.7, 10.4 Hz, 1H), 6.13 (dd, J = 16.7, 2.5 Hz, 1H), 5.70 (dd, J = 10.5, 2.5 Hz, 1H), 4.64 (d, J = 13.0 Hz, 1H), 4.23 (d, J = 13.7 Hz, 1H), 3.33 - 3.15 (m, 2H), 2.77 (t, J = 12.7 Hz, 1H), 1.97 (d, J = 12.7 Hz, 2H), 1.71 - 1.48 (m, 2H). Example 160: Synthesis of 2-fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 10, 5-((3-(piperidin-4-yl)pyridin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine was used. 2-Fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0367] (positive, ES, m / z): 397.39. 1H NMR (400 MHz, DMSO) δ 9.09 (s, 2H), 8.03 (dd, J = 4.8, 1.8 Hz, 1H), 7.92 (d, J = 7.4 Hz, 1H), 7.26 (dd, J = 7.5, 4.8 Hz, 1H), 5.34 - 5.11 (m, 2H), 4.47 (s, 1H), 4.06 (s, 1H), 3.30 (d, J = 14.6 Hz, 2H), 2.90 (s, 1H), 2.01 (d, J = 13.0 Hz, 2H), 1.70 (s, 2H). Example 161: Synthesis of 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 18, 2-chloronicotinic acid was used in step 1 and 4,4-difluoropiperidine was used in step 2. 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0368] (positive, ES, m / z): 365.32. 1 H NMR (400 MHz, DMSO) δ 8.28 (dd, J = 4.8, 1.9 Hz, 1H), 7.62 (dd, J = 7.4, 1.9 Hz, 1H), 6.95 (dd, J = 7.4, 4.8 Hz, 1H), 6.83 (dd, J = 16.7, 10.5 Hz, 1H), 6.15 (dd, J = 16.7, 2.4 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 4.00 - 3.85 (m, 1H), 3.82 - 3.50 (m, 5H), 3.34 - 3.21 (m, 6H), 2.15 - 1.87 (m, 4H). Example 162: Synthesis of 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 3, 2-chloroaniline was used in step 1. 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0369] (positive, ES, m / z): 398.28. 1 H NMR (400 MHz, DMSO) δ 7.94 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.33 - 7.21 (m, 1H), 7.16 - 6.95 (m, 5H), 6.82 (dd, J = 16.6, 10.4 Hz, 1H), 6.13 (dd, J = 16.7, 2.4 Hz, 1H), 5.69 (dd, J = 10.4, 2.4 Hz, 1H), 3.60 (s, 4H), 2.92 - 2.76 (m, 4H). Example 164: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Example 163) and 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one Scheme 25 [ka] Step 1: Synthesis of 4-(5-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(3-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A solution / mixture of 2H-pyrazole-3-carbaldehyde (6 g, 62.44 mmol, 1 equiv.), tert-butyl 4-(methanesulfonyloxy)piperidine-1-carboxylate (29.65 g, 106.15 mmol, 1.7 equiv.), and NaH (2.40 g, 99.91 mmol, 1.6 equiv.) in DMF (50 mL) was stirred at 80 °C under a nitrogen atmosphere for 8 h. The resulting mixture was diluted with water (50 mL). The resulting mixture was extracted with EtOAc (3 × 70 mL). The combined organic layers were washed with brine (3 × 30 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give a mixture of tert-butyl 4-(5-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(3-formyl-1H-pyrazol-1-yl)piperidine-1-carboxylate (9 g) as a yellow solid.

[0370] Step 2: Synthesis of tert-butyl 4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] A solution of 1-bromo-4-(trifluoromethyl)benzene (18.16 g, 80.69 mmol, 5 equiv.) and chloro(isopropyl)magnesium (50 mL) in THF (200 mL) was stirred at 0 °C for 40 min under a nitrogen atmosphere. A mixture of 3 and 3A (9 g, 16.14 mmol, 1 equiv.) was added dropwise to the Grignard reagent solution. The solution was stirred at 0 °C for 2 h under a nitrogen atmosphere. The resulting mixture was diluted with water (200 mL). The resulting mixture was extracted with EtOAc (2 × 200 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN in water (0.1% NH3.HO) with a gradient from 10% to 50% in 20 min; detection: UV 254 nm) to give a mixture of tert-butyl 4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-(hydroxy(4-(trifluoromethyl)phenyl)methyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (4 g) as a yellow solid.

[0371] Step 3: Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate and tert-butyl 4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate [ka] In a 100 mL round-bottom flask, a mixture of 4 and 4A (4 g, 9.40 mmol, 1 equiv.), PCC (4.05 g, 18.80 mmol, 2 equiv.), and DCM (40 mL, 629.22 mmol, 66.93 equiv.) were added at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was diluted with water (100 mL). The mixture was extracted with CHCl (2 × 100 mL). The combined organic layers were washed with water (1 × 100 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with PE / EA (1:1)) to give the crude product. The crude product was further purified by reverse-phase flash chromatography under the following conditions (column: C18 silica gel; mobile phase: MeCN in water (0.1% NH3.HO), gradient from 20% to 70% in 20 min; detection: UV 254 nm) to give tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (110 mg) and tert-butyl 4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (230 mg).

[0372] Step 4: Synthesis of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone [ka] In a 40 mL vial, tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (110 mg, 0.26 mmol, 1 equiv.), HCl (gas) in 1,4-dioxane (1 mL, 32.91 mmol, 126.70 equiv.), and DCM (3 mL, 47.19 mmol, 181.66 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0373] Step 5: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-yl)prop-2-en-1-one (Example 163) [ka] A solution of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone (100 mg, 0.31 mmol, 1 equiv.) in DCM was treated with TEA (93.89 mg, 0.93 mmol, 3 equiv.) under a nitrogen atmosphere at 0 °C for 5 min, followed by the dropwise addition of acryloyl chloride (27.99 mg, 0.31 mmol, 1 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CHCl (2 × 10 mL). The combined organic layers were washed with water (2 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (column: C18 silica gel; mobile phase: MeCN in water (0.1% NH3.HO) gradient from 10% to 60% in 20 min; detection: UV 254 nm) to give 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one (63 mg, 53.98%) as a white oil.

[0374] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 8.1 Hz, 2H), 8.10 (d, J = 2.5 Hz, 1H), 7.93 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 2.5 Hz, 1H), 6.87 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.71 - 4.62 (m, 1H), 4.55 (m, 1H), 4.20 (m, 1H), 3.24 (m, 1H), 2.86 (m, 1H), 2.14 (m, 2H), 1.96 - 1.81 (m, 2H). Step 4: Synthesis of (1-(piperidin-4-yl)-1H-pyrazol-5-yl)(4-(trifluoromethyl)phenyl)methanone [ka] In a 40 mL vial, tert-butyl 4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (230 mg, 0.54 mmol, 1 equiv.), HCl (gas) in 1,4-dioxane (3 mL, 98.74 mmol, 181.78 equiv.), and DCM (9 mL, 141.57 mmol, 260.64 equiv.) were added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0375] Step 5: Synthesis of 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one [ka] A solution of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone (220 mg, 0.68 mmol, 1 equiv) in DCM (5 mL) was treated with TEA (206.57 mg, 2.04 mmol, 3 equiv) at 0 °C for 5 min, followed by the dropwise addition of acryloyl chloride (61.59 mg, 0.68 mmol, 1 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with CHCl (2 × 20 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse-phase flash under the following conditions (column: C18 silica gel; mobile phase: MeCN in water (0.1% NH3.HO) gradient from 10% to 60% in 20 min; detection: UV 254 nm) to give 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one (60 mg, 23.32%) as a white solid.

[0376] 1H NMR (400 MHz, DMSO-d6) δ 8.05 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 2.0 Hz, 1H), 6.87 (m, 1H), 6.79 (s, 1H), 6.14 (m, 1H), 5.71 (m, 1H), 5.23 - 5.13 (m, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.22 (d, J = 13.8 Hz, 1H), 3.23 (m, 1H), 2.83 (m, 1H), 2.15 - 2.04 (m, 2H), 2.00 - 1.86 (m, 2H). Example 165: Synthesis of 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 25, 3-methyl-1H-pyrazole-5-carbaldehyde was used in Step 1. 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0377] (positive, ES, m / z): 392.34. 1 H NMR (400 MHz, DMSO) δ 8.30 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.0 Hz, 2H), 6.91 - 6.80 (m, 1H), 6.75 (d, J = 1.3 Hz, 1H), 6.13 (ddd, J = 16.8, 2.5, 1.1 Hz, 1H), 5.70 (ddd, J = 10.5, 2.5, 1.0 Hz, 1H), 4.60 (q, J = 14.4 Hz, 2H), 4.20 (d, J = 13.8 Hz, 1H), 3.26 (d, J = 11.9 Hz, 1H), 2.87 (t, J = 12.7 Hz, 1H), 2.02 (d, J = 12.6 Hz, 2H), 1.87 (d, J = 13.9 Hz, 2H). Example 166: Synthesis of 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one [ka] Following the general procedure in Scheme 25, 3-methyl-1H-pyrazole-5-carbaldehyde was used in Step 1. 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0378] (positive, ES, m / z): 392.38. 1 H NMR (400 MHz, DMSO) δ 8.04 (d, J = 8.1 Hz, 2H), 7.96 (d, J = 8.2 Hz, 2H), 6.88 (dd, J = 16.7, 10.4 Hz, 1H), 6.57 (s, 1H), 6.14 (dd, J = 16.7, 2.5 Hz, 1H), 5.71 (dd, J = 10.4, 2.4 Hz, 1H), 5.12 (td, J = 11.2, 5.5 Hz, 1H), 4.57 (d, J = 13.2 Hz, 1H), 4.21 (d, J = 13.9 Hz, 1H), 3.23 (t, J = 12.8 Hz, 1H), 2.81 (t, J = 12.9 Hz, 1H), 2.23 (s, 3H), 2.08 - 1.73 (m, 4H). Example 167: Synthesis of 4-(dimethylamino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one [ka] Following the general procedure in Scheme 10, (£)-4-(dimethylamino)but-2-enoic acid was used. 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one was obtained as a white solid.

[0379] (positive, ES, m / z): 435.32. 1H NMR (400 MHz, DMSO) δ 8.63 (d, J = 2.4 Hz, 1H), 8.02 - 7.89 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 15.2 Hz, 1H), 6.65 (dt, J = 15.0, 6.6 Hz, 1H), 3.79 (s, 4H), 3.52 (s, 6H), 3.15 (d, J = 6.1 Hz, 6H). Example 168: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one [ka] Following the general procedure in Scheme 1, acetyl chloride was used in step 4. 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one was obtained as a white solid.

[0380] (positive, ES, m / z): 366.2. 1 H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.94 - 7.87 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 3.68 (q, J = 4.9 Hz, 4H), 3.21 - 3.03 (m, 4H), 2.05 (s, 3H). Example 169: Synthesis of 2-chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one [ka] Following the general procedure in Scheme 1, 2-chloro-2-fluoroacetyl chloride was used in step 4. 2-Chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one was obtained as a white solid.

[0381] (positive, ES, m / z): 418.21. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.98 - 7.87 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.44 - 7.27 (m, 1H), 3.87 - 3.61 (m, 4H), 3.18 (dt, J = 15.4, 4.3 Hz, 4H). Example 170: Synthesis of 2-chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one [ka] Following the general procedure in Scheme 1, 2-chloroacetyl chloride was used in step 4. 2-chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one was obtained as a white solid.

[0382] (positive, ES, m / z): 400.26. 1 H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.97 - 7.86 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 4.45 (s, 2H), 3.82 - 3.65 (m, 4H), 3.26 - 3.05 (m, 4H). Example 171: Synthesis of 3-oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile [ka] Following the general procedure in Scheme 10 and using 2-cyanoacetic acid, 3-oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile was obtained as a white solid.

[0383] (positive, ES, m / z): 391.27. 1H NMR (400 MHz, DMSO) δ 8.63 (s, 1H), 7.93 (s, 1H), 7.91 - 7.88 (m, 2H), 7.84 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 4.12 (s, 2H), 3.71 (t, J = 5.3 Hz, 2H), 3.59 (d, J = 5.6 Hz, 2H), 3.23 - 3.07 (m, 4H). Example 172: Synthesis of oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone [ka] Following the general procedure in Scheme 10, oxirane-2-carboxylic acid was used. Oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone was obtained as a white solid.

[0384] (positive, ES, m / z): 394.28. 1 H NMR (400 MHz, DMSO) δ 8.64 (s, 1H), 7.98 - 7.88 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 3.97 - 3.80 (m, 3H), 3.71 (d, J = 6.6 Hz, 2H), 3.26 - 3.08 (m, 4H), 2.93 (dd, J = 6.3, 4.3 Hz, 1H), 2.81 (dd, J = 6.3, 2.6 Hz, 1H). Example 173: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one Scheme 26 [ka] Step 1: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one [ka] 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine (100 mg, 0.31 mmol, 1.00 equiv) and TEA (128 mmL, 0.77 mmol, 2.50 equiv) in DCM (2.00 mL) at 0 °C. To the above mixture was added 3-(trimethylsilyl)propionoyl chloride (56 mmL, 0.37 mmol, 1.20 equiv). The resulting mixture was stirred at 0 °C for an additional 0.5 h. The reaction was monitored by LCMS. To the resulting mixture was added 20.00 mL of HO and extracted with ethyl acetate (20.00 mL × 3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification.

[0385] Step 2: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one [ka] To a stirred mixture of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one (108 mg, 0.24 mmol, 1.00 equiv.) in THF (2.00 mL) was added TBAF (844 mmL, 0.84 mmol, 3.5 equiv.) in THF at room temperature. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluted with DCM:EA (4:1)) to afford 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one (61 mg, 67.34% yield) as a white solid.

[0386] (positive, ES, m / z): 376.22. 1H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.96 - 7.89 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 4.61 (s, 1H), 4.00 - 3.88 (m, 2H), 3.75 (dd, J = 6.3, 4.0 Hz, 2H), 3.22 (t, J = 5.2 Hz, 2H), 3.14 (t, J = 5.2 Hz, 2H). Example 174: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one [ka] Following the general procedure in Scheme 1, but-2-ynoyl chloride was used in step 4. 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one was obtained as a white solid.

[0387] (positive, ES, m / z): 390.28. 1 H NMR (400 MHz, DMSO) δ 8.61 (s, 1H), 7.99 - 7.88 (m, 3H), 7.85 (d, J = 2.8 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 3.92 (t, J = 5.1 Hz, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.27 - 3.08 (m, 4H), 2.04 (s, 3H). Example 175: Synthesis of 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile [ka] Following the general procedure in Scheme 2, 2-bromoacetonitrile was used. 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile was obtained as a white solid.

[0388] (positive, ES, m / z): 363.26.1 H NMR (400 MHz, DMSO) δ 8.59 (s, 1H), 7.93 - 7.78 (m, 4H), 7.63 (d, J = 8.5 Hz, 2H), 3.81 (s, 2H), 3.21 (s, 4H), 2.73 (t, J = 4.8 Hz, 4H). Example 176: Synthesis of 2-methyl-2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile Scheme 27 [ka] A mixture of 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (200 mg, 0.619 mmol, 1 equiv.), acetone (71.85 mg, 1.238 mmol, 2 equiv.), and KCN (80.56 mg, 1.238 mmol, 2 equiv.) in HO (2 mL) was stirred at 50 °C under a nitrogen atmosphere for 12 h. The resulting mixture was extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with water (1 × 10 mL) and dried over anhydrous NaSO. After filtration, the filtrate was concentrated under reduced pressure. This afforded 2-methyl-2-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazin-1-yl]propanenitrile (150 mg, 59.01%) as a brown solid.

[0389] LCMS: (ES, m / z): [M+H] + =391. 1 H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.94 - 7.81 (m, 4H), 7.62 (d, J = 8.6 Hz, 2H), 3.26 - 3.15 (m, 4H), 2.84 - 2.78 (m, 4H), 1.49 (s, 6H) Example 177: Synthes...

Claims

1. Formula (I): 【Chemistry 1】 [During the ceremony, Ring A is a 6-membered aryl or a 6-membered heteroaryl having 1, 2 or 3 nitrogen ring members; Ring B is C ６ -C １２ -Aryl, C ４ -C ７ -cycloalkyl or a 6-membered heteroaryl having 1 or 2 nitrogen ring members; Ring C is a 4-10 membered heterocycle containing 1 or 2 N ring members, which may be fused and may have 1-3 unsaturated bonds; L is -NH-, -O-, -CH ２ selected from the group consisting of -, -S-, -C(O)-, -CHOH-, and a bond; Where: R １ When attached to a carbon ring member, R １ is CN, halo, -[CH ２ ] ０、１ NHC(O)(C １ -C ６ -alkyl), -[CH ２ ] ０、１ NHC(O)(C ２ -C ６ -alkenyl) and -[CH ２ ] ０、１ NHC(O)(C ２ -C ６ -alkynyl), -[CH ２ ] ０、１ NHC(O)(C ３ -C １０ -cycloalkyl), -[CH ２ ] ０、１ NHC(O)(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S), —[CH ２ ] ０、１ N.H.S.O. ２ (C １ -C ６ -alkyl), -[CH ２ ] ０、１ N.H.S.O. ２ (C ２ -C ６ -alkenyl) and -[CH ２ ] ０、１ N.H.S.O. ２ (C ２ -C ６ -alkynyl), -[CH ２ ] ０、１ N.H.S.O. ２ (C ３ -C １０ -cycloalkyl) and -[CH ２ ] ０、１ N.H.S.O. ２ (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S); R １ is attached to a nitrogen ring member, R １ is CN, -C(O)(C １ -C ６ -alkyl), -C(O)(C ２ -C ６ -alkenyl), -C(O)(C ２ -C ６ -alkynyl), -C(O)(C ３ -C １０ -cycloalkyl), -C(O)(3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S), -C １ -C ６ -Alkyl (C ３ -C １０ -cycloalkyl), -SO ２ (C １ -C ６ -alkyl), -SO ２ (C ２ -C ６ -alkenyl), -SO ２ (C ２ -C ６ -alkynyl), -SO ２ (C ３ -C １０ -cycloalkyl) and -SO ２ (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S); R ２ Ha, Haro, C １ -C ６ -Haloalkyl, C １ -C ６ -haloalkoxy and -SF ５ selected from the group consisting of: Ring A, ring B and ring C are independently halo and C １ -C ６ - optionally substituted with 1 to 3 substituents independently selected from alkyl; and Any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl may be selected from halo, OH, CN, C １ -C ６ -Alkoxy, C １ -C ６ -Alkyl, C １ -C ６ -Haloalkyl, C １ -C ６ -hydroxyalkyl, (C ０ -C ６ -alkyl)NRR′, -(C ０ -C ６ -alkyl)-OC(O)R, -(C ０ -C ６ -alkyl)-C(O)OR, C ３ -C １０ -cycloalkyl, 3-6 membered heterocycloalkyl (wherein 1-4 ring members are independently selected from N, O and S), -(C １ -C ６ -alkyl) (3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O and S); where R and R′ are H, C １ -C ６ -Alkyl, C ２ -C ６ -Alkenyl and C ２ -C ６ -alkynyl, or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl having 2 or 3 nitrogen ring members.

3. Ring A is optionally substituted: 【Chemistry 2】 3. The compound according to claim 1 or 2, selected from the group consisting of:

4. Ring A is optionally substituted: 【Chemistry 3】 The compound according to any one of claims 1 to 3, wherein:

5. Ring A is optionally substituted: 【Chemistry 4】 The compound according to any one of claims 1 to 3, wherein:

6. Ring B is an optionally substituted C ６ -C １２ -aryl; or a pharma- ceutically acceptable salt thereof.

7. The compound according to any one of claims 1 to 6, wherein ring B is optionally substituted phenyl, or a pharma- ceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 5, wherein Ring B is an optionally substituted 6-membered heteroaryl having 1 or 2 nitrogen ring members, or a pharma- ceutically acceptable salt thereof.

9. Ring B is optionally substituted 【Chemistry 5】 The compound according to any one of claims 1 to 5 and 8, which is selected from the group consisting of:

10. The compound according to any one of claims 1 to 9, wherein ring C is an optionally substituted 4- to 8-membered heterocycle, or a pharma- ceutically acceptable salt thereof.

11. 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein Ring C contains one N ring member.

12. 11. The compound according to any one of claims 1 to 10, or a pharma- ceutically acceptable salt thereof, wherein Ring C contains two N ring members.

13. Ring C is optionally substituted 【Chemistry 6】 The compound according to any one of claims 1 to 10, which is selected from the group consisting of:

14. Ring C is optionally substituted: 【Chemistry 7】 12. The compound according to any one of claims 1 to 11, wherein:

15. The compound according to any one of claims 1 to 14, or a pharma- ceutically acceptable salt thereof, wherein L is -NH-.

16. R ２ But, C １ -C ６ 16. The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein: -haloalkyl.

17. R ２ But -CF ３ 17. The compound according to any one of claims 1 to 16, wherein:

18. R １ or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 17, wherein: is attached to a nitrogen ring member.

19. R １ But the formula: 【Chemistry 8】 [In the formula, R ３ , R ４ and R ４ａ is H, halo, CN, -C(O)OR and optionally substituted C １ -C ６ -alkyl; 19. The compound according to claim 18, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

20. R １ But the formula: 【Chemistry 9】 20. The compound according to claim 19, wherein:

21. R ３ is H, F, Cl, CH ２ F, C.F. ３ , C.N., C.H. ２ O.H., C.H. ２ OC(O)R and CH ２ NRR′; and R ４ and R ４ａ But, H, CH ２ F, C.H.F. ２ , C.H. ２ O.H., C.H. ２ NRR' and CH ２ -(3-6 membered heterocycloalkyl, where 1-4 ring members are independently selected from N, O, and S); 21. The compound according to claim 19 or 20, or a pharma- ceutically acceptable salt thereof.

22. R １ But the formula: 【Chemistry 10】 [In the formula, R ５ is H, C １ -C ６ -Alkyl, C １ -C ６ -Haloalkyl and C １ -C ６ -hydroxyalkyl] 19. The compound according to claim 18, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

23. R １ But the formula: 【Chemistry 11】 [In the formula, R ６ and R ６ａ is H, halo, CN and C １ -C ６ -alkyl, 19. The compound according to claim 18, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

24. R ６ and R ６ａ or a pharma- ceutically acceptable salt thereof.

24. The compound of claim 23, wherein at least one of: is halo; or a pharma- ceutically acceptable salt thereof.

25. R ６ and R ６ａ or a pharma- ceutically acceptable salt thereof.

25. The compound of claim 23 or 24, wherein each of is halo.

26. R ６ and R ６ａ or a pharma- ceutically acceptable salt thereof according to claim 23 or 24, wherein at least one of is CN.

27. R １ But the formula: 【Chemistry 12】 [In the formula, R ７ and R ７ａ are independently selected from the group consisting of H, optionally substituted alkyl, and -C(O)OR.

19. The compound according to claim 18, wherein the compound is represented by the following formula: or a pharma- ceutically acceptable salt thereof.

28. R １ が、-CN、 【Chemistry 13】 20. The compound of claim 1 or 18, selected from the group consisting of:

29. R １ but, 【Chemistry 14】 30. The compound of claim 1, 18 or 28, which is: or a pharma- ceutically acceptable salt thereof.

30. The compound has the formula (IA): 【Chemistry 15】 2. The compound according to claim 1, which is represented by the formula: or a pharma- ceutically acceptable salt thereof.

31. 31. The compound of claim 30, or a pharma- ceutically acceptable salt thereof, wherein L is -NH-.

32. R ２ But -CF ３ or -SF ５ 32. The compound of claim 30 or 31, which is: or a pharma- ceutically acceptable salt thereof.

33. R ２ The compound according to any one of claims 30 to 32, or a pharma- ceutically acceptable salt thereof, wherein: is at the para position.

34. The compound according to any one of claims 30 to 33, or a pharma- ceutically acceptable salt thereof, wherein ring C is a 4-6 membered heterocycle containing two N ring members.

35. Ring C is 【Chemistry 16】 The compound according to any one of claims 30 to 34, or a pharma- ceutically acceptable salt thereof,

36. The compound is selected from the group consisting of: 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonitrile; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide; N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide; N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide; N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]heptan-6-yl)acrylamide; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide; 1-(3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one; N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide; N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide; 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one; 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide; (S)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide; 2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide; (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile; (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile; 1-(2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(pentafluoro-16-sulfanayl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 4-((3-(4-acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (S)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one; 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-{4-[3-(4-tert-butylphenoxy)pyrazin-2-yl]piperazin-1-yl}prop-2-en-1-one; 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-(trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid; 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 3-(4-acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide; 3-(4-acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide; 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 3-(4-acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide; 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptan-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one; 2-fluoro-1-(4-(6-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one; 3-(1-acryloylpiperidin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrazin-2(1H)-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one; 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one; 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one; 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one; 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one; 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-(5-(trifluoromethyl)picolinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 2-fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridin]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 2-fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridine]-1'(2'H)-yl)prop-2-en-1-one; 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 2-fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one; 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one; 4-(dimethylamino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 2-chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 2-chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; 3-oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile; Oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one; 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one; 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile; 2-methyl-2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile; 2-methyl-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; (E)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; (E)-4-(methyl(prop-2-yn-1-yl)amino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one; 2,3-dihydroxy-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propan-1-one; (E)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (Z)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (E)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; (Z)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile; N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide; N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide; 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonyl)allyl acetate; 2-(fluoromethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-(pyrrolidin-1-ylmethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one; 2-(trifluoromethoxy)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one; N-methyl-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; N-(prop-2-yn-1-yl)-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; And, N-((4-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazin-2-yl)methyl)acrylamide; 2. The compound of claim 1, selected from:

37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

38. 37. A method of treating a disease in a subject suffering from the disease, comprising administering to the subject a compound according to any one of claims 1 to 36 or a pharma- ceutically acceptable salt thereof, wherein the disease is selected from the group consisting of: diabetic foot ulcer (DFU), venous ulcer (stasis ulcer), pressure ulcer, full or partial thickness burn, eczema, psoriasis, cellulitis, impetigo contagiousa, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acroexfoliating skin syndrome, Blau's syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, seborrheic dermatitis, capillaritis, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, lichen simplex chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, emphysema, silicosis, asbestos. disease, pneumoconiosis, aluminum disease, bauxite fibrosis, beryllium disease, siderosis, stannosis, talc disease, Labrador lung (mixed dust pneumoconiosis), sarcoidosis, hypersensitivity pneumonitis (HP) / extrinsic allergic alveolitis (EAA), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis interstitial lung disease (RBILD), acute interstitial pneumonia (AIP), nonspecific interstitial pneumonia (NSIP), idiopathic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), Idiopathic interstitial pneumonia: not specified, eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), e-cigarette or vaping use-associated lung injury (EVALI), hantavirus pulmonary syndrome (HPS), histoplasmosis, legionellosis, MAC lung disease, alpha-1 antitrypsin deficiency, aspergillosis, lymphangioleiomyoma (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacterial disease (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderin deposition diseases, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (with or without situs inversus), rare causes of hypersensitivity pneumonitis (all causes except farmer's lung disease and pigeon breeder's lung disease), pulmonary arteriovenous malformations in hereditary hemorrhagic telangiectasia (HHT), interstitial lung disease in systemic sclerosis, interstitial lung disease in rheumatoid arthritis, interstitial lung disease in idiopathic inflammatory myopathies (polymyositis, dermatomyositis, antisynthetase syndrome), interstitial lung disease in Sjogren's syndrome,Interstitial lung disease in mixed connective tissue disease (MCTD), interstitial lung disease in overlap syndrome, interstitial lung disease in undifferentiated connective tissue disease, obliterative bronchiolitis (non-transplant patients), infectious colitis, ulcerative colitis, Crohn's disease, ischemic colitis, radiation colitis, peptic ulcer, intestinal cancer, intestinal obstruction, rheumatoid arthritis, psoriatic arthritis, Hashimoto's thyroiditis, systemic lupus erythematosus, multiple sclerosis, Graves' disease, type 1 diabetes, psoriasis, ankylosing spondylitis, scleroderma, myositis, gout, antiphospholipid syndrome (APS), vasculitis, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, restrictive cardiomyopathy, systolic heart failure, Diastolic heart failure (heart failure with preserved ejection fraction), atrial septal defect, atrioventricular septal defect, coarctation of the aorta, double outlet right ventricle, d-transposition of the aorta, Epstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, single ventricle, tetralogy of Fallot, total anomalous pulmonary venous return, tricuspid atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, adult nephrotic syndrome, childhood nephrotic syndrome, hemolytic uremic syndrome, medullary sponge kidney, renal hypoplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, alopecia Rett syndrome, Wenger's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schonlein purpura, IgA nephropathy (Berger's disease), interstitial nephritis, minimal change disease, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult Still's disease, agammaglobulinemia, alopecia areata, autoimmune angioedema, autoimmune autonomic neuropathy, autoimmune encephalomyelitis, autoimmune hepatitis, autoimmune autoimmune myocarditis, autoimmune oophoritis, autoimmune orchitis, autoimmune pancreatitis, autoimmune retinopathy, autoimmune urticaria, axonal and neuronal neuropathy (AMAN), Barrow's disease, bullous pemphigoid, celiac disease, chronic relapsing multifocal osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Cogan's syndrome, cold agglutinin disease, coxsackie myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus erythematosus, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum,Essential mixed cryoglobulinemia, giant cell arteritis (temporal arteritis), giant cell myocarditis, granulomatosis with polyangiitis, Guillain-Barré syndrome, Hashimoto's thyroiditis, Henoch-Schönlein purpura (HSP), herpes gestationis or pemphigoid of gestation (PG), hypogammaglobulinemia, IgG4-related sclerosing disease, immune thrombocytopenic purpura (ITP), inclusion body myositis (IBM), Lambert-Eaton syndrome, leukocytoclastic vasculitis, linear IgA disease (LAD), microscopic polyangiitis (MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mukka-Habermann disease , multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, relapsing rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Paris-Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, type II, II Type I, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progestational dermatitis, pure red cell aplasia (PRCA), pyoderma gangrenosum, Raynaud's phenomenon, reactive arthritis, reflex sympathetic dystrophy, relapsing polychondritis, restless legs syndrome (RLS), retroperitoneal fibrosis, rheumatic fever, rheumatoid arthritis, sarcoidosis, Schmidt's syndrome, scleritis, scleroderma, Sjogren's syndrome, sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac's syndrome, sympathetic ophthalmia (SO) , Takayasu's arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcoholic liver disease, autoimmune hepatitis, biliary atresia, liver cirrhosis, lysosomal acid lipase deficiency (LAL-D), neonatal jaundice, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, primary biliary cholangitis (PBC), progressive familial intrahepatic cholestasis (PFIC), surgical scars, hypertrophic scars, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), adrenocortical carcinoma, Kaposi's sarcoma (soft tissue sarcoma), AIDS-related lymphoma (lymphoma),Primary central nervous system lymphoma (lymphoma), anal cancer, childhood astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma, brain tumor, breast cancer, bronchial tumor, Burkitt's lymphoma, carcinoid tumor (gastrointestinal tract), cardiac tumor, childhood, medulloblastoma, germ cell tumor, primary central nervous system lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CL) L), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasm, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, olfactory neuroblastoma (head and neck cancer), retinoblastoma, fallopian tube cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, childhood extracranial germ cell tumor, extragonadal germ cell tumor, ovarian germ cell tumor tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular carcinoma, histiocytosis, Langerhans cell, Hodgkin's lymphoma, hypopharyngeal cancer (head and neck cancer), intraocular melanoma, islet cell tumor, kidney (renal cell) cancer, Langerhans cell histiocytosis, laryngeal cancer (head and neck cancer), lip and oral cavity cancer, lung cancer (non-small cell, small cell, pleuropulmonary blastoma, and bronchial tumors), male breast cancer, melanoma, intraocular melanoma, meningioma, melanocytoma, Kell cell carcinoma (skin cancer), mesothelioma, malignant, squamous cell carcinoma of unknown primary cervical (head and neck cancer), midline carcinoma, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytoma, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, neuroblastoma, non-Hodgkin's lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer, oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated pleomorphic sarcoma of bone (undifferentiated pleomorphic sarcoma of bone) Pleomorphic Sarcoma of Bone Treatment), Ovarian Cancer, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors, Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pheochromocytoma, Pituitary Tumors, Plasma Cell Neoplasms / Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Primary Peritoneal Cancer, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Ewing Sarcoma (Osteosarcoma), Soft Tissue Sarcoma, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma of the Skin, Squamous Cell Carcinoma of the Neck of Unknown Primary, Metastatic (Head and Neck Cancer), Gastric Cancer, T-Cell Lymphoma, Skin - See Lymphoma (Mycosis Fungoides and Sezary Syndrome), Testicular Cancer,Nasopharyngeal carcinoma, oropharyngeal carcinoma, hypopharyngeal carcinoma, thymoma and thymic carcinoma, thyroid carcinoma, tracheobronchial tumor, transitional cell carcinoma of the renal pelvis and ureter, urethral carcinoma, uterine carcinoma, endometrial carcinoma, uterine sarcoma, vaginal carcinoma, vulvar carcinoma, and Wilms' tumor.

39. 39. The method of claim 38, wherein the disease is selected from the group consisting of brain tumor, gastric cancer, colon cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer, and soft tissue sarcoma.

40. 40. The method of claim 38 or 39, further comprising administering at least one additional chemotherapeutic agent.

41. 41. The method of claim 40, wherein the additional chemotherapeutic agent is selected from a B-RAF inhibitor, an epidermal growth factor receptor (EGFR) inhibitor, a MEK inhibitor, and an immune checkpoint inhibitor.

42. 42. The method of claim 41, wherein the B-RAF inhibitor is selected from the group consisting of vemurafenib, dabrafenib, and encorafenib.

43. 42. The method of claim 41, wherein the MEK inhibitor is selected from the group consisting of trametinib, cobimetinib, selumetinib, and binimetinib.

44. 42. The method of claim 41, wherein the EGFR inhibitor is selected from the group consisting of erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib, and vandetanib.

45. 42. The method of claim 41, wherein the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor and a PD-L1 inhibitor.

46. 46. ​​The method of claim 45, wherein the PD-1 inhibitor is selected from the group consisting of pembrolizumab, nivolumab, and cemiplimab.

47. 46. ​​The method of claim 45, wherein the PD-L1 inhibitor is selected from the group consisting of atezolizumab, avelumab, and durvalumab.

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