Small molecule inhibitors of TEA domain family members

Abstract

The present disclosure provides compounds of Formula (I): # imgabs0 # or tautomers or pharmaceutically acceptable salts thereof (wherein rings A, B, C and R1 and R2 are defined herein), pharmaceutical compositions thereof, and methods of use for the treatment of such diseases, the disease is susceptible to inhibition of a TEAD family transcription factor and / or to inhibition of growth promoting activity of the transcription co-activator YAP.

Description

[0001] Cross-references

[0002] This application claims the benefit of U.S. Provisional Application No. 63 / 269.733, filed on March 22, 2022, which is incorporated herein by reference in its entirety. Background Art

[0003] Initially discovered from fly organ overgrowth screens, the conserved Hippo pathway controls 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 matrix stiffness) lead to the activation of the kinases MST1 / 2 (serine / threonine-protein kinase 4 (STK4, known as MST1) and serine / threonine-protein kinase 3 (STK3, known as MST2) as well as LATS1 / 2 (large tumor suppressor kinase 1 and large tumor suppressor kinase 2). 2 Phosphotransfer through MST1 / 2 and LATS1 / 2 leads to phosphorylation and cytoplasmic sequestration of Yesassociated protein 1 (YAP1, referred to throughout as YAP). YAP is a transcriptional coactivator that, through its interaction with TEA domain family proteins (TEAD: genes TEAD1, TEAD2, TEAD3, and TEAD4), promotes pro-proliferative transcriptional programs that lead to cell expansion. 3

[0004] As YAP is central to growth control, several cancer types harbor mutations that inactivate members of the Hippo pathway, leading to constitutive activation of YAP and uncontrolled cell proliferation. 4 For example, YAP-activating mutations are present in more than 70 percent of all malignant pleural mesothelioma (MPM). 5 YAP additionally promotes immune evasion in solid tumors by directly regulating the transcription of PD-L1 as well as TNF-a, 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 promotes the expression of T regulatory cells (T reg) and inhibit the activation of CD4 and CD8 positive tumor-reactive T cells. 9，10 Although these data suggest that inhibition of YAP has high therapeutic utility in oncology and immuno-oncology indications, YAP does not possess a druggable protein domain. Summary of the invention

[0005] To address these deficiencies, among others, the present disclosure provides potent small molecule inhibitors of TEA domain family proteins (TEADs), which are DNA-binding transcription factors that allow locus-specific localization of YAP at TEAD-binding elements in the genome. 11 Each of the inhibitors is a compound of formula (I), a tautomer or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Ring A is a 6-membered aryl group or a 6-membered heteroaryl group having 1, 2 or 3 nitrogen ring members.

[0008] Ring B is C 6 -C 12 Aryl, C 4 -C 7 Cycloalkyl or 6-membered heteroaryl having 1 or 2 nitrogen ring members.

[0009] Ring C is a 4- to 10-membered heterocyclic ring containing 1 or 2 N ring members and which is optionally fused and optionally has 1 to 3 unsaturated bonds.

[0010] L is selected from -NH-, -O-, -CH 2 -, -S-, -C(O)-, -CHOH-, and bonds.

[0011] In various embodiments, R 1 Combined with carbon ring members, and R 1 Selected from CN, halogen, -–[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 -C10 Cycloalkyl), –-[CH 2 ] 0，1 NHC(O)(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), –[CH 2 ] 0，1 NHSO 2 (C 1 -C 6 alkyl), –-[CH 2 ] 0，1 NHSO 2 (C 2 -C 6 alkenyl) and -–[CH 2 ] 0，1 NHSO 2 (C 2 -C 6 Alkynyl), –-[CH 2 ] 0，1 NHSO 2 (C 3 -C 10 Cycloalkyl) and -–[CH 2 ] 0，1 NHSO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)).

[0012] In other embodiments, R 1 Combined with nitrogen ring members, and R 1 Selected from CN, -C(O)(C 1 -C 6 alkyl), -C(O)(C 2 -C 6 -C(O)(C 2 -C 6 Alkynyl), -C(O)(C 3 -C 10 cycloalkyl), -C(O)(3- to 6-membered heterocycloalkyl (wherein 1 to 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 -S 2 (C 2 -C 6 Alkynyl), -SO2 (C 3 -C 10 Cycloalkyl) and -SO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)).

[0013] R 2 Selected from halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy and -SF 5 .

[0014] Ring A, Ring B and Ring C are independently and optionally substituted by 1 to 3 independently selected from halogen and C 1 -C 6 The alkyl group is substituted with a substituent.

[0015] In formula (I), any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one to three substituents independently selected from the following: halogen, 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- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), -(C 1 -C 6 alkyl) (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0016] R and R' are independently selected from H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 Alkynyl.

[0017] In some embodiments, the present disclosure also provides a pharmaceutical composition comprising a compound as described herein or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. DETAILED DESCRIPTION

[0018] The compounds of the present disclosure are potent inhibitors of TEAD and are therefore useful as therapeutic agents for treating oncology and immuno-oncology indications in multiple embodiments. The need in the art is to develop treatments that affect the intrinsic growth process of tumors and simultaneously activate the adaptive immune response to tumors. The compounds of the present disclosure target TEAD family transcription factors and thereby achieve two desired activities by inhibiting the growth-promoting activity of the transcriptional coactivator YAP and by promoting the activation of multiple tumor-reactive T cell populations. Therefore, the compounds have robust utility in treating multiple tumor types.

[0019] The compounds engender many advantages. First, compared to known TEAD inhibitors, the compounds of formula (I) of the present disclosure have lower molecular weight and lower hydrophobicity. In this context, some known covalent inhibitors are characterized by electrophilic targeting groups (e.g., acrylamide) directly bound to the aromatic moiety, which increases the electrophilicity of such covalent targeting groups: this structural combination results in reduced selectivity of the inhibitor for TEAD. In contrast, the electrophilicity of the compounds of the present disclosure that conform to formula (I) is lower. The second advantage is that it was unexpectedly found that, as illustrated by the following examples, the compounds of the present disclosure inhibit cancer cell growth by selectively inhibiting TEAD: the use of covalent drugs to target TEAD is to improve the tolerability and safety of the compound, because lower doses of the compound are required to inactivate TEAD, especially in view of the long half-life of the compound in the cell (e.g., >24 hours).

[0020] Implementation

[0021] Embodiment 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof:

[0022]

[0023] in

[0024] Ring A is a 6-membered aryl group or a 6-membered heteroaryl group having 1, 2 or 3 nitrogen ring members,

[0025] Ring B is C 6 -C 12 Aryl, C 4 -C 7 Cycloalkyl or 6-membered heteroaryl having 1 or 2 nitrogen ring members;

[0026] Ring C is a 4- to 10-membered heterocyclic ring containing 1 or 2 N ring members and which is optionally fused and optionally has 1 to 3 unsaturated bonds;

[0027] L is selected from -NH-, -O-, -CH 2 -, -S-, -C(O)-, -CHOH-, and bonds;

[0028] in

[0029] In R 1 When bound to a carbon ring member,

[0030] R 1 Selected from CN, halogen, –-[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- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), –[CH 2 ] 0，1 NHSO 2 (C 1 -C 6 alkyl), -–[CH 2 ] 0， 1 NHSO 2 (C 2 -C 6 alkenyl) and -–[CH 2 ] 0，1 NHSO 2 (C 2 -C 6 Alkynyl), –-[CH 2 ] 0，1 NHSO 2 (C 3 -C 10 Cycloalkyl) and -–[CH 2 ] 0，1 NHSO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S))

[0031] In R1 When combined with nitrogen ring members,

[0032] R 1 Selected from 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- to 6-membered heterocycloalkyl (wherein 1 to 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 -S 2 (C 2 -C 6 Alkynyl), -SO 2 (C 3 -C 10 Cycloalkyl) and -SO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S));

[0033] R 2 Selected from halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy and -SF 5 ;

[0034] Ring A, Ring B and Ring C are independently and optionally substituted by 1 to 3 independently selected from halogen and C 1 -C 6 The alkyl group is substituted with a substituent; and

[0035] Any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three substituents independently selected from halogen, OH, CN, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C6 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- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), -(C 1 -C 6 alkyl) (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S),

[0036] Wherein R and R' are independently selected from H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 alkynyl).

[0037] Embodiment 2. The compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl group having 2 or 3 nitrogen ring members.

[0038] Embodiment 3. The compound according to Embodiment 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from optionally substituted:

[0039]

[0040] Embodiment 4. A compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted:

[0041]

[0042] Embodiment 5. A compound according to any one of Embodiments 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted:

[0043]

[0044] Embodiment 6. A compound according to any one of Embodiments 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted C 6 -C 12 Aryl.

[0045] 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.

[0046] Embodiment 8. The compound according to 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.

[0047] Embodiment 9. The compound according to any one of Embodiments 1 to 5 and 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of optionally substituted:

[0048]

[0049] 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 heterocyclic ring.

[0050] Embodiment 11. A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring C contains 1 N ring member.

[0051] Embodiment 12. A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring C contains 2 N ring members.

[0052] Embodiment 13. A compound according to any one of Embodiments 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Ring C is selected from optionally substituted:

[0053]

[0054] Embodiment 14. A compound according to any one of Embodiments 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring C is optionally substituted:

[0055]

[0056] Embodiment 15. A compound according to any one of Embodiments 1 to 14, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

[0057] Embodiment 16. A compound according to any one of Embodiments 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 It is C 1 -C 6 Halogenated alkyl.

[0058] Embodiment 17. A compound according to any one of Embodiments 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 Yes - CF 3 .

[0059] Embodiment 18. A compound according to any one of Embodiments 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 Combined with nitrogen ring members.

[0060] Embodiment 19. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

[0061]

[0062] Where R 3 , R 4 and R 4a are independently selected from H, halogen, CN, -C(O)OR, and optionally substituted C 1 -C 6 alkyl.

[0063] Embodiment 20. The compound according to Embodiment 19 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

[0064]

[0065] Embodiment 21. The compound according to Embodiment 19 or 20, or a pharmaceutically acceptable salt thereof, wherein:

[0066] R 3 Selected from H, F, Cl, CH 2 F. CF 3 、CN、CH 2 OH, CH 2 OC(O)R and CH 2 NRR'; and

[0067] R 4 and R 4a are independently selected from H, CH 2 F. CHF 2 , CH 2 OH, CH 2 NRR' and CH 2 -(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0068] Embodiment 22. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

[0069]

[0070] Where R 5 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6Hydroxyalkyl.

[0071] Embodiment 23. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

[0072]

[0073] Where R 6 and R 6a are independently selected from H, halogen, CN and C 1 -C 6 alkyl.

[0074] Embodiment 24. The compound according to Embodiment 23 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a At least one of them is a halogen.

[0075] Embodiment 25. The compound according to Embodiment 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a Each of is a halogen.

[0076] Embodiment 26. The compound according to Embodiment 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a At least one of them is CN.

[0077] Embodiment 27. The compound according to Embodiment 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

[0078]

[0079] Where R 7 and R 7a are independently selected from H, optionally substituted alkyl, and -C(O)OR.

[0080] Embodiment 28. The compound according to Embodiment 1 or 18, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from:

[0081]

[0082] Embodiment 29. The compound according to Embodiment 1, 18 or 28, or a pharmaceutically acceptable salt thereof, wherein R 1 yes:

[0083]

[0084] Embodiment 30. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound has Formula (IA):

[0085]

[0086] Embodiment 31. A compound according to Embodiment 30, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

[0087] Embodiment 32. The compound according to Embodiment 30 or 31, or a pharmaceutically acceptable salt thereof, wherein R 2 Yes - CF 3 or -SF 5 .

[0088] Embodiment 33. A compound according to any one of Embodiments 30 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 In the matchup.

[0089] Embodiment 34. A compound according to any one of Embodiments 30 to 33, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4- to 6-membered heterocyclic ring containing 2 N ring members.

[0090] Embodiment 35. A compound according to any one of Embodiments 30 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is:

[0091]

[0092] Embodiment 36. The compound according to Embodiment 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following:

[0093] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0094] 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonitrile;

[0095] N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide;

[0096] N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide;

[0097] N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide;

[0098] N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]hept-6-yl)acrylamide;

[0099] N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide;

[0100] 1-(3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one;

[0101] N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide;

[0102] N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide;

[0103] 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)prop-2-en-1-one;

[0104] 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one;

[0105] (R)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0106] (S)-1-(2-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0107] (R)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0108] (S)-1-(2-(hydroxymethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0109] (S)-1-(2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0110] (R)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide;

[0111] (S)-1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide;

[0112] 2-(1-Acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide;

[0113] (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile;

[0114] (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile;

[0115] 1-(2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0116] 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0117] 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridin-1-yl]prop-2-en-1-one;

[0118] 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one;

[0119] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one;

[0120] 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0121] 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0122] 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0123] 1-(4-(3-((4-(pentafluoro-16-sulfanyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0124] 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0125] 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0126] 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0127] 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0128] 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0129] 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0130] 4-((3-(4-Acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile;

[0131] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0132] 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0133] 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0134] 1-(4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0135] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one;

[0136] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0137] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0138] 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0139] 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0140] 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0141] 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0142] 1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0143] 2-Fluoro-1-(4-(3-((5-fluoro-6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0144] 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0145] (S)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0146] (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0147] (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0148] (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0149] (R)-1-(2-methyl-4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0150] 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;

[0151] 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;

[0152] 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;

[0153] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0154] 1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0155] 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0156] 2-fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0157] 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one;

[0158] 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0159] 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0160] 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;

[0161] 1-{4-[3-(4-tert-butylphenoxy)pyrazin-2-yl]piperazin-1-yl}prop-2-en-1-one;

[0162] 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0163] 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0164] 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0165] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0166] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one;

[0167] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one;

[0168] 2-Fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0169] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0170] 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0171] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0172] 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0173] 2-(Trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0174] 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid;

[0175] 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0176] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one;

[0177] 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;

[0178] 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid;

[0179] 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0180] 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0181] 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)-3,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one;

[0182] 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;

[0183] 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0184] 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0185] 1-(4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one;

[0186] 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0187] 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0188] 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0189] 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0190] 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0191] 3-(4-Acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide;

[0192] 3-(4-Acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide;

[0193] 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]heptane-2-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0194] 3-(4-Acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide;

[0195] 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0196] 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0197] 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0198] 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0199] 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0200] 1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0201] 2-Fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one;

[0202] 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]hept-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0203] 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0204] 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0205] 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0206] 1-(4-(5,6-dimethyl-3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)-2-fluoroprop-2-en-1-one;

[0207] 2-Fluoro-1-(4-(6-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0208] 1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0209] 2-Fluoro-1-(4-(5-methyl-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0210] 3-(1-Acryloylpiperidin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrazin-2(1H)-one;

[0211] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0212] 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0213] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0214] 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0215] 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one;

[0216] 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one;

[0217] 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one;

[0218] 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one;

[0219] 2-Fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one;

[0220] 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0221] 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;

[0222] 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;

[0223] 1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one;

[0224] 2-Fluoro-1-(4-(2-methyl-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one;

[0225] 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one;

[0226] 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one;

[0227] 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0228] 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0229] 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0230] 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0231] 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one;

[0232] 1-(4-(3-(5-(trifluoromethyl)methylpyridinyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0233] 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0234] 1-(4-(3-(hydroxy(6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0235] 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one;

[0236] 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one;

[0237] 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0238] 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0239] 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0240] 2-Fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0241] 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0242] 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0243] 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0244] 2-Fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0245] 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0246] 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0247] 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0248] 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0249] 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0250] 2-Fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one;

[0251] 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0252] 2-Fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one;

[0253] 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0254] 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one;

[0255] 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0256] 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0257] 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0258] 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one;

[0259] 4-(Dimethylamino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one;

[0260] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

[0261] 2-Chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

[0262] 2-Chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

[0263] 3-Oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propionitrile;

[0264] Oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone;

[0265] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one;

[0266] 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one;

[0267] 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile;

[0268] 2-methyl-2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propionitrile;

[0269] 2-methyl-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0270] (E)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one;

[0271] (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;

[0272] 2,3-Dihydroxy-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propan-1-one;

[0273] (E)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile;

[0274] (Z)-4-oxo-4-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile;

[0275] (E)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile;

[0276] (Z)-4-oxo-4-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-enenitrile;

[0277] N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide;

[0278] N-cyano-N-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxamide;

[0279] Allyl 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonyl)acetate;

[0280] 2-(Fluoromethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0281] 2-(Pyrrolidin-1-ylmethyl)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one;

[0282] 2-(trifluoromethoxy)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one;

[0283] N-methyl-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide;

[0284] N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide;

[0285] N-(prop-2-yn-1-yl)-N-(2-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)oxy)ethyl)acrylamide; and

[0286] N-((4-(6-(Trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydropyrazino[2,3-b]pyrazin-2-yl)methyl)acrylamide.

[0287] 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.

[0288] Embodiment 38. A method for treating a disease in a subject having the disease, comprising administering to the subject a compound according to any one of Embodiments 1 to 36, or a pharmaceutically 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, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acroderma extremis syndrome, Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, furunculosis, capillaris, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, simple lichen chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD ... chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary disease (COPD), chronic obstructive pulmonary Disease, COPD), emphysema, silicosis, asbestosis, pneumoconiosis, alumina pulmonary deposition, ferroalumina fibrosis, berylliosis, siderosis, tin pneumoconiosis, talcosis, Labrador lung (mixed 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), cryptogenic organizing pneumonia (Cryptogenic organizing pneumonia, etc. pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), idiopathic interstitial pneumonia: unknown, eosinophilic lung disease, tuberculosis (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, Legionnaires' disease, MAC lung disease, alpha-1-antitrypsin deficiency, aspergillosis, lymphangioleiomyomatosis (LAM), Middle Eastern Respiratory Syndrome (MERS), nontuberculous mycobacterial lung disease (PML), Disease (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (without or with situs inversus), rare causes of hypersensitivity pneumonitis (all except farmer's lung and pigeon breeder's lung), 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, mixed connective tissue disease (MCT) disease, MCTD), interstitial lung disease in overlap syndrome, interstitial lung disease in undifferentiated connective tissue disease, bronchiolitis obliterans (in 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 antibody syndrome (APS),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-type transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, univentricular heart, tetralogy of Fallot, 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, nephrotic syndrome in adults, nephrotic syndrome in children, hemolytic uremic syndrome, medullary sponge kidney, renal dysplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, Alport syndrome syndrome), Wegener's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schwann syndrome (, purpura), IgA nephropathy (Berger's disease), interstitial nephritis, subtle 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), Baló disease, bullous pemphigoid, celiac disease, chronic recurrent multifocal osteomyelitis osteomyelitis (CRMO), Churg-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Kogan syndrome, cold agglutinin disease, coxsackievirus myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic disease (neuromyelitis optica), discoid lupus, eosinophilic esophagitis (EoE), eosinophilic fasciitis, erythema nodosum, essential mixed cryoglobulinemia, giant cell arteritis (temporal arteritis), giant cell myocarditis, granulomatosis with polyangiitis, Guillain-Barre syndrome, Hashimoto's thyroiditis, Henoch-Schonlein purpura (HSP), herpes gestationis or pemphigoid gestationis 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),MPA), mixed connective tissue disease (MCTD), Mooren's ulcer, Mucha-Habermann disease, multifocal motor neuropathy (MMN) or MMNCB, multiple sclerosis, myasthenia gravis, myositis, narcolepsy, neonatal lupus, neuromyelitis optica, neutropenia, ocular cicatricial pemphigoid, optic neuritis, palindromic rheumatism (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parry Romberg syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PE), anemia, PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndrome type I, II, III, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone 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, Sjögren's syndrome (, syndrome), sperm and testicular autoimmunity, stiff person syndrome (SPS), subacute bacterial endocarditis (SBE), Susac syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcohol-related 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 (FAI), lipase deficiency (LAL-D ... 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 CNS lymphoma (lymphoma), anal cancer, childhood astrocytoma, atypical teratoid / rhabdoid tumors, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, Ewing's sarcoma, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt's lymphoma, carcinoid tumors (gastrointestinal), cardiac (heart) tumors, children, medulloblastoma, germ cell tumors, primary CNS lymphoma, cervical cancer, cholangiocarcinoma, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (Chronic Myelogenous Leukemia, CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, Ductal Carcinoma In Situ,DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, esophageal neuroblastoma (head and neck cancer), retinoblastoma, fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (Gastrointestinal Stromal Tumor Tumors, GIST), Germ Cell Tumors, Extracranial Germ Cell Tumors of Children, Extragonadal Germ Cell Tumors, Ovarian Germ Cell Tumors, Testicular Cancer, Gestational Trophoblastic Disease, Hairy Cell Leukemia, Head and Neck Cancer, Cardiac Tumors, Hepatocellular Carcinoma, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer (Head and Neck Cancer), Intraocular Melanoma, Islet Cell Tumors, 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 Blastomycin, and Tracheobronchial Tumors), Male Breast Cancer, Melanoma, Melanoma, Intraocular (Eye), Meningioma, Merkel Cell Carcinoma (Skin Cancer), Mesothelioma, Malignant Tumors, Metastatic squamous neck cancer (head and neck cancer) with occult primary, midline tract cancer, multiple endocrine neoplasia syndrome, multiple myeloma / plasma cell neoplasms, mycosis fungoides, myelodysplastic syndrome, myelodysplastic / myeloproliferative neoplasms, neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer and oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated 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 neoplasms / multiple myeloma, pleuropulmonary blastoma, pregnancy and breast cancer, primary central nervous system (Central Nervous System (CNS) lymphoma, primary peritoneal cancer, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, Ewing sarcoma (bone cancer), soft tissue sarcoma, Sezary syndrome, skin cancer, small cell lung cancer, small intestine cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous neck cancer with occult primary, metastatic (head and neck cancer), stomach (gastric) cancer, T-cell lymphoma, cutaneous - see lymphoma (mycosis fungoides and Sezary syndrome), testicular cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic cancer, thyroid cancer, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer, endometrium, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms' tumor. ,

[0289] Embodiment 39. The method according to embodiment 38, wherein the disease is selected from brain tumors, gastric cancer, colorectal cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer and soft tissue sarcoma.

[0290] Embodiment 40. The method of embodiment 38 or 39, further comprising administering at least one additional chemotherapeutic agent.

[0291] Embodiment 41. A method according to Embodiment 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.

[0292] Embodiment 42. The method of embodiment 41, wherein the B-RAF inhibitor is selected from vemurafenib, dabrafenib and encorafenib.

[0293] Embodiment 43. The method of Embodiment 41, wherein the MEK inhibitor is selected from trametinib, cobimetinib, selumetinib and binimetinib.

[0294] Embodiment 44. The method of embodiment 41, wherein the EGFR inhibitor is selected from erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necitumumab, mobocertinib and vandetanib.

[0295] Embodiment 45. The method according to Embodiment 41, wherein the immune checkpoint inhibitor is selected from a PD-1 inhibitor and a PD-L1 inhibitor.

[0296] Embodiment 46. The method according to Embodiment 45, wherein the PD-1 inhibitor is selected from pembrolizumab, nivolumab and cemiplimab.

[0297] Embodiment 47. The method according to Embodiment 45, wherein the PD-L1 inhibitor is selected from atezolizumab, avelumab and durvalumab.

[0298] definition

[0299] "Alkyl" refers to a straight or branched chain hydrocarbon group containing 1 to about 20 carbon atoms. For example, the alkyl group can have 1 to 10 carbon atoms or 1 to 6 carbon atoms. Exemplary alkyl groups include straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, etc.; and also include branched chain isomers of straight chain alkyl groups, such as, but not limited to

[0300] -CH(CH 3 ) 2 ,-CH(CH 3 )(CH 2 CH 3 ), -CH(CH 2 CH3) 2 , -C(CH 3 ) 3 , -C(CH 2 CH 3 ) 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH(CH 2 CH 3 ) 2 , -CH 2 C(CH 3 ) 3 , -CH 2 C(CH 2 CH 3 ) 3 ,-CH(CH 3 )CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 3 ) 2 , -CH 2 CH 2 CH(CH 3 )(CH 2 CH 3 ), -CH 2 CH 2 CH(CH 2 CH 3 ) 2, -CH 2 CH 2 C(CH 3 ) 3 , -CH 2 CH 2 C(CH 2 CH 3 ) 3 ,-CH(CH 3 )CH 2 CH(CH 3 ) 2 ,-CH(CH 3 )CH(CH 3 )CH(CH 3 ) 2 ,etc.

[0301] Thus, alkyl includes primary, secondary and tertiary alkyl.Alkyl groups may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0302] Each of the terms "halogen," "halide," and "halo" refers to -F or fluorine, -Cl or chlorine, -Br or bromine, or -I or iodine.

[0303] The term "alkenyl" refers to a straight or branched hydrocarbon group containing 2 to about 20 carbon atoms having 1 to 3, 1 to 2 or at least one carbon-carbon double bond. The alkenyl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0304] "Alkyne" or "alkynyl" refers to a straight or branched chain unsaturated hydrocarbon having the specified number of carbon atoms and at least one triple bond. 2 -C 8 Examples of 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 may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0305] The term "alkoxy" or "alkoxyl" refers to an -O-alkyl group having the specified number of carbon atoms. 1 -C 6 )Alkoxy includes -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 -O-neohexyl.

[0306] The term "cycloalkyl" refers to a saturated monocyclic, bicyclic, tricyclic or polycyclic 3 to 14 membered ring system, such as C 3 -C 8 Cycloalkyl. Cycloalkyl can be connected through any atom. Representative examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Polycyclic cycloalkyls contain rings that can be fused, bridged, and / or spiro-fused. Cycloalkyl can be unsubstituted or optionally substituted with one or more substituents as described herein.

[0307] "Aryl" when used alone or as part of another term means a carbocyclic aromatic radical, whether fused or not, having the number of carbon atoms specified, or if no number is specified, up to 14 carbon atoms, e.g., C 6 -C 10 Aryl or C 6 -C 14 Aryl. Examples of aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl, naphthacenyl, etc. (see, e.g., Lang's Handbook of Chemistry (Dean, JA, ed. 13th edition. Table 7-2

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

[0308] The term "heteroatom" refers to N, O and S. Compounds of the disclosure containing N or S atoms can be optionally oxidized to the corresponding N-oxide, sulfoxide or sulfone compounds.

[0309] "Heteroaryl" (alone or in combination with any other moiety described herein) is a monocyclic aromatic ring structure containing 5 to 10 (e.g., 5 or 6) ring atoms containing one or more (e.g., 1 to 4, 1 to 3, or 1 to 2) heteroatoms independently selected from O, S, and N, or a bicyclic aromatic group having 8 to 10 atoms. Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary ring nitrogen. The carbon or heteroatom is the point of attachment of the heteroaryl ring structure, thereby producing a stable compound. Examples of heteroaryl include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, quinoxalinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolyl, pyrimidinyl, pyrrolyl, pyrazolyl, Azolyl, thiazolyl, thienyl, iso Azolyl, Thiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl and indolyl. The heteroaryl group may be unsubstituted or optionally substituted with one or more substituents as described herein.

[0310] "Heterocycloalkyl" is a saturated or partially unsaturated non-aromatic monocyclic, bicyclic, tricyclic or polycyclic ring system, and the ring system has 3 to 14 (e.g., 3 to 6) atoms, wherein 1 to 3 carbon atoms in the ring are replaced by the heteroatoms of O, S or N. Polycyclic heterocycloalkyl includes rings that can be fused, bridged and / or spiral fused. In addition, heterocycloalkyl is optionally fused with aryl or heteroaryl of 5 to 6 ring members, and contains oxidized S or N, such as N-oxides of sulfinyl, sulfonyl and tertiary ring nitrogen. The connection point of the heterocycloalkyl ring is on carbon or heteroatom, so that stable rings are maintained. The example of heterocycloalkyl includes but is not limited to morpholino, tetrahydrofuranyl, dihydropyridyl, piperidyl, pyrrolidinyl, piperazinyl, dihydrobenzofuranyl and dihydroindole. Heterocycloalkyl can be unsubstituted or optionally substituted by one or more substituents as described herein.

[0311] The terms "nitrile" or "cyano" are used interchangeably and refer to a -CN group.

[0312] "Hydroxyl" or "hydroxy" refers to an -OH group.

[0313] The compounds described herein may exist in a variety of isomeric forms (including configurations, geometric isomers, 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 compounds of the present disclosure, including tautomeric forms of the compounds. The compounds of the present disclosure may also exist in open-chain or cyclized forms. In some cases, one or more of the cyclized forms may be produced by dehydration. The specific composition of the open-chain and cyclized forms may depend on how the compounds are separated, stored, or applied. For example, the compound exists primarily in an open-chain form under acidic conditions, but cyclizes under neutral conditions. All forms are included in the disclosure.

[0314] Some compounds described herein may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. Compounds as described herein may be in the form of optical isomers or diastereomers. Therefore, the present disclosure encompasses compounds and uses thereof in the form of optical isomers, diastereomers, and mixtures thereof (including racemic mixtures) as described herein. The optical isomers of compounds of the present disclosure may be obtained by known techniques such as asymmetric synthesis, chiral chromatography, simulated moving bed technology, or by chemically separating stereoisomers using optically active resolving agents.

[0315] Unless otherwise indicated, the term "stereoisomer" means one stereoisomer of a compound that is substantially free of other stereoisomers of the compound. Thus, a stereomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereoisomerically pure compound contains greater 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, such as greater 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 greater 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 greater 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 greater 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 considered as compositions containing two stereoisomers present in their respective weight percentages as described herein.

[0316] If there is a discrepancy between a structure shown and a name given to that structure, the structure shown shall prevail. In addition, if the stereochemistry of a structure or portion of a structure is not indicated by, for example, bold or dashed lines, the structure or portion of a structure should be interpreted as encompassing all stereoisomers thereof. However, in some cases, where there is more than one chiral center, the structure and name may be indicated as a single enantiomer to help describe the relevant stereochemistry. One skilled in the art of organic synthesis will know whether a compound is prepared as a single enantiomer by the process used to prepare it.

[0317] As used herein, and unless otherwise indicated to the contrary, the term "compound" is inclusive in that it encompasses 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.

[0318] 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 metal 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, camphensulfonate, carbonate, chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, glucoheptonate, gluconate, glutamate, glycollylarsanilate, hexafluorophosphate, hexylresorcinol salt, hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide

[0013] The invention further comprises the following: bis(2-hydroxy-3-naphthoate), bis(2-hydroxy-4-naphthoate), bis(2-hydroxy-5-naphthoate), bis(2-hydroxy-6-naphthoate), bis(2-hydroxy-7-naphthoate), bis(2-hydroxy-8-naphthoate), bis(2-hydroxy-9-naphthoate), bis(2-hydroxy-1-naphthoate), bis(2-hydroxy-1-naphthoate), bis(2-hydroxy-1-naphthoate), bis(2-hydroxy-1-naphthoate), bis(2-hydroxy-1-naphthoate), bis(2-hydroxy-2-naphthoate), bis(2-hydroxy-1 ... A pharmaceutically acceptable salt may have more than one charged atom in its structure. In this case, the pharmaceutically acceptable salt may have multiple counterions. Thus, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0319] The term "treat" and its variations refer to the improvement or eradication of a disease or symptoms associated with a disease. In various embodiments, the term refers to minimizing or slowing the spread, progression or worsening of such a disease as a result of administering one or more of the preventive or therapeutic compounds described herein to a patient suffering from the disease.

[0320] The term "prevent," "preventing," and variations thereof, refers to preventing the onset, recurrence, or spread of a disease in a patient as a result of the administration of a compound described herein.

[0321] The term "effective amount" refers to an amount of a compound or other active ingredient as described herein that is sufficient to provide a therapeutic or preventive benefit in the treatment or prevention of a disease, or to delay or minimize symptoms associated with a disease. In addition, a therapeutically effective amount of a compound as 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 conjunction with a compound as described herein, the term may encompass an amount that improves the overall treatment of a disease, alleviates or avoids symptoms or causes of a disease, or enhances the therapeutic efficacy of another therapeutic agent or acts synergistically with another therapeutic agent.

[0322] "Patient" or "subject" includes animals, such as humans, cows, horses, sheep, lambs, pigs, chickens, turkeys, quail, cats, dogs, mice, rats, rabbits, or guinea pigs. According to some embodiments, the animal is a mammal, such as a non-primate and a primate (e.g., monkeys and humans). In one embodiment, the patient is a human, such as a human infant, child, teenager, or adult. In the present disclosure, the terms "patient" and "subject" are used interchangeably.

[0323] Compound

[0324] In various embodiments, the present disclosure provides a compound of formula (I), a tautomer or a pharmaceutically acceptable salt thereof:

[0325]

[0326] Ring A is a 6-membered aryl group or a 6-membered heteroaryl group having 1, 2 or 3 nitrogen ring members.

[0327] Ring B is C 6 -C 12 Aryl, C 4 -C 7 Cycloalkyl or 6-membered heteroaryl having 1 or 2 nitrogen ring members.

[0328] Ring C is a 4- to 10-membered heterocyclic ring containing 1 or 2 N ring members and which is optionally fused and optionally has 1 to 3 unsaturated bonds.

[0329] L is selected from -NH-, -O-, -CH 2 -, -S-, -C(O)-, -CHOH-, and bonds.

[0330] In various embodiments, R 1 Combined with carbon ring members, and R 1 Selected from CN, halogen, -–[CH 2 ] 0，1 NHC(O)(C 1 -C 6alkyl), -–[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- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), –[CH 2 ] 0，1 NHSO 2 (C 1 -C 6 alkyl), –-[CH 2 ] 0，1 NHSO 2 (C 2 -C 6 alkenyl) and –-[CH 2 ] 0，1 NHSO 2 (C 2 -C 6 Alkynyl), –-[CH 2 ] 0，1 NHSO 2 (C 3 -C 10 Cycloalkyl) and -–[CH 2 ] 0，1 NHSO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)).

[0331] In other embodiments, R 1 Combined with nitrogen ring members, and R 1 Selected from CN, -C(O)(C 1 -C 6 alkyl), -C(O)(C 2 -C 6 -C(O)(C 2 -C 6 Alkynyl), -C(O)(C 3 -C 10 cycloalkyl), -C(O)(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), -C 1 -C6 Alkyl (C 3 -C 10 Cycloalkyl), -SO 2 (C 1 -C 6 Alkyl), -SO 2 (C 2 -C 6 -S 2 (C 2 -C 6 Alkynyl), -SO 2 (C 3 -C 10 Cycloalkyl) and -SO 2 (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)).

[0332] R 2 Selected from halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Haloalkoxy and -SF 5 .

[0333] Ring A, Ring B and Ring C are independently and optionally substituted by 1 to 3 independently selected from halogen and C 1 -C 6 The alkyl group is substituted with a substituent.

[0334] In formula (I), any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted by one to three substituents independently selected from the following: halogen, 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- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), -(C 1 -C 6 alkyl) (3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

[0335] R and R' are independently selected from H, C 1 -C 6 Alkyl, C 2 -C 6 Alkenyl and C 2 -C 6 Alkynyl.

[0336] In some embodiments, Ring A is a 6-membered heteroaryl group having 2 or 3 nitrogen ring members. Some illustrative examples of Ring A are selected from optionally substituted:

[0337]

[0338] Thus, in one embodiment, Ring A is optionally substituted In another embodiment, Ring A is optionally substituted

[0339] In other embodiments, optionally in combination with any other embodiments described herein, Ring B is an optionally substituted C 6 -C 12 In an illustrative embodiment, Ring B is optionally substituted phenyl.

[0340] In other embodiments, Ring B is an optionally substituted 6-membered heteroaryl having 1 or 2 nitrogen ring members. Some examples of Ring B are selected from the group of optionally substituted:

[0341]

[0342] In some embodiments, the disclosure also provides compounds of formula (I), wherein ring C is an optionally substituted 4- to 8-membered heterocycle. In one embodiment, ring C contains 1 N ring member. In another embodiment, ring C contains 2 N ring members. Some examples of ring C include those selected from the following optionally substituted:

[0343]

[0344] In some illustrative embodiments, Ring C is optionally substituted

[0345] According to various embodiments, optionally in combination with any other embodiments described herein, L is -NH-.

[0346] Other embodiments of the present disclosure provide compounds of formula (I), wherein R 2 It is C 1 -C 6 In one illustrative embodiment, R2 Yes - CF 3 .

[0347] In some embodiments, R 1 Combined with nitrogen ring members. For example, R 1 Can have the following formula:

[0348]

[0349] Where R 3 , R 4 and R 4a are independently selected from H, halogen, CN, -C(O)OR, and optionally substituted C 1 -C 6 In one illustrative embodiment, R 1 With formula

[0350] In these embodiments:

[0351] R 3 Selected from H, F, Cl, CH 2 F. CF 3 、CN、CH 2 OH, CH 2 OC(O)R and CH 2 NRR'; and

[0352] R 4 and R 4a Independently selected from H, CH 2 F. CHF 2 , CH 2 OH, CH 2 NRR' and CH 2 -(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S), wherein R and R' are as defined herein.

[0353] In other embodiments, wherein R 1 Combined with nitrogen ring members, R 1 Has the following formula:

[0354]

[0355] Where R 5 Selected from H, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and C 1 -C 6 Hydroxyalkyl.

[0356] In some other embodiments, wherein R 1 Combined with nitrogen ring members, R 1 Has the following formula:

[0357]

[0358] Where R 6 and R 6a are independently selected from H, halogen, CN and C 1 -C 6 In some embodiments, R 6 and R 6a In some other embodiments, at least one of R 6 and R 6a In some other embodiments, each of R 6 and R 6a At least one of is CN. All these combinations are contemplated.

[0359] In other embodiments, wherein R 1 Combined with nitrogen ring members, R 1 Has the following formula:

[0360]

[0361] Where R 7 and R 7a are independently selected from H, optionally substituted alkyl, and -C(O)OR, wherein R is as defined herein.

[0362] In various embodiments, the present disclosure provides compounds of formula (I), wherein R 1 Selected from:

[0363]

[0364] According to some embodiments and optionally in combination with any other embodiments described herein, R 1 A specific example is the following formula:

[0365]

[0366] According to various embodiments, some compounds of formula (I) as described herein also correspond to formula (IA):

[0367]

[0368] According to some embodiments, in Formula (IA), L is -NH-. In other embodiments, R 2 Yes - CF 3 or -SF 5. R 2 can be combined with any position on the benzene ring in formula (IA). In some illustrative embodiments, R 2 It is aligned relative to L, that is:

[0369]

[0370] In other embodiments, with respect to Formula (IA), Ring C is a 4- to 6-membered heterocyclic ring containing 2 N ring members. According to an illustrative embodiment, an example of Ring C is:

[0371]

[0372] In various embodiments, the present disclosure also provides compounds or tautomers or pharmaceutically acceptable salts thereof, as shown in Table 1.

[0373] Table 1: Exemplary compounds

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424]

[0425]

[0426]

[0427]

[0428] Pharmaceutical composition

[0429] The present disclosure also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds described herein or a pharmaceutically acceptable salt thereof, stereoisomers and / or tautomers mixed with a pharmaceutically acceptable carrier. In some embodiments, according to the approved practice of pharmaceutical compounding, the composition also comprises one or more other therapeutic agents, pharmaceutically acceptable excipients, diluents, adjuvants, stabilizers, emulsifiers, preservatives, colorants, buffers, flavor imparting agents.

[0430] 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.

[0431] The pharmaceutical compositions of the present disclosure are formulated, dosed, and applied in a manner consistent with good medical practice. Factors considered in this context include the specific condition being treated, the specific subject being treated, the clinical condition of the subject, the cause of the condition, the delivery site of the medicament, the method of administration, the time schedule of administration, and other factors known to medical practitioners.

[0432] The "therapeutically effective amount" of the compound or its pharmaceutically acceptable salt, stereoisomer and / or tautomer administered depends on such considerations and is the minimum amount required 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 an amount may be lower than the amount that is toxic to normal cells or the object as a whole. In general, the initial therapeutically effective amount of the compound of the present disclosure (or its pharmaceutically acceptable salt, stereoisomer or tautomer) administered is about 0.01 to about 200 mg / kg or about 0.1 to about 20 mg / kg patient body weight / day, with a typical initial range of about 0.3 to about 15 mg / kg / day. Oral unit dosage forms (e.g., tablets and capsules) may contain about 0.1 mg to about 1000 mg of the compound of the present disclosure (or its pharmaceutically acceptable salt, stereoisomer or tautomer). In another embodiment, such dosage forms comprise from about 50 mg to about 500 mg of a compound of the disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such dosage forms comprise from about 25 mg to about 200 mg of a compound of the disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such dosage forms comprise from about 10 mg to about 100 mg of a compound of the disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In another embodiment, such dosage forms comprise from about 5 mg to about 50 mg of a compound of the disclosure (or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof). In any of the foregoing embodiments, the dosage form may be administered once a day or twice a day.

[0433] The compositions of the present disclosure may be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.

[0434] Suitable oral compositions as 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.

[0435] In another aspect, also contemplated are pharmaceutical compositions suitable for a single unit dose, comprising a compound of the present disclosure, or a pharmaceutically acceptable stereoisomer, salt, or tautomer thereof, and a pharmaceutically acceptable carrier.

[0436] Compositions of the present disclosure suitable for oral use can be prepared according to any method known in the art for preparing pharmaceutical compositions. For example, liquid formulations of compounds of the present disclosure include one or more agents selected from sweeteners, flavoring agents, coloring agents, and preservatives to provide pharmaceutically palatable formulations of compounds of the present disclosure.

[0437] For tablet compositions, the compounds of the present disclosure are mixed with non-toxic pharmaceutically acceptable excipients for preparing tablets. 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 agents and disintegrants such as corn starch or alginic acid; binders such as starch, gelatin or gum arabic, 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 and thereby provide a sustained therapeutic effect over a desired period of time. For example, time-delayed substances such as glyceryl monostearate or glyceryl distearate may be used.

[0438] Formulations for oral use may also be presented as hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent (e.g., calcium carbonate, calcium phosphate or kaolin), or as soft gelatin capsules in which the active ingredient is mixed with water or an oil medium (e.g., peanut oil, liquid paraffin or olive oil).

[0439] For aqueous suspensions, the compounds of the present disclosure are mixed with excipients suitable for maintaining a stable suspension. Examples of such excipients include, but are not limited to, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic.

[0440] Oral suspensions may also include dispersants or wetting agents, such as naturally occurring phosphatides, such as lecithin, or condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate, or condensation products of ethylene oxide with long-chain fatty alcohols, such as 17-carbon ethyleneoxy hexadecanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, such as polyethylene sorbitan monooleate. Aqueous suspensions may also include one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweeteners, such as sucrose or saccharin.

[0441] Oily suspensions can be formulated by suspending a compound of the disclosure in a vegetable oil (e.g., peanut oil, olive oil, sesame oil, or coconut oil) or in a mineral oil (e.g., liquid paraffin). The oily suspensions may contain a thickening agent such as beeswax, hard paraffin, or cetyl alcohol.

[0442] 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.

[0443] Dispersible powders and granules suitable for preparing aqueous suspensions by adding water provide a compound of the disclosure mixed with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweeteners, flavoring agents and coloring agents may also be present.

[0444] The pharmaceutical composition of the present disclosure can also be in the form of an oil-in-water emulsion. The oil phase can be a vegetable oil (e.g., olive oil or peanut oil), or a mineral oil (e.g., liquid paraffin), or a mixture of these. Suitable emulsifiers can be naturally occurring gums (e.g., gum arabic or tragacanth), naturally occurring phospholipids (e.g., soybean, lecithin), and esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., condensation reaction products of sorbitan monooleate and the partial ester with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate)). Emulsions can also include sweeteners and flavoring agents.

[0445] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such preparations may also contain a demulcent, a preservative and flavoring and coloring agents.

[0446] The pharmaceutical composition can be in the form of a sterile injectable, aqueous suspension or oily suspension. The suspension can be prepared according to known techniques using those suitable dispersants or wetting agents and suspending agents mentioned above. The sterile injection preparation can also be a sterile injectable solution or suspension in a nontoxic, parenterally acceptable diluent or solvent, such as a solution in 1,3-butanediol. In acceptable carriers and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids (such as oleic acid) are found to be used to prepare injectables.

[0447] The compounds as 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 drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter and polyethylene glycol.

[0448] Compositions for parenteral administration are administered in a sterile medium. Depending on the carrier used and the concentration (concentration of the drug in the preparation), parenteral preparations can be suspensions or solutions containing dissolved drugs. Excipients (e.g., local anesthetics, preservatives, and buffers) can also be added to parenteral compositions.

[0449] How to use

[0450] In other embodiments, the disclosure provides a method for treating the disease in a subject suffering from the disease. The method includes administering a compound described herein or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, the disease is a disease caused by abnormal activity caused by TEA domain family proteins (TEAD1, TEAD2, TEAD3, and / or TEAD4). In other embodiments, the disease is associated with constitutive activation of YAP. Some specific examples of diseases include: diabetic foot ulcer (DFU), venous ulcer (stasis ulcer), pressure ulcer, full or partial thickness burns, eczema, psoriasis, cellulitis, impetigo, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acrodermal peeling syndrome, Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, furunculosis, capillaris, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, lichen simplex chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), pulmonary fibrosis (CPPD), acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ACE), acute respiratory syncytial virus (ACS), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), acute respiratory syncytial virus (ECD), chronic ... OPD), emphysema, silicosis, asbestosis, pneumoconiosis, alumina pulmonary deposition, ferroalumina fibrosis, berylliosis, siderosis, tin pneumoconiosis, talcosis, Labrador lung (mixed 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), cryptogenic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial Pneumonia (LIP), idiopathic interstitial pneumonia: unspecified, eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), electronic cigarette or waterpipe use-associated lung injury (EVALI), Hantavirus pulmonary syndrome (HPS), histoplasmosis, Legionnaires' disease, MAC lung disease, alpha-1-antitrypsin deficiency, aspergillosis, lymphangioleiomyomatosis (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacterial lung disease (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis Pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (without or with 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 syndromes,Interstitial lung disease in undifferentiated connective tissue disease, bronchiolitis obliterans (in 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 antibody 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-type transposition of the great arteries, Ebstein anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, univentricular heart, tetralogy of Fallot, anomalous total pulmonary venous return, tricuspid atresia, truncus arteriosus, ventricular septal defect, polycystic kidney disease, diabetes insipidus, Goodpasture's disease, IgA vasculitis, IgA nephropathy, lupus nephritis, nephrotic syndrome in adults, nephrotic syndrome in children, hemolytic uremic syndrome, medullary sponge kidney, renal dysplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, Alport syndrome, Wegener's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome ( HUS), Henoch-Schwann syndrome, IgA nephropathy (Berger's disease), interstitial nephritis, subtle change disease, nephrotic syndrome, thrombotic thrombocytopenic purpura (TTP), granulomatosis with polyangiitis (GPA), adult-onset 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), Barlow's disease, bullous pemphigoid, celiac disease, chronic recurrent multifocal osteomyelitis (CRMO), Zag-Strauss disease Stokes syndrome (CSS) or eosinophilic granuloma (EGPA), cicatricial pemphigoid, Kogan syndrome, cold agglutinin disease, coxsackievirus myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic disease (neuromyelitis optica), discoid lupus, 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-Schüller syndrome (HSP), herpes gestationis or pemphigoid 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, Mucha-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 rheumatic disease (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parkinson's disease, pars planitis (peripheral uveitis), Parsonage-Tur ner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, and III, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone 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, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man syndrome (SPS), subacute bacterial endocarditis (SB E), Susac syndrome, sympathetic ophthalmia (SO), Takayasu arteritis, temporal arteritis / giant cell arteritis, thrombocytopenic purpura (TTP), thyroid eye disease (TED), Alagille syndrome, alcohol-related 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 sarcoma (soft tissue sarcoma), AIDS-related lymphoma ( Lymphoma), primary CNS lymphoma (lymphoma), anal cancer, childhood astrocytoma, atypical teratoid / rhabdoid tumor, basal cell carcinoma of the skin, bile duct cancer, bladder cancer, Ewing sarcoma, osteosarcoma, malignant fibrous histiocytoma, brain tumors, breast cancer, bronchial tumors, Burkitt lymphoma, carcinoid tumors (gastrointestinal tract), cardiac (heart) tumors, children, medulloblastoma, germ cell tumors, primary CNS lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer,Esthenoblastoma (head and neck cancer), retinoblastoma, fallopian tube cancer, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, extracranial germ cell tumor of childhood, extragonadal germ cell tumor, ovarian germ cell tumor, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumor, hepatocellular carcinoma, histiocytosis, Langerhans cell, Hodgkin 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 tracheobronchial tumors), Male breast cancer, Melanoma, Melanoma, Intraocular (eye), Meningioma, Merkel cell carcinoma (skin cancer), Mesothelioma, Malignant neoplasms, Metastatic squamous neck cancer (head and neck cancer) with occult primary, Midline tract cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma / plasma cell neoplasms, Mycosis fungoides, Myelodysplastic syndrome, Myelodysplastic / myeloproliferative neoplasms, Neuroblastoma, Non-Hodgkin lymphoma, non-small cell lung cancer, oral cavity cancer, lip and oral cavity cancer and oropharyngeal cancer (head and neck cancer), osteosarcoma and undifferentiated 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 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 (bone cancer), soft tissue carcinoma Tumors, Sézary syndrome, skin cancer, small cell lung cancer, small bowel cancer, soft tissue sarcomas, squamous cell carcinoma of the skin, squamous neck cancer with occult primary, metastatic (head and neck cancer), stomach (stomach) (gastric) cancer, T-cell lymphoma, cutaneous - see lymphomas (mycosis fungoides and Sézary syndrome), testicular cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic cancer, thyroid cancer, 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.

[0451] In some illustrative embodiments, the disease is selected from a brain tumor, gastric cancer, colorectal cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer, and soft tissue sarcoma.

[0452] The compounds of the present disclosure are effective as monotherapeutic agents, for example, for the treatment of YAP-addicted cancers, including 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 before, after, or at the same time as the compounds of the present disclosure. Therefore, the compounds can be used as combination therapeutic agents because TEAD inhibition has been shown to produce synergistic effects when co-treated with other targeted therapies (e.g., EGFR inhibitors, MEK inhibitors, and ERK1 / 2 inhibitors). 15 Since YAP controls PD-L1 levels and reprograms the tumor microenvironment, TEAD inhibitors can be used as co-treatments with checkpoint inhibitors (e.g., PD-L1, PD1, and CTLA4 targeting antibodies).

[0453] In multiple embodiments, additional chemotherapeutic agents are selected from B-RAF inhibitors, epidermal growth factor receptor (EGFR) inhibitors, MEK inhibitors and immune checkpoint inhibitors. Some examples of B-RAF inhibitors include vemurafenib, dabrafenib and encofenib. Some examples of MEK inhibitors include trametinib, cobimetinib, selumetinib and bimetinib. In addition, some examples of EGFR inhibitors include erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, nacitozumab, mobotinib and vandetanib.

[0454] In various embodiments, the immune checkpoint inhibitor is selected from a PD-1 inhibitor and a PD-L1 inhibitor. Some examples of PD-1 inhibitors include pembrolizumab, nivolumab, and cemiplizumab. Some examples of PD-L1 inhibitors include atezolizumab, avelumab, and durvalumab.

[0455] Example

[0456] Some additional embodiments of the present disclosure are presented in the specific examples and data described in more detail herein.

[0457] Synthesis of Compounds. Compounds of the present disclosure were prepared according to and by adaptation of the following exemplary procedures.

[0458] Example 1. Synthesis of 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonitrile

[0459]

[0460] Solution 1

[0461] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate

[0462]

[0463] 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 Cs(II) portionwise at room temperature. 2 CO 3 (4.37 g, 13.43 mmol, 2.00 equiv). The resulting mixture was stirred at 80 °C for 4 h. The reaction was monitored by LCMS. The mixture was washed with 20.00 mL of H 2 O quenched, and extracted with ethyl acetate (20.00 mL × 3). The combined organic layer was washed with brine (50.00 mL), 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (5:1) to give tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (1.00 g, 49.86% yield) as a yellow solid. LCMS: (positive, ES, m / z): 299.2

[0464] Step 2: Synthesis of tert-butyl 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate

[0465]

[0466] To 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 CS 2 CO 3 A stirred mixture of Pd (1.96 g, 6.02 mmol, 2 eq.) in toluene (10.00 mL) was added portionwise. 2 (dba) 3(0.11 g, 0.12 mmol, 0.04 equiv). 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, 62.72% yield) as a yellow oil. LCMS: (positive, ES, m / z): 424.2

[0467] Step 3: Synthesis of 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine

[0468]

[0469] To a stirred 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) at 0°C was added HCl (gas) in 1,4-dioxane (1.48 mL, 5.91 mmol, 5.00 equiv). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 3-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (0.30 g, 78.58% yield) as a yellow oil. LCMS: (negative, ES, m / z): 322.1

[0470] Step 4: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0471]

[0472] To a 10 ml bottle at 0°C was added 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). To the above mixture was added acryloyl chloride (0.08 g, 0.93 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. To the resulting mixture was added 50.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (50.00 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The crude product was passed through (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), 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) was purified 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. LCMS: (positive, ES, m / z): 349.2.

[0473] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.60 (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).

[0474] Example 2: Synthesis of 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carbonitrile

[0475]

[0476] Solution 2

[0477] To a 10 ml bottle at 0°C was added 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). To the above mixture was added BrCN (0.07 g, 0.62 mmol, 1.00 equiv). The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. To the resulting mixture was added 50.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (50.00 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4After filtration, the filtrate was concentrated under reduced pressure. The crude product was passed through (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B to 90% B, 90% B in 10 minutes; wavelength: 254 nm; RT1 (min): 7; number of 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. LCMS: (positive, ES, m / z): 349.2.

[0478] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.55 (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).

[0479] Example 3. Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide

[0480]

[0481] Solution 3

[0482] Step 1: Synthesis of 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine

[0483]

[0484] To 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 Cs 2 CO 3 (25.15 g, 77.19 mmol, 2.00 equiv) in toluene (20.00 mL) was added Pd 2 (dba) 3 (2.83 g, 3.09 mmol, 0.10 eq.) 2 The resulting mixture was stirred at 90° C. for 3 h under a 3% CO atmosphere. The mixture was diluted with EA (150.00 mL) and washed with H2 O (3 × 50.00 mL), washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting 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.

[0485] (ES, m / z): [M+H] + =274. 1 H NMR (400 MHz, DMSO-d 6 ): δ9.17 (s, 1H), 8.22 (s, 1H), 7.95-7.93 (m, 3H), 7.68-7.66 (m, 2H).

[0486] Step 2: Synthesis of tert-butyl (1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)carbamate

[0487]

[0488] 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 Cs(II) portionwise at room temperature. 2 CO 3 (476.3 mg, 1.46 mmol, 2.00 equiv). The resulting mixture was stirred at 80 °C overnight. The reaction was monitored by LCMS. The mixture was washed with 20.00 mL of H 2 O quenched, and extracted with ethyl acetate (20.00 mL × 3). The combined organic layer was washed with brine (50.00 mL), 2 SO 4 The product was stirred for 2 hours at 4 ℃ for 10 minutes at 4 ℃ for 2 hours.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours at 4 ℃ for 4 hours at 5 ℃ for 8 hours.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours at 5 ...8 hours.Then the mixture was stirred for 2 hours at 4 ℃ for 3 hours at 5 ℃ for 4 hours at 5 ℃ for 8 hours.Then the mixture was stirred for

[0489] Step 3: Synthesis of 3-(3-aminoazetidin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine

[0490]

[0491] To a stirred mixture of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazine-2-yl)piperazine-1-carboxylate (250 mg, 0.0.61 mmol, 1.00 equiv) in dioxane (2.00 mL) at 0°C was added HCl (gas) in 1,4-dioxane (3.05 mL, 12.21 mmol, 20.00 equiv). The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 3-(3-aminoazetidine-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazine-2-amine (170 mg, 90.01% yield) as a yellow oil.

[0492] Step 4: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide

[0493]

[0494] 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 was added acryloyl chloride (32 mmL, 0.39 mmol, 1.20 equiv). The resulting mixture was stirred at 0°C for another 0.5 h. The reaction was monitored by LCMS. To the resulting mixture was added 50.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (50.00 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4 The reaction mixture was stirred for 2 hours at 4 ℃ for 1 h. Drying. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography eluting with DCM:EA (4:6) to give N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)azetidin-3-yl)acrylamide (53 mg, 45.12% yield) as a white solid.

[0495] 1H NMR (400MHz, DMSO) δ10.86-10.30 (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).

[0496] Example 4: Synthesis of N-((1r,3r)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide

[0497]

[0498] 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 provided as a white solid. (n, ES, m / z): 378.19.

[0499] 1 H NMR (400MHz, DMSO) δ 8.73-8.54 (m, 2H), 7.88 (d, J = 8.5Hz, 2H), 7.65 (d, J = 8.6Hz, 2H), 7.56 (d, J = 3.0Hz, 1H), 7.43 (d, J = 3.0Hz, 1H), 7.00 (d, J = 5.7Hz, 1H), 6.24 (dd, J=17.1, 10.1Hz, 1H), 6.10 (dd, J=17.0, 2.3Hz, 1H), 5.61 (dd , J=10.0, 2.3Hz, 1H), 4.51-4.39 (m, 2H), 2.34 (ddt, J=9.6, 5.5, 2.0Hz, 4H).

[0500] Example 5: Synthesis of N-((1s,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide

[0501]

[0502] Following the general procedure in Scheme 3, tert-butyl ((ls,3s)-3-aminocyclobutyl)carbamate was used in step 2. N-((ls,3s)-3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)cyclobutyl)acrylamide was provided as a white solid. (n, ES, m / z): 378.24.

[0503] 1 H NMR (400MHz, DMSO) δ 8.64 (s, 1H), 8.42 (d, J = 7.2Hz, 1H), 7.88 (d, J = 8.5Hz, 2H), 7.65 (d, J = 8.6Hz, 2H), 7.57 (d, J = 3.0Hz, 1H), 7.42 (d, J = 3. 0Hz, 1H), 6.93 (s, 1H), 6.27-6.05 (m, 2H), 5.60 (dd, J=9.9, 2.5Hz, 1H), 4.06 (dd, J=16.6, 8.7Hz, 2H), 2.84-2.72 (m, 2H), 1.98-1.84 (m, 2H).

[0504] Example 6: Synthesis of N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]hept-6-yl)acrylamide

[0505]

[0506] Following the general procedure in Scheme 3, tert-butyl (2-azaspiro[3.3]hept-6-yl)carbamate was used in step 2. N-(2-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2-azaspiro[3.3]hept-6-yl)acrylamide was provided as a white solid. (N, ES, m / z): 404.27. (400MHz, DMSO) δ8.45 (s, 1H), 8.36 (d, J=7.4Hz, 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, 2.6Hz, 1H), 4.16 (d, J=17.6Hz, 3H), 4.03 (s, 2H), 2.56-2.54 (m, 2H), 2.14 (td, J=8.8, 2.9Hz, 2H).

[0507] Example 7: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)pyrrolidin-3-yl)acrylamide

[0508]

[0509] 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 provided as a white solid. (N, ES, m / z): 378.28.

[0510] 1 H NMR (400MHz, DMSO) δ8.61 (s, 1H), 8.33 (d, J = 6.5Hz, 1H), 7.76 (d, J = 2.7Hz, 1H), 7.69-7.4 9 (m, 5H), 6.21 (dd, J=17.1, 10.0Hz, 1H), 6.08 (dd, J=17.1, 2.3Hz, 1H), 5.58 (dd, J=10.0, 2.3Hz, 1H), 4.35 (q, J=6.1Hz, 1H), 3.74 (dd, J=10.7, 6.5Hz, 1H), 3.56 (d, J=6.9Hz, 2H), 3 .31 (dd, J=10.7, 5.3Hz, 1H), 2.16 (dd, J=12.6, 6.4Hz, 1H), 1.86 (dd, J=12.5, 6.2Hz, 1H).

[0511] Example 8: Synthesis of 1-(3-((3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one

[0512]

[0513] 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 provided as a white solid. (N, ES, m / z): 378.28.

[0514] 1H NMR (400MHz, DMSO) δ8.61 (s, 1H), 8.33 (d, J = 6.5Hz, 1H), 7.76 (d, J = 2.7Hz, 1H), 7.69-7.4 9 (m, 5H), 6.21 (dd, J=17.1, 10.0Hz, 1H), 6.08 (dd, J=17.1, 2.3Hz, 1H), 5.58 (dd, J=10.0, 2.3Hz, 1H), 4.35 (q, J=6.1Hz, 1H), 3.74 (dd, J=10.7, 6.5Hz, 1H), 3.56 (d, J=6.9Hz, 2H), 3 .31 (dd, J=10.7, 5.3Hz, 1H), 2.16 (dd, J=12.6, 6.4Hz, 1H), 1.86 (dd, J=12.5, 6.2Hz, 1H).

[0515] Example 9: Synthesis of N-(1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-4-yl)acrylamide

[0516]

[0517] 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 provided as a white solid. (N, ES, m / z): 392.26.

[0518] 1 H NMR (400MHz, DMSO) δ8.52 (s, 1H), 8.12 (d, J = 7.4Hz, 1H), 7.88 (d, J = 8.5Hz, 2H), 7 .84-7.76 (m, 2H), 7.62 (d, J=8.6Hz, 2H), 6.26 (dd, J=17.1, 10.1Hz, 1H), 6.09 (dd , J=17.1, 2.3Hz, 1H), 5.57 (dd, J=10.1, 2.3Hz, 1H), 3.84 (d, J=11.2Hz, 1H), 3.51 (d, J=13.0Hz, 2H), 3.00-2.84 (m, 2H), 1.88 (d, J=12.3Hz, 2H), 1.77-1.65 (m, 2H).

[0519] Example 10: Synthesis of N-((1-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperidin-3-yl)methyl)acrylamide

[0520]

[0521] 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 provided as a white solid. (N, ES, m / z): 406.32.

[0522] 1 H NMR (400MHz, DMSO) δ8.33 (s, 1H), 8.18 (t, J=5.9Hz, 1H), 7.88-7.76 (m, 4H), 7.59 (d, J=8.7Hz, 2H), 6.13 (dd, J=17.1, 10.0Hz, 1H), 6.00 (dd, J=17.1, 2.3Hz, 1H), 5.49 (dd, J=10.0, 2.3Hz, 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).

[0523] Example 11: Synthesis of 1-(5-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-2,5-diazabicyclo[2.2.1]hept-2-yl)prop-2-en-1-one

[0524]

[0525] 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]hept-2-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 390.24.

[0526] 1 H NMR (400MHz, DMSO) δ8.46 (s, 1H), 7.75 (d, J=2.8Hz, 1H), 7.67 (dd, J=3.8, 2.8Hz, 1H), 7.61-7.53 (m, 4H), 6.75-6.31 (m, 1H), 6.1 0 (ddd, J=16.8, 9.3, 2.4Hz, 1H), 5.63 (ddd, J=14.3, 10.2, 2.4Hz, 1H), 4.91-4.67 (m, 2H), 4.04-3.61 (m, 4H), 1.98-1.85 (m, 2H).

[0527] Example 12: Synthesis of 1-((1R,5S)-3-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-3,8-diazabicyclo[3.2.1]oct-8-yl)prop-2-en-1-one

[0528]

[0529] 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]oct-8-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 404.30.

[0530] 1 H NMR (400MHz, DMSO) δ8.33 (s, 1H), 7.87 (q, J=2.7Hz, 2H), 7.72-7.54 (m, 4H), 6.74 (dd, J=16.7, 10.4Hz, 1H), 6.19 (dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.3, 2.4Hz, 1H), 4.61 (d, J=7.6Hz, 2H), 3.45 (d, J=12.0Hz, 2H), 2.97 (dd, J=17.1, 11.9Hz, 2H), 2.03-1.68 (m, 4H).

[0531] 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

[0532]

[0533] Following the general procedure in Scheme 3, (R)-tert-butyl 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 provided as a white solid. (n, ES, m / z): 392.1.

[0534] 1H NMR (400MHz, DMSO) δ8.34 (s, 1H), 7.89 (d, J=2.8Hz, 1H), 7.87-7.79 (m, 3H), 7.65 (d, J=8.6Hz, 2H), 6.81 (dd, J=16.7, 10.5Hz, 1H), 6.14 (dd, J=16 .6, 2.4Hz, 1H), 5.70 (dd, J=10.5, 2.4Hz, 1H), 3.56 (d, J=12.3Hz, 1H), 3.43-3.30 (m, 4H), 2.93 (s, 1H), 2.68 (d, J=9.5Hz, 1H), 1.42-1.22 (m, 3H).

[0535] 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

[0536]

[0537] Following the general procedure in Scheme 3, (S)-tert-butyl 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 provided as a white solid. (n, ES, m / z): 392.26.

[0538] 1 H NMR (400MHz, DMSO) δ8.36 (s, 1H), 7.95-7.81 (m, 4H), 7.66 (d, J=8.6Hz, 2H), 6.83 (dd, J=16.6, 10.5Hz, 1H), 6.15 (dd, J=16.7, 2.5H z, 1H), 5.71 (dd, J=10.5, 2.4Hz, 1H), 3.58 (d, J=12.5Hz, 1H), 3.35 (s, 4H), 2.94 (s, 1H), 2.81-2.62 (m, 1H), 1.36 (d, J=6.7Hz, 3H).

[0539] 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

[0540]

[0541] Following the general procedure in Scheme 3, (R)-tert-butyl 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 provided as a white solid. (n, ES, m / z): 408.38.

[0542] 1 H NMR (400MHz, DMsO) δ8.99 (s, 1H), 8.08 (d, J = 8.5Hz, 2H), 7.79 (d, J = 3.0Hz, 1H), 7.68 (d, J = 8.5Hz, 2H), 7.61 (d, J = 3.1Hz, 1H), 6.85 (td , J=16.0, 10.4Hz, 1H), 6.12 (dd, J=16.6, 2.4Hz, 1H), 5.68 (t, J=8.8Hz, 1H), 4.48-3.87 (m, 4H), 3.26-2.94 (m, 4H), 2.90-2.57 (m, 2H).

[0543] 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

[0544]

[0545] Following the general procedure in Scheme 3, (S)-tert-butyl 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 provided as a white solid. (n, ES, m / z): 408.46.

[0546] 1 H NMR (400MHz, DMSO) δ8.99 (s, 1H), 8.08 (d, J = 8.5Hz, 2H), 7.79 (d, J = 3.0Hz, 1H), 7.68 (d, J = 8.5Hz, 2H), 7.61 (d, J = 3.0Hz, 1H), 6.85 (td, J =16.0, 10.4Hz, 1H), 6.12 (dd, J=16.7, 2.4Hz, 1H), 5.68 (td, J=9.9, 2.5Hz, 1H), 4.48-3.89 (m, 4H), 3.21-2.94 (m, 4H), 2.90-2.59 (m, 2H).

[0547] 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

[0548]

[0549] Following the general procedure in Scheme 3, (S)-tert-butyl 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 provided as a white solid. (n, ES, m / z): 422.29.

[0550] 1 H NMR (400MHz, DMSO) δ8.97 (s, 1H), 8.10 (d, J=8.4Hz, 2H), 7.76 (d, J=3.0Hz, 1H), 7.71-7.51 (m, 3H), 6.80 (dd, J=16.6, 10.4Hz, 1H), 6.18-5.98 (m, 1H ), 5.73-5.53 (m, 1H), 4.52 (dq, J=11.0, 5.7Hz, 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).

[0551] Example 18: Synthesis of (R)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide

[0552]

[0553] Solution 4

[0554] Step 1: Synthesis of 1-(tert-butyl)2-methyl(R)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1,2-dicarboxylate

[0555]

[0556] To a 40 mL vial at room temperature were added 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (800 mg, 2.92 mmol, 1 eq), 1-tert-butyl 2-methyl (2R)-piperazine-1,2-dicarboxylate (749.91 mg, 3.07 mmol, 1.05 eq), toluene (10 mL), Pad(dppf)Cl2 (80mg) XantPhos (120mg) and Cs 2 CO 3 (2857.64 mg, 8.77 mmol, 3 eq.). Under nitrogen atmosphere, the resulting mixture was stirred at 90 ° C for 3 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EA (1: 1) to obtain 1-tert-butyl 2-methyl (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazine-2-yl)piperazine-1,2-dicarboxylate (754.9 mg, 53.63%) as an off-white solid.

[0557] Step 2: Synthesis of (R)-methyl 4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxylate

[0558]

[0559] At ℃, 1-tert-butyl 2-methyl (2R) -4- (3- { [4- (trifluoromethyl) phenyl] amino} pyrazin-2-yl) piperazine -1,2- dicarboxylate (600mg, 1.246mmol, 1 equivalent) DCM (9mL) and HCl / dioxane (2mL, 4M) were added to a 40mL vial. At room temperature, the resulting mixture was stirred for 1 hour. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0560] Step 3: Synthesis of (R)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide

[0561]

[0562] To a 40 mL vial was added (2R)-methyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-2-carboxylate (400 mg, 0.787 mmol, 1 eq) and NH 3 (g). The resulting mixture was stirred at 100° C. for 8 hours. The desired product was detected by LCMS. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0563] Step 4: Synthesis of (R)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide

[0564]

[0565] Under nitrogen atmosphere, a solution of (2R)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-2-carboxamide (250 mg, 0.68 mmol, 1 eq) in DCM (5 mL) was treated with TEA (207.17 mg, 2.046 mmol, 3 eq) at 0°C for 30 min, followed by the dropwise addition of acryloyl chloride (61.77 mg, 0.68 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 11 h. The desired product was detected by LCMS. The resulting mixture was purified by chromatography on CHCl. 2 Cl 2 The combined organic layers were extracted with H 2 O (2 × 25 mL), washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash chromatography under the following conditions (acetonitrile: water / 0.05% NaHCO 3 Water 33% to 70% 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.

[0566] LCMS (ES, m / z): [M+H] + =421. 1 H NMR (400MHz, chloroform-d) δ9.83 (s, 1H), 8.11 (d, J=8.4Hz, 2H), 7.95 (d, J=2.8Hz, 1H), 7.74 (d, J=2.8Hz, 1H), 7.61 (d, J=8.4Hz, 2H), 6.72 (d, J=16.8H z, 2H), 6.51 (d, J=1.8Hz, 1H), 5.94 (d, J=10.4Hz, 1H), 5.57 (s, 1H), 5.35 (s, 1H), 4.28-414 (m, 2H), 3.57-3.37 (m, 3H), 2.67 (d, J=12.8Hz, 1H).

[0567] Example 19: Synthesis of (S)-1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-2-carboxamide

[0568]

[0569] 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 provided as a white solid. (N, ES, m / z): 421.61.

[0570] 1 H NMR (400MHz, DMSO) δ9.60 (d, J=9.1Hz, 1H), 8.23 ​​(d, J=8.6Hz, 2H), 8.10-7.89 (m, 2H), 7.86-7.70 (m, 2H), 7.68 (d, J=8.6Hz, 2H), 6.97-6. 79 (m, 1H), 6.21 (dd, J=16.8, 2.3Hz, 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).

[0571] Example 20: Synthesis of 2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetamide

[0572]

[0573] 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 provided as a white solid. (normal, ES, m / z): 435.36.

[0574] 1 H NMR (400MHz, DMSO) δ8.71-8.33 (m, 1H), 7.97-7.80 (m, 4H), 7.66 (d, J=8.4Hz, 2H), 7.47 (s, 1H), 7.09-6.73 (m, 2H), 6.14 (d, J=16.6Hz, 1H), 5.72 (d, J=10.4Hz, 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).

[0575] Example 21: Synthesis of (R)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile

[0576]

[0577] Following the general procedure in Scheme 3, (R)-tert-butyl 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 provided as a white solid. (normal, ES, m / z): 417.26.

[0578] 1 H NMR (400MHz, DMSO) δ8.41 (s, 1H), 8.01-7.79 (m, 4H), 7.69 (d, J=8.5Hz, 2H), 6.25- 6.13 (m, 1H), 5.78 (d, J=10.4Hz, 1H), 5.10 (s, 1H), 3.84-3.49 (m, 4H), 3.01 (s, 3H).

[0579] Example 22: Synthesis of (S)-2-(1-acryloyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-2-yl)acetonitrile

[0580]

[0581] Following the general procedure in Scheme 3, (S)-tert-butyl 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 provided as a white solid. (normal, ES, m / z): 417.26.

[0582] 1 H NMR (400 MHz, CDCl 3 ) δ 8.07-8.02 (m, 2H), 7.98 (d, J = 2.2Hz, 1H), 7.56-7.44 (m, 3H), 6.55 (d, J = 2.3Hz, 1H), 6.19 (s, 1H), 4.38 (d, J = 12.3Hz, 1H), 4.26 (dd, J =12.3, 4.3Hz, 1H), 4.16 (dp, J=4.2, 2.0Hz, 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).

[0583] 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

[0584]

[0585] Solution 5

[0586] Step 1: Synthesis of 3-chloro-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine

[0587]

[0588] To a 500 mL round-bottom flask at room temperature were added 3-chloropyrazin-2-amine (20.0 g, 154.38 mmol, 1 eq.), 1-iodo-4-(trifluoromethyl)benzene (46.19 g, 169.82 mmol, 1.1 eq.), Pd 2 (dba) 3 (2.0 g, 2.18 mmol, 0.01 eq.), XantPhos (3.0 g, 5.18 mmol, 0.03 eq.), Cs 2 CO 3 (150.90 g, 463.14 mmol, 3 eq.) and DMF (200 mL). The resulting mixture was stirred at 90 °C for 6 hours under a nitrogen atmosphere. The resulting mixture was diluted with water (300 mL). The resulting mixture was extracted with EtOAc (3×300 mL). The combined organic layers were washed with water (2×300 mL) and dried over anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / EA (1:1) to give 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (15 g, 35.51%).

[0589] Step 2: Synthesis of tert-butyl 2-(2-methoxy-2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate

[0590]

[0591] To a 100 mL round-bottom flask at room temperature were added 3-chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (3.0 g, 10.96 mmol, 1 eq), tert-butyl 2-(2-methoxy-2-oxoethyl)piperazine-1-carboxylate (3.12 g, 12.06 mmol, 1.1 eq), Pd 2 (dba)3 (0.3 g, 0.33 mmol, 0.03 equiv), XantPhos (0.45 g, 0.78 mmol, 0.07 equiv), Cs 2 CO 3 (10.72 g, 32.89 mmol, 3 equivalents) and DMF (30 mL). The resulting mixture was stirred at 90 ° C for 4 hours under a nitrogen atmosphere. 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 Na 2 SO 4 The product was dried. 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%).

[0592] Step 3: Synthesis of tert-butyl 2-(2-hydroxyethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate

[0593]

[0594] 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 eq.) was treated with THF (30 mL) at 0°C for 5 min, followed by the addition of LiAlH 4 (0.84 g, 22.20 mmol, 5 eq.). 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 purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0595] Step 4: Synthesis of tert-butyl 2-(2-oxoethyl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate

[0596]

[0597] To a 40 mL vial was added tert-butyl 2-(2-hydroxyethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (600 mg, 1.28 mmol, 1 eq), Dess-Martin (1.09 g, 2.56 mmol, 2 eq) and DCM (10 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (20 mL). The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (1×20 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0598] Step 5: Synthesis of tert-butyl 2-(prop-2-yn-1-yl)-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carboxylate

[0599]

[0600] To a 40 mL vial at room temperature was added tert-butyl 2-(2-oxoethyl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperazine-1-carboxylate (158 mg, 0.34 mmol, 1 eq), Seyferth-Gilbert homologation (97.81 mg, 0.51 mmol, 1.5 eq), K 2 CO 3 (140.74 mg, 1.02 mmol, 3 equiv) and MeOH (5 mL). The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (10 mL). The resulting mixture was extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (1×10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[0601] Step 6: Synthesis of 3-(3-(prop-2-yn-1-yl)piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyrazin-2-amine

[0602]

[0603] To a 40 mL vial was added tert-butyl 2-(prop-2-yn-1-yl)-4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazine-2-yl)piperazine-1-carboxylate (120 mg, 0.26 mmol, 1 equivalent), TFA (6 mL) and DCM (18 mL) 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.

[0604] 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

[0605]

[0606] 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 eq) in DCM (10 mL) was treated with TEA (84.01 mg, 0.83 mmol, 3 eq) at 0°C for 5 minutes, followed by the dropwise addition of acryloyl chloride (25.05 mg, 0.27 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. 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 purified by anhydrous Na 2 SO 4 The crude product was purified by reverse phase rapid reaction under the following conditions ((acetonitrile: water / 0.05% ammonia 25% to 80% 19 minutes)) 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.

[0607] 1 H NMR (400MHz, chloroform-d) δ7.96 (s, 1H), 7.88-7.75 (m, 3H), 7.61 (d, J=8.5Hz, 2H), 7.31 (m, 1H), 6.64 (d, J=13.9Hz, 1H), 6.39 (d, J=16.7Hz, 1 H), 5.81 (m, 1H), 4.85 (m, 1H), 4.22 (m, 1H), 3.76 (m, 2H), 3.35 (d, J = 12.2Hz, 1H), 3.09 (m, 2H), 2.88 (m, 1H), 2.70 (m, 1H), 2.02 (s, 1H).

[0608] Example 24: Synthesis of 1-(3-methyl-4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0609]

[0610] 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 provided as a white solid. (n, ES, m / z): 392.26.

[0611] 1 H NMR (400MHz, DMSO) δ 8.69-8.61 (m, 1H), 7.97 (d, J = 9.4Hz, 3H), 7.89 (d, J = 2.8Hz, 1H), 7.66 (d, J = 8.5Hz, 2H), 6.87 (dd, J = 16.7, 10.4Hz, 1H), 6.17 (d, J=17.1Hz, 11H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 4.06-3.68 (m, 5H), 3.22 (d, J=9.6Hz, 2H), 2.86 (ddd.J=11.8, 6.9, 3.4Hz, 2H), 0.92 (d, J=6.0Hz, 3H).

[0612] 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

[0613]

[0614] Solution 6

[0615] Step 1: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0616]

[0617] In N 2 3-Chloro-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (1.00 g, 3.65 mmol, 1.00 equivalent), 4-(4,4,5,5-tetramethyl-1,3,2-difluoromethane)-1-[[(4-(trifluoromethyl)phenyl]pyrazin-2-amine]) (1.00 g, 3.65 mmol, 1.00 equivalent) and 1-[[(4-(trifluoromethyl)phenyl)pyrazin-2-amine]) (1.00 g, 3.65 mmol, 1.00 equivalent) were added to the mixture at 90°C under a 4% sodium hydroxide solution. Borane (dioxaborolan)-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.24 g, 4.02 mmol, 1.10 equivalents), K 2 CO 3 (1.01 g, 7.31 mmol, 2.00 equiv) and Pd(dppf)Cl 2 (0.27 g, 0.37 mmol, 0.10 equiv) in H 2 The solution in 2H 2 O (3.00 mL) and dioxane (9.00 mL) was stirred for 3 h. The mixture was cooled and extracted with EA (3×30.00 mL). The combined organic layers were washed with H 2 O (3 × 30.00 mL), washed with anhydrous Na 2 SO 4 The product was dried. 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.

[0618] LCMS-PH-CAL-Y-V2454220-1: (ES, m / z): [M+H] + =421

[0619] Step 2: Synthesis of 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (TFA salt)

[0620]

[0621] Into a 40 mL vessel was placed 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 in vacuo. This produced 3-(1,2,3,6-tetrahydropyridin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (230 mg, 81.59%) as a yellow oil. LCMS: (ES, m / z): [M+H] + =321.

[0622] 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

[0623]

[0624] Into a 40 ml vessel was placed 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). 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 hour. After the reaction was complete, the mixture was diluted with EA (45.00 mL) and washed with H 2 O (3 × 15.00 mL), washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product (300.00 mg) was purified by preparative HPLC under the following conditions: (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 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-{[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.

[0625] LCMS: (ES, m / z): [M+H] + =375. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.74 (s, 1H), 8.11 (s, 2H), 7.81 (d, J = 11.6Hz, 2H), 7.61 (d, J = 12.0Hz, 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).

[0626] Example 26: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one

[0627]

[0628] Solution 7

[0629] Step 1: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidine-1-carboxylate

[0630]

[0631] In H 2 A solution of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazine-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 (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 produced tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazine-2-yl)piperidine-1-carboxylate (500.00 mg, 99.52%) as a yellow solid. LCMS ES, m / z: [M+H] + =423.

[0632] Step 2: Synthesis of 3-(piperidin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine

[0633]

[0634] 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 at 0°C to room temperature for 1 hour. The resulting mixture was concentrated in vacuo. This produced 3-(piperidin-4-yl)-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (280.00 mg, 73.39%) as a yellow solid. LCMS ES, m / z: [M+H]+=323.

[0635] Step 3: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl)piperidin-1-yl]prop-2-en-1-one

[0636]

[0637] 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 then acryloyl chloride (73.01 mg, 0.81 mmol, 1.00 equiv) was added. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was extracted with EA (3×10 mL). The combined organic layers were washed with H 2 O (3 × 10.00 mL), washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by: (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), 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; number of 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.

[0638] LCMS ES, m / z: 377. 1 H NMR (400 MHz, DMSO-d 6 ): δ8.80 (s, 1H), 8.06 (s, 2H), 7.84 (d, J = 4.2Hz, 2H), 7.64 (d, J = 4.4Hz, 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).

[0639] Example 27: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)-1,4-diazepan-1-yl)prop-2-en-1-one

[0640]

[0641] 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-diazepane-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 392.26.

[0642] 1 H NMR (400MHz, DMSO) δ8.64-8.44(m, 1H), 7.86-7.68(m, 4H), 7.60(dd, J=8.6, 6.1Hz, 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).

[0643] Example 28: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0644]

[0645] Solution 8

[0646] Step 1: Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate

[0647]

[0648] Under nitrogen atmosphere, tert-butyl 4-(3-chloropyrazin-2-yl)piperazine-1-carboxylate (0.20 g, 0.67 mmol, 1.00 equiv) and (4-(trifluoromethyl)phenyl)boronic acid (0.153 g, 0.80 mmol, 1.20 equiv) and K were added in portions at room temperature. 2 CO 3 To a stirred mixture of Pd(PPh) (0.32 g, 2.34 mmol, 3.5 equiv) in dioxane (10.00 mL) was added Pd(PPh 3 ) 4 (0.077 g, 0.067 mmol, 0.1 eq.). The resulting mixture was stirred at 100°C overnight under nitrogen atmosphere. The mixture was cooled to room temperature and extracted with NaCl (saturated aqueous solution) and EA. The organic layer was purified by Na 2 SO 4Dry and concentrate in vacuo. Purify by silica gel column chromatography eluting with DCM:EA (10:1) to give tert-butyl 4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazine-1-carboxylate (178.00 mg, 65.11% yield) as a yellow solid.

[0649] Step 2: Synthesis of 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)pyrazine

[0650]

[0651] To a stirred 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) at 0°C was added HCl (gas) (2.18 mL, 8.72 mmol, 20.00 equiv) in 1,4-dioxane. The resulting mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenyl)pyrazine (130 mg, 96.75% yield) as a yellow oil.

[0652] Step 3: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0653]

[0654] 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) were added to DCM (2.00 mL) at 0°C. Acryloyl chloride (31 mmol, 0.39 mmol, 1.20 equiv) was added to the above mixture. The resulting mixture was stirred at 0°C for another 0.5 h. The reaction was monitored by LCMS. 50.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (50.00 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4 The product was dried. 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 give 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. (N, ES, m / z): 363.26.

[0655] 1 H NMR (400MHz, DMSO) δ8.31-8.21 (m, 2H), 8.14 (d, J=8.1Hz, 2H), 7.85 (d, J=8.2Hz, 2H), 6.77 (dd, J=16.6, 10. 4Hz, 1H), 6.10 (dd, J=16.7, 2.4Hz, 1H), 5.66 (dd, J=10.4, 2.4Hz, 1H), 3.58 (s, 4H), 3.12 (d, J=15.6Hz, 4H).

[0656] Example 29: Synthesis of 1-(4-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0657]

[0658] 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 provided as a white solid. (n, ES, m / z): 363.26.

[0659] 1 H NMR (400MHz, DMSO) δ8.29 (d, J=2.5Hz, 1H), 8.27-8.23 (m, 3H), 7.87-7.70 (m, 2H), 6.77 (dd, J=16.6, 10.4Hz, 1 H), 6.10 (dd, J=16.7, 2.4Hz, 1H), 5.67 (dd, J=10.4, 2.4Hz, 1H), 3.56 (d, J=12.8Hz, 4H), 3.10 (d, J=6.5Hz, 4H).

[0660] Example 30: Synthesis of 1-(4-(3-((3-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0661]

[0662] 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 provided as a white solid. (n, ES, m / z): 378.58.

[0663] 1H NMR (400MHz, DMSO) δ8.54 (s, 1H), 8.11 (t, J = 2.0Hz, 1H), 8.02 (d, J = 8.2Hz, 1H), 7.90-7.75 (m, 2H), 7.52 (t, J = 8.0Hz, 1H), 7.33-7.25 (m , 1H), 6.85 (dd, J=16.7, 10.5Hz, 1H), 6.14 (dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 3.78 (d, J=13.6Hz, 4H), 3.13 (s, 4H).

[0664] Example 31: Synthesis of 1-(4-(3-((4-(pentafluoro-16-sulfanyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0665]

[0666] Following the general procedure in Scheme 1, 4-(pentafluoro-16-sulfanyl)aniline was used in step 2. 1-(4-(3-((4-(pentafluoro-16-sulfanyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 436.1.

[0667] 1 H NMR (400MHz, DMSO) δ8.72 (s, 1H), 7.92-7.83 (m, 4H), 7.83-7.74 (m, 2H), 6.84 (dd, J=16.7, 10.5Hz, 1H), 6 .14 ​​(dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 3.77 (d, J=12.5Hz, 4H), 3.15 (d, J=6.1Hz, 4H).

[0668] Example 32: Synthesis of 1-(4-(3-((4-chlorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0669]

[0670] 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 provided as a white solid. (normal, ES, m / z): 344.1.

[0671] 1H NMR (400MHz, DMSO) δ8.31 (s, 1H), 7.81 (d, J=2.8Hz, 1H), 7.78-7.66 (m, 3H), 7.38-7.23 (m, 2H), 6.84 (dd, J=16.7, 10 .5Hz, 1H), 6.14 (dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 3.77 (d, J=9.7Hz, 4H), 3.10 (t, J=4.6Hz, 4H).

[0672] Example 33: Synthesis of 1-(4-(3-((4-fluorophenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0673]

[0674] 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 provided as a white solid. (normal, ES, m / z): 328.46.

[0675] 1 H NMR (400MHz, DMSO) δ8.20 (s, 1H), 7.77 (d, J=2.8Hz, 1H), 7.74-7.63 (m, 3H), 7.14 (t, J=8.9Hz, 2H), 6.85 (dd, J=16.7, 10.4Hz, 1H), 6.14 (dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 3.78 (d, J=11.7Hz, 4H), 3.17-2.95 (m, 4H).

[0676] Example 34: Synthesis of 1-(4-(3-((4-(trifluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0677]

[0678] 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 provided as a white solid. (n, ES, m / z): 394.55.

[0679] 1H NMR (400MHz, DMSO) δ8.39 (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, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.80 (s, 4H), 3.13 (s, 4H).

[0680] Example 35: Synthesis of 1-(4-(3-((4-(difluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0681]

[0682] 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 provided as a white solid. (n, ES, m / z): 376.1.

[0683] 1 H NMR (400MHz, DMSO) δ8.26 (s, 1H), 7.79 (d, J=2.8Hz, 1H), 7.72 (dd, J=9.4, 2.5Hz, 3H), 7.36-6.94 (m, 3H), 6.89-6. 76 (m, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.5, 2.4Hz, 1H), 3.87-3.70 (m, 4H), 3.12 (p, J=4.0Hz, 4H).

[0684] Example 36: Synthesis of 1-(4-(3-((4-(fluoromethoxy)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0685]

[0686] 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 provided as a white solid. (n, ES, m / z): 358.3.

[0687] 1H NMR (400MHz, DMSO) δ8.15 (s, 1H), 7.77 (d, J = 2.8Hz, 1H), 7.70 (d, J = 2.9Hz, 1H), 7.68-7.58 (m, 2H), 7.14-7.02 (m, 2H), 6.86 (dd, J =16.7, 10.4Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.89 (s, 1H), 5.83-5.65 (m, 2H), 3.79 (d, J=12.2Hz, 4H), 3.11 (d, J=6.5Hz, 4H).

[0688] Example 37: Synthesis of 1-(4-(3-((3-methoxy-4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0689]

[0690] 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 provided as a white solid. (n, ES, m / z): 408.34.

[0691] 1 H NMR (400MHz, DMSO) δ8.58 (s, 1H), 7.94-7.82 (m, 2H), 7.65 (s, 1H), 7.55-7.46 (m, 2H), 6.86 (dd, J=16.7, 10.4H z, 1H), 6.16 (dd, J=16.6, 2.4Hz, 1H), 5.73 (dd, J=10.3, 2.4Hz, 1H), 3.97-3.67 (m, 7H), 3.16 (d, J=5.9Hz, 4H).

[0692] Example 38: Synthesis of 4-((3-(4-acryloylpiperazin-1-yl)pyrazin-2-yl)amino)benzonitrile

[0693]

[0694] 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 provided as a white solid. (normal, ES, m / z): 335.24.

[0695] 1H NMR (400MHz, DMSO) δ8.78 (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, 1.9Hz, 1H), 5.72 (dt, J=10.6, 1.8Hz, 1H), 3.78 (d, J=12.8Hz, 4H), 3.16 (s, 4H).

[0696] Example 39: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0697]

[0698] 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 provided as a white solid. (n, ES, m / z): 379.27.

[0699] 1 H NMR (400MHz, DMSO) δ9.01 (s, 1H), 8.63 (dt, J=2.1, 1.0Hz, 1H), 8.15-8.04 (m, 2H), 7.99 (s, 2H), 6.85 (dd, J=16.7 , 10.4Hz, 1H), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.74 (d, J=14.9Hz, 4H), 3.16 (s, 4H).

[0700] Example 40: Synthesis of 1-(4-(3-((5-(difluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0701]

[0702] 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 provided as a white solid. (n, ES, m / z): 361.2.

[0703] 1H NMR (400MHz, DMSO) δ8.74 (s, 1H), 8.48 (s, 1H), 8.11 (d, J=8.7Hz, 1H), 8.06-7.92 (m, 3H), 7.25-6.90 (m, 1H), 6.85 (dd, J=16.7, 10.4Hz, 1H), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.75 (d, J=15.6Hz, 4H), 3.14 (s, 4H).

[0704] Example 41: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyrimidin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0705]

[0706] 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 provided as a white solid. (n, ES, m / z): 380.22.

[0707] 1 H NMR (400MHz, DMSO) δ10.36 (s, 1H), 8.89-8.74 (m, 2H), 8.15 (d, J=2.6Hz, 1H), 7.99 (d, J=2.6Hz, 1H), 6.79 (dd, J= 16.7, 10.5Hz, 1H), 6.11 (dd, J=16.6, 2.4Hz, 1H), 5.69 (dd, J=10.4, 2.4Hz, 1H), 3.50 (s, 4H), 3.32-3.28 (m, 4H).

[0708] 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

[0709]

[0710] Solution 9

[0711] Step 1: Synthesis of tert-butyl 4-(3-(methyl(5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazine-1-carboxylate

[0712]

[0713] Tert-butyl 4-(3-{[5-(trifluoromethyl)pyridin-2-yl]amino}pyrazin-2-yl)piperazine-1-carboxylate (1 g, 2.356 mmol, 1 eq), MeI (0.33 g, 2.356 mmol, 1 eq) and K 2 CO 3 A solution of (0.65 g, 4.712 mmol, 2 eq.) in DMF (10 mL) was stirred for 2 h. The product was precipitated by adding water. The crude product was used directly in the next step without further purification.

[0714] Step 2: Synthesis of N-methyl-3-(piperazin-1-yl)-N-(5-(trifluoromethyl)pyridin-2-yl)pyrazin-2-amine

[0715]

[0716] 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 eq) and TFA (1 mL, 13.463 mmol, 19.68 eq) in DCM (4 mL) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under reduced pressure. The remaining product was quickly purified by reverse phase 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.

[0717] 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

[0718]

[0719] A solution of N-methyl-3-(piperazin-1-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]pyrazin-2-amine (200 mg, 0.591 mmol, 1 eq) and acryloyl chloride (53.50 mg, 0.591 mmol, 1.00 eq) in DCM (2 mL) was stirred at room temperature for 1 hour. The resulting mixture was extracted with EtOAc (2×2 mL). The combined organic layers were washed with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue / crude product (300.00 mg) was purified by reverse phase flash chromatography (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2O), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B to 90% B, 90% B in 10 min; wavelength: 254 nm; RT 1 (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.

[0720] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.60-8.54 (m, 1H), 8.21 (d, J=2.5Hz, 1H), 8.04 (d, J=2.5Hz, 1H), 7.86 (dd, J=9.0, 2.6Hz, 1H), 6.81-6.69 ( m, 2H), 6.09 (dd, J=16.7, 2.4Hz, 1H), 5.67 (dd, J=10.5, 2.4Hz, 1H), 3.47 (s, 3H), 3.22 (dd, J=6.4, 3.7Hz, 4H).

[0721] 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

[0722]

[0723] 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 provided as a white solid. (n, ES, m / z): 376.22.

[0724] 1 H NMR (400MHz, DMSO) δ9.56 (d, J=12.2Hz, 1H), 8.53 (s, 1H), 8.28 (dd, J=11.1, 2.7Hz, 2H), 8.03 (dd, J=9.1, 2.6Hz, 1H), 7.78 (dd, J=15.9, 8.8Hz, 1H ), 6.98-6.61 (m, 1H), 6.29-6.08 (m, 2H), 5.71 (ddd, J=10.3, 4.8, 2.4Hz, 1H), 4.22-4.03 (m, 2H), 3.74 (dt, J=16.6, 5.6Hz, 2H), 2.66-2.53 (m, 2H).

[0725] Example 44: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0726]

[0727] 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 provided as a white solid. (n, ES, m / z): 378.28.

[0728] 1 H NMR (400MHz, DMSO) δ9.80 (s, 1H), 8.60 (dt, J=2.0, 1.0Hz, 1H), 8.33-8.15 (m, 2H), 8.04 (dd, J= 9.0, 2.6Hz, 1H), 7.84 (d, J=8.9Hz, 1H), 6.85 (dd, J=16.7, 10.5Hz, 1H), 6.12 (dd, J=16.7, 2.5Hz , 1H), 5.68 (dd, J=10.4, 2.5Hz, 1H), 4.56 (d, J=12.9Hz, 1H), 4.18 (d, J=13.7Hz, 1H), 3.63-3.47 (m, 1H), 3.25-3.11 (m, 1H), 2.77 (t, J=12.5Hz, 1H), 1.86 (d, J=12.8Hz, 2H), 1.75-1.48 (m, 2H).

[0729] Example 45: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0730]

[0731] 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 provided as a white solid. (n, ES, m / z): 379.19.

[0732] 1H NMR (400MHz, DMSO) δ9.03 (d, J=2.5Hz, 1H), 8.88 (s, 1H), 8.39 (dd, J=8.7, 2.5Hz, 1H), 7.99-7.86 (m, 2H), 7.83 (d, J=8.7Hz, 1H), 6. 86 (dd, J=16.7, 10.5Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.92-3.69 (m, 4H), 3.19 (d, J=6.1Hz, 4H).

[0733] 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

[0734]

[0735] Solution 10

[0736] A solution of 2-fluoroacrylic acid (0.032 g, 0.37 mmol, 1.2 eq) in DMF (2 mL) was stirred at 0°C for 5 min. HATU (0.14 g, 0.37 mmol, 1.2 eq) and DIPEA (153 mmol, 0.93 mmol, 3 eq) were then added dropwise, and after stirring for another 5 min, 3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine (0.1 g, 0.31 mmol, 1 eq) was added. The reaction was continued at 0°C for 1 h, after which it was treated with H 2 O (50 mL), NaCl (saturated aqueous solution, 20 mL) and EtOAc (20 mL) were quenched. The aqueous layer was separated and extracted with EA (3×20 mL). The combined organic phases were washed with Na 2 SO 4 The mixture was dried and concentrated in vacuo. Purification was performed by flash column chromatography eluting with EA:DCM (2:3) to give 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. (N, ES, m / z): 397.06.

[0737] 1H NMR (400MHz, DMSO) δ9.03 (d, J=2.5Hz, 1H), 8.88 (s, 1H), 8.39 (dd, J=8.7, 2.5Hz, 1H), 7.95-7.87 (m, 2H), 7.84 (d, J=8.7Hz, 1H), 5.41-5.13 (m, 2H), 3.78 (t, J=4.8Hz, 4H), 3.23 (t, J=5.1Hz, 4H).

[0738] Example 47: Synthesis of 1-(4-(3-((6-(difluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0739]

[0740] 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 provided as a white solid. (n, ES, m / z): 361.77.

[0741] 1 H NMR (400MHz, DMSO) δ8.96 (d, J=2.5Hz, 1H), 8.70 (s, 1H), 8.32 (dd, J=8.5, 2.6Hz, 1H), 7.97-7.82 (m, 2H), 7.65 (d, J=8.6Hz , 1H), 7.05-6.72 (m, 2H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.80 (d, J=13.1Hz, 4H), 3.17 (s, 4H).

[0742] Example 48: Synthesis of 1-(4-(3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0743]

[0744] 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 provided as a white solid. (n, ES, m / z): 395.01.

[0745] 1H NMR (400MHz, DMSO) δ8.65 (d, J=2.8Hz, 1H), 8.58 (s, 1H), 8.30 (dd, J=8.8, 2.8Hz, 1H), 7.82 (q, J=2.8Hz, 2H), 7.30 (d, J=8.8H z, 1H), 6.87 (dd, J=16.7, 10.4Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.80 (s, 4H), 3.16 (s, 4H).

[0746] Example 49: Synthesis of 1-(4-(3-((6-(difluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0747]

[0748] 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 provided as a white solid. (n, ES, m / z): 377.63.

[0749] 1 H NMR (400MHz, DMSO) δ8.53 (d, J=2.7Hz, 1H), 8.41 (s, 1H), 8.18 (dd, J=8.8, 2.8Hz, 1H), 7.87-7.43 (m, 3H), 7.09 (d, J=8.8Hz, 1H), 6.87 (dd, J=16.7, 10.4Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.80 (s, 4H), 3.15 (d, J=6.1Hz, 4H).

[0750] 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

[0751]

[0752] 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 provided as a white solid. (n, ES, m / z): 397.37.

[0753] 1 H NMR (400MHz, DMSO) δ9.20 (d, J=7.4Hz, 1H), 8.84 (d, J=9.0Hz, 1H), 8.42 (d, J=13.3Hz, 1H), 7.96 (d, J=7.8H z, 2H), 6.85 (d, J=14.0Hz, 1H), 6.16 (d, J=10.8Hz, 1H), 5.73 (d, J=11.4Hz, 1H), 3.78 (s, 4H), 3.19 (s, 4H).

[0754] 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

[0755]

[0756] The general procedure in Scheme 10 was followed using N-(5-fluoro-6-(trifluoromethyl)pyridin-3-yl)-3-(piperazin-1-yl)pyrazin-2-amine to afford 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. (n, ES, m / z): 397.37.

[0757] 1 H NMR (400MHz, DMSO) δ9.20 (s, 1H), 8.85 (s, 1H), 8.42 (d, J=13.6Hz, 1H), 7.97 (d, J=8.4Hz, 2H), 5.39-5.14 (m, 2H), 3.76 (s, 4H), 3.23 (s, 4H).

[0758] Example 52: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0759]

[0760] 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 provided as a white solid. (n, ES, m / z): 380.18.

[0761] 1 H NMR (400MHz, DMSO) δ9.34 (s, 2H), 9.10 (s, 1H), 7.99-7.87 (m, 2H), 6.87 (dd, J=16.7, 10.4Hz, 1H) , 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.80-5.65 (m, 1H), 3.79 (d, J=11.8Hz, 4H), 3.21 (d, J=6.4Hz, 4H).

[0762] 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

[0763]

[0764] Following the general procedure in Scheme 1, using (S)-tert-butyl 2-methylpiperazine-1-carboxylate in step 1 and 6-(trifluoromethyl)pyridin-3-amine 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 provided as a white solid. (n, ES, m / z): 393.26.

[0765] 1 H NMR (400MHz, DMSO) δ8.96 (d, J=2.5Hz, 1H), 8.60 (s, 1H), 8.32 (dd, J=8.7, 2.5Hz, 1 H), 7.91 (s, 2H), 7.85 (d, J=8.6Hz, 1H), 6.83 (dd, J=16.7, 10.4Hz, 1H), 6.15 (dd, J= 16.6, 2.4Hz, 1H), 5.72 (dd, J=10.5, 2.4Hz, 1H), 4.88-3.97 (m, 2H), 3.76-3.60 (m, 1 H), 3.62-3.35 (m, 2H), 3.01 (d, J=12.8Hz, 1H), 2.70 (s, 1H), 1.33 (d, J=6.7Hz, 3H).

[0766] 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

[0767]

[0768] Following the general procedure in Scheme 1, using (R)-tert-butyl 2-methylpiperazine-1-carboxylate in Step 1 and 6-(trifluoromethyl)pyridin-3-amine 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 provided as a white solid. (n, ES, m / z): 393.29.

[0769] 1 H NMR (400MHz, DMSO) δ8.96 (d, J=2.5Hz, 1H), 8.60 (s, 1H), 8.32 (dd, J=8.7, 2.6Hz, 1H), 7.91 (s, 2H), 7.85 (d, J=8.7Hz, 1H), 6.83 (dd, J=16.7, 10.5Hz, 1H ), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.5, 2.4Hz, 1H), 3.66 (d, J=12 .1Hz, 2H), 3.56-3.36(m, 2H), 3.02(s, 1H), 2.69(s, 1H), 1.46-1.22(m, 3H).

[0770] 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

[0771]

[0772] 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 provided as a white solid. (n, ES, m / z): 376.29.

[0773] 1H NMR (400MHz, DMSO) δ9.08-8.89 (m, 2H), 8.30 (d, J=8.7Hz, 1H), 8.16 (dt, J=14.0, 2.4Hz, 2H), 7.82 (d, J=8.6Hz, 1H), 7.00-6.72 (m, 1H), 6.37 ( d, J=14.9Hz, 1H), 6.19 (ddd, J=16.7, 9.6, 2.4Hz, 1H), 5.75 (td, J=9.6, 2.4Hz, 1H), 4.39-4.17 (m, 2H), 3.87-3.74 (m, 2H), 2.70-2.55 (m, 2H).

[0774] 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

[0775]

[0776] 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 provided as a white solid. (n, ES, m / z): 394.32.

[0777] 1 H NMR (400MHz, DMSO) δ9.04-8.88 (m, 2H), 8.30 (d, J=8.3Hz, 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=5.8Hz, 2H), 2.67 (s, 2H).

[0778] 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

[0779]

[0780] 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 provided as a white solid. (n, ES, m / z): 392.76.

[0781] 1 H NMR (400MHz, DMSO) δ8.70 (d, J=4.0Hz, 1H), 8.55 (s, 1H), 8.21 (d, J=8.5Hz, 1H), 8.06 (d, J=12.2Hz, 2H), 7.28 (d, J=8.8Hz, 1H), 6.99-6.75 ( m, 1H), 6.35 (d, J=14.0Hz, 1H), 6.18 (dd, J=17.1, 9.1Hz, 1H), 5.75 (t, J=9.4Hz, 1H), 4.39-4.18 (m, 2H), 3.81 (d, J=8.1Hz, 2H), 2.62 (s, 2H).

[0782] 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

[0783]

[0784] 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 provided as a white solid. (n, ES, m / z): 410.78.

[0785] 1 H NMR (400MHz, DMSO) δ8.71 (s, 1H), 8.56 (dd, J=2.7, 1.3Hz, 1H), 8.20 (dd, J=8.8, 2.6Hz, 1H), 8.11-7.98 (m, 2H), 7.28 (d, J=8.8Hz, 1H), 6.36 (s, 1H), 5.45-5.13 (m, 2H), 4.36-4.15 (m, 2H), 3.78 (t, J=5.7Hz, 2H), 2.65 (s, 2H).

[0786] 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

[0787]

[0788] 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 provided as a white solid. (n, ES, m / z): 410.78.

[0789] 1 H NMR (400MHz, DMSO) δ9.41-9.10 (m, 3H), 8.29-8.01 (m, 2H), 7.01-6.78 (m, 1H), 6.41 (d, J=12.7Hz, 1H), 6.19 (dd, J=16 .5, 10.4Hz, 1H), 5.75 (dd, J=11.2, 8.8Hz, 1H), 4.38-4.19 (m, 2H), 3.91-3.74 (m, 2H), 3.32 (s, 1H), 2.68-2.57 (m, 2H).

[0790] 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

[0791]

[0792] 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 provided as a white solid. (N, ES, m / z): 395.08.

[0793] 1H NMR (400MHz, DMSO) δ9.40-9.10 (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=5.6Hz, 2H), 3.32(s, 1H), 2.68(s, 2H).

[0794] Example 61: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0795]

[0796] 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 provided as a white solid. (n, ES, m / z): 378.27.

[0797] 1 H NMR (400MHz, DMSO) δ9.05 (s, 1H), 8.98 (d, J=2.6Hz, 1H), 8.33 (dd, J=8.7, 2.5Hz, 1H), 8.21-8.02 (m, 2H), 7.84 (d, J=8.6Hz, 1H), 6.87 (dd, J=16.7, 10.5Hz, 1H), 6.13 (dd, J=16.7, 2.5Hz, 1H), 5.69 (dd, J=10.5, 2.5Hz, 1H), 4.60 (d, J=12.9Hz, 1H), 4.22 (d, J=13.5Hz, 1H), 3.51 (dtd, J=11.6, 7.7, 4.0Hz, 1H), 3.26 (t, J=13.2Hz, 1H), 2.94-2.74 (m, 1H), 1.90 (d, J=13.0Hz, 2H), 1.76-1.50 (m, 2H)

[0798] 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

[0799]

[0800] 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 provided as a white solid. (n, ES, m / z): 365.2.

[0801] 1 H NMR (400MHz, DMSO) δ8.87 (d, J=8.4Hz, 2H), 8.41 (d, J=11.1Hz, 1H), 7.82 (q, J=6.3Hz, 1H), 7.71-7.47 (m, 2H), 7.28 (s, 1H), 6.36 ( d, J=14.6Hz, 1H), 6.14 (d, J=14.0Hz, 1H), 5.70 (d, J=10.8Hz, 1H), 4.62 (d, J=9.9Hz, 2H), 4.32 (s, 1H), 4.07 (s, 1H), 3.91 (s, 1H).

[0802] 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

[0803]

[0804] Following the general procedure in Scheme 10, N 2 -(azetidin-3-yl)-N 3 -(6-(trifluoromethyl)pyridin-3-yl)pyrazine-2,3-diamine. Provided as a white solid 2-fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one. (N, ES, m / z): 383.31.

[0805] 1H NMR (400MHz, DMSO) δ8.97-8.80 (m, 2H), 8.40 (dd, J=8.7, 2.6Hz, 1H), 7.83 (d, J=8.7Hz, 1H), 7.66 (d, J=2.9Hz, 1H), 7.54 (d, J=3.0Hz, 1H), 7.29 (d, J= 5.5Hz, 1H), 5.61-5.41(m, 1H), 5.33(dd, J=16.6, 3.6Hz, 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, 4.8Hz, 1H).

[0806] 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

[0807]

[0808] Following the general procedure in Scheme 10, N 2 -(azetidin-3-yl)-N 3 -(6-(trifluoromethoxy)pyridin-3-yl)pyrazine-2,3-diamine. Provided as a white solid 2-fluoro-1-(3-((3-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one. (n, ES, m / z): 399.2.

[0809] 1 H NMR (400MHz, DMSO) δ8.64-8.51 (m, 2H), 8.29 (dd, J=8.9, 2.8Hz, 1H), 7.58 (d, J=3.0Hz, 1H), 7.47 (d, J=3.0Hz, 1H), 7.29 (d, J=8.8Hz, 1H), 7. 19 (d, J=5.5Hz, 1H), 5.57-5.41 (m, 1H), 5.32 (dd, J=16.6, 3.6Hz, 1H), 4.85-4.62 (m, 2H), 4.44-4.33 (m, 1H), 4.23 (s, 1H), 4.01-3.88 (m, 1H).

[0810] 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

[0811]

[0812] Following the general procedure in Scheme 10, using 3-(azetidin-3-yloxy)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine. 2-Fluoro-1-(3-((3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyrazin-2-yl)oxy)azetidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 384.41.

[0813] 1 H NMR (400MHz, DMSO) δ9.33 (s, 1H), 9.17 (dd, J=5.6, 2.5Hz, 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=14.4Hz, 1H), 3.77 (q, J=17.3Hz, 1H).

[0814] Example 66: Synthesis of 1-(4-(3-((4,4-difluorocyclohexyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0815]

[0816] 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 provided as a white solid. (n, ES, m / z): 352.28.

[0817] 1 H NMR (400MHz, DMSO) δ7.70 (d, J=2.9Hz, 1H), 7.47 (d, J=2.9Hz, 1H), 6.86 (dd, J=16.7, 10.5Hz, 1H), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.92 (d, J =7.8Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 4.03 (s, 1H), 3.76 (d, J=14.1Hz, 4H), 3.02 (s, 4H), 2.16-1.84 (m, 6H), 1.74 (t, J=11.3Hz, 2H).

[0818] 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

[0819]

[0820] 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 provided as a white solid. (n, ES, m / z): 368.02.

[0821] 1 H NMR (400MHz, DMSO) δ7.76 (d, J=2.9Hz, 1H), 7.57 (d, J=2.8Hz, 1H), 7.05 (s, 1H), 6.85 (dd, J=16.7, 10.4Hz, 1H), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.75 (d, J=12.1Hz, 4H), 3.00 (s, 4H), 2.37 (s, 6H).

[0822] 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

[0823]

[0824] Following the general procedure in Scheme 10, using 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)bicyclo[1.1.1]pentan-2-yl)pyrazin-2-amine. 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 provided as a white solid. (N, ES, m / z): 386.66.

[0825] 1 H NMR (400MHz, DMSO) δ7.77 (d, J=2.8Hz, 1H), 7.57 (d, J=2.9Hz, 1H), 7.07 (s, 1H) , 5.36-5.13 (m, 2H), 3.74 (t, J=5.0Hz, 4H), 3.04 (t, J=5.1Hz, 4H), 2.37 (s, 6H).

[0826] Example 69. Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0827]

[0828] Solution 11

[0829] Step 1: Synthesis of tert-butyl 4-{3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl}piperazine-1-carboxylate

[0830]

[0831] At room temperature, 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), K 3 PO 4 (840.41 mg, 3.96 mmol, 3.00 equiv), N1,N2-bis(2-thienylmethyl)-oxalamide (25 mg, 0.08 mmol, 0.07 equiv) and DMSO (10 mL) were added to a 40 mL vial. The resulting mixture was stirred at 110 °C for 8 hours under a nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (1×50 mL) and washed with anhydrous Na 2 SO 4 The mixture was dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EA (2:1) to give tert-butyl 4-{3-[4-(trifluoromethyl)phenoxy]pyrazin-2-yl}piperazine-1-carboxylate (250 mg 18.4%) as a white solid. LCMS ES, m / z: [M+H] + =425

[0832] Step 2: Synthesis of 2-(piperazin-1-yl)-3-(4-(trifluoromethyl)phenoxy)pyrazine (HCl salt)

[0833]

[0834] 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) were stirred in CH 2 Cl 2The solution in (3.0 mL) was stirred at 0 °C for 2 hours under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS ES, m / z: [M+H] + =325

[0835] Step 3: Synthesis of 1-(4-(3-(4-(trifluoromethyl)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0836]

[0837] 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 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 under the following conditions (acetonitrile:water / 0.05% ammonia 25% to 67% 18 min) 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. LCMS (ES, m / z: [M+H] + =379.

[0838] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.02-7.98(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).

[0839] Example 70: Synthesis of 1-(4-(3-(4-methoxyphenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0840]

[0841] 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 provided as a white solid. (n, ES, m / z): 341.23.

[0842] 1 H NMR (400MHz, DMSO) δ7.90 (d, J=2.8Hz, 1H), 7.55 (d, J=2.7Hz, 1H), 7.18-7.05 (m, 2H), 7.04-6.92 (m, 2H), 6.86 (dd, J=16.7, 1 0.4Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.3Hz, 1H), 3.78 (s, 3H), 3.77-3.68 (m, 4H), 3.63-3.48 (m, 4H).

[0843] Example 71: Synthesis of 1-(4-(3-(4-(difluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0844]

[0845] 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 provided as a white solid. (n, ES, m / z): 377.13.

[0846] 1 H NMR (400MHz, DMSO) δ7.95 (d, J=2.8Hz, 1H), 7.58 (d, J=2.8Hz, 1H), 7.48-7.03 (m, 5H), 6.86 (dd, J=16.7, 10.4H z, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.83-3.64 (m, 4H), 3.58 (t, J=5.1Hz, 4H).

[0847] Example 72: Synthesis of 1-(4-(3-(4-(trifluoromethoxy)phenoxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0848]

[0849] 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 provided as a white solid. (n, ES, m / z): 395.27.

[0850] 1 H NMR (400MHz, DMSO) δ7.97 (d, J=2.8Hz, 1H), 7.59 (d, J=2.8Hz, 1H), 7.50-7.39 (m, 2H), 7.41-7.29 (m, 2H), 6.85 (dd, J=16.8 , 10.5Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.72 (d, J=17.7Hz, 4H), 3.57 (d, J=6.8Hz, 4H).

[0851] Example 73: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0852]

[0853] 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 provided as a white solid. (n, ES, m / z): 380.26.

[0854] 1 H NMR (400MHz, DMSO) δ8.69 (d, J=3.4Hz, 1H), 8.36 (dd, J=8.5, 3.1Hz, 1H), 8.15 (q, J=2.5Hz, 1H), 7.77 (q, J=2.5Hz, 1H), 7.49 (dd, J =9.0, 3.3Hz, 1H), 6.81 (dd, J=16.7, 10.6Hz, 1H), 6.13 (dt, J=16.7, 2.2Hz, 1H), 5.70 (dt, J=10.4, 2.3Hz, 1H), 3.69-3.45 (m, 8H).

[0855] 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

[0856]

[0857] 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 provided as a white solid. (n, ES, m / z): 377.21.

[0858] 1 H NMR (400MHz, DMSO) δ8.68 (d, J=2.6Hz, 1H), 8.65-8.54 (m, 1H), 8.37 (dd, J=8.7, 2.6Hz, 1H), 8.33-8.21 (m, 1H), 7.51 (d, J=8.6Hz, 1H), 6.93-6 .69 (m, 2H), 6.13 (dd, J=16.8, 2.4Hz, 1H), 5.70 (dd, J=10.4, 2.4Hz, 1H), 4.38-4.12 (m, 2H), 3.71 (dt, J=16.3, 5.7Hz, 2H), 2.77-2.54 (m, 2H).

[0859] Example 75: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0860]

[0861] 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 provided as a white solid. (n, ES, m / z): 391.54.

[0862] 1H NMR (400MHz, DMSO) δ8.84 (d, J=2.4Hz, 1H), 8.67-8.55 (m, 2H), 7.92 (dd, J=9.7, 2.8Hz, 1H) , 6.84 (td, J=10.7, 5.0Hz, 1H), 6.75 (d, J=9.7Hz, 1H), 6.12 (dd, J=16.7, 2.5Hz, 1H), 5.68 ( d, J=10.6Hz, 1H), 4.60-4.40 (m, 1H), 4.26-4.02 (m, 1H), 3.09 (t, J=13.0Hz, 1H), 2.93-2.7 9 (m, 1H), 2.76-2.61 (m, 1H), 1.89 (s, 1H), 1.74 (t, J=14.4Hz, 2H), 1.59 (d, J=12.9Hz, 1H).

[0863] 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

[0864]

[0865] Following the general procedure in Scheme 10, using 2-(piperidin-4-yl)-3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazine. 2-Fluoro-1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 397.03.

[0866] 1 H NMR (400MHz, DMSO) δ8.70 (s, 1H), 8.53 (d, J = 2.6Hz, 1H), 8.38 (d, J = 8.9Hz, 1H), 8.26 (d, J = 2.6Hz, 1H), 7.52 (d, J=8.7Hz, 1H), 5.33-5.08 (m, 2H), 3.31 (s, 2H), 1.94 (d, J=13.3Hz, 2H), 1.75 (s, 2H).

[0867] Example 77: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0868]

[0869] 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 provided as a white solid. (n, ES, m / z): 380.22.

[0870] 1 H NMR (400MHz, DMSO) δ8.77 (t, J=1.7Hz, 1H), 8.04 (t, J=2.3Hz, 3H), 7.61 (d, J=2.7Hz, 1H), 6.86 (dd, J=16.7, 10.4Hz, 1 H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.73 (dd, J=17.9, 5.7Hz, 4H), 3.61 (d, J=6.1Hz, 4H).

[0871] 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

[0872]

[0873] Following the general procedure in Scheme 10, using 2-(piperazin-1-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 398.17.

[0874] 1 H NMR (400MHz, DMSO) δ 8.77 (s, 1H), 8.04 (d, J=2.1Hz, 3H), 7.62 (t, J=2.3Hz, 1H), 5.39-5.15 (m, 2H), 3.77-3.63 (m, 8H).

[0875] Example 79: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0876]

[0877] 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 provided as a white solid. (n, ES, m / z): 379.23.

[0878] 1 H NMR (400MHz, DMSO) δ8.78 (d, J=1.7Hz, 1H), 8.41 (d, J=2.6Hz, 1H), 8.07 (dd, J=9.7, 2.2H z, 3H), 6.87 (dd, J=16.7, 10.4Hz, 1H), 6.13 (dd, J=16.7, 2.4Hz, 1H), 5.70 (dd, J=10.4, 2 .5Hz, 1H), 4.58 (d, J=13.0Hz, 1H), 4.22 (d, J=13.6Hz, 1H), 3.51 (tt, J=11.6, 3.7Hz, 1H) , 3.28 (t, J=13.0Hz, 1H), 2.86 (t, J=12.5Hz, 1H), 2.11-1.94 (m, 2H), 1.86-1.57 (m, 2H).

[0879] 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

[0880]

[0881] Following the general procedure in Scheme 10, using 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 447.1.

[0882] 1H NMR (400MHz, DMSO) δ8.78 (d, J=1.8Hz, 1H), 8.42 (d, J=2.7Hz, 1H), 8.07 (dd, J=13.1, 2.2Hz, 3H), 6.24 (s, 1H), 6.02 (s, 1H), 4.53 ( d, J=13.0Hz, 1H), 3.96 (d, J=13.5Hz, 1H), 3.54 (t, J=11.6Hz, 1H), 3.00 (d, J=12.9Hz, 1H), 2.17-1.97 (m, 2H), 1.90-1.53 ​​(m, 2H).

[0883] 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

[0884]

[0885] Following the general procedure in Scheme 10, using 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine and 2-(trifluoromethyl)acrylic acid, 2-(trifluoromethyl)-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 447.1.

[0886] 1 H NMR (400MHz, DMSO) δ8.78 (s, 1H), 8.42 (d, J = 2.6Hz, 1H), 8.15-7.97 (m, 3H), 6.24 (s, 1H), 6.02 (s, 1H), 4.53 (d, J = 13.0Hz, 1H), 3 .95 (d, J=13.6Hz, 1H), 3.54 (t, J=11.4Hz, 1H), 3.33 (s, 1H), 2.98 (t, J=13.1Hz, 1H), 2.05 (t, J=17.8Hz, 2H), 1.88-1.65 (m, 2H).

[0887] Example 82. Synthesis of 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid

[0888]

[0889] Solution 12

[0890] Step 1: Synthesis of 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine

[0891]

[0892] To a solution of 2,3-dichloropyrazine (18 g, 120.830 mmol, 1 eq), 6-(trifluoromethyl)pyridin-3-ol (15.77 g, 96.664 mmol, 0.8 eq) and Cs 2 CO 3 (59.05 g, 181.245 mmol, 1.5 eq.) and then stirred at room temperature for 2 hours. The reaction mixture was quenched with water (200 mL) and extracted with EtOAc (3×300 mL). The organic layers were combined and washed with saturated brine (2×300 mL) and washed with anhydrous Na 2 SO 4 Dry. 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 yielded 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (21 g, 63.06%) as a yellow solid. LCMS (n, ES, m / z): 276.1

[0893] Step 2: Synthesis of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate

[0894]

[0895] To 2-chloro-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (1.1 g, 3.991 mmol, 1 eq) 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 eq) was stirred in dioxane / H2O. 2 Add K to the solution in O (10 mL / 1 mL) 2 CO 3 (1.65 g, 11.973 mmol, 3 equiv) and Pd(dppf)Cl 2 .CH 2 Cl 2(0.33 g, 0.399 mmol, 0.1 eq.). After stirring at 100 °C for 5 hours under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE / THF (3:1). This produced 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. LCMS (n, ES, m / z): 423.2

[0896] Step 3: Synthesis of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate

[0897]

[0898] 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 eq) and Rh(PPh 3 ) 3 Cl 2 A solution of (181.60 mg, 0.189 mmol, 0.1 equivalent) in MeOH (6 ml) and THF (3 ml) was stirred overnight. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (1: 1). This produced tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine-2-yl)piperidine-1-carboxylate (720 mg, 89.44%) as a white solid. LCMS (positive, ES, m / z): 425.0.

[0899] Step 4: Synthesis of 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine

[0900]

[0901] A mixture of tert-butyl 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine-2-yl)piperidine-1-carboxylate (5 g, 11.781 mmol, 1 eq) in DCM (40 mL) and TFA (10 mL) was stirred at room temperature for 2 hours. The resulting mixture was concentrated under reduced pressure to give 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine) (3.6 g, 94.03%) as a white solid. The crude product was used directly in the next step without further purification. LCMS-PH (positive, ES, m / z): 325.3.

[0902] Step 5: Synthesis of methyl 2-{[4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-1-yl]methyl}prop-2-enoate

[0903]

[0904] To a solution of 2-(piperidin-4-yl)-3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazine (500 mg, 1.542 mmol, 1 eq) and methyl 2-(bromomethyl)prop-2-enoate (331.19 mg, 1.850 mmol, 1.2 eq) in MeCN (10 mL) was added NaI (277.32 mg, 1.850 mmol, 1.2 eq) and K 2 CO 3 (639.23 mg, 4.626 mmol, 3 eq.) and then stirred at 60 °C for 2 hours. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3×20 mL). The organic layers were combined and washed with saturated brine (2×20 mL) and washed with anhydrous Na 2 SO 4 Dried. After filtration, the filtrate was concentrated under reduced pressure to produce 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.

[0905] Step 6: Synthesis of 2-((4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)methyl)acrylic acid

[0906]

[0907] To 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 eq) was added THF / H 2 O (8 mL, 3:1) was added with LiOH·H 2 O (238.40 mg, 5.680 mmol, 4 eq) and stirred at room temperature for 12 h. The mixture was acidified to pH 6 with 1N HCl (aq) and extracted with EtOAc (3×30 mL). The organic layers were combined and washed with saturated brine (2×30 mL) and washed with anhydrous Na 2 SO 4The crude product was purified by (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B to 90% B, 90% B in 10 minutes; wavelength: 254 nm; RT1 (min): 7; number of runs: 5; to obtain 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. LCMS (positive, ES, m / z): 409.2.

[0908] 1 H NMR (300 MHz, DMSO-d 6 )δ8.75 (d, J=2.0Hz, 1H), 8.41 (d, J=2.7Hz, 1H), 8.05 (d, J=2.7Hz, 1H), 8.03 (d, J=1.7Hz, 2H), 5.88 (d, J=3.2Hz, 1 H), 5.38 (d, J=2.9Hz, 1H), 3.20 (s, 3H), 3.03 (d, J=11.2Hz, 2H), 2.18 (dd, J=12.1, 8.5Hz, 2H), 1.97-1.80 (m, 4H).

[0909] 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

[0910]

[0911] Solution 13

[0912] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate

[0913]

[0914] To a stirred solution of 2-bromo-3-chloropyrazine (1.6 g, 8.27 mmol, 1 eq.) in THF (20 mL) was added n-BuLi (1.06 g, 16.54 mmol, 2 eq.) dropwise at -78 °C under a nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1 hour. A solution of tert-butyl 4-oxopiperidine-1-carboxylate (1.81 g, 9.10 mmol, 1.1 eq.) in THF (10 mL) was added dropwise at -78 °C over 10 minutes. The resulting mixture was stirred at -78 °C for another 1 hour. After the reaction was complete, the reaction was heated to 40 °C for 1 hour. 2 O (20 ml). The resulting mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel using PE / EA (1:1) as eluent to give tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 50.09%) as a yellow oil. LCMS: (ES, m / z): [M+H] + =314

[0915] Step 2: Synthesis of tert-butyl 4-hydroxy-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate

[0916]

[0917] To a stirred solution of tert-butyl 4-(3-chloropyrazin-2-yl)-4-hydroxypiperidine-1-carboxylate (1.3 g, 4.14 mmol, 1 eq) and 6-(trifluoromethyl)pyridin-3-ol (743.30 mg, 4.56 mmol, 1.1 eq) in DMAc (15 mL, 161.32 mmol, 38.94 eq) was added K 2 CO 3 (1145.17 mg, 8.29 mmol, 2.0 equiv). The resulting mixture was stirred at 110 °C overnight. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (2×50 mL) and purified by anhydrous Na 2 SO 4The residue was purified by reverse phase flash chromatography under the following conditions: column, C18 silica gel; mobile phase, ACN (0.1% FA) in water, 10% to 40% gradient in 10 minutes; detector, UV 254nm. This produced tert-butyl 4-hydroxy-4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidine-1-carboxylate (250mg, 13.70%) as a white solid. LCMS (ES, m / z): [M+H] + =441.

[0918] Step 3: Synthesis of 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol

[0919]

[0920] 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 eq) in DCM (3 mL) at 0°C was added HCl (gas) in 1,4-dioxane (0.50 mL, 16.46 mmol, 29.0 eq) dropwise. The resulting mixture was stirred at 0°C for 1 hour. The resulting mixture 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 (10 mmol / L NH 4 HCO 3 ), gradient 5% to 25% in 10 minutes; detector, UV 254nm. This produced 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol (120 mg, 62.12%) as a yellow solid. LCMS (ES, m / z): [M+H] + =341.

[0921] 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

[0922]

[0923] A solution of 4-(3-{[6-(trifluoromethyl)pyridin-3-yl]oxy}pyrazin-2-yl)piperidin-4-ol (120 mg, 0.353 mmol, 1 eq) and TEA (71.37 mg, 0.70 mmol, 2 eq) in DCM (5 mL) was stirred at 0°C, followed by the dropwise addition of acryloyl chloride (63.83 mg, 0.70 mmol, 2 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. 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 purified by anhydrous Na 2 SO 4 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% NH 3 ·H 2 O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 16% B to 41% B, 41% B in 8 minutes; wavelength: 220 nm; RT (min): 7.56 to obtain 1-(4-hydroxy-4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one (4 mg, 2.88%) as a white solid. LCMS (ES, m / z): [M+H] - =395. 1 H NMR (400 MHz, DMSO-d 6 )δ8.68 (d, J=2.6Hz, 1H), 8.43 (d, J=2.6Hz, 1H), 8.18 (d, J=2.6Hz, 1H), 8.02 (d, J=8.6Hz, 1H), 7.93 (dd, J=8.5, 2.6Hz, 1H), 6.85 (dd, J=16.7, 10.5Hz, 1H), 6.09 (dd, J=16.7, 2.5Hz, 1H), 5.66 (dd, J=10.4, 2.5Hz, 1H), 5.53 (s, 1 H), 4.25 (m, 1H), 3.95 (m, 1H), 3.57 (m, 1H), 3.22 (m, 1H), 2.35-2.05 (m, 4H).

[0924] 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

[0925]

[0926] 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 provided as a white solid. (n, ES, m / z): 377.21.

[0927] 1 H NMR (400MHz, DMSO) δ8.78 (t, J=1.6Hz, 1H), 8.47 (t, J=2.5Hz, 1H), 8.13-7.97 (m, 3H), 7.06-6.76 (m, 2H), 6.17 (dt, J= 16.8, 3.3Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 4.47-4.25 (m, 2H), 3.80 (dt, J=14.1, 5.6Hz, 2H), 2.83-2.63 (m, 2H).

[0928] 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

[0929]

[0930] 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 provided as a white solid. (n, ES, m / z): 395.31.

[0931] 1 H NMR (400MHz, DMSO) δ8.78 (s, 1H), 8.47 (d, J = 2.5Hz, 1H), 8.07 (d, J = 16.8Hz, 3H), 7.0 2 (s, 1H), 5.42-5.15 (m, 2H), 4.44-4.17 (m, 2H), 3.78 (t, J=5.6Hz, 2H), 2.79 (s, 2H).

[0932] Example 86: Synthesis of 2-((3-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazin-2-yl)azetidin-1-yl)methyl)acrylic acid

[0933]

[0934] 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)meth)acrylic acid was provided as a white solid. (n, ES, m / z): 381.1.

[0935] 1 H NMR (400MHz, DMSO) δ8.74 (t, J=1.7Hz, 1H), 8.44 (d, J=2.7Hz, 1H), 8.11-7.95 (m, 3H), 5.70 (d, J =3.7Hz, 1H), 5.15 (d, J=3.6Hz, 1H), 4.10 (t, J=7.8Hz, 1H), 3.70 (t, J=7.4Hz, 2H), 3.21 (s, 2H).

[0936] Example 87: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0937]

[0938] 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 provided as a white solid. (n, ES, m / z): 381.02.

[0939] 1 H NMR (400MHz, DMSO) δ9.18 (s, 2H), 8.08 (d, J = 2.7Hz, 1H), 7.63 (d, J = 2.7Hz, 1H), 6.87 (dd, J = 16.7, 10.4Hz, 1H) , 6.17 (dd, J=16.7, 2.4Hz, 1H), 5.74 (dd, J=10.4, 2.4Hz, 1H), 3.83-3.67 (m, 4H), 3.63 (dd, J=6.7, 3.5Hz, 4H).

[0940] 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

[0941]

[0942] Following the general procedure in Scheme 10, using 5-((3-(piperazin-1-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 399.08.

[0943] 1 H NMR (400MHz, DMSO) δ9.17 (s, 2H), 8.08 (d, J=2.3Hz, 1H), 7.64 (d, J=2.4Hz, 1H), 5.40-5.16 (m, 2H), 3.77-3.65 (m, 8H).

[0944] 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

[0945]

[0946] 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 provided as a white solid. (n, ES, m / z): 378.3.

[0947] 1 H NMR (400MHz, DMSO) δ9.19 (s, 2H), 8.52 (d, J = 2.5Hz, 1H), 8.11 (s, 1H), 7.09-6.76 (m, 2H), 6.17 (d, J = 17.0H z, 1H), 5.74 (dd, J=10.5, 2.4Hz, 1H), 4.48-4.24 (m, 2H), 3.82 (dd, J=13.7, 7.0Hz, 2H), 2.79-2.70 (m, 2H).

[0948] 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

[0949]

[0950] Following the general procedure in Scheme 10, using 5-((3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine. 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 provided as a white solid. (n, ES, m / z): 396.1.

[0951] 1 H NMR (400MHz, DMSO) δ9.18 (d, J=8.1Hz, 2H), 8.52 (d, J=7.9Hz, 1H), 8.12 (d, J=7.4Hz, 1H) , 7.03 (s, 1H), 5.42-5.14 (m, 2H), 4.47-4.18 (m, 2H), 3.78 (d, J=7.7Hz, 2H), 2.78 (s, 2H).

[0952] Example 91: Synthesis of 1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one

[0953]

[0954] 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 provided as a white solid. (n, ES, m / z): 380.59.

[0955] 1 H NMR (400MHz, DMSO) δ9.18 (s, 2H), 8.45 (d, J = 2.7Hz, 1H), 8.11 (d, J = 2.7Hz, 1H), 6. 88 (dd, J=16.7, 10.5Hz, 1H), 6.13 (dd, J=16.7, 2.4Hz, 1H), 5.70 (dd, J=10.4, 2.5Hz , 1H), 4.59 (d, J=13.1Hz, 1H), 4.22 (d, J=13.7Hz, 1H), 3.60-3.46 (m, 1H), 3.23 (d, J=10.9Hz, 1H), 2.86 (t, J=12.8Hz, 1H), 2.03 (d, J=13.6Hz, 2H), 1.86-1.56 (m, 2H).

[0956] 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

[0957]

[0958] Following the general procedure in Scheme 10, using 5-((3-(piperidin-4-yl)pyrazin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine. 2-Fluoro-1-(4-(3-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyrazin-2-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 398.05.

[0959] 1 H NMR (400MHz, DMSO) δ9.18 (s, 2H), 8.46 (d, J = 2.7Hz, 1H), 8.11 (d, J = 2.7Hz, 1H), 5.39-5.08 (m, 2H), 4.43 (s, 1H), 4.06 (s, 1H), 3.56 (tt, J=11.4, 3.6Hz, 1H), 3.32 (s, 1H), 3.00 (s, 1H), 2.20-1.98 (m, 2H), 1.78 (s, 2H).

[0960] Example 93. Synthesis of 1-(4-{3-[(4,4-difluorocyclohexyl)oxy)pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one

[0961]

[0962] Solution 14

[0963] Step 1: Synthesis of tert-butyl 4-{3-[(4,4-difluorocyclohexyl)oxy]pyrazin-2-yl}piperazine-1-carboxylate

[0964]

[0965] 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%) at 0°C under nitrogen atmosphere 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 treated with H 2The aqueous layer was extracted with DCM (3×50.00 mL). The organic phase was washed with brine (4×50.00 mL) and washed with anhydrous Na 2 SO 4 After removal of the solvent, the residue was purified by silica gel column chromatography eluting 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. LCMS ES, m / z: 399.2.

[0966] Step 2: Synthesis of 2-((4,4-difluorocyclohexyl)oxy)-3-(piperazin-1-yl)pyrazine

[0967]

[0968] 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 hour. The mixture was concentrated under vacuum to give 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. LCMS ES, m / z: 299.2

[0969] Step 3: Synthesis of 1-(4-{3-[(4,4-difluorocyclohexyl)oxy)pyrazin-2-yl}piperazin-1-yl)prop-2-en-1-one

[0970]

[0971] In N 2 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 under atmosphere at 0°C. After the reaction was complete, the mixture was extracted with EA (3×15.00 mL). The combined organic layers were washed with H 2 O (3 × 15.00 mL), washed with anhydrous Na 2 SO 4After 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 NH 4 HCO 3 +0.05% NH 3 H 2 O, 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. LCMS ES, m / z: 353.2.

[0972] 1 H NMR (400 MHz, DMSO-d 6 ): 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), 5.7 1-5.68 (m, 1H), 5.28-5.27 (m, 1H), 3.69-3.65 (m, 4H), 3.46 (m, 4H), 2.07-1.91 (m, 8H).

[0973] Example 94: Synthesis of 1-(4-(3-((4-(trifluoromethyl)cyclohexyl)oxy)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0974]

[0975] 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 provided as a white solid. (n, ES, m / z): 385.33.

[0976] 1H NMR (400MHz, DMSO) δ7.77 (d, J=3.0Hz, 1H), 7.62 (d, J=2.9Hz, 1H), 6.84 (dd, J=16.7, 10.4Hz, 1H), 6.15 (d, J=16.7Hz, 1H), 5.72 (d, J=1 0.5Hz, 1H), 5.00 (s, 1H), 3.67 (d, J=18.0Hz, 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).

[0977] Example 95. Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0978]

[0979] Solution 15

[0980] Step 1: Synthesis of (3-bromopyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol

[0981]

[0982] A solution of 2-bromopyrazine (4 g, 25.15 mmol, 1 eq) in THF was treated with LDA (27 mL, 199.10 mmol, 7.91 eq) at -78 °C under nitrogen atmosphere for 20 min, followed by the dropwise addition of 4-(trifluoromethyl)benzaldehyde (6.57 g, 37.73 mmol, 1.5 eq) at -78 °C. The resulting mixture was stirred at -40 °C under nitrogen atmosphere for 30 min. The resulting mixture was heated at -40 °C with 100.00 mL H 2 O 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 Na 2 SO 4 Dried. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (5:1) to give (3-bromopyrazin-2-yl)[4-(trifluoromethyl)phenyl]methanol (4.3 g, 51.31%) as a yellow solid.

[0983] Step 2: Synthesis of (3-bromopyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanone

[0984]

[0985] A solution of (3-bromopyrazin-2-yl)[4-(trifluoromethyl)phenyl]methanol (1 g, 3.00 mmol, 1 eq) and Dess-Martin periodinane (2.55 g, 6.00 mmol, 2 eq) in DCM was stirred at room temperature under nitrogen atmosphere for 2 hours. To the resulting mixture was added 100.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (100.00 mL×3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE:EA (5:1) to give 2-bromo-3-[4-(trifluoromethyl)benzoyl]pyrazine (980 mg, 98.60%) as a white solid.

[0986] Step 3: Synthesis of tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazine-1-carboxylate

[0987]

[0988] 2-Bromo-3-[4-(trifluoromethyl)benzoyl]pyrazine (3 g, 9.06 mmol, 1 eq.), tert-butyl piperazine-1-carboxylate (2.53 g, 13.59 mmol, 1.5 eq.), XantPhos (0.47 g, 0.81 mmol, 0.09 eq.), Cs 2 CO 3 (8.86 g, 27.18 mmol, 3 eq), Pd 2 (dba) 3 (0.33 g, 0.36 mmol, 0.04 equiv) and 1,4-dioxane (30 mL) were added to a 40 mL vial. The resulting mixture was stirred at 80 °C for 3 hours under a nitrogen atmosphere. 100.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (100.00 mL×3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel using PE:EA (3:1) as eluent to give tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazine-1-carboxylate (3.6 g, 91.04%) as a white solid.

[0989] Step 4: Synthesis of (3-(piperazin-1-yl)pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanone (HCl salt)

[0990]

[0991] At room temperature, tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazine-2-yl}piperazine-1-carboxylate (530 mg, 1.21 mmol, 1 eq) and DCM (4 mL), HCl (gas) in 1,4-dioxane (2 mL) were added to a 40 mL vial. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 2-(piperazine-1-yl)-3-[4-(trifluoromethyl)benzoyl]pyrazine (400 mg, 98%) as a white solid.

[0992] Step 5: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0993]

[0994] A solution of 2-(piperazin-1-yl)-3-[4-(trifluoromethyl)benzoyl]pyrazine (400 mg, 1.18 mmol, 1 eq.) in DCM was treated with TEA (361.06 mg, 3.56 mmol, 3 eq.) for 3 minutes at 0°C under a nitrogen atmosphere, followed by the dropwise addition of acryloyl chloride (113.03 mg, 1.24 mmol, 1.05 eq.) at 0°C. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. 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% NH 3 ·H 2 O, mobile phase B: ACN; flow rate: 80 mL / min; gradient: 15% B to 50% B-17 min) to obtain 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. LCMS: (ES, m / z): [M+H] + =391.

[0995] 1H NMR (400MHz, DMSO-d6) δ8.37 (d, J=2.0Hz, 1H), 8.15 (d, J=8.0Hz, 2H), 8.02 (d, J=2.4Hz, 1H), 7.93 (d, J=8.0Hz, 2H), 6 .75 (d, J=10.4Hz, 1H), 6.13 (d, J=2.4Hz, 1H), 5.69 (d, J=2.4Hz, 1H), 3.66 (d, J=27.8Hz, 4H), 3.46 (d, J=23.2Hz, 4H).

[0996] Example 96: Synthesis of 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[0997]

[0998] 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 provided as a white solid. (n, ES, m / z): 392.22.

[0999] 1 H NMR (400MHz, DMSO) δ9.28 (d, J=2.0Hz, 1H), 8.65-8.53 (m, 1H), 8.42 (d, J=2.1Hz, 1H), 8.12 (dd, J=8.2, 0.9Hz, 1H), 8.05 (d, J=2.2Hz, 1 H), 6.79 (dd, J=16.6, 10.4Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.83-3.62 (m, 4H), 3.64-3.44 (m, 4H).

[1000] Example 97. Synthesis of 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1001]

[1002] Scheme 16

[1003] Step 1: Synthesis of tert-butyl 4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazine-1-carboxylate

[1004]

[1005] At room temperature, tert-butyl 4-{3-[4-(trifluoromethyl)benzoyl]pyrazin-2-yl}piperazine-1-carboxylate (500 mg, 1.14 mmol, 1 equivalent), NaBH 4 (43.34 mg, 1.14 mmol, 1 eq) and MeOH (5 mL) were added to a 40 mL vial. The resulting mixture was stirred at room temperature for 30 min under a nitrogen atmosphere. The desired product was detected by LCMS. 50 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give tert-butyl 4-(3-{hydroxy[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.

[1006] Step 2: Synthesis of (3-(piperazin-1-yl)pyrazin-2-yl)(4-(trifluoromethyl)phenyl)methanol (HCl salt)

[1007]

[1008] At room temperature, tert-butyl 4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazine-2-yl)piperazine-1-carboxylate (400 mg, 0.91 mmol, 1 eq) and DCM (3 mL), HCl (gas) in 1,4-dioxane (4M, 1.5 mL) were added to a 40 mL vial. The resulting mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to give 1-[4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazine-2-yl)piperazine-1-yl]prop-2-ene-1-one (450 mg, 97.00%) as a white solid.

[1009] Step 3: Synthesis of 1-(4-(3-(hydroxy(4-(trifluoromethyl)phenyl)methyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1010]

[1011] A solution of [3-(piperazin-1-yl)pyrazin-2-yl][4-(trifluoromethyl)phenyl]methanol (200 mg, 0.59 mmol, 1 eq.) in DMA was treated with NaHCO at 0 °C under nitrogen atmosphere. 3(148.98 mg, 1.77 mmol, 3 eq.) was treated for 3 minutes, followed by the dropwise addition of acryloyl chloride (56.18 mg, 0.62 mmol, 1.05 eq.) at 0 °C. The resulting mixture was stirred at room temperature for 2 hours under a nitrogen atmosphere. The desired product was detected by LCMS. 20.00 mL of H 2 O and extracted with ethyl acetate (50.00 mL×3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), 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 provide 1-[4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazin-2-yl)piperazin-1-yl]prop-2-en-1-one as a yellow solid. LCMS: (ES, m / z): [M+H] + =393.

[1012] 1 H NMR (400 MHz, CDCl 3 )δ8.42-8.29 (m, 2H), 7.61 (d, J=8.0Hz, 2H), 7.50 (d, J=8.0Hz, 2H), 6.58 (d, J=10.4Hz, 1H), 6.34 (d, J=16.8, Hz , 1H), 6.06 (s, 1H), 5.76 (d, J=10.4Hz, 1H), 3.72-3.58 (m, 4H), 3.22 (dt, J=10.8Hz, 2H), 3.01 (d, J=5.2Hz, 2H).

[1013] Example 98. Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1014]

[1015] Solution 17

[1016] Step 1: Synthesis of 2-(piperazin-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine

[1017]

[1018] Under nitrogen atmosphere at room temperature, a solution of tert-butyl 4-(3-{hydroxy[4-(trifluoromethyl)phenyl]methyl}pyrazine-2-yl)piperazine-1-carboxylate (400mg, 0.91mmol, 1 equivalent) and triethylsilane (106.08mg, 0.91mmol, 1 equivalent) in TFA was stirred for 2 hours. The resulting mixture was concentrated under reduced pressure to obtain 2-(piperazine-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine (360mg, crude) as a white solid. The crude product can be directly used in the next step without further purification.

[1019] Step 2: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1020]

[1021] A solution of 2-(piperazin-1-yl)-3-{[4-(trifluoromethyl)phenyl]methyl}pyrazine (300 mg, 0.93 mmol, 1 eq) in DCM was treated with TEA (282.54 mg, 2.79 mmol, 3 eq) at 0°C under nitrogen atmosphere for 3 minutes, followed by the dropwise addition of acryloyl chloride (88.45 mg, 0.97 mmol, 1.05 eq) at 0°C. The resulting mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. The desired product was detected by LCMS. 50 mL of H O was added to the resulting mixture. 2 O, and the resulting mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product (100 mg) was purified by (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 60 mL / min; gradient: 40% B to 60% B, 56% B in 16 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to obtain 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. LCMS: (ES, m / z): [M+H]+=377.

[1022] 1H NMR (400MHz, DMSO-d6) δ8.20 (d, J=2.8Hz, 2H), 7.65 (d, J=8.0Hz, 2H), 7.46 (d, J=8.0Hz, 2H), 6.85 (d, J=10 .4Hz, 1H), 6.14 (d, J=2.4Hz, 1H), 5.71 (d, J=2.4Hz, 1H), 4.31 (s, 2H), 3.71 (s, 4H), 3.12 (t, J=5.2Hz, 4H).

[1023] Example 99. Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide

[1024]

[1025] Scheme 18

[1026] Step 1: Synthesis of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid

[1027]

[1028] 3-Chloropyrazine-2-carboxylic acid (1580 mg, 10 mmol, 1 eq.) and tert-butyl piperazine-1-carboxylate (2790 mg, 15 mmol, 1.5 eq.) were reacted in CH 3 To a stirred solution in CN (30 mL) was added t-BuONa (1920 mg, 20 mmol, 2.0 eq) and stirred at room temperature for 2 h. The mixture was washed with H 2 O (30 mL), adjusted pH to 5-6 with 1N HCl (aq.), extracted with EA (3 x 50 mL). The combined organic phases were washed with brine (1 x 100 mL), 2 SO 4 Dry, concentrate under reduced pressure and pass through C18 column chromatography (ACN / H 2 O: 20%) to give 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid (2100 mg, 68.18%) as a white solid.

[1029] Step 2: Synthesis of tert-butyl 4-[3-(cyclobutylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate

[1030]

[1031] To a stirred solution of 3-[4-(tert-butoxycarbonyl)piperazin-1-yl]pyrazine-2-carboxylic acid (802 mg, 2.60 mmol, 1 eq), cyclobutylamine (222 mg, 3.12 mmol, 1.2 eq) and DIEA (1008 mg, 7.80 mmol, 3 eq) in DCM (8 mL) was added HATU (1186 mg, 3.12 mmol, 1.2 eq) portionwise and stirred at room temperature for 1 h. The mixture was washed with H 2 O (30 mL) and extracted with DCM (3×50 mL). The combined organic phases were washed with brine and purified by anhydrous Na 2 SO 4 Dried, 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.

[1032] Step 3: Synthesis of N-cyclobutyl-3-(piperazin-1-yl)pyrazine-2-carboxamide

[1033]

[1034] To a stirred solution of tert-butyl 4-[3-(cyclobutylcarbamoyl)pyrazin-2-yl]piperazine-1-carboxylate (342 mg, 0.94 mmol, 1 eq) in DCM (4 mL) was added HCl (gas) in 1,4-dioxane (1 mL, 4 mmol, 4.255 eq) at room temperature and stirred for 1 hour. 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.

[1035] Step 4: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclobutylpyrazine-2-carboxamide

[1036]

[1037] To a stirred solution of N-cyclobutyl-3-(piperazin-1-yl)pyrazine-2-carboxamide (342 mg, 1.309 mmol, 1.0 eq) and TEA (397.29 mg, 3.927 mmol, 3 eq) in DCM (4 mL) was added acryloyl chloride (142.14 mg, 1.571 mmol, 1.2 eq) dropwise at 0 °C and stirred for 1 hour. 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) and washed with anhydrous Na 2 SO 4The crude product was purified by Prep-HPLC under the following conditions (column: XBridge C18, 19*150 mm, 5 μm; mobile phase A: 20 mM NH 4 HCO 3 +0.05% NH 3 H 2 O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 minutes) to give N-cyclobutyl-3-[4-(prop-2-enoyl)piperazin-1-yl]pyrazine-2-carboxamide (63 mg, 15.26%) as a white solid. LCMS (ES, m / z): [M+H] + =316.

[1038] 1 H NMR (400MHz, Chloroform-d) δ8.20 (d, J=2.3Hz, 1H), 7.94 (d, J=2.2Hz, 1H), 7.84 (d, J=8.3Hz, 1H), 6.59 (dd, J=16.8, 10.5Hz, 1H), 6.32 (dd, J=16.8, 1.9 Hz, 1H), 5.73 (dd, J=10.5, 1.9Hz, 1H), 4.52 (m, 1H), 3.80 (d, J=26.6Hz, 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).

[1039] Example 100: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide

[1040]

[1041] Following the general procedure in Scheme 18, 3,3-difluorocyclobutane-1-amine was used in step / / 2. 3-(4-acryloylpiperazin-1-yl)-N-(3,3-difluorocyclobutyl)pyrazine-2-carboxamide was provided as a white solid. (N, ES, m / z): 352.36.

[1042] 1H NMR (400MHz, DMSO) δ9.19 (d, J=6.8Hz, 1H), 8.27 (d, J=2.4Hz, 1H), 8.00 (d, J=2.3Hz, 1H), 6.83 (dd, J=16.7, 10.4Hz, 1H), 6.15 (dd, J=16.8, 2.3Hz, 1H), 5 .72(dd, J=10.4, 2.4Hz, 1H), 4.31-4.13(m, 1H), 3.72-3.58(m, 4H), 3.45-3. 43 (m, 4H), 3.32 (d, J=3.2Hz, 1H), 2.96 (t, J=7.0Hz, 2H), 2.87-2.67 (m, 2H).

[1043] 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

[1044]

[1045] 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 provided as a white solid. (n, ES, m / z): 410.36.

[1046] 1 H NMR (400MHz, DMSO) δ8.23 (t, J=2.6Hz, 1H), 7.97 (t, J=2.7Hz, 1H), 6.83 (dd, J=16.7, 10.5Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H) , 5.73 (dd, J=10.4, 2.4Hz, 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).

[1047] Example 102: Synthesis of 3-(4-acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide

[1048]

[1049] Following the general procedure in Scheme 18, cyclopentylamine was used in step 2. 3-(4-Acryloylpiperazin-1-yl)-N-cyclopentylpyrazine-2-carboxamide was provided as a white solid. (N, ES, m / z): 330.02.

[1050] 1 H NMR (400MHz, DMSO) δ8.58 (s, 1H), 8.23 ​​(d, J = 8.3Hz, 1H), 7.97 (d, J = 8.1Hz, 1H), 6.84 (s, 1H), 6.16 (d, J=15.3Hz, 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).

[1051] Example 103: Synthesis of 1-(4-(3-(4-(trifluoromethyl)piperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1052]

[1053] 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 provided as a white solid. (n, ES, m / z): 398.32.

[1054] 1 H NMR (400MHz, DMSO) δ8.26 (d, J=2.5Hz, 1H), 8.02 (d, J=2.5Hz, 1H), 6.83 (dd, J=16.7, 10.4Hz, 1H), 6 .15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 4.60 (d, J=13.2Hz, 1H), 3.71-3.61 (m, 4 H), 3.46 (td, J=12.8, 6.0Hz, 4H), 3.22-3.11 (m, 1H), 2.87 (td, J=13.1, 2.9Hz, 1H), 2.69 (s, 1H), 1. 97 (d, J=12.7Hz, 1H), 1.80 (d, J=12.9Hz, 1H), 1.43 (pd, J=12.8, 4.5Hz, 2H), 1.28 (t, J=2.3Hz, 1H).

[1055] Example 104: Synthesis of 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1056]

[1057] 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 provided as a white solid. (normal, ES, m / z): 366.1.

[1058] 1 H NMR (400MHz, DMSO) δ 8.25 (s, 1H), 7.99 (s, 1H), 6.81 (d, J=14.6Hz, 1H), 6.16 (d, J=14.8Hz, 1H), 5.72 (s, 1H), 3.93-3.53 (m, 12H), 2.04 (s, 4H).

[1059] Example 105: Synthesis of 1-(4-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1060]

[1061] 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 provided as a white solid. (N, ES, m / z): 370.35.

[1062] 1 H NMR (400MHz, DMSO) δ7.85-7.73 (m, 2H), 6.87 (dd, J=16.6, 10.4Hz, 1H), 6.15 (dd, J=16.6, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2 .4Hz, 1H), 4.17 (d, J=12.8Hz, 2H), 3.85-3.62 (m, 4H), 2.66 (t, J=12.2Hz, 2H), 1.95 (d, J=12.6Hz, 2H), 1.64-1.43 (m, 2H).

[1063] Example 106: Synthesis of 1-(4-(3-(3-phenylazetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1064]

[1065] 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 provided as a white solid. (n, ES, m / z): 350.3.

[1066] 1 H NMR (400MHz, DMSO) δ7.81 (d, J=2.8Hz, 1H), 7.69 (t, J=2.5Hz, 1H), 7.47-7.21 (m, 6H), 6.90-6.77 (m, 1H), 6.14 (ddd, J=16.9, 4.0, 2.5Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 4.43 (t, J=8.2Hz, 2H), 4.04-3.87 (m, 3H), 3.72 (d, J=14.7Hz, 4H), 3.63 (d, J=6.7Hz, 1H), 3.14 (s, 4H).

[1067] Example 107: Synthesis of 1-(4-(3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1068]

[1069] 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 provided as a white solid. (n, ES, m / z): 368.29.

[1070] 1 H NMR (400MHz, DMSO) δ7.81 (d, J=2.8Hz, 1H), 7.69 (d, J=2.8Hz, 1H), 7.53-7.39 (m, 2H), 7.25-7.10 (m, 2H), 6.85 (dd, J=16.7, 10.5Hz, 1H), 6.14 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 4.49-4.35 (m, 2H), 4.04-3.86 (m, 3H), 3.72 (d, J=13.9Hz, 4H), 3.14 (s, 4H).

[1071] 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

[1072]

[1073] 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 provided as a white solid. (n, ES, m / z): 354.79.

[1074] 1 H NMR (400MHz, DMSO) δ7.48 (q, J=3.9Hz, 4H), 7.19 (t, J=8.8Hz, 2H), 6.43 (d, J=6.3Hz, 1H), 6.37-6.26 (m, 1H), 6.10 (d, J= 17.2Hz, 1H), 5.67 (dd, J=10.0, 2.2Hz, 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).

[1075] 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

[1076]

[1077] Following the general procedure in Scheme 10, using N-(azetidin-3-yl)-3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-amine. 2-Fluoro-1-(3-((3-(3-(4-fluorophenyl)azetidin-1-yl)pyrazin-2-yl)amino)azetidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 372.71.

[1078] 1H NMR (400MHz, DMSO) δ7.48 (q, J=4.8Hz, 4H), 7.19 (t, J=8.7Hz, 2H), 6.43 (d, J=5.5Hz, 1H), 5.56-5.23 (m, 2H ), 4.63 (s, 2H), 4.47 (q, J=8.8Hz, 2H), 4.25 (d, J=7.3Hz, 2H), 4.04 (q, J=8.0Hz, 2H), 3.90 (q, J=7.7Hz, 2H).

[1079] Example 110: Synthesis of 1-(4-(3-(6-(trifluoromethyl)-2-azaspiro[3.3]hept-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1080]

[1081] 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]hept-2-yl)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 382.39.

[1082] 1 H NMR (400MHz, DMSO) δ7.76 (d, J=2.8Hz, 1H), 7.64 (d, J=2.8Hz, 1H), 6.85 (dd, J=16.7, 10.5Hz, 1H), 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=1 0.5, 2.4Hz, 1H), 4.04 (s, 2H), 3.96 (s, 2H), 3.72 (d, J=13.5Hz, 4H), 3.09 (s, 5H), 2.46 (dd, J=13.1, 9.1Hz, 2H), 2.30 (dd, J=13.1, 7.4Hz, 2H).

[1083] Example 111. Synthesis of 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1084]

[1085] Solution 19

[1086] Step 1: Synthesis of 5-bromo-6-chloropyrazin-2-ol

[1087]

[1088] At 0 °C, 5-bromo-6-chloropyrazin-2-amine (10 g, 48.5 mmol, 1.00 equiv) was added in H 2 SO 4 The stirred solution in 1% NaNO (60 mL) was added in portions 2 (3.68 g, 53.3 mmol, 1.10 equiv). The resulting mixture was stirred at 0°C for 1 hour. The reaction was quenched by the addition of ice water (200 mL) at 0°C. The precipitated solid was collected by filtration and washed with water (2×300 mL), then dried to give 5-bromo-6-chloropyrazin-2-ol (5.5 g, 54.78%) as an off-white solid.

[1089] Step 2: Synthesis of 5-(benzyloxy)-2-bromo-3-chloropyrazine

[1090]

[1091] To a stirred solution of 5-bromo-6-chloropyrazin-2-ol (5.4 g, 25.784 mmol, 1 eq) and benzyl bromide (8.82 g, 51.568 mmol, 2 eq) in toluene (60 mL) was added Ag at 0 °C. 2 CO 3 (7.47 g, 27.073 mmol, 1.05 equiv.). The resulting mixture was stirred at room temperature for 3 hours. The resulting 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) and dried over anhydrous Na 2 SO 4 Dried 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.

[1092] Step 3: Synthesis of 6-(benzyloxy)-3-bromo-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine

[1093]

[1094] To a stirred solution of 5-(benzyloxy)-2-bromo-3-chloropyrazine (2.512 g, 8.386 mmol, 1 eq.) and t-BuOK (1.88 g, 16.772 mmol, 2 eq.) in DMAc (50 mL) was added p-trifluoromethylaniline (1.62 g, 10.063 mmol, 1.2 eq.) at room temperature. The resulting 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 x 200 mL). The combined organic phases were washed with brine (1 x 100 mL) and concentrated. The residue was purified by silica gel column chromatography eluting 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. LCMS-PH-CAL-Y-V2475860-3: (ES, m / z): [M+H] - =424

[1095] Step 4: Synthesis of tert-butyl 4-[5-(benzyloxy)-3-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-yl]piperazine-1-carboxylate

[1096]

[1097] To a stirred solution of 6-(benzyloxy)-3-bromo-N-[4-(trifluoromethyl)phenyl]pyrazin-2-amine (1.945 g, 4.585 mmol, 1 eq) and tert-butyl piperazine-1-carboxylate (1.02 g, 5.502 mmol, 1.2 eq) in DMF (20 mL) was added Cs 2 CO 3 (2.99 g, 9.170 mmol, 2 equivalents), Pa 2 (dba) 3 (0.41 g, 0.45 mmol, 0.1 eq) and Xphos. The resulting mixture was stirred at 100°C for 3 hours. Water (60 mL) was added to the mixture, and the mixture was extracted with EA (3×60 mL), washed with brine (2×60 mL), and dried over anhydrous Na 2 SO 4 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. LCMS (ES, m / z): [M+H] + =530

[1098] Step 5: Synthesis of 5-(piperazin-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol

[1099]

[1100] 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 eq) in DCM (8 mL) was added TFA (2 mL) at 80°C and stirred for 1 hour. The resulting mixture was concentrated under reduced pressure to give 5-(piperazin-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol (440 mg, 98.10%) as a brown oil. LCMS (ES, m / z): [M+H] + =340

[1101] Step 6: Synthesis of 1-(4-(5-hydroxy-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1102]

[1103] To a stirred solution of 5-(piperazine-1-yl)-6-{[4-(trifluoromethyl)phenyl]amino}pyrazin-2-ol (400 mg, 1.179 mmol, 1 eq) in DCM (10 mL) at 0 °C, acryloyl chloride (128.03 mg, 1.415 mmol, 1.2 eq) and TEA (357.87 mg, 3.537 mmol, 3 eq) were added dropwise and then stirred at room temperature for 1 hour. The resulting solution was stirred at 100 °C for 3 hours. Water (20 mL) was added to the mixture and the aqueous layer was extracted with DCM (3×30 mL). The combined organic phases were washed with Na 2 SO 4 The product was dried and 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 NH 4 HCO 3 +0.05% NH 3 H 2 O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 minutes) 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. LCMS (ES, m / z): [M+H] - =394.

[1104] 1 H NMR (400 MHz, DMSO-d 6 ) δ10.70 (s, 1H), 8.46 (s, 1H), 8.02 (d, = 8.5Hz, 2H), 7.63 (d, = 8.5Hz, 2H), 7.31 (s, 1H), 6.85 (dd, J = 16 .7, 10.5Hz, 1H), 6.14 (dd, J=16.5, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 1H), 3.79 (s, 4H), 2.92 (s, 4H).

[1105] Example 112: Synthesis of 1-(4-(6-methyl-3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1106]

[1107] 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 provided as a white solid. (n, ES, m / z): 322.29.

[1108] 1 H NMR (400MHz, DMSO) δ8.52 (s, 1H), 7.88-7.74 (m, 3H), 7.62 (d, J=8.5Hz, 2H), 685 (dd, J=16.7, 10.5Hz, 1H), 6. 15 (dd, J=16.7, 2.4Hz, 1H), 5.72 (dd, J=10.4, 2.4Hz, 1H), 3.77 (d, J=13.6Hz, 4H), 3.14 (s, 4H), 2.33 (s, 3H).

[1109] 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

[1110]

[1111] 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 provided as a white solid. (N, ES, m / z): 407.58.

[1112] 1 H NMR (400MHz, DMSO) δ9.04 (d, J=2.5Hz, 1H), 8.71 (s, 1H), 8.40-8.26 (m, 1H), 7.79 (d, J=8.7Hz, 1H), 6.85 (dd, J=16.7, 10.4Hz, 1H), 6.15 (dd, J=16.8, 2.4Hz, 1H), 5.72 (dd, J=10.5, 2.4Hz, 1H), 3.76 (d, J=13.1Hz, 4H), 3.08 (s, 4H), 2.35 (d, J=5.2Hz, 6H).

[1113] 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

[1114]

[1115] Following the general procedure in Scheme 10, using 5,6-dimethyl-3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-amine. 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 provided as a white solid. (N, ES, m / z): 425.49.

[1116] 1 H NMR (400MHz, DMSO) δ9.04 (s, 1H), 8.71 (s, 1H), 8.34 (d, J=8.4Hz, 1H), 7.79 (d, J=8.7H z, 1H), 5.38-5.12 (m, 2H), 3.74 (d, J=5.7Hz, 4H), 3.12 (s, 4H), 2.35 (d, J=5.7Hz, 6H).

[1117] 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

[1118]

[1119] Following the general procedure in Scheme 10, using 5-methyl-3-(piperidin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine. 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 provided as a white solid. (n, ES, m / z): 411.62.

[1120] 1 H NMR (400MHz, DMSO) δ8.73 (d, J=2.5Hz, 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=13.2Hz, 2H), 1.77 (s, 2H).

[1121] 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

[1122]

[1123] 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 provided as a white solid. (n, ES, m / z): 393.79.

[1124] 1 H NMR400MHz, DMSO) δ8.76 (d, J=2.4Hz, 1H), 8.30 (s, 1H), 8.08-7.91 (m, 2H), 6.9 4-6.80 (m, 1H), 6.12 (ddd, J=16.7, 2.4, 1.0Hz, 1H), 5.69 (ddd, J=10.4, 2.5, 1. 0Hz, 1H), 4.56 (d, J = 13.0Hz, 1H), 4.20 (d, J = 13.7Hz, 1H), 3.33-3.19 (m, 2H), 2 .83(t, J=12.6Hz, 1H), 2.31(s, 3H), 1.97(d, J=13.1Hz, 2H), 1.84-1.55(m, 2H)

[1125] 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

[1126]

[1127] Following the general procedure in Scheme 10, using 5-methyl-2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrazine. 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 provided as a white solid. (n, ES, m / z): 411.81.

[1128] 1 H NMR (400MHz, DMSO) δ8.76 (d, J=2.3Hz, 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).

[1129] Example 118. Synthesis of 3-(1-acryloylpiperidin-4-yl)-1-(5-(trifluoromethyl)pyrimidin-2-yl)pyrazin-2(1H)-one

[1130]

[1131] Solution 20

[1132] Step 1: Synthesis of tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate

[1133]

[1134] A solution of tert-butyl 4-iodopiperidine-1-carboxylate (3.11 g, 9.98 mmol, 1.2 eq) and Zn (0.82 g, 12.47 mmol, 1.5 eq) in DMAc (15 mL) was stirred for 0.5 h at 60 °C under nitrogen atmosphere. 2-Chloro-3-iodopyrazine (2 g, 8.31 mmol, 1 eq), CuI (0.32 g, 1.66 mmol, 0.2 eq) and Pd(dppf)Cl were added at 60 °C. 2(0.61 g, 0.83 mmol, 0.1 eq) in DMAC (15 mL) was stirred 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 purified by anhydrous Na 2 SO 4 The product was dried. 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 give tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (1.4 g, 56.52%) as a yellow solid. LCMS (ES, m / z): [M+H] + =298

[1135] Step 2: Synthesis of tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate

[1136]

[1137] Tert-butyl 4-(3-chloropyrazin-2-yl)piperidine-1-carboxylate (1.2 g, 4.03 mmol, 1 eq.) and KOH (3.39 g, 60.45 mmol, 15 eq.) were dissolved in DMSO (20 mL) and H2O at 80 °C. 2 O (5mL) was stirred for 2 hours. The resulting mixture was diluted with water (60mL). The mixture was acidified to pH = 3 with citric acid solution (4M, 40mL). The resulting mixture was extracted with EtOAc (3×100mL). The combined organic layers were washed with brine (1×100mL) and washed with anhydrous Na 2 SO 4 Dry. After filtration, the filtrate was concentrated under reduced pressure. This produced tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate (1 g, 88.83%) as a yellow solid. LCMS (ES, m / z): [M+H] + =280.

[1138] Step 3: Synthesis of tert-butyl 4-(3-oxo-4-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-ylpiperidine-1-carboxylate

[1139]

[1140] To a stirred solution of tert-butyl 4-(3-hydroxypyrazin-2-yl)piperidine-1-carboxylate (0.8 g, 2.86 mmol, 1 eq) in ACN (8 mL) was added K 2 CO3 (1.19 g, 8.59 mmol, 3 eq.) and 2-chloro-5-(trifluoromethyl)pyrimidine (0.63 g, 3.43 mmol, 1.2 eq.). The resulting mixture was stirred at 80 °C for 4 hours. Two peaks with the desired Ms were shown in LCMS. The second peak is 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 purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase rapid purification under the following conditions (XBridge C18, 19*150mm, 5μm; mobile phase A: 20mM+0.05% NH 3 H 2 O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 minutes. ) to give tert-butyl 4-(3-oxo-4-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-ylpiperidine-1-carboxylate (700 mg, 57.46%) as a yellow solid. LCMS (ES, m / z): [M+H] + =426.

[1141] 1 H NMR (400 MHz, DMSO-d 6 )δ9.54 (s, 2H), 7.73 (d, J = 4.6Hz, 1H), 7.39 (d, J = 4.6Hz, 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).

[1142] Step 4: Synthesis of 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one

[1143]

[1144] 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 eq) in DCM (2 mL) at room temperature was added HCl / dioxane (2 mL, 8.00 mmol, 4.86 eq). The resulting mixture was stirred at room temperature for 1 hour. After the reaction was complete. The resulting mixture was concentrated under reduced pressure. This produced 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one (500 mg, 93.41%) as a white solid. LCMS (ES, m / z): [M+H] + =326

[1145] Step 5: Synthesis of 3-[1-(prop-2-enoyl)piperidin-4-yl]-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one

[1146]

[1147] To a stirred solution of 3-(piperidin-4-yl)-1-[5-(trifluoromethyl)pyrimidin-2-yl]pyrazin-2-one (300 mg, 0.92 mmol, 1 eq) in DCM (5 mL) at 0 °C was added DIEA (595.98 mg, 4.61 mmol, 5 eq) and acryloyl chloride (166.94 mg, 1.84 mmol, 2 eq). The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (150 mL). The resulting mixture was extracted with DCM (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase rapid purification under the following conditions (XBridge C18, 19*150mm, 5μm; mobile phase A: 20mM 0.05% NH 3 H 2 O, mobile phase B: ACN; flow rate: 20 mL / min; gradient: 10% to 65% in 8 minutes. ) to obtain 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. LCMS (ES, m / z): [M+H] + =380.

[1148] 1 H NMR (400 MHz, DMSO-d 6)δ9.54 (s, 2H), 7.73 (d, J = 4.6Hz, 1H), 7.38 (d, J = 4.6Hz, 1H), 6.83 (dd, J = 16.7, 10.5Hz, 1H), 6.10 (dd, J = 16.7, 2.4Hz, 1H), 5.67 (dd, J=10.5, 2.5Hz, 1H), 4.50 (d, J=12.7Hz, 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).

[1149] Example 119: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1150]

[1151] 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 provided as a white solid. (n, ES, m / z): 378.28.

[1152] 1 H NMR (400MHz, DMSO) δ8.68 (d, J=5.2Hz, 1H), 8.55 (s, 1H), 7.88 (d, J=8.5Hz, 2H), 7.66 (d, J=8.5Hz, 2H), 7.15 (d, J=5.3Hz, 1H), 6.85 ( dd, J=16.7, 10.5Hz, 1H), 6.16 (dd, J=16.7, 2.4Hz, 1H), 5.73 (dd, J=10.4, 2.4Hz, 1H), 3.77 (d, J=13.8Hz, 4H), 3.04 (t, J=4.9Hz, 4H).

[1153] Example 120: Synthesis of 1-(4-(3-((5-(trifluoromethyl)pyridin-2-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1154]

[1155] 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 provided as a white solid. (n, ES, m / z): 379.65.

[1156] 1 H NMR (400MHz, DMSO) δ9.12 (s, 1H), 8.78 (d, J = 5.4Hz, 1H), 8.61 (s, 1H), 8.10 (d, J = 8.9Hz, 1H), 7.96 (d, J = 8.9Hz, 1H), 7.22 (d, J = 5.4 Hz, 1H), 6.84 (dd, J=16.7, 10.4Hz, 1H), 6.15 (d, J=17.0Hz, 1H), 5.77-5.66 (m, 1H), 3.68 (d, J=15.1Hz, 4H), 3.09 (d, J=5.6Hz, 4H).

[1157] Example 121: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1158]

[1159] 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 provided as a white solid. (n, ES, m / z): 379.27.

[1160] 1 H NMR (400MHz, DMSO) δ8.99 (s, 1H), 8.79 (s, 1H), 8.72 (d, J = 5.2Hz, 1H), 8.42-8.32 (m, 1H), 7.85 (d, J = 8.6Hz, 1H), 7.18 (d , J=5.4Hz, 1H), 6.86 (dd, J=16.7, 10.4Hz, 1H), 6.16 (d, J=16.5Hz, 1H), 5.73 (d, J=10.5Hz, 1H), 3.78 (s, 4H), 3.06 (s, 4H)

[1161] Example 122: Synthesis of 1-(4-(5-((4-(trifluoromethyl)phenyl)amino)pyridazin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1162]

[1163] 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 provided as a white solid. (n, ES, m / z): 378.28.

[1164] 1 H NMR (400MHz, DMSO) δ8.85 (s, 1H), 8.79 (d, J = 2.6Hz, 2H), 7.63 (d, J = 8.4Hz, 2H), 7.11 (d, J = 8.4Hz, 2H), 6.79 (dd, J = 16.6, 10.4Hz, 1H), 6.12 (dd, J=16.7, 2.4Hz, 1H), 5.69 (dd, J=10.4, 2.4Hz, 1H), 3.44 (d, J=14.7Hz, 4H), 3.08 (t, J=5.1Hz, 4H).

[1165] Example 123. Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one

[1166]

[1167] Solution 21

[1168] Step 1: Synthesis of tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazine-1-carboxylate

[1169]

[1170] To 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 Cs 2 CO 3 (1744.86 mg, 5.36 mmol, 2 eq) in toluene (6.00 mL) was added Pd 2 (dba) 3 (245.20 mg, 0.27 mmol, 0.1 eq.). 2 The mixture was stirred at 90°C for 3 hours under a 3% CO atmosphere. The reaction mixture was diluted with EA (90.00 mL). The organic layer was washed with H 2 O (3 × 20.00 mL), washed with anhydrous Na2 SO 4 The mixture was dried. 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-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazine-1-carboxylate (650.00 mg, 57.33%) as a yellow solid. LCMS (ES, m / z): [M+H] + =424

[1171] Step 2: Synthesis of 4-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine

[1172]

[1173] 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) was placed in a 40 mL container. 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 vacuum. This produced 4-(piperazine-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-2-amine (300.00 mg, 87.31%) as a yellow solid. LCMS (ES, m / z): [M+H] + =324

[1174] Step 3: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-4-yl)piperazin-1-yl]prop-2-en-1-one

[1175]

[1176] 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) was placed in a 40 mL container. 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 hour. The mixture was diluted with EA (45.00 mL) and washed with H 2 O (3 × 15.00 mL), washed with anhydrous Na 2 SO 4After 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% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 50 mL / min; gradient: 60% B to 90% B, 90% B in 10 min; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to obtain 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. LCMS (ES, m / z): [M+H] + =378.

[1177] 1 H NMR (400 MHz, DMSO-d 6 ): δ9.56 (s, 1H), 8.07 (s, 1H), 8.05 (d, J = 14.0Hz, 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).

[1178] Example 124: Synthesis of 1-(4-(methyl(2-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one

[1179]

[1180] 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 provided as a white solid. (n, ES, m / z): 406.32.

[1181] 1H NMR (400MHz, DMSO) δ10.21 (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, 2.5Hz, 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=12.9Hz, 1H), 1.71 (s, 4H).

[1182] Scheme 22. Synthesis of 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one (Example 125)

[1183]

[1184] Step 1: Synthesis of tert-butyl 4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazine-1-carboxylate

[1185]

[1186] To 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 Cs 2 CO 3 (1417.69 mg, 4.35 mmol, 2.00 equiv) in toluene (5.00 mL) was added Pd 2 (dba) 3 (199.22 mg, 0.22 mmol, 0.10 equiv). 2 The mixture was stirred at 90°C for 3 hours under a 3-h atmosphere. The mixture was diluted with EA (75.00 mL) and washed with H 2 O (3 × 25.00 mL), washed with anhydrous Na 2 SO 4 The mixture was dried. 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-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazine-1-carboxylate (600.00 mg, 65.13%) as a yellow solid. LCMS (ES, m / z): [M+H] + =424

[1187] Step 2: Synthesis of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine

[1188]

[1189] 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) was placed in a 40 mL container. 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 vacuum. This produced 2-(piperazine-1-yl)-N-[4-(trifluoromethyl)phenyl]pyrimidin-4-amine (300.00 mg, 87.31%) as a yellow solid. LCMS (ES, m / z): [M+H] + =324.

[1190] Step 3: Synthesis of 1-[4-(4-{[4-(trifluoromethyl)phenyl]amino}pyrimidin-2-yl)piperazin-1-yl]prop-2-en-1-one

[1191]

[1192] 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) was placed in a 40 mL container. 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 hour. The mixture was diluted with EA (45.00 mL) and washed with H 2 O (3 × 15.00 mL), washed with anhydrous Na 2 SO 4 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% NH 3 .H 2O), 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 obtain 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. LCMS (ES, m / z): [M+H] + =378

[1193] 1 H NMR (300 MHz, DMSO-d 6 ): δ9.7 (s, 1H), 8.05 (s, 1H), 7.83 (d, J = 2.9Hz, 2H), 7.69 (d, J = 3.5Hz, 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).

[1194] Example 126: Synthesis of 1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one

[1195]

[1196] 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 provided as a white solid. (n, ES, m / z): 379.39.

[1197] 1 H NMR (400MHz, DMSO) δ8.90-8.55 (m, 3H), 8.08 (d, J=1.6Hz, 2H), 6.87 (dd, J=16.7, 10.5Hz, 1H), 6.13 (dd, J=16.7, 2.5Hz, 1H), 5.70 (dd, J=10.5, 2. 5Hz, 1H), 4.64 (d, J=13.1Hz, 1H), 4.24 (d, J=13.8Hz, 1H), 3.29-3.12 (m, 2H), 2.78 (t, J=12.7Hz, 1H), 2.01 (d, J=12.8Hz, 2H), 1.88-1.60 (m, 2H).

[1198] 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

[1199]

[1200] Following the general procedure in Scheme 10, using 5-(piperidin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine. 2-Fluoro-1-(4-(4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidin-5-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 397.79.

[1201] 1 H NMR (400MHz, DMSO) δ8.79 (s, 1H), 8.73 (s, 1H), 8.65 (s, 1H), 8.08 (d, J = 1.6Hz, 2H), 5.36-5.10 (m, 2H), 4.47 ( s, 1H), 4.07 (s, 1H), 3.29 (ddd, J=12.6, 8.7, 3.6Hz, 2H), 2.92 (s, 1H), 2.13-1.98 (m, 2H), 1.91-1.69 (m, 2H).

[1202] Example 128: Synthesis of 1-(4-(2-methyl-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1203]

[1204] 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 provided as a white solid. (n, ES, m / z): 392.19.

[1205] 1 H NMR (400MHz, DMSO) δ8.30 (s, 1H), 8.08 (s, 1H), 7.48 (d, J = 8.5Hz, 2H), 6.77 (dd, J = 16.7, 10.4Hz, 1H), 6.69 (d, J = 8.5Hz, 2H), 6.10 (dd, J=16.7, 2.4Hz, 1H), 5.67 (dd, J=10.4, 2.4Hz, 1H), 3.59 (t, J=4.8Hz, 4H), 3.52-3.39 (m, 4H), 2.46 (s, 3H).

[1206] 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

[1207]

[1208] 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 provided as a white solid. (n, ES, m / z): 391.27.

[1209] 1 H NMR (400MHz, DMSO) δ8.78 (d, J=1.7Hz, 1H), 8.60 (d, J=2.2Hz, 1H), 8.06 (d, J=1.6Hz, 2H), 6.95-6.75 (m, 1H), 6.27 (s, 1H), 6.1 6 (d, J=16.4Hz, 1H), 5.72 (d, J=10.5Hz, 1H), 4.38-4.17 (m, 2H), 3.77 (dt, J=12.0, 5.7Hz, 2H), 2.71-2.55 (m, 2H), 2.42 (s, 3H).

[1210] 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

[1211]

[1212] Following the general procedure in Scheme 10, using 2-methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine. 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 provided as a white solid. (n, ES, m / z): 409.19.

[1213] 1H NMR (400MHz, DMSO) δ8.78 (t, J=1.7Hz, 1H), 8.61 (s, 1H), 8.06 (d, J=1.6Hz, 2H), 6.27 (s, 1H ), 5.40-5.11(m, 2H), 4.35-4.11(m, 2H), 3.75(t, J=5.6Hz, 2H), 2.66(s, 2H), 2.43(s, 3H).

[1214] 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

[1215]

[1216] 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 provided as a white solid. (n, ES, m / z): 391.27.

[1217] 1 H NMR (400MHz, DMSO) δ8.78 (d, J=1.7Hz, 1H), 8.60 (d, J=2.2Hz, 1H), 8.06 (d, J=1.6Hz, 2H), 6.95-6.75 (m, 1H), 6.27 (s, 1H), 6.1 6 (d, J=16.4Hz, 1H), 5.72 (d, J=10.5Hz, 1H), 4.38-4.17 (m, 2H), 3.77 (dt, J=12.0, 5.7Hz, 2H), 2.71-2.55 (m, 2H), 2.42 (s, 3H).

[1218] 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

[1219]

[1220] Following the general procedure in Scheme 10, using 2-methyl-5-(piperidin-4-yl)-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyrimidine. 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 provided as a white solid. (n, ES, m / z): 411.2.

[1221] 1 H NMR (400MHz, DMSO) δ8.82-8.58(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=12.3Hz, 2H), 2.88 (s, 1H), 2.43-2.31 (m, 3H), 2.01 (d, J=12.8Hz, 2H), 1.86-1.66 (m, 2H).

[1222] Example 133: Synthesis of 1-(4-(2-methoxy-5-((4-(trifluoromethyl)phenyl)amino)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one

[1223]

[1224] 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 provided as a white solid. (n, ES, m / z): 393.2.

[1225] 1 H NMR (400MHz, DMSO) δ8.80-8.56 (m, 1H), 8.35-8.04 (m, 2H), 7.82-7.68 (m, 2H), 7.36 (d d, J=8.5, 2.8Hz, 1H), 6.91-6.74 (m, 1H), 6.12 (ddd, J=16.7, 5.3, 2.5Hz, 1H), 5.69 (dd d, J=10.4, 4.4, 2.4Hz, 1H), 4.57 (d, J=13.1Hz, 1H), 4.27-4.16 (m, 1H), 3.22-3.06 (m, 2H), 2.84 (t, J=12.4Hz, 1H), 2.42-2.31 (m, 4H), 1.96 (s, 2H), 1.49 (d, J=14.0Hz, 2H).

[1226] Example 134. Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one

[1227]

[1228] Solution 23

[1229] Step 1: Synthesis of tert-butyl 4-(3-bromopyridin-2-yl)piperazine-1-carboxylate

[1230]

[1231] 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 Cs 2 CO 3 A solution of (3.70 g, 11.36 mmol, 2.00 equiv) in DMF (6.00 mL) was placed in a 40 mL container. The mixture was stirred at 80 °C overnight. The mixture was diluted with EA (60.00 mL). The organic layer was washed with H 2 O (3 × 20.00 mL), washed with anhydrous Na 2 SO 4 The residue was purified by column chromatography on silica gel using PE: EA (2: 1) as eluent to give tert-butyl 4-(3-bromopyridin-2-yl)piperazine-1-carboxylate (850.00 mg, 43.71%) as a yellow solid. LCMS (ES, m / z): [M+H] + =342

[1232] Step 2: Synthesis of tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazine-1-carboxylate

[1233]

[1234] In N 2 Under atmosphere at 90°C, 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), Cs 2 CO 3 (1850.37 mg, 4.85 mmol, 2.00 equiv) and Pd 2 (dba) 3A solution of 2-(222.08 mg, 0.24 mmol, 0.1 eq.) in toluene (5.00 mL) was stirred for 3 h. The mixture was diluted with EA (75.00 mL) and washed with H 2 O (3 × 25.00 mL), washed with anhydrous Na 2 SO 4 The mixture was dried. 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 give tert-butyl 4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazine-1-carboxylate (640.00 mg, 62.47%) as a yellow solid. LCMS (ES, m / z): [M+H] - =423

[1235] Step 3: Synthesis of 2-(piperazin-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine

[1236]

[1237] 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) was placed in a 40 mL container. 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 vacuum. This produced 2-(piperazine-1-yl)-N-[4-(trifluoromethyl)phenyl]pyridin-3-amine (300.00 mg, 87.37%) as a yellow solid. LCMS (ES, m / z): [M+H] + =323

[1238] Step 4: Synthesis of 1-[4-(3-{[4-(trifluoromethyl)phenyl]amino}pyridin-2-yl)piperazin-1-yl]prop-2-en-1-one

[1239]

[1240] 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 hour. After the reaction was complete, it was diluted with EA (45.00 mL) and washed with H 2 O (3 × 15.00 mL), washed with anhydrous Na 2 SO 4 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% NH 3 .H 2 O), 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 obtain 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. LCMS (ES, m / z): [M+H] + =377.

[1241] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.15 (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).

[1242] 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

[1243]

[1244] Following the general procedure in Scheme 10, using 2-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-3-amine, 2-fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (N, ES, m / z): 396.1.

[1245] 1 H NMR (400MHz, DMSO) δ8.53 (s, 1H), 8.31 (d, J=2.7Hz, 1H), 8.09 (dd, J=4.8, 1.6Hz, 1H), 7.71-7.56 (m, 2H), 7.24 (dd , J=8.6, 2.7Hz, 1H), 7.04 (dd, J=7.8, 4.7Hz, 1H), 5.31-5.05 (m, 2H), 3.47 (t, J=5.0Hz, 4H), 3.19 (d, J=5.3Hz, 4H).

[1246] Example 136: Synthesis of 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1247]

[1248] 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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 409.1.

[1249] 1 H NMR (400MHz, DMSO) δ8.52 (d, J=2.8Hz, 1H), 8.26-8.16 (m, 2H), 8.09 (dd, J=4.9, 1.8Hz, 1H), 7.50 (dd, J=7.4, 1.9Hz, 1H), 7.22 (d, J=8.8Hz, 1H ), 6.91 (dd, J=7.4, 4.9Hz, 1H), 5.91 (s, 1H), 5.41-5.13 (m, 2H), 4.31-4.08 (m, 2H), 3.76 (d, J=5.7Hz, 2H), 3.41 (d, J=1.0Hz, 2H), 2.47 (s, 2H).

[1250] Example 137: Synthesis of 2-fluoro-1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3′,6′-dihydro-[2,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1251]

[1252] 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′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 394.1.

[1253] 1 H NMR (400MHz, DMSO) δ8.54 (dd, J=13.7, 3.8Hz, 2H), 7.89 (d, J=8.8Hz, 1H), 7.71 (dd, J=15.8, 8.3Hz, 1H), 7.53 (s, 1 H), 7.43 (dd, J=8.3, 4.5Hz, 1H), 6.46 (s, 1H), 5.36-5.06 (m, 2H), 4.10 (s, 2H), 3.63 (t, J=5.7Hz, 2H), 2.68 (s, 2H).

[1254] Example 138: Synthesis of 1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one

[1255]

[1256] 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 provided as a white solid. (n, ES, m / z): 378.1.

[1257] 1H NMR (400MHz, DMSO) δ8.63 (d, J=2.8Hz, 1H), 8.47 (dd, J=4.6, 1.4Hz, 1H), 7.92 (d, J=8.7Hz, 1H ), 7.58 (td, J=9.1, 2.1Hz, 2H), 7.37 (dd, J=8.2, 4.6Hz, 1H), 6.84 (dd, J=16.7, 10.4Hz, 1H), 6. 11 (dd, J=16.7, 2.5Hz, 1H), 5.67 (dd, J=10.5, 2.4Hz, 1H), 4.52 (d, J=13.2Hz, 1H), 4.14 (d, J=1 3.7Hz, 1H), 3.32-3.27 (m, 1H), 3.13 (d, J=15.4Hz, 1H), 2.78-2.68 (m, 1H), 1.86-1.64 (m, 4H).

[1258] 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

[1259]

[1260] Following the general procedure in Scheme 10, using 2-(piperidin-4-yl)-3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine. 2-Fluoro-1-(4-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-2-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 396.1.

[1261] 1 H NMR (400MHz, DMSO) δ8.63 (d, J=2.8Hz, 1H), 8.55-8.40 (m, 1H), 7.92 (d, J=8.8Hz, 1H), 7.62-7.49 (m, 2H), 7.37 (dd, J =8.2, 4.6Hz, 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).

[1262] Example 140: Synthesis of 1-(4-(3-(5-(trifluoromethyl)methylpyridinyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1263]

[1264] 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 provided as a white solid. (N, ES, m / z): 391.27.

[1265] 1 H NMR (400MHz, DMSO) δ9.08 (d, J=2.2Hz, 1H), 8.51 (dd, J=8.3, 2.3Hz, 1H), 8.40 (dd, J=4.7, 1.9Hz, 1H), 8.22 (d, J=8.2Hz, 1H), 7.85 (dd, J=7.6, 1.9Hz, 1H), 6.99 (dd, J=7.6, 4.7Hz, 1H), 6.72 (dd, J=16.7, 10.4Hz, 1H), 6.09 (dd, J=16. 7, 2.4Hz, 1H), 5.67 (dd, J=10.4, 2.4Hz, 1H), 3.39 (s, 4H), 3.22-3.15 (m, 4H).

[1266] Example 141: Synthesis of 1-(4-(3-(6-(trifluoromethyl)nicotinoyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1267]

[1268] 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 provided as a white solid. (N, ES, m / z): 391.00.

[1269] 1 H NMR (400MHz, DMSO) δ9.06 (d, J=2.1Hz, 1H), 8.46 (dd, J=4.7, 1.9Hz, 1H), 8.39 (dd, J=8.2, 2.1Hz, 1H), 8.10 (d, J=8.1Hz, 1H), 7.88 (dd, J=7.6, 1.9Hz, 1H), 7.05 (dd, J=7.6, 4.7Hz, 1H), 6.72 (dd, J=16.7, 10.5Hz, 1H), 6.09 (dd, J=16. 7, 2.3Hz, 1H), 5.67 (dd, J=10.4, 2.4Hz, 1H), 3.34-3.26 (m, 4H), 3.21 (s, 4H).

[1270] 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

[1271]

[1272] 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 provided as a white solid. (n, ES, m / z): 393.29.

[1273] 1 H NMR (400MHz, DMSO) δ8.78 (s, 1H), 8.28 (dd, J=4.8, 1.9Hz, 1H), 7.98 (d, J=8.1Hz, 1H), 7.91-7.78 (m, 2H), 7.19 (dd, J=7.6, 4.7Hz, 1H), 6.85 ( dd, J=16.7, 10.4Hz, 1H), 6.38 (s, 1H), 6.27-6.09 (m, 2H), 5.71 (dd, J=10.5, 2.4Hz, 1H), 3.86-3.54 (m, 4H), 3.20-3.06 (m, 2H), 2.80 (s, 2H).

[1274] Example 143. Scheme 24. Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one

[1275]

[1276] Solution 24

[1277] Step 1: Synthesis of tert-butyl 4-(2-aminopyridin-3-yl)piperazine-1-carboxylate

[1278]

[1279] Under nitrogen atmosphere at room temperature, 3-bromopyridin-2-amine (1.50 g, 8.67 mmol, 1.00 equiv), Pd 2 (dba) 3A solution of (0.32g, 0.35mmol, 0.04 equivalent) and Ruphos (0.16g, 0.35mmol, 0.04 equivalent) in THF (40.00mL) is placed in a three-necked flask. Piperazine-1-carboxylic acid tert-butyl ester (2.42g, 13.01mmol, 1.50 equivalents) and LiHMDS (21.67mL, 21.68mmol, 2.50 equivalents) are added to the reaction mixture. The resulting mixture is stirred at room temperature for 12 hours under a nitrogen atmosphere. The desired product is detected by LCMS. The mixture is purified by adding saturated NH 4 The solution was quenched with Cl solution (150.00 mL) and then extracted with EA (3×100.00 mL). The combined organic layers were washed with brine (2×100.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting with DCM:EA (1:1) to give tert-butyl 4-(2-aminopyridin-3-yl)piperazine-1-carboxylate (0.71 g, 29.42%) as a yellow solid. LCMS (positive, ES, m / z): 279.2

[1280] Step 2: Synthesis of tert-butyl 4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazine-1-carboxylate

[1281]

[1282] To 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), Cs 2 CO 3 To a stirred solution of Pd(R) (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 2 (dba) 3 (0.02 g, 0.025 mmol, 0.01 equiv). The reaction mixture was stirred at 90 °C for 12 h under nitrogen atmosphere. The desired product was detected by LCMS. The mixture was purified by H 2 O (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 Na 2 SO 4Drying. After filtration, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluting 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. LCMS (negative, ES, m / z): 421.2

[1283] Step 3: Synthesis of 3-(piperazin-1-yl)-N-(4-(trifluoromethyl)phenyl)pyridin-2-amine

[1284]

[1285] To a stirred solution of 2-[4-(2-oxo-1H-pyridine-3-amido)piperidin-1-yl]ethyl 7-[(3R)-3-[(tert-butyloxycarbonyl)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 give 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. LCMS: (negative, ES, m / z): 321.1.

[1286] Step 4: Synthesis of 1-[4-(2-{[4-(trifluoromethyl)phenyl]amino}pyridin-3-yl)piperazin-1-yl]prop-2-en-1-one

[1287]

[1288] 3-(Piperazine-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 to a 10 ml bottle at 0 °C. Acryloyl chloride (0.09 g, 1.02 mmol, 1.10 equiv) was added to the above mixture. The resulting mixture was stirred at room temperature for an additional 2 hours. The reaction was monitored by LCMS. The resulting mixture was washed with 50.00 mL of H 2O quenched and extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine (100.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by (column: Welch Xtimate C18 ExRS, 250 mm, 10 μm; mobile phase A: water (0.05% NH 3 .H 2 O), mobile phase B: ACN; flow rate: 90 mL / min; gradient: 90% B to 90% B, 90% B in 10 minutes; wavelength: 254 nm; RT1 (min): 7; number of runs: 5) to obtain 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. LCMS (positive, ES, m / z): 377.2.

[1289] 1 H NMR (400 MHz, DMSO-d 6 ): δ8.43 (s, 1H), 8.03-7.99 (m, 3H), 7.62 (d, J = 8.8Hz, 2H), 7.50 (d, J = 7.6Hz, 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).

[1290] 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

[1291]

[1292] Following the general procedure in Scheme 10, using 3-(piperazin-1-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine, 2-fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (N, ES, m / z): 396.42.

[1293] 1H NMR (400MHz, DMSO) δ9.07 (d, J=8.1Hz, 1H), 8.69-8.45 (m, 2H), 8.02 (d, J=8.5Hz, 1H), 7.80 (s, 1 H), 7.55 (s, 1H), 6.96 (d, J=8.6Hz, 1H), 5.40-5.12 (m, 2H), 3.80 (s, 4H), 2.91 (d, J=9.4Hz, 4H).

[1294] Example 145: Synthesis of 1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1295]

[1296] 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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 375.1.

[1297] 1 H NMR (400MHz, DMSO) δ8.91 (d, J=2.5Hz, 1H), 8.55 (d, J=7.8Hz, 1H), 8.28 (d, J=8.9Hz , 1H), 8.19 (dd, J=4.9, 1.8Hz, 1H), 7.76 (d, J=8.7Hz, 1H), 7.57 (d, J=7.5Hz, 1H), 7.0 1 (dd, J=7.5, 4.9Hz, 1H), 6.94-6.77 (m, 1H), 6.24-6.11 (m, 1H), 5.95 (d, J=10.5Hz, 1 H), 5.82-5.69 (m, 1H), 4.38-4.10 (m, 2H), 3.80 (d, J=6.1Hz, 2H), 2.46-2.33 (m, 2H).

[1298] Example 146: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1299]

[1300] Following the general procedure in Scheme 10, using N-(6-(trifluoromethyl)pyridin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridinyl]-2-amine. 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridinyl]-1′(2′H)-yl)prop-2-en-1-one was provided as a white solid. (N, ES, m / z): 393.1.

[1301] 1 H NMR (400MHz, DMSO) δ8.91 (d, J=2.6Hz, 1H), 8.56 (s, 1H), 8.32-8.13 (m, 2H), 7.76 (d, J=8.7Hz, 1H), 7.58 (dd, J=7.5, 1.9H z, 1H), 7.01 (dd, J=7.5, 4.9Hz, 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).

[1302] Example 147: Synthesis of 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1303]

[1304] 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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 391.2.

[1305] 1 H NMR (400MHz, DMSO) δ8.55 (d, J=2.8Hz, 1H), 8.21 (dd, J=9.3, 3.7Hz, 2H), 8.10 (dd, J=4.8, 1.9Hz, 1H), 7.57-7.43 (m, 1H), 7.23 (d, J=8.8Hz, 1H) , 7.00-6.75 (m, 2H), 6.24-6.08 (m, 1H), 5.93 (d, J=9.4Hz, 1H), 5.81-5. 67 (m, 1H), 4.44-4.12 (m, 2H), 3.81 (d, J=6.0Hz, 2H), 2.47-2.30 (m, 2H).

[1306] Example 148: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1307]

[1308] Following the general procedure in Scheme 10, using N-(6-(trifluoromethoxy)pyridin-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridinyl]-2-amine. 2-Fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3′,6′-dihydro-[3,4′-bipyridinyl]-1′(2′H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 409.1.

[1309] 1 H NMR (400MHz, DMSO) δ8.52 (d, J=2.8Hz, 1H), 8.26-8.16 (m, 2H), 8.09 (dd, J=4.9, 1.8Hz, 1H), 7.50 (dd, J=7.4, 1.9Hz, 1H), 7.22 (d, J=8.8Hz, 1H ), 6.91 (dd, J=7.4, 4.9Hz, 1H), 5.91 (s, 1H), 5.41-5.13 (m, 2H), 4.31-4.08 (m, 2H), 3.76 (d, J=5.7Hz, 2H), 3.41 (d, J=1.0Hz, 2H), 2.47 (s, 2H).

[1310] Example 149: Synthesis of 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one

[1311]

[1312] 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 provided as a white solid. (n, ES, m / z): 377.44.

[1313] 1H NMR (400MHz, DMSO) δ8.91 (d, J=2.5Hz, 1H), 8.72 (s, 1H), 8.26 (dd, J=8.9, 2.5Hz, 1H), 8.11 (dd, J=4.8, 1.7 Hz, 1H), 7.77 (d, J=8.7Hz, 1H), 7.65 (dd, J=7.7, 1.8Hz, 1H), 6.98 (dd, J=7.6, 4.8Hz, 1H), 6.87 (dd, J=16.7, 10.4Hz, 1H), 6.13 (dd, J=16.7, 2.5Hz, 1H), 5.70 (dd, J=10.4, 2.5Hz, 1H), 4.64 (d, J=13.0Hz, 1H), 4.23 (d, J=13.6Hz, 1H), 3.25 (q, J=12.7Hz, 2H), 2.79 (t, J=12.7Hz, 1H), 1.87 (d, J=12.9Hz, 2H), 1.64-1.40 (m, 2H).

[1314] 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

[1315]

[1316] Following the general procedure in Scheme 10, using N3-(piperidin-4-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2-amine. 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (N, ES, m / z): 395.44.

[1317] 1 H NMR (400MHz, DMSO) δ8.90 (d, J=2.5Hz, 1H), 8.73 (s, 1H), 8.25 (dd, J=8.5, 2.5Hz , 1H), 8.12 (dd, J=4.8, 1.8Hz, 1H), 7.77 (d, J=8.7Hz, 1H), 7.68 (dd, J=7.7, 1.8Hz , 1H), 6.99 (dd, J=7.6, 4.8Hz, 1H), 5.35-5.12 (m, 2H), 4.48 (s, 1H), 4.07 (s, 1H), 3.28 (d, J=12.0Hz, 2H), 3.01-2.82 (m, 1H), 1.90 (d, J=13.0Hz, 2H), 1.58 (s, 2H).

[1318] Example 151: Synthesis of 1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one

[1319]

[1320] 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 provided as a white solid. (n, ES, m / z): 393.1.

[1321] 1 H NMR (400MHz, DMSO) δ 8.59-8.35 (m, 2H), 8.19 (s, 1H), 8.02 (d, J = 9.5Hz, 1H), 7.57 (d, J = 6.9Hz, 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=12.3Hz, 1H), 1.87 (s, 2H), 1.49 (s, 2H).

[1322] 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

[1323]

[1324] Following the general procedure in Scheme 10, using N3-(piperidin-4-yl)-N-(6-(trifluoromethoxy)pyridin-3-yl)pyridin-2-amine. 2-Fluoro-1-(4-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (N, ES, m / z): 411.1.

[1325] 1H NMR (400MHz, DMSO) δ8.54 (d, J=2.8Hz, 1H), 8.43 (s, 1H), 8.19 (dd, J=8.9, 2.8Hz, 1H ), 8.03 (dd, J=4.8, 1.7Hz, 1H), 7.60 (dd, J=7.5, 1.8Hz, 1H), 7.25 (d, J=8.8Hz, 1H), 6 .89 (dd, J=7.6, 4.8Hz, 1H), 5.32-5.11 (m, 2H), 4.47 (s, 1H), 4.06 (s, 1H), 3.22 (d, J =11.9Hz, 1H), 2.91 (s, 1H), 2.72-2.57 (m, 1H), 1.91 (d, J = 12.9Hz, 2H), 1.57 (s, 2H).

[1326] Example 153: Synthesis of 1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1327]

[1328] 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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 376.2.

[1329] 1 H NMR (400MHz, DMSO) δ8.67 (d, J=2.6Hz, 1H), 8.08 (dd, J=4.8, 1.8Hz, 1H), 7.99 (d, J=8.6Hz, 1H), 7.89 (dd, J=15.5, 8.0Hz, 2H), 7.27 (dd, J=7 .5, 4.8Hz, 1H), 6.95-6.76 (m, 1H), 6.21-6.07 (m, 2H), 5.71 (d, J=8.1Hz, 1H), 4.35-4.15 (m, 2H), 3.75 (dt, J=11.5, 5.9Hz, 2H), 2.62 (s, 2H).

[1330] Example 154: Synthesis of 2-fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1331]

[1332] 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′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 394.2.

[1333] 1 H NMR (400MHz, DMSO) δ8.67 (d,.J=2.6Hz, 1H), 8.09 (dd, J=4.8, 1.8Hz, 1H), 8.00 (d, J=8.6Hz, 1H), 7.89 (ddd, J=14.4, 8.1, 2.3Hz , 2H), 7.27 (dd, J=7.5, 4.8Hz, 1H), 6.18 (s, 1H), 5.33 (d, J=16.9Hz, 2H), 4.34-4.13 (m, 2H), 3.73 (t, J=5.6Hz, 2H), 2.65 (s, 2H).

[1334] Example 155: Synthesis of 1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one

[1335]

[1336] 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 provided as a white solid. (n, ES, m / z): 378.1.

[1337] 1H NMR (400MHz, DMSO) δ8.67 (d, J=2.6Hz, 1H), 8.01 (dd, J=6.5, 4.2Hz, 2H), 7.93-7.79 (m, 2H ), 7.21 (dd, J=7.5, 4.8Hz, 1H), 6.86 (dd, J=16.7, 10.5Hz, 1H), 6.12 (dd, J=16.7, 2.5Hz, 1 H), 5.69 (dd, J=10.4, 2.4Hz, 1H), 4.63 (d, J=13.1Hz, 1H), 4.22 (d, J=13.7Hz, 1H), 3.24 (d , J=15.0Hz, 2H), 2.77 (t, J=12.8Hz, 1H), 1.95 (d, J=12.9Hz, 2H), 1.63 (t, J=14.4Hz, 2H).

[1338] 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

[1339]

[1340] Following the general procedure in Scheme 10, using 3-(piperidin-4-yl)-2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridine. 2-Fluoro-1-(4-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 396.2.

[1341] 1 H NMR (400MHz, DMSO) δ8.67 (d, J=2.6Hz, 1H), 8.08-7.97 (m, 2H), 7.89 (ddd, J=9.6, 8,0, 2.3Hz, 2H), 7.22 (dd, J=7.5.4.9Hz , 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=13.0Hz, 2H), 1.69 (s, 2H).

[1342] Example 157: Synthesis of 1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1343]

[1344] 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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 377.36.

[1345] 1 H NMR (400MHz, DMSO) δ9.09 (s, 2H), 8.09 (dd, J=4.9, 1.8Hz, 1H), 7.90 (d, J=7.4Hz, 1H), 7.30 (dd, J=7.5, 4.8Hz, 1H), 6.95-6.74 (m, 1H), 6.26-6.11 (m, 2H), 5.72 (d, J=10.2Hz, 1H), 4.39-4.14 (m, 2H), 3.77 (dt, J=11.1, 5.7Hz, 2H), 2.66 (d, J=15.4Hz, 2H).

[1346] Example 158: Synthesis of 2-fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3′,6′-dihydro-[3,4′-bipyridyl]-1′(2′H)-yl)prop-2-en-1-one

[1347]

[1348] 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′-bipyridine]-1′(2′H)-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 395.36.

[1349] 1 H NMR (400MHz, DMSO) δ9.09 (s, 2H), 8.10 (dd, J=4.9, 1.8Hz, 1H), 7.91 (dd, J=7.5, 1.9Hz, 1H), 7.31 (dd, J= 7.5, 4.9Hz, 1H), 6.22 (s, 1H), 5.42-5.14 (m, 2H), 4.37-4.11 (m, 2H), 3.75 (t, J=5.7Hz, 2H), 2.68 (s, 2H).

[1350] Example 159: Synthesis of 1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one

[1351]

[1352] 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 provided as a white solid. (n, ES, m / z): 379.39.

[1353] 1 H NMR (400MHz, DMSO) δ9.09 (s, 2H), 8.03 (dd, J=4.8, 1.8Hz, 1H), 7.89 (dd, J=7.5, 1.8Hz, 1H), 7.25 (dd, J=7.5, 4.8Hz, 1H), 6.87 (dd, J=16.7, 10.4Hz, 1H), 6.13 (dd, J=16.7, 2.5 Hz, 1H), 5.70 (dd, J=10.5, 2.5Hz, 1H), 4.64 (d, J=13.0Hz, 1H), 4.23 (d, J=13.7Hz, 1H), 3.33-3.15 (m, 2H), 2.77 (t, J=12.7Hz, 1H), 1.97 (d, J=12.7Hz, 2H), 1.71-1.48 (m, 2H).

[1354] 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

[1355]

[1356] Following the general procedure in Scheme 10, using 5-((3-(piperidin-4-yl)pyridin-2-yl)oxy)-2-(trifluoromethyl)pyrimidine. 2-Fluoro-1-(4-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)pyridin-3-yl)piperidin-1-yl)prop-2-en-1-one was provided as a white solid. (n, ES, m / z): 397.39.

[1357] 1H NMR (400MHz, DMSO) δ9.09 (s, 2H), 8.03 (dd, J=4.8, 1.8Hz, 1H), 7.92 (d, J=7.4Hz, 1H), 7.26 (dd, J=7.5, 4.8Hz, 1H), 5. 34-5.11 (m, 2H), 4.47 (s, 1H), 4.06 (s, 1H), 3.30 (d, J=14.6Hz, 2H), 2.90 (s, 1H), 2.01 (d, J=13.0Hz, 2H), 1.70 (s, 2H).

[1358] Example 161: Synthesis of 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one

[1359]

[1360] Following the general procedure in Scheme 18, using 2-chloronicotinic acid in step 1 and 4,4-difluoropiperidine in step 2, 1-(4-(3-(4,4-difluoropiperidine-1-carbonyl)pyridin-2-yl)piperazin-1-yl)prop-2-en-1-one was provided as a white solid. (normal, ES, m / z): 365.32.

[1361] 1 H NMR (400MHz, DMSO) δ8.28 (dd, J=4.8, 1.9Hz, 1H), 7.62 (dd, J=7.4, 1.9Hz, 1H), 6.95 (dd, J=7.4, 4.8Hz, 1H), 6.83 (dd, J=16.7, 10.5Hz, 1H) , 6.15 (dd, J=16.7, 2.4Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz, 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).

[1362] Example 162: Synthesis of 1-(4-(2-((4-(trifluoromethyl)phenyl)amino)phenyl)piperazin-1-yl)prop-2-en-1-one

[1363]

[1364] 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 provided as a white solid. (n, ES, m / z): 398.28.

[1365] 1 H NMR (400MHz, DMSO) δ7.94 (s, 1H), 7.50 (d, J=8.5Hz, 2H), 7.33-7.21 (m, 1H), 7.16-6.95 (m, 5H), 6.82 (dd, J=16 .6, 10.4Hz, 1H), 6.13 (dd, J=16.7, 2.4Hz, 1H), 5.69 (dd, J=10.4, 2.4Hz, 1H), 3.60 (s, 4H), 2.92-2.76 (m, 4H).

[1366] 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

[1367]

[1368] Solution 25

[1369] 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

[1370]

[1371] A solution / mixture of 2H-pyrazole-3-carboxaldehyde (6 g, 62.44 mmol, 1 eq.) and tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (29.65 g, 106.15 mmol, 1.7 eq.) and NaH (2.40 g, 99.91 mmol, 1.6 eq.) in DMF (50 mL) was stirred at 80 °C under a nitrogen atmosphere for 8 hours. 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 washed with anhydrous Na 2 SO 4 In 4- (5-formyl-1H-pyrazole-1-yl) piperidine-1-carboxylic acid tert-butyl ester and 4- (3-formyl-1H-pyrazole-1-yl) piperidine-1-carboxylic acid tert-butyl ester as yellow solid (9g) .

[1372] 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

[1373]

[1374] A solution of 1-bromo-4-(trifluoromethyl)benzene (18.16 g, 80.69 mmol, 5 equivalents) and chloro(isopropyl)magnesium (50 mL) in THF (200 mL) was stirred for 40 minutes at 0°C under a nitrogen atmosphere. A mixture of 3&3A (9 g, 16.14 mmol, 1 equivalent) was added dropwise to the above Grignard reagent solution. The solution was stirred at 0°C for 2 hours 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 purified by anhydrous Na 2 SO 4 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 (0.1% NH 3 .H 2 O), gradient 10% to 50% in 20 minutes; detector, UV 254nm, 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 as a yellow solid (4g).

[1375] 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

[1376]

[1377] A mixture of 4&4A (4 g, 9.40 mmol, 1 eq), PCC (4.05 g, 18.80 mmol, 2 eq) and DCM (40 mL, 629.22 mmol, 66.93 eq) was added to a 100 mL round bottom flask at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with water (100 mL). The resulting mixture was washed with CH 2 Cl2 The combined organic layers were washed with water (1×100 mL) and purified by anhydrous Na 2 SO 4 The residue was purified by silica gel column chromatography and eluted with PE / EA (1:1) to give a crude product. The crude product was further purified by reverse phase rapid chromatography under the following conditions: (column, C18 silica gel; mobile phase, MeCN (0.1% NH 3 .H 2 O), gradient 20% to 70% in 20 minutes; detector, UV 254nm) to give tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (110mg) and tert-butyl 4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (230mg).

[1378] Step 4: Synthesis of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone

[1379]

[1380] At room temperature, tert-butyl 4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (110 mg, 0.26 mmol, 1 eq), HCl (gas) in 1,4-dioxane (1 mL, 32.91 mmol, 126.70 eq) and DCM (3 mL, 47.19 mmol, 181.66 eq) were added to a 40 mL vial. 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.

[1381] Step 5: Synthesis of 1-(4-(3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one (Example 163)

[1382]

[1383] A solution of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone (100 mg, 0.31 mmol, 1 eq) in DCM was treated with TEA (93.89 mg, 0.93 mmol, 3 eq) at 0°C under nitrogen atmosphere for 5 minutes, followed by the dropwise addition of acryloyl chloride (27.99 mg, 0.31 mmol, 1 eq) at 0°C. The resulting mixture was stirred at room temperature for 1 hour. The resulting mixture was diluted with water (10 mL). The resulting mixture was washed with CH 2 Cl 2 The combined organic layers were washed with water (2×10 mL) and purified by anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% NH 3 .H 2 O), gradient 10% to 60% in 20 minutes; detector, 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.

[1384] 1 H NMR (400 MHz, DMSO-d 6 )δ8.32 (d, J=8.1Hz, 2H), 8.10 (d, J=2.5Hz, 1H), 7.93 (d, J=8.1Hz, 2H), 6.98 (d, J=2.5Hz, 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).

[1385] Step 4: Synthesis of (1-(piperidin-4-yl)-1H-pyrazol-5-yl)(4-(trifluoromethyl)phenyl)methanone

[1386]

[1387] At room temperature, tert-butyl 4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (230 mg, 0.54 mmol, 1 eq.), HCl (gas) in 1,4-dioxane (3 mL, 98.74 mmol, 181.78 eq.) and DCM (9 mL, 141.57 mmol, 260.64 eq.) were added to a 40 mL vial. 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.

[1388] Step 5: Synthesis of 1-(4-(5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one

[1389]

[1390] A solution of (1-(piperidin-4-yl)-1H-pyrazol-3-yl)(4-(trifluoromethyl)phenyl)methanone (220 mg, 0.68 mmol, 1 eq) in DCM (5 mL) was treated with TEA (206.57 mg, 2.04 mmol, 3 eq) at 0°C for 5 min, followed by the dropwise addition of acryloyl chloride (61.59 mg, 0.68 mmol, 1 eq) 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 washed with CH 2 Cl 2 (2 × 20 mL) and extracted with anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase rapid chromatography under the following conditions (column, C18 silica gel; mobile phase, MeCN (0.1% NH 3 .H 2 O), gradient 10% to 60% in 20 minutes; detector, 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.

[1391] 1 H NMR (400 MHz, DMSO-d 6)δ8.05 (d, J=8.1Hz, 2H), 7.96 (d, J=8.2Hz, 2H), 7.68 (d, J=2.0Hz, 1H), 6.87 (m, 1H), 6.79 (s, 1H), 6.14 (m, 1H), 5.71 (m, 1H), 5.2 3-5.13 (m, 1H), 4.57 (d, J=13.2Hz, 1H), 4.22 (d, J=13.8Hz, 1H), 3.23 (m, 1H), 2.83 (m, 1H), 2.15-2.04 (m, 2H), 2.00-1.86 (m, 2H).

[1392] Example 165: Synthesis of 1-(4-(5-methyl-3-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one

[1393]

[1394] 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 provided as a white solid. (normal, ES, m / z): 392.34.

[1395] 1 H NMR (400MHz, DMSO) δ8.30 (d, J=8.0Hz, 2H), 7.92 (d, J=8.0Hz, 2H), 6.91-6.80 (m, 1H), 6.75 (d, J=1.3Hz, 1H), 6.13 (ddd, J=16.8, 2.5, 1.1Hz, 1H), 5.70 (ddd, J=10.5 , 2.5, 1.0Hz, 1H), 4.60 (q, J=14.4Hz, 2H), 4.20 (d, J=13.8Hz, 1H), 3.26 (d, J=11. 9Hz, 1H), 2.87 (t, J=12.7Hz, 1H), 2.02 (d, J=12.6Hz, 2H), 1.87 (d, J=13.9Hz, 2H).

[1396] Example 166: Synthesis of 1-(4-(3-methyl-5-(4-(trifluoromethyl)benzoyl)-1H-pyrazol-1-yl)piperidin-1-yl)prop-2-en-1-one

[1397]

[1398] 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 provided as a white solid. (normal, ES, m / z): 392.38.

[1399] 1 H NMR (400MHz, DMSO) δ8.04 (d, J=8.1Hz, 2H), 7.96 (d, J=8.2Hz, 2H), 6.88 (dd, J=16. 7, 10.4Hz, 1H), 6.57 (s, 1H), 6.14 (dd, J=16.7, 2.5Hz, 1H), 5.71 (dd, J=10.4, 2.4Hz , 1H), 5.12 (td, J=11.2, 5.5Hz, 1H), 4.57 (d, J=13.2Hz, 1H), 4.21 (d, J=13.9Hz, 1H ), 3.23 (t, J=12.8Hz, 1H), 2.81 (t, J=12.9Hz, 1H), 2.23 (s, 3H), 2.08-1.73 (m, 4H).

[1400] Example 167: Synthesis of 4-(dimethylamino)-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-en-1-one

[1401]

[1402] Following the general procedure in Scheme 10, (E)-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 provided as a white solid. (n, ES, m / z): 435.32.

[1403] 1 H NMR (400MHz, DMSO) δ8.63 (d, J=2.4Hz, 1H), 8.02-7.89 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d, J=8.6Hz, 2H ), 6.82 (d, J=15.2Hz, 1H), 6.65 (dt, J=15.0, 6.6Hz, 1H), 3.79 (s, 4H), 3.52 (s, 6H), 3.15 (d, J=6.1Hz, 6H).

[1404] Example 168: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one

[1405]

[1406] 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 provided as a white solid. (normal, ES, m / z): 366.2.

[1407] 1 H NMR (400MHz, DMSO) δ8.61 (s, 1H), 7.94-7.87 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7 .65 (d, J=8.6Hz, 2H), 3.68 (q, J=4.9Hz, 4H), 3.21-3.03 (m, 4H), 2.05 (s, 3H).

[1408] Example 169: Synthesis of 2-chloro-2-fluoro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one

[1409]

[1410] 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 provided as a white solid. (N, ES, m / z): 418.21.

[1411] 1 H NMR (400MHz, DMSO) δ8.63 (s, 1H), 7.98-7.87 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d , J=8.6Hz, 2H), 7.44-7.27 (m, 1H), 3.87-3.61 (m, 4H), 3.18 (dt, J=15.4, 4.3Hz, 4H).

[1412] Example 170: Synthesis of 2-chloro-1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)ethan-1-one

[1413]

[1414] 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 provided as a white solid. (N, ES, m / z): 400.26.

[1415] 1 H NMR (400MHz, DMSO) δ 8.63 (s, 1H), 7.97-7.86 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 4.45 (s, 2H), 3.82-3.65 (m, 4H), 3.26-3.05 (m, 4H).

[1416] Example 171: Synthesis of 3-oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propionitrile

[1417]

[1418] Following the general procedure in Scheme 10, 2-cyanoacetic acid was used. 3-Oxo-3-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)propanenitrile was provided as a white solid. (n, ES, m / z): 391.27.

[1419] 1 H NMR (400MHz, DMSO) δ8.63 (s, 1H), 7.93 (s, 1H), 7.91-7.88 (m, 2H), 7.84 (d, J=2.8Hz, 1H), 7.65 ( d, J=8.5Hz, 2H), 4.12 (s, 2H), 3.71 (t, J=5.3Hz, 2H), 3.59 (d, J=5.6Hz, 2H), 3.23-3.07 (m, 4H).

[1420] Example 172: Synthesis of oxiran-2-yl(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)methanone

[1421]

[1422] 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 provided as a white solid. (N, ES, m / z): 394.28.

[1423] 1H NMR (400MHz, DMSO) δ8.64 (s, 1H), 7.98-7.88 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d, J=8.6Hz, 2H), 3.97-3.8 0 (m, 3H), 3.71 (d, J=6.6Hz, 2H), 3.26-3.08 (m, 4H), 2.93 (dd, J=6.3, 4.3Hz, 1H), 2.81 (dd, J=6.3, 2.6Hz, 1H).

[1424] Example 173. Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one

[1425]

[1426] Scheme 26

[1427] Step 1: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)-3-(trimethylsilyl)prop-2-yn-1-one

[1428]

[1429] 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)propioyl chloride (56 mmL, 0.37 mmol, 1.20 equiv). The resulting mixture was stirred at 0°C for another 0.5 h. The reaction was monitored by LCMS. To the resulting mixture was added 20.00 mL of H 2 O, and the resulting mixture was extracted with ethyl acetate (20.00 mL×3). The combined organic layers were washed with brine (50.00 mL) and dried over anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification.

[1430] Step 2: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)prop-2-yn-1-one

[1431]

[1432] To a stirred solution 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 in THF (844 mmL, 0.84 mmol, 3.5 equiv) 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 eluting with DCM:EA (4:1) to give 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. (N, ES, m / z): 376.22.

[1433] 1 H NMR (400MHz, DMSO) δ8.61 (s, 1H), 7.96-7.89 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d, J=8.5Hz, 2H), 4.6 1 (s, 1H), 4.00-3.88 (m, 2H), 3.75 (dd, J=6.3, 4.0Hz, 2H), 3.22 (t, J=5.2Hz, 2H), 3.14 (t, J=5.2Hz, 2H).

[1434] Example 174: Synthesis of 1-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)but-2-yn-1-one

[1435]

[1436] 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 provided as a white solid. (n, ES, m / z): 390.28.

[1437] 1 H NMR (400MHz, DMSO) δ8.61 (s, 1H), 7.99-7.88 (m, 3H), 7.85 (d, J=2.8Hz, 1H), 7.65 (d, J=8 .6Hz, 2H), 3.92 (t, J=5.1Hz, 2H), 3.73 (t, J=5.1Hz, 2H), 3.27-3.08 (m, 4H), 2.04 (s, 3H).

[1438] Example 175: Synthesis of 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile

[1439]

[1440] Following the general procedure in Scheme 2, using 2-bromoacetonitrile, 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazin-1-yl)acetonitrile was provided as a white solid. (normal, ES, m / z): 363.26.

[1441] 1 H NMR (400MHz, DMSO) δ 8.59 (s, 1H), 7.93-7.78 (m, 4H), 7.63 (d, J = 8.5Hz, 2H), 3.81 (s, 2H), 3.21 (s, 4H), 2.73 (t, J = 4.8Hz, 4H). ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in Ring A is a 6-membered aryl group or a 6-membered heteroaryl group 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- to 10-membered heterocyclic ring containing 1 or 2 N ring members and which is optionally fused and optionally has 1 to 3 unsaturated bonds; L is selected from -NH-, -O-, -CH2-, -S-, -C(O)-, -CHOH-, and a bond; in In R 1 When bound to a carbon ring member, R 1 Selected from CN, halogen, –[CH2] 0,1 NHC(O)(C1-C6 alkyl), –[CH2] 0,1 NHC(O)(C2-C6 alkenyl) and -–[CH2] 0, 1NHC(O)(C2-C6 alkynyl), -–[CH2] 0,1 NHC(O)(C3-C 10 Cycloalkyl), –-[CH2] 0,1 NHC(O)(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)), -[CH2] 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, 1NHSO2(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)) In R 1 When combined with nitrogen ring members, R 1 Selected from CN, -C(O)(C1-C6 alkyl), -C(O)(C2-C6 alkenyl), -C(O)(C2-C6 alkynyl), -C(O)(C3-C 10 -C(O)(3- to 6-membered heterocycloalkyl (wherein 1 to 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 -(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S)); R 2 is selected from halogen, C1-C6 haloalkyl, C1-C6 haloalkoxy and -SF5; Ring A, Ring B and Ring C are independently and optionally substituted with 1 to 3 substituents independently selected from halogen and C1-C6 alkyl; and Any alkyl, alkenyl, alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with one to three substituents independently selected from the group consisting of halogen, OH, CN, C1-C6 alkoxy, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, (C0-C6 alkyl)NRR', -(C0-C6 alkyl)-OC(O)R, -(C0-C6 alkyl)-C(O)OR, C3-C6 alkyl 10 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), wherein R and R' are independently selected from H, C1-C6 alkyl, C2-C6 alkenyl and C2-C6 alkynyl).

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is a 6-membered heteroaryl group having 2 or 3 nitrogen ring members.

3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from optionally substituted:

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted:

5. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is optionally substituted:

6. The compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein ring B is an optionally substituted C6-C 12 Aryl.

7. The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Ring B is an optionally substituted phenyl group.

8. The compound according to any one of claims 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.

9. The compound according to any one of claims 1 to 5 and 8, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from the group consisting of optionally substituted: 10 . The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein Ring C is an optionally substituted 4- to 8-membered heterocyclic ring.

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

12. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring C contains 2 N ring members.

13. The compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein ring C is selected from optionally substituted:

14. The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Ring C is optionally substituted:

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

16. A compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R 2 It is a C1-C6 haloalkyl group.

17. A compound according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CF3.

18. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R 1 Combined with nitrogen ring members.

19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula: Where R 3 , R 4 and R 4a Independently selected from H, halogen, CN, -C(O)OR and optionally substituted C1-C6 alkyl.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula:

21. The compound according to claim 19 or 20, or a pharmaceutically acceptable salt thereof, wherein: R 3 is selected from the group consisting of H, F, Cl, CH2F, CF3, CN, CH2OH, CH2OC(O)R and CH2NRR'; and R 4 and R 4a independently selected from H, CH2F, CHF2, CH2OH, CH2NRR' and CH2-(3- to 6-membered heterocycloalkyl (wherein 1 to 4 ring members are independently selected from N, O and S).

22. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula: Where R 5 Selected from H, C1-C6 alkyl, C1-C6 haloalkyl and C1-C6 hydroxyalkyl.

23. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula: Where R 6 and R 6a Independently selected from H, halogen, CN and C1-C6 alkyl.

24. The compound according to claim 23 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a At least one of them is a halogen.

25. The compound according to claim 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a Each of is a halogen.

26. The compound according to claim 23 or 24, or a pharmaceutically acceptable salt thereof, wherein R 6 and R 6a At least one of them is CN.

27. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein R 1 Has the following formula: Where R 7 and R 7a are independently selected from H, optionally substituted alkyl, and -C(O)OR.

28. The compound according to claim 1 or 18, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from: (wherein R is a substituted alkyl group), 29. The compound according to claim 1, 18 or 28, or a pharmaceutically acceptable salt thereof, wherein R 1 yes:

30. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has formula (IA):

31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein L is -NH-.

32. The compound according to claim 30 or 31, or a pharmaceutically acceptable salt thereof, wherein R 2 It is -CF3 or -SF5.

33. A compound according to any one of claims 30 to 32, or a pharmaceutically acceptable salt thereof, wherein R 2 In the matchup.

34. The compound according to any one of claims 30 to 33, or a pharmaceutically acceptable salt thereof, wherein Ring C is a 4- to 6-membered heterocyclic ring containing 2 N ring members.

35. The compound according to any one of claims 30 to 34, or a pharmaceutically acceptable salt thereof, wherein Ring C is:

36. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following: 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]hept-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]hept-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]oct-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-sulfanyl)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]hept-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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 1-(3-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[2,4'-bipyridyl]-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)methylpyridinyl)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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethoxy)pyridin-3-yl)amino)-3',6'-dihydro-[3,4'-bipyridyl]-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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((6-(trifluoromethyl)pyridin-3-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-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'-bipyridyl]-1'(2'H)-yl)prop-2-en-1-one; 2-Fluoro-1-(2-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)-3',6'-dihydro-[3,4'-bipyridyl]-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)propionitrile; 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)propionitrile; 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; Allyl 2-(4-(3-((4-(trifluoromethyl)phenyl)amino)pyrazin-2-yl)piperazine-1-carbonyl)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.

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

38. A method for 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 pharmaceutically 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, atopic dermatitis, epidermolysis bullosa, lichen sclerosus, ichthyosis, vitiligo, acrodermal desquamation syndrome, Blau syndrome, primary cutaneous amyloidosis, skin abscess, blepharitis, furunculosis, capillaris, cellulitis, corneal abrasion, corneal erosion, xerosis, lichen planus, lichen simplex chronicus, idiopathic pulmonary fibrosis (IPF), acute respiratory distress syndrome Syndrome (ARDS), chronic obstructive pulmonary disease (COPD), emphysema, silicosis, asbestosis, pneumoconiosis, alumina pulmonary deposition, ferroalumina fibrosis, berylliosis, siderosis, tin pneumoconiosis, talcosis, Labrador lung (mixed 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), cryptogenic organizing pneumonia (COP = idiopathic BOOP), secondary organizing pneumonia (BOOP), lymphocytic interstitial pneumonia (LIP), idiopathic interstitial pneumonia: unspecified , eosinophilic lung disease, tuberculosis (TB), pulmonary edema, interstitial lung disease, cryptogenic organizing pneumonia (COP), e-cigarette or waterpipe use-associated lung injury (EVALI), Hantavirus pulmonary syndrome (HPS), histoplasmosis, Legionnaires' disease, MAC lung disease, alpha-1-antitrypsin deficiency, aspergillosis, lymphangioleiomyomatosis (LAM), Middle East respiratory syndrome (MERS), nontuberculous mycobacterial lung disease (NTM), pulmonary embolism, Goodpasture's syndrome, idiopathic pulmonary hemosiderosis, pulmonary alveolar proteinosis, pulmonary amyloidosis, primary pulmonary lymphoma, primary ciliary dyskinesia (without or with situs inversus), rare causes of hypersensitivity pneumonitis (except farmer's lung disease and pigeon breeding) all causes except lung disease in patients with pulmonary dysplasia, hereditary hemorrhagic telangiectasia (HHT), pulmonary arteriovenous malformations 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 syndromes, interstitial lung disease in undifferentiated connective tissue disease, bronchiolitis obliterans (in 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 antibody 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-type transposition of the great arteries, Ebstein's anomaly, hypoplastic left heart syndrome, interrupted aortic arch, pulmonary atresia, univentricular heart, 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 Kidney disease, lupus nephritis, nephrotic syndrome in adults, nephrotic syndrome in children, hemolytic uremic syndrome, medullary sponge kidney, renal dysplasia, renal artery stenosis, renovascular hypertension, renal tubular acidosis, Allport syndrome, Wegener's granulomatosis, Alagille syndrome, cystinosis, Fabry disease, focal segmental glomerulosclerosis (FSGS), glomerulonephritis, aHUS (atypical hemolytic uremic syndrome), hemolytic uremic syndrome (HUS), Henoch-Schwann syndrome, 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), Barlow's disease, bullous pemphigoid, celiac disease, chronic recurrent multifocal osteomyelitis (CRMO), Chargar-Strauss syndrome (CSS) or eosinophilic granulomatosis (EGPA), cicatricial pemphigoid, Kogan syndrome, cold agglutinin disease, coxsackievirus myocarditis, CREST syndrome, dermatitis herpetiformis, dermatomyositis, Devic's disease (neuromyelitis optica), discoid lupus , 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-Schullan syndrome (HSP), herpes gestationis or pemphigoid 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 corneal ulcer, Mucha-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 rheumatic disease (PR), PANDAS, paraneoplastic cerebellar degeneration (PCD), paroxysmal nocturnal hemoglobinuria (PNH), Parkinson-Rodriguez syndrome, pars planitis (peripheral uveitis), Parsonage-Turner syndrome, pemphigus, peripheral neuropathy, perivenous encephalomyelitis, pernicious anemia (PA), POEMS syndrome, polyarteritis nodosa, polyglandular syndromes type I, II, and III, polymyalgia rheumatica, polymyositis, primary biliary cirrhosis, primary sclerosing cholangitis, progesterone 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, Sjögren's syndrome, sperm and testicular autoimmunity, stiff-man 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, alcohol-related liver disease, autoimmunity Autoimmune hepatitis, biliary atresia, 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 CNS 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 tumors, Burkitt's lymphoma, carcinoid tumors (gastrointestinal), cardiac (heart) tumors, children, medulloblastoma, germ cell tumors, primary CNS lymphoma, cervical cancer, bile duct cancer, chordoma, chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), chronic myeloproliferative neoplasms, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, ductal carcinoma in situ (DCIS), endometrial cancer (uterine cancer), ependymoma, esophageal cancer, esthesioneuroblastoma (head and neck cancer), retinoblastoma, fallopian tube cancer, gallbladder cancer, stomach (gastric) cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), germ cell tumors, extracranial germ cell tumors in children, extragonadal germ cell tumors,Ovarian germ cell tumors, testicular cancer, gestational trophoblastic disease, hairy cell leukemia, head and neck cancer, heart tumors, hepatocellular carcinoma, histiocytosis, Langerhans cell, Hodgkin lymphoma, hypopharyngeal cancer (head and neck cancer), intraocular melanoma, islet cell tumors, 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 tracheobronchial tumors), male breast cancer, melanoma, melanoma Tumors, Intraocular (eye), Meningioma, Merkel Cell Carcinoma (skin cancer), Mesothelioma, Malignant neoplasms, Metastatic squamous neck cancer with occult primary (head and neck cancer), Midline tract cancer, Multiple endocrine neoplasia syndrome, Multiple myeloma / plasma cell neoplasms, Mycosis fungoides, Myelodysplastic syndrome, Myelodysplastic / myeloproliferative neoplasms, Neuroblastoma, Non-Hodgkin lymphoma, Non-small cell lung cancer, Oral cancer, Lip and oral cavity cancer and Oropharyngeal cancer (head and neck cancer), Osteosarcoma and Bone treatment Undifferentiated pleomorphic sarcoma, ovarian cancer, pancreatic cancer, pancreatic neuroendocrine tumors, papillomatosis, paraganglioma, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pituitary tumor, 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 (bone cancer), soft tissue sarcoma, Sezary syndrome, skin cancer , small cell lung cancer, small intestinal cancer, soft tissue sarcoma, squamous cell carcinoma of the skin, squamous neck cancer with occult primary, metastatic (head and neck cancer), stomach (gastric) cancer, T-cell lymphoma, cutaneous - see lymphoma (mycosis fungoides and Sezary syndrome), testicular cancer, nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer, thymoma and thymic cancer, thyroid cancer, tracheobronchial tumors, transitional cell carcinoma of the renal pelvis and ureter, urethral cancer, uterine cancer, endometrial, uterine sarcoma, vaginal cancer, vulvar cancer, and Wilms tumor. , 39. The method of claim 38, wherein the disease is selected from the group consisting of brain tumors, gastric cancer, colorectal cancer, mesothelioma, non-small cell lung cancer, meningioma, head and neck cancer, and soft tissue sarcoma.

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

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. The method of claim 41, wherein the B-RAF inhibitor is selected from vemurafenib, dabrafenib, and encofenib.

43. The method of claim 41, wherein the MEK inhibitor is selected from trametinib, cobimetinib, selumetinib, and bimetinib.

44. The method of claim 41, wherein the EGFR inhibitor is selected from erlotinib, osimertinib, neratinib, gefitinib, cetuximab, panitumumab, dacomitinib, lapatinib, necituzumab, mobotinib, and vandetanib.

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

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

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

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