Substituted pyrazine-2-carboxamide inhibitors as HPK1 inhibitors for cancer treatment

Abstract

Certain substituted pyrazine-2-carboxamides of formula (I), and pharma- ceutically acceptable salts thereof, are disclosed, along with compositions containing them, and their use in therapy. The compounds are inhibitors of hematopoietic progenitor kinase 1 (HPK1), and are therefore particularly useful in the treatment or prevention of cancer. [Case 1] TIFF2024527623000305.tif30161

Description

[Technical Field]

[0001] This technical field relates to specific pyrazine 2-carboxamides of formula (I) and pharmaceutically acceptable salts thereof, as well as compositions containing them and their use in therapeutics. Compounds of formula (I) are inhibitors of hematopoietic precursor kinase 1 (HPK1) and are therefore particularly useful in the treatment or improvement of abnormal cell proliferation disorders such as cancer. [Background technology]

[0002] In recent years, the discovery of immunological checkpoints and their inhibitors has revealed new ways to target cancer by utilizing the body's own immune system to fight tumors. While checkpoint therapy has shown great promise in some tumor types, it only responds to a portion of cancer patients, and novel therapies are needed to reach a wider range of patients.

[0003] T cells are crucial in the cancer immune cycle (Non-Patent Literature 1; Non-Patent Literature 2), acting as effector cells that recognize and kill tumor cells. In cancer patients, T cells become exhausted and dysfunctional in the tumor microenvironment due to chronic exposure to antigens. Furthermore, inhibitory signals in tumors, such as PGE2, TGFβ, and adenosine, interfere with the function of these cells. Therefore, therapies that enhance T cell function and rescue the function of exhausted T cells lead to improved tumor control.

[0004] HPK1 (hematopoietic progenitor kinase 1), also known as mitogenic factor-activated protein kinase 1 (MAP4K1), is a Ste20-related serine / threonine kinase expressed only in hematopoietic cells and acts as a negative regulator of T cell signaling and tumor-killing cytokine production. After TCR ligation, HPK1 phosphorylates its target SLP76 at Ser376, associating SLP76 with 14-3-3, thereby leading to the dissociation of the LAT signalosome (Non-Patent Literature 3; Non-Patent Literature 4), and thus restricting T cell activation (Non-Patent Literature 5). Loss of HPK1 or inactive kinase (kinase dead) enhances T cell activation, resulting in increased cytokine secretion and proliferation (Non-Patent Literature 4; Non-Patent Literature 6). HPK1 can also inhibit T cell signaling in response to immunosuppressive prostaglandin E2 (PGE2) via protein kinase A (PKA) (Non-Patent Literature 7; Non-Patent Literature 8; Non-Patent Literature 9). Recent literature describes the essential function of the HPK1 kinase domain in advancing tumor surveillance, and inactivation of the HPK1 kinase domain prevents tumor progression in mouse tumor models. Importantly, studies comparing wild-type mice and kinase-dead mice have shown that loss of HPK1 kinase function can rescue T cells from exhaustion in chronic viral infection and PGE2 hypertumor models (Non-Patent Literature 4; Non-Patent Literature 6). Apart from its function in T cells, HPK1 has also been reported to act as a negative regulator in other immune cells such as B cells, dendritic cells, and NK cells, which may also contribute to tumor immunity (Non-Patent Literature 10). The kinase activity of HPK1 has been suggested to be essential for regulating T cell function (Non-Patent Literature 6), supporting the development of small molecule inhibitors of HPK1 for use in cancer immunotherapy to enhance T cell function and other immune cell types. The HPK1 protein contains an N-terminal kinase domain, a regulatory domain containing ATP-binding amino acids 23-46 (Non-Patent Literature 11). The intermediate domain has a proline-rich motif with binding sites for SH3-containing proteins such as Crkl, Grb2, and HIP-55, suggesting scaffolding function.The citron homology domain is located at the C-terminus and can act as a regulatory domain in molecular interactions, including T cell adhesion. LCK and ZAP70 induce HPK1 Tyr-379 phosphorylation and kinase activation (Non-Patent Literature 12; Non-Patent Literature 13; Non-Patent Literature 14). Essential adapters for signaling in T cells (SLP76) and B cells (BLNK) have been reported to bind to activated HPK1, assisting in the blockade of downstream signaling in both T cells and B cells (Non-Patent Literature 15). In summary, there is strong rationale for targeting HPK1 with small molecule kinase inhibitors for cancer immunotherapy.

[0005] HPK1 inhibitors can be used alone or in combination with other therapeutic agents for the treatment of cancer. HPK1 inhibitors can be used in combination with checkpoint blockade PD-(L)1 axis or CTLA4 to enhance the response rate to checkpoint blockade. Primary or secondary resistance to checkpoint blockade may be a potential indication for HPK1 inhibitors. Further combinations may include radiotherapy, chemotherapy, surgery, tumor targeting agents, or other immunotherapy agents.

[0006] HPK1 inhibitors can be used as therapeutic agents for a variety of cancer indications.

[0007] Many small molecule inhibitors of HPK1 are disclosed in patent applications, for example, summarized in Expert Opinion on Therapeutic Patents, DOI:10.1080:13543776.2021-1924671. Patent Document 1: HPK1 inhibitors and methods of using the same Patent Document 2: Azaindoles as inhibitors of HPK1 Patent Document 3: Spirocyclic 2,3-dihydro-7-azaindoles and uses there of Patent Document 4 Isoquinolines as inhibitors of HPK1 Patent Document 5: Naphthyridine compounds and uses thereof Patent Document 6: Isoquinoline compound and uses thereof Patent Document 7: Cinnoline compounds and for the treatment of HPK1-dependent disorders such as cancer Patent Document 8: Isoquinoline compounds for the treatment of cancer Patent Document 9 8-Aminoisoquinoline compounds and uses thereof Patent Document 10 Methods for Human T-cell activation Patent Document 11: Anilinopyrimidines as Haematopoietic progenitor kinase 1 (HPK1) inhibitors Patent Document 12: Substituted pyrrolopyridine-derivatives as MAP4K1 modulators for the treatment of cancer diseases Patent Document 13: Preparation of substituted pyrrolopyridine derivatives as anticancer agents Patent Document 14: Preparation of substituted pyrrolopyridine derivatives as anticancer agents Patent Document 15: Substituted pyrrolopyridine derivatives Patent Document 16: Substituted pyrrolopyridine derivatives Patent Document 17: Substituted 6-azabenzimidazole compounds having HPK1 inhibitory activity Patent Document 18: Substituted 6-azabenzimidazole compounds as HPK1 inhibitors Patent Document 19: Substituted exo-methylene-oxindoles which are HPK1 / MAP4K1 inhibitors Patent Document 20: HPK1 inhibitors Patent Document 21 Bicyclic HPK1 inhibitors Patent Document 22: 2,3-Dihydro-1H-pyrrolo[3,4-C]pyridine-1-one derivatives as HPK1 inhibitors for the treatment of cancer Patent Document 23: Indoline compounds for use as MAP4K1 inhibitors Patent Document 24: Oxindole compounds for use as MAP4K1 inhibitors Patent Document 25: Pyrrolo[2,3-b]pyridines or pyrrolo[2,3-b]pyrazines as HPK1 inhibitor and the use thereof Patent Document 26: Pyrrolo[2,3-b]pyridines as HPK1 inhibitor and uses thereof Patent Document 27: Pyrrolo[2,3-b]pyrazines as HPK1 inhibitor and the use thereof Patent Document 28: Tricyclic compound as HPK1 inhibitor and use thereof Patent Document 29: Aminopyrazine compounds as HPK1 inhibitor and the use thereof Patent Document 30: HPK1 inhibitors and uses thereof Patent Document 31: HPK1 inhibitors, preparation method and application thereof Patent Document 32: Heterobifunctional Compounds as Degraders of HPK1 Patent Document 33 Isofuranone compounds useful as HPK1 inhibitors in the treatment of cancer and viral infections and their preparation Patent Document 34: Preparation of pyrazolopyrimidine derivatives as HPK1 modulators and their use for the treatment of cancer Patent Document 35: Pyrazolopyridone derivatives as HPK1 modulator and uses thereof for the treatment of cancer Patent Document 36: Pyrazolopyridine derivatives as HPK1 modulator and uses thereof for the treatment of cancer Patent Document 37: Pyrazolopyridine derivatives as HPK1 modulators and uses thereof for the treatment of cancer Patent Document 38: Pyrazolopyridine compounds and uses thereof Patent Document 39 6-Cyano-indazole compounds as Hematopoietic Progenitor Kinase 1(HPK1) Modulators Patent Document 40: Preparation of indazolyl pyrimidine compounds and uses thereof. Patent Document 41: Indazole compounds and uses thereof Patent Document 42: Preparation of benzimidazole and indole compounds for inhibiting HPK1 activity Patent Document 43 N-(Phenyl)-2-(phenyl) pyrimidine-4-carboxamide derivatives and related compounds as HPK1 inhibitors for treating cancer Patent Document 44: Preparation of benzothiazole as HPK1 inhibitors for the treatment and prevention of cancer Patent Document 45: Solid Forms of an HPK1 inhibitor Patent Document 46: 2,3-Dihydro-1H-pyrrolo[3,4-C]pyridine-1-one derivatives as HPK1 inhibitors for the treatment of cancer Patent Document 47: HPK1 antagonists and uses thereof [Prior art documents] [Patent Documents]

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[0009] [Non-Patent Document 1] Nature, 541 (2017), 321-330 [Non-Patent Document 2] Nature Reviews Immunology,20,(2020),651-668 [Non-Patent Document 3] J.Cell Biol.,195(2011),839-853 [Non-Patent Document 4] Nat.Immunol.,8(2007),84-91 [Non-Patent Document 5] J.Exp.Med.,204(2007),681-91 [Non-Patent Document 6] Cell Reports, 25(2018), 80-94 [Non-Patent Document 7] Blood, 101 (2003), 3687-89 [Non-Patent Document 8] J.Biol.Chem.,282(2007),34693-99 [Non-Patent Document 9] Cancer Immunol. Immunother.,59(2010),419-29 [Non-Patent Document 10] Elife, 2020, 9 [Non-Patent Document 11] EMBO J., 15, 1996, 7013-25 [Non-Patent Document 12] Oncogene, 20(2001), 1703-14 [Non-Patent Document 13] Immunity, 12(2000), 399-408 [Non-Patent Document 14] J.Biol.Chem.,276(2001),45207-16 [Non-Patent Document 15] J.Biol.Chem.,276(2001),18908-14 [Overview of the Initiative] [Means for solving the problem]

[0010] A compound that is an inhibitor of hematopoietic precursor kinase 1 (HPK1), its use as a drug, a pharmaceutical composition containing this compound, and a synthetic route for its manufacture are provided.

[0011] In one embodiment, the compound of formula (I) [ka] [In the formula, X 1 , X 2 and X 3 CR is independent 5or selected from N, provided that when X 1 is N, X 3 is CR 5 and when X 3 is N, X 1 is CR 5 ); R 1 is cyclopropyl or C 1~3 alkyl (wherein said C 1~3 alkyl is substituted by 0, 1, 2 or 3 F); R 2 is H, NH2 or C 1~2 alkyl (wherein said C 1~2 alkyl is substituted by 0, 1, 2 or 3 F); R 3 is H, R 6 , OR 6 , NHR 6 , Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH((5-6 membered) heteroaryl containing 1 or 2 N), NH(C 1~2 alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 4 is selected from aryl or heteroaryl (wherein said aryl or heteroaryl is substituted by 0, 1, 2, 3 or 4 substituents independently selected from F, Cl and R 6 , and NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 , CH(CH3)R 8 and CH2R 8 by 0, 1 or 2 substituents independently selected from); R 5 is independently selected from H, F, Cl and C 1~2 alkyl (wherein said C1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R 11 Selected from (which has been replaced by); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11(CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0012] The compound of formula (I) is an HPK1 inhibitor. Therefore, the compound of formula (I) can be used as a drug, particularly as a drug for disorders, diseases, or conditions that respond to HPK1 inhibition, and more specifically as a drug for cancer.

[0013] In another embodiment, a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) is provided, which has undefined stereochemistry and is, for example, a racemic mixture or a mixture of diastereomers.

[0014] In another embodiment, a pharmaceutical formulation is provided comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I), and a pharmaceutically acceptable diluent, additive, and / or inert carrier.

[0015] In further embodiments, pharmaceutical formulations are provided comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the treatment of conditions in which inhibition of HPK1 would be beneficial.

[0016] In further embodiments, compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) are provided for use in the treatment of cancers, particularly in mammals (especially humans).

[0017] Further embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a drug for the treatment of cancer.

[0018] In further embodiments, HPK1 levels are reduced in mammals (particularly humans) by administration of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).

[0019] In another embodiment, a process is provided for preparing a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) and intermediates used in the preparation thereof.

[0020] The compound of formula (I) exemplified herein exhibits an IC50 of less than 100 nmol / L with respect to HPK1 in enzyme activity assays. 50 The compound of formula (I) also exhibits a promising pharmacological profile by separating desired and undesirable effects in vivo. [Brief explanation of the drawing]

[0021] [Figure 1] Example 8 shows the X-ray powder diffraction pattern of form A: 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide). [Figure 2]Example 8, Form A: DSC / TGA thermogram of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide is shown. [Figure 3] Example 8, Form F: X-ray powder diffraction pattern of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide. [Figure 4] Example 8, Form F: DSC / TGA thermogram of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide is shown. [Figure 5] Example 8, Form F: The molecular structure of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide is shown. [Figure 6] Example 8, Form G: X-ray powder diffraction pattern of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide. [Figure 7] The DSC / TGA thermogram of Example 8, Form G: 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide) is shown. [Figure 8] Example 8 shows the X-ray powder diffraction pattern of Form I: 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide). [Figure 9] Example 8, Form I: DSC / TGA thermogram of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide) is shown. [Figure 10]Example 8, Form I: The molecular structure of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide) is shown. [Figure 11] Example 213, Form A: X-ray powder diffraction pattern of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 12] Example 213, Form A: DSC / TGA thermogram of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 13] Example 213, Form B: X-ray powder diffraction pattern of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 14] Example 213, Form B: DSC / TGA thermogram of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 15] Example 213, Form C: X-ray powder diffraction pattern of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 16] Example 213, Form C: DSC / TGA thermogram of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 17] Example 213, Form D: X-ray powder diffraction pattern of 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 18] Example 213, Form A, shows the X-ray powder diffraction pattern of the HCl salt: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 19] Example 213, Form A, shows the DSC / TGA thermogram of the HCl salt: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 20] Example 213, Form B, shows the X-ray powder diffraction pattern of the HCl salt: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 21] Example 213, Form B, shows the DSC / TGA thermogram of the HCl salt: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 22] Example 213, Form A, shows the X-ray powder diffraction pattern of methanesulfonate: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 23]Example 213, Form A, shows the DSC / TGA thermogram of methanesulfonate: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 24] Example 213, Form B, shows the X-ray powder diffraction pattern of methanesulfonate: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 25] Example 213, Form B, shows the DSC / TGA thermogram of methanesulfonate: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Figure 26] Example 213, Form C, shows the DSC / TGA thermogram of methanesulfonate: 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide. [Modes for carrying out the invention]

[0022] This detailed description and its specific examples illustrate embodiments, but are intended solely as examples. Therefore, it is not limited to the exemplary embodiments described herein. Furthermore, it should be recognized that various features described in relation to separate embodiments for clarity may be combined to form a single embodiment. Conversely, various features described in relation to a single embodiment for conciseness may also be combined to form partial combinations thereof.

[0023] The definitions of various terms used in this specification and in the claims are listed below.

[0024] In this specification, when a group is modified with “as defined above,” it should be understood that the group encompasses each and all of the first and broadest definitions as well as the other definitions relating to that group.

[0025] In this specification, "C 1~4 Please understand that "" refers to a carbon group having 1, 2, 3, or 4 carbon atoms.

[0026] In this specification, "C 1~3 Please understand that "" refers to a carbon group having one, two, or three carbon atoms.

[0027] In this specification, "C 1~2 Please understand that "" refers to a carbon group having one or two carbon atoms. In this specification, unless otherwise specified, the term “alkyl” includes both linear and branched alkyl groups and may be, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, or tert-butyl. In this specification, "aryl" should be understood to mean an aromatic or partially aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl. In this specification, "heteroaryl" should be understood to mean a monocyclic or bicyclic aromatic ring or partially aromatic ring having 5 to 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. In this specification, "(5-6 membered) heteroaryl" should be understood to mean an aromatic ring having 5-6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. In this specification, "(6-membered) heteroaryl" should be understood to mean an aromatic ring having six atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. In this specification, "(6-membered) heteroaryl" should be understood to mean, for example, 2-pyridone. In this specification, "(5-membered) heteroaryl" should be understood to mean an aromatic ring having five atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. In this specification, “heterocycloalkyl” should be understood to mean a partially or fully saturated monocyclic, bicyclic, or bridging hydrocarbon ring system having 4 to 10 atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur. In this specification, "(5-8 member) heterocycloalkyl" should be understood to mean a partially or fully saturated monocyclic, bicyclic, or bridging hydrocarbon ring system containing a total of 5 or 6 ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur. In this specification, "(5-6 member) heterocycloalkyl" should be understood to mean a partially or fully saturated monocyclic, bicyclic, or bridging hydrocarbon ring system containing a total of 5 or 6 ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur. In this specification, "(7-membered) heterocycloalkyl" should be understood to mean a partially or fully saturated monocyclic, bicyclic, or bridging hydrocarbon ring system containing a total of seven ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur. In this specification, "(6-membered) heterocycloalkyl" should be understood to mean a partially or fully saturated monocyclic, bicyclic, or bridging hydrocarbon ring system containing a total of six ring atoms, in which at least one of the ring carbon atoms is replaced by a heteroatom independently selected from nitrogen, oxygen, or sulfur. In this specification, it should be understood that "heterocycloalkyl" substituents may be bonded via nitrogen atoms with appropriate valencies or via any ring carbon atoms. Unless otherwise specified herein, the term "pharmaceutically acceptable" is used to characterize portions (e.g., salts, dosage forms, or excipients) that are suitable for use in accordance with normal medical judgment. Generally, pharmaceutically acceptable portions have one or more advantages that outweigh any harmful effects the portion may have. Harmful effects can include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0028] A compound of formula (I) wherein X 1 , X 2 , X 3 and R 1 ~R 11 are as defined in formula (I) is provided.

[0029] In one embodiment, X 1 , X 2 and X 3 are independently selected from CR 5 or N, provided that when X 1 is N, X 3 is CR 5 , and when X 3 is N, X 1 is CR 5 . In a further embodiment, X 1 , X 2 and X 3 are CR 5 . In yet a further embodiment, X 2 is N, and X 1 and X 3 are CR 5 . In yet a further embodiment, X 1 and X 2 are N, and X 2 is CR 5 . In yet a further embodiment, X 2 and X 3 are N, and X 1 is CR 5 . R 5 is H, F, Cl and C 1~2Selected independently of alkyl, the C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl.

[0030] In one embodiment, R 1 is cyclopropyl or C 1~3 Alkyl, and the C 1~3 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 1 is cyclopropyl or C 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 1 It is cyclopropyl or CH3. In further embodiments, R 1 It is cyclopropyl. In further embodiments, R 1 It is CH3. In further embodiments, R 1 This is CH2F. In further embodiments, R 1 It is CHF2. In further embodiments, R 1 This is CF3.

[0031] In one embodiment, R 2 is H, NH2, or C 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 2 It is NH2. In further embodiments, R 2 is C 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 2 It is CH3. In further embodiments, R 2 This is CH2F. In further embodiments, R 2 It is CHF2. In further embodiments, R 2 This is CF3. In further embodiments, R 2 H is H.

[0032] In one embodiment, R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl, and O-cyclopropyl. In further embodiments, R 3 is R 6 , OR 6 NHR 6 and cyclopropyl are selected. In further embodiments, R 3 is R 6 NHR 6 and cyclopropyl are selected. R 6 is C 1~4 Alkyl, and the C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 It is substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O. In further embodiments, R 3 is C 1~4 Selected from alkyl, the C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 3is C 1~2 Selected from alkyl, the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 3 It is CH3. In further embodiments, R 3 This is CH2F. In further embodiments, R 3 It is CHF2. In further embodiments, R 3 This is CF3. In further embodiments, R 3 It is cyclopropyl. In further embodiments, R 3 is NHC 1~4 And the above C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 3 is NHC 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 3 It is NHCH3. In further embodiments, R 3 It is NHCH2. In further embodiments, R 3 It is NHCHF2. In further embodiments, R 3 It is NHCF3.

[0033] In one embodiment, R 4 The aryl or heteroaryl is selected from aryl or heteroaryl, and the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8, C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it. R 6 is C 1~4 Alkyl, and the C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 It is substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O. R 7 NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R 11 Selected from (which has been replaced by). R 8 The heterocycloalkyl is selected from SO2CH3 or heterocycloalkyl, and the heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2. R 9 is OR 10 , N(R 10 )2, NR 11(CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms and 0 or 1 cyclopropyl atom.

[0034] In further embodiments, R 4 The aryl is selected from aryls, and the aryls are F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0035] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0036] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 0, 1, 2, or 3 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0037] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8, C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0038] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0039] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted by a substituent selected from the following.

[0040] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is NH2, CN, OR 6 , R 7 , R8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted by a substituent selected from the following.

[0041] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Zero or one substituent selected from, and OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , OR 8 OCH2R 8 and CH2R 8 It is substituted by a substituent selected from the following.

[0042] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from heterocycloalkyls, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0043] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from (6-membered) heterocycloalkyls, wherein the (6-membered) heterocycloalkyl is F, Cl, R 6 and OR 6It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0044] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from (6-membered) heterocycloalkyls, wherein the (6-membered) heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0045] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from (6-membered) heterocycloalkyls, wherein the (6-membered) heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0046] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0047] In a further embodiment, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0048] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0049] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (5-8 membered) heterocycloalkyl groups, wherein the (5-8 membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0050] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (6-membered) heterocycloalkyl groups, wherein the (6-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0051] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (6-membered) heterocycloalkyl groups, wherein the (6-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted by 0, 1, 2, 3, or 4 substituents selected independently of it.

[0052] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (6-membered) heterocycloalkyl groups, wherein the (6-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents selected independently of it. In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (7-membered) heterocycloalkyl groups, wherein the (7-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2.

[0053] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (7-membered) heterocycloalkyl groups, wherein the (7-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted by 0, 1, 2, 3, or 4 substituents selected independently of it.

[0054] In further embodiments, R 4 The phenyl is selected from phenyl, and the phenyl is F, Cl and R 6 Substituting with 0 or 1 substituent selected from and substituents selected from CH2 (7-membered) heterocycloalkyl groups, wherein the (7-membered) heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0055] In a further embodiment, R 4 The heteroaryl is selected from heteroaryls, and the heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0056] In a further embodiment, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 60, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0057] In a further embodiment, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0058] In a further embodiment, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8CH(CH3)R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0059] In further embodiments, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, and OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0060] In further embodiments, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0061] In further embodiments, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 It is substituted with 0, 1, or 2 substituents independently selected from the above, and 0 or 1 substituent selected from (5-8 membered) heterocycloalkyl and CH2(5-8 membered) heterocycloalkyl.

[0062] In further embodiments, R 4 The (6-membered) heteroaryl is selected from F, Cl and R 6 It is substituted with 0, 1, or 2 substituents independently selected from the above, and 0 or 1 substituent selected from (6-membered) heterocycloalkyl and CH2(6-membered) heterocycloalkyl.

[0063] In a further embodiment, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0064] In a further embodiment, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0065] In further embodiments, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, and OR 6 , R 7 , R 8 , R 9 , OR8 OCH2R 8 , C(O)R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0066] In further embodiments, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 8 and CH2R 8 It is substituted with 0 or 1 substituent selected from the following.

[0067] In further embodiments, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 It is substituted with 0, 1, or 2 substituents independently selected from the above, and 0 or 1 substituent selected from (5-8 membered) heterocycloalkyl and CH2(5-8 membered) heterocycloalkyl.

[0068] In further embodiments, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 It is substituted with 0, 1, or 2 substituents independently selected from the above, and 0 or 1 substituent selected from (6-membered) heterocycloalkyl and CH2(6) heterocycloalkyl groups.

[0069] In further embodiments, R 4 The (5-membered) heteroaryl is selected from F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 7 It is substituted with 0 or 1 substituent selected from the following.

[0070] In further embodiments, R 4 is pyrazolyl, and the pyrazolyl is F, Cl and R6 0, 1, or 2 substituents independently selected from, and R 7 It is substituted with 0 or 1 substituent selected from the following.

[0071] In further embodiments, R 4 is 1H-pyrazole-4-yl, and the 1H-pyrazole-4-yl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 7 It is substituted with 0 or 1 substituent selected from the following.

[0072] In further embodiments, R 4 is 1H-pyrazole-4-yl, and the 1H-pyrazole-4-yl is F, Cl and R 6 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0073] In further embodiments, R 4 is 1H-pyrazole-4-yl, and the 1H-pyrazole-4-yl is R 6 It is substituted with 0, 1, or 2 substituents selected independently of it.

[0074] In one embodiment, R 5 H, F, Cl and C 1~2 Selected independently of alkyl, the C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. In further embodiments, R 5 H is H. In further embodiments, R 5 is C 1~2 Alkyl, and the C 1~2 Alkyls are F, CN, NH2 and OC 1~2Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. In further embodiments, R 5 is C 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F. In further embodiments, R 5 It is CH3. In further embodiments, R 5 This is CH2F. In further embodiments, R 5 It is CHF2. In further embodiments, R 5 This is CF3.

[0075] In one embodiment, R 6 is C 1~4 Alkyl, and the C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 It is substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O. In further embodiments, R 6 is C 1~4 Alkyl, and the C 1~4 The alkyl group is substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing 0, 1, 2, or 3 F atoms, and OH, CN, N(CH3)2, and 1 O atom. In further embodiments, R 6 is C 1~4 Alkyl, and the C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 F atoms, and 0 or 1 substituent selected from OH, CN, and N(CH3)2. In further embodiments, R 6 is C 1~4 Alkyl, and the C1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. In further embodiments, R 6 is C 1~2 Alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms.

[0076] In one embodiment, R 7 NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R 11 Selected from (which has been replaced by).

[0077] In further embodiments, R 7 The compound is selected from cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH, or SO2CH3) and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH). In further embodiments, R 7 The substituent is selected from cyclopropyl, and the cyclopropyl substituent is substituted with 0 or 1 substituent selected from F, CN, OH, or SO2CH3. In further embodiments, R 7 The compound is selected from cyclobutyl, and the cyclobutyl is substituted with 0 or 1 OH group.

[0078] In one embodiment, R 8The heterocycloalkyl is selected from SO2CH3 or heterocycloalkyl, and the heterocycloalkyl is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2.

[0079] In further embodiments, R 8 The heterocycloalkyl group is selected from (5-8 member) heterocycloalkyl groups, and the heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2. In further embodiments, R 8 The heterocycloalkyl group is selected from (5-6 member) heterocycloalkyl groups, and the heterocycloalkyl group is F, Cl, R 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2.

[0080] In further embodiments, R 8 The (6-membered) heterocycloalkyl is selected from F, Cl, and R. 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2.

[0081] In further embodiments, R 8The (5-membered) heterocycloalkyl is selected from F, Cl, and R. 6 and OR 6 It is substituted with 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2.

[0082] In one embodiment, R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; In further embodiments, R 9 R is selected from -(CH2)2 (5-6 membered) heterocycloalkyl groups, and the (5-6 membered) heterocycloalkyl group is R 11 It is substituted with 0 or 1 substituent selected from the following. In further embodiments, R 9 is -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl (substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3).

[0083] In one embodiment, R 10 H and C 1~2 Selected independently of alkyl, the C 1~2 Alkyls are F, CN, NH2 and OC 1~2Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. In further embodiments, R 10 H is H. In further embodiments, R 10 is C 1~2 Selected independently of alkyl, the C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. In further embodiments, R 10 is C 1~2 Selected independently of alkyl, the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F, CN, and NH2. In further embodiments, R 10 is C 1~2 Selected independently of alkyl, the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F.

[0084] In one embodiment, a compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR is independent 5 Selected from; R 5 H, F, Cl and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R 11 Selected from (which has been replaced by); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0085] In further embodiments, compounds of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 60, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CHC(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0086] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH 3、Selected from SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0087] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from aryls (where the aryls are F, Cl and R 6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0088] In further embodiments, the compound of formula (IA) [ka] (In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where the C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0089] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 H is; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R6 and OR 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0090] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2); and R 6 is C 1~4 It is alkyl (where C 1~4 (Alkyl is substituted with 0, 1, 2, or 3 F atoms.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0091] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 H is; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from the original compound); R 6 is C 1~4 It is alkyl (where C 1~4Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 Selected from (CH2)2N(CH3)2 and -(CH2)2(5-6 membered) heterocycloalkyl (where the (5-6 membered) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10is H and C 1~2 independently selected from alkyl (wherein said C 1~2 alkyl is independently selected from F, CN, NH2 and OC 1~2 alkyl and is substituted by 0, 1, 2 or 3 substituents independently selected from F, Cl; and 1~2 R is C 11 alkyl (wherein said C 1~3 alkyl is substituted by 0, 1, 2 or 3 F and 0 or 1 cyclopropyl)]] 1~3 or a pharmaceutically acceptable salt thereof is provided. In yet a further embodiment, a compound of formula (IA)

[0092] wherein:

Chemical formula

[0093] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, and OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 and CH2R 8 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10, N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5 - 6 member) heterocycloalkyl (wherein the (5 - 6 member) heterocycloalkyl is substituted with 0 or 1 substituent selected from R 11 ), -O(CH2)2(5 - 6 member) heterocycloalkyl (wherein the (5 - 6 member) heterocycloalkyl is substituted with 0 or 1 substituent selected from R 11 ), and is selected from azetidinyl substituted with 0 or 1 substituent selected from N(CH3)2 and C(O)CH3; R 10 is independently selected from H and C 1~2 alkyl (wherein the C 1-2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F, CN, NH2 and OC 1~2 alkyl, and the C 1~2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl); and R 11 is C 1~3 alkyl (wherein the C 1~3 alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 cyclopropyl)] or a pharmaceutically acceptable salt thereof is provided.

[0094] In still further embodiments, the compound of formula (IA)

Chemical formula

[0095] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from (5-8 membered) heterocycloalkyl and CH2(5-8 membered) heterocycloalkyl); and R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0096] In further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 CR 5 and; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 60, 1, or 2 substituents independently selected from, and R 7 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 F atoms; and R 7 (wherein the cyclopropyl group is selected from cyclopropyl, and the cyclopropyl group is substituted with 0 or 1 substituent selected from F, CN, OH, or SO2CH3.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0097] In one embodiment, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 H, F, Cl and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R11 Selected from (which has been replaced by); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0098] In further embodiments, compounds of formula (IB) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R10 H and C 1~2 Selected independently of alkyl (where C 1~2 These are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0099] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 Independent CR 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R 6 0, 1, 2, 3, or 4 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8, C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11(substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0100] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from aryls (where the aryls are F, Cl and R6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0101] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 0 or 1 substituent selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0102] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2); R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0103] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from phenyl (where phenyl is F, Cl and R 6 Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2); R 6 is C 1~4 It is alkyl (where C 1~4 (Alkyl is substituted with 0, 1, 2, or 3 F atoms.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0104] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0, 1, or 2 substituents independently selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0105] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, as well as NH2, CN, OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 , C(O)CH3, C(O)NHCH3, CH2C(O)NHCH3, C(CH3)2R 8 CH(CH3)R 8 and CH2R 8 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7 cyclopropyl (where the cyclopropyl is F, CN, OH or SO2CH3, NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3(The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0106] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, and OR 6 , R 7 , R 8 , R 9 , OR 8 OCH2R 8 , C(O)R 8 and CH2R 8 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 7cyclopropyl (where the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3), NH-cyclopropyl, [dimethyl(oxo)-λ 6 -Sulfanylidene]amino, (C 1~4 Selected from alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SO2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH group); R 8 The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and OR 6 Substituted by 0, 1, 2, 3, or 4 substituents independently selected from, and 0, 1, or 2 substituents independently selected from, cyclopropyl, OH, C(O)CH2OH, 4-methylpiperazinyl, C(O)CH3, and C(O)N(CH3)2); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, -(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 (substituted with 0 or 1 substituent selected from), -O(CH2)2(5-6 member) heterocycloalkyl (where the (5-6 member) heterocycloalkyl is R 11 Selected from azethinyl, which is substituted with 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 H and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted by 0, 1, 2, or 3 substituents independently selected from the alkyl, and the C 1~2The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R 11 is C 1~3 It is alkyl (where C 1~3 (The alkyl group is substituted with 0, 1, 2, or 3 F atoms and 0 or 1 cyclopropyl atom.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0107] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 8 and CH2R 8 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 Substituted by 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing alkyl, OH, CN, N(CH3)2, and 1 O); R 8The is selected from SO2CH3 or heterocycloalkyl (where the heterocycloalkyl is F, Cl, R 6 and 6 Provided are (substituted with 0, 1, 2, 3, or 4 substituents independently selected from and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2) or pharmaceutically acceptable salts thereof.

[0108] Further embodiments include compounds of formula (IB). [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 Substituted by 0, 1, or 2 substituents independently selected from, and 0 or 1 substituent selected from (5-8 membered) heterocycloalkyl and CH2(5-8 membered) heterocycloalkyl); and R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0109] Further embodiments include compounds of formula (IB). [ka] (In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 4 is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R 6 0, 1, or 2 substituents independently selected from, and R 7 Substituted by 0 or 1 substituent selected from; R 6 is C 1~4 It is alkyl (where C 1~4 The alkyl group is substituted with 0, 1, 2, or 3 F atoms; and R 7 (wherein the cyclopropyl group is selected from cyclopropyl, and the cyclopropyl group is substituted with 0 or 1 substituent selected from F, CN, OH, or SO2CH3.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0110] In one embodiment, a compound of formula (IC) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 H, F, Cl and C 1~2 Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. R 1 is cyclopropyl or C 1~3 It is alkyl (where C 1~3 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0111] In further embodiments, compounds of formula (IC) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 H, F, Cl and C 1~2Selected independently of alkyl (where C 1~2 Alkyls are F, CN, NH2 and OC 1~2 Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC 1~2 The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl. R 1 is C 1~3 It is alkyl (where C 1~3 The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 3 H, R 6 , OR 6 NHR 6 Cl, CN, CCH, NH2, SCH3, cyclopropyl, cyclobutyl, NH(a (5-6 member) heteroaryl containing 1 or 2 N), NH(C 1~2 Selected from alkyl)N(CH3)2, oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 Alkyl groups consist of 0, 1, 2, or 3 F, O(C) 1~2 (Alkyl) and substituted with 0 or 1 substituent selected from (4-5 member) heterocycloalkyl groups containing OH, CN, N(CH3)2 and 1 O). Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0112] In further embodiments, compounds of formula (IC) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 1 is C 1~3 It is alkyl (where C 1~3The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. R 3 is R 6 NHR 6 Selected from cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 (Alkyl is substituted with 0, 1, 2, or 3 F atoms.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0113] In further embodiments, the compound of formula (IC) [ka] [In the formula, X 1 and X 3 CR is independent 5 Selected from; R 5 is H; R 1 It is CH3; R 3 It is cyclopropyl; R 6 is C 1~4 It is alkyl (where C 1~4 (Alkyl is substituted with 0, 1, 2, or 3 F atoms.) Alternatively, a pharmaceutically acceptable salt thereof is provided.

[0114] One or more of the above embodiments can be combined to provide further specific embodiments.

[0115] In one embodiment, the compound of formula (I) is selected from the following: 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(ethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide, 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(propa-2-inylamino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 5-(cyanomethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-fluoropropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-fluoropropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide, 5-Ethinyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-5-[(1-methylpyrazole-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide, 5-Ethoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyano-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(1-methylimidazo[4,5-d]pyridazine-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-ethylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-cyclopropylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-[3-(difluoromethyl)imidazo[4,5-c]pyridine-7-yl]-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-chloro-1-methyl-benzimidazole-4-yl-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-cyano-1-methyl-benzimidazole-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3,4-dimethylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 3-(2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2,3-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-3-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(2,3,5-trifluoro-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(2-fluoro-5-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3,5-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(3-methyl-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(3,5-dimethyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-cyano-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[3-(difluoromethyl)-4-morpholino-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(2-methyl-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(2-methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(5-methyl-6-morpholino-3-pyridyl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(3S)-3-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(2S)-2-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[6-[(3R)-3-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[(5-cyano-6-morpholino-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-((4-(1,4-oxazepan-4-yl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-5-(methylamino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(3R)-3-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 3-[2-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[2,3,5-trifluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)anilino]pyrazine-2-carboxamide, 3-anilino-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(difluoromethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(4-isopropoxyanilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, [4-[[3-carbamoyl-6-(methylamino)-5-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-yl]amino]phenyl]methanesulfonate, 3-[4-(2-methoxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethoxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(2-hydroxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-morpholinoethoxy)anilino]pyrazine-2-carboxamide, 3-(4-aminoanilino)-5-(methylamino)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[2-methoxyethyl(methyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[bis(2-methoxyethyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(2-methyl-4-pyridyl)amino]pyrazine-2-carboxamide forate, 3-[(2-methoxy-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)pyrazine-2-carboxamide hydrochloride, 3-[(2,6-dimethyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(2,6-dimethyl-4-pyridyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[2-(2-methoxyethoxy)-6-methyl-4-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-cyano-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(1,5-dimethyl-6-oxo-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(difluoromethyl)-6-oxo-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 5-(methylamino)-3-[4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]-3,5-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[4-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-3-[4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-3,5-dimethyl-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethyl-methyl-amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 3-[4-[3-(dimethylamino)azetidine-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 3-[3-cyano-4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[4-(4-methylpiperazine-1-yl)-1-piperidyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[6-(4-isopropylpiperazine-1-yl)-5-methyl-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[5-methoxy-6-(4-methylpiperazine-1-yl)-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[[5-chloro-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(6-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(6-ethyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(6-isopropyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[(dimethylamino)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(pyrrolidine-1-ylmethyl)anilino]pyrazine-2-carboxamide bis-formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-oxa-6-azaspiro[3,3]heptan-6-ylmethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1R)-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1S)-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1R)-1-morpholinoethyl]anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1S)-1-morpholinoethyl]anilino]pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[1-methyl-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methyl-1-morpholinoethyl)anilino]pyrazine-2-carboxamide, (R)-3-((4-((3-fluoropyrrolidine-1-yl)methyl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-5-(methylamino)pyrazine-2-carboxamidoformate, 3-[4-[[(3S)-3-fluoropyrrolidine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[(3,3-difluoropyrrolinidine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[[(3S)-3,4-dimethylpiperazine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide tris-formate, 3-[4-[[(3R)-3,4-dimethylpiperazine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[6-(morpholinomethyl)-3-pyridyl]amino]pyrazine-2-carboxamidoformate, 3-[2-fluoro-4-[(4-methylpiperazine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[3-chloro-4-[(4-methylpiperazine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-fluoro-4-[[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-fluoro-4-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-chloro-4-(2-oxa-6-azaspiro[3,3]heptan-6-ylmethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-morpholinoethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[2-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(pyrrolidine-1-ylmethyl)anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(3S)-4-methylmorpholine-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(3R)-4-methylmorpholine-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(2R)-4-methylmorpholine-2-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(2S)-4-methylmorpholine-2-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(4-piperidyloxy)anilino]pyrazine-2-carboxamide, 3-[4-[(1-acetyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 3-[4-[[1-(2-hydroxyacetyl)-4-piperidyl]oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 3-[3,5-difluoro-4-[(1-methyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(1-isopropyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-methoxy-1-methylpyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2S,4R)-4-methoxy-1-methylpyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[3-(4-methylpiperazine-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[3-(1-methyl-4-piperidyl)anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(4-methylimidazole-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-([1,2,4]triazolo[4,3-a]pyridine-6-ylamino)pyrazine-2-carboxamide, 3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-imino-2-oxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Methoxy-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxo-1,4-thiadinan-4-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -Sulfanylidene]amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -Sulfanylidene]amino]-2-fluoroanilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -Sulfanylidene]amino]-2,3-difluoroanilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide forate, 3-[4-(1,1-dioxo-1,2-thiazolidined-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxothiazinan-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-4-methylsulfonyl-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, (R)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, (S)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(tert-butylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(1-methylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 3-[(1-isopropylpyrazole-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1,1-dioxothian-4-yl)pyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide forate, 3-[(1,3-dimethylpyrazole-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-3-methyl-pyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-5-methylpyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methylpyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1,3-dimethylpyrazole-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(2,2-difluoroethyl)-3-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methylpyrazole-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyanocyclopropyl)-3-methyl-pyrazole-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1,5-dimethylpyrazole-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(3-methyl-1H-pyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(oxetan-3-yl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-(oxetan-3-yl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(2,2-difluoroethyl)-5-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(3,3-difluoropropyl)-3-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(3,3-difluoropropyl)-5-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(3-methyl-1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(5-methyl-1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-[[5-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, and their pharmaceutically acceptable salts.

[0116] It should be noted that any one of these specific compounds may be excluded from any of the embodiments described herein.

[0117] In one embodiment, a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I), as well as intermediates used in the preparation thereof, are provided.

[0118] Another embodiment is a product obtained by any of the processes or examples disclosed herein.

[0119] Medical and pharmaceutical use The compounds of formula (I) and their pharmaceutically acceptable salts are beneficial because they possess pharmacological activity as inhibitors of hematopoietic precursor kinase 1 (HPK1), and are therefore particularly useful in treating or improving common cell proliferation disorders such as cancer.

[0120] The compound of formula (I) is an HPK1 inhibitor. Therefore, the compound of formula (I) can be used as a drug, particularly as a drug for disorders, diseases, or conditions that respond to HPK1 inhibition, and more specifically as a drug for cancer. In further embodiments, pharmaceutical formulations are provided comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the treatment of conditions in which inhibition of HPK1 would be beneficial.

[0121] Further embodiments provide compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) for use in the treatment, in particular for the prevention or treatment of cancer in mammals (especially humans).

[0122] Further embodiments provide the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a drug for the treatment of cancer.

[0123] In further embodiments, HPK1 levels are reduced in mammals (particularly humans) by administration of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I).

[0124] Regarding the therapeutic indicators mentioned above, the dosage administered will naturally vary depending on the compound used, the method of administration, and the desired treatment. However, generally, satisfactory results can be obtained when the compound is administered in solid doses of 1-2000 mg / day. Compounds of formula (I) and their pharmaceutically acceptable derivatives are used either in themselves or as compounds or

[0125] The derivative may be used in the form of a suitable pharmaceutical composition in the form of a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. Therefore, another aspect relates to a pharmaceutical composition comprising a novel compound of formula (I) or a pharmaceutically acceptable salt thereof in the form of a mixture with a pharmaceutically acceptable adjuvant, diluent, or carrier. Administration may be, but is not limited to, enteral (oral, sublingual, or rectal, etc.), intranasal, inhalation, intravenous, topical, or other parenteral routes. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are, for example, in Pharmaceuticals - The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2 nd This is described in Ed.2002. The pharmaceutical composition preferably contains less than 80%, more preferably less than 50%, of the compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0126] Pharmacological properties Compounds of formula (I) or pharmaceutically acceptable salts thereof are considered useful for the prevention or treatment of disorders, diseases, or conditions that respond to HPK1 inhibition, more specifically, cancer.

[0127] To avoid uncertainty, the term “treatment” as used herein includes therapeutic and / or preventive measures.

[0128] When any compound or salt described herein is administered as a therapy for the treatment of a disorder, the “therapeutic effective dose” is an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder, to cure the disorder, to reverse, completely halt or slow the progression of the disorder, or to reduce the risk of the disorder worsening.

[0129] Therefore, the compounds described herein are indicated for both therapeutic and / or prophylactic treatment of these conditions.

[0130] The compounds described herein have advantages over known compounds of the prior art, such as being more potent, less toxic, more selective, more potent, having fewer side effects, being more readily absorbed, and / or having a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance).

[0131] Combination therapy The compound of formula (I) or a pharmaceutically acceptable salt thereof may also be administered in combination with other compounds used to treat the above-mentioned conditions.

[0132] Another embodiment is a combination therapy in which a compound of formula (I) or a pharmaceutically acceptable salt thereof and a second active ingredient are administered simultaneously, sequentially, or in combination for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more further active ingredients.

[0133] Compounds of formula (I) or pharmaceutically acceptable salts thereof can be used in combination with checkpoint blockade PD-(L)1 axis or CTLA4 to enhance the response rate to checkpoint blockade. Primary or secondary resistance to checkpoint blockade may be a potential indication of compound (I) or pharmaceutically acceptable salts thereof. Further combinations may include radiotherapy, chemotherapy, surgery, tumor targeting agents, or other immunotargeting agents.

[0134] When used in combination therapy, the compound of formula (I) or a pharmaceutically acceptable salt thereof, and other active ingredients may be administered in a single composition, in completely separate compositions, or in combination thereof. Furthermore, the active ingredients may be administered together, simultaneously, sequentially, or individually.

[0135] The specific composition and dosage of a combination therapy will vary depending on various factors, including, for example, the route of administration, the condition being treated, the patient's species, any potential interactions between active ingredients when combined in a single composition, any interactions between active ingredients when administered to animal patients, and various other factors known to physicians (with respect to human patients), veterinarians (with respect to non-human patients), and others skilled in the art.

[0136] Pharmaceutical composition A method for treating a condition requiring inhibition of HPK1 is provided, comprising administering a therapeutically effective amount of a compound of formula (I) to a person having or being susceptible to such a condition.

[0137] Compounds of formula (I) are typically administered in the form of pharmaceutical formulations containing the active ingredient or a pharmaceutically acceptable salt thereof, by oral, topical, parenteral, intravenous, intramuscular, subcutaneous, or other injectable methods, via oral, rectal, vaginal, transdermal and / or nasal routes, and / or by inhalation. The compositions may be administered in various doses depending on the disorder to be treated, the patient, and the route of administration. Conventional procedures for selecting and preparing suitable pharmaceutical formulations are, for example, seen in Pharmaceuticals - The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2 nd It is described in Ed. 2002.

[0138] The preferred daily dose of the compound of formula (I) in therapeutic treatment for humans is approximately 0.0001 to 100 mg / kg body weight, preferably 0.01 to 10 mg / kg body weight.

[0139] Oral formulations are preferred, and in particular, tablets or capsules that can be formulated by methods known to those skilled in the art to provide the active compound in doses ranging from 0.007 mg to 700 mg are preferred.

[0140] The optimal dosage and frequency of administration will vary depending on the specific medical condition being treated and its severity; the patient's species; the patient's age, sex, size, weight, diet, and overall physical condition; the brain-to-body weight ratio; other medications the patient may take; the route of administration; the formulation; and various other factors known to physicians and those skilled in the art.

[0141] Accordingly, according to further embodiments, pharmaceutical formulations are provided that include a compound of formula (I) or a pharmaceutically acceptable derivative thereof in the form of a mixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0142] The compound of formula (I) may be included in a pharmaceutical formulation at a concentration of 0.1 to 99.5% by weight, for example, 0.5 to 95% by weight, relative to the entire formulation.

[0143] Protection and deprotection of functional groups are described in Protective Groups in Organic Synthesis, 4. th Ed, TW Greene and PGM Wuts, Wiley-Interscience (2006) and Protecting Groups, 3 rd This is described in Ed., PJ Kocienski, and Georg Thieme Verlag (2005).

[0144] Further embodiments include pharmaceutically acceptable salts of the compound of formula (I). Salts of the compound of formula (I) may be advantageous due to one or more chemical or physical properties, such as stability at various temperatures and humidity levels, or desirable solubility in H2O, oil, or other solvents. In some cases, the salt may be used to aid in the isolation or purification of the compound. In some embodiments (particularly when the salt is intended for administration to animals (e.g., humans) or is a reagent for use in the manufacture of a compound or salt intended for administration to animals), the salt is pharmaceutically acceptable.

[0145] The term "pharmaceutically acceptable" is used to characterize a portion (e.g., a salt, dosage form, or excipient) that is suitable for use in accordance with appropriate medical judgment. Generally, a pharmaceutically acceptable portion has one or more benefits that outweigh any potential adverse effects it may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0146] If the compound is sufficiently basic, pharmaceutically acceptable salts include, but are not limited to, inorganic acid addition salts or organic acid addition salts.

[0147] For a review of suitable salts, see Berge et al., J. Pharm. Sci., 1977, 66, 1-19, or Handbook of Pharmaceutical Salts: Properties, Selection, and Use, PH Stahl, PG Vermuth, IUPAC, Wiley-VCH, 2002.

[0148] If the acid co-former is solid at room temperature, and there is no or only partial proton transfer between the compound of formula (I) and the acid co-former, a cocrystal of the co-former and the compound of formula (I) may be formed, rather than a salt. All such co-crystalline forms of the compound of formula (I) are encompassed herein.

[0149] It should also be understood that certain compounds of formula (I) may exist in solvated forms (e.g., hydrates), such as solvates of pharmaceutically acceptable salts of compounds of formula (I).

[0150] In further embodiments, the specific compounds of formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomer mixtures. The specific compounds of formula (I) may also contain bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amine bonds) in which bond rotation is restricted with respect to that particular bond, for example, due to the presence of ring bonds or double bonds. Stereoisomers can be separated using conventional techniques (e.g., chromatography or fractional crystallization) and can also be produced by stereoselective synthesis.

[0151] In further embodiments, the compound of formula (I) encompasses any isotopically labeled (or "radiationally labeled") derivatives of the compound of formula (I). Such derivatives are derivatives of the compound of formula (I) in which one or more atoms are replaced by atoms having atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated include: 2 One example is H (also written as "D" for deuterium).

[0152] In further embodiments, the compound of formula (I) may be administered in the form of a prodrug that is broken down in the body of a human or animal to produce the compound of formula (I).

[0153] Various forms of prodrugs are known in this field. For examples of prodrug derivatives, see Nature Reviews Drug Discovery 2008, 7, 255 and the references cited therein.

[0154] The intermediate compounds also exist in enantiomer form and can be used as purified enantiomers, diastereomers, racemates, or mixtures.

[0155] Pharmacological activity Assay description HPK1, GLK, and LCK ICs 50 Assay: The activity of N-terminal GST-tagged recombinant human HPK1, GLK, and LCK enzymes expressed in insect cells and purified (HPK1: amino acids 1-346, ThermoFisher Scientific, #PV6356, Carlsbad, CA; GLK: amino acids 1-380, ThermoFisher Scientific, #PV6351, Carlsbad, CA; LCK: full length, Abcam, #ab79626, Cambridge, MA) was determined in vitro by quantifying the amount of ADP produced in the kinase reaction using the ADP-Glo ​​Max Assay (Promega, #V7002, Madison, WI) and a luminescent ADP detection assay.

[0156] The generated luminescence signal was proportional to the ADP concentration produced in the kinase assay in the presence and absence of the compound and correlated with kinase activity. Two microliters (μl) of an enzyme mixture consisting of 10 nM HPK1, 30 nM GLK, or 2 nM LCK in 1× reaction buffer (50 mM HEPES (pH 7.2), 1 mM DL-dithiothreitol (DTT), 0.005% (v / v) Brij35, 20 mM MgCl2) was spotted onto a low-volume Greiner 384-well plate containing 0.1 μl of the compound. The mixture was then administered at final test concentrations of 100, 31.25, 12.5, 3.19, 1, 0.32, 0.1, 0.032, 0.01, and 0.003 μM and pre-incubated at room temperature for 30 minutes. The enzymatic reaction was initiated using 2 μl of peptide substrate / ATP mixture in 1× reaction buffer (HPK1: 10 μM LRRKtide (RLGRDKYKTLRQIRQ-amide; Cambridge Research Biochemicals, Billingham, UK), 30 μM ATP; GLK: 14 μM LRRKtide, 60 μM ATP; LCK: 100 μM LCKtide (EQEDEDEPEGIYGVLE-amide; Intonation, Boston, MA), 50 μM ATP) and incubated at room temperature for 60 minutes. The reaction was stopped by adding 4 μl of ADP-Glo ​​reagent to deplete the remaining ATP and incubated at room temperature for 60 minutes. Finally, 8 μl of ADP-Glo ​​Max detection reagent was added to simultaneously convert ADP to ATP and incubated at room temperature for 60 minutes. The newly synthesized ATP was converted to light by the luciferase / luciferin reaction. The light emission was read using a PHERAstar FSX plate reader (BMG LABTECH, Cary, NC), and the data was captured using PHERAstar FSX MARS data analysis software. An IC was then analyzed using a GeneData Screener (GeneData AG, Basel, Switzerland). 50 The value was calculated.

[0157] T cell assay material RPMI 1640 (Sigma R5886) Heat-inactivated FBS (Gibco 10270-10 Glutamax 100X(ThermoFisher 35050061) HEPES 1M(ThermoFisher 15630080) Dalbecco PBS (Sigma D8537) MultiCyt® QBeads® Human PlexScreen (2) for Plex, 1 x 384 plate (Sartorius 90602) Ultra-LEAF® Purified Anti-Human CD28 Antibody (Biolegend 302933) CD3 monoclonal antibody (OKT3), functional grade, eBioscience® (ThermoFisher 16-0037-85) β-mercaptoethanol (Sigma M3148) Propidium iodide (Abcam ab14083) Pen / Strep (Sigma P0781) Non-essential amino acids (Sigma M7145) Sodium pyruvate (Sigma S8636)

[0158] Preparation of T cell culture medium To prepare the original culture medium with a final concentration of 100 mM, use RPMI 1640 + 10% heat-inactivated FBS + 1% Glutamax (100x) + 1% Pen / Strep + 1% non-essential amino acids + 1M HEPES 14.3M undiluted β-mercaptoethanol solution containing 1% sodium pyruvate + 1.75 µl.

[0159] method Cryopreserved human CD3+ T cells are harvested overnight in warm T cell medium. The harvested T cells are seeded at a rate of 70,000 cells per well in a 384-well black / clear round-bottom ultra-low adhesion surface spheroid microplate (Corning 3830). Compounds from an assay-ready 384-well plate (Greiner 781280) are added to the seeded T cells using a Bravo liquid handler. The T cells are then incubated in a humidified incubator at 37°C for 1 hour. At the end of incubation, the cells are transferred to a 384-well flat-bottom plate (Greiner 781090) coated with anti-CD3 antibody (5 ug / mL anti-CD3 in PBS, incubated overnight at 4°C). Anti-CD28 antibody in the T cell medium is also added to the cells at a rate of 5 ug / mL or 1 ug / mL using a Bravo liquid handler, in a donor-dependent manner. Next, the T cells are incubated in a humidified incubator at 37°C for 4 hours. After 4 hours of incubation, the cell culture supernatant is collected in a V-bottom 384-well plate (Greiner 781280) using a Bravo liquid handler. IL2 is detected using an iQue Screener flow cytometer (Sartorius) with the IL2 MultiCyt® QBeads® kit. In short, the capture beads are diluted 50-fold with the supplied capture bead diluent. Using a ThermoFisher multichannel pipette, 10 μl of diluted capture beads per well is added to each well of the V-bottom 384-well plate (Greiner 781280). Using a Bravo liquid handler, 10 μl of cell culture supernatant is transferred to the V-bottom plate containing the diluted capture beads. The plate is then sealed in foil and incubated at room temperature for 1 hour in a plate shaker set to 900 rpm. At the end of incubation, 10 μL of the supplied detection reagent is added per well using a ThermoFisher multichannel pipette. The plate is then sealed in foil and incubated again at room temperature for 2 hours in a plate shaker set to 900 rpm, followed by detection using an iQue Screener.The iQue Screener flow cytometer detects IL2 in each sample well using a pre-configured analysis template provided with the IL2 MultiCyt® QBeads® kit.

[0160] Example Compound IC 50 / EC 50 The values ​​are shown in Table 1 of this specification below.

[0161] [Table 1]

[0162] [Table 2]

[0163] [Table 3]

[0164] [Table 4]

[0165] [Table 5]

[0166] [Table 6]

[0167] [Table 7]

[0168] [Table 8]

[0169] [Table 9] [Examples]

[0170] The following examples are non-restrictive.

[0171] The following abbreviations are used herein: BINAP(2,2'-bis(diphenylphosphino)-1,1'-binaphthyl), also known as [1-(2-diphenylphosphanyl-1-naphthyl)-2-naphthyl]-diphenylphosphane BrettPhos Dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphan BrettPhos Pd G3[(dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphan)-2'-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate cataCXium A bis(1-adamantyl)-butyl-phosphane cataCXium A Pd G2 Chloro[(bis(1-adamantyl)-butyl-phosphane)-2-(2-aminobiphenyl)]palladium(II) cataCXium A Pd G3[(bis(1-adamantyl)-butyl-phosphane)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate dba dibenzylideneacetone, also known as (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one DCE 1,2-Dichloroethane DCM Dichloromethane Also known as DIPEA N,N-diisopropylethylamine and N-ethyl-N-isopropyl-propane-2-amine. DMF (N,N-dimethylformamide) DPEPhos[2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphan DSC (Differential Scanning Calorimetry) HATU Azabenzotriazole tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethyl-1-(3-oxide triazolo[4,5-b]pyridine-3-ium-1-yl)methanediamine; also known as hexafluorophosphate. DIAD, also known as diisopropyl azodicarboxylate or isopropyl (NE)-N-isopropoxycarbonyliminocarbamate. DMA N,N-dimethylacetamide Also known as DMAP N,N-dimethylaminopyridine or N,N-dimethylpyridine-4-amine. DMSO (Dimethyl Sulfoxide) Dppf 1,1'-bis(diphenylphosphino)ferrocene, also known as (ferrocene-1,1'-diyl)bis(diphenylphosphan). DTBAD, also known as di-t-butyl azodicarboxylate or tert-butyl (NE)-Nt-butoxycarbonyliminocarbamate. EPhos Dicyclohexyl-[2-isopropoxy-6-(2,4,6-triisopropylphenyl)phenyl]phosphane EPhos Pd G4[(Dicyclohexyl-[2-Isopropoxy-6-(2,4,6-Triisopropylphenyl)phenyl]phosphan)-2-(2'-Methylamino-1,1'-Biphenyl)]Palladium(II) Methanesulfonate ES Electrospray HPLC (High-Performance Liquid Chromatography) Also known as IPA isopropanol or propan-2-ol. Ir(dFCF3ppy)2(dtbbpy)[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate LCMS Liquid Chromatography-Mass Spectrometry mCPBA is also known as meta-chloroperbenzoic acid or 3-chlorobenzenecarboperoxoic acid. MDAP Mass Directed Automated Purification MHz (megahertz) MTBE is also known as methyl tert-butyl ether, or 2-methoxy-2-methylpropane. m / z mass / charge NMP 1-methylpyrrolidine-2-one NMR nuclear magnetic resonance PCy3Pd G3[(Tricyclohexylphosphan)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate Pd-PEPPSI-IPent[(di(1-adamantyl)-butylphosphine)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate sCO2 Supercritical Carbon Dioxide SFC Supercritical Fluid Chromatography TBAF Tetrabutylammonium Fluoride t-BuXPhos Di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane t-BuXPhos Pd G3[(di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane)-2-(2'-amino-1,1'-biphenyl)]palladium(II)methanesulfonate TFA 2,2,2-trifluoroacetic acid TGA thermogravimetric analysis THF (Tetrahydrofuran) XantPhos(5-diphenylphosphanyl-9,9-dimethylxanthen-4-yl)-diphenylphosphan XantPhos Pd G3[((5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphan)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Xphos Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphan XPhos Pd G3 (Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphan)[2'-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0172] The following general experimental procedure was used: Unless otherwise specified, operations should be performed at room temperature, i.e., within the range of 18-25°C.

[0173] The organic solvent was evaporated using a rotary evaporator under reduced pressure (4.5-30 mmHg) and a bath temperature of up to 60°C.

[0174] Generally, TLC or liquid chromatography / mass spectrometry was performed after the reaction process, but the reaction time is shown for illustrative purposes only; The yields shown are for illustrative purposes only and do not necessarily reflect the results obtained through meticulous process development. When more material was needed, the preparation was repeated.

[0175] Microwave reactions were carried out using Biotage microwave vials with either a Biotage Initiator or an Emrys Optimizer.

[0176] Silica gel chromatography was performed using Biotage Selekt, Biotage Isolera, or Teledyne ISCO Combiflash Companion automated purification systems, with Biotage Sfar, Biotage SNAP, Agela Claricep, RediSep Rf Gold Silica, or Buchi FlashPure columns, in sizes ranging from 5g to 300g as needed.

[0177] Reverse-phase chromatography was performed using Biotage Selekt, Biotage Isolera, Teledyne ISCO Combiflash Companion, or Agela Technologies automated purification systems, with Biotage Sfar C18 Duo, RediSep Rf C18, or RediSep Rf Gold C18 columns, in sizes ranging from 5g to 300g as needed.

[0178] MDAP purification was performed using Agilent InfinityLab LC / MSD with Agilent 1260 Infinity II (autosampler, DAD, quaternary pump, and isocratic pump) and Agilent 1290 Infinity II (preparative pump and fraction collector). The column and gradient are specified in the examples.

[0179] Preparative HPLC purification was performed using Waters FractionLynx systems equipped with Acquity QDa mass detectors, or instruments including Waters 2545, 2767, and 2489 equipped with QDa or SQ Detector2ESCi mass spectrometers. Columns and gradients are specified in the examples.

[0180] Preparative and analytical SFC purification is performed using Sepiatec Prep SFC100, Sepiatec Prep SFC250, Waters Prep100, Waters SFC Method Station X5, and Waters Acquity UPC. 2 Acquity UPC, equipped with Berger Multigram III and Waters Xevo TQ-S Micro Triple Quadrupole Mass Spectrometer. 2 The analysis was performed using Waters Prep 80, Waters Prep 150, or Waters Prep 350. The column and gradient are specified in the examples.

[0181] Ion exchange chromatography was performed using a Waters PoraPak Rxn CX cartridge.

[0182] 1 ¹H NMR measurements were performed using Bruker Avance Neo 300, Bruker Avance III 300, Bruker Avance IIIHD 300, Bruker Avance IIIHD 400, Jeol JNM-ECZ400S / L1, Bruker AV3HD Nano 400, Bruker NEO500, or Bruker DRK 500 mass spectrometers (operating at 1H frequencies of 300, 300, 300, 400, 400, 400, 400, 400, 500, and 500 MHz, respectively). Experiments were typically recorded at 27°C. Shifts were referenced according to IUPAC 2001 guidelines as described in DOI:10.1006 / snmr.2002.0063, and are Rev3 truncations as described in DOI:10.1006 / snmr.2002.0063. In most cases, the shift is due to the residue of the deuterated solvent. 1 The data was re-referenced during processing according to the H chemical shift.

[0183] UPLC-MS was performed using one of the following: 1) a solvent gradient from 2% B to 98% B over 1.5 minutes at a flow rate of 1 mL / min (total operating time for equilibration back to starting conditions: 2 minutes) Waters Acquity UPLC and Waters SQ mass spectrometer (column temperature 30°C, detection UV = 210-400 nm, mass spectrometry = ESI with positive / negative switching), A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile (for acid function), or A = 0.1% ammonium hydroxide in water and B = acetonitrile (for base function). The column used for acid analysis was Waters Acquity HSS T3, 1.8 micron, 2.1 mm × 30 mm; the column used for base analysis was Waters Acquity BEH C18, 1.7 micron, 2.1 mm × 30 mm; or 2) Shimadzu LCMS-2020 (20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA detector and LCMS2020) Equipped with an MS detector, electrospray ionization is performed in positive ion detection mode, using one of the following three conditions: a) Halo-C18 column (2.0 microns, 3 mm × 30 mm) with a gradient of (A) water and formic acid (0.1%) and (B) acetonitrile and formic acid (0.1%) (from 5% B to 100% B in 1.2 mins), flow rate 1.5 mL / min; b) Halo-C18 column (2.0 microns, 3 mm × 30 mm) with a gradient of (A) water and trifluoroacetic acid (0.05%) and (B) acetonitrile and trifluoroacetic acid (0.05%) (from 5% B to 100% B in 1.2 mins), flow rate 1.5 mL / min; c) Poroshell HPH with a gradient of (A) 46 mM ammonium carbonate aqueous solution / ammonia buffer (pH 10) and (B) acetonitrile (from 10% B to 95% B in 2 mins). C18 column (2.7 microns, 3 mm x 50 mm), flow rate 1.2 mL / min.

[0184] Photo-oxidation-reduction chemistry is known as HepatoChem and EvoluChem. TM The experiment was conducted in a PhotoRedOx reactor using a 34W Kessil H150 blue LED lamp (440nm) as the light source.

[0185] Optical rotation data was obtained at 25°C using a Jasco P-2000 polarimeter, with a path length of 100 mm, using a 0.40 w / v% solution of the compound in DMSO, and under sodium D line (589 nm).

[0186] X-ray diffraction analysis was performed according to standard methods found, for example, in Kitaigorodsky, AI (1973), Molecular Crystals and Molecules, Academic Press, New York; Bunn, CW (1948), Chemical Crystallography, Clarendon Press, London; or Klug, HP & Alexander, LE (1974), X-ray Diffraction Procedures, John Wiley & Sons, New York. The sample was mounted on a single silicon crystal (SSC) wafer mount, and powder X-ray diffraction was recorded using PANalytical X'Pert PRO (reflection configuration, X-ray wavelength of 1.5418 Å nickel-filtered Cu radiation, voltage 45 kV, filament emission 40 mA). The sample was rotated during measurement using an auto-variable divergence and anti-scattering slit. Using a PIXCEL detector (effective length 3.35° 2-theta), samples were scanned from 2–50° 2-theta or 2–40° 2-theta using a step size of 0.013° and count times of 44–233 seconds.

[0187] In the art, it is known that X-ray powder diffraction patterns with one or more measurement errors can be obtained depending on the measurement conditions (e.g., the apparatus, sample preparation, or the machine used). In particular, it is generally known that the intensity of the X-ray powder diffraction pattern can vary depending on the measurement conditions and sample preparation. For example, those skilled in the art will understand that the relative intensity of peaks may vary depending on the orientation of the sample being tested and the type and settings of the equipment used. Those skilled in the art will also understand that the position of reflections can be affected by the exact height at which the sample is positioned in the diffractometer and the zero calibration of the diffractometer. The surface flatness of the sample may also have some effect. Therefore, those skilled in the art will recognize that the diffraction pattern data presented herein should not be interpreted as absolute, and that any crystal form that gives substantially the same powder diffraction pattern as disclosed herein is within the scope of this disclosure (for further information, see Jenkins, R & Snyder, RL, 'Introduction to X-Ray Powder Diffractometry,' John Wiley & Sons, 1996). In general, the measurement error of the diffraction angle in X-ray powder diffractograms can be approximately ±0.1°²theta, and this degree of measurement error should be taken into consideration when considering X-ray powder diffraction data. Furthermore, it should be understood that the intensity can vary depending on the experimental conditions and sample preparation (e.g., preferred orientation). Relative intensity (%) was defined as follows: 81-100%, vs (very strong); 41-80%, str (strong); 21-40%, med (intermediate); 10-20%, w (weak); 1-9%, vw (very weak).

[0188] The chemical IUPAC names were generated by BioviaDraw using OpenEye Metachem 1.5.0 software.

[0189] General intermediate Intermediate 1 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole [ka] (a) 3-bromo-N-methyl-2-nitroaniline 1-Bromo-3-fluoro-2-nitrobenzene (25.0 g, 114 mmol) was added at 0°C to a solution of 33% methanamine (114 mL, 916 mmol) in ethanol. The resulting solution was stirred at 25°C for 5 hours. The reaction product was then concentrated. The resulting residue was dissolved in ethyl acetate, washed three times with water, dried over sodium sulfate, filtered, and concentrated to obtain 3-bromo-N-methyl-2-nitroaniline (27.3 g, quantitative) as a bright orange solid; 1H NMR (500 MHz, dichloromethane-d2): 2.94 (3H, s), 5.51-5.90 (1H, m), 6.82 (1H, d), 6.99 (1H, dd), 7.23 (1H, t); m / z: (ES+), [M+H]+ = 231.1

[0190] (b) 3-bromo-N1-methylbenzene-1,2-diamine Iron powder (61.3 g, 1.10 mol) was added to a solution of 3-bromo-N-methyl-2-nitroaniline (25.4 g, 110 mmol) and ammonium chloride (58.8 g, 1.10 mol) in methanol (146 mL). The resulting suspension was stirred at 60°C for 2 hours. The reaction mixture was then concentrated. The resulting residue was partitioned between ethyl acetate and saturated potassium carbonate aqueous solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-100% ethyl acetate-hexane as the eluent to obtain 3-bromo-N1-methylbenzene-1,2-diamine (22g, 100%) as a purple oily substance; 1H NMR (500MHz, dichloromethane-d2) 2.89(3H,s), 6.62-6.67(1H,d), 6.69-6.75(1H,t), 6.96(1H,d); m / z: (ES+), [M+H]+=200.9 (c) 4-bromo-1-methyl-benzimidazole

[0191] 3-Bromo-N1-methylbenzene-1,2-diamine (22.1 g, 110 mmol) was added to a solution of 4-toluenesulfonic acid (2.09 g, 11.0 mmol) in trimethyl orthoformate (36.5 mL, 330 mmol). The resulting suspension was stirred at 60°C for 3 hours. The reaction product was then concentrated. The obtained residue was dissolved in ethyl acetate, washed three times with 10% potassium carbonate aqueous solution, dried over sodium sulfate, filtered, and evaporated to obtain 4-bromo-1-methyl-benzimidazole (21.6 g, 93%) as a purple solid; 1H NMR (500 MHz, dichloromethane-d2) 3.87 (3H, s), 7.21-7.27 (1H, m), 7.40-7.46 (1H, m), 7.48-7.53 (1H, m), 7.95 (1H, s); m / z: (ES+), [M+H]+ = 210.9

[0192] (d) 1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole 4-bromo-1-methyl-1H-benzo[d]imidazole (5.00 g, 23.7 mmol), cataCXium A Pd G3 (1.73 g, 2.37 mmol), cataCXium A (0.849 g, 2.37 mmol), bis(pinacolate)diborone (15.0 g, 59.2 mmol), and potassium acetate (6.97 g, 71.1 mmol) were mixed in a three-necked flask, then degassed under vacuum, and filled with nitrogen three times. Cyclopentyl methyl ether (120 mL) was added, and the reaction mixture was stirred at 80°C for 24 hours. The reaction mixture was then diluted with ether (100 mL), filtered through celite, and washed with ether. The filtrate was concentrated to obtain a brown solid, which was sonicated in hexane (600 mL) for 40 minutes, then allowed to stand for 90 minutes, then filtered, and washed with a small amount of hexane to obtain 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (4.77 g, 78%, 68 wt%) as a light gray solid; 1H NMR (500 MHz, dichloromethane-d2) 1.39 (12H, s), 3.83 (3H, s), 7.31 (1H, t), 7.53 (1H, d), 7.70 (1H, d), 7.91 (1H, s). Malfunction by LC-MS.

[0193] Intermediate 2 (1-Methylbenzimidazole-4-yl)boronic acid [ka] PdCl2(dppf) (5.20 g, 7.11 mmol) was added to a suspension of potassium acetate (13.95 g, 142.1 mmol), 4-bromo-1-methyl-benzimidazole (10.00 g, 47.38 mmol), and bis(pinacolate)diborone (24.06 g, 94.76 mmol) in dioxane (400 mL). The resulting mixture was stirred at 100°C for 3 days. The reaction product was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 50 mm × 150 mm, XBridge Prep C18 OBD column with a MeCN-water mixture (which reduces polarity) as the eluent and 1% formic acid as a modifier to obtain (1-methylbenzimidazole-4-yl)boronic acid (8.00 g, 96% yield) as a yellow solid. ¹H NMR (300 MHz, DMSO) δ 3.85 (3H, s), 7.26 (1H, t), 7.56 (1H, d), 7.68 (1H, d), 8.22 (1H, s). B(OH)2 protons extended to the baseline. m / z: (ES+), [M+H]+=177.1

[0194] Intermediate 3 7-Bromo-3-methylimidazo[4,5-c]pyridine [ka] 0.5 M sodium methoxide in methanol (425 mL, 213 mmol) was added to a mixture of 5-bromopyridine-3,4-diamine (10.0 g, 53.2 mmol) and paraformaldehyde (1.63 g, 54.3 mmol). The resulting mixture was stirred at 25°C for 4 hours. Sodium borohydride (2.01 g, 53.2 mmol) was added to the reaction mixture. The resulting mixture was stirred at 60°C for 1 hour. The reaction mixture was then concentrated. The resulting residue was treated with water and extracted with ethyl phosphate. The extract was dried over sodium sulfate, filtered, and concentrated. The resulting residue was suspended in triethyl orthoformate (200 mL) and stirred at 145°C for 1 hour. The reaction mixture was then cooled to 0°C and acidified with 4 M HCl in dioxane (16.0 mL, 64.0 mmol). The resulting precipitate was filtered to obtain a yellow solid, which was partitioned between saturated potassium carbonate aqueous solution and ethyl acetate, and extracted twice with ethyl acetate. The combined organic layer was dried over magnesium sulfate, filtered, and concentrated to obtain 7-bromo-3-methylimidazo[4,5-c]pyridine (9.00 g, 80%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 3.96(3H,s), 8.48(1H,s), 8.51(1H,s), 8.97(1H,s); m / z: (ES+)[M+H]+=212.0.

[0195] Intermediate 4 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)[4,5-c]pyridine [ka] A mixture of 7-bromo-3-methylimidazo[4,5-c]pyridine (24.00 g, 113 mmol), bis(pinacolate)diborone (35.90 g, 141.5 mmol), palladium(II) acetate (2.54 g, 11.3 mmol), cataCXium A (8.12 g, 22.6 mmol), and potassium acetate (33.30 g, 339.5 mmol) was degassed under vacuum and filled with nitrogen three times. 2-methyltetrahydrofuran (700 mL) was added, and this mixture was degassed under vacuum two more times and filled with nitrogen. The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with DCM (700 mL), filtered through Celite, and concentrated. The resulting residue was used in the next step without further purification.

[0196] Intermediate 5 (3-methylimidazo[4,5-c]pyridine-7-yl)boronic acid [ka] Dichlorobis(tricyclohexylphosphine)palladium(II) (418 mg, 0.570 mmol) was added under nitrogen to a suspension of 7-bromo-3-methyl-3H-imidazo[4,5-c]pyridine (600 mg, 2.83 mmol), bis(pinacolate)diborone (2.16 g, 8.49 mmol), and potassium acetate (833 mg, 8.49 mmol) in toluene (2 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeCN-water as the eluent and 0.1% formic acid as a modifier to obtain (3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)boronic acid (460 mg crude) as a white solid. m / z:(ES+),[M+H]+=178.1

[0197] Intermediate 6 2-(3-methylimidazo[4,5-c]pyridine-7-yl)-1,3,6,2-dioxazabolocan [ka] A suspension of 7-bromo-3-methylimidazo[4,5-c]pyridine (29.7 g, 140 mmol), bis(pinacolate)diborone (42.7 g, 168 mmol), palladium(II) acetate (3.14 g, 14.0 mmol), cataCXium A (10.04 g, 28.00 mmol), and potassium acetate (41.2 g, 420.00 mmol) in 2-methyltetrahydrofuran (879 mL) was sparged with argon for 20 minutes. The resulting mixture was stirred under argon at 86°C for 16 hours. The reaction mixture was then cooled to room temperature, diluted with DCM (879 mL), filtered through a celite pad, and washed twice with DCM (100 mL each time). The resulting filtrate was concentrated. The resulting solid was redissolved in 2-methyltetrahydrofuran (281 mL) and acetonitrile (167 mL). Diethanolamine (16.88 mL, 175.0 mmol) was added. The resulting mixture was stirred at room temperature for 16 hours. Additional 2-methyltetrahydrofuran (50 mL) and diethanolamine (6.75 mL, 70 mmol) were added. The resulting mixture was stirred at room temperature for 5 hours. The reaction product was then filtered and washed with MeCN to obtain 2-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-1,3,6,2-dioxazabolocan (30.0 g, yield 87%) as a pale yellow solid. ¹H NMR (500 MHz, heavy water) 3.02(4H,br t), 3.78(4H,br t), 3.94(3H,s), 8.32(1H,s), 8.34(1H,s), 8.77(1H,s).NH protons were exchanged in D2O.

[0198] Example 1 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl carboxylate Triethylamine (0.141 mL, 1.01 mmol) was added at 25°C to a solution of methyl 3,6-dibromopyrazine-2-carboxylate (100 mg, 0.34 mmol) and 4-morpholinoaniline (60 mg, 0.34 mmol) in MeOH (10 mL). The resulting mixture was stirred at 70°C for 16 hours. The solvent was then removed under reduced pressure. The residue was purified by silica gel chromatography using 60-70% toluene-petroleum ether as the eluent, yielding methyl 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate (80 mg, 60%) as a red solid; 1H NMR (300 MHz, DMSO-d6) δ 3.05(4H,t), 3.72(4H,t), 3.90(3H,s), 6.92(2H,d), 7.40(2H,d), 8.49(1H,s), 9.74(1H,s); m / z: (ES+), [M+H]+ 393.1.

[0199] (b) 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (30 mL, 210 mmol) was added to methyl 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate (2.00 g, 5.09 mmol) at 25°C. The resulting mixture was stirred at 60°C for 2 hours. Next, the solvent was removed under reduced pressure to obtain 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxamide (1.80 g, 94%) as a red solid; 1H NMR (400 MHz, DMSO-d6) δ 3.05-3.10 (4H,m), 3.70-3.79 (4H,m), 6.91-6.98 (2H,m), 7.44-7.49 (2H,m), 8.02 (1H,s), 8.27 (1H,s), 8.47 (1H,s), 10.99 (1H,s); m / z: (ES-), [MH]- = 377.1

[0200] (c) 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 1,1'-Bis(di-tert-butylphosphino)ferrocene palladium dichloride (35 mg, 0.050 mmol) was added to (1-methylbenzimidazole-4-yl)boronic acid (186 mg, 1.06 mmol), 6-bromo-3-((4-morpholinophenyl)amino)pyrazine-2-carboxamide (200 mg, 0.53 mmol), and potassium carbonate (219 mg, 1.59 mmol) in 1,4-dioxane (8 mL) and water (2 mL) under nitrogen at 25°C. The resulting mixture was stirred at 100°C for 4 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using a 5 micron, 50 mm × 150 mm XBridge Prep C18 OBD column, with a mixture of MeCN-H2O (which reduces polarity) as the eluent, and 0.1% formic acid as a modifier. 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (100 mg, 44%) was obtained as a brown solid; 1H NMR (400 MHz, DMSO-d6)δ 3.14(4H,s),3.79(4H,s),4.04(3H,s),7.06(2H,s),7.52-7.71(3H,m),7.85(1H,d),8.13(1H,d ),8.24(1H,d),8.53(1H,s),9.12(1H,s),9.47(1H,s),11.25(1H,s);m / z:(ES+)[M+H]+=430.3.

[0201] Example 2 5-Methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-bromo-5-methylpyrazine-2-carboxylic acid N-bromosuccinimide (209.0 g, 1175 mmol) was added to 3-amino-5-methylpyrazine-2-carboxylic acid (180.0 g, 1175 mmol) in acetonitrile (1.4 L). The resulting mixture was stirred at 82°C for 30 minutes. The reaction was then cooled to 0°C. The resulting precipitate was isolated by filtration, washed with acetonitrile, and dried under vacuum to obtain 3-amino-6-bromo-5-methylpyrazine-2-carboxylic acid (248 g, 91% yield) as a beige solid. ¹H NMR (400 MHz, DMSO) δ 2.37 (3H, s), 7.36 (2H, s), 13.08 (1H, br s).

[0202] (b) 3-amino-6-bromo-5-methylpyrazine-2-carboxylate methyl 3-amino-6-bromo-5-methylpyrazine-2-carboxylic acid (9.06 g, 39.1 mmol) in MeOH (200 ml) was mixed with sulfuric acid (6.00 ml, 113 mmol). The resulting mixture was stirred at 70°C for 17 hours. The reaction product was then concentrated. The resulting residue was dissolved in water and basicized with saturated sodium carbonate aqueous solution. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to obtain methyl 3-amino-6-bromo-5-methylpyrazine-2-carboxylic acid (8.41 g, 88%) as a purple solid; 1H NMR (500 MHz, DMSO-d6) 2.45 (3H, s), 3.82 (3H, s), 7.45 (2H, br s). m / z: (ES+), [M+2+H] = 248.0

[0203] (c) 3-amino-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl MeOH (14 mL) was added to a mixture of (1-methylbenzimidazole-4-yl)boronic acid (0.499 g, 2.84 mmol), methyl 3-amino-6-bromo-5-methylpyrazine-2-carboxylate (0.540 g, 2.19 mmol), CsF (1.000 g, 6.58 mmol), and PdCl2 (dppf) (0.161 g, 0.22 mmol). The resulting mixture was degassed, purged with nitrogen, and then heated in a Biotage microwave reactor at 100°C for 1 hour. The reaction mixture was then concentrated. The residue was purified by silica gel chromatography using 0-9% MeOH-DCM as the eluent, yielding methyl 3-amino-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (0.646 g, 99%) as a brown solid; ¹H NMR (500 MHz, DMSO-d6) 2.26(3H,s), 3.80(3H,s), 3.88(3H,s), 7.21(1H,dd), 7.32(2H,s), 7.36(1H,t), 7.64(1H,dd), 8.20(1H,s); m / z: (ES+)[M+H]+=298.1.

[0204] (d) 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl 1,4-Dioxane (30 mL) was added to a mixture of methyl 3-amino-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (1.18 g, 3.98 mmol), 4-(4-bromophenyl)morpholine (0.963 g, 3.98 mmol), BrettPhos Pd G3 (0.721 g, 0.800 mmol), and cesium carbonate (3.89 g, 11.9 mmol). The resulting mixture was degassed, purged three times with nitrogen, and then stirred at 100°C for 7 hours. The reaction mixture was then treated with water, the resulting precipitate was filtered, washed with water, and dried under vacuum. The obtained solid was purified four times by silica gel chromatography, once using 0-5% MeOH-DCM as the eluent, and in subsequent times using 0-3% MeOH-DCM as the eluent, to obtain methyl 5-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.912 g, 50%) as an orange solid; 1H NMR(500MHz,DMSO-d6)2.32(3H,s),3.05-3.11(4H,m),3.71-3.77(4H,m),3.87(3H,s),3.89(3H,s),6.94-6.99(2H, m),7.27(1H,dd),7.39(1H,t),7.58-7.62(2H,m),7.66(1H,dd),8.21(1H,s),9.86(1H,s);m / z:(ES+)[M+H]+=459.3.

[0205] (e) 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (20 mL, 140 mmol) was added to methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (0.538 g, 1.17 mmol). The resulting mixture was stirred at 40°C for 16 hours. 7N methanolic ammonia (10 mg, 70 mmol) was further added, and the reaction mixture was stirred at 40°C for 5 hours. The reaction product was then filtered and washed with MeOH. The resulting solid was purified by silica gel chromatography using 0-5% MeOH-DCM as the eluent to obtain a yellow solid. This substance was further purified by reverse-phase chromatography (C18) using 10-60% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as a modifier to obtain 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.438 g, 84%) as a yellow solid; ¹H NMR (500 MHz, DMSO-d6) 2.35 (3H, s), 3.03-3.10 (4H, m), 3.71-3.77 (4H, m), 3.88 (3H, s), 6.96 (2H, d), 7.36-7.41 (2H, m), 7.61 (2H, d), 7.63-7.67 (1H, m), 7.81 (1H, br d),8.02(1H,br d),8.22(1H,s),11.01(1H,s);m / z:(ES+)[M+H]+=444.2.

[0206] Example 3 5-Methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate methyl carboxylate 3-amino-5,6-dichloropyrazine-2-carboxylate methyl (10 g, 45 mmol) and potassium carbonate (18.7 g, 135 mmol) were suspended in MeOH (175 mL). The resulting suspension was stirred at 25°C for 16 hours. The solvent was removed under reduced pressure, and the resulting residue was dissolved in water (400 mL). The resulting suspension was vigorously stirred at 25°C for 2 hours. The suspension was filtered, and the filter cake was dried under vacuum to obtain 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate methyl (6.9 g, 70%) as a beige solid; 1H NMR (500 MHz, DMSO-d6) 3.79 (3H, s), 3.96 (3H, s), 7.60 (2H, br s); m / z: (ES+), [M+H]+ = 218.1

[0207] (b) Methyl 6-chloro-3-fluoro-5-methoxypyrazine-2-carboxylate Sodium nitrite (2.3 g, 33 mmol) was added in small increments at 10°C to methyl 3-amino-6-chloro-5-methoxypyrazine-2-carboxylate (6.90 g, 31.7 mmol) in HF-pyridine (20 mL, 580 mmol). The resulting suspension was stirred at 25°C for 1 hour. The reaction mixture was then diluted with DCM (50 mL) and quenched with water (200 mL). The layers were separated, and the aqueous layer was extracted twice with DCM (20 mL each time). The combined organic matter was dried over magnesium sulfate, filtered, and concentrated to obtain methyl 6-chloro-3-fluoro-5-methoxypyrazine-2-carboxylate (6.80 g, 97%) as a pink solid; ¹H NMR (500 MHz, DMSO-d6) 3.87 (3H, s), 4.06 (3H, s); m / z: (ES+), [M+H]+=221.1.

[0208] (c)6-Chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl carboxylate DIPEA (6 mL, 34.35 mmol) was added to a solution of methyl e 6-chloro-3-fluoro-5-methoxypyrazine-2-carboxylate (6.80 g, 30.8 mmol) and 4-morpholinoaniline (5.77 g, 32.4 mmol) in DMF (18 mL). The resulting solution was stirred at 100°C for 15 minutes. The reaction mixture was then removed from the heat and cooled to room temperature. The reaction mixture was filtered and washed with a small amount of toluene to obtain methyl 6-chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylate (9.28 g, 79%) as a yellow solid; ¹H NMR (500 MHz, DMSO-d6) 2.93-3.13 (4H, m), 3.61-3.78 (4H, m), 3.86 (3H, s), 3.98 (3H, s), 6.95 (2H, d), 7.50 (2H, d), 10.01 (1H, s); m / z: (ES+), [M+H]+ = 379.5.

[0209] (d) 5-Methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl The reaction was repeated five times to fit into microwave vials. In each vial, methyl 6-chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.73 g, 4.57 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (2.43 g, 63 wt%, 5.94 mmol), Pd(dppf)Cl2 (0.400 g, 0.490 mmol), and cesium fluoride (2.08 g, 13.7 mmol) were mixed and purged under nitrogen. MeOH (15 mL) was added to each, and the reaction mixtures were stirred at 100°C for 3 hours in a Biotage microwave reactor. Next, the reaction vials were combined, concentrated, loaded onto Celite, and purified by silica gel chromatography using 0-10% methanol-DCM as the eluent and 0-1% ammonia as a modifier to obtain an orange solid. Methanol (30 mL) was added to this solid, and the resulting suspension was stirred at 40°C for 1 hour, and then allowed to stand at 25°C for 30 minutes. The suspension was filtered and washed with a small amount of methanol to obtain methyl 5-methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (9.99 g, 92%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 3.05-3.11 (4H,m), 3.69-3.75 (4H,m), 3.84 (3H,s), 3.84 (3H,s), 3.86 (3H,s), 6.98 (2H,d), 7.18-7.29 (1H,m), 7.33 (1H,t), 7.55-7.71 (3H,m), 8.13 (1H,s), 10.16 (1H,s); m / z: (ES+), [M+H]+ = 475.4

[0210] (e) 5-Methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide The reaction was repeated five times to fit into microwave vials. In each vial, methyl 5-methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (2.00 g, 4.22 mmol) was suspended in 7N methanolic ammonia (20 mL, 140 mmol). Each reaction was stirred at 100°C for 8 hours in a Biotage microwave reactor. The reaction vials were cooled, then combined, filtered, and washed with a small amount of MeOH to obtain 8.0 g of a yellow solid. This substance was combined with another batch of the same substance (3.64 g), then loaded onto celite, and purified by silica gel chromatography using 0-5% MeOH-DCM as the eluent and 0-0.5% ammonia as a modifier to obtain a yellow solid. Methanol (70 mL) was added, and the resulting suspension was stirred at 40°C for 1 hour, then allowed to stand at 25°C for 1 hour. The suspension was filtered and dried under vacuum to obtain 5-methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (9.77 g, 84%) as a yellow solid; 1H NMR(600MHz,DMSO-d6)3.03-3.12(4H,m),3.68-3.76(4H,m),3.86(3H,s),3.89(3H,s),6.92-7.01(2H,m),7.33(1H, t),7.45(1H,dd),7.56-7.62(3H,m),7.64(1H,d),7.85(1H,d),8.16(1H,s),11.18(1H,s);m / z:(ES+),[M+H]+=460.4

[0211] Example 4 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-[2-(dimethylamino)ethoxy]pyrazine-2-carboxylate methyl carboxylate Sodium (0.311 g, 13.5 mmol) was added to methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (3.00 g, 13.5 mmol) and 2-(dimethylamino)ethanol (5.00 mL, 13.5 mmol). The resulting mixture was stirred at 25°C for 3 hours. The solvent was then removed under reduced pressure. The residue was purified by silica chromatography using 0-20% MeOH-DCM as the eluent to obtain methyl 3-amino-6-chloro-5-[2-(dimethylamino)ethoxy]pyrazine-2-carboxylate (1.50 g, 40%) as a yellow solid. 1H NMR(300MHz,DMSO-d6)δ 2.21(6H,s),2.65(2H,t),3.79(3H,s),4.44(2H,t),7.59(2H,s);m / z:(ES+),[M+H]+=275.0.

[0212] (b) 3-amino-5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl 1,4-Dioxane (10 mL) was added to a mixture of (1-methylbenzimidazole-4-yl)boronic acid (480 mg, 2.73 mmol), methyl 3-amino-6-chloro-5-[2-(dimethylamino)ethoxy]pyrazine-2-carboxylate (500 mg, 1.82 mmol), CsF (829 mg, 5.46 mmol), and PdCl2(dppf)-DCM adduct (223 mg, 0.27 mmol). The resulting mixture was stirred at 100°C for 2 hours. The solvent was then removed under reduced pressure. The residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-H2O as the eluent and 10 mM ammonium bicarbonate as a modifier to obtain methyl 3-amino-5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (180 mg, 27%) as a yellow gum-like substance; 1H NMR (300 MHz, DMSO-d6)δ 2.04(6H,s),2.40-2.5(2H,m),3.78(3H,s),3.87(3H,s),4.25-4.40(2H,m),7.21(1H ,d),7.32(1H,t),7.50(2H,s),7.60(1H,d),8.14(1H,s);m / z:(ES+),[M+H]+=371.3.

[0213] (c) 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid 1,4-Dioxane (18 mL) was added to a mixture of methyl 3-amino-5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (170 mg, 0.46 mmol), 4-(4-bromophenyl)morpholine (220 mg, 0.92 mmol), BrettPhos Pd G3 (62 mg, 0.070 mmol), and cesium carbonate (449 mg, 1.38 mmol). The resulting mixture was stirred at 25°C for 8 hours. The solvent was removed under reduced pressure. The obtained residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-H2O as the eluent to obtain 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (80 mg, 34%) as a yellow gum-like substance; 1H NMR (300 MHz, DMSO-d6)δ 2.39 (6H,s), 2.81-2.96 (2H,m), 3.04-3.12 (4H,m), 3.69-3.79 (4H,m), 3.89 (3H,s), 4.49-4.61 (2H,m), 6.96 (2H,d), 7.39 (2H,s), 7.51-7.72 (3H,m), 8.34 (1H,s); NH and COOH signals were extended to baseline; m / z: (ES+)[M+H]+=518.4.

[0214] (d) 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide Triethylamine (0.061 mL, 0.43 mmol) was added to a suspension of 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (75 mg, 0.14 mmol), ammonium chloride (47 mg, 0.87 mmol), and HATU (72 mg, 0.19 mmol) in DMF (5 mL). The resulting mixture was stirred at 25°C for 2 hours. The solvent was then removed under reduced pressure. The obtained residue was purified by reverse-phase chromatography using c18 with 0-100% MeCN-H2O as the eluent and 10 mmol / L ammonium bicarbonate as a modifier to obtain 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (28.0 mg, 37%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6)δ 2.13(6H,s),3.08(4H,t),3.30(2H,s),3.71-3.78(4H,m),3.87(3H,s),4.44(2H,s),6.97(2H,d),7.34(1H,t),7 .54(2H,d),7.57-7.62(2H,m),7.67(1H,s),7.88(1H,s),8.21(1H,s),11.14(1H,s);m / z:(ES+),[M+H]+=517.6.

[0215] Example 5 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-cyclopropylpyrazine-2-carboxylate methyl carboxylate Potassium cyclopropyl trifluoroborate (0.800 g, 5.40 mmol) was added to a suspension of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.00 g, 4.50 mmol), palladium(II) acetate (0.15 g, 0.68 mmol), cataCXium A (0.484 g, 1.35 mmol), and cesium carbonate (2.93 g, 9.01 mmol) in water (1.5 mL) and toluene (15 mL). The resulting mixture was stirred at 100°C for 10 hours. The solvent was then removed under reduced pressure. The obtained residue was purified by silica gel chromatography using 0-30% toluene-pentane as the eluent to obtain methyl 3-amino-6-chloro-5-cyclopropyl-pyrazine-2-carboxylate (0.65 g, 63%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 1.02 (2H,d), 1.11 (2H,dt), 2.36 (1H,tt), 3.77 (3H,s), 7.35 (2H,s). m / z: (ES+), [M+H]+ = 227.90

[0216] (b) 3-amino-5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl (1-Methylbenzimidazole-4-yl)boronic acid (580 mg, 3.3 mmol) was added to a suspension of methyl 3-amino-6-chloro-5-cyclopropyl-pyrazine-2-carboxylate (625 mg, 2.75 mmol), PdCl2 (dppf) (402 mg, 0.550 mmol), and CsF (1.25 g, 8.24 mmol) in 1,4-dioxane (10 mL). The resulting mixture was stirred at 100°C for 14 hours. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. The obtained residue was purified by reverse-phase chromatography using c18 with 0-30% MeCN-H2O as the eluent and 0.1% formic acid as the modifier to obtain 3-amino-5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl (405 mg, 46%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 0.81(2H,dt),0.98(2H,q),1.78(1H,tt),3.79(3H,s),3.91(3H,s),7.25(2H,s),7.38(1H,t),7.65(1H,dd),8.19(2H,s). m / z:(ES+),[M+H]+=324.2.

[0217] (c) 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl 4-(4-bromophenyl)morpholine (313 mg, 1.29 mmol) was added to a suspension of 3-amino-5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl (380 mg, 1.18 mmol), cesium carbonate (766 mg, 2.35 mmol), and Brettphos Pd G3 (107 mg, 0.120 mmol) in 1,4-dioxane (4 mL). The resulting mixture was stirred at 100°C for 12 hours. The solvent was then removed under reduced pressure. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (130 mg, 23%) as an orange solid; 1H NMR (300 MHz, DMSO-d6)δ 0.76-0.94(4H,m),1.83-1.95(1H,m),3.09-3.11(4H,m),3.71-3.80(4H,m),3.80(3H,s),3.87(3H,s),6.95-7.0 1(2H,m),7.25(1H,d),7.27-7.31(1H,m),7.40(2H,q),7.51-7.56(2H,m),9.90(1H,s);m / z:(ES+),[M+H]+=485.2

[0218] (d) 5-Cyclopropyl-6-(1-Methylbenzimidazole-4-yl)-3-(4-Molfolinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (6.0 mL, 42 mmol) was added to 5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (110 mg, 0.23 mmol). The resulting suspension was stirred at 70°C for 3 hours. The solvent was then removed under reduced pressure. The obtained residue was purified by preparative HPLC using a SunFire C18 OBD 5μm, 19mm × 250mm column, with 19% to 33% MeCN / H2O as the eluent and 0.05% trifluoroacetic acid as a modifier, yielding 5-cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (35 mg, 33%) as an orange solid; 1H NMR (400 MHz, DMSO-d6)δ 1.00(2H,dt),1.13(2H,dt),1.98(1H,dq),3.04-3.19(4H,m),3.72-3.80(4H,m),4.09(3H,s)6.9 4-7.02(2H,m),7.51-7.57(2H,m),7.66-7.79(2H,m),7.88(1H,s),7.95-8.05(2H,m),9.41(1H,br s),11.15(1H,s);m / z:(ES+),[M+H]+=470.2.

[0219] Example 6 5-Methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate methyl PdCl2(dppf) (370 mg, 0.51 mmol) was added under nitrogen to a suspension of CsF (773 mg, 5.09 mmol), methyl 3-amino-6-chloro-5-methylpyrazine-2-carboxylate (513 mg, 2.54 mmol), and (3-methylimidazo[4,5-c]pyridine-7-yl)boronic acid (450 mg, 2.54 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100°C for 16 hours. The solvent was then removed under reduced pressure. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate methyl (300 mg, yield 40%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 2.30(3H,s), 3.82(3H,s), 4.00(3H,s), 7.41(2H,s), 8.37(1H,s), 8.43(1H,s), 9.06(1H,s); m / z: (ES+), [M+H]+=299.1

[0220] (b) 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl Methyl 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate (280 mg, 0.94 mmol) was added to a suspension of 4-(4-bromophenyl)morpholine (227 mg, 0.940 mmol), cesium carbonate (612 mg, 1.88 mmol), and Brettphos Pd G3 (170 mg, 0.19 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100°C for 16 hours. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography using 0-40% MeOH-DCM as the eluent to obtain methyl 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (200 mg, 46%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 2.37(3H,s), 3.10(4H,t), 3.75(4H,s), 3.90(3H,s), 4.01(3H,s), 6.98(2H,d), 7.61(2H,d), 8.40(1H,s), 8.45(1H,s), 9.06(1H,s), 9.90(1H,s); m / z: (ES+), [M+2H] 2+ =230.7.

[0221] (c) 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (8.0 mL, 56 mmol) was added to methyl 5-methyl-6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-3-((4-morpholinophenyl)amino)pyrazine-2-carboxylate methyl (190 mg, 0.41 mmol). The resulting suspension was stirred at 80°C for 1 hour. The solvent was then removed under reduced pressure. The obtained residue was purified by preparative HPLC using a 5 micron, 30 × 150 mm Sunfire prep C18 column with 10-28% MeCN-water as the eluent and 0.1% formic acid as a modifier to obtain 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (26 mg, 14%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6)δ 2.38(3H,s),3.02-3.11(4H,m),3.69-3.78(4H,m),3.99(3H,s),6.96(2H,d),7.61(2H,d),7.83 (1H,s),8.13(1H,s),8.44(1H,s),8.53(1H,s),9.02(1H,s),11.05(1H,s).(ES+)[M+H]+=445.2.

[0222] Example 7 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate methyl 2M methylamine in THF / MeOH (99 mL, 198.00 mmol) was added to methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (11.0 g, 49.5 mmol). The resulting suspension was stirred at 25°C for 30 minutes. It was then concentrated to half its original volume, diluted with water (200 mL), filtered, and washed with water. The filtered cake was dried under vacuum to obtain methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (9.88 g, 92%) as a pale yellow solid; ¹H NMR (500 MHz, DMSO-d6) 2.85(3H,d), 3.72(3H,s), 7.25(2H,br s), 7.53(1H,br d). m / z: (ES+), [M+H]+=217.1

[0223] (b) 6-chloro-3-fluoro-5-(methylamino)pyrazine-2-carboxylate methyl Sodium nitrite (3.30 g, 47.89 mmol) was added in small amounts at -10°C to a suspension of methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (9.88 g, 45.6 mmol) in HF-pyridine (20 mL, 580 mmol). The reaction mixture was stirred at 25°C for 1 hour. The reaction was then quenched with DCM (50 mL) and water (100 mL). The layers were separated, and the aqueous layer was extracted three times (50 mL each) with DCM. The combined organic layers were washed with saturated ammonium chloride aqueous solution (50 mL). The combined aqueous layer was finally extracted with DCM (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to obtain methyl 6-chloro-3-fluoro-5-(methylamino)pyrazine-2-carboxylate (9.50 g, 95%) as a pink solid; ¹H NMR (500 MHz, DMSO-d6) 2.88(3H,d), 3.78(3H,s), 8.34(1H,br d); m / z: (ES+), [M+H]+=220.1

[0224] (c)6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl carboxylate DIPEA (10.0 mL, 57.3 mmol) was added to methyl 6-chloro-3-fluoro-5-(methylamino)pyrazine-2-carboxylate (8.53 g, 38.8 mmol) and 4-morpholinoaniline (7.3 g, 41 mmol) in DMF (30 mL). The reaction mixture was stirred at 100 °C for 90 minutes. The reaction mixture was then cooled to room temperature and quenched with water (300 mL). The resulting suspension was filtered, and the filter cake was dried under vacuum to obtain methyl 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (9.48 g, 65%) as a yellowish-brown solid; ¹H NMR (500 MHz, DMSO-d6) 2.90 (3H, d), 3.01-3.09 (4H, m), 3.70-3.75 (4H, m), 3.79 (3H, s), 6.92 (2H, br d), 7.54 (2H, d), 7.82 (1H, br d), 10.08 (1H, s); m / z: (ES-), [MH]- = 376.4

[0225] (d) 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl In a microwave vial, methyl 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.50 g, 3.97 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (1.63 g, 69 wt%, 4.37 mmol), Pd(dppf)Cl2 (0.29 g, 0.40 mmol), and cesium fluoride (1.81 g, 11.9 mmol) were mixed, then the vial was degassed under vacuum and filled with nitrogen three times. MeOH (15 mL) was added, and the reaction mixture was stirred in a Biotage microwave reactor at 100°C for 8 hours. Next, the reaction mixture was concentrated and loaded onto Celite. Purification was performed by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain a yellowish-brown solid. This substance was suspended in MeOH (40 mL), stirred at 40°C for 30 minutes, and then allowed to stand for 1 hour. Next, the resulting suspension was filtered and washed with a small amount of MeOH to obtain methyl 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.49 g, 79%) as a dark yellow solid; ¹H NMR (500 MHz, DMSO-d6) 2.90 (3H, d), 3.04-3.10 (4H, m), 3.68-3.78 (4H, m), 3.80 (3H, s), 3.90 (3H, s), 6.95 (2H, d), 7.36-7.44 (1H, m), 7.44-7.51 (1H, m), 7.58-7.74 (3H, m), 8.04 (1H, br d),8.30(1H,s),10.23(1H,s);m / z:(ES+),[M+H]+=474.4

[0226] (e) 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate bis-trifluoroacetate Lithium hydroxide monohydrate (2.64 g, 63.0 mmol) was added to a suspension of methyl 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (2.98 g, 6.30 mmol) in water (16 mL) and MeOH (16 mL). The resulting mixture was stirred at 100°C for 90 minutes in a Biotage microwave reactor. The reaction mixture was cooled to room temperature, diluted with water (70 mL), concentrated to a volume of 40 mL, filtered, and washed with water. The resulting yellow filtration cake was purified by reverse-phase chromatography using 0-50% MeCN / H2O as the eluent and 0.1% TFA as a modifier to obtain 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (3.00 g, 70%) as an orange solid, which was presumed to be bis-trifluoroacetate; 1H NMR (500 MHz, DMSO-d6) 2.87 (3H, br s), 3.04-3.11 (4H, m), 3.13-3.17 (3H, m), 3.62-3.86 (4H, m), 4.06 (3H, br s),6.86-7.10(2H,m),7.12-7.46(1H,m),7.53-7.77(4H,m),7.94(1H,br d),8.98-9.57(1H,m),10.50(1H,br s),12.09(1H,br s);m / z:(ES+),[M+H]+=460.3

[0227] (f) 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide DIPEA (7.00 mL, 40.1 mmol) was added to a suspension of 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid, nitrifluoroacetate (5.52 g, 8.05 mmol), ammonium chloride (5.16 g, 96.6 mmol), and HATU (4.59 g, 12.1 mmol) in DMF (60 mL). The resulting mixture was stirred at 25°C for 3 hours. The reaction was then diluted with saturated sodium bicarbonate aqueous solution (60 mL) and water (200 mL). The resulting yellow suspension was stirred at 25°C for 30 minutes, then filtered and washed with water. The bright yellow filter cake was dried under vacuum for 20 hours to obtain a yellow solid. This substance was suspended in MeOH (70 mL), stirred at 40°C for 2 hours, sonicated for 1 hour, and allowed to stand for 3 hours. The resulting suspension was filtered, washed with a small amount of MeOH, and dried under vacuum to obtain 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (3.54 g, 96%) as a yellow solid; 1H NMR (600 MHz, DMSO-d6) 2.93 (3H, d), 3.02-3.08 (4H, m), 3.66-3.77 (4H, m), 3.90 (3H, s), 6.94 (2H, d), 7.30 (1H, br s), 7.40 (1H, t), 7.59-7.64 (3H, m), 7.64-7.68 (2H, m), 8.16 (1H, br q),8.33(1H,s),11.23(1H,s);m / z:(ES+),[M+H]+=459.4

[0228] Example 8 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0229] (a) 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate methyl 33% methaneamine was added to a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (100 g, 450 mmol) in EtOH (280 mL, 2.25 mol) in MeOH (1 L). The resulting mixture was stirred at 65°C for 16 hours. The reaction was then cooled to 0°C, filtered, washed with MeOH, and dried under vacuum to obtain methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (69.0 g, yield 71%) as a pale beige solid. ¹H NMR (500 MHz, DMSO-d6) 2.87(3H,d), 3.73(3H,s), 7.27(2H,br s), 7.55(1H,br d). m / z: (ES+), [M+H]+ = 217.0

[0230] (b) 5-chloro-6-(methylamino)-2-oxo-1H-pyrazine-3-carboxylate methyl carboxylate A solution of sodium nitrite (12.23 g, 177.3 mmol) in water (100 mL) was added in small amounts over 2 hours to a suspension of 25% sulfuric acid (400 mL, 1.2 mol), hexane (100 mL), and methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (32.00 g, 147.7 mmol) in (400 mL). The resulting mixture was vigorously stirred at room temperature for 30 minutes. The reaction product was then filtered, washed with water, and dried under vacuum to obtain methyl 5-chloro-6-(methylamino)-2-oxo-1H-pyrazine-3-carboxylate (31.4 g, yield 98%) as a mono-yellow solid. 1H NMR(500MHz,DMSO-d6)2.90(3H,d),3.82(3H,s),7.97(1H,br d),11.50(1H,s).m / z:(ES+),[M+H]+=218.0

[0231] (c)6-chloro-5-(methylamino)-3-(trifluoromethylsulfonyloxy)pyrazine-2-carboxylate methyl carboxylate Trifluoromethanesulfonic anhydride (21.4 mL, 126.4 mmol) was added in small amounts at 0°C to a suspension of methyl 5-chloro-6-(methylamino)-2-oxo-1H-pyrazine-3-carboxylate (25.0 g, 115 mmol) and DIPEA (40.0 mL, 230 mmol) in DCM (500 mL). The resulting mixture was stirred at 0°C for 30 minutes. The reaction product was then concentrated. The resulting solid was used in the next step without further purification.

[0232] (d) 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl A mixture of methyl 6-chloro-5-(methylamino)-3-(trifluoromethylsulfonyloxy)pyrazine-2-carboxylate (40.0 g, 114 mmol), 4-morpholinoaniline (24.47 g, 137.3 mmol), and DIPEA (59.9 mL, 343 mmol) was stirred at 100°C for 3 hours. The reaction mixture was then cooled to room temperature, diluted with ethyl acetate, and filtered. The resulting filtrate was washed with water, dried over sodium sulfate, filtered, and concentrated. The resulting solid was used in the next step without further purification.

[0233] (e) 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl A mixture of 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (25.0 g, 66.2 mmol), 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[4,5-c]pyridine (20.5 g, 79.1 mmol), PdCl2(dppf) dichloromethane adduct (5.40 g, 6.62 mmol), and cesium fluoride (20.10 g, 132.3 mmol) in 1,4-dioxane (500 mL) and water (50 mL) was degassed under vacuum and filled with nitrogen three times. The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was then cooled to room temperature, diluted with water (500 mL), and filtered. The filtered cake was dried under vacuum. The obtained solid was used in the next step without further purification.

[0234] (f) 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid A 2N aqueous solution of KOH (160 mL, 320 mmol) was added to a suspension of methyl 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (31.4 g, 66.2 mmol) in MeOH (100 mL) and THF (100 mL). The resulting mixture was stirred at 50°C for 1 hour. The reaction mixture was then cooled to room temperature and acidified with 1N HCl (190 mL, 380 mmol). The resulting mixture was evaporated, and the residue was used in the next step without further purification.

[0235] (g) 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide DIPEA (69.4 mL, 397 mmol) was added to a mixture of 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (30.5 g, 66.2 mmol), ammonium chloride (14.17 g, 264.9 mmol), and HATU (50.40 g, 132.5 mmol) in DMF (400 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% methanol-dichloromethane as the eluent to obtain 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (15.75 g, yield 52%) as a yellow solid. This substance was mixed with a batch of the same size in MeOH (1 L) and stirred at room temperature for 10 minutes. The resulting slurry was filtered. This solid residue was found to be crystalline by XRPD (morphology A), and a typical diffractogram is shown in Figure 1. Characteristic peak positions are listed in Tables 3 and 4 below.

[0236] [Table 10]

[0237] [Table 11]

[0238] Morphology A was further analyzed using thermal techniques. DSC analysis showed that desolvation of morphology A began at 29°C, peaking at 54°C, followed by several thermal events between 190°C and 290°C. TGA showed that heating morphology A from approximately 25°C to approximately 100°C resulted in a mass loss of approximately 1.3%. A representative DSC / TGA thermogram of morphology A is shown in Figure 2.

[0239] A filtration cake consisting of form A was suspended in 99.5% EtOH (750 mL) and treated with 20 mg of a seed crystal of form F 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (obtained by placing 3-5 mg of form A in a TGA or DSC pan, heating at a rate of 10°C / min to 300°C, and then cooling to room temperature). The resulting suspension was stirred at room temperature for 16 hours and then filtered. The filtration cake was dried under vacuum to obtain 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (31.5 g) as a yellow solid. This solid residue was found to be crystalline by XRPD (morphology F), and a typical diffractogram is shown in Figure 3. Characteristic peak positions are listed in Tables 5 and 6 below.

[0240] [Table 12]

[0241] [Table 13]

[0242] Morphology F was further analyzed using thermal techniques. DSC analysis showed that morphology F has a melting / thermal decomposition temperature that starts at 334°C and peaks at 338°C. TGA showed that morphology F has a mass loss of approximately 0.5% when heated from approximately 25°C to approximately 100°C. A representative DSC / TGA thermogram of morphology F is shown in Figure 4.

[0243] A single crystal of morphology F was obtained by evaporation of the EtOH solution. Single crystal structure analysis confirmed that morphology F was in its anhydrous form. The molecular structure of Example 8 - Morphology F is shown in Figure 5. Crystallographic data: Space group monoclinic system Pc, lattice constants: a=7.9965(4)Å, b=9.5420(4)Å, c=14.3408(6)Å, β=92.333(1)°, V=1093.33(8)Å 3 .

[0244] A 50 mg filter cake consisting of morphology A was suspended in 1.0 mL of ACN, and this slurry was stirred at room temperature for 5 days. After filtration and air drying, 45 mg of a yellow solid was obtained. This solid residue was found to be crystalline by XRPD (morphology G), and a typical diffractogram is shown in Figure 6. Characteristic peak positions are listed in Tables 7 and 8 below.

[0245] [Table 14]

[0246] [Table 15]

[0247] Morphology G was further analyzed using thermal techniques. DSC analysis showed that morphology G has a melting / thermal decomposition temperature that starts at 344°C and peaks at 345°C. TGA showed that morphology G has a mass loss of approximately 0.1% when heated from approximately 25°C to approximately 100°C. A representative DSC / TGA thermogram of morphology G is shown in Figure 7.

[0248] A 50 mg filter cake consisting of morphology A was suspended in 0.5 mL of H2O, 0.5 mL of MeOH, and 0.5 mL of DCM. This slurry was stirred at room temperature for 5 days, and after filtration and air drying, 48 mg of a yellow solid was obtained. This solid residue was found to be crystalline by XRPD (morphology I), and a typical diffractogram is shown in Figure 8. Characteristic peak positions are listed in Tables 9 and 10 below.

[0249] [Table 16]

[0250] [Table 17]

[0251] Morphology I was further analyzed using thermal techniques. DSC analysis showed that morphology I has a melting / thermal decomposition temperature that begins desolvation at 66°C, peaks at 73°C, and then begins at 344°C and peaks at 245°C. TGA showed that morphology I has a mass loss of approximately 3.7% when heated from approximately 25°C to approximately 100°C. A representative DSC / TGA thermogram of morphology I is shown in Figure 9.

[0252] A single crystal of form I was obtained by evaporation of a MeOH / DCM / H2O (1:1:1) solution. Single crystal structure analysis confirmed that form I is the anhydrous form. The molecular structure of Example 8 - Form I is shown in Figure 10. Crystallographic data: Space group monoclinic P2(1) / c, lattice constants: a=21.504(6)Å, b=4.5841(12)Å, c=22.777(6)Å, β=90.683(5)°, V=2245.2(10)Å 3 . 1H NMR(500MHz,DMSO-d6)2.94(3H,d),3.02-3.13(4H,m),3.70-3.80(4H,m),4.02(3H,s),6.96(2H,d),7.31(1H,br s),7.67(2H,d),7.71(1H,br s),8.00(1H,br q),8.52(1H,s),8.73(1H,s),9.01(1H,s),11.30(1H,s).m / z:(ES+),[M+H]+=459.9

[0253] Example 9 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-methylsulfanylpyrazine-2-carboxylate methyl A 21 wt% aqueous solution of sodium methanethiolate (22 mL, 66 mmol) was added to a suspension of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (10 g, 45 mmol) in THF (100 mL). The resulting suspension was stirred at 25°C for 3 hours. The reaction mixture was then concentrated to 1 / 6 of its original volume. The resulting orange suspension was diluted with water (100 mL), stirred for 10 minutes, filtered, washed with a large amount of water, and dried under vacuum to obtain methyl 3-amino-6-chloro-5-methylsulfanylpyrazine-2-carboxylate (9.65 g, 92%) as a yellow solid; ¹H NMR (500 MHz, DMSO-d6,) 2.52 (3H, s), 3.81 (3H, s), 7.59 (2H, br s); m / z: (ES+), [M+H]+ = 233.9.

[0254] (b) 3-amino-6-(1-methylbenzimidazole-4-yl)-5-methylsulfanylpyrazine-2-carboxylate methyl A mixture of 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (497 mg, 1.93 mmol), methyl 3-amino-6-chloro-5-methylsulfanylpyrazine-2-carboxylate (250 mg, 1.07 mmol), cesium fluoride (488 mg, 3.21 mmol), and PdCl2 (dppf) (78 mg, 0.11 mmol) in MeOH (5 mL) was degassed and purged with nitrogen. The reaction mixture was stirred in a sealed vial at 120°C for 18 hours. The reaction mixture was then filtered through Celite and concentrated. The obtained residue was purified by silica gel chromatography using 0-100% toluene-hexane as the eluent, followed by 0-20% MeOH-DCM as the eluent, to obtain 3-amino-6-(1-methylbenzimidazole-4-yl)-5-methylsulfanylpyrazine-2-carboxylate methyl (150 mg, 43%) as a dark brown solid. m / z: (ES+), [M+H]+ = 330.1.

[0255] (c)6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid 3-amino-6-(1-methylbenzimidazole-4-yl)-5-methylsulfanylpyrazine-2-carboxylate methyl (80 mg, 0.24 mmol) was added to 1,4-dioxane (1.5 mL). The resulting solution was sparged with nitrogen for 5 minutes. 4-(4-bromophenyl)morpholine (70.6 mg, 0.29 mmol), BrettPhos Pd G3 (22.02 mg, 0.02 mmol), and d-sodium tert-butoxide (117 mg, 1.21 mmol) were added to the reaction mixture, and the mixture was stirred at 80°C for 2 hours. 1 M HCl was added, and the aqueous layer was washed with DCM / IPA in a 3:1 ratio, and then concentrated. The resulting residue was used directly in the next step without purification, assuming a 100% yield. m / z: (ES+), [M+H]+ = 477.

[0256] (d) 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide DIPEA (0.253 mL, 1.45 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (115 mg, 0.24 mmol), ammonium chloride (51.6 mg, 0.97 mmol), and HATU (184 mg, 0.48 mmol) in DMF (2 mL). The resulting mixture was stirred at 25°C for 90 minutes, and then directly purified by reverse-phase chromatography in c18 using 0-80% MeCN-H2O as the eluent and 0.1% ammonium hydroxide as a modifier, yielding 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (9.0 mg, 7.8%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 2.41 (3H, s), 3.07 (4H, br s), 3.73 (4H, br d), 3.87 (3H, s), 6.93-6.99 (2H, m), 7.29 (1H, br d), 7.33-7.39 (1H, m), 7.58 (2H, br d),7.65(1H,br d),7.72(1H,br s),7.85(1H,br s),8.17(1H,s),11.16(1H,s);m / z:(ES+),[M+H]+=476.2

[0257] Example 10 5-(ethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0258] (a) 6-(1-methylbenzimidazole-4-yl)-5-methylsulfonyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide mCPBA (21 mg, 77 wt%, 0.090 mmol) was added at 0°C to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (20 mg, 0.04 mmol) in DCM (1 mL). The resulting mixture was stirred at 0°C for 30 minutes, and then stirred at 25°C for 90 minutes. The reaction was then quenched with saturated sodium bicarbonate aqueous solution and extracted with a 3:1 DCM / IPA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-100% MeOH-DCM to obtain a yellow substance. This was then purified by reverse-phase chromatography in c18 using 0-80% MeCN / H2O as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 6-(1-methylbenzimidazole-4-yl)-5-methylsulfonyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (15.00 mg, 68%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 2.88 (2H,br d), 3.36 (3H,s), 3.78 (2H,dd), 3.90 (3H,s), 4.03 (2H,td), 4.43 (2H,br t),7.35-7.40(1H,m),7.45(1H,d),7.67(1H,d),7.87(2H,d),8.16-8.24(3H,m),8.27(2H,br s),11.55(1H,s);m / z:(ES-),[MH]-=522.1.

[0259] (b) 5-(ethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 2M methanolic ethanamine (0.028 mL, 0.056 mmol) and DIPEA (0.024 mL, 0.14 mmol) were added to a solution of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfonyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (24 mg, 0.050 mmol) in THF (1 mL). The resulting mixture was stirred at 25°C for 3 hours. Sodium bisulfite (14.1 mg, 0.140 mmol) was added, and the reaction mixture was stirred at 25°C for 16 hours. The reaction mixture was then concentrated. The obtained residue was purified by reverse-phase chromatography in C18 using 0-80% MeCN / H2O as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 55-(ethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (10.0 mg, 46%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 1.20 (3H,t), 3.02-3.11 (4H,m), 3.45 (2H,quintet), 3.68-3.76 (4H,m), 3.90 (3H,s), 6.93 (2H,d), 7.33 (1H,br s),7.36-7.49(1H,m),7.57-7.75(5H,m),8.35(1H,s),8.43(1H,br t),11.22(1H,s);m / z:(ES+),[M+H]+=473.3.

[0260] Example 11 5-(cyclopropylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] Cyclopropylamine (0.040 mL, 0.57 mmol) and DIPEA (0.10 mL, 0.57 mmol) were added to a solution of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfonyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (100 mg, 0.19 mmol) in DMF (1.5 mL). The resulting mixture was stirred at 25°C for 1 hour. Sodium bisulfite (60 mg, 0.57 mmol) was added, and the resulting mixture was stirred at 25°C for 1 hour. The reaction product was then concentrated. The obtained residue was purified by reverse-phase chromatography using C18 with 10-80% MeCN / H2O as the eluent to obtain 5-(cyclopropylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (20 mg, 22%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 0.43-0.52 (2H,m), 0.79-0.87 (2H,m), 2.88 (1H,ddd), 3.02-3.09 (4H,m), 3.69-3.76 (4H,m), 3.90 (3H,s), 6.94 (2H,d), 7.35-7.43 (2H,m), 7.63 (1H,d), 7.70 (1H,br s),7.73(1H,d),7.80(2H,d),8.38(1H,s),9.08(1H,d),11.24(1H,s);m / z:(ES+),[M+H]+=485.4.

[0261] Example 12 5-amino-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0262] (a) 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide A solution of mCPBA (0.17 g, 0.75 mmol) in DCM (3 mL) was added dropwise at 0°C to a mixture of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.157 g, 0.330 mmol) in DCM (5.00 mL). The reaction mixture was stirred at 0°C for 5 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution, extracted once with DCM, and extracted once again with a 5:1 DCM / IPA mixture. The combined organic layer was dried over sodium sulfate, concentrated, and used in the next step without purification, considering the yield to be 100%.

[0263] (b) 5-amino-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (10 mL, 70 mmol) was added to 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (0.255 g, 0.500 mmol). The resulting suspension was stirred at 70°C for 2.5 hours. The reaction product was then concentrated. The resulting residue was suspended in water, filtered, and washed with water. The filtered cake was dried under vacuum to obtain 5-amino-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.198 g, 88%) as a yellow solid; (500 MHz, DMSO-d6) δ 3.03-3.12 (4H, m), 3.73-3.77 (4H, m), 4.05 (3H, s), 6.93 (2H, br d), 7.39 (1H, br s), 7.56-7.71 (4H, m), 7.77 (1H, br d), 7.88 (1H, br d), 9.14-9.41 (1H, m), 11.22 (1H, s). The aminoNH2 proton was buried beneath the peak of residual water. m / z:(ES+),[M+H]+=445.4

[0264] Example 13 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (R)-1-aminopropan-2-ol (77 mg, 1.02 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes in a Biotage microwave reactor. The reaction product was then concentrated. The resulting residue was partitioned between DCM and water. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as a modifier to obtain 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (11 mg, 43%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2) δ 1.22 (3H,d), 3.02-3.09 (1H,m), 3.10-3.15 (4H,m), 3.80-3.87 (5H,m), 3.90 (3H,s), 4.17-4.28 (1H,m), 4.85 (1H,br s), 5.21 (1H,br s), 6.56 (1H,br t),6.91(2H,d),7.43-7.56(3H,m),7.57-7.64(2H,m),7.67(1H,dd),7.98(1H,s),10.86(1H,s);m / z:(ES+),[M+H]+=503.3

[0265] Example 14 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (2S)-1-aminopropan-2-ol (77 mg, 1.02 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes in a Biotage microwave reactor. The reaction product was then concentrated. The resulting residue was partitioned between DCM and water. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as a modifier to obtain 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (12 mg, 47%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2) δ 1.22 (3H,d), 3.02-3.09 (1H,m), 3.09-3.17 (4H,m), 3.80-3.87 (5H,m), 3.90 (3H,s), 4.18-4.27 (1H,m), 4.85 (1H,br s), 5.21 (1H,br s), 6.57 (1H,br t),6.91(2H,d),7.45-7.54(3H,m),7.59-7.63(2H,m),7.67(1H,dd),7.98(1H,s),10.86(1H,s);m / z:(ES+),[M+H]+=503.3.

[0266] Example 15 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide [ka] 2,2,2-trifluoroethaneamine (101 mg, 1.02 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated, and the resulting residue was partitioned between DCM and H2O. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide (4.2 mg, 16%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2) δ 3.08-3.15 (4H,m), 3.80-3.87 (4H,m), 3.91 (3H,s), 4.27 (2H,qd), 6.89-6.97 (2H,m), 7.45-7.60 (5H,m), 7.78 (1H,dd), 7.97 (1H,s), 9.44 (1H,br t), 10.83 (1H, s). One carboxamide NH2 proton was replaced at baseline. m / z: (ES+), [M+H]+=527.2

[0267] Example 16 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] 2,2-Difluoroethanamine (83 mg, 1.0 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes and then heated at 140°C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated, and the resulting residue was partitioned between DCM and H2O. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (9.6 mg, 37%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2)δ 3.09-3.15(4H,m),3.82-3.86(4H,m),3.86-3.94(5H,m),5.45-5.59(1H,m),6.03(1H,tt),6. 89-6.96(2H,m),7.45-7.53(2H,m),7.54-7.64(3H,m),7.73(1H,dd),7.99(1H,s),8.84(1H,br t),10.81(1H,s).m / z:(ES+),[M+H]+=509.2

[0268] Example 17 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] N',N'-dimethylethane-1,2-diamine (90 mg, 1.0 mmol) was added to a suspension of 4-(4-((3-carbamoyl-5-(1-methyl-1H-benzo[d]imidazole-4-yl)-6-(methylsulfinyl)pyrazine-2-yl)amino)phenyl)morpholine 4-oxide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes in a Biotage microwave reactor. The reaction was then concentrated, and the resulting residue was partitioned between DCM and H2O. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (9.4 mg, 36%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2) δ 2.20 (6H,s), 2.53-2.56 (2H,m), 3.08-3.13 (4H,m), 3.58-3.65 (2H,m), 3.81-3.87 (4H,m), 3.90 (3H,s), 5.19 (1H,br s),6.88-6.94(2H,m),7.43-7.55(3H,m),7.63(1H,dd),7.66-7.70(2H,m),7.89-7.95(2H,m),10.89(1H,s).m / z:(ES+),[M+H]+=516.3

[0269] Example 18 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] 2-aminoethanol (62.3 mg, 1.02 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (26 mg, 0.051 mmol) in n-butanol (1 mL). The resulting mixture was stirred at 140°C for 20 minutes in a Biotage microwave reactor. The reaction product was then concentrated. The resulting residue was partitioned between DCM and water. The layers were separated, the organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as a modifier to obtain 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (12 mg, 47%) as a yellow solid; 1H NMR (500 MHz, dichloromethane-d2) δ 3.08-3.14 (4H, m), 3.66 (2H, q), 3.80-3.87 (6H, m), 3.91 (3H, s), 4.54 (1H, br s), 5.20 (1H, br s), 6.48 (1H, br t),6.92(2H,d),7.42-7.56(3H,m),7.61(2H,d),7.67(1H,dd),7.98(1H,s),10.88(1H,s).m / z:(ES+),[M+H]+=489.3.

[0270] Example 19 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(propa-2-inylamino)pyrazine-2-carboxamide [ka] Propa-2-in-1-amine (0.071 mL, 1.1 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (28 mg, 0.060 mmol) in 1,4-dioxane (1 mL). The resulting mixture was stirred at 110°C for 30 minutes. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-5% MeOH-DCM to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(propa-2-inylamino)pyrazine-2-carboxamide (4.6 mg, 17%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6)δ 3.03-3.09(4H,m),3.11(1H,t),3.70-3.76(4H,m),3.91(3H,s),4.16(2H,dd),6.93(2H,d),7.37- 7.44(2H,m),7.63-7.74(5H,m),8.37(1H,s),8.94(1H,t),11.22(1H,s).m / z:(ES+)[M+H]+=483.3

[0271] Examples 20 and 21 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide and 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide [ka] Rac-(1R,2R)-2-methylcyclopropanamine (30 μL, 0.38 mmol) and DIPEA (340 μL, 1.95 mmol) were sequentially added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide in n-butanol (0.5 mL). The resulting mixture was stirred at 140°C for 30 minutes in a Biotage microwave reactor. The reaction product was then concentrated. The resulting residue was purified by reverse-phase chromatography using C18 with 0-100% MeOH-H2O as the eluent and 0.1% TFA as a modifier to obtain an orange oily substance. This oily substance was further purified by chiral HPLC using a Chiralpak AD 4.6 mm × 100 mm 5 micron column, with a fixed composition of 40% methanol-sCO2 as the eluent and 0.2% ammonium hydroxide as a modifier, to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide (7.0 mg, 19%) and 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide (6.5 mg, 18%) as yellow solids; 1H NMR(500MHz,DMSO-d6)0.51-0.63(1H,m),0.64-0.70(1H,m),0.76-0.90(1H,m ),1.11(3H,d),2.63-2.68(1H,m),2.95-3.07(4H,m),3.63-3.79(4H,m),3.90( 3H,s),6.91(2H,d),7.33-7.42(2H,m),7.62(1H,d),7.66-7.73(2H,m),7.77(2 H,d),8.37(1H,s),8.91-8.96(1H,m),11.27(1H,s);m / z:(ES+),[M+H]+=499.4

[0272] Example 22 5-(cyanomethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] 2-aminoacetonitrile (0.093 g, 1.7 mmol) was added to a suspension of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (0.042 g, 0.08 mmol) in dioxane (1.5 mL). The resulting mixture was stirred at 110°C for 30 minutes. The reaction was then quenched with water and extracted by DCM. The organic layer was concentrated. The obtained residue was purified by reverse-phase chromatography using c18 with 10-45% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as a modifier to obtain 5-(cyanomethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (7.0 mg, 18%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 3.04-3.13 (4H,m), 3.70-3.78 (4H,m), 3.91 (3H,s), 4.37 (2H,d), 6.94 (2H,d), 7.42 (1H,t), 7.48 (1H,br d), 7.62-7.71 (4H,m), 7.77 (1H,br s),8.37(1H,s),8.84(1H,t),11.27(1H,s).m / z:(ES+),[M+H]+=484.3

[0273] Example 23 5-[[(2R)-2-fluoropropylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] Potassium carbonate (0.12 g, 0.88 mmol) was added to a suspension of (2R)-2-fluoropropan-1-amine hydrochloride (0.066 g, 0.58 mmol) and 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (0.042 g, 0.08 mmol) in dioxane (1.5 mL). The resulting mixture was stirred at 110°C for 30 minutes. The reaction was then quenched with water and extracted with DCM. The organic layer was concentrated. The obtained residue was purified by reverse-phase chromatography using c18 with 10-55% MeOH-H2O as the eluent and 0.2% NH4OH as the modifier to obtain 5-[[(2R)-2-fluoropropylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (7.0 mg, 17%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 1.33 (3H,dd), 3.02-3.11 (4H,m), 3.52-3.71 (2H,m), 3.71-3.80 (4H,m), 3.91 (3H,s), 4.81-4.99 (1H,m), 6.93 (2H,d), 7.36 (1H,br d),7.41(1H,t),7.55(2H,d),7.64(1H,d),7.67(1H,br d),7.69(1H,d),8.35(1H,s),8.75(1H,t),11.16(1H,s).m / z:(ES+),[M+H]+=505.3

[0274] Example 24 5-[[(2S)-2-fluoropropylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] Potassium carbonate (0.120 g, 0.88 mmol) was added to a suspension of (2S)-2-fluoropropan-1-amine hydrochloride (0.047 g, 0.41 mmol) and 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (0.042 g, 0.080 mmol) in dioxane (1.5 mL). The resulting mixture was stirred at 110°C for 30 minutes. The reaction was then quenched with water and extracted with DCM. The organic layer was concentrated. The obtained residue was purified by reverse-phase chromatography using c18 with 10-55% MeOH-H2O as the eluent and 0.2% 4 as the modifier to obtain 5-[[(2S)-2-fluoropropylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (6.0 mg, 14%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 1.33 (3H,dd), 3.01-3.11 (4H,m), 3.52-3.71 (2H,m), 3.71-3.76 (4H,m), 3.91 (3H,s), 4.80-5.01 (1H,m), 6.93 (2H,d), 7.36 (1H,br d),7.41(1H,t),7.55(2H,d),7.64(1H,d),7.67(1H,br d),7.69(1H,d),8.35(1H,s),8.75(1H,t),11.16(1H,s);m / z:(ES+),[M+H]=505.4

[0275] Example 25 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide [ka] Oxetane-3-ylmethaneamine (36 mg, 0.41 mmol) was added to a solution of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfinyl-3-[4-(4-oxidemorpholine 4-ium-4-yl)anilino]pyrazine-2-carboxamide (35 mg, 0.070 mmol) in DMF (690 μL). The resulting mixture was stirred at 25C for 16 hours. The reaction was then quenched with sodium bisulfite (36 mg, 0.34 mmol) and stirred at 25C for 1 hour. The resulting mixture was purified by C18 reverse-phase chromatography using 0-100% MeCN-H2O as the eluent to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide; 1 ¹H NMR (500MHz, DMSO-d6): 3.05 (4H,t), 3.69 (2H,t), 3.74 (4H,t), 3.90 (3H,s), 4.38 (2H,t), 4.63-4.70 (2H,m), 6.93 (2H,d), 7.31-7.37 (1H,m), 7.41 (1H,t), 7.58 (2H,d), 7.61-7.67 (2H,m), 7.71 (1H,d), 8.34 (1H,s), 8.61 (1H,t), 11.18 (1H,s); Oxetanylmethine protons were buried beneath the residual water peak; m / z: (ES+), [M+H]+=515.3

[0276] Example 26 5-Ethinyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-(1-methylbenzimidazole-4-yl)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl Tricyclohexylphosphonium tetrafluoroborate (136 mg, 0.370 mmol) was added under nitrogen to a mixture of methyl 3-amino-6-chloro-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (680 mg, 1.85 mmol), (1-methylbenzimidazole-4-yl)boronic acid (650 mg, 3.70 mmol), potassium phosphate (785 mg, 3.70 mmol), and PCy3Pd G3 (240 mg, 0.370 mmol) in 1,4-dioxane / H2O (20 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 3-amino-6-(1-methylbenzimidazole-4-yl)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl (500 mg, 58% yield) as a yellow oily substance, which was left to solidify. m / z:(ES+),[M+H]+=464.2

[0277] (b) 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl BrettPhos Pd G3 (36 mg, 0.040 mmol) was added under nitrogen to a suspension of methyl 3-amino-6-(1-methylbenzimidazole-4-yl)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (110 mg, 0.24 mmol), 4-(4-bromophenyl)morpholine (48 mg, 0.20 mmol), and cesium carbonate (193 mg, 0.590 mmol) in 1,4-dioxane (15 mL). The resulting mixture was stirred at 100°C for 5 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-30% MeOH-DCM as the eluent to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl as a red solid.

[0278] (c) 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethinyl)pyrazine-2-carboxamide 7N methanolic ammonia (8.0 mL, 56 mmol) was added to methyl 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (260 mg, 0.42 mmol). The resulting mixture was stirred at 70°C for 2 hours. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxamide (250 mg, 99%) as a brown solid. m / z:(ES+),[M+H]+=610.4

[0279] (d) 5-Ethinyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 1M TBAF (2.0 mL, 2.00 mmol) in THF was added to 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxamide (100 mg, 0.16 mmol) in THF (5 mL). The resulting mixture was stirred at room temperature for 16 hours. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography using 0-8% MeOH-DCM as the eluent. The obtained residue was further purified by preparative HPLC using a 5 micron, 19 mm × 150 mm SunFire Prep C18 OBD column, with a mixture of MeCN-H2O (which reduces polarity) as the eluent, and 0.1% formic acid as a modifier, to obtain 5-ethinyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (28 mg, 38%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6)δ 3.09(4H,t),3.72-3.79(4H,m),3.89(3H,s),4.23(1H,s),6.99(2H,d),7.37(1H,t),7.44-7.50(1H,m),7.53-7 .62(2H,m),7.62-7.68(1H,m),8.00(1H,s),8.10(1H,s),8.20(1H,s),11.03(1H,s);m / z:(ES+),[M+H]+=454.2

[0280] Example 27 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(difluoromethyl)pyrazine-2-carboxylate methyl 500 mg, 2.25 mmol of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate was added under nitrogen to a mixture of 129 mg, 0.230 mmol of bis(dibenzylideneacetone)palladium, 243 mg, 0.450 mmol of DPEPhos, and 1.24 g, 2.25 mmol of [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene]-(difluoromethyl)silver in toluene (30 mL). The resulting solution was stirred at 80°C for 18 hours. The reaction product was then concentrated. The obtained residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-H2O as the eluent to obtain methyl 3-amino-6-chloro-5-(difluoromethyl)pyrazine-2-carboxylate (410 mg, 77%) as a brown solid; ¹H NMR (400 MHz, CDCl3) δ 4.02 (3H, s), 6.79 (1H, t); aminoprotons were exchanged in CDCl3. m / z: (ES+), [M+H]+=238.0

[0281] (b) 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl Pd(dppf)Cl2 (123 mg, 0.170 mmol) was added under nitrogen to a mixture of methyl 3-amino-5-chloro-6-(difluoromethyl)pyrazine-2-carboxylate (400 mg, 1.68 mmol), (1-methylbenzimidazole-4-yl)boronic acid (296 mg, 1.68 mmol), and cesium fluoride (511 mg, 3.37 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then filtered through Celite. The filtrate was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent. The obtained residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-H2O as the eluent to obtain methyl 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (120 mg, 21%) as a yellow solid; 1H NMR (400 MHz, DMSO-d6) δ 3.78(3H,s), 3.91(3H,s), 6.88(1H,t), 7.34(1H,dd), 7.42(1H,t), 7.60-7.75(3H,m), 8.27(1H,s); m / z: (ES+), [M+H]+=334.1

[0282] (c) 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl BrettPhos Pd G3 (27 mg, 0.030 mmol) was added under nitrogen to a suspension of 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl (100 mg, 0.30 mmol), 4-(4-bromophenyl)morpholine (73 mg, 0.30 mmol), and cesium carbonate (196 mg, 0.600 mmol) in 1,4-dioxane (2 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-6% MeOH-DCM as the eluent to obtain 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (90 mg, 61%) as a yellow solid. m / z:(ES+),[M+H]+=495.1

[0283] (d) 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 5.0 mL, 35 mmol of 7N methanolic ammonia was added to methyl 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (80 mg, 0.16 mmol). The resulting mixture was stirred at 60°C for 16 hours. The reaction product was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 30 × 100 mm SunFire Prep C18 OBD column, with a mixture of MeCN-H2O (which reduces polarity) as the eluent and 0.1% formic acid as a modifier, to obtain 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (55 mg, 71%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6)δ 3.10(4H,t),3.75(4H,t),3.92(3H,s),6.75-7.28(3H,m),7.45(1H,t),7.60(1H,dd), 7.64-7.77(3H,m),8.12(1H,s),8.31(2H,s),11.21(1H,s);m / z:(ES+),[M+H]+=480.3

[0284] Example 28 5-Chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-[(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate methyl (4-methoxyphenyl)methanol (3.42 ml, 24.8 mmol) was added to a suspension of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (5.00 g, 22.5 mmol) and potassium phosphate (14.3 g, 67.6 mmol) in MeCN (30 mL). The resulting mixture was stirred at 80°C for 1 hour. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain methyl 3-amino-6-chloro-5-[(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate (2.3g, 32%) as a yellow solid; 1H NMR (400MHz, DMSO-d6) δ 3.73(3H,s), 3.74-3.81(3H,m), 4.41(2H,s), 6.84-6.90(2H,m), 6.95(2H,dq), 7.18-7.25(2H,m); m / z:(ES+),[M+H]+=324.1

[0285] (b) 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl PdCl2(dppf) (0.45 g, 0.62 mmol) was added to a suspension of methyl 3-amino-6-chloro-5-[(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate (2.00 g, 6.18 mmol), (1-methylbenzimidazole-4-yl)boronic acid (1.09 g, 6.18 mmol), and cesium fluoride (1.88 g, 12.4 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100°C for 4 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate methyl (1.80 g, 70%) as a brown solid; 1H NMR (300 MHz, DMSO-d6) δ 3.71(3H,s), 3.78(3H,s), 3.87(3H,s), 5.27(2H,s), 6.83(2H,d), 6.91-6.98(2H,m), 7.28-7.58(5H,m), 8.17(1H,s). m / z: (ES+)[M+H]+=420.1

[0286] (c) 5-[(4-Methoxyphenyl)Methoxy]-6-(1-Methylbenzimidazole-4-yl)-3-(4-Molfolinoanilino)pyrazine-2-carboxylate methyl Brettphos Pd G3 (0.389 g, 0.430 mmol) was added to a suspension of methyl 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxylate (1.80 g, 4.29 mmol), 4-(4-bromophenyl)morpholine (1.04 g, 4.29 mmol), and cesium carbonate (4.19 g, 12.9 mmol) in 1,4-dioxane (20 mL). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (1.90 g, 76%) as a brown solid; 1H NMR (400 MHz, DMSO-d6)δ 3.00-3.27(4H,m),3.70(3H,s),3.70-3.80(4H,m),3.86(3H,s),3.87(3H,s),5.27(2H,s),6.82(2H,d),6.9 7(3H,d),7.18-7.27(3H,m),7.50(2H,d),7.58(1H,d),8.20(1H,s),10.10(1H,s).m / z:(ES+),[M+H]+=581.3

[0287] (d) 5-hydroxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl 5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (1.8 g, 3.10 mmol) was added to a mixture of TFA (5 mL) and DCM (20 mL). The resulting mixture was stirred at 25°C for 1 hour. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 5-hydroxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (1.10 g, 77%) as a brown solid; 1H NMR (300 MHz, DMSO-d6)δ 3.12-3.20(4H,m),3.74-3.81(4H,m),3.93(3H,s),4.13(3H,s),7.02-7.07(2H,m),7.54(2H,d),7.73(1 H,t),7.97-8.03(1H,m),8.22(1H,d),8.44(1H,s),9.70(1H,s),10.09(1H,s);m / z:(ES+),[M+H]+=461.2

[0288] (e) 5-Chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl Phosphoryl chloride (5.00 mL, 53.7 mmol) was added to methyl 5-hydroxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.30 g, 0.65 mmol). The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The resulting residue was redissolved in pharmaceutically acceptable solution and washed sequentially with saturated sodium bicarbonate aqueous solution and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was purified by silica gel chromatography using 0-20% MeOH-DCM as the eluent to obtain 5-chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (0.200 g, 64%) as a brown solid; 1H NMR (400 MHz, DMSO-d6) δ 3.14-3.18 (4H,m), 3.55-3.59 (4H,m), 3.92 (3H,s), 4.07 (3H,s), 7.04 (2H,d), 7.49-7.73 (5H,m), 8.01 (1H,s), 10.00 (1H,s); m / z: (ES+), [M+H]+ = 479.2

[0289] (f) 5-Chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (10 mL, 70 mmol) was added to methyl 5-chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (200 mg, 0.42 mmol). The resulting suspension was stirred at 25°C for 1 hour. The reaction product was then concentrated. The resulting residue was purified by preparative HPLC using a 30 mm × 150 mm, 5 μm, CSH OBD column with 20-35% MeCN-H2O as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 5-chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (17 mg, 8.8%) as an orange solid; 1H NMR (400 MHz, DMSO-d6)δ 3.10(4H,t),3.75(4H,t),3.89(3H,s),7.00(2H,d),7.35-7.46(2H,m),7.54(2H,d),7.68 (1H,dd),7.98(1H,s),8.08(1H,s),8.21(1H,s),11.14(1H,s).m / z:(ES+),[M+H]+=464.2

[0290] Example 29 6-(1-methylbenzimidazole-4-yl)-5-[(1-methylpyrazole-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] mCPBA (63 mg, 0.27 mmol) in DCM (2.1 mL) was added dropwise at -5°C to a solution of 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (50 mg, 0.11 mmol) in DCM (2.1 mL). The resulting mixture was stirred at room temperature for 5 minutes. The reaction product was then concentrated. The resulting residue was redissolved in NMP (2 mL). 1-Methylpyrazole-4-amine (31 mg, 0.32 mmol) was added. The resulting mixture was stirred at 150°C for 3 hours. The reaction product was then concentrated. The obtained residue was purified by preparative HPLC using a 5 micron, 19 mm × 100 mm Xbridge C18 column with 20-50% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as the eluent to obtain a bright yellow solid. This substance was suspended in MeOH (2 mL) and sonicated for 30 minutes. The resulting suspension was filtered to obtain 6-(1-methylbenzimidazole-4-yl)-5-[(1-methylpyrazole-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide (8.0 mg, 15%) as a bright yellow solid; 1H NMR (500 MHz, DMSO-d6) δ 3.09-3.12 (4H,m), 3.67 (3H,s), 3.71-3.77 (4H,m), 3.92 (3H,s), 7.00 (2H,br d), 7.32-7.40 (4H,m), 7.43 (1H,br t), 7.62-7.68 (2H,m), 7.70 (1H,br s), 7.80 (1H,br d),8.39(1H,s),10.79(1H,s),10.90(1H,s);m / z:(ES+),[M+H]+=525.4

[0291] Example 30 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate methyl 60 wt% sodium hydride (397 mg, 9.92 mmol) in mineral oil was added to a solution of pyridine-2-amine (856 mg, 9.10 mmol) in THF (36 mL). The resulting mixture was stirred at room temperature for 1 hour. Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.74 g, 7.85 mmol) and DMF (9 mL) were added sequentially. The resulting suspension was stirred at room temperature for 12 hours. The reaction product was then concentrated. The resulting residue was triturated in water, then filtered, dried under air, and obtained under vacuum. Water was added to the mixture. The resulting solid was then filtered and air-dried to obtain methyl 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate (2.20 g, yield 95%) as a pale yellow solid. 1H NMR(500MHz,DMSO-d6)3.98(3H,s),7.15(1H,ddd),7.75-7.92(3H,m),8.15(1H,d),8.33(1H,dd),9.63(1H,s).m / z:(ES+),[M+2+H]+=281.9

[0292] (b) 6-chloro-3-fluoro-5-(2-pyridylamino)pyrazine-2-carboxylate methyl Sodium nitrite (154 mg, 2.24 mmol) is administered in small amounts to HF * To a solution of methyl 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate (521 mg, 1.86 mmol) in pyridine (8.40 mL, 245 mmol), the methyl 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate was added at -10°C. The reaction mixture was then stirred at 25°C for 1 hour. The reaction mixture was then quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to obtain methyl 6-chloro-3-fluoro-5-(2-pyridylamino)pyrazine-2-carboxylate (0.420 g, yield 80%) as an orange solid. m / z:(ES-),[MH]-=281.3

[0293] (c)6-Chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxylate methyl DIPEA (234 μL, 1.34 mmol) was added to a solution of 6-chloro-3-fluoro-5-(2-pyridylamino)pyrazine-2-carboxylate methyl (189 mg, 0.67 mmol) and 4-morpholinoaniline (119 mg, 0.670 mmol) in DMF (4 mL). The resulting mixture was heated at 100 °C for 12 hours. The reaction product was then diluted with water. The resulting precipitate was collected by filtration and air-dried to obtain 6-chloro-3-(4-morpholinoaniline)-5-(2-pyridylamino)pyrazine-2-carboxylate methyl (0.280 g, 95%) as a brown solid. m / z: (ES-), [MH]- = 439.3

[0294] (d) 6-Chloro-3-(4-Molfolinoanilino)-5-(2-Pyridylamino)pyrazine-2-carboxamide 7N methanolic ammonia (4.0 mL, 28 mmol) was added to methyl 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxylate (230 mg, 0.52 mmol). The resulting suspension was stirred at 100°C for 12 hours. The reaction product was then concentrated to obtain 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide as a brown solid (165 mg, yield 74%).

[0295] (e)6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide PdCl2 (dppf) (28 mg, 0.040 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole (185 mg, 65 wt%, 0.46 mmol), cesium fluoride (177 mg, 1.16 mmol), and 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide (165 mg, 0.39 mmol) were mixed in a microwave vial, degassed under vacuum, and packed three times with nitrogen. Dioxane (1.55 mL) and water (0.39 mL) were added. The resulting mixture was stirred at 100°C for 12 hours. The reaction product was then concentrated. The obtained residue was purified by preparative HPLC using 30-70% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as a modifier to obtain 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide (50 mg, 25%) as a pale yellow solid; 1H NMR (400 MHz, DMSO-d6)δ 3.04-3.13(4H,m),3.67-3.80(4H,m),3.95(3H,s),6.92(2H,d),6.97(1H,dd),7 .42-7.51(3H,m),7.55-7.65(2H,m),7.69-7.78(2H,m),7.88(1H,d),7.91(1H,br s),8.17-8.24(1H,m),8.51(1H,s),10.92(1H,s),11.05(1H,s);m / z:(ES+),[M+H]+=522.3

[0296] Example 31 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(oxetan-3-yl)pyrazine-2-carboxylate methyl 3-amino-5,6-dichloropyrazine-2-carboxylate methyl (500 mg, 2.25 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (60 mg, 0.23 mmol), Ir(dFCF3ppy)2(dtbbpy) hexafluorophosphate (25 mg, 0.020 mmol), and NiCl2 diglyme (50 mg, 0.23 mmol) were mixed in a vial and spurged with nitrogen for 5 minutes. Then, DME (13.6 mL) was added. 3-iodooxetane (400 μL, 4.5 mmol), 1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (1.04 mL, 3.38 mmol), and sodium carbonate (477 mg, 4.50 mmol) were added sequentially. The resulting mixture was again sparged with nitrogen for 5 minutes, and then stirred in a photoreactor under blue light at ambient temperature without operating a cooling fan for 16 hours. The reaction product was then concentrated. The resulting residue was purified by flash silica gel chromatography using 0-30% toluene-hexane as the eluent to obtain methyl 3-amino-6-chloro-5-(oxetan-3-yl)pyrazine-2-carboxylate (0.120 g, 22%) as a yellow solid; 1H NMR (500 MHz, chloroform-d) δ 3.99 (3H, s), 4.61 (1H, tt), 4.92-4.99 (2H, m), 5.00-5.06 (2H, m). The NH2 signal was exchanged with chloroform-d; m / z: (ES+), [M+H]+ = 244.1

[0297] (b) 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxylate methyl DMF (2.4 mL) was added to a mixture of bis(pinacolate)diborone (299 mg, 1.18 mmol), cataCXium A (17 mg, 0.050 mmol), cataCXium A Pd G3 (34 mg, 0.050 mmol), potassium acetate (139 mg, 1.41 mmol), and 7-bromo-3-methylimidazo[4,5-c]pyridine (100 mg, 0.47 mmol). The resulting suspension was sparged with nitrogen for 5 minutes, stirred at 80°C for 16 hours, and then stirred at 100°C for 24 hours. The reaction mixture was then cooled to room temperature and left to stand.

[0298] Sodium nitrite (37 mg, 0.54 mmol) is used in HF *3-amino-6-chloro-5-(oxetan-3-yl)pyrazine-2-carboxylate methyl (120 mg, 0.49 mmol) was added to pyridine (5.30 mL, 155 mmol) at 0°C. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction product was then poured into 75 mL of water and extracted three times (20 mL each) with DCM. The combined organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was dissolved in DMF (2.4 mL). DIPEA (85 μL, 0.49 mmol) and 4-morpholinoaniline (87 mg, 0.49 mmol) were added. The resulting mixture was stirred at 100°C for 1 hour. The reaction product was then concentrated. Pd(dppf)Cl2 DCM (24 mg, 0.030 mmol) and cesium fluoride (90 mg, 0.59 mmol) were added to the resulting residue. A boronation mixture was added. The resulting suspension was sparged with nitrogen for 5 minutes, then stirred at 100°C for 2 hours. The reaction product was then concentrated on celite. The obtained substance was purified by silica gel chromatography using 0-10% MeOH-DCM containing 0-1% ammonia as the eluent to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxylate methyl (0.089 g, 60%) as a brown solid; 1H NMR (500 MHz, DMSO-d6)δ 3.04-3.13(4H,m),3.68-3.77(4H,m),3.91(3H,s),4.00(3H,s),4.29-4.39(1H,m),4.51(2H,dd),4.67-4.75(2 H,m),6.99(2H,d),7.71(2H,d),8.36(1H,s),8.42(1H,s),9.04(1H,s),9.99(1H,s);m / z:(ES+),[M+H]+=502.3

[0299] (c)6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetane-3-yl)pyrazine-2-carboxamide 7N methanolic ammonia (2.0 mL, 14 mmol) was added to methyl 6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-3-((4-morpholinophenyl)amino)-5-(oxetan-3-yl)pyrazine-2-carboxylate (89 mg, 0.18 mmol). The resulting mixture was stirred at 100°C for 2 hours in a Biotage microwave reactor. The reaction product was then concentrated. The obtained residue was purified by preparative HPLC using a 5 micron, 19 mm × 250 mm XSelect CSH Prep C18 OBD column, with a mixture of MeCN-H2O (which reduces polarity) as the eluent, and 0.2% ammonium hydroxide as a modifier, to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide (0.016 g, 18%) as a yellow solid; 1H NMR(500MHz,DMSO-d6)2.97-3.16(4H,m),3.65-3.82(4H,m),4.01(3H,s),4.29-4.46(1H,m),4.58(2H,dd),4.68-4.83(2H,m),6.99( 2H,d),7.75(2H,d),7.84-7.97(1H,m),8.23(1H,s),8.44(1H,s),8.56(1H,s),9.04(1H,s),11.20(1H,s);m / z:(ES+),[M+H]+=487.2

[0300] Example 32 5-Ethoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-ethoxypyrazine-2-carboxylate ethyl carboxylate 21% sodium ethoxide (3.03 mL, 8.11 mmol) in ethanol was added to a mixture of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.20 g, 5.40 mmol) in anhydrous ethanol (25 mL). The resulting mixture was stirred at 80°C for 3 hours. The reaction product was then concentrated. The resulting residue was treated with water and filtered. The solid was recovered, washed with water, and dried to obtain ethyl 3-amino-6-chloro-5-ethoxypyrazine-2-carboxylate (0.995 g, yield 75%) as a beige solid. ¹H NMR (500 MHz, DMSO-d6) 1.28(3H,t), 1.35(3H,t), 4.26(2H,q), 4.40(2H,q), 7.56(2H,br s). m / z: (ES+), [M+H]+=246.1

[0301] (b) 6-Chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid t-BuXPhos Pd G3 (0.133 g, 0.170 mmol) was added under nitrogen to a suspension of ethyl 3-amino-6-chloro-5-ethoxypyrazine-2-carboxylate (0.410 g, 1.67 mmol), 4-(4-bromophenyl)morpholine (0.808 g, 3.34 mmol), t-BuXPhos (0.071 g, 0.17 mmol), and sodium tert-butoxide (0.321 g, 3.34 mmol) in THF (16 mL). The resulting mixture was stirred at 40°C for 3 hours. The reaction product was then diluted with water and extracted with ELISA. The organic layer was washed with saturated sodium bicarbonate aqueous solution and water. The combined organic layers were acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried to obtain 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (0.390 g, yield 62%). ¹H NMR (500 MHz, DMSO-d6) showed 1.36 (3H,t), 3.04-3.08 (4H,m), 3.71-3.74 (4H,m), 4.41 (2H,q), 6.93 (2H,d), 7.47 (2H,d). NH and COOH protons were expanded to the baseline. m / z: (ES+), [M+H]+ = 379.3

[0302] (c) 6-Chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide Triethylamine (0.727 mL, 5.22 mmol) was added to a mixture of 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (0.494 g, 1.30 mmol), ammonium chloride (0.349 g, 6.52 mmol), and HATU (0.744 g, 1.96 mmol) in DMF (10 mL). The resulting mixture was stirred at room temperature for 3.5 hours. The reaction product was then diluted with saturated sodium bicarbonate aqueous solution and water. The precipitate was collected by filtration, washed with water, and dried to obtain 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.366 g, yield 74%) as a brown solid. 1H NMR(500MHz,DMSO-d6)1.37(3H,t),3.03-3.08(4H,m),3.70-3.74(4H,m),4.42(2H,q),6.94(2H,d),7.47(2H,d),7.65(1H,br s),7.87(1H,s),11.17(1H,s).m / z:(ES+),[M+H]+=378.5

[0303] (d) 5-Ethoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide A mixture of 2-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-1,3,6,2-dioxazavolocan (0.069 g, 0.28 mmol), 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.053 g, 0.14 mmol), and PdCl2(dppf) (10.3 mg, 0.0100 mmol) in a 2M aqueous potassium phosphate solution (0.21 mL, 0.42 mmol) and 1,4-dioxane (1.5 mL) was purged with nitrogen. The reaction mixture was stirred in a microwave reactor at 100°C for 2 hours. The reaction product was then concentrated. The resulting residue was washed with water and purified by flash silica gel chromatography using 0-10% MeOH-DCM as the eluent. The product was further purified by reverse-phase C18 flash chromatography using 0-20% MeCN-H2O as the eluent and 0.1% ammonium hydroxide as a modifier to obtain 5-ethoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.041 g, yield 62%) as a yellow solid. 1H NMR(500MHz,DMSO-d6)1.27(3H,t),3.00-3.15(4H,m),3.67-3.80(4H,m),3.97(3H,s),4.41(2H,q),6.97(2H,d),7.57(2H,d),7.66(1H,br m / z:(ES+),[M+H]+=475.2

[0304] Example 33 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide [ka] (a) Ethyl 3,3-diamino-2-nitrosopropa-2-enoate Ethyl hydrochloride 3-ethoxy-3-imino-propanoate (5.00 g, 25.6 mmol) was added to 2 M ethanolic ammonia (40 mL, 80 mmol) at 0°C. The reaction mixture was stirred at 0°C for 30 minutes and then at 25°C for 3.5 hours. A solution of sodium nitrite (1.94 g, 28.1 mmol) in water (8 mL) was added. 6N aqueous HCl (15 mL, 90 mmol) was added. The resulting mixture was stirred overnight at 25°C. The reaction mixture was then concentrated under reduced pressure to 1 / 3 of its volume and neutralized with saturated aqueous sodium bicarbonate. The resulting suspension was filtered, washed with water, and air-dried to obtain ethyl 3,3-diamino-2-nitrosopropa-2-enoate (1.59 g, 39%); 1H NMR (500 MHz, DMSO-d6) δ 1.27 (3H, t), 4.26 (2H, q), 7.53 (2H, br s), 10.08 (2H, br s). Malfunction by LC-MS.

[0305] (b) Ethyl 2,3-diamino-3-imino-propanoate A mixture of ethyl 3,3-diamino-2-nitrosopropanate (0.935 g, 5.88 mmol), 10 wt% palladium carbon (0.313 g, 0.290 mmol), and 6 M aqueous HCl (17.0 mL, 102 mmol) in ethanol (25 mL) was stirred at 25 °C for 16 hours under a hydrogen atmosphere. The reaction product was then filtered through Celite. The filtrate was concentrated to obtain ethyl 2,3-diamino-3-iminopropanoate (1.080 g, quantitative) as a white solid; 1H NMR (500 MHz, DMSO-d6) δ 1.24 (3H, t), 4.28 (2H, q), 5.24 (1H, s), 9.49 (2H, br s). AminoNH2 guanidinoNH was expanded to the baseline. m / z:(ES+),[M+H]+=146.1

[0306] (c) 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate ethyl and 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate ethyl A 20 wt% aqueous solution of 3,3,3-trifluoro-2-oxopropanal (9.96 g, 15.8 mmol) was added to a solution of ethyl 2,3-diamino-3-imino-propanoate (0.854 g, 5.88 mmol) in water (30 mL). Sodium acetate (3.38 g, 41.2 mmol) was added. The resulting mixture was stirred at 25°C for 16 hours. The reaction product was basicized with saturated sodium bicarbonate aqueous solution. The resulting suspension was filtered, washed with water, and air-dried to obtain a 1:1 mixture of ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate and ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate (498 mg, yield 36%); 1H NMR (500 MHz, DMSO-d6) δ 1.32 (3H, t), 4.35 (2H, q), 7.80 (2H, br s), 8.30 (1H, s), 8.67 (1H, s). m / z: (ES+), [M+H]+ = 236.1

[0307] (d) 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate ethyl N-bromosuccinimide (0.338 g, 1.90 mmol) was added to a solution of ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate and ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate (1:1) (0.446 g, 1.90 mmol) in acetonitrile (15 mL). The reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was then concentrated. The obtained residue was purified twice by silica gel chromatography, both times using 0-20% toluene-hexane as the eluent, to obtain ethyl 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate (0.270 g, yield 45%) as a pale yellow solid; ¹H NMR (500 MHz, DMSO-d6) δ 1.32 (3H, t), 4.36 (2H, q), 7.89 (2H, br s). m / z: (ES+), [M+H]+ = 314.1

[0308] (e)3-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate ethyl DMF (2 mL) was added to a mixture of 7-bromo-3-methylimidazo[4,5-c]pyridine (115 mg, 0.54 mmol), bis(pinacolate)diborone (165 mg, 0.65 mmol), potassium acetate (159 mg, 1.62 mmol), cataCXium A Pd G3 (39 mg, 0.050 mmol), and cataCXium A (19 mg, 0.050 mmol). The resulting mixture was degassed under vacuum, nitrogen was added three times, and the mixture was stirred at 80°C for 23 hours. An additional 2 mL of DMF was added. The reaction mixture was degassed under vacuum and nitrogen was added three times. The reaction mixture was stirred at 100°C for 24 hours. The reaction mixture was cooled to room temperature and left to stand.

[0309] In a microwave vial, ethyl 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate (121 mg, 0.390 mmol), PdCl2 (dppf) (28 mg, 0.040 mmol), and cesium fluoride (117 mg, 0.770 mmol) were mixed, degassed under vacuum, and filled with nitrogen three times. The boronation mixture was added by syringe. The resulting mixture was stirred at 100°C for 2 hours. The reaction was then diluted with water. The resulting suspension was filtered, washed with water, and air-dried. The filtrate was treated with saturated sodium bicarbonate aqueous solution and then extracted with 5:1 DCM / IPA. The organic layer was dried over sodium sulfate, filtered, and concentrated. The obtained residue was combined with the filter cake and purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 3-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate ethyl (0.042 g, 30%) as a brown gum-like substance; 1H NMR (500 MHz, DMSO-d6) δ 1.26(3H,t), 3.98(3H,s), 4.33(2H,q), 7.77-7.97(2H,m), 8.30(1H,s), 8.37(1H,s), 9.05(1H,s). m / z: (ES+), [M+H]+=367.2

[0310] (f)6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxylic acid A mixture of 4-(4-bromophenyl)morpholine (0.056 g, 0.23 mmol), 3-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate ethyl (0.085 g, 0.23 mmol), BrettPhos Pd G3 (0.042 g, 0.05 mmol), and cesium carbonate (0.227 g, 0.70 mmol) in 1,4-dioxane (2.0 mL) was degassed under vacuum and filled with nitrogen three times. The resulting mixture was stirred at 100°C for 4 hours. The reaction product was then concentrated. The obtained residue was purified by C18 reverse-phase chromatography using 0-35% MeCN-H2O as the eluent and 0.1% TFA as a modifier to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxylic acid (0.025 g, 22%) as a solid; 1H NMR (500 MHz, DMSO-d6) δ 3.10-3.14 (4H, m), 3.73-3.75 (4H, m), 4.09 (3H, s), 7.02 (2H, br d), 7.61(2H,d), 8.71(1H,s), 8.90(1H,s), 9.55(1H,s), 10.41(1H,s); COOH protons were spread out and indistinguishable from the baseline; m / z: (ES+), [M+H]+=500.3

[0311] (g)6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide DIPEA (0.026 mL, 0.15 mmol) was added to a mixture of 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxylic acid (0.025 g, 0.050 mmol), ammonium chloride (0.013 g, 0.25 mmol), and HATU (0.029 g, 0.080 mmol) in DMF (0.80 mL). The resulting mixture was stirred at 25°C for 2 hours. The reaction product was then treated with saturated sodium bicarbonate aqueous solution and extracted with a 5:1 DCM / IPA. The organic layer was concentrated. The obtained residue was purified by C18 reverse-phase chromatography using 10-50% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as a modifier to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide (18 mg, 72%) as an orange solid; 1H NMR (500 MHz, DMSO-d6) δ 3.03-3.14 (4H,m), 3.66-3.78 (4H,m), 3.99 (3H,s), 7.00 (2H,d), 7.61 (2H,d), 8.13 (1H,br s), 8.26 (1H,br s),8.40(1H,s),8.44(1H,s),9.05(1H,s),11.28(1H,s);m / z:(ES+),[M+H]+=499.3

[0312] Example 34 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-chloro-3-fluoro-5-methylsulfanylpyrazine-2-carboxylate methyl carboxylate Sodium nitrite (3.00 g, 43.5 mmol) was added in small amounts at -10°C to a suspension of methyl 3-amino-6-chloro-5-(methylthio)pyrazine-2-carboxylate (9.65 g, 41.3 mmol) in HF-pyridine (20 mL, 580 mmol). The reaction mixture was then stirred at 25°C for 3 hours. The reaction mixture was then diluted with DCM (30 mL) and quenched with water (50 mL). The layers were separated, and the aqueous layer was extracted twice with DCM (10 mL each time). The combined organic matter was dried over MgSO4, filtered, and concentrated to obtain methyl 6-chloro-3-fluoro-5-methylsulfanylpyrazine-2-carboxylate (9.46 g, 97%) as a pale yellow solid; ¹H NMR (500 MHz, DMSO-d6) 2.59 (3H, s), 3.88 (3H, s); m / z: (ES+), [M+H]+ = 237.0

[0313] (b) 6-Chloro-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl DIPEA (4.00 mL, 22.9 mmol) was added to a solution of methyl 6-chloro-3-fluoro-5-methylsulfanylpyrazine-2-carboxylate (5.00 g, 21.1 mmol) and 4-morpholinoaniline (3.95 g, 22.2 mmol) in DMF (17 mL). The resulting brown solution was stirred at 100°C for 15 minutes. The reaction mixture was cooled to room temperature, then filtered, washed with RINKAN, and dried under vacuum to obtain methyl 6-chloro-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (6.23 g, 75%) as a pale orange solid; ¹H NMR (500 MHz, DMSO-d6) 2.50 (3H, s), 3.02-3.16 (4H, m), 3.66-3.81 (4H, m), 3.89 (3H, s), 6.95 (2H, d), 7.49 (2H, d), 9.92 (1H, s); m / z: (ES+), [M+2+H]+ = 397.0.

[0314] (c)6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl 7-Bromo-3-methylimidazo[4,5-c]pyridine (1.00 g, 4.72 mmol), bis(pinacolate)diborone (2.39 g, 9.42 mmol), cataCXium A Pd G3 (0.343 g, 0.470 mmol), cataCXium A (0.169 g, 0.470 mmol), and potassium acetate (0.895 g, 9.12 mmol) were mixed in a multi-necked flask, degassed under vacuum, and filled with nitrogen three times. DMF (15 mL) was added, and the resulting mixture was stirred at 80°C for 24 hours. The reaction mixture was then cooled to room temperature.

[0315] 6-chloro-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (1.50 g, 3.80 mmol), Pd(dppf)Cl2 (0.278 g, 0.380 mmol), and cesium fluoride (1.73 g, 11.4 mmol) were mixed in a multi-necked flask, degassed under vacuum, and filled with nitrogen three times. The boration mixture was added by syringe. The resulting mixture and reaction product were stirred at 100°C for 3 hours. The reaction product was then cooled to room temperature, diluted with water (150 mL), and extracted three times (50 mL each) with a 3:1 DCM / IPA. The combined organic layer was dried over magnesium sulfate, filtered, and concentrated on Celite. Next, the obtained substance was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (0.742 g, 40%) as a dark orange foamy solid; 1H NMR(500MHz,DMSO-d6)2.39(3H,s),3.05-3.15(4H,m),3.67-3.82(4H,m),3.85(3H,s),3.99(3H,s),6.9 7(2H,d),7.57(2H,d),8.32(1H,s),8.38(1H,s),9.05(1H,s),10.05(1H,s);m / z:(ES+),[M+H]+=492.1.

[0316] (d) 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (6.0 mL, 42 mmol) was added to 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (742 mg, 1.51 mmol). The resulting dark orange suspension was stirred at 100°C for 4 hours in a Biotage microwave reactor. The reaction mixture was cooled to room temperature, then filtered and washed with MeOH. The resulting yellowish-brown solid was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.370 g, 51%) as a bright yellow solid; 1H NMR (500 MHz, DMSO-d6) 2.44(3H,s), 3.01-3.12(4H,m), 3.69-3.77(4H,m), 3.98(3H,s), 6.97(2H,d), 7.58(2H,d), 7.74(1H,br d), 7.93(1H,br s),8.39(1H,s),8.42(1H,s),9.03(1H,s),11.20(1H,s);m / z:(ES+),[M+H]+=477.1.

[0317] Example 35 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] mCPBA (194 mg, 0.790 mmol) was added as a solution in DCM (1 mL) to a suspension of 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (75 mg, 0.16 mmol) in DCM (3 mL) at 0°C. The resulting suspension was stirred at 25°C for 2 hours. The reaction product was then concentrated. The resulting yellow solid was dissolved in DMF (2 mL). 1-methylcyclopropanamine hydrochloride (85 mg, 0.79 mmol) and DIPEA (500 μL, 2.86 mmol) were added, and the resulting mixture was stirred at 100°C for 1 hour. Tetrahydroxydiborone (42 mg, 0.47 mmol) was then added, and the resulting mixture was stirred at 100°C for 5 minutes. The reaction mixture was cooled to room temperature, then diluted with water (20 mL), and extracted three times (25 mL each time) with a 3:1 DCM / IPA solution. The collected organic matter was washed with a 5% lithium chloride aqueous solution (10 mL), dried over magnesium sulfate, filtered, and concentrated with Celite. This substance was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (18 mg, 23%) as a fluffy yellow solid; 1H NMR (500 MHz, DMSO-d6) 0.70-0.82 (4H, m), 1.46 (3H, s), 3.01-3.10 (4H, m), 3.70-3.77 (4H, m), 4.00 (3H, s), 6.95 (2H, d), 7.35 (1H, br d), 7.76 (1H, br s),7.83(2H,d),8.47-8.58(2H,m),8.76(1H,s),8.98(1H,s),11.31(1H,s);m / z:(ES+),[M+H]+=500.2.

[0318] Example 36 5-Cyano-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] mCPBA (194 mg, 0.790 mmol) was added as a solution in DCM (1 mL) to a suspension of 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (75 mg, 0.16 mmol) in DCM (3 mL) at 0°C. The resulting suspension was stirred at room temperature for 2 hours. The reaction mixture was then concentrated into a yellow solid and dissolved in DMF (2 mL). Sodium cyanide (77 mg, 1.57 mmol) was added, and the resulting mixture was stirred at 100°C for 2 hours. The reaction mixture was then cooled to room temperature and treated with sodium bisulfite (82 mg, 0.79 mmol), and stirred for 10 minutes. Additional sodium bisulfite (82 mg, 0.79 mmol) was added, and the resulting mixture was stirred for 1 hour. Next, the reaction mixture was diluted with water (40 mL) and extracted three times (25 mL each) with a 3:1 DCM / IPA solution. The combined organic matter was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain a red solid. This substance was then further purified by preparative HPLC using a 5 micron, 30 mm × 150 mm Xselect CSH column, with 25-50% MeCN-H2O as the eluent and 0.2% ammonium hydroxide as a modifier to obtain 5-cyano-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (12 mg, 17%) as an orange solid; 1H NMR(500MHz,DMSO-d6)3.05-3.14(4H,m),3.68-3.79(4H,m),4.02(3H,s),7.01(2H,d) ,7.54(2H,d),8.12-8.32(1H,m),8.51(2H,s),8.75(1H,s),9.10(1H,s),11.22(1H,br s);m / z:(ES+),[M+H]+=456.2

[0319] Example 37 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] A solution of mCPBA (396 mg, 1.61 mmol) in DCM (2 mL) was added dropwise at -10C to a suspension of 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (153 mg, 0.320 mmol) in DCM (3 mL). The reaction mixture was stirred at 25C for 90 minutes. The reaction mixture was then concentrated. The resulting orange solid was dissolved in DMF (2 mL). Cyclopropylamine (0.050 mL, 0.71 mmol) and DIPEA (0.500 mL, 2.86 mmol) were added sequentially, and the reaction mixture was stirred at 25C for 30 minutes. The reaction mixture was stirred at 100C for 1 hour in a Biotage microwave reactor. The reaction mixture was then cooled to room temperature. Sodium bisulfite (0.133 g, 1.28 mmol) was added, and the reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was then diluted with water (25 mL) and extracted three times (20 mL each time) with a 3:1 DCM / IPA solution. The combined organic layer was dried over magnesium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as a modifier to obtain 39 mg of an orange solid. This substance was further purified by preparative HPLC using a 5 micron, 30 mm × 100 mm Waters XSelect CSH C18 OBD Prep column, with 30-60% MeCN-H2O as the eluent and 0.1% ammonium hydroxide as a modifier, to obtain 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (23 mg, 15%) as a yellow solid; 1H NMR(500MHz,DMSO-d6)0.43-0.61(2H,m),0.76-0.93(2H,m),2.89(1H,tt), 3.00-3.12(4H,m),3.65-3.79(4H,m),4.02(3H,s),6.96(2H,d),7.39(1H,br s),7.74-7.89(3H,m),8.57(1H,s),8.81(1H,br d),8.84(1H,s),9.00(1H,s),11.32(1H,s);m / z:(ES+),[M+H]=486.2

[0320] Example 38 5-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(cyclopropylamino)pyrazine-2-carboxylate methyl carboxylate Cyclopropanamine (1.029 g, 18.02 mmol) was added to a suspension of methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (1.00 g, 4.50 mmol) in THF (20 mL). The resulting mixture was stirred at 25°C for 4 hours. The reaction product was then concentrated. The resulting residue was treated with water. The resulting suspension was filtered, and the solid was dried under vacuum to obtain methyl 3-amino-6-chloro-5-(cyclopropylamino)pyrazine-2-carboxylate (1.10 g, quantitatively) as an orange solid; ¹H NMR (500 MHz, DMSO-d6) 0.54-0.80 (4H, m), 2.77-2.93 (1H, m), 3.72 (3H, s), 7.26 (2H, br s), 7.48 (1H, br d); m / z: (ES+), [M+H]+=243.1.

[0321] (b) 3-amino-5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate methyl

[0322] CataCXium A (17 mg, 0.050 mmol), cataCXium A Pd G3 (34 mg, 0.050 mmol), 7-bromo-3-methylimidazo[4,5-c]pyridine (100 mg, 0.47 mmol), potassium acetate (139 mg, 1.41 mmol), and bis(pinacolate)diborone (240 mg, 0.94 mmol) were mixed in a microwave vial, degassed under vacuum, and filled with nitrogen three times. DMF (3 mL) was added. The resulting mixture was stirred at 80°C for 20 hours. The reaction mixture was then cooled to room temperature and left to stand.

[0323] Pd(dppf)Cl2 (35 mg, 0.05 mmol), CsF (107 mg, 0.710 mmol), and methyl 3-amino-6-chloro-5-(cyclopropylamino)pyrazine-2-carboxylate (114 mg, 0.470 mmol) were mixed in a microwave vial, degassed under vacuum, and filled with nitrogen three times. The boronated mixture was added by syringe. The resulting mixture was heated at 100°C for 2 hours. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography using 0-70% MeOH-DCM as the eluent to obtain methyl 3-amino-5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate (80 mg, yield 50%) as an off-white powder.

[0324] (c) 5-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide BrettPhos Pd G3 (21 mg, 0.020 mmol) was added to a suspension of methyl 3-amino-5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxylate (80 mg, 0.24 mmol), 4-(4-bromophenyl)morpholine (57 mg, 0.24 mmol), and cesium carbonate (154 mg, 0.470 mmol) in 1,4-dioxane (2 mL). The resulting mixture was heated at 90°C for 4 hours. The reaction product was then concentrated. The resulting residue was purified by silica gel chromatography using 0-70% MeOH-DCM as the eluent to obtain a brown solid. This substance was suspended in 7N methanolic ammonia (510 μL, 3.57 mmol). The resulting suspension was heated at 100°C for 14 hours. The reaction product was then concentrated. The obtained residue was purified by preparative HPLC using a 5 micron, 19 mm × 150 mm Xbridge C18 column with 20-50% MeCN-H2O as the eluent and 0.2% NH4OH as a modifier to obtain 5-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (2.0 mg, 1.9%); 1H NMR (500 MHz, DMSO-d6) 2.99-3.11 (4H, m), 3.67-3.79 (4H, m), 4.00 (3H, s), 6.91 (2H, d), 7.36 (1H, br s), 7.50 (2H, br s), 7.63 (2H, d), 7.79 (1H, br s),8.53(1H,s),8.80(1H,s),8.98(1H,s),11.18(1H,s);m / z:(ES+),[M+H]+=446.3

[0325] Example 39 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl CataCXium A Pd G2 (17 mg, 0.03 mmol) was added under nitrogen to a suspension of bis(pinacolate)diborone (129 mg, 0.510 mmol), 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (100 mg, 0.25 mmol), potassium acetate (75 mg, 0.76 mmol), and bis(1-adamantyl)-butyl-phosphonium tetrafluoroborate (11 mg, 0.030 mmol) in DMF (10 mL). The resulting mixture was stirred at 80°C for 16 hours. The reaction mixture was then cooled to room temperature and left to stand.

[0326] A mixture of cesium fluoride (97 mg, 0.64 mmol), 7-bromo-3-methylimidazo[4,5-c]pyridine (54 mg, 0.25 mmol), and PdCl2 (dppf) (18.61 mg, 0.03 mmol) was degassed under vacuum and packed three times. The borated mixture was added by syringe. The resulting mixture was stirred at 100°C for 16 hours. The reaction product was then concentrated. The resulting residue was dissolved in MeOH (10 mL). Thionyl chloride (2.00 mL, 27.4 mmol) was added. The resulting mixture was stirred at 60°C for 2 hours. The reaction product was then concentrated. The obtained residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to obtain 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (30 mg, 27%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6)δ 3.11(4H,t),3.72-3.81(4H,m),4.02(3H,s),4.05(3H,s),6.99(2H,d),7.55-7.63(2H,m), 8.57(1H,s),9.01(1H,s),9.06(1H,s),9.82(1H,d),9.96(1H,s).m / z:(ES+),[M+H]+=446.2

[0327] (b) 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (1.0 mL, 7.0 mmol) was added to a suspension of 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (30 mg, 0.07 mmol) in MeOH (1 mL). The resulting mixture was stirred at 80°C for 24 hours. The reaction product was then concentrated. The obtained residue was purified by preparative HPLC using a 5 micron, 30 mm × 150 mm Xbridge Shield RP18 OBD column with 12-22% MeCN-H2O as the eluent and 0.1% formic acid as a modifier, yielding 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (10 mg, 35%) as a yellow solid; 1H NMR (300 MHz, DMSO-d6)δ 3.04-3.14(4H,m),3.70-3.79(4H,m),4.02(3H,s),6.92-7.02(2H,m),7.55-7.66(2H,m),8.04(1H,s),8 .55(1H,s),8.73(1H,s),9.00(1H,s),9.45(1H,s),9.90(1H,s),11.28(1H,s);m / z:(ES+),[M+H]+=431.1

[0328] Example 40 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-Chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (5.0 mL, 35 mmol) was added to methyl 6-chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylate (555 mg, 1.47 mmol). The resulting suspension was stirred at 100°C for 2 hours in an Emrys microwave reactor. The reaction product was then filtered and washed with MeOH. The filtered cake was dried under vacuum to obtain 6-chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (291 mg, 61%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 2.99-3.10 (4H, m), 3.69-3.77 (4H, m), 3.99 (3H, s), 6.94 (2H, d), 7.43-7.57 (2H, m), 7.66 (1H, br s), 7.89 (1H, s), 11.19 (1H, s) m / z: (ES-), [MH]- = 362.3

[0329] (b) 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7-Bromo-3-methylimidazo[4,5-c]pyridine (100 mg, 0.47 mmol), bis(pinacolate)diborone (299 mg, 1.18 mmol), cataCXium A (17 mg, 0.050 mmol), cataCXium A Pd G3 (34 mg, 0.050 mmol), and potassium acetate (139 mg, 1.41 mmol) were mixed in a microwave vial, degassed under vacuum, and filled with nitrogen three times. DMF (2.3 mL) was added, and the resulting mixture was stirred at 80°C for 24 hours. The reaction mixture was cooled to room temperature and allowed to stand.

[0330] 6-Chloro-5-methoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (137 mg, 0.380 mmol), Pd(dppf)Cl2 dichloromethane adduct (31 mg, 0.040 mmol), and cesium fluoride (172 mg, 1.13 mmol) were mixed in a microwave vial, degassed under vacuum, and filled with nitrogen three times. The boration reaction mixture was added to the vial using a syringe. The resulting mixture was stirred at 100°C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (40 mL), and filtered. The filtered cake was purified by reverse-phase chromatography using 0-50% MeCN-H2O as the eluent and 0.1% trifluoroacetic acid as a modifier to obtain an orange residue. The aqueous filtrate was diluted with saturated sodium bicarbonate aqueous solution (20 mL) and extracted three times (30 mL each) using a 3:1 DCM / IPA ratio. The combined organic layer was concentrated. The resulting residue was purified by reverse-phase chromatography using 0-50% MeCN-H2O as the eluent and 0.1% trifluoroacetic acid as a modifier to obtain an orange residue. The orange residues from the two columns were dissolved in water (20 mL), basicized with saturated sodium bicarbonate aqueous solution (10 mL), and extracted three times (20 mL each) using DCM. The combined organic material was dried over magnesium sulfate, filtered, and concentrated to obtain 5-methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (50 mg, 29%) as a yellow solid. 1H NMR(500MHz,DMSO-d6)3.01-3.11(4H,m),3.67-3.77(4H,m),3.92(3H,s),3.97(3H,s),6.97(2H,d),7.60(2H,d),7.67(1H,br s),7.94(1H,br s),8.38(1H,s),8.60(1H,s),8.97(1H,s),11.22(1H,s);m / z:(ES+),[M+H]+=461.3

[0331] Example 41 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-chloro-5-cyclopropyl-3-fluoropyrazine-2-carboxylate methyl carboxylate Sodium nitrite (68.4 mg, 0.990 mmol) was added at 0°C to a solution of methyl 3-amino-6-chloro-5-cyclopropyl-pyrazine-2-carboxylate (215 mg, 0.940 mmol) in HF-pyridine (3.0 mL, 87 mmol). The reaction mixture was stirred at 25°C for 30 minutes. The reaction mixture was then diluted with DCM (5 mL) and quenched with water (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to obtain methyl 6-chloro-5-cyclopropyl-3-fluoropyrazine-2-carboxylate (0.233 g, quantitatively) as a yellow oil; ¹H NMR (500 MHz, DMSO-d6) 1.03-1.13 (2H, m), 1.25-1.34 (2H, m), 2.50-2.56 (1H, m), 3.89 (3H, s); m / z: (ES+), [M+H]+=231.1

[0332] (b) 6-Chloro-5-cyclopropyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl carboxylate DIPEA (0.180 mL, 1.03 mmol) was added to a solution of methyl 6-chloro-5-cyclopropyl-3-fluoropyrazine-2-carboxylate (0.217 g, 0.940 mmol) and 4-morpholinoaniline (0.176 g, 0.990 mmol) in DMF (3 mL). The reaction mixture was stirred at 100 °C for 40 minutes. The reaction mixture was then cooled to room temperature, diluted with water (80 mL), and extracted three times with ethyl acetate (25 mL each time). The combined organic layers were washed once with 15 mL of 5% aqueous lithium chloride solution, then dried over sodium sulfate, filtered, and concentrated. The resulting red solid was purified by silica gel chromatography using 0-80% toluene-hexane as the eluent to obtain methyl 6-chloro-5-cyclopropyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.213 g, 58%) as an orange solid; ¹H NMR (500 MHz, DMSO-d6) 0.95-1.09 (2H,m), 1.11-1.22 (2H,m), 2.39-2.44 (1H,m), 2.97-3.15 (4H,m), 3.66-3.77 (4H,m), 3.89 (3H,s), 6.93 (2H,d), 7.40 (2H,d), 9.75 (1H,s); m / z: (ES-), [MH]- = 387.2

[0333] (c) 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl 6-Chloro-5-cyclopropyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (107 mg, 0.270 mmol), 2-(3-methylimidazo[4,5-c]pyridine-7-yl)-1,3,6,2-dioxazabolocan (99 mg, 82 wt%, 0.33 mmol), Pd(dppf)Cl2 (23 mg, 0.030 mmol), and CsF (125 mg, 0.820 mmol) were mixed in a microwave vial, degassed under vacuum, and filled with nitrogen three times. MeOH (1.7 mL) was added, and the resulting mixture was stirred in a Biotage microwave reactor at 100°C for 2 hours. The reaction product was then concentrated. The resulting red residue was purified by silica gel chromatography using 0-10% methanol-DCM as the eluent and 0-1% ammonia as a modifier to obtain 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (0.061 g, 46%) as an orange solid; 1H NMR(500MHz,DMSO-d6)0.84-0.94(2H,m),0.97-1.08(2H,m),1.79-1.88(1H,m),2.98-3.14(4H,m),3.65-3.78(4H,m),3.87(3 M / z:(ES+),[M+H]+=486.2.

[0334] (d) 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (2.0 mL, 14 mmol) was added to 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl (61 mg, 0.13 mmol). The resulting suspension was stirred at 100°C for 1 hour in a Biotage microwave reactor. Additional 7N methanolic ammonia (1.0 mL, 7.0 mmol) was added, and the reaction mixture was stirred at 100°C for 1 hour in a Biotage microvial. Next, the reaction product was filtered and washed with methanol to obtain 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.036 g, 61%) as an ochre solid; 1H NMR (500 MHz, DMSO-d6) 0.83-0.97 (2H,m), 0.99-1.12 (2H,m), 1.86-1.98 (1H,m), 3.01-3.12 (4H,m), 3.66-3.82 (4H,m), 4.00 (3H,s), 6.97 (2H,d), 7.54 (2H,d), 7.80 (1H,br s),8.06(1H,s),8.45(1H,s),8.54(1H,s),9.05(1H,s),11.08(1H,s)

[0335] Example 42 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) methyl 3-amino-6-bromopyrazine-2-carboxylate Acetonitrile (100 mL) was added to a mixture of methyl 3-aminopyrazine-2-carboxylate (5.00 g, 32.7 mmol) and N-bromosuccinimide (5.81 g, 32.7 mmol). The resulting solution was stirred at 80°C for 45 minutes. The reaction product was then concentrated. The resulting red residue was triturated in isopropanol (100 mL) and filtered to obtain a red solid. The filtrate was concentrated to obtain a red solid, which was dissolved in DCM (60 mL) and washed once with saturated sodium thiosulfate aqueous solution (50 mL) and three times with saturated sodium bicarbonate aqueous solution (25 mL each). The organic layer was then dried over magnesium sulfate, filtered, and concentrated to obtain a red solid, which was divided into two parts. One part was purified by silica gel chromatography using 0-40% toluene-hexane as the eluent to obtain methyl 3-amino-6-bromopyrazine-2-carboxylate (1.33 g, 18%) as an off-white solid. The other portion was suspended in MeOH, then filtered and washed with a large amount of MeOH to obtain methyl 3-amino-6-bromopyrazine-2-carboxylate (2.89 g, 38%) as a beige microcrystalline solid; ¹H NMR (500 MHz, DMSO-d6) 3.84 (3H, s), 7.53 (2H, br s), 8.41 (1H, s); m / z: (ES+), [M+H]+=232.0

[0336] (b) 3-amino-6-bromo-5-(difluoromethyl)pyrazine-2-carboxylate methyl TFA (0.66 mL, 8.6 mmol) was added to a suspension of methyl 3-amino-6-bromopyrazine-2-carboxylate (1.00 g, 4.31 mmol) and zinc difluoromethanesulfinic acid (2.55 g, 8.62 mmol) in DCM (10 mL) and water (4 mL). 70 wt% aqueous tert-butyl hydroperoxide (1.80 mL, 13.1 mmol) was added dropwise to the reaction mixture. The reaction mixture was stirred at 25°C for 16 hours. Additional zinc difluoromethanesulfinic acid (2.55 g, 8.62 mmol) and 70 wt% aqueous tert-butyl hydroperoxide (1.80 mL, 13.1 mmol) were added, and the reaction mixture was stirred at 25°C for 2 days. The reaction mixture was then quenched with saturated sodi...

Claims

1. Compound of formula (I) 【Chemistry 1】 [In the formula, X １ , X ２ and X ３ are each independently selected from CR ５ or N (provided that if X １ is N, then X ３ is CR ５ and if X ３ is N, then X １ is CR ５ ); R １ is cyclopropyl or C １～３ It is alkyl (where C １～３ (The alkyl group is substituted with 0, 1, 2, or 3 F atoms); R ２ H, NH ２ or C １～２ It is alkyl (where C １～２ (The alkyl group is substituted with 0, 1, 2, or 3 F atoms); R ３ H, R ６ , OR ６ NHR ６ , Cl, CN, CCH, NH ２ SCH ３ , cyclopropyl, cyclobutyl, NH((5-6 member) heteroaryl containing 1 or 2 N), NH(C １～２ Alkyl)N(CH ３ ) ２ Selected from oxetan-3-yl, NH-cyclopropyl and O-cyclopropyl; R ４ is selected from aryl or heteroaryl (where the aryl or heteroaryl is F, Cl and R ６ 0, 1, 2, 3, or 4 substituents independently selected from, and NH ２ , CN, OR ６ , R ７ , R ８ , R ９ , OR ８ , OCH ２ R ８ , C(O)R ８ C(O)CH ３ C(O)NHCH ３ ,CH ２ C(O)NHCH ３ , C (CH ３ ) ２ R ８ , CH (CH ３ ) R ８ and CH ２ R ８ (Substituted by 0, 1, or 2 substituents independently selected from the original); R ５ H, F, Cl and C １～２ Selected independently of alkyl (where C １～２ Alkyl is F, CN, NH ２ and OC １～２ Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, the OC １～２ The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; R ６ is C １～４ It is alkyl (where C １～４ Alkyl groups consist of 0, 1, 2, or 3 F, O(C) １～２ Alkyl) and OH, CN, N(CH ３ ) ２ (and substituted with zero or one substituent selected from (4-5 membered) heterocycloalkyl groups containing one oxygen atom); R ７ NH-cyclopropyl, [dimethyl(oxo)-λ ６ -Sulfanylidene]amino, (C １～４ Alkyl) sulfonimidoyl, SO ２ CH ３ OSO ２ CH ３ , C (CH ３ ) ２ SO ２ CH ３ SO ２ NHCH ３ SO ２ N(CH ３ ) ２ Morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH ３ , cyclopropyl (wherein the cyclopropyl is F, CN, OH or SO ２ CH ３ (substituted with 0 or 1 substituent selected from), cyclobutyl (where the cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (where the imidazolyl is substituted with 0 or 1 R) １１ Selected from (which has been replaced by); R ８ is SO ２ CH ３ or selected from heterocycloalkyls (where the heterocycloalkyl is F, Cl, R ６ and OR ６ 0, 1, 2, 3, or 4 substituents independently selected from, and cyclopropyl, OH, C(O)CH ２ OH, 4-methylpiperazinyl, C(O)CH ３ and C(O)N(CH ３ ) ２ (Substituted by 0, 1, or 2 substituents independently selected from the original); R ９ is OR １０ N(R １０ ) ２ 、NR １１ (CH ２ ) ２ N(CH ３ ) ２ 、-(CH ２ ) ２ (5- to 6-membered) heterocycloalkyl (wherein said (5- to 6-membered) heterocycloalkyl is substituted with 0 or 1 substituent selected from R １１ ), -O(CH ２ ) ２ (5- to 6-membered) heterocycloalkyl (wherein said (5- to 6-membered) heterocycloalkyl is substituted with 0 or 1 substituent selected from R １ ), and is selected from azetidinyl substituted with 0 or 1 substituent selected from N(CH ３ ) ２ and C(O)CH ３ ; R １０ H and C １～２ Selected independently of alkyl (where C １～２ Alkyl is F, CN, NH ２ and OC １～２ Substituted with 0, 1, 2, or 3 substituents independently selected from alkyl, and the C １～２ The alkyl group is substituted with 0, 1, 2, or 3 substituents independently selected from F and Cl; and R １１ is C １～３ It is alkyl (where C １～３ (The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms and 0 or 1 cyclopropyl atom.) or a pharmaceutically acceptable salt thereof.

2. X １ , X ２ and X ３ CR is independent ５ Selected from, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. X １ and X ３ CR is independent ５ Selected from; X ２ is N, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Formula (IA) 【Chemistry 2】 (In the formula, X １ , X ２ and X ３ CR is independent ５ Selected from; R ５ (is H) The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ３ is R ６ NHR ６ and selected from cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (Alkyl is substituted with 0, 1, 2, or 3 F atoms); R ４ is selected from phenyl (where phenyl is F, Cl and R ６ Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R ６ and OR ６ O, one, or two substituents independently selected from, as well as cyclopropyl, C(O)CH ３ and C(O)N(CH ３ ) ２ (Substituted by 0 or 1 substituent selected from) The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

6. R ３ is R ６ NHR ６ and selected from cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (where is replaced by 0, 1, 2, or 3 Fs); R ４ is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R ６ 0, 1, or 2 substituents independently selected from, and R ７ (Substituted by 0 or 1 substituent selected from the following); R ７ is selected from cyclopropyl (where the cyclopropyl is F, CN, OH, or SO ２ CH ３ (Substituted by 0 or 1 substituent selected from) The compound according to claim 4, or a pharmaceutically acceptable salt thereof.

7. Formula (IB) 【Transformation 3】 (In the formula, X １ and X ３ CR is independent ５ Selected from; X ２ is N; R ５ (is H) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ３ is R ６ NHR ６ and selected from cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (where is replaced by 0, 1, 2, or 3 Fs); R ４ is selected from phenyl (where phenyl is F, Cl and R ６ Substituted by zero or one substituent selected from and substituents selected from morpholinyl, wherein morpholinyl is F, Cl, R ６ and OR ６ O, one, or two substituents independently selected from, as well as cyclopropyl, C(O)CH ３ and C(O)N(CH ３ ) ２ (Substituted by 0 or 1 substituent selected from) The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

9. R ３ is R ６ NHR ６ and selected from cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (where is replaced by 0, 1, 2, or 3 Fs); R ４ is selected from (5-membered) heteroaryls (where the (5-membered) heteroaryl is F, Cl and R ６ 0, 1, or 2 substituents independently selected from, and R ７ (Substituted by 0 or 1 substituent selected from the following); R ７ is selected from cyclopropyl (where the cyclopropyl is F, CN, OH, or SO ２ CH ３ (Substituted by 0 or 1 substituent selected from) The compound according to claim 7, or a pharmaceutically acceptable salt thereof.

10. Formula (IC) 【Chemistry 4】 (In the formula, X １ and X ３ CR is independent ５ Selected from; X ２ is N; R ５ is H; R １ is C １～３ It is alkyl (where C １～３ The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms. The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. R １ is C １～３ It is alkyl (where C １～３ (where is replaced by 0, 1, 2, or 3 Fs); or a pharmaceutically acceptable salt thereof: R ３ is R ６ NHR ６ and selected from cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (This is replaced by 0, 1, 2, or 3 Fs.) The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

12. R ３ It is cyclopropyl; R ６ is C １～４ It is alkyl (where C １～４ (The alkyl group is substituted with 0, 1, 2, or 3 fluorine atoms.) The compound according to claim 10, or a pharmaceutically acceptable salt thereof.

13. 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methoxy-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(ethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide, 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(propa-2-inylamino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 5-(cyanomethylamino)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-fluoropropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-fluoropropyl]amino]-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide, 5-Ethinyl-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Chloro-6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-5-[(1-methylpyrazole-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazole-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide, 5-Ethoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyano-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(1-methylimidazo[4,5-d]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-ethylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-cyclopropylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-[3-(difluoromethyl)imidazo[4,5-c]pyridine-7-yl]-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-chloro-1-methyl-benzimidazole-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-cyano-1-methyl-benzimidazole-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3,4-dimethylimidazo[4,5-c]pyridine-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 3-(2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2,3-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-3-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(2,3,5-trifluoro-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(2-fluoro-5-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3,5-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(3-methyl-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(3,5-dimethyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-cyano-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(3-methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[3-(difluoromethyl)-4-morpholino-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-(2-methyl-4-morpholino-anilino)pyrazine-2-carboxamide, 3-(2-methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(5-methyl-6-morpholino-3-pyridyl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(3S)-3-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(2S)-2-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[6-[(3R)-3-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[(5-cyano-6-morpholino-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-((4-(1,4-oxazepan-4-yl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-5-(methylamino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(3R)-3-methylmorpholine-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 3-[2-fluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[2,3,5-trifluoro-4-[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-oxa-6-azaspiro[3,3]heptan-6-yl)anilino]pyrazine-2-carboxamide, 3-anilino-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(difluoromethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(4-isopropoxyanilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, [4-[[3-carbamoyl-6-(methylamino)-5-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-yl]amino]phenyl]methanesulfonate, 3-[4-(2-methoxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethoxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(2-hydroxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-morpholinoethoxy)anilino]pyrazine-2-carboxamide, 3-(4-aminoanilino)-5-(methylamino)-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[2-methoxyethyl(methyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[bis(2-methoxyethyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(2-methyl-4-pyridyl)amino]pyrazine-2-carboxamidoformate, 3-[(2-methoxy-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazine-4-yl)pyrazine-2-carboxamide hydrochloride, 3-[(2,6-dimethyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(2,6-dimethyl-4-pyridyl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[2-(2-methoxyethoxy)-6-methyl-4-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-cyano-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(1,5-dimethyl-6-oxo-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(difluoromethyl)-6-oxo-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[4-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 5-(methylamino)-3-[4-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]-3,5-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[4-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-3-[4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]-3,5-dimethyl-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethyl-methyl-amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 3-[4-[3-(dimethylamino)azetidine-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide bis-formate, 3-[3-cyano-4-[(3S,5R)-3,5-dimethylpiperazine-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[4-(4-methylpiperazine-1-yl)-1-piperidyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[6-(4-isopropylpiperazine-1-yl)-5-methyl-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[5-methoxy-6-(4-methylpiperazine-1-yl)-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[[5-chloro-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(6-methyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(6-ethyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(6-isopropyl-5,7-dihydropyrrolo[3,4-b]pyridine-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[(dimethylamino)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(pyrrolidine-1-ylmethyl)anilino]pyrazine-2-carboxamide bis-formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-oxa-6-azaspiro[3,3]heptan-6-ylmethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1R)-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1S)-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1R)-1-morpholinoethyl]anilino]pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[rel-(1S)-1-morpholinoethyl]anilino]pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[1-methyl-1-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methyl-1-morpholino-ethyl)anilino]pyrazine-2-carboxamide, (R)-3-((4-((3-fluoropyrrolidine-1-yl)methyl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridine-7-yl)-5-(methylamino)pyrazine-2-carboxamidoformate, 3-[4-[[(3S)-3-fluoropyrrolidine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[(3,3-difluoropyrrolinidine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[[(3S)-3,4-dimethylpiperazine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide tris-formate, 3-[4-[[(3R)-3,4-dimethylpiperazine-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[6-(morpholinomethyl)-3-pyridyl]amino]pyrazine-2-carboxamide forate, 3-[2-fluoro-4-[(4-methylpiperazine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[3-chloro-4-[(4-methylpiperazine-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-fluoro-4-[[(1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-fluoro-4-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[[(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2-chloro-4-(2-oxa-6-azaspiro[3,3]heptan-6-ylmethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(2-morpholinoethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[2-(4-methylpiperazine-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(pyrrolidine-1-ylmethyl)anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(4-methylpiperazine-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(3S)-4-methylmorpholine-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(3R)-4-methylmorpholine-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(2R)-4-methylmorpholine-2-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazole-4-yl)-3-[4-[rel-(2S)-4-methylmorpholine-2-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(4-piperidyloxy)anilino]pyrazine-2-carboxamide, 3-[4-[(1-acetyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 3-[4-[[1-(2-hydroxyacetyl)-4-piperidyl]oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 3-[3,5-difluoro-4-[(1-methyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[(1-isopropyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-methoxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidine-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[3-(4-methylpiperazine-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[3-(1-methyl-4-piperidyl)anilino]pyrazine-2-carboxamide forate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(4-methylimidazole-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-([1,2,4]triazolo[4,3-a]pyridine-6-ylamino)pyrazine-2-carboxamide, 3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[(2-imino-2-oxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(ethylsulfonimidoyl)-3,5-dimethylanilino]-5-methyl-6-(1-methylbenzimidazole-4-yl)pyrazine-2-carboxamide, 3-[(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Methoxy-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazole-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxo-1,4-thiadinan-4-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2-fluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanylidene]amino]-2,3-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamidoformate, 3-[4-(1,1-dioxo-1,2-thiazolidin-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxothiazinan-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-4-methylsulfonyl-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, (R)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, (S)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[4-(tert-butylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(1-methylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 3-[(1-isopropylpyrazole-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1,1-dioxothian-4-yl)pyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazole-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide forate, 3-[(1,3-dimethylpyrazole-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-3-methylpyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-5-methylpyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazole-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1,3-dimethylpyrazole-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-(2,2,2-trifluoroethyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(2,2-difluoroethyl)-3-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazole-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyanocyclopropyl)-3-methylpyrazole-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1,5-dimethylpyrazole-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(3-methyl-1H-pyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[3-methyl-1-(oxetan-3-yl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[[5-methyl-1-(oxetan-3-yl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(2,2-difluoroethyl)-5-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(3,3-difluoropropyl)-3-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(3,3-difluoropropyl)-5-methylpyrazole-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridine-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(3-methyl-1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridine-7-yl)-3-[(5-methyl-1-tetrahydropyran-4-ylpyrazole-4-yl)amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(1-methylbenzimidazole-4-yl)-3-[[5-methyl-1-(1-methyl-4-piperidyl)pyrazole-4-yl]amino]pyrazine-2-carboxamide, and these pharmaceutically acceptable salts A compound according to claim 1, selected from the following.

14. A pharmaceutical product comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, mixed with an optionally pharmaceutically acceptable auxiliary agent, diluent, or carrier.

16. A pharmaceutical product according to claim 14 for treating cancer.

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