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

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] The technical field relates to certain substituted pyrazine 2-carboxamides of formula (I) and pharmaceutically acceptable salts thereof, as well as compositions containing them and their use in therapy. The compounds of formula (I) are inhibitors of hematopoietic progenitor kinase 1 (HPK1) and are therefore particularly useful in the treatment or amelioration of abnormal cell proliferative disorders, such as cancer. [Background technology]

[0002] In recent years, the discovery of immunological checkpoints and their inhibition has revealed new avenues for targeting cancer by harnessing the body's own immune system to fight tumors. While checkpoint therapies have shown great promise in some tumor types, only a fraction of cancer patients respond, and novel therapies are needed to reach a wider range of patients.

[0003] T cells are important in the cancer immune cycle (Non-Patent Document 1; Non-Patent Document 2), and they are effector cells that recognize and kill tumor cells. In cancer patients, T cells become exhausted and non-functional 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, treatments that enhance T cell function and rescue the function of exhausted T cells can lead to improved tumor control.

[0004] HPK1 (hematopoietic progenitor kinase 1), also known as mitogen-activated protein kinase 1 (MAP4K1), is an Ste20-related serine / threonine kinase expressed exclusively in hematopoietic cells and acts as a negative regulator of T cell signaling and tumoricidal cytokine production. After TCR ligation, HPK1 phosphorylates its target SLP76 at Ser376, causing SLP76 to associate with 14-3-3, thereby dissociating the LAT signalosome (Non-Patent Document 3; Non-Patent Document 4), thus limiting T cell activation (Non-Patent Document 5). Loss of HPK1 or an inactive kinase (kinase-dead) enhances T cell activation, resulting in increased cytokine secretion and proliferation (Non-Patent Document 4; Non-Patent Document 6). HPK1 can also inhibit T cell signaling in response to the immunosuppressant prostaglandin E2 (PGE2) via protein kinase A (PKA) (Non-Patent Document 7; Non-Patent Document 8; Non-Patent Document 9). Recent studies have documented the essential function of the kinase domain of HPK1 in promoting tumor surveillance, and inactivation of the kinase domain of HPK1 prevents tumor progression in mouse tumor models. Importantly, studies comparing wild-type and kinase-dead mice have shown that loss of the kinase function of HPK1 can rescue T cells from exhaustion in chronic viral infection and PGE2-high tumor models (Non-Patent Document 4; Non-Patent Document 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 contribute to tumor immunity (Non-Patent Document 10). The kinase activity of HPK1 has been suggested to be essential for regulating T cell function (Non-Patent Document 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 amino acids 23–46 of the ATP-binding site (Non-Patent Document 11). The middle domain contains a proline-rich motif with binding sites for SH3-containing proteins such as Crkl, Grb2 and HIP-55, suggesting a scaffolding function.The citron homology domain is located at the C-terminus, which may act as a regulatory domain in molecular interactions involving T cell adhesion. LCK and ZAP70 induce HPK1 Tyr-379 phosphorylation and kinase activation (Non-Patent Document 12; Non-Patent Document 13; Non-Patent Document 14). Essential adaptors for signal transduction in T cells (SLP76) and B cells (BLNK) have been reported to bind activated HPK1, which helps block downstream signaling in both T and B cells (Non-Patent Document 15). Taken together, there is a 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 of the 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 radiation, chemotherapy, surgery, tumor-targeted agents, or other immune-targeted agents.

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

[0007] Many small molecule inhibitors of HPK1 have been disclosed in patent applications, as summarized, for example, 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 thereof Patent Document 4 Isoquinolines as inhibitors of HPK1 Patent Document 5: Naphthyridine compounds and uses thereof Patent Document 6: Isoquinoline compounds 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 inhibitors and the use thereof Patent Document 26: Pyrrolo[2,3-b]pyridines as HPK1 inhibitors and uses thereof Patent Document 27 Pyrrolo[2,3-b]pyrazines as HPK1 inhibitors and the use thereof Patent Document 28: Tricyclic compounds as HPK1 inhibitors and use thereof Patent Document 29: Aminopyrazine compounds as HPK1 inhibitors 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 modulators and uses thereof for the treatment of cancer Patent Document 36: Pyrazolopyridine derivatives as HPK1 modulators 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 Summary of the Invention [Means for solving the problem]

[0010] Provided are compounds that are inhibitors of hematopoietic progenitor kinase 1 (HPK1), their use as medicaments, pharmaceutical compositions containing the compounds, and synthetic routes for their production.

[0011] In one embodiment, the compound of formula (I) [ka] [In the formula, X 1 , X 2 and X 3 is an independent CR 5or N (where X 1 If N, then X 3 is CR 5 and X 3 If N, then X 1 is CR 5 is); R 1 is cyclopropyl or C 1~3 alkyl (wherein the C 1~3 alkyl is substituted by 0, 1, 2 or 3 F; R 2 is H, NH2 or C 1~2 alkyl (wherein the 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 selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 5 are H, F, Cl and C 1~2 alkyl (wherein the C1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl; R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH or SO2CH3), cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH), and imidazolyl (wherein said imidazolyl is substituted with zero or one R 11 (substituted with); R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11(CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0012] The compounds of formula (I) are inhibitors of HPK1. Accordingly, the compounds of formula (I) may be used as medicines, particularly as medicines for disorders, diseases or conditions that respond to inhibition of HPK1, more particularly as medicines for cancer.

[0013] In another embodiment, there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) where the stereochemistry is undefined, for example a racemate or a mixture of diastereomers.

[0014] In another embodiment, there is provided a pharmaceutical formulation 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, excipient and / or inert carrier.

[0015] In a further embodiment, there is provided a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the treatment of a condition in which inhibition of HPK1 would be beneficial.

[0016] In a further embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in therapy, particularly in the treatment of cancer in a mammal, particularly a human.

[0017] In a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.

[0018] In a further embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) reduces the level of HPK1 in a mammal, particularly a human.

[0019] According to another aspect, there is provided a process for preparing a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) and intermediates used in their preparation.

[0020] The compounds of formula (I) exemplified herein have an IC of less than 100 nmol / L for HPK1 in an enzyme activity assay. 50 The compounds of formula (I) also exhibit a promising pharmacological profile by dissociating desired and undesired effects in vivo. [Brief explanation of the drawings]

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

[0022] While this detailed description and its specific examples illustrate embodiments, they are intended for illustrative purposes only. Accordingly, the present invention is not limited to the exemplary embodiments described herein. Additionally, it should be recognized that various features that are described for clarity in the context of separate embodiments may be combined to form a single embodiment. Conversely, various features that are described for brevity in the context of a single embodiment may also be combined to form subcombinations thereof.

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

[0024] As used herein, when a group is modified by "as defined above," it is to be understood that the group includes the first and broadest definition, as well as each and every other definition of the group.

[0025] In this specification, "C 1~4 " is understood to mean a carbon group having 1, 2, 3 or 4 carbon atoms.

[0026] In this specification, "C 1~3 " is understood to mean a carbon group having 1, 2 or 3 carbon atoms.

[0027] In this specification, "C 1~2 " is understood to mean a carbon group having 1 or 2 carbon atoms. In this specification, unless stated otherwise, the term "alkyl" includes both straight and branched chain alkyl groups, which may be, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, or tert-butyl. As used herein, "aryl" should be understood to mean an aromatic or partially aromatic group having from 6 to 10 carbon atoms, such as, for example, phenyl or naphthyl. As used herein, "heteroaryl" should be understood to mean a monocyclic or bicyclic aromatic or partially aromatic ring having from 5 to 10 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, "(5- to 6-membered) heteroaryl" is understood to mean an aromatic ring having 5 to 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, "(6-membered) heteroaryl" is understood to mean an aromatic ring having 6 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, "(6-membered)heteroaryl" is understood to mean, for example, 2-pyridone. As used herein, "(5-membered) heteroaryl" is understood to mean an aromatic ring having 5 atoms and containing one or more heteroatoms independently selected from nitrogen, oxygen, or sulfur. As used herein, "heterocycloalkyl" is understood to mean a partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon ring system having from 4 to 10 atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. As used herein, "(5- to 8-membered)heterocycloalkyl" is understood to mean a partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 5 or 6 ring atoms, in which at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. As used herein, "(5- to 6-membered)heterocycloalkyl" is understood to mean a partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 5 or 6 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. As used herein, "(7-membered)heterocycloalkyl" is understood to mean a partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 7 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. As used herein, "(6-membered)heterocycloalkyl" is understood to mean a partially or fully saturated monocyclic, bicyclic or bridged hydrocarbon ring system containing a total of 6 ring atoms, wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen or sulfur. It is understood that, as used herein, a "heterocycloalkyl" substituent may be attached via a nitrogen atom or via any ring carbon atom having an appropriate valence. As used herein, unless otherwise specified, the term "pharmaceutically acceptable" is used to characterize a moiety (e.g., a salt, dosage form, or excipient) that is appropriate for use in accordance with sound medical judgment. Generally, a pharmaceutically acceptable moiety has one or more benefits that outweigh any adverse effects that the moiety may have. Adverse effects may include, for example, excessive toxicity, irritation, allergic reactions, and other problems and complications.

[0028] Compounds of formula (I) comprising X 1 , X 2 , X 3 and R 1 ~R 11 is as defined in formula (I).

[0029] In one embodiment, X 1 , X 2 and X 3 is an independent CR 5 or N, provided that X 1 If N, then X 3 is CR 5 and X 3 If N, then X 1 is CR 5 is. In a further embodiment, X 1 , X 2 and X 3 is CR 5 is. In still further embodiments, X 2 is N and X 1 and X 3 is CR 5 is. In still further embodiments, X 1 and X 2 is N and X 2 is CR 5 is. In still further embodiments, X 2 and X 3 is N and X 1 is CR 5 is. R 5 are H, F, Cl and C 1~2alkyl, 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 The alkyl 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, 1~3 The alkyl is substituted with 0, 1, 2 or 3 F. In a further embodiment, R 1 is cyclopropyl or C 1~2 alkyl, 1~2 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 1 is cyclopropyl or CH3. In still further embodiments, R 1 is cyclopropyl. In still further embodiments, R 1 is CH3. In still further embodiments, R 1 is CH2F. In still further embodiments, R 1 is CHF2. In still further embodiments, R 1 is CF3.

[0031] In one embodiment, R 2 is H, NH2 or C 1~2 alkyl, 1~2 The alkyl is substituted with 0, 1, 2 or 3 F. In a further embodiment, R 2 is NH2. In still further embodiments, R 2 is C 1~2 alkyl, 1~2 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 2 is CH3. In still further embodiments, R 2 is CH2F. In still further embodiments, R 2 is CHF2. In still further embodiments, R 2 is CF3. In still further embodiments, R 2 is H.

[0032] In one embodiment, 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. In a further embodiment, R 3 is R 6 , OR 6 , NHR 6 and cyclopropyl. In still further embodiments, R 3 is R 6 , NHR 6 and cyclopropyl. R 6 is C 1~4 alkyl, 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 and (4-5 membered) heterocycloalkyl containing OH, CN, N(CH3)2, and 1 O. In still further embodiments, R 3 is C 1~4 alkyl, wherein C 1~4 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 3is C 1~2 alkyl, wherein C 1~2 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 3 is CH3. In still further embodiments, R 3 is CH2F. In still further embodiments, R 3 is CHF2. In still further embodiments, R 3 is CF3. In still further embodiments, R 3 is cyclopropyl. In still further embodiments, R 3 is NHC 1~4 and C 1~4 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 3 is NHC 1~2 alkyl, 1~2 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 3 is NHCH3. In still further embodiments, R 3 is NHCH2. In still further embodiments, R 3 is NHCHF2. In still further embodiments, R 3 is NHCF3.

[0033] In one embodiment, R 4 is selected from aryl or heteroaryl, wherein the aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from: R 6 is C 1~4 alkyl, 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 and (4-5 membered) heterocycloalkyl containing OH, CN, N(CH3)2, and 1 O. R 7 is NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH or SO2CH3), cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH), and imidazolyl (wherein said imidazolyl is substituted with zero or one R 11 (substituted with). R 8 is selected from SO2CH3 or heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH). R 9 is OR 10 , N(R 10 )2, NR 11(CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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 The alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 cyclopropyl).

[0034] In still further embodiments, R 4 is selected from aryl, wherein the aryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0035] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0036] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and 0, 1, 2 or 3 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0037] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0038] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 0 or 1 substituent selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0039] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 0 or 1 substituent selected from NH, 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 is substituted by a substituent selected from:

[0040] In still further embodiments, R 4 is selected from phenyl, wherein said phenyl is selected from NH, 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 is substituted by a substituent selected from:

[0041] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and zero or one substituent selected from OR 6 , R 7 , R 8 , R 9 , OR 8 , OCH2R 8 , OR 8 , OCH2R 8 and CH2R 8 is substituted by a substituent selected from:

[0042] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and heterocycloalkyl, wherein the heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0043] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and (6-membered) heterocycloalkyl, wherein the (6-membered) heterocycloalkyl is selected from F, Cl, R 6 and OR 6and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0044] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and (6-membered) heterocycloalkyl, wherein the (6-membered) heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0045] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and (6-membered) heterocycloalkyl, wherein the (6-membered) heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0 or 1 substituent selected from cyclopropyl, C(O)CH3 and C(O)N(CH3)2.

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

[0047] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and morpholinyl, wherein the morpholinyl is substituted by zero or one substituent selected from F, Cl, R 6 and OR 6 is substituted by 0, 1 or 2 substituents independently selected from:

[0048] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH heterocycloalkyl, wherein the heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0049] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(5-8 membered)heterocycloalkyl, wherein the (5-8 membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0050] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6and CH2(6-membered)heterocycloalkyl, wherein the (6-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0051] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(6-membered)heterocycloalkyl, wherein the (6-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and is substituted by 0, 1, 2, 3 or 4 substituents independently selected from:

[0052] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(6-membered)heterocycloalkyl, wherein the (6-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 is substituted by 0, 1 or 2 substituents independently selected from: In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(7-membered)heterocycloalkyl, wherein the (7-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH).

[0053] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(7-membered)heterocycloalkyl, wherein the (7-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and is substituted by 0, 1, 2, 3 or 4 substituents independently selected from:

[0054] In still further embodiments, R 4 is selected from phenyl, wherein the phenyl is selected from F, Cl and R 6 and CH2(7-membered)heterocycloalkyl, wherein the (7-membered)heterocycloalkyl is selected from F, Cl, R 6 and OR 6 is substituted by 0, 1 or 2 substituents independently selected from:

[0055] In yet a further embodiment, R 4 is selected from heteroaryl, wherein the heteroaryl is selected from F, Cl, and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0056] In yet a further embodiment, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0057] In yet a further embodiment, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0058] In yet a further embodiment, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 is substituted by 0 or 1 substituent selected from:

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

[0060] In still further embodiments, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from 8 and CH2R 8 is substituted by 0 or 1 substituent selected from:

[0061] In still further embodiments, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6 and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8-membered)heterocycloalkyl.

[0062] In still further embodiments, R 4 is selected from (6-membered) heteroaryl, wherein the (6-membered) heteroaryl is selected from F, Cl, and R 6 and 0 or 1 substituent selected from (6-membered)heterocycloalkyl and CH2(6-membered)heterocycloalkyl.

[0063] In yet a further embodiment, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 is substituted by 0, 1 or 2 substituents independently selected from:

[0064] In yet a further embodiment, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 is substituted by 0 or 1 substituent selected from:

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

[0066] In still further embodiments, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from 8 and CH2R 8 is substituted by 0 or 1 substituent selected from:

[0067] In still further embodiments, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8-membered)heterocycloalkyl.

[0068] In still further embodiments, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0 or 1 substituent selected from (6-membered)heterocycloalkyl and CH2(6)heterocycloalkyl.

[0069] In still further embodiments, R 4 is selected from (5-membered) heteroaryl, wherein the (5-membered) heteroaryl is selected from F, Cl, and R 6 and 0, 1, or 2 substituents independently selected from 7 is substituted by 0 or 1 substituent selected from:

[0070] In still further embodiments, R 4 is pyrazolyl, wherein the pyrazolyl is selected from the group consisting of F, Cl and R6 and 0, 1, or 2 substituents independently selected from 7 is substituted by 0 or 1 substituent selected from:

[0071] In still further embodiments, R 4 is 1H-pyrazol-4-yl, wherein the 1H-pyrazol-4-yl is selected from the group consisting of F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 7 is substituted by 0 or 1 substituent selected from:

[0072] In still further embodiments, R 4 is 1H-pyrazol-4-yl, wherein the 1H-pyrazol-4-yl is selected from the group consisting of F, Cl and R 6 is substituted with 0, 1 or 2 substituents independently selected from:

[0073] In still further embodiments, R 4 is 1H-pyrazol-4-yl, and said 1H-pyrazol-4-yl is R 6 is substituted with 0, 1 or 2 substituents independently selected from:

[0074] In one embodiment, R 5 are H, F, Cl and C 1~2 alkyl, 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl. In a further embodiment, R 5 is H. In still further embodiments, R 5 is C 1~2 alkyl, 1~2 Alkyl is F, CN, NH2 and OC 1~2substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl. In still further embodiments, R 5 is C 1~2 alkyl, 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F. In still further embodiments, R 5 is CH3. In still further embodiments, R 5 is CH2F. In still further embodiments, R 5 is CHF2. In still further embodiments, R 5 is CF3.

[0075] In one embodiment, R 6 is C 1~4 alkyl, 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 and (4-5 membered) heterocycloalkyl containing OH, CN, N(CH3)2, and 1 O. In a further embodiment, R 6 is C 1~4 alkyl, 1~4 The alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 substituent selected from OH, CN, N(CH3)2 and 1 O-containing (4-5 membered) heterocycloalkyl. In still further embodiments, R 6 is C 1~4 alkyl, 1~4 The alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 substituent selected from OH, CN and N(CH3)2. In still further embodiments, R 6 is C 1~4 alkyl,1~4 The alkyl is substituted by 0, 1, 2 or 3 F. In still further embodiments, R 6 is C 1~2 alkyl, 1~2 The alkyl is substituted by 0, 1, 2 or 3 F.

[0076] In one embodiment, R 7 is NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH or SO2CH3), cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH), and imidazolyl (wherein said imidazolyl is substituted with zero or one R 11 (substituted with).

[0077] In a further embodiment, R 7 is selected from cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH, or SO2CH3) and cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH). In still further embodiments, R 7 is selected from cyclopropyl, said cyclopropyl being substituted with 0 or 1 substituent selected from F, CN, OH or SO2CH3. In still further embodiments, R 7 is selected from cyclobutyl, said cyclobutyl being substituted by 0 or 1 OH.

[0078] In one embodiment, R 8is selected from SO2CH3 or heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH).

[0079] In a further embodiment, R 8 is selected from (5-8 membered) heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH). In still further embodiments, R 8 is selected from (5-6 membered) heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH).

[0080] In still further embodiments, R 8 is selected from (6-membered) heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH).

[0081] In still further embodiments, R 8is selected from (5-membered) heterocycloalkyl, wherein the heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH).

[0082] In one embodiment, R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; In a further embodiment, R 9 is selected from —(CH)(5- to 6-membered)heterocycloalkyl, wherein said (5- to 6-membered)heterocycloalkyl is R 11 is substituted with 0 or 1 substituent selected from: In still further embodiments, R 9 is —O(CH)(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by zero or one substituent selected from N(CH3)2 and C(O)CH3.

[0083] In one embodiment, R 10 is H and C 1~2 alkyl, 1~2 Alkyl is F, CN, NH2 and OC 1~2substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl. In a further embodiment, R 10 is H. In still further embodiments, R 10 is C 1~2 alkyl, 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl. In still further embodiments, R 10 is C 1~2 alkyl, 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F, CN and NH2. In still further embodiments, R 10 is C 1~2 alkyl, 1~2 The alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F.

[0084] In one embodiment, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is an independent CR 5 Selected from; R 5 are H, F, Cl and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl;1~2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl; 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 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH or SO2CH3), cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH), and imidazolyl (wherein said imidazolyl is substituted with zero or one R 11 (substituted with); R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0085] In a further embodiment, a compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; 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 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH, and C(O)N(CHC(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0086] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0087] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from aryl, wherein said aryl is selected from F, Cl and R 6 0 or 1 substituent selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2alkyl 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.

[0088] In still further embodiments, the compound of formula (IA) [ka] (In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 0 or 1 substituent selected from NH, 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 C1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0089] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 and morpholinyl, wherein the morpholinyl is substituted by zero or one substituent selected from F, Cl, R6 and OR 6 and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2; R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0090] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 and morpholinyl, wherein the morpholinyl is substituted by zero or one substituent selected from F, Cl, R 6 and OR 6 and 0 or 1 substituent selected from cyclopropyl, C(O)CH and C(O)N(CH); and R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted with 0, 1, 2 or 3 F). or a pharmaceutically acceptable salt thereof.

[0091] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 alkyl (wherein the C 1~4Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl, wherein said (5-6 membered)heterocycloalkyl is selected from R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0092] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0093] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10, N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1-2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0094] In still further embodiments, the compound of formula (IA) [ka] (In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 8 and CH2R 8 substituted by 0 or 1 substituent selected from: R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; and R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH). or a pharmaceutically acceptable salt thereof.

[0095] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8-membered)heterocycloalkyl); and R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0096] In still further embodiments, the compound of formula (IA) [ka] [In the formula, X 1 , X 2 and X 3 is CR 5 and; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6and 0, 1, or 2 substituents independently selected from 7 substituted by 0 or 1 substituent selected from: R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; and R 7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituent selected from F, CN, OH, or SO2CH3. or a pharmaceutically acceptable salt thereof.

[0097] In one embodiment, a compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 are H, F, Cl and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl; 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 6 is C 1~4 alkyl (wherein the C 1~4Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4 alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON2N(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, cyclopropyl (wherein said cyclopropyl is substituted with zero or one substituent selected from F, CN, OH or SO2CH3), cyclobutyl (wherein said cyclobutyl is substituted with zero or one OH), and imidazolyl (wherein said imidazolyl is substituted with zero or one R11 (substituted with ); R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0098] In a further embodiment, a compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; 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 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R10 is H and C 1~2 alkyl (wherein the C 1~2 are F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0099] In still further embodiments, the compound 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 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is selected from F, Cl and R 6 and 0, 1, 2, 3, or 4 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0100] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from aryl, wherein said aryl is selected from F, Cl and R6 0 or 1 substituent selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0101] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 0 or 1 substituent selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0102] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 and morpholinyl, wherein the morpholinyl is substituted by zero or one substituent selected from F, Cl, R 6 and OR 6 and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2; R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0103] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from phenyl, wherein said phenyl is selected from F, Cl and R 6 and morpholinyl, wherein the morpholinyl is substituted by zero or one substituent selected from F, Cl, R 6 and OR 6 and 0 or 1 substituent selected from cyclopropyl, C(O)CH3, and C(O)N(CH3)2; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted with 0, 1, 2 or 3 F). or a pharmaceutically acceptable salt thereof.

[0104] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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.

[0105] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from NH, 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7 is cyclopropyl (wherein the cyclopropyl is F, CN, OH or SO2CH3, NH-cyclopropyl, [dimethyl(oxo)-λ 6 -sulfanylidene]amino, (C 1~4alkyl)sulfonimidoyl, SO2CH3, OSO2CH3, C(CH3)2SO2CH3, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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 1~3alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 cyclopropyl). or a pharmaceutically acceptable salt thereof.

[0106] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 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 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 7is cyclopropyl (wherein said 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, SO2NHCH3, SON(CH3)2, morpholine-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCH3, and cyclobutyl, wherein said cyclobutyl is substituted with 0 or 1 OH; R 8 is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1, or 2 substituents independently selected from cyclopropyl, OH, C(O)CHOH, 4-methylpiperazinyl, C(O)CH and C(O)N(CH); R 9 is OR 10 , N(R 10 )2, NR 11 (CH2)2N(CH3)2, —(CH2)2(5-6 membered)heterocycloalkyl (wherein the (5-6 membered)heterocycloalkyl is R 11 substituted with 0 or 1 substituent selected from the group consisting of —O(CH)(5-6 membered)heterocycloalkyl, wherein the (5-6 membered)heterocycloalkyl is R 11 and azetinyl substituted by 0 or 1 substituents selected from N(CH3)2 and C(O)CH3; R 10 is H and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2alkyl 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.

[0107] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 8 and CH2R 8 substituted by 0 or 1 substituent selected from: R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing one O; R 8is selected from SO2CH3 or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R 6 and OR 6 and 0, 1 or 2 substituents independently selected from cyclopropyl, C(O)CH and C(O)N(CH) or a pharmaceutically acceptable salt thereof.

[0108] In still further embodiments, the compound of formula (IB) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0 or 1 substituent selected from (5- to 8-membered)heterocycloalkyl and CH2(5- to 8-membered)heterocycloalkyl); and R 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0109] In still further embodiments, the compound of formula (IB) [ka] (In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; R 4 is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R 6 and 0, 1, or 2 substituents independently selected from 7 substituted by 0 or 1 substituent selected from: R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted by 0, 1, 2 or 3 F; and R 7 is selected from cyclopropyl, wherein said cyclopropyl is substituted by 0 or 1 substituent selected from F, CN, OH, or SO2CH3. or a pharmaceutically acceptable salt thereof.

[0110] In one embodiment, a compound of formula (IC) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 are H, F, Cl and C 1~2 alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 alkyl is substituted with 0, 1, 2 or 3 substituents independently selected from F and Cl; R 1 is cyclopropyl or C 1~3 alkyl (wherein the C 1~3 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 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0111] In a further embodiment, a compound of formula (IC) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 are H, F, Cl and C 1~2alkyl (wherein the C 1~2 Alkyl is F, CN, NH2 and OC 1~2 substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 1~2 alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl); R 1 is C 1~3 alkyl (wherein the C 1~3 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 6 is C 1~4 alkyl (wherein the C 1~4 Alkyl is 0, 1, 2 or 3 F, O(C 1~2 alkyl) and 0 or 1 substituent selected from OH, CN, N(CH3)2, and (4-5 membered) heterocycloalkyl containing 1 O)] or a pharmaceutically acceptable salt thereof.

[0112] In a further embodiment, a compound of formula (IC) [ka] [In the formula, X 1 and X 3 is an independent CR 5 Selected from; R 5 is H; R 1 is C 1~3 alkyl (wherein the C 1~3alkyl is substituted by 0, 1, 2 or 3 F; R 3 is R 6 , NHR 6 and cyclopropyl; R 6 is C 1~4 alkyl (wherein the C 1~4 alkyl is substituted with 0, 1, 2 or 3 F). or a pharmaceutically acceptable salt thereof.

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

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

[0115] In one embodiment, the compound of formula (I) is selected from: 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methoxy-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(ethylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide, 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(prop-2-ynylamino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 5-(cyanomethylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-fluoropropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-fluoropropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide, 5-ethynyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-5-[(1-methylpyrazol-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide, 5-ethoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-cyano-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-amino-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-ethylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-cyclopropylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-[3-(difluoromethyl)imidazo[4,5-c]pyridin-7-yl]-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-chloro-1-methyl-benzimidazol-4-yl-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-cyano-1-methyl-benzimidazol-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3,4-dimethylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 3-(2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2,3-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-3-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3,5-difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-(3-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-cyano-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[3-(difluoromethyl)-4-morpholino-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(5-methyl-6-morpholino-3-pyridyl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-[[5-methyl-6-[(2S)-2-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[6-[(3R)-3-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[(5-cyano-6-morpholino-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-((4-(1,4-oxazepan-4-yl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-5-(methylamino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-6-[(3R)-3-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(difluoromethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(4-isopropoxyanilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, [4-[[3-carbamoyl-6-(methylamino)-5-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazin-2-yl]amino]phenyl]methanesulfonate, 3-[4-(2-methoxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethoxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(2-hydroxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(2-morpholinoethoxy)anilino]pyrazine-2-carboxamide, 3-(4-aminoanilino)-5-(methylamino)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[2-methoxyethyl(methyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[bis(2-methoxyethyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(2-methyl-4-pyridyl)amino]pyrazine-2-carboxamide formate, 3-[(2-methoxy-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazin-4-yl)pyrazine-2-carboxamide hydrochloride, 3-[(2,6-dimethyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(2,6-dimethyl-4-pyridyl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[2-(2-methoxyethoxy)-6-methyl-4-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-cyano-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(1,5-dimethyl-6-oxo-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(difluoromethyl)-6-oxo-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-3,5-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide formate, 5-(methylamino)-3-[4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethyl-methyl-amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide bis-formate, 3-[4-[3-(dimethylamino)azetidin-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide bis-formate, 3-[3-cyano-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[6-(4-isopropylpiperazin-1-yl)-5-methyl-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[5-methoxy-6-(4-methylpiperazin-1-yl)-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(6-methyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(6-ethyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(6-isopropyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[(dimethylamino)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(pyrrolidin-1-ylmethyl)anilino]pyrazine-2-carboxamide bis-formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-[4-[rel-(1R)-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1S)-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1R)-1-morpholinoethyl]anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1S)-1-morpholinoethyl]anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[1-methyl-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methyl-1-morpholino-ethyl)anilino]pyrazine-2-carboxamide, (R)-3-((4-((3-fluoropyrrolidin-1-yl)methyl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-5-(methylamino)pyrazine-2-carboxamide formate, 3-[4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[(3,3-difluoropyrrolidin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[[(3S)-3,4-dimethylpiperazin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide tris-formate, 3-[4-[[(3R)-3,4-dimethylpiperazin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[6-(morpholinomethyl)-3-pyridyl]amino]pyrazine-2-carboxamide formate, 3-[2-fluoro-4-[(4-methylpiperazin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[3-chloro-4-[(4-methylpiperazin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(2-morpholinoethyl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[2-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(pyrrolidin-1-ylmethyl)anilino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 3-[2-fluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(3S)-4-methylmorpholin-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(3R)-4-methylmorpholin-3-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(2R)-4-methylmorpholin-2-yl]anilino]pyrazine-2-carboxamide, 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(2S)-4-methylmorpholin-2-yl]anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[(1-isopropyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[3-(4-methylpiperazin-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[3-(1-methyl-4-piperidyl)anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(4-methylimidazol-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-([1,2,4]triazolo[4,3-a]pyridin-6-ylamino)pyrazine-2-carboxamide, 3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-imino-2-oxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazol-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-methoxy-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxo-1,4-thiazinan-4-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -sulfanylidene]amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -sulfanylidene]amino]-2-fluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ 6 -sulfanylidene]amino]-2,3-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-(1,1-dioxo-1,2-thiazolidin-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxothiazinan-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-fluoro-4-methylsulfonyl-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, (R)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, (S)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(tert-butylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(1-methylpyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(1-tetrahydropyran-4-ylpyrazol-4-yl)amino]pyrazine-2-carboxamide, 3-[(1-isopropylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1,1-dioxothian-4-yl)pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazol-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide formate, 3-[(1,3-dimethylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(2,2-difluoroethyl)-5-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(1,3-dimethylpyrazol-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyanocyclopropyl)-3-methyl-pyrazol-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(1,5-dimethylpyrazol-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(3-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(2,2-difluoroethyl)-5-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(3,3-difluoropropyl)-3-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(3,3-difluoropropyl)-5-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-[[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, and pharmaceutically acceptable salts thereof.

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

[0117] In one embodiment, there is provided 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.

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

[0119] Medical and Pharmaceutical Uses The compounds of formula (I) and their pharmaceutically acceptable salts are advantageous because they possess pharmacological activity as inhibitors of hematopoietic progenitor kinase 1 (HPK1), making them particularly useful in the treatment or amelioration of common cell proliferative disorders, such as cancer.

[0120] The compounds of formula (I) are inhibitors of HPK1. Accordingly, the compounds of formula (I) may be used as medicines, particularly for disorders, diseases or conditions that respond to inhibition of HPK1, more particularly for cancer. In a further embodiment, there is provided a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in the treatment of a condition in which inhibition of HPK1 would be beneficial.

[0121] In a further embodiment there is provided a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for use in therapy, particularly the prevention or treatment of cancer in a mammal, especially a human.

[0122] In a further embodiment, there is provided the use of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer.

[0123] In a further embodiment, administration of a compound of formula (I) or a pharmaceutically acceptable salt of a compound of formula (I) reduces the level of HPK1 in a mammal, particularly a human.

[0124] With respect to the above therapeutic indications, the dosage administered will, of course, vary depending on the compound used, the method of administration, and the treatment desired, but generally, satisfactory results are obtained when the compound is administered in a solid dosage of 1 to 2000 mg / day. The compounds of formula (I) and their pharmaceutically acceptable derivatives may be used per se or in combination with other compounds or

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

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

[0127] For the avoidance of doubt, the term "treatment" as used herein includes therapeutic and / or prophylactic treatment.

[0128] When a compound or salt described herein is administered as therapy to treat a disorder, a "therapeutically effective amount" is an amount sufficient to reduce or completely alleviate the symptoms or other adverse effects of the disorder, cure the disorder, reverse, halt completely or slow the progression of the disorder, or reduce the risk of the disorder worsening.

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

[0130] The compounds described herein have the advantage that they are more effective, less toxic, more selective, more potent, have fewer side effects, are more readily absorbed, and / or have a better pharmacokinetic profile (e.g., higher oral bioavailability and / or lower clearance) than known compounds in the prior art.

[0131] Combination therapy The compounds of formula (I), or pharmaceutically acceptable salts thereof, may also be administered in combination with other compounds used in the treatment of the above 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 admixture for the treatment of one or more of the conditions listed above. Such combinations may be used in combination with one or more additional active ingredients.

[0133] The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used in combination with checkpoint blockade of the PD-(L)1 axis or CTLA4 to enhance response rates to checkpoint blockade. Primary or secondary resistance to checkpoint blockade can be a potential indication for the compound of formula (I) or a pharmaceutically acceptable salt thereof. Further combinations can include radiation, chemotherapy, surgery, tumor-targeted agents, or other immune-targeted agents.

[0134] When used in combination therapy, it is contemplated that the compound of formula (I) or a pharmaceutically acceptable salt thereof and the other active ingredient(s) may be administered in a single composition, in completely separate compositions, or in any combination thereof, and it is contemplated that the active ingredients may be administered together, simultaneously, sequentially, or separately.

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

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

[0137] The compounds of formula (I) are usually administered orally, topically, parenterally, intravenously, intramuscularly, subcutaneously or by other injectable means, via the buccal, rectal, vaginal, transdermal and / or nasal routes, and / or via inhalation in the form of pharmaceutical preparations containing the active ingredient or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable dosage form. The compositions may be administered in various doses depending on the disorder and patient to be treated and the route of administration. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations can be found, for example, in Pharmaceuticals - The Science of Dosage Form Designs, MEAulton, Churchill Livingstone, 2002. nd It is described in Ed.2002.

[0138] A suitable daily dose of a compound of formula (I) in the therapeutic treatment of humans is about 0.0001 to 100 mg / kg body weight, preferably 0.01 to 10 mg / kg body weight.

[0139] Oral formulations are preferred, particularly tablets or capsules which can be formulated by methods known to those skilled in the art to provide dosages of active compound in the range of 0.007 mg to 700 mg.

[0140] The optimal dosage and frequency of administration will vary depending on the particular condition being treated and its severity; the patient species; the age, sex, size, weight, diet, and general physical condition of the particular patient; the brain / body weight ratio; other medications the patient may be taking; the route of administration; the formulation; and a variety of other factors known to physicians and those skilled in the art.

[0141] Thus, according to a further aspect, there is provided a pharmaceutical formulation comprising a compound of formula (I) or a pharmaceutically acceptable derivative thereof in admixture with a pharmaceutically acceptable adjuvant, diluent and / or carrier.

[0142] The compound of formula (I) may be contained in the pharmaceutical preparation at a concentration of 0.1 to 99.5% by weight, for example 0.5 to 95% by weight, based on the total weight of the preparation.

[0143] The 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 Ed., PJ Kocienski, Georg Thieme Verlag (2005).

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

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

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

[0147] For a review on 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 a solid at room temperature and there is no or only partial proton transfer between the compound of Formula (I) and such acid co-former, a co-crystal of the co-former with the compound of Formula (I) may result, rather than a salt. All such co-crystalline forms of the compound of Formula (I) are encompassed herein.

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

[0150] In further embodiments, certain compounds of formula (I) may exist as racemates and racemic mixtures, single enantiomers, individual diastereomers, and diastereomeric mixtures. Certain compounds of formula (I) may also contain bonds (e.g., carbon-carbon bonds, carbon-nitrogen bonds such as amine bonds) where bond rotation is restricted about that particular bond, for example, due to the presence of a ring bond or a double bond. Stereoisomers may be separated using conventional techniques (e.g., chromatography or fractional crystallization) or may be prepared by stereoselective synthesis.

[0151] In a further embodiment, the compounds of formula (I) include any isotopically labeled (or "radiolabeled") derivatives of compounds of formula (I). Such derivatives are derivatives of compounds of formula (I) in which one or more atoms have been replaced with atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that may be incorporated include: 2 H (also written as "D" for deuterium).

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

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

[0154] Intermediate compounds may also exist in enantiomeric forms and may be used as purified enantiomers, diastereomers, racemates or mixtures.

[0155] Pharmacological activity Assay description HPK1, GLK and LCK IC 50 Assay: The activity of N-terminally GST-tagged recombinant human HPK1, GLK, and LCK enzymes expressed and purified in insect cells (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), a luminescent ADP detection assay.

[0156] The luminescent signal generated is proportional to the ADP concentration generated in the kinase assay in the presence and absence of compound and correlates with kinase activity. Two microliters (μl) of enzyme mixtures 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) Brij 35, 20 mM MgCl) were spotted onto a Greiner 384-well low-volume plate containing 0.1 μl of compound to give 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 preincubated at room temperature for 30 minutes. The enzymatic reaction was initiated with 2 μl of peptide substrate / ATP mixture (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; Information, Boston, MA), 50 μM ATP) in 1× reaction buffer and incubated at room temperature for 60 min. The reaction was stopped by adding 4 μl of ADP-Glo ​​reagent to deplete the remaining ATP and incubated at room temperature for 60 min. Finally, 8 μl of ADP-Glo ​​Max detection reagent was added to simultaneously convert ADP to ATP and incubated at room temperature for 60 min. The newly synthesized ATP is converted to light by the luciferase / luciferin reaction. Luminescence was read using a PHERAstar FSX plate reader (BMG LABTECH, Cary, NC) and data were captured using PHERAstar FSX MARS data analysis software. IC was analyzed using GeneData Screener (GeneData AG, Basel, Switzerland). 50 values ​​were calculated.

[0157] T cell assay material RPMI 1640 (Sigma R5886) Heat-inactivated FBS (Gibco 10270-10 Glutamax 100X(ThermoFisher 35050061) HEPES 1M(ThermoFisher 15630080) Dulbecco's PBS (Sigma D8537) MultiCyt® QBeads® Human PlexScreen(2)Plex for 1 x 384 plates (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 medium Original medium: RPMI 1640 + 10% heat-inactivated FBS + 1% Glutamax (100x) + 1% Pen / Strep + 1% non-essential amino acids + 1M HEPES to make a final concentration of 100 mM Sodium pyruvate 1% + 1.75 ul of 14.3 M stock solution β-mercaptoethanol

[0159] method Cryopreserved human CD3+ T cells are recovered overnight in warm T cell medium. The recovered T cells are seeded at 70,000 cells per well into a 384-well black / clear round-bottom ultra-low attachment surface spheroid microplate (Corning 3830). Compounds in assay-ready 384-well plates (Greiner 781280) are added to the seeded T cells using a Bravo liquid handler. The T cells are then placed in a humidified incubator at 37°C for 1 hour. At the end of the incubation, the cells are transferred to a 384-well flat-bottom plate (Greiner 781090) coated with anti-CD3 antibody (5 μg / mL anti-CD3 in PBS, incubated overnight at 4°C). Anti-CD28 antibody in T cell medium is also added to the cells using a Bravo liquid handler at 5 μg / mL or 1 μg / mL, depending on the donor. The T cells are then incubated for 4 hours at 37°C in a humidified incubator. After 4 hours of incubation, the cell culture supernatant is collected into a V-bottom 384-well plate (Greiner 781280) using a Bravo liquid handler. IL2 is detected using the IL2 MultiCyt® QBeads® kit on an iQue Screener flow cytometer (Sartorius). Briefly, the capture beads are diluted 50-fold with the provided capture bead diluent. Using a ThermoFisher multichannel pipette, 10 μl of diluted capture beads per well is added to each well of a 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 for 1 hour at room temperature on a plate shaker set at 900 rpm. At the end of the 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 for 2 hours at room temperature on a plate shaker set at 900 rpm before detection with the 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] IC of example compounds 50 / EC 50 The values ​​are shown in Table 1 herein 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] [Example]

[0170] The following examples are non-limiting examples.

[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]-diphenyl-phosphane BrettPhos Dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane BrettPhos Pd G3 [(dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane)-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 DIPEA N,N-Diisopropylethylamine, also known as N-ethyl-N-isopropyl-propan-2-amine DMF N,N-dimethylformamide DPEPhos[2-(2-diphenylphosphanylphenoxy)phenyl]-diphenyl-phosphane DSC Differential Scanning Calorimetry HATU Azabenzotriazole tetramethyluronium hexafluorophosphate, N,N,N',N'-tetramethyl-1-(3-oxidotriazolo[4,5-b]pyridin-3-ium-1-yl)methanediamine; also known as hexafluorophosphate DIAD Diisopropyl azodicarboxylate, also known as (NE)-N-isopropoxycarbonyliminocarbamate DMA N,N-dimethylacetamide DMAP N,N-dimethylaminopyridine, also known as N,N-dimethylpyridin-4-amine DMSO dimethyl sulfoxide Dppf 1,1'-bis(diphenylphosphino)ferrocene, also known as (ferrocene-1,1'-diyl)bis(diphenylphosphane) DTBAD Di-t-butyl azodicarboxylate, also known as 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]phosphane)-2-(2'-methylamino-1,1'-biphenyl)]palladium(II) methanesulfonate ES Electrospray HPLC High Performance Liquid Chromatography IPA isopropanol, also known as 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 meta-chloroperbenzoic acid, also known as 3-chlorobenzenecarboperoxoic acid MDAP Mass Directed Automated Purification MHz Megahertz MTBE Methyl tert-butyl ether, also known as 2-methoxy-2-methyl-propane m / z mass / charge NMP 1-methylpyrrolidin-2-one NMR nuclear magnetic resonance PCy3Pd G3 [(tricyclohexylphosphane)-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-dimethyl-xanthen-4-yl)-diphenyl-phosphane XantPhos Pd G3 [((5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate Xphos Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane XPhos Pd G3 (Dicyclohexyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate

[0172] The following general experimental procedures were used: Unless otherwise specified, operations are carried out at room temperature, i.e., in the range of 18-25°C.

[0173] Evaporation of the organic solvent was carried out using a rotary evaporator under reduced pressure (4.5 to 30 mmHg) at a bath temperature of up to 60°C.

[0174] Generally, the course of the reactions was followed by TLC or liquid chromatography / mass spectrometry, but reaction times are given for illustrative purposes only; Yields are given for illustrative purposes only and are not necessarily those that can be obtained by rigorous process development. If more material was required, the preparation was repeated.

[0175] Microwave reactions were performed in a Biotage Initiator or Emrys Optimizer using Biotage microwave vials.

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

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

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

[0179] Preparative HPLC purification was performed on instruments including a Waters FractionLynx system equipped with an Acquity QDa mass detector or a Waters 2545, 2767 and 2489 equipped with a QDa or SQ Detector2ESCi mass spectrometer. Columns and gradients are specified in the examples.

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

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

[0182] 1 H NMR measurements were performed on a 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 spectrometer (operating at H 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. Rev. 3 truncations are listed. In most cases, the shift is due to residual deuterated solvent. 1 The data were re-referenced during processing according to the 1 H chemical shift.

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

[0184] Photoredox chemistry: HepatoChem EvoluChem TM The experiments were carried out in a PhotoRedOx reactor using a 34W Kessil H150 blue LED lamp (440 nm) as the light source.

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

[0186] X-ray diffraction analysis was performed according to standard methods that can be 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. Samples were mounted on single silicon crystal (SSC) wafer mounts, and powder X-ray diffraction was recorded on a PANalytical X'Pert PRO (reflection geometry, wavelength of X-rays 1.5418 Å, nickel-filtered Cu radiation, voltage 45 kV, filament emission 40 mA). Automatic variable divergence and anti-scatter slits were used, and the sample was rotated during the measurement. A PIXCEL detector (effective length 3.35° 2-theta) was used to scan the sample from 2 to 50° 2-theta or 2 to 40° 2-theta using a 0.013° step width and a 44-233 s count time.

[0187] It is known in the art that X-ray powder diffraction patterns may be obtained with one or more measurement errors depending on the measurement conditions (e.g., the instrument, sample preparation, or the machine used). In particular, it is generally known that the intensities of X-ray powder diffraction patterns may vary depending on the measurement conditions and sample preparation. For example, those skilled in the art of X-ray powder diffraction will understand that the relative intensities of peaks may vary depending on the orientation of the sample being tested and the type and settings of the instrument being used. Those skilled in the art will also understand that the position of reflections may be affected by the exact height at which the sample is positioned within the diffractometer and the zero calibration of the diffractometer. The surface planarity 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 construed as absolute, and that any crystalline form that gives a powder diffraction pattern substantially identical to that disclosed herein is within the scope of the present disclosure (see Jenkins, R & Snyder, R L 'Introduction to X-Ray Powder Diffractometry' John Wiley & Sons, 1996 for further information). Generally, the measurement error of the diffraction angle in an X-ray powder diffractogram can be ±0.1° 2-theta, and this degree of measurement error should be taken into consideration when considering X-ray powder diffraction data. Furthermore, it should be understood that intensities can vary depending on experimental conditions and sample preparation (e.g., preferred orientation). The following definitions were used for relative intensities (%): 81-100%, vs (very strong); 41-80%, str (strong); 21-40%, med (medium); 10-20%, w (weak); and 1-9%, vw (very weak).

[0188] 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-nitro-aniline 1-Bromo-3-fluoro-2-nitro-benzene (25.0 g, 114 mmol) was added to a solution of 33% methanamine (114 mL, 916 mmol) in ethanol at 0 °C. The resulting solution was stirred at 25 °C for 5 hours. The reaction was then concentrated. The resulting residue was dissolved in ethyl acetate, washed three times with water, dried over sodium sulfate, filtered, and concentrated to give 3-bromo-N-methyl-2-nitro-aniline (27.3 g, quantitative) as a light 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-methyl-benzene-1,2-diamine Iron powder (61.3 g, 1.10 mol) was added to a solution of 3-bromo-N-methyl-2-nitro-aniline (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 aqueous potassium carbonate solution. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-100% ethyl acetate-hexane as the eluent to give 3-bromo-N1-methyl-benzene-1,2-diamine (22 g, 100%) as a purple oil; 1H NMR (500 MHz, 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-methyl-benzene-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 was then concentrated. The resulting residue was dissolved in ethyl acetate, washed three times with 10% aqueous potassium carbonate, dried over sodium sulfate, filtered, and evaporated to give 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(pinacolato)diboron (15.0 g, 59.2 mmol), and potassium acetate (6.97 g, 71.1 mmol) were combined in a three-neck flask, which was then evacuated and backfilled with nitrogen three times. Cyclopentyl methyl ether (120 mL) was added, and the reaction was stirred at 80 °C for 24 h. The reaction was then diluted with ether (100 mL), filtered through celite, and rinsed with ether. The filtrate was concentrated to a brown solid, which was sonicated in hexane (600 mL) for 40 min, then allowed to stand for 90 min, then filtered and washed with a small amount of hexane to give 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). Bad behavior by LCMS.

[0193] Intermediate 2 (1-Methylbenzimidazol-4-yl)boronic acid [ka] PdCl(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(pinacolato)diboron (24.06 g, 94.76 mmol) in dioxane (400 mL). The resulting mixture was stirred at 100 °C for 3 days. The reaction was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 50 mm × 150 mm, XBridge Prep C18 OBD column, eluting with decreasingly polar MeCN-water mixtures and 1% formic acid as a modifier, to afford (1-methylbenzimidazol-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 were broadened to the baseline. m / z: (ES+), [M+H]+ = 177.1

[0194] Intermediate 3 7-Bromo-3-methyl-imidazo[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 EtOAc. 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 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 give a yellow solid, which was partitioned between saturated aqueous potassium carbonate and ethyl acetate and extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 7-bromo-3-methyl-imidazo[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-methyl-imidazo[4,5-c]pyridine (24.00 g, 113 mmol), bis(pinacolato)diboron (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 evacuated and backfilled with nitrogen three times. 2-Methyltetrahydrofuran (700 mL) was added, and the mixture was evacuated and backfilled with nitrogen two more times. The resulting mixture was stirred at 80 °C for 16 h. The reaction 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]pyridin-7-yl)boronic acid [ka] Dichlorobis(tricyclohexylphosphine)palladium(II) (418 mg, 0.570 mmol) was added to a suspension of 7-bromo-3-methyl-3H-imidazo[4,5-c]pyridine (600 mg, 2.83 mmol), bis(pinacolato)diboron (2.16 g, 8.49 mmol), and potassium acetate (833 mg, 8.49 mmol) in toluene (2 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction 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 the modifier to give (3-methyl-3H-imidazo[4,5-c]pyridin-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]pyridin-7-yl)-1,3,6,2-dioxazaborocane [ka] A suspension of 7-bromo-3-methyl-imidazo[4,5-c]pyridine (29.7 g, 140 mmol), bis(pinacolato)diboron (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 at 86 °C under argon for 16 hours. The reaction was then cooled to room temperature, diluted with DCM (879 mL), filtered through a pad of celite, and washed twice with DCM (100 mL each). The 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 was then filtered and washed with MeCN to give 2-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-1,3,6,2-dioxazaborocane (30.0 g, 87% yield) as a pale yellow solid. 1H NMR (500 MHz, deuterium oxide): 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). The NH protons were exchanged in DO.

[0198] Example 1 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl ester Triethylamine (0.141 mL, 1.01 mmol) was added 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) at 25° C. The resulting mixture was stirred at 70° C. for 16 h. The solvent was then removed under reduced pressure. The residue was purified by silica gel chromatography using 60–70% EtOAc-petroleum ether as the eluent to give 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. The solvent was then removed under reduced pressure to give 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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 1,1'-Bis(di-tert-butylphosphino)ferrocenepalladium dichloride (35 mg, 0.050 mmol) was added to (1-methylbenzimidazol-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 x 150 mm, XBridge Prep C18 OBD column, eluting with mixtures of decreasing polarity MeCN-HO using 0.1% formic acid as a modifier to give 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (100 mg, 44%) as a brown solid; H NMR (400 MHz, DMSO-d) 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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-bromo-5-methyl-pyrazine-2-carboxylic acid N-Bromosuccinimide (209.0 g, 1175 mmol) was added to 3-amino-5-methyl-pyrazine-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 give 3-amino-6-bromo-5-methyl-pyrazine-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-methyl-pyrazine-2-carboxylate methyl ester To 3-amino-6-bromo-5-methyl-pyrazine-2-carboxylic acid (9.06 g, 39.1 mmol) in MeOH (200 ml) was added sulfuric acid (6.00 ml, 113 mmol). The resulting mixture was stirred at 70° C. for 17 hours. The reaction was then concentrated. The resulting residue was dissolved in water and basified with saturated aqueous sodium carbonate. The resulting precipitate was collected by filtration, washed with water, and dried under vacuum to give methyl 3-amino-6-bromo-5-methyl-pyrazine-2-carboxylate (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-methylbenzimidazol-4-yl)pyrazine-2-carboxylate methyl ester MeOH (14 mL) was added to a mixture of (1-methylbenzimidazol-4-yl)boronic acid (0.499 g, 2.84 mmol), methyl 3-amino-6-bromo-5-methyl-pyrazine-2-carboxylate (0.540 g, 2.19 mmol), CsF (1.000 g, 6.58 mmol), and PdCl(dppf) (0.161 g, 0.22 mmol). The resulting mixture was degassed, purged with nitrogen, and then heated at 100 °C in a Biotage microwave reactor 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 to give methyl 3-amino-5-methyl-6-(1-methylbenzimidazol-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) methyl 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate 1,4-Dioxane (30 mL) was added to a mixture of methyl 3-amino-5-methyl-6-(1-methylbenzimidazol-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 and purged with nitrogen three times, then stirred at 100 °C for 7 hours. The reaction mixture was then treated with water, and the resulting precipitate was filtered, washed with water, and dried under vacuum. The resulting solid was purified by silica gel chromatography four times, once using 0-5% MeOH-DCM as the eluent and then again using 0-3% MeOH-DCM as the eluent, to give methyl 5-methyl-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (20 mL, 140 mmol) was added to methyl 5-methyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.538 g, 1.17 mmol). The resulting mixture was stirred at 40 °C for 16 h. An additional 7N methanolic ammonia (10 mg, 70 mmol) was added, and the reaction mixture was stirred at 40 °C for 5 h. The reaction 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 give a yellow solid. This material was further purified by reverse phase chromatography, C18, using 10-60% MeCN-HO as eluent and 0.2% ammonium hydroxide as modifier to give 5-methyl-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-methoxy-pyrazine-2-carboxylate methyl ester Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (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 h. 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 h. The suspension was filtered, and the filter cake was dried under vacuum to give methyl 3-amino-6-chloro-5-methoxy-pyrazine-2-carboxylate (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) 6-chloro-3-fluoro-5-methoxy-pyrazine-2-carboxylate methyl ester Sodium nitrite (2.3 g, 33 mmol) was added portionwise to methyl 3-amino-6-chloro-5-methoxy-pyrazine-2-carboxylate (6.90 g, 31.7 mmol) in HF-pyridine (20 mL, 580 mmol) at 10° C. The resulting suspension was stirred at 25° C. for 1 h. The reaction 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). The combined organics were dried over magnesium sulfate, filtered, and concentrated to give methyl 6-chloro-3-fluoro-5-methoxy-pyrazine-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 ester DIPEA (6 mL, 34.35 mmol) was added to a solution of methyl 6-chloro-3-fluoro-5-methoxy-pyrazine-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 was then removed from the heat and allowed to cool to room temperature. The reaction was filtered and washed with a small amount of EtOAc to give 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) methyl 5-methoxy-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate The reaction was repeated five times to fit into a microwave vial. 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)Cl (0.400 g, 0.490 mmol), and cesium fluoride (2.08 g, 13.7 mmol) were combined and purged under nitrogen. MeOH (15 mL) was added to each, and each reaction was stirred at 100 °C for 3 h in a Biotage microwave reactor. The reaction vials were then combined, concentrated, loaded onto Celite, and purified by silica gel chromatography using 0-10% methanol-DCM as the eluent and 0-1% ammonia as the modifier to give an orange solid. Methanol (30 mL) was added to the solid, and the resulting suspension was stirred at 40°C for 1 h and then allowed to stand at 25°C for 30 min. The suspension was filtered and washed with a small amount of methanol to give methyl 5-methoxy-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide The reaction was repeated five times to fit the microwave vials. In each vial, methyl 5-methoxy-6-(1-methylbenzimidazol-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 h in a Biotage microwave reactor. The reaction vials were cooled, then combined, filtered, and washed with a small amount of MeOH to give 8.0 g of a yellow solid. This material was combined with 3.64 g of the same material from another batch, then loaded onto Celite, and purified by silica gel chromatography using 0-5% MeOH-DCM as the eluent and 0-0.5% ammonia as the modifier to give 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 give 5-methoxy-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-[2-(dimethylamino)ethoxy]pyrazine-2-carboxylate methyl ester Sodium (0.311 g, 13.5 mmol) was added to methyl 3-amino-5,6-dichloro-pyrazine-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 eluent to give 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) methyl 3-amino-5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate 1,4-Dioxane (10 mL) was added to a mixture of (1-methylbenzimidazol-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 PdCl(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-HO as eluent and 10 mM ammonium bicarbonate as modifier to give methyl 3-amino-5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (180 mg, 27%) as a yellow gum; 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-methylbenzimidazol-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-methylbenzimidazol-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 resulting residue was purified by C18 reverse phase chromatography using 0-50% MeCN-HO as the eluent to give 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (80 mg, 34%) as a yellow gum; 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 broadened to baseline; m / z: (ES+) [M+H]+ = 518.4.

[0214] (d) 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-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-methylbenzimidazol-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 resulting residue was purified by reverse-phase chromatography using 0–100% MeCN-HO as the eluent and 10 mmol / L ammonium bicarbonate as the modifier to give 5-[2-(dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (28.0 mg, 37%) as a yellow solid; H NMR (400 MHz, DMSO-d) 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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-cyclopropyl-pyrazine-2-carboxylate methyl ester Potassium cyclopropyltrifluoroborate (0.800 g, 5.40 mmol) was added to a suspension of methyl 3-amino-5,6-dichloro-pyrazine-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 resulting residue was purified by silica gel chromatography using 0-30% EtOAc-pentane as the eluent to give 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-methylbenzimidazol-4-yl)pyrazine-2-carboxylate methyl ester (1-Methylbenzimidazol-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), PdCl(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 h. The reaction mixture was filtered through celite, and the solvent was removed under reduced pressure. The resulting residue was purified by reverse-phase chromatography using 0–30% MeCN-HO as the eluent and 0.1% formic acid as the modifier to give methyl 3-amino-5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl ester 4-(4-Bromophenyl)morpholine (313 mg, 1.29 mmol) was added to a suspension of methyl 3-amino-5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (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 resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (6.0 mL, 42 mmol) was added to methyl 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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 resulting residue was purified by preparative HPLC using a SunFire C18 OBD 5 μm, 19 mm × 250 mm column, 19% to 33% MeCN / HO as the eluent, and 0.05% trifluoroacetic acid as the modifier to give 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (35 mg, 33%) as an orange solid; H NMR (400 MHz, DMSO-d) 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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate methyl ester PdCl(dppf) (370 mg, 0.51 mmol) was added to a suspension of CsF (773 mg, 5.09 mmol), methyl 3-amino-6-chloro-5-methyl-pyrazine-2-carboxylate (513 mg, 2.54 mmol), and (3-methylimidazo[4,5-c]pyridin-7-yl)boronic acid (450 mg, 2.54 mmol) in 1,4-dioxane (15 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The solvent was then removed under reduced pressure. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate (300 mg, 40% yield) 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) methyl 5-methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate Methyl 3-amino-5-methyl-6-(3-methylimidazo[4,5-c]pyridin-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 resulting residue was purified by silica gel chromatography using 0-40% MeOH-DCM as the eluent to give methyl 5-methyl-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-7-yl)-3-((4-morpholinophenyl)amino)pyrazine-2-carboxylate (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 resulting residue was purified by preparative HPLC using a 5 micron, 30 x 150 mm, Sunfire prep C18 column, eluting with 10-28% MeCN-water and 0.1% formic acid as a modifier to give 5-methyl-6-(3-methylimidazo[4,5-c]pyridin-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate methyl ester 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 of its original volume, diluted with water (200 mL), filtered, and washed with water. The filter cake was dried under vacuum to give 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 ester Sodium nitrite (3.30 g, 47.89 mmol) was added in small portions 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) at −10° C. The reaction was stirred at 25° C. for 1 h. 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 with DCM (50 mL each). The combined organic layers were washed with saturated aqueous ammonium chloride solution (50 mL). The combined aqueous layers were finally extracted with DCM (50 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 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 ester 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 was stirred at 100° C. for 90 minutes. The reaction 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 give methyl 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (9.48 g, 65%) as a tan 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) methyl 5-(methylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate 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)Cl (0.29 g, 0.40 mmol), and cesium fluoride (1.81 g, 11.9 mmol) were combined in a microwave vial, which was then evacuated and backfilled with nitrogen three times. MeOH (15 mL) was added, and the reaction was stirred at 100 °C for 8 h in a Biotage microwave reactor. The reaction was then concentrated, loaded onto Celite, and purified by silica gel chromatography using 0-10% MeOH-DCM as eluent and 0-1% ammonia as modifier to give a tan solid, which was suspended in MeOH (40 mL), stirred at 40 °C for 30 min, and allowed to stand for 1 h. The resulting suspension was then filtered and washed with a small amount of MeOH to give methyl 5-(methylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid bis-trifluoroacetate Lithium hydroxide monohydrate (2.64 g, 63.0 mmol) was added to a suspension of methyl 5-(methylamino)-6-(1-methylbenzimidazol-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 was cooled to room temperature, diluted with water (70 mL), and concentrated to a volume of 40 mL, then filtered and washed with water. The resulting yellow filter cake was purified by reverse-phase chromatography using 0–50% MeCN / HO as the eluent and 0.1% TFA as the modifier to give 5-(methylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (3.00 g, 70%) as an orange solid, presumed to be the bis-trifluoroacetate salt; 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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid, ditrifluoroacetate (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 aqueous sodium bicarbonate (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 give a yellow solid. This material was suspended in MeOH (70 mL), stirred at 40° C. for 2 h, sonicated for 1 h, and allowed to stand for 3 h. The resulting suspension was filtered, washed with a small amount of MeOH, and dried under vacuum to give 5-(methylamino)-6-(1-methylbenzimidazol-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0229] (a) 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate methyl ester 33% Methanamine in EtOH (280 mL, 2.25 mol) was added to a mixture of methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate (100 g, 450 mmol) in MeOH (1 L). The resulting mixture was stirred at 65 °C for 16 h. The reaction was then cooled to 0 °C, filtered, washed with MeOH, and dried under vacuum to give methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (69.0 g, 71% yield) as a light 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 ester A solution of sodium nitrite (12.23 g, 177.3 mmol) in water (100 mL) was added in small portions over 2 hours to a suspension of methyl 3-amino-6-chloro-5-(methylamino)pyrazine-2-carboxylate (32.00 g, 147.7 mmol) in 25% sulfuric acid (400 mL, 1.2 mol), hexane (100 mL), and (400 mL). The resulting mixture was stirred vigorously at room temperature for 30 minutes. The reaction was then filtered, washed with water, and dried under vacuum to give methyl 5-chloro-6-(methylamino)-2-oxo-1H-pyrazine-3-carboxylate (31.4 g, 98% yield) as a pale 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 ester Trifluoromethanesulfonic anhydride (21.4 mL, 126.4 mmol) was added in small portions 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) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes. The reaction 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 ester 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 was then cooled to room temperature, diluted with EtOAc, 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) methyl 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate A mixture of methyl 6-chloro-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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), PdCl(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 backfilled with nitrogen three times. The resulting mixture was stirred at 80 °C for 2 hours. The reaction was then cooled to room temperature, diluted with water (500 mL), and filtered. The filter cake was dried under vacuum. The resulting solid was used in the next step without further purification.

[0234] (f) 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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 h. The reaction 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]pyridin-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]pyridin-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% methanol-dichloromethane as the eluent to give 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (15.75 g, 52% yield) as a yellow solid. This material was mixed with an equal-sized batch in MeOH (1 L) and stirred at room temperature for 10 minutes. The resulting slurry was filtered. The solid residue was found to be crystalline by XRPD (Form 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] Form A was further analyzed by thermal techniques. DSC analysis showed that Form A began to desolvate at 29 °C, peaking at 54 °C, followed by several thermal events between 190 °C and 290 °C. TGA showed that Form A experienced a mass loss of approximately 1.3% upon heating from approximately 25 °C to approximately 100 °C. A representative DSC / TGA thermogram of Form A is shown in Figure 2.

[0239] The filter cake, consisting of Form A, was suspended in 99.5% EtOH (750 mL) and treated with 20 mg of seed crystals of Form F 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (obtained by placing 3-5 mg of Form A in a TGA or DSC pan, heating to 300 °C at 10 °C / min, and then cooling to room temperature). The resulting suspension was stirred at room temperature for 16 hours and then filtered. The filter cake was dried under vacuum to give 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (31.5 g) as a yellow solid. The solid residue was found to be crystalline by XRPD (Form 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] Form F was further analyzed by thermal techniques. DSC analysis showed that Form F has a melting / thermal decomposition temperature with an onset at 334° C. and a peak at 338° C. TGA showed that Form F had a mass loss of about 0.5% upon heating from about 25° C. to about 100° C. A representative DSC / TGA thermogram of Form F is shown in FIG. 4.

[0243] Evaporation of the EtOH solution yielded single crystals of Form F. Single crystal structure analysis confirmed that Form F is an anhydrous form. The molecular structure of Example 8 - Form F is shown in Figure 5. Crystallographic data: space group monoclinic Pc, lattice parameters: 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] 50 mg of the filter cake consisting of Form A was suspended in 1.0 mL of ACN and the slurry was stirred at room temperature for 5 days to give 45 mg of a yellow solid after filtration and air-drying. The solid residue was found to be crystalline by XRPD (Form 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] Form G was further analyzed by thermal techniques. DSC analysis showed that Form G has a melting / thermal decomposition temperature with an onset at 344° C. and a peak at 345° C. TGA showed that Form G had a mass loss of about 0.1% upon heating from about 25° C. to about 100° C. A representative DSC / TGA thermogram of Form G is shown in FIG. 7.

[0248] 50 mg of the filter cake consisting of Form A was suspended in 0.5 mL of HO, 0.5 mL of MeOH, and 0.5 mL of DCM, and the slurry was stirred at room temperature for 5 days to give 48 mg of a yellow solid after filtration and air-drying. The solid residue was found to be crystalline by XRPD (Form 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] Form I was further analyzed by thermal techniques. DSC analysis showed that Form I has a melting / thermal decomposition temperature with desolvation beginning at 66° C. and peaking at 73° C., followed by an onset at 344° C. and peak at 245° C. TGA showed that Form I experienced a mass loss of about 3.7% upon heating from about 25° C. to about 100° C. A representative DSC / TGA thermogram of Form I is shown in FIG. 9.

[0252] Single crystals of Form I were obtained by evaporation of a MeOH / DCM / H2O (1:1:1) solution. Single crystal structure analysis confirmed that Form I is an anhydrous form. The molecular structure of Example 8 - Form I is shown in Figure 10. Crystallographic data: space group monoclinic P2(1) / c, lattice parameters: 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-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-methylsulfanyl-pyrazine-2-carboxylate methyl ester Aqueous sodium methanethiolate, 21 wt % (22 mL, 66 mmol) was added to a suspension of methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate (10 g, 45 mmol) in THF (100 mL). The resulting suspension was stirred at 25 °C for 3 h. The reaction was then concentrated to 1 / 6 of its original volume. The resulting orange suspension was diluted with water (100 mL), stirred for 10 min, then filtered, washed with copious amounts of water, and dried under vacuum to give methyl 3-amino-6-chloro-5-methylsulfanyl-pyrazine-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-methylbenzimidazol-4-yl)-5-methylsulfanyl-pyrazine-2-carboxylate methyl ester 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-methylsulfanyl-pyrazine-2-carboxylate (250 mg, 1.07 mmol), cesium fluoride (488 mg, 3.21 mmol), and PdCl(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 h. The reaction mixture was then filtered through Celite and concentrated. The resulting residue was purified by silica gel chromatography using 0-100% EtOAc-hexane as eluent followed by 0-20% MeOH-DCM as eluent to give methyl 3-amino-6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-pyrazine-2-carboxylate (150 mg, 43%) as a dark brown solid. m / z: (ES+), [M+H]+ = 330.1.

[0255] (c) 6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid Methyl 3-amino-6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-pyrazine-2-carboxylate (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 sodium tert-butoxide (117 mg, 1.21 mmol) were added to the reaction mixture, which was then stirred at 80 °C for 2 hours. 1 M HCl was added, and the aqueous layer was washed with 3:1 DCM / IPA 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-methylbenzimidazol-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-methylbenzimidazol-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 min and then directly purified by reverse-phase chromatography on a 18 column using 0–80% MeCN-HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0258] (a) 6-(1-methylbenzimidazol-4-yl)-5-methylsulfonyl-3-[4-(4-oxidomorpholin-4-ium-4-yl)anilino]pyrazine-2-carboxamide mCPBA (21 mg, 77 wt%, 0.090 mmol) was added to a suspension of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (20 mg, 0.04 mmol) in DCM (1 mL) at 0° C. The resulting mixture was stirred at 0° C. for 30 minutes and then at 25° C. for 90 minutes. The reaction was then quenched with saturated aqueous sodium bicarbonate and extracted with 3:1 DCM / IPA. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-100% MeOH-DCM to give a yellow material, which was purified by reverse-phase chromatography on c18 using 0-80% MeCN / HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 6-(1-methylbenzimidazol-4-yl)-5-methylsulfonyl-3-[4-(4-oxidomorpholin-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 2 M methanolic ethanamine (0.028 mL, 0.056 mmol) and DIPEA (0.024 mL, 0.14 mmol) were added to a solution of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfonyl-3-[4-(4-oxidomorpholin-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 was stirred at 25° C. for 16 hours. The reaction was then concentrated. The resulting residue was purified by reverse-phase chromatography on C18 using 0–80% MeCN / HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 55-(ethylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfonyl-3-[4-(4-oxidomorpholin-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 was then concentrated. The resulting residue was purified by reverse-phase chromatography on C18 using 10–80% MeCN / HO as the eluent to give 5-(cyclopropylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka]

[0262] (a) 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 to a mixture of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.157 g, 0.330 mmol) in DCM (5.00 mL) at 0 °C. The reaction was stirred at 0 °C for 5 min. The reaction was quenched with saturated aqueous sodium bicarbonate and extracted once with DCM and once with 5:1 DCM / IPA. The combined organic layers were dried over sodium sulfate, concentrated, and used in the next step without purification, assuming a 100% yield.

[0263] (b) 5-amino-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (10 mL, 70 mmol) was added to 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 was then concentrated. The resulting residue was suspended in water, filtered, and washed with water. The filter cake was dried under vacuum to give 5-amino-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.198 g, 88%) as a yellow solid; (500 MHz, DMSO-d) 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 amino NH proton was buried under the residual water peak. m / z: (ES+), [M+H]+ = 445.4

[0264] Example 13 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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. The resulting residue was partitioned between DCM and water. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as the modifier to give 5-[[(2R)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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. The resulting residue was partitioned between DCM and water. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as the modifier to give 5-[[(2S)-2-hydroxypropyl]amino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide [ka] 2,2,2-Trifluoroethanamine (101 mg, 1.02 mmol) was added to a suspension of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 HO. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as the modifier to give 6-(1-methylbenzimidazol-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 m / z: (ES+), [M+H]+ = 527.2 (1H, s). One of the carboxamide NH2 protons was exchanged to the baseline.

[0267] Example 16 5-(2,2-Difluoroethylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 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 HO. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as the modifier to give 5-(2,2-difluoroethylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-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]imidazol-4-yl)-6-(methylsulfinyl)pyrazin-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 HO. The layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0.1% ammonium hydroxide as the modifier to give 5-[2-(dimethylamino)ethylamino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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. The resulting residue was partitioned between DCM and water. The layers were separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 1% ammonium hydroxide as the modifier to give 5-(2-hydroxyethylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(prop-2-ynylamino)pyrazine-2-carboxamide [ka] Prop-2-yn-1-amine (0.071 mL, 1.1 mmol) was added to a suspension of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-5% MeOH-DCM to give 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(prop-2-ynylamino)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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide and 6-(1-methylbenzimidazol-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 added sequentially to a suspension of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-4-ium-4-yl)anilino]pyrazine-2-carboxamide in n-butanol (0.5 mL). The resulting mixture was stirred at 140 °C for 30 min in a Biotage microwave reactor. The reaction was then concentrated. The resulting residue was purified by reverse-phase chromatography on a C18 column using 0–100% MeOH-HO as the eluent and 0.1% TFA as the modifier to give an orange oil. This oil was further purified by chiral HPLC using a Chiralpak AD 4.6 mm x 100 mm 5 micron column with isocratic 40% methanol-sCO as eluent and 0.2% ammonium hydroxide as modifier to give 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide (7.0 mg, 19%) and 6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 resulting residue was purified by reverse-phase chromatography with c18 using 10–45% MeCN-HO as the eluent and 0.2% ammonium hydroxide as the modifier to give 5-(cyanomethylamino)-6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 resulting residue was purified by reverse-phase chromatography with c18 using 10–55% MeOH-HO as the eluent and 0.2% NH4OH as the modifier to give 5-[[(2R)-2-fluoropropylamino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-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-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-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 resulting residue was purified by reverse-phase chromatography with c18 using 10–55% MeOH-HO as the eluent and 0.2% 4 as the modifier to give 5-[[(2S)-2-fluoropropylamino]-6-(1-methylbenzimidazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide [ka] Oxetan-3-ylmethanamine (36 mg, 0.41 mmol) was added to a solution of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfinyl-3-[4-(4-oxidomorpholin-4-ium-4-yl)anilino]pyrazine-2-carboxamide (35 mg, 0.070 mmol) in DMF (690 μL). The resulting mixture was stirred at 25° C. for 16 hours. The reaction was then quenched with sodium bisulfite (36 mg, 0.34 mmol) and stirred at 25° C. for 1 hour. The resulting mixture was purified by C18 reverse phase chromatography using 0-100% MeCN-H2O as the eluent to give 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide; 1 H NMR (500 MHz, 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); oxetanyl methine protons buried under residual water peak; m / z: (ES+), [M+H]+ = 515.3

[0276] Example 26 5-ethynyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-(1-methylbenzimidazol-4-yl)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl ester Tricyclohexylphosphonium tetrafluoroborate (136 mg, 0.370 mmol) was added to a mixture of methyl 3-amino-6-chloro-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (680 mg, 1.85 mmol), (1-methylbenzimidazol-4-yl)boronic acid (650 mg, 3.70 mmol), potassium phosphate (785 mg, 3.70 mmol), and PCyPd G3 (240 mg, 0.370 mmol) in 1,4-dioxane / HO (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 3-amino-6-(1-methylbenzimidazol-4-yl)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate (500 mg, 58% yield) as a yellow oil that solidified upon standing. m / z: (ES+), [M+H]+ = 464.2

[0277] (b) 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate methyl ester BrettPhos Pd G3 (36 mg, 0.040 mmol) was added to a suspension of methyl 3-amino-6-(1-methylbenzimidazol-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) under nitrogen. The resulting mixture was stirred at 100° C. for 5 hours. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-30% MeOH-DCM as eluent to give methyl 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxylate as a red solid.

[0278] (c) 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-triisopropylsilylethynyl)pyrazine-2-carboxamide 7N methanolic ammonia (8.0 mL, 56 mmol) was added to methyl 6-(1-methylbenzimidazol-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 was then concentrated. The resulting residue was purified by silica gel chromatography to give 6-(1-methylbenzimidazol-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-ethynyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 1 M TBAF in THF (2.0 mL, 2.00 mmol) was added to 6-(1-methylbenzimidazol-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-8% MeOH-DCM as the eluent. The resulting residue was further purified by preparative HPLC using a 5 micron, 19 mm x 150 mm SunFire Prep C18 OBD column with mixtures of MeCN-HO of decreasing polarity as eluent and 0.1% formic acid as modifier to give 5-ethynyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (28 mg, 38%) as a yellow solid; H NMR (400 MHz, DMSO-d) 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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(difluoromethyl)pyrazine-2-carboxylate methyl ester Methyl 3-amino-5,6-dichloropyrazine-2-carboxylate (500 mg, 2.25 mmol) was added to a mixture of bis(dibenzylideneacetone)palladium (129 mg, 0.230 mmol), DPEPhos (243 mg, 0.450 mmol), and [1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-ylidene]-(difluoromethyl)silver (1.24 g, 2.25 mmol) in toluene (30 mL) under nitrogen. The resulting solution was stirred at 80° C. for 18 hours. The reaction was then concentrated. The resulting residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-H2O as the eluent to give 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); amino protons were exchanged in CDCl3. m / z: (ES+), [M+H]+ = 238.0

[0281] (b) 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate methyl ester Pd(dppf)Cl2 (123 mg, 0.170 mmol) was added to a mixture of methyl 3-amino-5-chloro-6-(difluoromethyl)pyrazine-2-carboxylate (400 mg, 1.68 mmol), (1-methylbenzimidazol-4-yl)boronic acid (296 mg, 1.68 mmol), and cesium fluoride (511 mg, 3.37 mmol) in 1,4-dioxane (20 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 16 h. The reaction 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 resulting residue was purified by C18 reverse-phase chromatography using 0-50% MeCN-HO as the eluent to give methyl 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazol-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) methyl 5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate BrettPhos Pd G3 (27 mg, 0.030 mmol) was added to a suspension of methyl 3-amino-5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (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) under nitrogen. The resulting mixture was stirred at 100° C. for 16 hours. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-6% MeOH-DCM as the eluent to give methyl 5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (90 mg, 61%) as a yellow solid. m / z: (ES+), [M+H]+ = 495.1

[0283] (d) 5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (5.0 mL, 35 mmol) was added to methyl 5-(difluoromethyl)-6-(1-methylbenzimidazol-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 was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 30×100 mm SunFire Prep C18 OBD column with mixtures of MeCN-HO of decreasing polarity as eluent and 0.1% formic acid as modifier to give 5-(difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (55 mg, 71%) as a yellow solid; H NMR (300 MHz, DMSO-d) 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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-[(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate methyl ester (4-Methoxyphenyl)methanol (3.42 ml, 24.8 mmol) was added to a suspension of methyl 3-amino-5,6-dichloro-pyrazine-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 3-amino-6-chloro-5-[(4-methoxyphenyl)methoxy]pyrazine-2-carboxylate (2.3 g, 32%) as a yellow solid; 1H NMR (400 MHz, 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) methyl 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate PdCl(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-methylbenzimidazol-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxylate (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) methyl 5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate Brettphos Pd G3 (0.389 g, 0.430 mmol) was added to a suspension of methyl 3-amino-5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-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 was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl ester Methyl 5-[(4-methoxyphenyl)methoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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 h. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 5-hydroxy-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.10 g, 77%) as a brown solid; H 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) methyl 5-chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate Phosphoryl chloride (5.00 mL, 53.7 mmol) was added to methyl 5-hydroxy-6-(1-methylbenzimidazol-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 was then concentrated. The resulting residue was redissolved in EtOAc and washed successively with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel chromatography using 0-20% MeOH-DCM as the eluent to give methyl 5-chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (10 mL, 70 mmol) was added to methyl 5-chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (200 mg, 0.42 mmol). The resulting suspension was stirred at 25 °C for 1 h. The reaction 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-HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 5-chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (17 mg, 8.8%) as an orange solid; H NMR (400 MHz, DMSO-d) 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-methylbenzimidazol-4-yl)-5-[(1-methylpyrazol-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] mCPBA (63 mg, 0.27 mmol) in DCM (2.1 mL) was added dropwise to a solution of 6-(1-methylbenzimidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (50 mg, 0.11 mmol) in DCM (2.1 mL) at −5° C. The resulting mixture was stirred at room temperature for 5 minutes. The reaction was then concentrated. The resulting residue was redissolved in NMP (2 mL). 1-Methylpyrazol-4-amine (31 mg, 0.32 mmol) was added. The resulting mixture was stirred at 150° C. for 3 hours. The reaction was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 19 mm x 100 mm Xbridge C18 column with 20-50% MeCN-HO as eluent and 0.2% ammonium hydroxide as eluent to give a bright yellow solid. This material was suspended in MeOH (2 mL) and sonicated for 30 minutes. The resulting suspension was filtered to give 6-(1-methylbenzimidazol-4-yl)-5-[(1-methylpyrazol-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-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate methyl ester Sodium hydride (397 mg, 9.92 mmol) 60 wt% in mineral oil was added to a solution of pyridin-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-dichloro-pyrazine-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 was then concentrated. The resulting residue was triturated in water, filtered, dried under air, and then added to the mixture under vacuum. The resulting solid was then filtered and air-dried to give methyl 3-amino-6-chloro-5-(2-pyridylamino)pyrazine-2-carboxylate (2.20 g, 95% yield) 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 ester Sodium nitrite (154 mg, 2.24 mmol) was added in small portions 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) was added at −10° C. The reaction was then stirred at 25° C. for 1 hour. The reaction was then quenched with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give methyl 6-chloro-3-fluoro-5-(2-pyridylamino)pyrazine-2-carboxylate (0.420 g, 80% yield) as an orange solid. m / z: (ES−), [MH]− = 281.3

[0293] (c) 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxylate methyl ester DIPEA (234 μL, 1.34 mmol) was added to a solution of methyl 6-chloro-3-fluoro-5-(2-pyridylamino)pyrazine-2-carboxylate (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 was then diluted with water. The resulting precipitate was collected by filtration and air-dried to give methyl 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxylate (0.280 g, 95%) as a brown solid. m / z: (ES−), [MH]− = 439.3

[0294] (d) 6-chloro-3-(4-morpholinoanilino)-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 was then concentrated to give 6-chloro-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide as a brown solid (165 mg, 74% yield).

[0295] (e) 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide PdCl(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 combined in a microwave vial, evacuated, and backfilled with nitrogen three times. Dioxane (1.55 mL) and water (0.39 mL) were added. The resulting mixture was stirred at 100 °C for 12 hours. The reaction was then concentrated. The resulting residue was purified by preparative HPLC using 30-70% MeCN-HO as the eluent and 0.2% ammonium hydroxide as the modifier to give 6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide (50 mg, 25%) as a pale yellow solid; H NMR (400 MHz, DMSO-d) 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]pyridin-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 ester Methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate (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 sparged with nitrogen for 5 minutes. DME (13.6 mL) was then 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 the cooling fan on for 16 hours. The reaction was then concentrated. The resulting residue was purified by flash silica gel chromatography using 0–30% EtOAc-hexane as the eluent to give 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 displaced in chloroform-d; m / z: (ES+), [M+H]+ = 244.1.

[0297] (b) methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxylate DMF (2.4 mL) was added to a mixture of bis(pinacolato)diboron (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-methyl-imidazo[4,5-c]pyridine (100 mg, 0.47 mmol). The resulting suspension was sparged with nitrogen for 5 minutes and stirred at 80 °C for 16 hours, followed by stirring at 100 °C for 24 hours. The reaction was then cooled to room temperature and allowed to stand.

[0298] Sodium nitrite (37 mg, 0.54 mmol) was dissolved in HF *Methyl 3-amino-6-chloro-5-(oxetan-3-yl)pyrazine-2-carboxylate (120 mg, 0.49 mmol) in pyridine (5.30 mL, 155 mmol) was added at 0° C. The resulting mixture was warmed to room temperature and stirred for 1 hour. The reaction was then poured into 75 mL of water and extracted three times with DCM (20 mL each). The combined organic layers were 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 was then concentrated. Pd(dppf)Cl2 in DCM (24 mg, 0.030 mmol) and cesium fluoride (90 mg, 0.59 mmol) were added to the resulting residue. The boronation mixture was added. The resulting suspension was sparged with nitrogen for 5 minutes and then stirred at 100°C for 2 hours. The reaction was then concentrated onto celite. The resulting material was purified by silica gel chromatography using 0-10% MeOH-DCM containing 0-1% ammonia as the eluent to give methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxylate (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]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-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]pyridin-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 was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 19 mm × 250 mm, XSelect CSH Prep C18 OBD column with mixtures of MeCN-HO of decreasing polarity as eluent and 0.2% ammonium hydroxide as modifier to give 6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) Ethyl 3-amino-6-chloro-5-ethoxy-pyrazine-2-carboxylate 21% sodium ethoxide in ethanol (3.03 mL, 8.11 mmol) was added to a mixture of methyl 3-amino-5,6-dichloro-pyrazine-2-carboxylate (1.20 g, 5.40 mmol) in absolute ethanol (25 mL). The resulting mixture was stirred at 80 °C for 3 hours. The reaction was then concentrated. The resulting residue was treated with water and filtered. The solid was collected, washed with water, and dried to give ethyl 3-amino-6-chloro-5-ethoxy-pyrazine-2-carboxylate (0.995 g, 75% yield) 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 to a suspension of ethyl 3-amino-6-chloro-5-ethoxy-pyrazine-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) under nitrogen. The resulting mixture was stirred at 40 °C for 3 h. The reaction was then diluted with water and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium bicarbonate and water. The combined organic layer was acidified with 1 N HCl. The precipitate was collected by filtration, washed with water, and dried to give 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxylic acid (0.390 g, 62% yield). H NMR (500 MHz, DMSO-d) 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 extended to 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 was then diluted with saturated aqueous sodium bicarbonate and water. The precipitate was collected by filtration, washed with water, and dried to give 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.366 g, 74% yield) 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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide A mixture of 2-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-1,3,6,2-dioxazaborocane (0.069 g, 0.28 mmol), 6-chloro-5-ethoxy-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.053 g, 0.14 mmol), and PdCl(dppf) (10.3 mg, 0.0100 mmol) in 2 M aqueous potassium phosphate (0.21 mL, 0.42 mmol) and 1,4-dioxane (1.5 mL) was purged with nitrogen. The reaction mixture was stirred at 100 °C in a microwave reactor for 2 h. The reaction 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-HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 5-ethoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.041 g, 62% yield) 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]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide [ka] (a) Ethyl 3,3-diamino-2-nitroso-prop-2-enoate Ethyl 3-ethoxy-3-imino-propanoate hydrochloride (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 at 25° C. for 3.5 hours. A solution of sodium nitrite (1.94 g, 28.1 mmol) in water (8 mL) was added. 6 N aqueous HCl (15 mL, 90 mmol) was added. The resulting mixture was stirred at 25° C. overnight. The reaction was then concentrated under reduced pressure to one-third volume and neutralized with saturated aqueous sodium bicarbonate. The resulting suspension was filtered, washed with water, and air-dried to give ethyl 3,3-diamino-2-nitroso-prop-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). Poor performance by LCMS.

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

[0306] (c) Ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate and ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate A 20 wt% aqueous solution of 3,3,3-trifluoro-2-oxo-propanal (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 was basified with saturated aqueous sodium bicarbonate. The resulting suspension was filtered, washed with water, and air-dried to give a 1:1 mixture of ethyl 3-amino-5-(trifluoromethyl)pyrazine-2-carboxylate and ethyl 3-amino-6-(trifluoromethyl)pyrazine-2-carboxylate (498 mg, 36% yield); 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) Ethyl 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate 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 was stirred at 80° C. for 2 hours. The reaction was then concentrated. The resulting residue was purified twice by silica gel chromatography using 0-20% EtOAc-hexane as the eluent to give ethyl 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate (0.270 g, 45% yield) 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) ethyl 3-amino-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate DMF (2 mL) was added to a mixture of 7-bromo-3-methyl-imidazo[4,5-c]pyridine (115 mg, 0.54 mmol), bis(pinacolato)diboron (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 evacuated and backfilled with nitrogen three times and then stirred at 80° C. for 23 hours. Additional DMF (2 mL) was added. The reaction mixture was evacuated and backfilled with nitrogen three times. The reaction mixture was stirred at 100° C. for 24 hours. The reaction was cooled to room temperature and allowed to stand.

[0309] Ethyl 3-amino-6-bromo-5-(trifluoromethyl)pyrazine-2-carboxylate (121 mg, 0.390 mmol), PdCl(dppf) (28 mg, 0.040 mmol), and cesium fluoride (117 mg, 0.770 mmol) were combined in a microwave vial, which was then evacuated and backfilled with nitrogen three times. The boronation mixture was added via syringe. The resulting mixture was stirred at 100 °C for 2 h. The reaction was then diluted with water. The resulting suspension was filtered, washed with water, and air-dried. The filtrate was treated with saturated aqueous sodium bicarbonate and then extracted with 5:1 DCM / IPA. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resulting residue was combined with the filter cake and purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give ethyl 3-amino-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate (0.042 g, 30%) as a brown gum; 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]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxylic acid A mixture of 4-(4-bromophenyl)morpholine (0.056 g, 0.23 mmol), ethyl 3-amino-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxylate (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 backfilled with nitrogen three times. The resulting mixture was stirred at 100 °C for 4 hours. The reaction was then concentrated. The resulting residue was purified by C18 reverse-phase chromatography using 0-35% MeCN-HO as the eluent and 0.1% TFA as the modifier to give 6-(3-methylimidazo[4,5-c]pyridin-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 broadened and indistinguishable from the baseline; m / z: (ES+), [M+H]+ = 500.3

[0311] (g) 6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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 was then treated with saturated aqueous sodium bicarbonate and extracted with 5:1 DCM / IPA. The organic layer was concentrated. The resulting residue was purified by C18 reverse-phase chromatography using 10–50% MeCN-HO as the eluent and 0.2% ammonium hydroxide as the modifier to give 6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-chloro-3-fluoro-5-methylsulfanyl-pyrazine-2-carboxylate methyl ester Sodium nitrite (3.00 g, 43.5 mmol) was added in small portions 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) at −10° C. The reaction was then stirred at 25° C. for 3 hours. The reaction 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). The combined organics were dried over MgSO4, filtered, and concentrated to give methyl 6-chloro-3-fluoro-5-methylsulfanyl-pyrazine-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 ester DIPEA (4.00 mL, 22.9 mmol) was added to a solution of methyl 6-chloro-3-fluoro-5-methylsulfanyl-pyrazine-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 was allowed to cool to room temperature, then filtered, washed with EtOAc, and dried under vacuum to give 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) methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate 7-Bromo-3-methyl-imidazo[4,5-c]pyridine (1.00 g, 4.72 mmol), bis(pinacolato)diboron (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 combined in a multi-neck flask, which was evacuated and backfilled with nitrogen three times. DMF (15 mL) was added, and the resulting mixture was stirred at 80 °C for 24 h. The reaction was then cooled to room temperature.

[0315] Methyl 6-chloro-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (1.50 g, 3.80 mmol), Pd(dppf)Cl (0.278 g, 0.380 mmol), and cesium fluoride (1.73 g, 11.4 mmol) were combined in a split-neck multi-neck flask, which was evacuated and backfilled with nitrogen three times. The boronation mixture was added via syringe. The resulting mixture and reaction were stirred at 100 °C for 3 h. The reaction was then cooled to room temperature, diluted with water (150 mL), and extracted three times with 3:1 DCM / IPA (50 mL each). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated onto Celite. The resulting material was then purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as the modifier to give methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (6.0 mL, 42 mmol) was added to methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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 was cooled to room temperature, then filtered and washed with MeOH. The resulting ochre solid was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as the modifier to give 6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] A solution of mCPBA (194 mg, 0.790 mmol) in DCM (1 mL) was added to a suspension of 6-(3-methylimidazo[4,5-c]pyridin-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 h. The reaction 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 h. Tetrahydroxydiboron (42 mg, 0.47 mmol) was then added, and the resulting mixture was stirred at 100 °C for 5 min. The reaction was cooled to room temperature, then diluted with water (20 mL) and extracted three times (25 mL each) with 3:1 DCM / IPA. The combined organics were washed with 5% aqueous lithium chloride (10 mL), dried over magnesium sulfate, filtered, and concentrated onto Celite. This material was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent and 0-1% ammonia as the modifier to give 5-[(1-methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] A solution of mCPBA (194 mg, 0.790 mmol) in DCM (1 mL) was added to a suspension of 6-(3-methylimidazo[4,5-c]pyridin-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 was then concentrated to 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 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. The reaction was then diluted with water (40 mL) and extracted three times (25 mL each) with 3:1 DCM / IPA. The combined organics were 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 the modifier to give a red solid. This material was then further purified by preparative HPLC using a 5 micron, 30 mm x 150 mm Xselect CSH column using 25-50% MeCN-HO as the eluent and 0.2% ammonium hydroxide as the modifier to give 5-cyano-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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 to a suspension of 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (153 mg, 0.320 mmol) in DCM (3 mL) at -10°C. The reaction was stirred at 25°C for 90 minutes. The reaction 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 was stirred at 25°C for 30 minutes. The reaction was stirred at 100°C for 1 hour in a Biotage microwave reactor. The reaction was then cooled to room temperature. Sodium bisulfite (0.133 g, 1.28 mmol) was added, and the reaction was stirred at room temperature for 10 minutes. The reaction was then diluted with water (25 mL) and extracted three times (20 mL each) with 3:1 DCM / IPA. The combined organic layers were 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 the modifier to give 39 mg of an orange solid. This material 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-HO as the eluent and 0.1% ammonium hydroxide as the modifier to give 5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) methyl 3-amino-6-chloro-5-(cyclopropylamino)pyrazine-2-carboxylate Cyclopropanamine (1.029 g, 18.02 mmol) was added to a suspension of methyl 3-amino-5,6-dichloro-pyrazine-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 mixture was then concentrated. The resulting residue was treated with water. The resulting suspension was filtered and the solid dried under vacuum to give methyl 3-amino-6-chloro-5-(cyclopropylamino)pyrazine-2-carboxylate (1.10 g, quantitative) 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) methyl 3-amino-5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate

[0322] CataCXium A (17 mg, 0.050 mmol), cataCXium A Pd G3 (34 mg, 0.050 mmol), 7-bromo-3-methyl-imidazo[4,5-c]pyridine (100 mg, 0.47 mmol), potassium acetate (139 mg, 1.41 mmol), and bis(pinacolato)diboron (240 mg, 0.94 mmol) were combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. DMF (3 mL) was added. The resulting mixture was stirred at 80 °C for 20 h. The reaction was then cooled to room temperature and allowed to stand.

[0323] Pd(dppf)Cl (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 combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. The boronation mixture was added via syringe. The resulting mixture was heated at 100 °C for 2 h. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0–70% MeOH-DCM as the eluent to afford methyl 3-amino-5-(cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate (80 mg, 50% yield) as an off-white powder.

[0324] (c) 5-amino-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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 h. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-70% MeOH-DCM as the eluent to give a brown solid. This material was suspended in 7 N methanolic ammonia (510 μL, 3.57 mmol). The resulting suspension was heated at 100 °C for 14 h. The reaction was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 19 mm × 150 mm Xbridge C18 column with 20–50% MeCN-HO as the eluent and 0.2% NH4OH as the modifier to give 5-amino-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate CataCXium A Pd G2 (17 mg, 0.03 mmol) was added to a suspension of bis(pinacolato)diboron (129 mg, 0.510 mmol), methyl 6-bromo-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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) under nitrogen. The resulting mixture was stirred at 80 °C for 16 h. The reaction was then cooled to room temperature and allowed to stand.

[0326] A mixture of cesium fluoride (97 mg, 0.64 mmol), 7-bromo-3-methyl-imidazo[4,5-c]pyridine (54 mg, 0.25 mmol), and PdCl2(dppf) (18.61 mg, 0.03 mmol) was vacuum degassed and filled three times. The boronation mixture was added via syringe. The resulting mixture was stirred at 100 °C for 16 h. The reaction 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 h. The reaction was then concentrated. The resulting residue was purified by silica gel chromatography using 0-10% MeOH-DCM as the eluent to give methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (1.0 mL, 7.0 mmol) was added to a suspension of methyl 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (30 mg, 0.07 mmol) in MeOH (1 mL). The resulting mixture was stirred at 80° C. for 24 hours. The reaction was then concentrated. The resulting residue was purified by preparative HPLC using a 5 micron, 30 mm × 150 mm, Xbridge Shield RP18 OBD column with 12–22% MeCN-HO as the eluent and 0.1% formic acid as the modifier to give 6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (10 mg, 35%) as a yellow solid; H NMR (300 MHz, DMSO-d) 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]pyridin-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 was then filtered and washed with MeOH. The filter cake was dried under vacuum to give 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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7-Bromo-3-methyl-imidazo[4,5-c]pyridine (100 mg, 0.47 mmol), bis(pinacolato)diboron (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 combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. DMF (2.3 mL) was added, and the resulting mixture was stirred at 80 °C for 24 h. 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)Cl dichloromethane adduct (31 mg, 0.040 mmol), and cesium fluoride (172 mg, 1.13 mmol) were combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. The boronation reaction mixture was added to the vial via syringe. The resulting mixture was stirred at 100 °C for 4 h. The reaction was cooled to room temperature, diluted with water (40 mL), and filtered. The filter cake was purified by reverse-phase chromatography using 0–50% MeCN-HO as the eluent and 0.1% trifluoroacetic acid as the modifier to give an orange residue. The aqueous filtrate was diluted with saturated aqueous sodium bicarbonate (20 mL) and extracted three times (30 mL each) with 3:1 DCM / IPA. The combined organic layers were concentrated. The resulting residue was purified by reverse-phase chromatography using 0–50% MeCN-HO as the eluent and 0.1% trifluoroacetic acid as the modifier to give an orange residue. The orange residue from the two columns was dissolved in water (20 mL), basified with saturated aqueous sodium bicarbonate (10 mL), and extracted three times (20 mL each) with DCM. The combined organics were dried over magnesium sulfate, filtered, and concentrated to give 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-chloro-5-cyclopropyl-3-fluoro-pyrazine-2-carboxylate methyl ester Sodium nitrite (68.4 mg, 0.990 mmol) was added 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) at 0° C. The reaction was stirred at 25° C. for 30 minutes. The reaction 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 give methyl 6-chloro-5-cyclopropyl-3-fluoro-pyrazine-2-carboxylate (0.233 g, quantitative) 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 ester DIPEA (0.180 mL, 1.03 mmol) was added to a solution of methyl 6-chloro-5-cyclopropyl-3-fluoro-pyrazine-2-carboxylate (0.217 g, 0.940 mmol) and 4-morpholinoaniline (0.176 g, 0.990 mmol) in DMF (3 mL). The reaction was stirred at 100° C. for 40 minutes. The reaction was then cooled to room temperature, diluted with water (80 mL), and extracted three times with EtOAc (25 mL each). The combined organic layers were washed once with 5% aqueous lithium chloride solution (15 mL), then dried over sodium sulfate, filtered, and concentrated. The resulting red solid was purified by silica gel chromatography using 0-80% EtOAc-hexane as the eluent to give 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) methyl 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate Methyl 6-chloro-5-cyclopropyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (107 mg, 0.270 mmol), 2-(3-methylimidazo[4,5-c]pyridin-7-yl)-1,3,6,2-dioxazaborocane (99 mg, 82 wt%, 0.33 mmol), Pd(dppf)Cl (23 mg, 0.030 mmol), and CsF (125 mg, 0.820 mmol) were combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. MeOH (1.7 mL) was added, and the resulting mixture was stirred at 100 °C for 2 h in a Biotage microwave reactor. The reaction 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 the modifier to give methyl 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (2.0 mL, 14 mmol) was added to methyl 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (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 was stirred at 100° C. for 1 hour in a Biotage microvial. The reaction was then filtered and washed with methanol to give 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 3-amino-6-bromo-pyrazine-2-carboxylic acid methyl ester 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 was then concentrated. The resulting red residue was triturated in isopropanol (100 mL) and filtered to give a red solid. The filtrate was concentrated to give a red solid, which was dissolved in DCM (60 mL) and washed once with saturated aqueous sodium thiosulfate (50 mL) and three times (25 mL each) with saturated aqueous sodium bicarbonate. The organic layer was then dried over magnesium sulfate, filtered, and concentrated to give a red solid, which was divided into two portions. One portion was purified by silica gel chromatography using 0–40% EtOAc-hexane as the eluent to give 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 copious amounts of MeOH to give 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 ester 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 difluoromethanesulfinate (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 difluoromethanesulfinate (2.55 g, 8.62 mmol) and 70 wt% aqueous tert-butyl hydroperoxide (1.80 mL, 13.1 mmol) were added, and the reaction was stirred at 25° C. for 2 days. The reaction was then quenched with saturated aqueous sodium bicarbonate (50 mL) and diluted with DCM (50 mL) and saturated aqueous ammonium chloride (20 mL). The layers were separated, and the aqueous layer was extracted twice with DCM (20 mL each). The combined organics were dried over sodium sulfate, filtered, and concentrated. The resulting pale yellow solid was purified by silica gel chromatography using 0–35% EtOAc-hexane as eluent to give methyl 3-amino-6-bromo-5-(difluoromethyl)pyrazine-2-carboxylate (0.16 g, 13%) as a pale yellow solid; 1H NMR (500 MHz, DMSO-d6) 3.87 (3H, s), 7.03 (1H, t), 7.34–8.32 (2H, br s); m / z: (ES+), [M+H]+ = 282.0

[0337] (c) 6-bromo-5-(difluoromethyl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl ester Sodium nitrite (63 mg, 0.91 mmol) was added to a solution of methyl 3-amino-6-bromo-5-(difluoromethyl)pyrazine-2-carboxylate (245 mg, 0.870 mmol) in HF-pyridine (3.0 mL, 87 mmol) at 0° C. The reaction was stirred at 25° C. for 15 minutes. The reaction was then diluted with DCM (5 mL) and quenched with water (20 mL). The layers were separated, and the aqueous layer was extracted twice with DCM (10 mL each). The combined organics were dried over sodium sulfate, filtered, and concentrated to give a pale yellow oil. 4-Morpholinoaniline (0.163 g, 0.910 mmol) was added to the oil, and the resulting mixture was dissolved in DMF (2 mL). To this reaction mixture was added DIPEA (0.17 mL, 0.97 mmol). The resulting solution was stirred at 100° C. for 30 minutes. The reaction was allowed to cool to room temperature and then diluted with water (70 mL). The resulting suspension was filtered. The filter cake was dried under vacuum to give methyl 6-bromo-5-(difluoromethyl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.337 g, 87%) as a brick-red solid; 1H NMR (500 MHz, DMSO-d6) 3.00-3.13 (4H, m), 3.65-3.77 (4H, m), 3.94 (3H, s), 6.95 (2H, d), 7.08 (1H, t), 7.53 (2H, d), 9.89 (1H, s); m / z: (ES+), [M+H]+ = 443.1

[0338] (d) methyl 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate 7-Bromo-3-methyl-imidazo[4,5-c]pyridine (176 mg, 0.830 mmol), cataCXium A Pd G3 (60 mg, 0.08 mmol), cataCXium A (30 mg, 0.08 mmol), bis(pinacolato)diboron (527 mg, 2.08 mmol), and potassium acetate (244 mg, 2.49 mmol) were combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. DMF (3.5 mL) was added, and the reaction mixture was stirred at 80 °C for 24 h. The reaction was then cooled to room temperature and allowed to stand.

[0339] Separately, methyl 6-bromo-5-(difluoromethyl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (337 mg, 0.760 mmol), Pd(dppf)Cl (61 mg, 0.081 mmol), and CsF (378 mg, 2.49 mmol) were combined in a microwave vial, which was evacuated and backfilled with nitrogen three times. The reaction mixture from the boronation step was added via syringe. The resulting mixture was stirred at 100 °C for 4 h. The reaction was then cooled to room temperature, diluted with water (30 mL), and extracted three times with 3:1 chloroform / isopropanol (30 mL each). The combined organic layers were washed once with 5% aqueous lithium chloride solution, then dried over sodium sulfate, filtered, and concentrated. The resulting red residue was purified by silica gel chromatography using 0-5% methanol-DCM as the eluent and 0-0.5% ammonia as the modifier to give methyl 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (0.12 g, 29%) as a dark red solid; 1H NMR(500MHz,DMSO-d6)3.07-3.13(4H,m),3.72-3.77(4H,m),3.93(3H,s),4.01(3H,s),6.90 -7.14(3H,m),7.66(2H,d),8.48(2H,d),9.08(1H,s),9.99(1H,s);m / z:(ES+),[M+H]+=496.1

[0340] (e) 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (2.00 mL, 14.0 mmol) was added to methyl 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxylate (120 mg, 0.24 mmol), and the resulting suspension was stirred at 100° C. for 1 hour in a Biotage microwave reactor. The resulting suspension was filtered and washed with a small amount of methanol to give 5-(difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.060 g, 52%) as an orange solid; 1H NMR (500 MHz, DMSO-d6) 3.00-3.18 (4H, m), 3.67-3.83 (4H, m), 4.00 (3H, s), 6.99 (2H, d), 7.11 (1H, t), 7.67 (2H, d), 8.10 (1H, br s), 8.40 (1H, br s),8.50(1H,s),8.69(1H,s),9.07(1H,s),11.24(1H,s);m / z:(ES+),[M+H]+=481.3

[0341] Example 43 5-Methyl-6-(1-methylimidazo[4,5-d]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 6-Bromo-3-fluoro-5-methyl-pyrazine-2-carboxylate methyl ester

[0342] Sodium nitrite (1.750 g, 25.36 mmol) was dissolved in pyridine at -10°C. *Methyl 3-amino-6-bromo-5-methyl-pyrazine-2-carboxylate (1.56 g, 6.34 mmol) in HF (20.0 mL, 583 mmol) was added portionwise. The resulting mixture was stirred at -10 °C for 2.5 hours. The reaction was then neutralized with saturated aqueous sodium bicarbonate (450 mL) and extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give methyl 6-bromo-3-fluoro-5-methyl-pyrazine-2-carboxylate (1.400 g, 89%). 1H NMR (500 MHz, DMSO-d6) δ 2.63 (3H, s), 3.90 (3H, s). m / z: (ES+), [M+2+H] = 251.0

[0343] (b) 6-bromo-5-methyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate methyl ester

[0344] DIPEA (0.926 mL, 5.30 mmol) was added to 4-morpholinoaniline (1.01 g, 5.64 mmol) and methyl 6-bromo-3-fluoro-5-methyl-pyrazine-2-carboxylate (1.32 g, 5.30 mmol) in DMF (10 mL). The resulting mixture was stirred at 110° C. for 1 hour in a Biotage microwave reactor. The reaction mixture was concentrated and used directly in the next step, assuming a 100% yield.

[0345] (c) 6-bromo-5-methyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide 7N methanolic ammonia (20 mL, 140 mmol) was added to methyl 6-bromo-5-methyl-3-(4-morpholinoanilino)pyrazine-2-carboxylate (2.29 g, 5.63 mmol). The resulting suspension was stirred at 25° C. for 3 days. The reaction was then concentrated. The resulting residue was suspended in DCM (10 mL) and 7N methanolic ammonia (40 mL, 280 mmol) was added. The resulting mixture was stirred at 25° C. for 16 hours. The resulting suspension was filtered, washed with MeOH and water, and dried under vacuum to give 6-bromo-5-methyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (1.92 g, 87%) as an orange solid; 1H NMR (500 MHz, DMSO-d6) 2.50 (3H, s), 2.99-3.14 (4H, m), 3.66-3.80 (4H, m), 6.85-6.99 (2H, m), 7.42-7.54 (2H, m), 7.89 (1H, s), 8.11 (1H, s), 10.93 (1H, s). m / z: (ES+), [M+2+H] = 394.1

[0346] (d) 3-Methyl-6H-imidazo[4,5-d]pyridazin-7-one Hydrazine hydrate (0.267 g, 3.52 mmol) was added to a solution of ethyl 5-formyl-1-methyl-imidazole-4-carboxylate (0.534 g, 2.93 mmol) in ethanol (20 mL). The resulting mixture was stirred at 25° C. for 90 minutes. Acetic acid (0.839 mL, 14.7 mmol) was then added. The resulting mixture was stirred at 100° C. for 19 hours. The reaction mixture was then concentrated. The resulting residue was suspended in EtOH, filtered, washed with EtOH, and dried under vacuum to give 3-methyl-6H-imidazo[4,5-d]pyridazin-7-one (0.355 g, 81%) as a white solid; 1H NMR (500 MHz, DMSO-d6) 3.88 (3H, s), 8.23 ​​(1H, s), 8.45 (1H, s), 12.63 (1H, br s). m / z: (ES+), [M+H3O]+ = 169.2

[0347] (e) 4-chloro-1-methyl-imidazo[4,5-d]pyridazine Phosphoryl chloride (6.00 mL, 64.4 mmol) was added to 1-methyl-1,5-dihydro-4H-imidazo[4,5-d]pyridazin-4-one (0.210 g, 1.40 mmol). The reaction mixture was stirred at 100° C. for 5.5 hours. The reaction mixture was then concentrated. The residue was treated with ice water, basified with saturated aqueous sodium bicarbonate, and extracted with 5:1 DCM / IPA. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 4-chloro-1-methyl-imidazo[4,5-d]pyridazine (0.208 g, 88%) as a yellow solid; 1H NMR (500 MHz, DMSO-d6) 4.00 (3H, s), 8.68 (1H, s), 9.71 (1H, s); m / z: (ES+), [M+H]+ = 169.1

[0348] (f) 5-methyl-6-(1-methylimidazo[4,5-d]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide 1,4-Dioxane (1.5 mL) was added to a mixture of bis(pinacolato)diboron (0.040 g, 0.16 mmol), 6-bromo-5-methyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.052 g, 0.13 mmol), PdCl(dppf) (9.70 mg, 0.01 mmol), and potassium acetate (0.026 g, 0.27 mmol). The resulting mixture was degassed under vacuum, filled with nitrogen, and then stirred at 80 °C for 3 h. The reaction was cooled to room temperature and allowed to stand.

[0349] MeOH (1 mL) was added to a mixture of 4-chloro-1-methyl-imidazo[4,5-d]pyridazine (0.044 g, 0.26 mmol), PdCl(dppf) (9.5 mg, 0.010 mmol), and potassium phosphate (0.055 g, 0.26 mmol). The boronation mixture was added via syringe. The resulting mixture was degassed under vacuum, filled with nitrogen, and then stirred at 100 °C for 4 h. The reaction mixture was diluted with water, and the resulting suspension was filtered. The filtrate was extracted with DCM. The organic layer was concentrated. The resulting residue was combined with the filter cake and purified by silica gel chromatography using 0-15% MeOH-DCM to give a yellow solid. This material was further purified by reverse phase chromatography, C18, using 0-20% MeCN-HO as eluent and 0.1% formic acid as modifier to give 5-methyl-6-(1-methylimidazo[4,5-d]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide (0.018 g, 31%) as a yellow solid; 1H NMR(500MHz,DMSO-d6)2.51(3H,s),3.04-3.12(4H,m),3.69-3.78(4H,m),4.03(3H,s),6.98(2H,d),7. 64(2H,d),7.93(1H,s),8.05(1H,s),8.62(1H,s),9.73(1H,s),11.08(1H,s).m / z:(ES+),[M+H]+=446.3

[0350] Example 44 5-Methyl-6-(7-methylimidazo[4,5-c]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide [ka] (a) 5-chloro-N3-methyl-pyridazine-3,4-diamine A 40 wt% aqueous solution of methanamine (10.0 mL, 116 mmol) was added to 3,5-dichloropyridazin-4-amine (0.525 g, 3.20 mmol). The resulting mixture was stirred at 100 °C for 2 hours in a Biotage microwave reactor. The reaction was then concentrated to half of its original volume, diluted with water, filtered, washed with water, and dried under vacuum to give 5-chloro-N3-methyl-pyridazine-3,4-diamine (0.360 g, 71%) as a white solid; 1H NMR (500 MHz, DMSO-d6) 2.91 (3H, d), 6.09 (2H, br s), 6.23 (1H, br d), 8.12 (1H, s); m / z: (ES+), [M+H] = 159.0

[0351] (b) 4-chloro-7-methyl-imidazo[4,5-c]pyridazine Triethyl orthoformate (10 mL, 60 mmol) was added to 5-chloro-N3-methyl-pyridazine-3,4-diamine (0.333 g, 2.10 mmol), and the resulting mixture was stirred at 150° C. for 90 minutes.

[0352] The reaction was then concentrated. The resulting residue was treated with saturated aqueous sodium bicarbonate and then extracted three times with 5:1 DCM / IPA. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated to give 4-chloro-7-methyl-imidazo[4,5-c]pyridazine (0.310 g, 88%) as a beige solid; 1H NMR (500 MHz, DMSO-d6) 4.01 (3H, s)...

Claims

1. The compound of formula (I) 【Chemical Formula 1】 [wherein,[[]]END]] X １ , X ２ and X ３ are 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 alkyl (wherein said C １～３ alkyl is substituted by 0, 1, 2 or 3 F); R ２ is H, NH ２ or C １～２ alkyl (wherein the C １～２ alkyl is substituted by 0, 1, 2 or 3 F; R ３ is H, R ６ , OR ６ , N.H.R. ６ , Cl, CN, CCH, NH ２ , S.C.H. ３ , cyclopropyl, cyclobutyl, NH((5-6 membered) heteroaryl containing 1 or 2 N), NH(C １～２ alkyl)N(CH ３ ) ２ oxetan-3-yl, NH-cyclopropyl, and O-cyclopropyl; R ４ is selected from aryl or heteroaryl, wherein said aryl or heteroaryl is independently selected from 0, 1, 2, 3 or 4 substituents selected from F, Cl and R ６ , 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 is substituted 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 C １～２ alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F, CN, NH ２ and OC １～２ alkyl, and said OC １～２ alkyl is substituted by 0, 1, 2 or 3 substituents independently selected from F and Cl)); R ６ is C １～４ alkyl (wherein said C １～４ alkyl is substituted by 0, 1, 2 or 3 F, O(C １～２ alkyl) as well as OH, CN, N(CH ３ ), ２ and is substituted by 0 or 1 substituent selected from (4-5 membered) heterocycloalkyl containing 1 O); R ７ is NH-cyclopropyl, [dimethyl(oxo)-λ ６ -sulfanilylidene]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 、morpholin-4-sulfonyl, 4-methylpiperazine-sulfonyl, morpholinyl, CCCCH ３ 、cyclopropyl (wherein said cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO ２ CH ３ ), cyclobutyl (wherein said cyclobutyl is substituted with 0 or 1 OH) and imidazolyl (wherein said imidazolyl is substituted with 0 or 1 R １１ ) and is selected from; R ８ is SO ２ CH ３ or heterocycloalkyl, wherein said heterocycloalkyl is selected from F, Cl, R ６ and OR ６ and 0, 1, 2, 3 or 4 substituents independently selected from: 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: 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 is H and C １～２ alkyl (wherein the C １～２ Alkyl is F, CN, NH ２ and O.C. １～２ substituted by 0, 1, 2 or 3 substituents independently selected from alkyl; 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 said C １～３ alkyl is substituted with 0, 1, 2 or 3 F and 0 or 1 cyclopropyl)] or a pharmaceutically acceptable salt thereof.

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

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

4. Formula (IA) 【Chemical 2】 [wherein,[[]]END]] X １ 、 X ２ and X ３ are independently selected from CR ５ ; R ５ is H) The compound according to claim 1 of or a pharmaceutically acceptable salt thereof.

5. R ３ is selected from R ６ , NHR ６ and cyclopropyl; R ６ is C １～４ alkyl (wherein said C １～４ alkyl is substituted by 0, 1, 2 or 3 F); R ４ is selected from phenyl (wherein said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R ６ , and a substituent selected from morpholinyl, and said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R ６ and OR ６ , and 0 or 1 substituent selected from cyclopropyl, C(O)CH ３ and C(O)N(CH ３ ). ２ ). The compound according to claim 4,[[]]END]] or a pharmaceutically acceptable salt thereof.

6. R ３ is selected from R ６ , NHR ６ and cyclopropyl; R ６ is C １～４ alkyl (wherein said C １～４ is substituted by 0, 1, 2 or 3 F); R ４ is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R ６ and 0, 1, or 2 substituents independently selected from ７ substituted by 0 or 1 substituent selected from: R ７ is selected from cyclopropyl, wherein the cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO ２ CH ３ and is substituted with 0 or 1 substituent selected from The compound according to claim 4,[[]]END]] or a pharmaceutically acceptable salt thereof.

7. Formula (IB) 【Chemical Formula 3】 [wherein,[[]]END]] X １ and X ３ are independently selected from CR ５ ; X ２ is N; R ５ is H) The compound according to claim 1 of or a pharmaceutically acceptable salt thereof.

8. R ３ is selected from R ６ , NHR ６ and cyclopropyl; R ６ is C １～４ alkyl (wherein the C １～４ is substituted by 0, 1, 2 or 3 F; R ４ is selected from phenyl, where said phenyl is substituted by 0 or 1 substituent selected from F, Cl and R ６ and a substituent selected from morpholinyl, where said morpholinyl is substituted by 0, 1 or 2 substituents independently selected from F, Cl, R ６ and OR ６ and 0 or 1 substituent selected from cyclopropyl, C(O)CH ３ and C(O)N(CH ３ ) ２ and is substituted by 0 or 1 substituent selected from The compound according to claim 7,[[]]END]] or a pharmaceutically acceptable salt thereof.

9. R ３ is selected from R ６ , NHR ６ and cyclopropyl; R ６ is C １～４ alkyl (wherein said C １～４ is substituted by 0, 1, 2 or 3 F); R ４ is selected from (5-membered) heteroaryl, wherein said (5-membered) heteroaryl is selected from F, Cl and R ６ and is independently substituted with 0, 1 or 2 substituents selected from, and R ７ and is substituted with 0 or 1 substituent selected from); R ７ is selected from cyclopropyl, wherein said cyclopropyl is substituted with 0 or 1 substituent selected from F, CN, OH or SO ２ CH ３ ). The compound according to claim 7,[[]]END]] or a pharmaceutically acceptable salt thereof.

10. Formula (IC) 【Chemical Formula 4】 [wherein,[[]]END]] X １ and X ３ is independent, CR ５ Selected from: X ２ is N; R ５ is H; R １ is C １～３ alkyl (wherein the C １～３ The alkyl is substituted by 0, 1, 2 or 3 F. The compound according to claim 1 of or a pharmaceutically acceptable salt thereof.

11. R １ is C １～３ alkyl (wherein said C １～３ is substituted by 0, 1, 2 or 3 F); or a pharmaceutically acceptable salt thereof:[[]]END]] R ３ is R ６ , N.H.R. ６ and cyclopropyl; R ６ is C １～４ alkyl (wherein said C １～４ is substituted by 0, 1, 2 or 3 Fs) The compound according to claim 10,[[]]END]] or a pharmaceutically acceptable salt thereof.

12. R ３ is cyclopropyl; R ６ is C １～４ alkyl (wherein the C １～４ The alkyl is substituted by 0, 1, 2 or 3 F. The compound according to claim 10,[[]]END]] or a pharmaceutically acceptable salt thereof.

13. 6-(1-Methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-Methyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-Methoxy-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-[2-(Dimethylamino)ethoxy]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-Cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-Methyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-(Methylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide,[[]]END]] 6-(1-Methyl-1H-benzo[d]imidazol-4-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Ethylamino)-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Cyclopropylamino)-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Amino-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-Hydroxypropyl]amino]-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-Hydroxypropyl]amino]-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-Methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)-5-(2,2,2-trifluoroethylamino)pyrazine-2-carboxamide, 5-(2,2-Difluoroethylamino)-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[2-(Dimethylamino)ethylamino]-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(2-Hydroxyethylamino)-6-(1-methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-Methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)-5-(prop-2-yn-1-ylamino)pyrazine-2-carboxamide, 6-(1-Methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1R,2R)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 6-(1-Methyl-1H-benzo[d]imidazol-4-yl)-3-(4-morpholinoanilino)-5-[[rel-(1S,2S)-2-methylcyclopropyl]amino]pyrazine-2-carboxamide, 5-(Cyanomethylamino)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2R)-2-Fluoropropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[[(2S)-2-Fluoropropyl]amino]-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-Methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-ylmethylamino)pyrazine-2-carboxamide, 5-Ethynyl-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Difluoromethyl)-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Chloro-6-(1-methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-Methylbenzimidazol-4-yl)-5-[(1-methylpyrazol-4-yl)amino]-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(1-Methylbenzimidazol-4-yl)-3-(4-morpholinoanilino)-5-(2-pyridylamino)pyrazine-2-carboxamide, 6-(3-Methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(oxetan-3-yl)pyrazine-2-carboxamide, 5-Ethoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-Methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)-5-(trifluoromethyl)pyrazine-2-carboxamide, 6-(3-Methylimidazo[4,5-c]pyridin-7-yl)-5-methylsulfanyl-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-[(1-Methylcyclopropyl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyano-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Cyclopropylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Amino-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-Methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 5-(Methylamino)-6-(7-methylimidazo[4,5-c]pyridazin-4-yl)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-Ethylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3-Cyclopropylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-[3-(Difluoromethyl)imidazo[4,5-c]pyridin-7-yl]-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-Chloro-1-methyl-benzimidazol-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(7-Cyano-1-methyl-benzimidazol-4-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 6-(3,4-Dimethylimidazo[4,5-c]pyridin-7-yl)-5-(methylamino)-3-(4-morpholinoanilino)pyrazine-2-carboxamide, 3-(2-Fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2,3-Difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-Fluoro-3-methyl-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-Chloro-2-fluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3,5-Difluoro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-Chloro-4-morpholino-anilino)-5-(methylamino)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-(3-Chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-Cyano-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(3-Methoxy-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[3-(Difluoromethyl)-4-morpholino-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-Chloro-4-morpholino-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(5-methyl-6-morpholino-3-pyridyl)amino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-[[5-methyl-6-[(2S)-2-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[6-[(3R)-3-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 3-[(5-cyano-6-morpholino-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-((4-(1,4-oxazepan-4-yl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-5-(methylamino)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-6-[(3R)-3-methylmorpholin-4-yl]-3-pyridyl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(difluoromethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(4-isopropoxyanilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, [4-[[3-carbamoyl-6-(methylamino)-5-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazin-2-yl]amino]phenyl]methanesulfonate, 3-[4-(2-methoxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethoxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(2-hydroxyethoxy)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(2-morpholinoethoxy)anilino]pyrazine-2-carboxamide, 3-(4-Aminoanilino)-5-(methylamino)-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[2-Methoxyethyl(methyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[Bis(2-methoxyethyl)amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(2-methyl-4-pyridyl)amino]pyrazine-2-carboxamide formate, 3-[(2-Methoxy-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-Methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(7-methylimidazo[4,5-c]pyridazin-4-yl)pyrazine-2-carboxamide hydrochloride, 3-[(2,6-Dimethyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(2,6-dimethyl-4-pyridyl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-Methoxy-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[2-(2-Methoxyethoxy)-6-methyl-4-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-Cyano-6-methyl-4-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(1,5-Dimethyl-6-oxo-3-pyridyl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(difluoromethyl)-6-oxo-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-5-(trifluoromethyl)pyrazine-2-carboxamide, 3-[4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]-3,5-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide formate, 5-(methylamino)-3-[4-[(1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]anilino]-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[2-(dimethylamino)ethyl-methyl-amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide bis-formate, 3-[4-[3-(dimethylamino)azetidin-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide bis-formate, 3-[3-cyano-4-[(3S,5R)-3,5-dimethylpiperazin-1-yl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[2,3-difluoro-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[6-(4-isopropylpiperazin-1-yl)-5-methyl-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[5-methoxy-6-(4-methylpiperazin-1-yl)-3-pyridyl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(6-methyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(6-ethyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(6-Isopropyl-5,7-dihydropyrrolo[3,4-b]pyridin-3-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[(Dimethylamino)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(pyrrolidin-1-ylmethyl)anilino]pyrazine-2-carboxamide bis-formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)-3-[4-[rel-(1R)-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1S)-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1R)-1-morpholinoethyl]anilino]pyrazine-2-carboxamide formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[rel-(1S)-1-morpholinoethyl]anilino]pyrazine-2-carboxamide formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[1-methyl-1-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methyl-1-morpholino-ethyl)anilino]pyrazine-2-carboxamide, (R)-3-((4-(((3-fluoropyrrolidin-1-yl)methyl)phenyl)amino)-6-(3-methyl-3H-imidazo[4,5-c]pyridin-7-yl)-5-(methylamino)pyrazine-2-carboxylate, 3-[4-[[(3S)-3-fluoropyrrolidin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate, 3-[4-[(3,3-difluoropyrrolidin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate, 3-[4-[[(3S)-3,4-dimethylpiperazin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide tris-formate, 3-[4-[[(3R)-3,4-dimethylpiperazin-1-yl]methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[6-(morpholinomethyl)-3-pyridyl]amino]pyrazine-2-carboxylate, 3-[2-fluoro-4-[(4-methylpiperazin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[3-chloro-4-[(4-methylpiperazin-1-yl)methyl]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxylate, 3-[2-Fluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[2,3-Difluoro-4-(morpholinomethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-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]pyridin-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]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide formate, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(2-morpholinoethyl)anilino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[2-(4-methylpiperazin-1-yl)ethyl]anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(pyrrolidin-1-ylmethyl)anilino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-Methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(Difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(4-methylpiperazin-1-yl)methyl]anilino]pyrazine-2-carboxamide, 5-(Difluoromethyl)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(morpholinomethyl)anilino]pyrazine-2-carboxamide, 3-[2-Fluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[2,3-Difluoro-4-(morpholinomethyl)anilino]-5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-Methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(3S)-4-methylmorpholin-3-yl]anilino]pyrazine-2-carboxamide, 5-Methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(3R)-4-methylmorpholin-3-yl]anilino]pyrazine-2-carboxamide, 5-Methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(2R)-4-methylmorpholin-2-yl]anilino]pyrazine-2-carboxamide, 5-Methyl-6-(1-methylbenzimidazol-4-yl)-3-[4-[rel-(2S)-4-methylmorpholin-2-yl]anilino]pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-[(1-methyl-4-piperidyl)oxy]anilino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-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]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[(1-isopropyl-4-piperidyl)oxy]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-[[(2S,4R)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-hydroxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2R,4S)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 3-[4-[[(2S,4R)-4-methoxy-1-methyl-pyrrolidin-2-yl]methoxy]anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[3-(4-methylpiperazin-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[3-(1-methyl-4-piperidyl)anilino]pyrazine-2-carboxamide formate, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(4-methylimidazol-1-yl)anilino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-([1,2,4]triazolo[4,3-a]pyridin-6-ylamino)pyrazine-2-carboxamide, 3-[4-(1-hydroxy-1-methyl-ethyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[6-(1-hydroxy-1-methyl-ethyl)-3-pyridyl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[(2-imino-2-oxo-1,3-dihydro-2-benzothiophen-5-yl)amino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazol-4-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(ethylsulfonimidoyl)-3,5-dimethyl-anilino]-5-methyl-6-(1-methylbenzimidazol-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]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-Methoxy-3-[(1-methyl-2,2-dioxo-3H-2,1-benzothiazol-5-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxo-1,4-thiazinan-4-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanilylidene]amino]anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanilylidene]amino]-2-fluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-[[dimethyl(oxo)-λ6-sulfanilylidene]amino]-2,3-difluoro-anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide formate, 3-[4-(1,1-dioxo-1,2-thiazolidin-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(1,1-dioxothiazinan-2-yl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-(2-Fluoro-4-methylsulfonyl-anilino)-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, (R)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, (S)-3-[4-(ethylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, rel-(R)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, rel-(S)-3-[4-(isopropylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[4-(tert-butylsulfonimidoyl)anilino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[4-(1-methylsulfonylcyclopropyl)anilino]pyrazine-2-carboxamide, 5-methoxy-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(1-methylpyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(1-tetrahydropyran-4-ylpyrazol-4-yl)amino]pyrazine-2-carboxamide, 3-[(1-isopropylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1,1-dioxothian-4-yl)pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-(methylamino)-6-(1-methylbenzimidazol-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide formate, 3-[(1,3-Dimethylpyrazol-4-yl)amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-(Methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 3-[[1-(2,2-Difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(2,2-Difluoroethyl)-5-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-Cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-5-(methylamino)-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-3-[(1,3-dimethylpyrazol-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-(2,2,2-trifluoroethyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-Cyclopropyl-3-[[1-(2,2-difluoroethyl)-3-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-Cyano-1-methyl-ethyl)-3-methyl-pyrazol-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 3-[[1-(1-cyanocyclopropyl)-3-methyl-pyrazol-4-yl]amino]-5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[(1,5-dimethylpyrazol-4-yl)amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(3-methyl-1H-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-[rel-(2R)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-[rel-(2S)-2,3-difluoropropyl]pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[3-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[[5-methyl-1-(oxetan-3-yl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(2,2-difluoroethyl)-5-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(3,3-difluoropropyl)-3-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-3-[[1-(3,3-difluoropropyl)-5-methyl-pyrazol-4-yl]amino]-6-(3-methylimidazo[4,5-c]pyridin-7-yl)pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(3-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(3-methylimidazo[4,5-c]pyridin-7-yl)-3-[(5-methyl-1-tetrahydropyran-4-yl-pyrazol-4-yl)amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-[[3-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, 5-cyclopropyl-6-(1-methylbenzimidazol-4-yl)-3-[[5-methyl-1-(1-methyl-4-piperidyl)pyrazol-4-yl]amino]pyrazine-2-carboxamide, and pharmaceutically acceptable salts thereof 2. The compound of claim 1 selected from:

14. A pharmaceutical comprising the 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, optionally mixed with a pharmaceutically acceptable adjuvant, diluent or carrier.

16. The pharmaceutical composition of claim 14 for treating cancer.

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