Imidazopyridine derivative having bicyclic structure

Abstract

The present invention addresses the problem of providing a novel compound having an SMG1 inhibitory activity and an anticancer activity, a pharmaceutically acceptable salt thereof, or the like. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof. (In formula (1), R1, R2, R3, R4, X, Y, and Z are each as defined in the description) # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound having a specific chemical structure and having SMG1 inhibitory activity or a pharmaceutically acceptable salt thereof. Background Art

[0002] SMG1 is a serine / threonine kinase identified as the human ortholog of smg-1 of C. elegans, and is classified into the PI3K-related protein kinase (PIKK) family like mTOR, etc. SMG1 plays an indispensable role in the nonsense mutation-mediated mRNA degradation mechanism (NMD), contributing to the degradation of transcripts with premature stop codons. In addition, it is reported that this function requires SMG1 kinase activity (Non-patent Document 1).

[0003] It is reported that the inhibition of SMG1 reduces the responsiveness to ER stress and DNA damage in cancer cells, and increases their sensitivity and vulnerability (Non-patent Documents 2 to 4). Therefore, compounds that inhibit SMG1 are expected to become pharmaceuticals that show efficacy against malignant tumors. In addition, SMG1 inhibitors are also expected to become pharmaceuticals in genetic diseases such as cystic fibrosis and congenital muscular dystrophy (Non-patent Documents 5 and 6).

[0004] In recent years, the mechanism of increasing tumor novel antigens by SMG1 inhibition suggests that it can effectively treat malignant tumors. For example, it has been demonstrated that by inhibiting the expression of SMG 1 or other NMD-related factors in tumors, anti-tumor effects can be observed in mouse homologous transplant models, and the effect is mediated by T cell-based cellular immunity (non-patent literature 7). As its mechanism of action, the following mechanism is investigated: by SMG1 inhibition, the transcription products of somatic mutations derived from tumors and the transcription products of abnormal splicing bodies increase and accumulate, thereby becoming novel antigens and activating tumor immunity (non-patent literature 7, 8).

[0005] In addition, there are reports on the regulation of the activation mechanism of immune cells achieved by SMG1 inhibition (non-patent document 9). Furthermore, papers suggesting the importance of NMD in clinical tumor immunity (non-patent document 10), the importance of novel antigens in the therapeutic effects of immune checkpoint inhibitors, and the involvement of NMD are reported (non-patent documents 11 to 13). It should be noted that, to date, the compounds shown below are known as compounds with NMD and SMG1 inhibitory activity (non-patent documents 14 to 17, patent documents 1, 2).

[0006] Prior art literature

[0007] Patent Literature

[0008] Patent Document 1: International Publication No. WO2018 / 152095 Pamphlet

[0009] Patent Document 2: International Publication No. WO2017 / 112954 Pamphlet

[0010] Non-patent literature

[0011] Non-patent document 1: A Yamashita et al., Genes & Dev. 2001, 15, 2215-2228

[0012] Non-patent document 2: KM Brumbaugh et al., Mol Cell. 2004, 14(5), 585-98

[0013] Non-patent document 3: SC Gehen et al., Oncogene 2008, 27(29), 4065-4074

[0014] Non-patent document 4: E Gubanova et al., Clin Cancer Res. 2012, 18(5), 1257-1267

[0015] Non-patent document 5: F Usuki et al., Ann Neurol. 2004, 55, 740-744

[0016] Non-patent document 6: DR McHugh et al., Int J Mol Sci. 2021, 22(1), 344

[0017] Non-patent document 7: F Pastor et al., Nature 2010, 465(7295), 227-30

[0018] Non-patent document 8: J El-Bchiri et al., PLoS ONE 2008, 3(7), e2583

[0019] Non-patent document 9: T Mino et al., Nucleic Acids Res. 2019, 47(16), 8838-8859

[0020] Non-patent document 10: B Zhao et al., PLoS Comput Biol. 2019, 15(10), e1007467

[0021] Non-patent document 11: RGH Lindeboom et al., Nat Genetics 2019, 51(11), 1645-1651

[0022] Non-patent document 12: K Litchfield et al., Nat Commun. 2020, 11, 3800 Non-patent document 13: K Litchfield et al., Cell 2021, 184(3), 596-614e14

[0023] Non-patent document 14: A Gopalsamy et al., Bioorg. Med. Chem. Lett. 2012, 22(21), 6636-6641

[0024] Non-patent document 15: A Nickless et al., Cell Biosci. 2017, 7, 26

[0025] Non-patent document 16: Cheruiyot et al., Cancer Res. 2021, 81(17), 4499-4513

[0026] Non-patent literature 17: JP Becker et al., iScience 2021, 24(4), 102389 Summary of the invention

[0027] Problems to be solved by the invention

[0028] An object of the present invention is to provide a novel compound or a pharmaceutically acceptable salt thereof having SMG1 inhibitory activity and anticancer activity.

[0029] Means for solving problems

[0030] In order to solve the above problems, the inventors of the present application synthesized compounds with various structures and explored compounds that have the effect of inhibiting SMG1 and showing anticancer effects. As a result, the compounds of the present invention and pharmaceutically acceptable salts thereof were found, thereby completing the present invention. That is, the present invention is as described below.

[0031] That is, the present invention includes the following aspects.

[0032] [1] A compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0033] [Chemical formula 1]

[0034]

[0035] In formula (1),

[0036] R 1represents a hydrogen atom, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a hydroxyl group or a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (the phenyl group may be substituted with an amino group or a halogen atom), a 2-tert-butylamino-2-oxoethyl group, a [dimethyl(oxy)-λ6-sulfanylidene]amino group, or a group represented by the following formula (2), or -NR 1d R 1e ,

[0037] [Chemical formula 2]

[0038]

[0039] (In formula (2),

[0040] W a Indicates CH 2 , oxygen atom or NR 1f ,

[0041] W b represents CH, nitrogen atom or C-OH,

[0042] R 1a , R 1b , R 1c are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted by a halogen atom, an amino group or an oxo group,

[0043] n represents 0, 1, or 2. )

[0044] R 1d , R 1e are the same or different and each independently represents a hydrogen atom, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a halogen atom or a 4-7 membered heterocyclic group), a 4-7 membered heterocyclic group, or a C3-C6 cycloalkyl group which may be substituted with a hydroxyl group,

[0045] R 1f represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group,

[0046] R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted by a C1-C6 alkyl group, a 2,4-dimethylpyrazolyl group, or any group selected from the following formula (3),

[0047] [Chemical formula 3]

[0048]

[0049] (In formula (3),

[0050] Dashed lines represent single or double bonds.

[0051] Va Represents CR 2f or nitrogen atoms,

[0052] V b Represents CR 2g or nitrogen atoms,

[0053] V c Represents CR 2j or nitrogen atoms,

[0054] V d Represents CR 2k or nitrogen atoms,

[0055] V g represents CH or nitrogen atom,

[0056] V h Indicates CHN(CH 3 ) 2 NR 2l or oxygen atoms,

[0057] n 2 Indicates 1 or 2,

[0058] R 2a , R 2b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted by a hydroxyl group, a halogen atom or a 4-7 membered heterocyclic group), a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted by a halogen atom or deuterium), or a C3-C6 cycloalkyl group,

[0059] R 2c represents a C3-C6 cycloalkyl group or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted by a C3-C6 cycloalkyl group or a halogen atom),

[0060] R 2d represents a hydrogen atom, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group or a C3-C6 cycloalkyl group,

[0061] R 2e represents a C1-C6 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, a benzenesulfonyl group (the benzenesulfonyl group may be substituted with a C1-C6 alkyl group or a halogen atom), a C3-C6 cycloalkylcarbonyl group, a C1-C6 alkylcarbonyl group or a benzoyl group (the benzoyl group may be substituted with a C1-C6 alkyl group or a halogen atom),

[0062] R 2f , R 2g are the same or different and each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkoxy group which may be substituted by a halogen atom, or a C1-C6 alkyl group which may be substituted by a hydroxyl group, or the following formula (4),

[0063] [Chemical formula 4]

[0064]

[0065] (In formula (4),

[0066] R 2h , R 2i are the same or different, each independently representing a C1-C6 alkyl group,

[0067] Or, R 2h , R 2i They may be bonded to each other to form a 4-7 membered heterocyclic group which may be substituted by a C1-C6 alkyl group.

[0068] R 2j , R 2k are the same or different and each independently represents a hydrogen atom, a C1-C6 alkyl group which may be substituted by a halogen atom, or a C3-C6 cycloalkyl group,

[0069] Or, R 2c With R 2k can be bonded to each other to form the following groups,

[0070] [Chemical formula 5]

[0071]

[0072] R 2l represents a C1-C6 alkyl group or a C3-C6 cycloalkyl group. )

[0073] Or, R 1 With R 2 can be bonded to each other to form a group represented by the following formula (5),

[0074] (The bond at the left end of each group represents the bond between the aromatic ring of the compound of formula (1) and R 1 The bond on the right represents the bond between the aromatic ring of the compound of formula (1) and R 2 The key between . )

[0075] [Chemical formula 6]

[0076]

[0077] (In formula (5),

[0078] A represents an aryl group, a heteroaryl group or a 4-7 membered heterocyclic group,

[0079] R 6a represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a C1-C6 alkoxy group,

[0080] D stands for -NR 6e CO-, or -CONR 6f -,

[0081] E stands for -CR 6g R 6h -、-NR 6i -, -O-, -S-, -SO-, or -SO 2 -, when there are multiple E, each of the multiple E may be the same or different,

[0082] R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i Each independently represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or,

[0083] R 6b With R 6c , R 6b With R 6e , or R 6c With R 6d can bond to each other to form a ring,

[0084] m 1 Indicates 0 or 1,

[0085] m 2 means 1, 2, 3, 4 or 5,

[0086] m 3 Indicates 0, 1, 2, or 3. )

[0087] R 3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a 1-methyl-3,6-dihydro-2H-pyrazin-5-yl group,

[0088] R 4 represents a hydrogen atom or a halogen atom,

[0089] XY represents C=CH or N-CH 2 ,

[0090] Z represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group, a cyano group or a C1-C6 alkoxycarbonyl group.

[0091] [2] The compound or a pharmaceutically acceptable salt thereof according to [1], wherein R 1 represents a hydrogen atom, a C1-C6 alkyl group, -NR 11dR 11e Or any group selected from the following formula (6).

[0092] [Chemical formula 7]

[0093]

[0094] (In formula (6),

[0095] R 11a , R 11b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group or a C1-C6 alkyl group.

[0096] R 11d , R 11e are the same or different and each independently represents a hydrogen atom or a C1-C6 alkyl group which may be substituted by a halogen atom.

[0097] [3] The compound or pharmaceutically acceptable salt thereof according to [1] or [2], wherein R 2 It represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7).

[0098] [Chemical formula 8]

[0099]

[0100] (In formula (7),

[0101] V 2a Represents CR 21e or nitrogen atoms,

[0102] V 2b Represents CR 21f or nitrogen atoms,

[0103] R 21a , R 21b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group,

[0104] R 21c represents a C1-C6 alkyl group which may be substituted by a halogen atom,

[0105] R 21d represents a hydrogen atom or a C3-C6 cycloalkyl group,

[0106] R 21e represents a hydrogen atom or a halogen atom,

[0107] R 21f represents a hydrogen atom or a halogen atom. )

[0108] [4] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to [3], wherein R 3 represents a hydrogen atom,

[0109] R 4 represents a hydrogen atom,

[0110] XY represents C=CH or N-CH 2 ,

[0111] Z represents a halogen atom.

[0112] [5] The compound or a pharmaceutically acceptable salt thereof according to [1], wherein R 1 represents any group selected from ethyl, 2,2-difluoroethylamino or [(2R)-1,1,1-trifluoropropane-2-yl]amino,

[0113] R 2 represents 2-methoxypyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or a group represented by the following formula (8),

[0114] [Chemical formula 9]

[0115]

[0116] (In formula (8),

[0117] R 22 represents a C1-C6 alkyl group which may be substituted by a halogen atom, a C1-C6 alkoxy group which may be substituted by a halogen atom, or a C3-C6 cycloalkyl group.

[0118] R 3 represents a hydrogen atom,

[0119] R 4 represents a hydrogen atom,

[0120] XY represents C=CH or N-CH 2 ,

[0121] Z represents a halogen atom.

[0122] [6] The compound according to [1] or a pharmaceutically acceptable salt thereof, which is selected from the following compounds.

[0123] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0124] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0125] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0126] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0127] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0128] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one, or

[0129] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.

[0130] [7] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.

[0131] [8] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate.

[0132] [9] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate.

[0133]

[10] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one benzenesulfonate.

[0134]

[11] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate.

[0135]

[12] An SMG1 inhibitor comprising the compound described in any one of [1] to

[11] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0136]

[13] An NMD inhibitor comprising the compound described in any one of [1] to

[11] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0137]

[14] A pharmaceutical composition comprising the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition may contain a pharmaceutically acceptable carrier.

[0138]

[15] The pharmaceutical composition according to [9], which is used for treating cancer.

[0139]

[16] The pharmaceutical composition according to

[10] , characterized in that the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] is administered in combination with an immune checkpoint inhibitor.

[0140]

[17] The pharmaceutical composition according to

[11] , characterized in that the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.

[0141]

[18] The pharmaceutical composition according to

[16] , characterized in that the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] and an immune checkpoint inhibitor are contained as active ingredients in a single preparation.

[0142]

[19] The pharmaceutical composition of any one of

[16] to

[18] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0143]

[20] The pharmaceutical composition of any one of

[15] to

[19] , wherein the cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

[0144]

[21] An anticancer agent comprising the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof as an active ingredient.

[0145]

[22] A method for treating cancer, comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] .

[0146]

[23] A method for treating cancer, characterized in that the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] is administered in combination with an immune checkpoint inhibitor.

[0147]

[24] The method of

[23] , characterized in that the compound or pharmaceutically acceptable salt thereof described in any one of [1] to

[11] and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.

[0148]

[25] The method of treatment described in

[23] , characterized in that the compound or pharmaceutically acceptable salt thereof described in any one of [1] to

[11] and the immune checkpoint inhibitor are contained in a single preparation as active ingredients and administered.

[0149]

[26] The treatment method according to any one of

[23] to

[25] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0150]

[27] A treatment method as described in any one of

[22] to

[26] , wherein the cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

[0151]

[28] The compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

[0152]

[29] The compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] , for use in the treatment of cancer, characterized in that it is administered in combination with an immune checkpoint inhibitor.

[0153]

[30] The compound or pharmaceutically acceptable salt thereof according to

[29] , wherein the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.

[0154]

[31] The compound or pharmaceutically acceptable salt thereof according to

[29] , wherein the compound or pharmaceutically acceptable salt thereof according to any one of [1] to

[11] and the immune checkpoint inhibitor are contained in a single preparation as active ingredients and administered.

[0155]

[32] The compound or pharmaceutically acceptable salt thereof according to any one of

[29] to

[31] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0156]

[33] A compound or a pharmaceutically acceptable salt thereof as described in any one of

[28] to

[32] , wherein the cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

[0157]

[34] Use of the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] in the manufacture of a medicament for treating cancer.

[0158]

[35] The use according to

[34] , characterized in that the compound or a pharmaceutically acceptable salt thereof according to any one of [1] to

[11] is administered in combination with an immune checkpoint inhibitor.

[0159]

[36] The use as described in

[35] , characterized in that the compound or pharmaceutically acceptable salt thereof described in any one of [1] to

[11] and the immune checkpoint inhibitor are contained in different preparations as active ingredients and are administered simultaneously or at different times.

[0160]

[37] The use according to

[35] , characterized in that the compound or pharmaceutically acceptable salt thereof described in any one of [1] to

[11] and the immune checkpoint inhibitor are contained in a single preparation as active ingredients and administered.

[0161]

[38] The use as described in any one of

[35] to

[37] , wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

[0162]

[39] The use as described in any one of

[34] to

[38] , wherein the cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

[0163] Effects of the Invention

[0164] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits SMG1 and NMD inhibitory activity, and also exhibits an anticancer effect as a single agent and an anticancer effect by combined use with an immune checkpoint inhibitor. BRIEF DESCRIPTION OF THE DRAWINGS

[0165] [ Figure 1 ] is a graph showing a diffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 angstroms, scanning speed=20° / min) of the crystals of the salt obtained in Example 138. The vertical axis of the graph represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

[0166] [ Figure 2 ] is a graph showing a diffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 angstroms, scanning speed=20° / min) of the crystals of the salt obtained in Example 155. The vertical axis of the graph represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

[0167] [ Figure 3 ] is a graph showing a diffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 angstroms, scanning speed=20° / min) of the crystals of the salt obtained in Example 156. The vertical axis of the graph represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

[0168] [ Figure 4] is a graph showing a diffraction pattern of powder X-ray diffraction (CuKα, λ=1.54 angstroms, scanning speed=20° / min) of the crystals of the salt obtained in Example 157. The vertical axis of the graph represents the diffraction intensity as relative line intensity, and the horizontal axis represents the value of the diffraction angle 2θ.

[0169] [ Figure 5 ] is a graph showing the anti-tumor effect of the compound of Example 32 administered alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-L1 antibody) on mice subcutaneously transplanted with MC38 mouse colon cancer cell lines. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume.

[0170] [ Figure 6 ] is a graph showing the anti-tumor effect of the compound of Example 117 alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-L1 antibody) on mice subcutaneously transplanted with MC38 mouse colon cancer cell lines. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume.

[0171] [ Figure 7 ] is a graph showing the anti-tumor effect of the compound of Example 26 administered alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-L1 antibody) on mice subcutaneously transplanted with MC38 mouse colon cancer cell lines. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume.

[0172] [ Figure 8 ] is a graph showing the anti-tumor effect of the compound of Example 138 alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-1 antibody) on mice subcutaneously transplanted with MC38 mouse colon cancer cell lines. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume.

[0173] [ Fig. 9 ] is a graph showing the anti-tumor effect of the compound of Example 146 administered alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-L1 antibody) on mice subcutaneously transplanted with MC38 mouse colon cancer cell lines. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents the tumor volume. DETAILED DESCRIPTION

[0174] Hereinafter, substituents and terms used in the present invention will be described.

[0175] The "C1-C6 alkyl group" in the present specification is a straight-chain or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include methyl, ethyl, 1-propyl, isopropyl, 1-butyl, 2-butyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 2-ethyl-1-butyl, 2,2-dimethyl-1-butyl, or 2,3-dimethyl-1-butyl.

[0176] As used herein, the “halogen atom” includes, for example, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

[0177] The "C3-C6 cycloalkyl group" in the present specification is a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0178] The "C3-C8 cycloalkyl group" in the present specification is a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0179] The "4-7 membered heterocyclic group" in the present specification is a group of a 4-7 membered heterocyclic ring containing 1-3 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, and may contain 1 or 2 unsaturated bonds in the ring, and the ring may be cross-linked by 1-3 methylene groups, heteroatoms or a combination thereof. For example, azetidinyl, pyrrolidinyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, piperidinyl, azepanyl, piperazinyl, hexahydropyrimidinyl, morpholinyl, thiomorpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thioxanyl group, dihydropyridinyl, 3-oxa-8-azabicyclo[3.2.1]octanyl and the like may be mentioned.

[0180] The "aryl group" in the present specification refers to an aromatic hydrocarbon group in which a single benzene ring such as phenyl or naphthyl is present, or benzene rings are condensed together.

[0181] The "heteroaryl group" in the present specification is a group containing a 5- or 6-membered monocyclic heteroaromatic ring of 1 to 3 atoms selected from the group consisting of nitrogen atoms, oxygen atoms and sulfur atoms, and examples thereof include thienyl, pyridyl and pyrazolyl.

[0182] The "C1-C6 alkylsulfonyl group" in the present specification is a group in which a C1-C6 alkyl group is bonded to a sulfonyl group, and examples thereof include a methylsulfonyl group, an ethylsulfonyl group, a 1-propylsulfonyl group, an isopropylsulfonyl group, a 1-butylsulfonyl group, a 2-butylsulfonyl group, a 2-methyl-1-propylsulfonyl group, a 2-methyl-2-propylsulfonyl group, a 1-pentylsulfonyl group, a 2-pentylsulfonyl group, a 3-pentylsulfonyl group, a 2-methyl-2-butylsulfonyl group, a 3-methyl-2-butylsulfonyl group, a 1-hexylsulfonyl group, a 2-hexylsulfonyl group, a 3-hexylsulfonyl group, a 2-methyl-1-pentylsulfonyl group, a 3-methyl-1-pentylsulfonyl group, a 2-ethyl-1-butylsulfonyl group, a 2,2-dimethyl-1-butylsulfonyl group, and a 2,3-dimethyl-1-butylsulfonyl group.

[0183] The "C3-C6 cycloalkylsulfonyl group" in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to a sulfonyl group, and examples thereof include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, and a cyclohexylsulfonyl group.

[0184] The "C1-C6 alkylcarbonyl group" in the present specification is a group obtained by bonding a C1-C6 alkyl group to a carbonyl group, and examples thereof include methylcarbonyl, ethylcarbonyl, 1-propylcarbonyl, isopropylcarbonyl, 1-butylcarbonyl, 2-butylcarbonyl, 2-methyl-1-propylcarbonyl, 2-methyl-2-propylcarbonyl, 1-pentylcarbonyl, 2-pentylcarbonyl, 3-pentylcarbonyl, 2-methyl-2-butylcarbonyl, 3-methyl-2-butylcarbonyl, 1-hexylcarbonyl, 2-hexylcarbonyl, 3-hexylcarbonyl, 2-methyl-1-pentylcarbonyl, 3-methyl-1-pentylcarbonyl, 2-ethyl-1-butylcarbonyl, 2,2-dimethyl-1-butylcarbonyl, and 2,3-dimethyl-1-butylcarbonyl.

[0185] The "C3-C6 cycloalkylcarbonyl group" in the present specification is a group in which a C3-C6 cycloalkyl group is bonded to a carbonyl group, and examples thereof include a cyclopropylcarbonyl group, a cyclobutylcarbonyl group, a cyclopentylcarbonyl group, and a cyclohexylcarbonyl group.

[0186] The term "pharmaceutically acceptable salt thereof" refers to a salt that can be used as medicine. When a compound has an acidic group or a basic group, it can be converted into a basic salt or an acidic salt by reacting with a base or an acid, and thus the term "pharmaceutically acceptable salt thereof" refers to a salt thereof.

[0187] The pharmaceutically acceptable "basic salt" of the compound is preferably an alkali metal salt such as sodium salt, potassium salt, and lithium salt; an alkaline earth metal salt such as magnesium salt and calcium salt; an organic base salt such as N-methylmorpholine salt, triethylamine salt, tributylamine salt, diisopropylethylamine salt, dicyclohexylamine salt, N-methylpiperidinium salt, pyridine salt, 4-pyrrolidinylpyridine salt, and methylpyridine salt; or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, and aspartate.

[0188] As the pharmaceutically acceptable "acid salt" of the compound, preferably, hydrohalide salts such as hydrofluoride, hydrochloride, hydrobromide, and hydroiodide, inorganic acid salts such as nitrate, perchlorate, sulfate, and phosphate; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, and 1,2-ethanedisulfonate, aryl sulfonates such as benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate, and 1,5-naphthalenedisulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, adipate and the like organic acid salts; or amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate.

[0189] The compound of the present invention or a pharmaceutically acceptable salt thereof may absorb moisture when left in the air or recrystallized, and may carry adsorbed water or become a hydrate. The present invention also includes such various hydrates, solvates and polymorphic compounds.

[0190] The compounds of the present invention, their pharmaceutically acceptable salts or their solvates may exist in various isomers such as cis-isomers, trans-isomers, tautomers, rotational isomers or optical isomers (including enantiomers and diastereomers) such as d-isomers and l-isomers according to the types and combinations of substituents. In the absence of special restrictions, the compounds of the present invention include all the above isomers, stereoisomers and any ratio of these isomers and stereoisomer mixtures. These isomer mixtures can be separated by known resolution means.

[0191] The compounds of the present invention also include labeled compounds, that is, compounds in which one or two or more atoms of the compound are substituted with isotopes (eg, 2H, 3H, 13C, 14C, 35S, etc.).

[0192] The compounds of the present invention are generally named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC).

[0193] In the names of the compounds of the present invention, when the compound has an atom that serves as a chiral center in the structure of the compound, the absolute configuration may be indicated by R and S (described together with a position number).

[0194] In the case of relative configuration, when the configuration of the chiral center is initially described as R or S, an asterisk (*) may be added to the configuration designation (R * and S * ), or by setting the prefix (symbol) rel- (relative) before the name.

[0195] Racemic mixtures are not usually specifically designated by R and S to indicate their absolute configuration, but the symbols RS and SR are sometimes used instead of R. * and S * , or by setting the prefix (symbol) rac- (meaning racemic) before the name.

[0196] In addition, the present invention also includes so-called prodrugs. The so-called prodrug is a compound having a group such as an amino group, a hydroxyl group, a carboxyl group, etc. that can be converted into a compound by hydrolysis or under physiological conditions. The group forming such a prodrug is a group described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc. More specifically, as the prodrug,

[0197] (1) When there is an amino group in the compound,

[0198] Examples include compounds in which the amino group is acylated, alkylated, or phosphorylated (for example, compounds in which the amino group is eicosanolylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolan-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidinylmethylated, pivaloyloxymethylated, or tert-butylated, etc.),

[0199] (2) When there is a hydroxyl group in the compound,

[0200] Examples include compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group is acetylated, palmitoylated, propionylated, pivaloylated, succinylated, fumarylated, alanylated, or dimethylaminomethylcarbonylated, etc.),

[0201] (3) In addition, when a carboxyl group is present in the compound,

[0202] Examples include compounds in which the carboxyl group is esterified or amidated (for example, compounds in which the carboxyl group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, amidated or methylamidated, etc.).

[0203] It is also believed that the compounds of the present invention utilize their strong binding ability to SMG1, which is their characteristic, to bind to the ligand of E3 ubiquitin ligase via a linker structure from any part of their chemical structure, and are thus suitable as partial structures of degradation-derived substances targeting target proteins, collectively referred to as TPD (Targeted Protein Degradation). TPD to which the compound of the present invention is applicable can be prepared by any known method, for example, by the method described in the following patent documents, WO2015 / 160845, WO2016 / 197032, WO2019 / 199816, WO2017 / 011371, WO2016 / 105518, US10849980 B, US10464925 B, WO2013106643, US10730862 B, WO2022 / 081927, WO2022 / 081928, WO2017 / 197051, WO2019 / 060742, WO2019 / 060693, WO2019 / 099868, WO2018 / 237026, etc.

[0204] Hereinafter, other aspects of the present invention will be described in detail.

[0205] One embodiment of the present invention is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof.

[0206] [Chemical formula 10]

[0207]

[0208] (In formula (1), R 1 , R 2 , R 3 , R 4 , X, Y, and Z have the same meanings as above. )

[0209] Other preferred embodiments of the compound represented by formula (1) of the present invention or a pharmaceutically acceptable salt thereof are shown below.

[0210] R 1 Preferably, it is a hydrogen atom, a C1-C6 alkyl group, -NR 11d R 11e or any group selected from the following formula (6),

[0211] [Chemical formula 11]

[0212]

[0213] (In formula (6),

[0214] R 11a , R 11b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group or a C1-C6 alkyl group.

[0215] R 11d , R 11e are the same or different and each independently represents a hydrogen atom or a C1-C6 alkyl group which may be substituted by a halogen atom.

[0216] More preferably R 1 It is ethyl, 2,2-difluoroethylamino, or [(2R)-1,1,1-trifluoropropan-2-yl]amino.

[0217] R 2 It is preferably a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7),

[0218] [Chemical formula 12]

[0219]

[0220] (In formula (7),

[0221] V 2a Represents CR 21e or nitrogen atoms,

[0222] V 2b Represents CR 21f or nitrogen atoms,

[0223] R 21a , R 21b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group,

[0224] R 21c represents a C1-C6 alkyl group which may be substituted by a halogen atom,

[0225] R 21d represents a hydrogen atom or a C3-C6 cycloalkyl group,

[0226] R 21e represents a hydrogen atom or a halogen atom,

[0227] R 21f represents a hydrogen atom or a halogen atom. ),

[0228] More preferably R 2 It is 2-methoxypyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or a group represented by the following formula (8).

[0229] [Chemical formula 13]

[0230]

[0231] (In formula (8),

[0232] R 22 represents a C1-C6 alkyl group which may be substituted by a halogen atom, a C1-C6 alkoxy group which may be substituted by a halogen atom, or a C3-C6 cycloalkyl group.

[0233] As another way, R 1 With R 2 They may bond to each other to form a group represented by the following formula (5).

[0234] [Chemical formula 14]

[0235]

[0236] (In formula (5), R 6a , R 6b , R 6c , R 6d , A, D, E, m 1 、m 2 、m 3 Meanings the same as above.)

[0237] In a preferred embodiment of the group of formula (5),

[0238] A is phenyl, a 5-6-membered heteroaryl group containing 1-3 heteroatoms, or a saturated or partially unsaturated 4-7-membered heterocyclic group containing 1-2 heteroatoms.

[0239] As a more preferred embodiment of the group of formula (5), it is any group selected from the following groups. (The bond at the left end of each group represents the bond between the aromatic ring of the compound represented by formula (1) and R 1 The bond on the right represents the bond between the aromatic ring of the compound represented by formula (1) and R 2 The key between . )

[0240] [Chemical formula 15]

[0241]

[0242] R3 Preferred is a hydrogen atom.

[0243] R 4 Preferred is a hydrogen atom.

[0244] XY is preferably C═CH or N—CH 2 .

[0245] Z is preferably a halogen atom, more preferably a chlorine atom.

[0246] As another preferred embodiment, R 1 is a hydrogen atom, a methyl group, an ethyl group, an isopropyl group or any group selected from the following groups.

[0247] [Chemical formula 16]

[0248]

[0249] As another more preferred embodiment, R 1 It is ethyl or any group selected from the following groups.

[0250] [Chemical formula 17]

[0251]

[0252] As another preferred embodiment, R 2 It is a hydrogen atom, a methyl group, an ethyl group or any group selected from the following groups.

[0253] [Chemical formula 18]

[0254]

[0255] As another more preferred embodiment, R 2 It is any group selected from the following groups.

[0256] [Chemical formula 19]

[0257]

[0258] Preferred combinations of substituents in the compound represented by formula (1) in other embodiments are shown below.

[0259] R 1 represents a hydrogen atom, a C1-C6 alkyl group, -NR 11d R 11e or any group selected from the following formula (6),

[0260] [Chemical formula 20]

[0261]

[0262] (In formula (6),

[0263] R 11a , R 11b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group or a C1-C6 alkyl group.

[0264] R 11d , R 11e are the same or different and each independently represents a hydrogen atom or a C1-C6 alkyl group which may be substituted by a halogen atom.

[0265] R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7),

[0266] [Chemical formula 21]

[0267]

[0268] (In formula (7),

[0269] V 2a Represents CR 21e or nitrogen atoms,

[0270] V 2b Represents CR 21f or nitrogen atoms,

[0271] R 21a , R 21b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group,

[0272] R 21c represents a C1-C6 alkyl group which may be substituted by a halogen atom,

[0273] R 21d represents a hydrogen atom or a C3-C6 cycloalkyl group,

[0274] R 21e represents a hydrogen atom or a halogen atom,

[0275] R 21f represents a hydrogen atom or a halogen atom. )

[0276] R 3 represents a hydrogen atom,

[0277] R 4 represents a hydrogen atom,

[0278] XY represents C=CH or N-CH2 ,

[0279] Z represents a halogen atom.

[0280] Another embodiment of the present invention is a compound selected from the following compounds or a pharmaceutically acceptable salt thereof.

[0281] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0282] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(1-methylcyclopropyl)-1,6-naphthyridin-2(1H)-one,

[0283] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-7-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0284] 3-{6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0285] 3-{6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0286] 3-(6-chloro-4-{methyl[1-(tetrahydro-2H-pyran-4-yl)ethyl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one,

[0287] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-1,6-naphthyridin-2(1H)-one,

[0288] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-(dimethylamino)piperidin-1-yl]-1,6-naphthyridin-2(1H)-one,

[0289] 3-[4-(5-amino-3,3-difluoropiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0290] 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0291] 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(tetrahydro-2H-pyran-4-yl)-1,6-naphthyridin-2(1H)-one,

[0292] 3-{6-chloro-4-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0293] 3-{6-chloro-4-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-methyl-1,6-naphthyridin-2(1H)-one,

[0294] 3-{6-chloro-4-[(2R,3S)-3-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-ethyl-1,6-naphthyridin-2(1H)-one,

[0295] 3-{6-chloro-4-[(2R)-2-methylazetidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-methyl-1,6-naphthyridin-2(1H)-one,

[0296] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-methyl-1,6-naphthyridin-2(1H)-one,

[0297] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one,

[0298] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5,7-dimethyl-1,6-naphthyridin-2(1H)-one,

[0299] 3-[6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0300] 3-(6-chloro-4-propyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-methyl-1,6-naphthyridin-2(1H)-one,

[0301] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0302] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-ethyl-1,6-naphthyridin-2(1H)-one,

[0303] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5,c]pyridin-2-yl]-5-(1-methylcyclopropyl)-1,6-naphthyridin-2(1H)-one,

[0304] 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one,

[0305] 3-[6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0306] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0307] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluorophenyl)-1,6-naphthyridin-2(1H)-one,

[0308] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one,

[0309] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one,

[0310] 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one,

[0311] 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one,

[0312] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0313] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(difluoromethoxy)-2-methylphenyl]-1,6-naphthyridin-2(1H)-one,

[0314] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0315] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0316] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0317] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0318] 3-[6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0319] 3-(6-chloro-4-cyclopropyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0320] 3-[6-chloro-4-(1-hydroxyethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0321] 3-[6-chloro-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0322] N-tert-butyl-2-[6-chloro-2-(5-{2-[( 2 H 3 )methyloxy]phenyl}-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-1H-imidazo[4,5-c]pyridin-4-yl]acetamide,

[0323] 3-[6-chloro-4-(3-oxopiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0324] 3-(6-chloro-4-{[dimethyl(oxo)-λ6-sulfanylidene]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0325] 2-[3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl]-3-fluorobenzonitrile,

[0326] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(2-hydroxypropane-2-yl)phenyl]-1,6-naphthyridin-2(1H)-one,

[0327] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(3-oxa-8-azabicyclo[3.2.1]octan-8-ylmethyl)phenyl]-1,6-naphthyridin-2(1H)-one,

[0328] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0329] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0330] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0331] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one,

[0332] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0333] 3-{6-chloro-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0334] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0335] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0336] 3-[4-(3-aminopiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0337] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0338] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0339] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0340] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0341] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0342] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0343] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0344] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(propan-2-yl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0345] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0346] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0347] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0348] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0349] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0350] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0351] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0352] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(4-methoxy-2-methylpyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0353] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0354] 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2,4-dimethoxypyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0355] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2,4-dimethoxypyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0356] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-ethyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0357] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0358] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-cyclopropyl-4-(difluoromethoxy)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0359] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0360] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0361] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0362] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4,6-dimethoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0363] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0364] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0365] 3-{6-chloro-4-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0366] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1-methyl-1H-pyrrol-3-yl)-1,6-naphthyridin-2(1H)-one,

[0367] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,4-dimethyl-1H-pyrazol-5-yl)-1,6-naphthyridin-2(1H)-one,

[0368] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0369] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,3,5-trimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0370] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylmethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0371] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0372] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0373] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-cyclopropyl-1-(2,2-difluoroethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0374] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(difluoromethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0375] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0376] 3-{6-chloro-4-[(2R)-2-methylazetidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0377] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1,6-naphthyridin-2(1H)-one,

[0378] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one,

[0379] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0380] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0381] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one,

[0382] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one,

[0383] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one,

[0384] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0385] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylcarbonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0386] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one,

[0387] 7-Chloro-18-fluoro-10,14-dimethyl-3,8,10,14,21,25,31-heptaazahexacyclo[18.6.2.2 16,19 .1 2 ,5 .0 4,9 .0 24,28 ] Henty-undecene-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione,

[0388] 7-Chloro-10,14,30-trimethyl-3,8,10,14,22,26,31-heptaazahexacyclo[19.6.2.1 2,5 .1 16, 20 .0 4,9 .0 25,29 ] Henty-undecene-1(28),2,4,6,8,16(30),17,19,21(29),22,24-undecene-15,27-dione,

[0389] 7-Chloro-10,14,18-trimethyl-3,8,10,14,21,25,31-heptaazahexacyclo[18.6.2.2 16,19 .1 2, 5 .0 4,9 .0 24,28 ] Henty-one carbon-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-13,26-dione,

[0390] 7-Chloro-32-methyl-17-oxa-3,8,10,14,24,28,35-heptaazaheptacyclo[21.6.2.2 10,14 .1 2, 5 .1 18,22 .0 4,9 .0 27,31 ]35-pentadecan-1(30),2,4,6,8,18(32),19,21,23(31),24,26-undecene-15,29-dione,

[0391] 7-Chloro-12,12,31-trimethyl-16-oxa-3,8,10,13,23,27,32-heptaazahexacyclo[20.6.2.1 2 ,5 .1 17,21 .0 4,9 .0 26,30 ]triacontahedral-1(29),2,4,6,8,17(31),18,20,22(30),23,25-undecene-14,28-dione,

[0392] 7-Chloro-17-thia-3,8,10,14,24,28,35-heptaazaheptacyclic [21.6.2.2 10,14 .1 2,5 .1 18,22 .0 4, 9 .0 27,31 ]35-pentadecan-1(30),2,4,6,8,18(32),19,21,23(31),24,26-undecene-15,29-dione 17,17-dioxide,

[0393] 7-Chloro-10,15,20,31-tetramethyl-3,8,10,15,18,19,23,27,32-nonaazahexacyclo[20.6.2.1 2 ,5 .1 18,21 .0 4,9 .0 26,30 ]triacontahedral-1(29),2,4,6,8,19,21(31),22(30),23,25-decene-16,28-dione,

[0394] 7-Chloro-10,14,16,19,30-pentamethyl-3,8,10,14,17,18,22,26,31-nonaazahexacyclo[19.6.2.1 2,5 .1 17,20 .0 4,9 .0 25,29 ] Henty-one carbon-1(28),2,4,6,8,18,20(30),21(29),22,24-decene-15,27-dione,

[0395] 7-Chloro-12,12,19,30-tetramethyl-3,8,10,14,17,18,22,26,31-nonaazahexacyclo[19.6.2.1 2 ,5 .1 17,20 .0 4,9 .0 25,29] hexadecene-1(28),2,4,6,8,18,20(30),21(29),22,24-decene-15,27-dione, or

[0396] 7-Chloro-3,8,10,14,18,19,23,27,34-nonaazaheptacyclic [20.6.2.2 10,14 .1 2,5 .1 18,21 .0 4, 9 .0 26,30 ]triacontahedral-1(29),2,4,6,8,19,21(31),22(30),23,25-decene-15,28-dione

[0397] A preferred embodiment of the present invention is a compound selected from the following compounds or a pharmaceutically acceptable salt thereof.

[0398] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0399] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-(dimethylamino)piperidin-1-yl]-1,6-naphthyridin-2(1H)-one,

[0400] 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one,

[0401] 3-{6-chloro-4-[(2R)-2-methylazetidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-methyl-1,6-naphthyridin-2(1H)-one,

[0402] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-methyl-1,6-naphthyridin-2(1H)-one,

[0403] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one,

[0404] 3-[6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0405] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one,

[0406] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-ethyl-1,6-naphthyridin-2(1H)-one,

[0407] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5,c]pyridin-2-yl]-5-(1-methylcyclopropyl)-1,6-naphthyridin-2(1H)-one,

[0408] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0409] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one,

[0410] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one,

[0411] 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one,

[0412] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0413] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0414] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0415] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0416] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0417] 3-[6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0418] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one,

[0419] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0420] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0421] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one,

[0422] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0423] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0424] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one,

[0425] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one,

[0426] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0427] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0428] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0429] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0430] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(propan-2-yl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0431] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0432] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2,4-dimethoxypyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0433] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2,4-dimethoxypyrimidin-5-yl)-1,6-naphthyridin-2(1H)-one,

[0434] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-ethyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0435] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0436] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0437] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0438] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0439] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4,6-dimethoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0440] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0441] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0442] 3-{6-chloro-4-[(2R,4S)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0443] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0444] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0445] 3-{6-chloro-4-[(2R)-2-methylazetidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one,

[0446] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0447] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one, or

[0448] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[0449] A more preferred embodiment of the present invention is a compound selected from the following compounds or a pharmaceutically acceptable salt thereof.

[0450] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one,

[0451] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0452] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one,

[0453] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0454] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one,

[0455] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one, or

[0456] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[0457] As a preferred embodiment of the present invention in another embodiment, it is a salt of a compound selected from the following compounds.

[0458] 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one trifluoroacetate,

[0459] 3-[4-(3-aminopiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one hydrochloride,

[0460] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0461] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0462] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-ethyl-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0463] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5,c]pyridin-2-yl]-5-(1-methylcyclopropyl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0464] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0465] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0466] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0467] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0468] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0469] 3-{6-chloro-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0470] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0471] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0472] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0473] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0474] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-ethyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0475] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0476] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0477] 3-{6-chloro-4-[(2,2,2-trifluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0478] 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0479] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4,6-dimethoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0480] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0481] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0482] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0483] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0484] 3-{6-chloro-4-[(2R)-2-methylazetidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0485] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-1H-pyrazol-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0486] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0487] 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0488] 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0489] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one methanesulfonate,

[0490] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate,

[0491] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0492] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-onebenzenesulfonate, or

[0493] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate.

[0494] More preferably:

[0495] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate

[0496] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate,

[0497] 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-onebenzenesulfonate, or

[0498] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate.

[0499] In a preferred embodiment of the present invention in another embodiment, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is a crystal.

[0500] In the present invention, the term "crystal" refers to a solid in which atoms or atomic groups, molecules, and ions are regularly arranged in space in its internal structure, and is distinguished from an amorphous solid or non-crystal which does not have such a regular internal structure.

[0501] In the present invention, the compound represented by formula (1) or its pharmaceutically acceptable salt is in crystalline form. This can be confirmed by observation based on a polarizing microscope, powder X-ray crystallography, or single crystal X-ray diffraction measurement. In addition, by comparing with data based on various indicators of pre-determined crystal characteristics, the type of the crystal can also be determined. Therefore, according to a preferred embodiment of the present invention, the crystal based on the present invention is a substance that can be confirmed as a crystal using such a measurement method. In the present invention, the difference in crystal form can be distinguished by powder X-ray diffraction.

[0502] In the present invention, not only crystals with completely consistent diffraction angles in powder X-ray diffraction are included, but also crystals with consistent diffraction angles within the range of ±0.2 are included in the present invention. This is a general practice, and the reason is that, generally speaking, due to the influence of the inhomogeneity of particle size (particle diameter), selective orientation, etc., even for the same crystal, there is an inherent change in the peak value each time it is measured (each time a sample as a measurement object is prepared) (for example, see the 18th revised edition of the Japanese Pharmacopoeia, "2.58 Powder X-ray Diffraction Measurement Method", "5. Qualitative Analysis (Identification of Phases)"). This is because the diffraction angle (2θ) in powder X-ray diffraction may produce an error within the range of ±0.2, so it is necessary to understand that the value of the above diffraction angle also includes a numerical value within the range of about ±0.2.

[0503] The crystals of the compound of the present invention or its pharmaceutically acceptable salt are preferably the following crystals:

[0504] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate, wherein in powder X-ray diffraction using CuKα rays, the crystal has peaks at at least five of diffraction angles (2θ) selected from the group consisting of 6.33±0.2, 8.40±0.2, 12.68±0.2, 16.87±0.2, 18.36±0.2, 20.73±0.2, 22.39±0.2, 24.33±0.2, and 25.55±0.2;

[0505] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate, wherein in powder X-ray diffraction using CuKα radiation, the crystal has peaks at at least five diffraction angles (2θ) selected from the group consisting of 4.65±0.2, 9.33±0.2, 10.13±0.2, 12.73±0.2, 18.76±0.2, 19.51±0.2, 21.73±0.2, 23.92±0.2, 26.02±0.2, and 27.11±0.2;

[0506] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one benzenesulfonate, wherein in powder X-ray diffraction using CuKα rays, the crystal has peaks at at least five of diffraction angles (2θ) selected from the group consisting of 5.75±0.2, 7.08±0.2, 11.55±0.2, 12.76±0.2, 13.34±0.2, 16.04±0.2, 17.18±0.2, 22.91±0.2, 25.41±0.2 and 25.73±0.2; or

[0507] The invention relates to a crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate, wherein in powder X-ray diffraction using CuKα rays, the crystal has peaks at at least five diffraction angles (2θ) selected from the group consisting of 6.76±0.2, 8.11±0.2, 12.23±0.2, 13.54±0.2, 15.88±0.2, 16.75±0.2, 18.88±0.2, 19.71±0.2, 21.35±0.2 and 25.76±0.2.

[0508] More preferably, the following crystals are used:

[0509] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate, wherein in powder X-ray diffraction using CuKα rays, the crystal has peaks at diffraction angles (2θ) of 6.33±0.2, 12.68±0.2, 16.87±0.2, 18.36±0.2 and 20.73±0.2;

[0510] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate, wherein in powder X-ray diffraction using CuKα radiation, the crystal has peaks at diffraction angles (2θ) of 4.65±0.2, 9.33±0.2, 12.73±0.2, 18.76±0.2 and 27.11±0.2;

[0511] A crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one benzenesulfonate, wherein in powder X-ray diffraction using CuKα rays, the crystal has peaks at diffraction angles (2θ) of 5.75±0.2, 7.08±0.2, 11.55±0.2, 13.34±0.2, 25.41±0.2, and 25.73±0.2; or

[0512] The present invention relates to a crystal of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate, and in powder X-ray diffraction using CuKα rays, the crystal has peaks at diffraction angles (2θ) of 6.76±0.2, 8.11±0.2, 13.54±0.2, 21.35±0.2 and 25.76±0.2.

[0513] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits SMG1 inhibitory activity, NMD inhibitory activity, anticancer activity as a single agent, and anticancer activity by combined use with an immune checkpoint inhibitor, and is useful as a medicine.

[0514] One embodiment of the present invention relates to a pharmaceutical composition for treating cancer, comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and the pharmaceutical composition may contain a pharmaceutically acceptable carrier.

[0515] Another aspect of the present invention relates to a method for treating cancer, characterized by administering an effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof.

[0516] In the present invention, the type of cancer to be treated is not particularly limited, as long as it is a cancer that is confirmed to be sensitive to the compound of the present invention. It should be noted that "cancer" in this specification is synonymous with malignant tumors, which can be roughly divided into solid cancers including epithelial cell cancer and sarcoma, or blood cancers, and also includes rare cancers such as mesothelioma.

[0517] The so-called "blood cancer" is a cancer caused by the canceration of blood cells, and examples thereof include leukemia, lymphoma, and multiple myeloma.

[0518] The so-called "solid cancer" is a general term for epithelial cell cancer and sarcoma. Among them, "epithelial cell cancer" is a cancer that arises from epithelial cells, and examples thereof include gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, bile duct cancer, thymus cancer, bladder cancer and brain tumors.

[0519] The so-called "sarcoma" is a malignant tumor that can form in connective tissues such as bones and soft tissues (fat, muscle, nerves, etc.), and examples thereof include osteosarcoma, chordoma, chondrosarcoma, and Ewing sarcoma.

[0520] Preferably, the cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

[0521] The term "treatment" and its derivatives as used herein refers to alleviation, alleviation and / or delay of aggravation of the clinical status of cancer in patients already suffering from cancer.

[0522] Another aspect of the present invention relates to a pharmaceutical composition for treating cancer, characterized in that the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

[0523] Another aspect of the present invention relates to a method for treating cancer, characterized in that the compound of the present invention or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

[0524] The compound of the present invention or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor may be contained in different preparations as active ingredients, or may be contained in a single preparation. When contained as active ingredients in different preparations, they may be administered simultaneously or at different times.

[0525] The “immune checkpoint inhibitor” in this specification refers to a drug that releases the inhibition of T cell activation by binding to an immune checkpoint molecule or its ligand and inhibiting the transmission of immunosuppressive signals.

[0526] Examples of immune checkpoint inhibitors include anti-PD-1 antibodies, anti-PD-L1 antibodies, and anti-CTLA-4 antibodies. Examples of anti-PD-1 antibodies include nivolumab and pembrolizumab, examples of anti-PD-L1 antibodies include atezolizumab, avelumab, and durvalumab, and examples of anti-CTLA-4 antibodies include ipilimumab, but are not limited thereto.

[0527] Another embodiment of the present invention is a SMG1 inhibitor comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0528] The "SMG1 inhibitor" in this specification is a drug that has SMG1 kinase activity inhibitory activity and exerts a pharmacological action. The kinase activity of SMG1 is essential for the nonsense mutation-mediated mRNA degradation mechanism (NMD), and therefore, the SMG1 inhibitor is a drug that has NMD inhibitory activity.

[0529] Another embodiment of the present invention is an NMD inhibitor comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0530] The “NMD inhibitor” in the present specification is an agent that inhibits the nonsense mutation-mediated mRNA degradation mechanism (NMD) and exerts a pharmacological action.

[0531] The so-called nonsense mutation-mediated mRNA degradation mechanism (NMD) is one of the mRNA quality control mechanisms. Specifically, it is the following mechanism: due to nonsense mutations, frameshift mutations in the genome, or due to abnormalities in splicing, premature stop codons generated in mRNA are recognized by NMD and induced to degradation. In addition, some long non-coding RNAs are also the targets of NMD.

[0532] The so-called premature stop codon is a stop codon that appears upstream of the original stop codon.

[0533] (Manufacturing method)

[0534] Representative methods for producing the compound represented by formula (1) or a pharmaceutically acceptable salt thereof are described below. The compound of the present invention can be produced by various production methods, and the production method described below is an example, and the present invention should not be construed as being limited thereto.

[0535] For the compound represented by formula (1) or its pharmaceutically acceptable salt, various known manufacturing methods can be used to manufacture the compound based on the characteristics of its basic skeleton or substituent type. As known methods, for example, there are methods described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS", 2nd edition, Academic Press, Inc., 1989, "Comprehensive Organic Transformations", VCH Publishers Inc., 1989, etc.

[0536] At this time, depending on the type of functional group present in the compound, it may be effective in terms of production technology to protect the functional group with an appropriate protecting group in advance at the stage of raw materials or intermediates, or to replace it with a group that can be easily converted into the functional group in advance.

[0537] Examples of such functional groups include amino, hydroxyl and carboxyl groups, and examples of their protecting groups include those described in “Greene's Protective Groups in Organic Synthesis (4th edition, John Wiley & Sons, Inc., 2006)” by TW Greene and PG Wuts.

[0538] The protecting group or the group that can be easily converted into the functional group may be appropriately selected and used according to the reaction conditions of each production method for producing the compound.

[0539] According to such a method, after the group is introduced and the reaction is carried out, the protecting group can be removed as necessary or converted into a desired group, thereby obtaining a desired compound.

[0540] The compound represented by formula (1) can be produced by, for example, the following [A1 method], [A2 method], [B1 method], [B2 method], [B3 method], [B4 method], [C1 method], [C2 method], [C3 method], [D1 method], [D2 method], [D3 method], and [E method]. In the present production method, it can be obtained by using commercially available compounds or the production methods shown in the following reference examples.

[0541] [A1 method]

[0542] Method A1 is a method for producing 1a among compounds represented by formula (1).

[0543] [Chemical formula 22]

[0544]

[0545] [Where R 1 , R 2 and R 3 has the same meaning as above. Q represents hydrogen or alkoxycarbonyl.]

[0546] (Step A1-1) Step of constructing 1,6-naphthyridin-2(1H)-one structure

[0547] This is a step in which compounds 1b and 1c are reacted in a solvent using a base to obtain compound 1a.

[0548] Examples of the base include piperidine, pyrrolidine, triethylamine, N,N-diisopropylethylamine, and pyridine.

[0549] Examples of the solvent include ethanol, n-butanol, 2-propanol, methanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran.

[0550] The reaction temperature is usually 50°C to 120°C, and the reaction time is usually about 1 hour to 24 hours.

[0551] [A2 method]

[0552] When the structure of compound 1a is represented by 1a-1, method A2 is a method for producing compound 1a-1.

[0553] [Chemical formula 23]

[0554]

[0555] [Where R 17a Indicates NR 19a or CHR 19a , R 18a represents a C1-C6 alkyl group which may be substituted by a C1-C6 alkyl group, or a C3-C8 cycloalkyl group, R 27a represents phenyl, heteroaryl or 4-7 membered heterocyclic group, n 1 Represents 0, 1, or 2, R 5 represents hydrogen, C1-C6 alkyl which may be substituted with halogen, or C3-C8 cycloalkyl, R 19a represents a hydrogen atom or a C1-C6 alkyl group. 19a With R 5 They may be bonded to each other to form a ring structure. In addition, Boc represents a tert-butyloxycarbonyl group, and t-Bu represents a tert-butyl group.]

[0556] (A2-1 step) Deprotection step

[0557] The process is as follows: Compound 1a-2 is reacted with an acid in a solvent to obtain compound 1a-3.

[0558] Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid, and hydrogen chloride.

[0559] Examples of the solvent include dichloromethane, 1,4-dioxane, toluene, and ethyl acetate.

[0560] The reaction temperature is usually room temperature to about 100° C., and the reaction time is usually about 30 minutes to 24 hours.

[0561] (Step A2-2) Step of constructing a macrocyclic ring

[0562] The process is as follows: Compound 1a-3 is reacted with a base and a condensing agent in a solvent to obtain compound 1a-1.

[0563] Examples of the base include N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and pyridine.

[0564] Examples of the condensing agent include O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and N,N′-dicyclohexylcarbodiimide.

[0565] Examples of the solvent include N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, tetrahydrofuran, and acetonitrile.

[0566] The reaction temperature is usually room temperature to about 80°C, and the reaction time is usually about 1 hour to 3 days.

[0567] [B1 method]

[0568] Method B1 is a method for producing compound 1b.

[0569] [Chemical formula 24]

[0570]

[0571] [Where R 1 Has the same meaning as above.]

[0572] (B1-1 step) Step of reducing the nitro group

[0573] The process is as follows: Compound 2b is reacted in a solvent using an acid and a metal having a reducing power to obtain compound 3b.

[0574] Examples of the acid include ammonium chloride, hydrochloric acid, and acetic acid.

[0575] Examples of the metal include iron, tin, and zinc.

[0576] Examples of the solvent include ethanol, methanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, water, and a mixture thereof.

[0577] The reaction temperature is usually about 50°C to 120°C, and the reaction time is usually about 1 hour to 2 days.

[0578] (Step B1-2) Step of constructing an imidazo[4,5-c]pyridine structure

[0579] The process is as follows: Compound 1b is obtained by reacting compound 3b with ethyl 3-ethoxy-3-iminopropionate hydrochloride in a solvent.

[0580] Examples of the solvent include ethanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, and mixtures thereof.

[0581] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to 2 days.

[0582] [B2 method]

[0583] When the structure of compound 2b is represented by 2b-1, method B2 is a method for producing compound 2b-1.

[0584] [Chemical formula 25]

[0585]

[0586] [Where R 17b-1 represents a C1-C6 alkyl group, a hydroxyl group, an amino group, an alkoxycarbonyl group, an aminocarbonyl group, a C3-C8 cycloalkyl group, a phenyl group, a heteroaryl group or a 4-7 membered heterocyclic group which may be substituted by halogen, 2 Represents 0, 1, or 2, R 17b-2 represents hydrogen or C1-C6 alkyl. 17b-1 With R 17b-2 Can bond to each other to form a ring structure.]

[0587] (Step B2-1) Step of performing aromatic nucleophilic substitution

[0588] The process is as follows: Compound 2b-1 is obtained by reacting compound 4b with compound 5b and a base in a solvent.

[0589] Examples of the base include calcium carbonate, cesium carbonate, sodium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, sodium hydride, and 1,8-diazabicyclo[5,4,0]-7-undecene.

[0590] Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 2-propanol, ethanol, and methanol.

[0591] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to about 6 days.

[0592] [B3 method]

[0593] When the structure of compound 2b is represented by 2b-2, method B3 is a method for producing compound 2b-2.

[0594] [Chemical formula 26]

[0595]

[0596] [Where R 17b-3 represents a C1-C6 alkyl group, a C3-C8 cycloalkyl group, a phenyl group, or a heteroaryl group which may be halogenated, and M represents an organic boron such as a dialkoxy boron group, an organic zinc such as a monoalkyl zinc group, an organic tin such as a zinc halide or a trialkyl tin group, an organic aluminum such as a magnesium halide or a dialkyl aluminum group, or an organic zirconium such as a monoalkyl zirconium group.]

[0597] (B3-1 step) Cross-coupling step

[0598] This is a step in which compound 6b is reacted with compound 4b, a palladium catalyst, and, if necessary, a base in a solvent to obtain compound 2b-2.

[0599] Examples of the palladium catalyst include [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and bis(triphenylphosphine)dichloropalladium(II).

[0600] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and triethylamine.

[0601] Examples of the solvent include 1,4-dioxane, 2,2-dimethoxyethane, tetrahydrofuran, toluene, N,N-dimethylformamide, water, and a mixture thereof.

[0602] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to 2 days.

[0603] [B4 method]

[0604] When the structure of compound 3b is represented by 3b-1, method B4 is a method for producing compound 3b-1.

[0605] [Chemical formula 27]

[0606]

[0607] [wherein, U represents a dihydroxyboryl group or a (pinacol)boryl group, and J represents an oxygen atom or NR 17b-4 , n 3 and n 4 are the same or different, each independently representing 1, 2 or 3, R 17b-4 represents hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, or tert-butoxycarbonyl.]

[0608] (B4-1 step) Cross-coupling step

[0609] The process is as follows: Compound 8b is obtained by reacting Compound 7b with Compound 5b, a palladium catalyst and a base in a solvent.

[0610] The process can be carried out using the same palladium catalyst and base as in step B3-1, and at the same reaction temperature and reaction time.

[0611] (B4-2 step) Step of reducing double bonds and nitro groups

[0612] The process is as follows: Compound 8b is reacted using hydrogen and a platinum catalyst to obtain compound 3b-1.

[0613] Examples of the platinum catalyst include platinum (IV) oxide and platinum (sulfide) carbon.

[0614] Examples of the solvent include ethanol, tetrahydrofuran, ethyl acetate, methanol, and mixtures thereof.

[0615] The reaction temperature is usually room temperature to about 80°C, and the reaction time is usually about 1 hour to 2 days.

[0616] Compounds 6b and 7b are known, or can be prepared by using known compounds as starting materials according to known methods or methods analogous thereto. Known compounds can be purchased from commercial suppliers, or can be easily synthesized using methods described in the literature or methods analogous thereto. As known literature, for example, J. Am. Chem. Soc., 132, 50, 17701-17703 (2010), Angew. Chem. Int. Ed., 50, 8230-8232 (2011), WO2010018113, US20100298575, Chem. Commun.,

[0617] (18),2143-2145(2008), Adv.Synth.&Catal.,359,2741-2746(2017), Heterocycles,91,1654-1659(2015), WO2008156726A1, WO2009048527 A1, US20090118284A1, WO2009058801A1, US20090197864 A1, Eur.J.Org.Chem.,2021,6551-6560(2021), Angew.Chem.Int.Ed.,47,4851-4854(2008), J.Am.Chem.S oc., 139, 7741-7744 (2017), Eur. J. Org. Chem., 2016, 83-86 (2016), J. Org. Chem., 65, 5653-5658 (2000), etc.

[0618] [C1 method]

[0619] When the structure of compound 1c is represented by 1c-1, method C1 is a method for producing compound 1c-1.

[0620] [Chemical formula 28]

[0621]

[0622] [Where R 3 , Q and n 2 Same as above. 27c-1 represents a C1-C6 alkyl group, a hydroxyl group, an amino group, a halo group, an alkoxycarbonyl group, an aminocarbonyl group, a C3-8 cycloalkyl group, a phenyl group, a heteroaryl group or a 4-7 membered heterocyclic group which may be substituted with halogen, and R 27c-2 represents hydrogen or C1-C6 alkyl. 27c-1 With R 27c-2 Can bond to each other to form a ring structure.]

[0623] (Step C1-1) Step of performing aromatic nucleophilic substitution

[0624] The process is as follows: Compound 2c is reacted with compound 3c and a base in a solvent to obtain compound 1c-1.

[0625] Examples of the base include calcium carbonate, cesium carbonate, sodium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, sodium hydride, and 1,8-diazabicyclo[5,4,0]-7-undecene.

[0626] Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 2-propanol, ethanol, and methanol.

[0627] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to about 6 days.

[0628] [C2 method]

[0629] When the structure of compound 1c is represented by 1c-2, method C2 is a method for producing compound 1c-2.

[0630] [Chemical formula 29]

[0631]

[0632] [Where R 3 , M and Q have the same meanings as above. 27c-3 represents a phenyl group, a heteroaryl group, a C1-C6 alkyl group or a C3-C8 cycloalkyl group, and G represents a chloro group, a bromo group or an iodo group.]

[0633] (C2-1 step) Cross-coupling step

[0634] This is a step in which compound 4c is reacted with compound 5c, a palladium catalyst, and, if necessary, a base in a solvent to obtain compound 1c-2.

[0635] Examples of the palladium catalyst include [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and bis(triphenylphosphine)dichloropalladium(II).

[0636] Examples of the base include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and triethylamine.

[0637] Examples of the solvent include 1,4-dioxane, 2,2-dimethoxyethane, tetrahydrofuran, toluene, N,N-dimethylformamide, water, and a mixture thereof.

[0638] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to 2 days.

[0639] [C3 method]

[0640] When the structure of compound 1c is represented by 1c-3, method C3 is a method for producing compound 1c-3.

[0641] [Chemical formula 30]

[0642]

[0643] [Where R 3 , G, U, J, Q, n 3 and n 4Synonymous with the previous text.]

[0644] (C3-1 step) Cross-coupling step

[0645] The process is as follows: Compound 6c is reacted with compound 5c, a palladium catalyst and a base in a solvent to obtain compound 7c.

[0646] The process can be carried out using the same palladium catalyst and base as in step C2-1, and at the same reaction temperature and reaction time.

[0647] (Step C3-2) Step of reducing double bonds

[0648] The process is as follows: Compound 1c-3 is obtained by reacting compound 7c in a solvent using hydrogen and a transition metal catalyst.

[0649] Examples of the transition metal catalyst include palladium carbon, platinum (IV) oxide, platinum (sulfide) carbon, and tris(triphenylphosphine)rhodium (I) chloride.

[0650] Examples of the solvent include ethyl acetate, ethanol, tetrahydrofuran, methanol, toluene, and mixtures thereof.

[0651] The reaction temperature is usually room temperature to about 80°C, and the reaction time is usually about 1 hour to 2 days.

[0652] Compound 4c and compound 6c are known, or known compounds are used as starting materials and are manufactured according to known methods or methods similar thereto. Known compounds can be purchased from commercial suppliers, or can be easily synthesized using methods described in documents or methods similar thereto. As known documents, documents identical to those described in the manufacture methods of compounds 6b and 7b can be cited.

[0653] [D1 method]

[0654] The D1 method is a method for producing 1e among the compounds represented by the formula (1).

[0655] [Chemical formula 31]

[0656]

[0657] [Where R 1 , R 2 , R 3 and Boc have the same meaning as above.]

[0658] (Step D1-1) Step of constructing a 2-aminoimidazo[4,5-c]pyridine structure

[0659] The process is as follows: Compound 2e is reacted with compound 3b, a base and an imide compound in a solvent to obtain compound 3e.

[0660] Examples of the base include imidazole, pyridine, and 4-dimethylaminopyridine.

[0661] Examples of the imide compound include N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0662] Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, and acetonitrile.

[0663] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to about 24 hours.

[0664] (Step D1-2) Step of constructing a 3,4-dihydropyrido[4,3-d]pyrimidine structure

[0665] This is a step of removing the Boc group from compound 3e using an acid, and then reacting the compound 3e using a base and 1,1'-carbonyldiimidazole in a solvent, or reacting the compound 3e using a base in a solvent.

[0666] Examples of the acid include hydrogen chloride and trifluoroacetic acid.

[0667] Examples of the base include triethylamine, sodium hydride, N,N-diisopropylethylamine, and N-methylmorpholine.

[0668] Examples of the solvent include dichloromethane, 1,4-dioxane, tetrahydrofuran, and ethyl acetate.

[0669] The reaction temperature is usually room temperature to about 110°C, and the reaction time is usually about 1 hour to about 24 hours.

[0670] [D2 method]

[0671] Method D2 is a method for preparing compound 2e.

[0672] [Chemical formula 32]

[0673]

[0674] [Where R 2 , R 3 and Boc have the same meaning as above.]

[0675] (Step D2-1) Step of reducing the formyl group

[0676] The process is as follows: Compound 4e is obtained by reacting compound 1c with a reducing agent in a solvent.

[0677] Examples of the reducing agent include sodium borohydride and the like.

[0678] Examples of the solvent include methanol, ethanol, tetrahydrofuran, water, and mixtures thereof.

[0679] The reaction temperature is usually room temperature to about 80°C, and the reaction time is usually about 1 hour to about 10 hours.

[0680] (D2-2 step) Azide step

[0681] This is a step in which compound 4e is reacted with an azidating reagent and, if necessary, a base in a solvent to obtain compound 5e.

[0682] Examples of the azidating agent include diphenylphosphoryl azide alone, a combination of carbon tetrachloride and sodium azide, a combination of ethyl azodicarboxylate, triphenylphosphine and hydrazoic acid, and a combination of triphenylphosphine, iodine and sodium azide.

[0683] Examples of the base include 1,8-diazabicyclo[5,4,0]-7-undecene, imidazole, and triethylamine.

[0684] Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide.

[0685] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to about 24 hours.

[0686] (D2-3 step) step of isothiocyanate conversion

[0687] The process is as follows: Compound 5e is reacted with triphenylphosphine and carbon disulfide in a solvent to obtain compound 2e.

[0688] Examples of the solvent include acetonitrile, tetrahydrofuran, dichloromethane, chloroform, and toluene.

[0689] The reaction temperature is usually room temperature to about 110° C., and the reaction time is usually about 1 hour to 2 days.

[0690] [D3 method]

[0691] The D3 method is a method for producing compound 3e instead of the E1 method.

[0692] [Chemical formula 33]

[0693]

[0694] [Where R1 , R 2 , R 3 and Boc have the same meaning as above.]

[0695] (Step D3-1) Step of reducing an azide group

[0696] The process is as follows: Compound 5e is reacted with triphenylphosphine in a solvent to obtain Compound 6e.

[0697] Examples of the solvent include a mixture of tetrahydrofuran and water, methanol, and the like.

[0698] The reaction temperature is usually room temperature to about 60°C, and the reaction time is usually about 1 hour to 2 days.

[0699] (Step D3-2) Step of constructing a 2-aminoimidazo[4,5-c]pyridine structure

[0700] This is a step in which compound 6e is reacted with compound 3b, 1,1'-thiocarbonyldiimidazole and an imide compound in a solvent to obtain compound 3e.

[0701] Examples of the imide compound include N,N′-diisopropylcarbodiimide, N,N′-dicyclohexylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.

[0702] Examples of the solvent include acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, and tetrahydrofuran.

[0703] The reaction temperature is usually room temperature to about 120° C., and the reaction time is usually about 1 hour to about 24 hours.

[0704] [E Method]

[0705] Method E is a method for producing a methanesulfonate of the compound represented by formula (1).

[0706] [Chemical formula 34]

[0707]

[0708] [Where R 1 , R 2 , R 3 , X and Y have the same meanings as above.]

[0709] (E-1 step) step of methanesulfonation

[0710] This is a step in which a compound represented by formula (1) is reacted with methanesulfonic acid to obtain a salt thereof.

[0711] Examples of the solvent include ethanol, acetonitrile, dichloromethane, and ethyl acetate.

[0712] The reaction temperature is usually room temperature to about 90° C., and the reaction time is usually about 1 hour to about 24 hours.

[0713] The compound produced by the above method can be isolated and purified by a known method such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization, and the like.

[0714] In addition, when a compound or a manufactured intermediate has a chiral carbon, optical isomers exist. For these optical isomers, conventional methods such as fractional recrystallization (salt resolution) and column chromatography with appropriate salts can be used to separate and purify each isomer. As a reference for the method of resolving optical isomers from racemates, "Enantiomers, Racemates and Resolution, John Wiley And Sons, Inc." by J. Jacques et al. can be cited.

[0715] The SMG1 kinase inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof can be measured by, for example, the following method. Purified human SMG1 protein and substrate peptide can be used as materials, and the kinase activity can be measured by ADP-Glo ​​Kinase Assay Kit (ADP-Glo ​​Kinase Assay), and the SMG1 kinase inhibitory activity of the test substance can be evaluated by comparing the kinase activity when the test substance is added with the kinase activity when the test substance is not added.

[0716] The determination of the NMD inhibitory activity in cells of the compound of the present invention or its pharmaceutically acceptable salt can be performed using, for example, the following method. The EMT6 mouse breast cancer cell line was treated with the test substance in vitro for 6 hours, and the increase in the transcription product of Snhg1, a known NMD target gene, was regarded as an indicator of NMD inhibition and quantified. Quantification was performed by real-time PCR.

[0717] The in vivo NMD inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof can be determined by, for example, the following method. Using mice subcutaneously transplanted with EMT6 mouse breast cancer cell lines, tumor tissues were removed 6 hours after oral administration of the test substance, and the increase in Snhg1 transcripts was quantified as an indicator of NMD inhibition in the tumor in the same manner as in vitro.

[0718] The evaluation of the anti-tumor effect of the compound of the present invention or its pharmaceutically acceptable salt in the homologous transplant model can be carried out using, for example, the following method. MC38 mouse colorectal cancer cell line was subcutaneously transplanted into C57BL6 / J mice, and the tumor volume was measured over time. At this time, the inhibition of tumor proliferation in the group to which the test substance (single dose), immune checkpoint inhibitor (single dose), and the test substance and immune checkpoint inhibitor (combination) were administered was quantified as an anti-tumor effect, thereby evaluating the test substance alone and the combined effect with immune checkpoint inhibitors.

[0719] The compound of the present invention or a pharmaceutically acceptable salt thereof is not limited to the immune checkpoint inhibitor, and can be used in combination with various therapeutic agents or preventive agents for diseases for which the compound or a pharmaceutically acceptable salt thereof is considered to show effectiveness.

[0720] The compound of the present invention or its pharmaceutically acceptable salt can also be used in combination with other antitumor agents. As other antitumor agents, for example, alkylating agents, metabolic antagonists, antitumor antibiotics, antitumor plant ingredients, BRM (biological response modifiers), hormones, vitamins, antitumor antibodies, molecular targeted drugs, other antitumor agents, etc. can be cited.

[0721] More specifically, examples of the alkylating agent include alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide or chlorambucil, aziridine-based alkylating agents such as carboquinone or thiotepa, epoxide-based alkylating agents such as dibromomannitol or dibromodulcitol, nitrosourea-based alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozotocin, chlorozotocin or ranimustine, busulfan, improsulfan tosylate or dacarbazine, and the like.

[0722] Examples of various metabolic antagonists include purine metabolic antagonists such as 6-mercaptopurine, 6-thioguanine or thioinosine, pyrimidine metabolic antagonists such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, bromouracil, cytarabine or enocitabine, and folic acid metabolic antagonists such as pemetrexed, methotrexate or trimetrexate.

[0723] Examples of the antitumor antibiotics include anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, pelocycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin or epirubicin, chromatin A3 or actinomycin D, etc.

[0724] Examples of the antitumor plant ingredients include vinca alkaloids such as vindesine, vincristine, and vinblastine, taxanes such as paclitaxel and docetaxel, and epipodophyllotoxins such as etoposide and teniposide.

[0725] Examples of BRM include tumor necrosis factor and indomethacin.

[0726] Examples of the hormone include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfostirol, ethinylestradiol, chlormadinone acetate, and medroxyprogesterone acetate.

[0727] Examples of vitamins include vitamin C and vitamin A.

[0728] Examples of antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib, gefitinib, erlotinib, sunitinib, lapatinib, sorafenib, dasatinib, nilotinib, vemurafenib, and osimertinib.

[0729] Examples of other antitumor agents include cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and versicolor polysaccharide.

[0730] The combined use may be administered simultaneously, or may be administered separately and continuously, or may be administered at a desired interval. The preparations for simultaneous administration may be a mixed preparation or may be prepared separately.

[0731] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, and may comprise a pharmaceutically acceptable carrier, and may be administered in the form of various injections such as intravenous injection, intramuscular injection, subcutaneous injection, or by various methods such as oral administration or transdermal administration. The so-called pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) that participates in transporting the compound of the present invention or a composition comprising the compound of the present invention from a certain organ or organ to another organ or organ.

[0732] The preparation containing the compound of the present invention or its pharmaceutically acceptable salt as an active ingredient can be prepared using additives such as carriers and excipients used in conventional preparations. The administration of the compound of the present invention can be based on oral administration such as tablets, pills, capsules, granules, powders, liquids, etc., or based on injections for intra-articular, intravenous, intramuscular, etc., suppositories, eye drops, eye ointments, transdermal liquids, ointments, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, etc., in any form of non-oral administration.

[0733] As a solid composition for oral administration, tablets, powders, granules, etc. can be used. Such solid compositions are formed by one or more active ingredients and at least one inactive excipient, such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone and / or magnesium aluminum metasilicate, etc. In this solid composition, inactive additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, solubilizers can be contained according to a conventional method. Tablets or pills can be coated with a film of sugar coating or gastric soluble or enteric material as required.

[0734] When used in the form of tablets, as carriers, for example, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid can be used; binders such as water, ethanol, propanol, monosyrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, and polyvinyl pyrrolidone can be used; disintegrants such as dry starch, sodium alginate, agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid monoglyceride, starch, and lactose can be used; disintegration inhibitors such as white sugar, hard fat, cocoa butter, and hydrogenated oil can be used; absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate can be used; humectants such as glycerol and starch can be used; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid can be used; lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used; Furthermore, the tablets may be coated with common coating materials, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layer tablets or multi-layer tablets as required.

[0735] When used in the form of pills, as carriers, for example, excipients such as glucose, lactose, cocoa butter, starch, hydrogenated vegetable oil, kaolin, talc, etc.; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, etc.; disintegrants such as laminarin and agar, etc. can be used.

[0736] As liquid compositions for oral administration, pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs can be used. In such liquid compositions, commonly used inactive diluents, such as purified water or ethanol, can be added. In addition to the inactive diluent, the liquid composition may also contain auxiliary agents such as solubilizers and wetting agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0737] As an injection for parenteral administration, sterile aqueous or non-aqueous solutions, suspensions or emulsions can be used. As aqueous solvents, for example, distilled water for injection or physiological saline are provided. As non-aqueous solvents, for example, vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, or polysorbate 80 are provided. In such an injection composition, isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or cosolvents can also be included. These injection compositions can be sterilized by, for example, filtering through a bacteria-retaining filter, the coordination of a bactericide or irradiation. In addition, with respect to these injection compositions, sterile solid compositions can also be manufactured, which are dissolved or suspended in sterile water or a sterile injection solvent before use and used.

[0738] When used in the form of an injection, it can be used in the form of a liquid, emulsion or suspension. These liquids, emulsions or suspensions are preferably sterilized and isotonic with blood. The solvent used to make these liquids, emulsions or suspensions is not particularly limited as long as it can be used as a diluent for medical use. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. can be cited. It should be noted that, in this case, the preparation can contain salt, glucose or glycerol in an amount sufficient for preparing an isotonic solution, and in addition, it can also contain a common solubilizing agent, a buffer, an analgesic, etc.

[0739] Furthermore, the above-mentioned preparations may contain colorants, preservatives, fragrances, flavors, sweeteners, etc. as necessary, and may further contain other pharmaceutical products.

[0740] The amount of the compound contained in the above-mentioned preparation is not particularly limited and can be appropriately selected within a wide range. Generally, it is contained in an amount of 0.5 to 70% by weight, preferably 1 to 30% by weight, based on the total composition.

[0741] The dosage and the number of administrations of the compound of the present invention can be appropriately determined by considering the symptoms, age, etc. of the patient (warm-blooded animal, especially human). Usually, in the case of oral administration, the dosage per day is suitable for about 0.001-100 mg / kg per unit body weight, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg, which is administered once, or divided into 2 or more times. In the case of intravenous administration, the dosage per day is suitable for about 0.0001-10 mg / kg per unit body weight, and is administered once a day or divided into multiple times.

[0742] Example

[0743] Hereinafter, reference examples and embodiments are given to specifically describe the present invention, but the present invention is not limited thereto, and they are not interpreted restrictively in any sense. In addition, in this specification, reagents, solvents and starting materials not particularly described can be easily obtained from commercially available supply sources.

[0744] Reference Example 1

[0745] Production of ethyl {6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0746] [Chemical formula 35]

[0747]

[0748] (Step 1) 6-Chloro-2-[(3R)-3-methylmorpholin-4-yl]-3-nitropyridin-4-amine

[0749] Potassium carbonate (8.00 g) was added to a solution of (R)-3-methylmorpholine (4.00 mL) and 2,6-dichloro-3-nitropyridine-4-amine (6.00 g) in N,N-dimethylformamide (60 mL) at room temperature, and the mixture was stirred at the same temperature for 23 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed twice with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (6.93 g).

[0750] 1 H-NMR (CDCl 3 )δ:6.04(1H,s),6.01(2H,br s),4.59-4.51(1H,m),3.88-3.83(1H,m),3.79(1H,dd,J=11.6,3.1Hz),3.72( 1H,d,J=11.6Hz),3.61-3.51(2H,m),2.84-2.74(1H,m),1.37(3H,d,J=6.7Hz).

[0751] (Step 2) 6-Chloro-2-[(3R)-3-methylmorpholin-4-yl]pyridine-3,4-diamine

[0752] Iron powder (4.30 g) and ammonium chloride (1.36 g) were added to a mixed solution of ethanol (100 mL) / water (50 mL) of the compound (6.93 g) obtained in the above step 1 at room temperature, and the mixture was stirred at 80°C for 2.5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the residue was washed with ethyl acetate and water. The combined filtrate was concentrated under reduced pressure, and after the ethanol was distilled off, extraction was performed three times with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and a mixed solution of n-hexane / ethyl acetate (1:1) was added to the residue to solidify it. The precipitated solid was separated by filtration to obtain the title compound (4.47 g).

[0753] 1 H-NMR (CDCl 3)δ:6.49(1H,s),3.96(2H,br s),3.95-3.85(2H,m),3.76(1H,td,J=11.0,2.6Hz),3.60(2H,br s),3.52-3.44(1H,m),3.37(1H,dd,J=11.0,9.2Hz),3.02(1H,ddd,J=12.2,9.2,2.6Hz),2.83(1H,dt,J=12.2,2.6Hz),0.83(3H,d,J=6.1Hz).

[0754] (Step 3) Ethyl {6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0755] A mixture of the compound obtained in step 2 (5.04 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (8.11 g) and ethanol (70 mL) was stirred for 9 hours under heating and reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The obtained oily substance was solidified by a mixture of n-hexane / ethyl acetate (10:1). The precipitated solid was separated by filtration, washed with n-hexane, and dried under reduced pressure to obtain the title compound (6.33 g).

[0756] 1 H-NMR (CDCl 3 )δ:10.07(1H,br s),6.76(1H,s),5.48-5.37(1H,m),4.77(1H,d,J=13.4Hz),4.30(2H,q,J=7.3Hz),4.06-4.01(1H,m),4.00(2H,s),3.87(1H ,dd,J=11.0,3.1Hz),3.80(1H,d,J=11.0Hz),3.69(1H,td,J=11.0,3.1Hz),3.47(1H,td,J=12.8,3.1Hz),1.38-1.33(6H,m).

[0757] Reference Example 2

[0758] Production of ethyl {6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0759] [Chemical formula 36]

[0760]

[0761] (Step 1) (3S)-4-Benzylmorpholine-3-carbaldehyde

[0762] 2-Hydroxy-2-azaadamantane (11.1 mg), copper (I) chloride (7.2 mg), 2,2'-bipyridine (11.3 mg) and 4-dimethylaminopyridine (17.7 mg) were added to a solution of [(3R)-4-benzylmorpholin-3-yl]methanol (300 mg, manufactured by BLD PHAR M) in acetonitrile (15 mL) at room temperature, and stirred at the same temperature for 17 hours. Saturated aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution were added to the reaction mixture, and extracted three times with dichloromethane. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (297 mg).

[0763] (Step 2) (3S)-4-Benzyl-3-(difluoromethyl)morpholine

[0764] To a solution of the compound (297 mg) obtained in step 1 above in dichloromethane (7 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (0.78 mL) at 0°C, and the mixture was stirred at room temperature for 4 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and extraction was performed three times with dichloromethane. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (71.4 mg).

[0765] 1 H-NMR (CDCl 3 )δ:7.39-7.22(5H,m),6.21(1H,td,J=55.5,5.5Hz),3.93(1H,dd,J=14.1,3.1H z),3.90-3.79(2H,m),3.78-3.64(3H,m),2.90-2.80(2H,m),2.45-2.37(1H,m).

[0766] (Step 3) (3S)-3-(Difluoromethyl)morpholine hydrochloride

[0767] To a solution of the compound (70 mg) obtained in step 2 above in 1,2-dichloroethane (1 mL) was added 1-chloroethyl chloroformate (0.1 mL) at room temperature, and the mixture was stirred under heating reflux for 8 hours. Then, the reaction mixture was cooled to room temperature, methanol (1 mL) was added, and the mixture was stirred under heating reflux for 1 hour. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure to obtain a crude title compound (54 mg).

[0768] (Step 4) 6-Chloro-2-[(3S)-3-(difluoromethyl)morpholin-4-yl]-3-nitropyridin-4-amine

[0769] To a solution of the compound (50.1 mg) obtained in the above step 3 in 1,4-dioxane (1.5 mL) were added N,N-diisopropylethylamine (155 μL) and 2,6-dichloro-3-nitropyridin-4-amine (60 mg) at room temperature, and the mixture was stirred at 90° C. for 7.5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain a crude title compound (64.5 mg).

[0770] (Step 5) 6-Chloro-2-[(3S)-3-(difluoromethyl)morpholin-4-yl]pyridine-3,4-diamine

[0771] Iron powder (76 mg) and ammonium chloride (36 mg) were added to a mixed solution of ethanol (2 mL) / water (1 mL) of the compound (64.5 mg) obtained in the above step 4 at room temperature, and stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the residue was washed with ethyl acetate and water. The combined filtrate was extracted twice with dichloromethane, and the obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (37.9 mg).

[0772] (Step 6) Ethyl {6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0773] A mixture of the compound obtained in step 5 (37.9 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (68 mg) and ethanol (1 mL) was stirred for 1.5 hours under heating and reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (22.3 mg).

[0774] 1 H-NMR (CDCl 3 )δ:10.14(1H,br s),6.81(1H,s),6.26(1H,td,J=56.3,5.9Hz),5.80-5.78(1H,m),4.81(1H,d,J=14.1Hz),4.32-4.22(3H,m),4.05(1H,dd,J=11.7,3 .1Hz), 3.99 (2H, d, J = 1.8Hz), 3.90-3.80 (1H, m), 3.69 (1H, td, J = 11.7, 3.1Hz), 3.49 (1H, td, J = 13.0, 3.3Hz), 1.34 (3H, t, J = 7.4Hz).

[0775] Reference Example 3

[0776] Production of ethyl {6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0777] [Chemical formula 37]

[0778]

[0779] (Step 1) trans-4-[(4-amino-6-chloro-3-nitropyridin-2-yl)(methyl)amino]cyclohexanol

[0780] Potassium carbonate (276 mg) was added to a solution of trans-4-(methylamino)cyclohexanol (155 mg) and 2,6-dichloro-3-nitropyridine-4-amine (208 mg) in N,N-dimethylformamide (3.3 mL) at room temperature, and the mixture was stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure to obtain a crude title compound.

[0781] (Steps 2 and 3) Ethyl {6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0782] The title compound was obtained by using the compound obtained in the above step 1 as a production raw material and carrying out the same operations as steps 5 and 6 of reference example 2.

[0783] 1 H-NMR (DMSO-D 6)δ:12.57(1H,s),6.70(1H,s),5.24-5.06(1H,m),4.58(1H,d,J=4.9Hz),4.14(2H,q,J=7.0Hz),3.93(2H,s),3 .45-3.37(1H,m),3.14(3H,s),1.93-1.85(2H,m),1.70-1.56(4H,m),1.37-1.25(2H,m),1.21(3H,t,J=7.0Hz).

[0784] Reference Example 4

[0785] Production of ethyl (6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl)amino]-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0786] [Chemical formula 38]

[0787]

[0788] (Step 1) 6-Chloro-3-nitro-N-2-[(2R)-1,1,1-trifluoropropane-2-yl]pyridine-2,4-diamine

[0789] A mixture of (R)-1,1,1-trifluoropropane-2-amine hydrochloride (863 mg), 2,6-dichloro-3-nitropyridin-4-amine (600 mg), N,N-diisopropylethylamine (2.00 mL) and dimethyl sulfoxide (6.0 mL) was stirred at 120°C for 7 hours.

[0790] The reaction mixture was cooled to room temperature, water was added, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed twice with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (723 mg).

[0791] 1 H-NMR (CDCl 3 )δ:9.00(1H,br d,J=9.4Hz),6.07(1H,s),5.31-5.17(1H,m),2.62(2H,s),1.44(3H,d,J=7.0Hz).

[0792] (Steps 2 and 3) (6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl)amino]-1H-imidazo[4,5-c]pyridin-2-yl)acetic acid ethyl ester

[0793] The title compound was obtained by using the compound obtained in the above step 1 as a production raw material and carrying out the same operations as steps 5 and 6 of reference example 2.

[0794] 1 H-NMR (DMSO-D 6 )δ:12.69(1H,s),7.56(1H,d,J=9.4Hz),6.84(1H,s),5.31-5.10(1H,m),4.1 3(2H,q,J=7.0Hz),3.96(2H,s),1.38(3H,d,J=7.0Hz),1.20(3H,t,J=7.0Hz)

[0795] Reference Example 5

[0796] (6-chloro-4-{[dimethyl(oxo)-λ 6 Preparation of ethyl 1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0797] [Chemical formula 39]

[0798]

[0799] (Step 1) 6-chloro-2-{[dimethyl(oxo)-λ 6 -sulfanyl]amino}-3-nitropyridin-4-amine

[0800] A mixture of S,S-dimethylsulfinyl imide (559 mg), 2,6-dichloro-3-nitropyridine-4-amine (416 mg), N,N-diisopropylethylamine (1.05 mL) and 1,4-dioxane (5.0 mL) was stirred for 128 hours under heating reflux. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution and water were added, and ethyl acetate was used for two extractions. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was solidified using a mixed solution of ethyl acetate (3 mL) / n-hexane (9 mL). The precipitated solid was separated by filtration, washed with a mixed solution of n-hexane / ethyl acetate, and dried under reduced pressure to obtain the title compound (346 mg).

[0801] 1 H-NMR (DMSO-D 6 )δ:6.96(2H,s),6.30(1H,s),3.39(6H,s).

[0802] (Steps 2 and 3) (6-chloro-4-{[dimethyl(oxo)-λ6 -sulfanyl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetic acid

[0803] The title compound was obtained by using the compound obtained in the above step 1 as a production raw material and carrying out the same operations as steps 5 and 6 of reference example 2.

[0804] 1 H-NMR (CDCl 3 )δ:10.51-10.22(1H,m),7.18-6.91(1H,m),4.32-4.23(2H,m),4.08-4.03(2H,m),3.51-3.43(6H,m),1.36-1.30(3H,m).

[0805] The same operations as in any of the steps of Reference Examples 1 to 5 were carried out to synthesize the following compounds (Table 1-1 and Table 1-2).

[0806] [Table 1-1]

[0807]

[0808]

[0809] [Table 1-2]

[0810]

[0811]

[0812] Reference Example 12

[0813] Preparation of tert-butyl (2R, 4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate

[0814] [Chemical formula 40]

[0815]

[0816] (Step 1) 1-tert-Butyl 2-methyl (2S, 4R)-4-hydroxypyrrolidine-1,2-dicarboxylate

[0817] Potassium carbonate (1.8 g) and iodomethane (1.1 mL) were added to a solution of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.0 g) in N,N-dimethylformamide (20 mL) at 0°C, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed once with a 5% sodium thiosulfate aqueous solution, twice with water, and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.0 g).

[0818] 1 H-NMR (CDCl 3 )δ:4.55-4.49(1H,m),4.48-4.36(1H,m),3.77-3.71(3H,m),3.68-3.62(1H,m),3.59-3.54(0.67H,m ),3.49-3.43(0.33H,m),2.36-2.20(1H,m),2.14-2.02(1H,m),1.76-1.68(1H,m),1.49-1.38(9H,m).

[0819] (Step 2) 1-tert-Butyl 2-methyl (2S, 4R)-4-{[tert-butyl (dimethyl) silyl] oxy} pyrrolidine-1,2-dicarboxylate

[0820] To a solution of the compound (2.0 g) obtained in the above step 1 in N,N-dimethylformamide (20 mL) were added imidazole (1.1 g) and tert-butyldimethylsilyl chloride (1.4 g) at 0°C, and the mixture was stirred at room temperature for 7.5 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain a crude title compound (3.0 g).

[0821] (Step 3) tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate

[0822] Sodium borohydride (1.2 g) was added to an ethanol (30 mL) solution of the compound (3.0 g) obtained in the above step 2 at 0°C, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.5 g).

[0823] 1 H-NMR (CDCl 3 )δ:4.92(1H,d,J=8.0Hz),4.28(1H,br s),3.73-3.66(1H,m),3.58-3.51(1H,m),3.43(1H,d,J=11.7Hz),3.34(1H,dd,J=11.7 ,3.7Hz),1.98-1.93(1H,m),1.61-1.54(1H,m),1.47(9H,s),0.87(9H,s),0.06(6H,s).

[0824] (Step 4) tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate

[0825] Triethylamine (3.1 mL) and methanesulfonic anhydride (2.9 g) were added to a dichloromethane (30 mL) solution of the compound (2.5 g) obtained in step 3 at 0°C, and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture to separate into two layers, and the aqueous layer was extracted twice with chloroform. The combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.9 g).

[0826] (Step 5) tert-Butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpyrrolidine-1-carboxylate

[0827] To a tetrahydrofuran (30 mL) solution of the compound (2.9 g) obtained in step 4 was added a 1.01 M tetrahydrofuran solution of lithium triethylborohydride (35 mL) at 0°C, and the mixture was stirred at room temperature for 3.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.5 g).

[0828] 1 H-NMR (CDCl 3 )δ:4.36-4.31(1H,m),4.03-3.70(1H,m),3.49-3.23(2H,m),2.04-1.93(1H,m),1.46(9H,s),1.32-1.18(4H,m),0.87(9H,s),0.05(6H,s).

[0829] (Step 6) (2R,4R)-4-Hydroxy-2-methylpyrrolidine-1-carboxylic acid tert-butyl ester

[0830] To a solution of the compound (2.5 g) obtained in step 5 above in tetrahydrofuran (20 mL) was added a 1.0 M tetra-n-butylammonium fluoride solution in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.3 g).

[0831] 1 H-NMR (CDCl 3 )δ:4.42-4.37(1H,m),4.29-3.94(1H,m),3.51-3.43(2H,m),2.16-2.04(1H,m),1.76-1.68(1H,m),1.47(9H,s),1.24(3H,d,J=5.5Hz)

[0832] The same operation as in any step 1 to 6 of Reference Example 12 was carried out to synthesize the following compounds (Table 2-1 and Table 2-2).

[0833] [Table 2-1]

[0834]

[0835] [Table 2-2]

[0836]

[0837] Reference Example 17

[0838] Preparation of tert-butyl (2R, 3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate

[0839] [Chemical formula 41]

[0840]

[0841] (Step 1) tert-Butyl (2R,3S)-3-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)pyrrolidine-1-carboxylate

[0842] 4-Methylbenzenesulfonyl chloride (0.66 g) was added to a pyridine (2.0 mL) solution of the compound obtained in Reference Example 15 at room temperature, and stirred at the same temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with water three times, washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (0.55 g).

[0843] 1 H-NMR (CDCl 3 )δ:7.77(2H,d,J=6.7Hz),7.39-7.31(2H,m),4.39(1H,br s),4.21-3.73(3H,m),3.59-3.32(2H,m),2.45(3H,s),2.14-1.73(3H,m),1.33-1.44(9H,m).

[0844] (Step 2) (2R,3S)-tert-butyl 3-hydroxy-2-methylpyrrolidine-1-carboxylate

[0845] The crude title compound was obtained by using the compound obtained in the above step 1 as a raw material in the same manner as in step 5 of reference example 12.

[0846] Reference Example 18

[0847] Production of ethyl {6-chloro-4-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0848] [Chemical formula 42]

[0849]

[0850] (Step 1) (3R,5R)-5-Methylpyrrolidin-3-ol hydrochloride

[0851] To the compound obtained in step 6 of Reference Example 12 (1.3 g) was added a 4M 1,4-dioxane solution (5 mL) of hydrogen chloride at room temperature, and stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, toluene was added to the obtained residue, and the mixture was concentrated under reduced pressure again to obtain a crude title compound (0.90 g).

[0852] (Step 2) (3R,5R)-1-(4-amino-6-chloro-3-nitropyridin-2-yl)-5-methylpyrrolidin-3-ol

[0853] 2,6-dichloro-3-nitropyridine-4-amine (1.0 g) and potassium carbonate (2.0 g) were added to a solution of the compound (0.90 g) obtained in step 1 in N,N-dimethylformamide (20 mL) at room temperature, and stirred at the same temperature for 27 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (1.6 g).

[0854] (Step 3) (3R,5R)-1-(3,4-diamino-6-chloropyridin-2-yl)-5-methylpyrrolidin-3-ol

[0855] The compound (1.6 g) obtained in the above step 2, iron powder (1.3 g), ammonium chloride (0.13 g), ethanol (20 mL) and water (5 mL) were stirred at 90 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the residue was washed with ethanol. The combined filtrate was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution was added to the residue, ethyl acetate was extracted 3 times, and the obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (1.4 g).

[0856] (Step 4) Ethyl 6-chloro-4-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0857] A mixture of the compound obtained in step 3 (1.4 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.9 g), ethanol (20 mL) and acetic acid (2.7 mL) was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.15 g).

[0858] 1 H-NMR (CDCl 3 )δ:10.00(1H,br s),6.65(1H,s),4.90-4.83(1H,m),4.61-4.55(1H,m),4.27(2H,q,J=7.1Hz),4.21-4.15(1H,m),4.06(1H,dd,J=12. 2,4.3Hz),3.97(2H,s),2.26-2.19(1H,m),1.95-1.88(1H,m),1.67(1H,d,J=4.9Hz),1.58(9H,s),1.35-1.31(6H,m).

[0859] The same operations as steps 1 to 4 of Reference Example 18 were carried out to synthesize the following compounds (Table 3-1).

[0860] [Table 3-1]

[0861]

[0862]

[0863] Reference Example 23

[0864] Production of ethyl [6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0865] [Chemical formula 43]

[0866]

[0867] (Step 1) 6-Chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine

[0868] Under nitrogen atmosphere, a mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (8.48 g), 2,6-dichloro-3-nitropyridine-4-amine (8.00 g), potassium carbonate (10.6 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (785 mg), 1,4-dioxane (80 mL) and water (20 mL) was stirred at 90° C. for 7 hours. After the reaction mixture was cooled to room temperature, water and ethyl acetate were added, and the insoluble matter was removed by diatomaceous earth filtration. The filtrate was extracted 3 times with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (6.08 g).

[0869] 1 H-NMR (CDCl 3 )δ:6.66(1H,s),5.95-5.88(1H,m),5.63(2H,br s),4.25(2H,q,J=2.7Hz),3.91(2H,t,J=5.2Hz),2.53-2.44(2H,m).

[0870] (Step 2) 6-Chloro-2-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diamine

[0871] To a solution of the compound (4.00 g) obtained in the above step 1 in ethanol (100 mL) was added 5%-platinum (sulfide) carbon (916 mg) at room temperature, and stirred at 50°C for 7 hours under a hydrogen atmosphere. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration through celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate (300 mL) was added to the obtained residue, the insoluble matter was filtered off, and the solvent was distilled off under reduced pressure to obtain a crude title compound (2.95 g).

[0872] (Step 3) Ethyl [6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0873] A mixture of the compound obtained in step 2 (3.10 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (5.33 g), ethanol (50 mL) and acetic acid (3.9 mL) was stirred for 4 hours under heating reflux. After the reaction mixture was cooled to room temperature, water was added and extracted three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. The obtained organic layer was filtered and concentrated under reduced pressure. Toluene was added to the residue and concentrated again under reduced pressure. The obtained residue was solidified with ether. The precipitated solid was separated by filtration, washed with a mixture of n-hexane / ethyl acetate (1:3), and dried under reduced pressure to obtain the title compound (2.10 g).

[0874] 1 H-NMR (CD 3 OD)δ:7.36(1H,s),4.21(2H,q,J=7.2Hz),4.13-3.99(4H,m),3.72-3.56(3H,m),2.21-2.03(2H,m),1.83-1.71(2H,m),1.26(3H,t,J=7.2Hz).

[0875] Reference Example 24

[0876] Production of ethyl [6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0877] [Chemical formula 44]

[0878]

[0879] (Step 1) Nonafluorobutane-1-sulfonic acid 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl ester

[0880] To a solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (708 mg) in tetrahydrofuran (15 mL) was added a 1.08 M solution of lithium diisopropylamide in n-hexane-tetrahydrofuran (6.2 mL) at -70°C, and stirred at the same temperature for 1 hour, then a solution of nonafluorobutane-1-sulfonyl fluoride (1.16 mL) in tetrahydrofuran (2.0 mL) was added, and the mixture was heated to 0°C and stirred for further 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed twice with hexane, and the obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain a mixture (1.60 g) of the title compound and a positional isomer of a double bond (nonafluorobutane-1-sulfonic acid 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl ester).

[0881] 1 H-NMR (CDCl 3 )δ:5.85-5.81(0.75H,m),5.74-5.71(0.25H,m),4.30-4.25(1.5H,m),3.93-3.88(0.5 H,m),2.42-2.38(0.5H,m),2.32-2.28(1.5H,m),1.33(1.5H,s),1.31-1.27(4.5H,m).

[0882] (Step 2) 6-Chloro-2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine

[0883] Under a nitrogen atmosphere, a mixture of the compound obtained in the above step 1 (1.00 g), bis(pinacolato)diboron (743 mg), potassium acetate (718 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (200 mg) and 1,4-dioxane (12 mL) was stirred at 80°C for 7.5 hours. After the reaction mixture was cooled to room temperature, 2,6-dichloro-3-nitropyridin-4-amine (360 mg), cesium carbonate (1.67 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (100 mg) and water (3.0 mL) were added, and stirred at 100°C for 2 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration through celite, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give a mixture (299 mg) of the title compound and a positional isomer of the double bond (6-chloro-2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine).

[0884] 1 H-NMR (CDCl 3 )δ:6.66-6.63(1H,m),5.93-5.90(0.72H,m),5.71-5.69(0.28H,m),5.57(2H,br s),4.28-4.23(1.44H,m),3.95-3.89(0.56H,m),2.47-2.42(0.56H,m),2.37-2.33(1.44H,m),1.31(6.48H,s),1.27(2.52H,d,J=4.9Hz).

[0885] (Step 3) 6-Chloro-2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridine-3,4-diamine

[0886] A mixture of the compound obtained in step 2 (299 mg), iron powder (590 mg), ammonium chloride (290 mg), ethanol (8.0 mL) and water (4.0 mL) was stirred at 80 ° C for 2.5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration through diatomaceous earth. The filtrate was extracted with dichloromethane, and the obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a mixture of the crude title compound and the positional isomer of the double bond (6-chloro-2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridine-3,4-diamine) (262 mg).

[0887] (Step 4) Ethyl [6-chloro-4-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0888] A mixture of the compound obtained in step 3 (260 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (400 mg), ethanol (14 mL) and acetic acid (0.50 mL) was stirred for 3 hours under heating and reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain a mixture (223 mg) of the title compound and a positional isomer of the double bond (ethyl [6-chloro-4-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate).

[0889] 1 H-NMR (CDCl 3 )δ:10.90-10.66(0.5H,m),10.47-10.29(0.5H,m),7.77(0.5H,s),7.53(0.5H,d,J=13.4Hz),7.33-7.19(0.5H,m),6.55-6.38(0 .5H,m),4.52-4.44(1.5H,m),4.36-4.24(2H,m),4.16-4.05(2H,m),4.02-3.94(0.5H,m),2.85-2.65(2H,m),1.70-1.19(9H,m).

[0890] (Step 5) Ethyl [6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0891] To a mixed solution of the compound (88.0 mg) obtained in step 4 above in 2-propanol (2.8 mL) / dichloromethane (0.40 mL) was added tris(2,2,6,6-tetramethyl-3,5-heptanedione)manganese (III) (15 mg) at 0°C, and stirred at room temperature for 3 hours under an oxygen atmosphere. Ethyl acetate and a saturated sodium thiosulfate aqueous solution were added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (31.7 mg).

[0892] 1 H-NMR (CDCl 3 )δ:11.12-10.39(1H,m),7.55-7.32(1H,m),4.38-4.24(3H,m),4.11-4.07(2H,m),3.94-3.79(1H,m),2.8 2-2.67(1H,m),2.56-2.48(1H,m),1.80-1.57(2H,m),1.52(3H,s),1.39-1.32(3H,m),1.31-1.25(3H,m).

[0893] Reference Example 25

[0894] Preparation of ethyl 2-{4-[3-(tert-butoxycarbonylamino)phenyl]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0895] [Chemical formula 45]

[0896]

[0897] (Step 1) tert-Butyl N-[3-(4-amino-6-chloro-3-nitro-2-pyridyl)phenyl]carbamate

[0898] Under a nitrogen atmosphere, a mixture of 3-(N-tert-butoxycarbonylamino)phenylboronic acid (228 mg), 2,6-dichloro-3-nitropyridine-4-amine (200 mg), cesium carbonate (284 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (42.7 mg), 1,4-dioxane (4.0 mL) and water (1.0 mL) was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (138 mg).

[0899] 1 H-NMR (CDCl 3 )δ:7.59(1H,br s),7.41-7.36(1H,m),7.31(1H,t,J=7.8Hz),7.12-7.08(1H,m),6.71(1H,s),6.61(1H,br s),5.81(2H,s),1.52(9H,s).

[0900] (Step 2) tert-Butyl N-[3-(3,4-diamino-6-chloro-2-pyridyl)phenyl]carbamate

[0901] Iron powder (211 mg) was added to a mixture of the compound (138 mg) obtained in the above step 1, ammonium chloride (20 mg), ethanol (4 mL) and water (2 mL) at 80 ° C, and stirred for 2 hours at the same temperature. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and ethyl acetate was used for 2 extractions. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (120 mg).

[0902] (Step 3) Ethyl 2-{4-[3-(tert-butoxycarbonylamino)phenyl]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[0903] A mixture of the compound obtained in step 2 (120 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (140 mg), acetic acid (0.4 mL) and ethanol (4 mL) was stirred at 90° C. for 8 hours. The reaction mixture was cooled to room temperature, insoluble matter was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (114 mg).

[0904] 1 H-NMR (DMSO-D 6 )δ:10.93(0.3H,br s),10.60(0.7H,br s),8.34-8.22(1H,m),8.05-7.97(0.3H,m),7.75-7.50(1H,m),7.48-7.27(1.7H,m),6. 74-6.54(1H,m),4.29(2H,q,J=7.0Hz),4.12(2H,s),1.54(9H,s),1.34(3H,t,J=7.0Hz).

[0905] Reference Example 26

[0906] Production of ethyl [6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0907] [Chemical formula 46]

[0908]

[0909] (Steps 1 to 3) Ethyl [6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0910] The title compound was obtained by carrying out the same operations as steps 1 to 3 of Reference Example 25 except that 2-fluorophenylboronic acid was used as a raw material.

[0911] 1 H-NMR (CDCl 3 )δ:11.01-10.87(1H,m),8.04-8.02(1H,m),7.67(1H,s),7.47-7.37(2H,m) ,7.25-7.16(1H,m),4.31(2H,q,J=6.1Hz),4.14(2H,s),1.36-1.34(3H,m).

[0912] Reference Example 27

[0913] Production of ethyl (6-chloro-4-{[(3S)-tetrahydrofuran-3-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0914] [Chemical formula 47]

[0915]

[0916] (Steps 1 to 3)ethyl (6-chloro-4-{[(3S)-tetrahydrofuran-3-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0917] The title compound was obtained by carrying out the same operation as in step 1 of Reference Example 1 and steps 2 and 3 of Reference Example 25 using (S)-3-aminotetrahydrofuran as a production raw material.

[0918] 1 H-NMR (CDCl 3 )δ:10.19(1H,br s),6.72(1H,s),5.52(1H,d,J=8.0Hz),4.92-4.85(1H,m),4.28(2H,q,J=7.2Hz),3.99(2H,s),4.07-3.96(2H,m ),3.90-3.82(1H,m),3.77(1H,dd,J=9.2,3.7Hz),2.42-2.33(1H,m),1.98-1.88(1H,m),1.33(3H,t,J=7.2Hz).

[0919] Reference Example 28

[0920] Production of ethyl (6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0921] [Chemical formula 48]

[0922]

[0923] Ethyl (6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0924] A mixture of 6-chloro-3,4-pyridinediamine (16.7 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (25.0 g) and acetic acid (50 mL) was stirred at 100°C for 4 hours. After the reaction mixture was cooled to room temperature, water (150 mL) was added and cooled to 0°C. The precipitated solid was separated by filtration, washed twice with cold water, and dried to obtain a crude product. Ethanol (50 mL) and water (250 mL) were added to the obtained crude product, stirred at 60°C for 20 minutes, and the insoluble matter was filtered off while hot. The filtrate was cooled to 0°C, the precipitated solid was separated by filtration, washed with water, and dried under reduced pressure to obtain the title compound (14.9 g).

[0925] 1 H-NMR (DMSO-D 6 )δ:13.25-12.83(1H,m),8.67(1H,s),7.64(1H,br s),4.15(2H,q,J=7.0Hz),4.07(2H,s),1.21(3H,t,J=7.0Hz).

[0926] Reference Example 29

[0927] Production of ethyl (6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0928] [Chemical formula 49]

[0929]

[0930] (Step 1) 6-Chloro-2-methyl-3-nitropyridin-4-amine

[0931] To a solution of 2,6-dichloro-3-nitropyridin-4-amine (2.08 g) and tetrakis(triphenylphosphine)palladium(0) (1.16 g) in N,N-dimethylformamide (24 mL) was added a 2.0 M toluene solution of trimethylaluminum (6.0 mL) at room temperature, and the mixture was stirred at 70°C for 3 hours. The reaction mixture was cooled to room temperature, and ice water and ethyl acetate were added, and the insoluble matter was filtered off. The filtrate obtained was extracted twice with ethyl acetate, and then a saturated sodium bicarbonate aqueous solution was added to the water layer, and the mixture was further extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (855 mg).

[0932] 1 H-NMR (CDCl 3 )δ:6.64(1H,s),5.94(2H,br s),2.71(3H,s).

[0933] (Step 2) 6-Chloro-2-methylpyridine-3,4-diamine

[0934] A mixture of the compound obtained in step 1 (853 mg), iron powder (635 mg), ammonium chloride (608 mg), ethanol (16 mL) and water (8.0 mL) was stirred at 80°C for 2.5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by filtration through diatomaceous earth. A saturated aqueous sodium bicarbonate solution was added to the filtrate, extracted 4 times with dichloromethane, 2 times with ethyl acetate, and 2 times with a mixed solution of ethyl acetate / tetrahydrofuran (4:1), and the combined organic layer was dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (629 mg).

[0935] (Step 3) Ethyl (6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0936] A mixture of the compound obtained in step 2 (629 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (1.56 g) and ethanol (20 mL) was stirred at 80°C for 4.5 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The product was solidified with a mixture of ethyl acetate (2 mL) / n-hexane (8 mL), filtered, washed with a mixture of n-hexane / ethyl acetate (4:1), and dried under reduced pressure to obtain the title compound (660 mg).

[0937] 1 H-NMR (DMSO-D 6 )δ:12.89(1H,br s),7.45(1H,s),4.14(2H,q,J=7.0Hz),4.04(2H,s),2.64(3H,s),1.21(3H,t,J=7.0Hz).

[0938] Reference Example 30

[0939] Production of ethyl (6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0940] [Chemical formula 50]

[0941]

[0942] (Step 1) 6-Chloro-2-ethyl-3-nitropyridin-4-amine

[0943] To a mixture of 2,6-dichloro-3-nitropyridine-4-amine (4.00 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (785 mg) and 1,4-dioxane (40 mL) was added a 1.12 M n-hexane solution of diethylzinc (21.0 mL) at room temperature, and stirred at 70°C for 3 hours. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium bicarbonate solution was added, and stirred at room temperature for 10 minutes. The insoluble matter was filtered off, and the filtrate was extracted with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.87 g).

[0944] 1 H-NMR (CDCl 3)δ: 6.61 (1H, s), 5.75 (2H, br s), 2.93 (2H, q, J = 7.4Hz), 1.33 (3H, t, J = 7.4Hz).

[0945] (Step 2) 6-Chloro-2-ethylpyridine-3,4-diamine

[0946] Iron powder (1.55 g) was added to a mixed solution of the compound (1.87 g) obtained in step 1 above in tetrahydrofuran (20 mL) / ethanol (10 mL) / water (5.0 mL) at room temperature, and the mixture was heated to 70° C., and then ammonium chloride (51.2 mg) was added, and the mixture was stirred at the same temperature for 3 hours. The reaction mixture was cooled to room temperature, and then filtered through celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure and dried to obtain a crude title compound (1.61 g).

[0947] (Step 3) Ethyl (6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[0948] A mixture of the compound obtained in step 2 (1.61 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.63 g) and ethanol (25 mL) was stirred at 80°C for 9 hours. After the reaction mixture was cooled to room temperature, a 10% aqueous citric acid solution was added and stirred at room temperature for several minutes. Next, a saturated aqueous sodium bicarbonate solution was added to the mixture, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The obtained oily substance was solidified with a mixed solution of ethyl acetate (2.0 mL) / n-hexane (20 mL), filtered and separated, washed with a mixed solution of n-hexane / ethyl acetate (10:1), and dried under reduced pressure to obtain the title compound (1.91 g).

[0949] 1 H-NMR (DMSO-D 6 )δ:13.21-12.74(1H,m),7.44(1H,br s),4.15(2H,q,J=7.0Hz),4.05(2H,s),3.09-2.92(2H,m),1.28(3H,t,J=7.4Hz),1.21(3H,t,J=7.0Hz).

[0950] Reference Example 31

[0951] Production of ethyl [6-chloro-4-(propane-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0952] [Chemical formula 51]

[0953]

[0954] (Step 1) 6-Chloro-3-nitro-2-(prop-1-en-2-yl)pyridin-4-amine

[0955] Under a nitrogen atmosphere, a mixture of isopropenylboronic acid pinacol ester (677 μL), 2,6-dichloro-3-nitropyridine-4-amine (624 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (86 mg), potassium carbonate (829 mg), 1,4-dioxane (12 mL) and water (4.0 mL) was stirred at 90°C for 6 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration. The filtrate was extracted 3 times with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (356 mg).

[0956] 1 H-NMR (CDCl 3 )δ:6.65(1H,s),5.64(2H,s),5.21(1H,s),5.06(1H,s),2.16(3H,s).

[0957] (Step 2) 6-Chloro-2-(propan-2-yl)pyridine-3,4-diamine

[0958] Under a hydrogen atmosphere, a mixture of the compound obtained in step 1 (354 mg), platinum (IV) oxide (56 mg) and ethanol (17 mL) was stirred for 6 hours at 50° C. The reaction mixture was cooled to room temperature, filtered through celite to remove insoluble matter, and the solvent was distilled off under reduced pressure to obtain a crude title compound.

[0959] (Step 3) Ethyl [6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate

[0960] The title compound (338 mg) was obtained by carrying out the same operation as in Step 3 of Reference Example 25 using the compound obtained in the above Step 2 as a raw material.

[0961] 1H-NMR (DMSO-D 6 )δ:12.87(1H,s),7.43(1H,s),4.15(2H,q,J=7.3Hz),4.05(2H,s),3.71-3.57(1H,m),1.29(6H,d,J=7.3Hz),1.21(3H,t,J=7.3Hz).

[0962] Reference Example 32

[0963] Production of 6-chloro-3-nitro-2-propylpyridin-4-amine

[0964] [Chemical formula 52]

[0965]

[0966] 6-Chloro-3-nitro-2-propylpyridin-4-amine

[0967] To a mixture of 2,6-dichloro-3-nitropyridin-4-amine (624 mg), bis(triphenylphosphine)palladium(II) dichloride (211 mg), and tetrahydrofuran (7.5 mL) was added a 0.5 M tetrahydrofuran solution of propylzinc bromide (12 mL) at room temperature, and stirred at 70° C. for 5.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and (n-hexane / dichloromethane) to obtain the title compound (395 mg).

[0968] 1 H-NMR (CDCl 3 )δ:6.60(1H,s),5.69(2H,s),2.90-2.83(2H,m),1.82-1.71(2H,m),1.00(3H,t,J=7.3Hz).

[0969] Reference Example 33

[0970] Production of 6-chloro-2-cyclopropyl-3-nitropyridine-4-amine

[0971] [Chemical formula 53]

[0972]

[0973] 6-Chloro-2-cyclopropyl-3-nitropyridin-4-amine

[0974] The title compound was obtained by the same procedure as in Reference Example 32 except that 0.5 M cyclopropylzinc bromide tetrahydrofuran solution was used as the raw material.

[0975] 1H-NMR (CDCl 3 )δ:6.47(1H,s),5.60(2H,s),2.48-2.39(1H,m),1.24-1.19(2H,m),1.09-1.03(2H,m).

[0976] Reference Example 34

[0977] Production of 2-(4-amino-6-chloro-3-nitropyridin-2-yl)-N-tert-butylacetamide

[0978] [Chemical formula 54]

[0979]

[0980] (Step 1) (4-amino-6-chloro-3-nitropyridin-2-yl)(cyano)acetic acid tert-butyl ester

[0981] To a solution of 2,6-dichloro-3-nitropyridine-4-amine (500 mg) in N,N-dimethylformamide (8.0 mL) was added tert-butyl cyanoacetate (343 μL) and potassium carbonate (664 mg) at room temperature, and the mixture was stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature, 1M hydrochloric acid was added, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure to obtain a crude title compound (752 mg).

[0982] (Step 2) 2-(4-amino-6-chloro-3-nitropyridin-2-yl)-N-tert-butylacetamide

[0983] Trifluoroacetic acid (2.50 mL) was added to a dichloromethane (5.0 mL) solution of the compound (752 mg) obtained in the above step 1 at room temperature, and stirred at the same temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated sodium bicarbonate aqueous solution was added, and extracted three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (132 mg).

[0984] 1 H-NMR (CDCl 3 )δ:6.67(1H,s),6.29(2H,br s),5.64(1H,br s),3.97(2H,s),1.39(9H,s).

[0985] The same operations as steps 2 and 3 of Reference Example 25 were carried out to synthesize the following compounds (Table 4-1).

[0986] [Table 4-1]

[0987]

[0988]

[0989] Reference Example 38

[0990] Production of ethyl [6-chloro-4-(1-hydroxyethyl)-1H-benzimidazol-2-yl]acetate

[0991] [Chemical formula 55]

[0992]

[0993] (Step 1) 1-(4-amino-6-chloro-3-nitropyridin-2-yl)ethanone

[0994] Tributyl(1-ethoxyvinyl)tin (4.60 mL) and bis(triphenylphosphine)palladium(II) chloride (232 mg) were added to a solution of 2,6-dichloro-3-nitropyridin-4-amine (2.75 g) in N,N-dimethylformamide (25 mL) at room temperature, and the mixture was stirred at 90°C for 3.5 hours. The reaction mixture was cooled to room temperature, and water was added, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed twice with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. 1,4-dioxane (25 mL) and 2M hydrochloric acid (30 mL) were added to the obtained residue, and the mixture was stirred at room temperature for 1 hour. 1M sodium hydroxide aqueous solution (60 mL) was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was solidified with a mixture of n-hexane / ethyl acetate / dichloromethane (10:1:1). The precipitated solid was separated by filtration, washed with a mixture of n-hexane / ethyl acetate / dichloromethane (10:1:1), and dried under reduced pressure to obtain a crude title compound (2.24 g).

[0995] (Step 2) 1-(3,4-diamino-6-chloropyridin-2-yl)ethanol

[0996] Sodium borohydride (1.18 g) was added to an ethanol (40 mL) solution of the compound (2.24 g) obtained in the above step 1 at 0°C, and after stirring at room temperature for 1 hour, sodium borohydride (590 mg) was added again, and further stirred at the same temperature for 1 hour. Water was added to the reaction mixture, and the insoluble matter was removed by filtration through diatomaceous earth. The filtrate was extracted 3 times with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (1.55 g).

[0997] (Step 3) 2-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-chloropyridine-3,4-diamine

[0998] To a solution of the compound (1.55 g) obtained in step 2 above in N,N-dimethylformamide (21 mL) was added imidazole (1.55 g) and tert-butyldimethylsilyl chloride (3.50 g) at room temperature, and the mixture was stirred at the same temperature for 16 hours. Ice was added to the reaction mixture, and the mixture was stirred at room temperature for 30 minutes. The precipitated solid was separated by filtration, washed twice with water and twice with hexane, and then dried under reduced pressure to obtain a crude title compound (1.64 g).

[0999] (Step 4) Ethyl 4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate

[1000] A mixture of the compound (1.64 g) obtained in the above step 3, ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.13 g) and ethanol (14 mL) was stirred for 2.5 hours under heating and reflux. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.47 g).

[1001] 1 H-NMR (CDCl 3 )δ:10.86(1H,br s),7.50(1H,s),5.23(1H,q,J=6.1Hz),4.30(2H,q,J=7.3Hz),4.09(2H,s),1. 57-1.51(3H,m),1.34(3H,t,J=7.3Hz),0.92(9H,s),0.18(3H,s),0.10(3H,s).

[1002] (Step 5) Ethyl [6-chloro-4-(1-hydroxyethyl)-1H-benzimidazol-2-yl]acetate

[1003] To a solution of the compound (1.47 g) obtained in step 4 above in 1,4-dioxane (12 mL) was added 6M-hydrochloric acid (3.0 mL) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. A 1M-sodium hydroxide aqueous solution (19 mL) was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The residue was solidified with a mixture of n-hexane / ethyl acetate (2:1), and the precipitated solid was separated by filtration. The obtained solid was suspended in ethyl acetate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (836 mg).

[1004] 1 H-NMR (CDCl 3 )δ:11.05-10.45(1H,m),7.57-7.32(1H,m),5.47-5.24(1H,m),4.39-4.24(2H,m),4.10(2H,s),1.73-1.60(3H,m),1.42-1.26(3H,m).

[1005] Reference Example 39

[1006] Preparation of tert-butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate

[1007] [Chemical formula 56]

[1008]

[1009] (Step 1) tert-Butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-hydroxyethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate

[1010] To a solution of the compound (60.0 mg) obtained in step 5 of Reference Example 38 in tetrahydrofuran (1.0 mL) were added di-tert-butyl dicarbonate (51.0 mg) and 4-dimethylaminopyridine (5.0 mg) at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (71.9 mg).

[1011] 1H-NMR (CDCl 3 )δ:7.76(1H,s),5.43-5.31(1H,m),4.27(2H,s),4.21(2H,q,J=7.1Hz),1.69(9H,s),1.64(3H,d,J=6.7Hz),1.27(3H,t,J=7.1Hz).

[1012] (Step 2) tert-Butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate

[1013] To a solution of the compound (71 mg) obtained in step 1 above in dichloromethane (1 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride (80 μL) at −78° C., the mixture was heated to 0° C., and stirred for 3 hours. The reaction mixture was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (59 mg).

[1014] 1 H-NMR (CDCl 3 )δ:7.83(1H,d,J=1.2Hz),6.20(1H,dq,J=47.3,6.7Hz),4.29(2H,s),4.21(2H, q,J=7.1Hz),1.84(3H,dd,J=23.8,6.7Hz),1.69(9H,s),1.27(3H,t,J=7.1Hz).

[1015] Reference Example 40

[1016] Production of ethyl {4-[{4-[(tert-butoxycarbonyl)(methyl)amino]butyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[1017] [Chemical formula 57]

[1018]

[1019] (Step 1) tert-butyl {4-[(4-amino-6-chloro-3-nitropyridin-2-yl)(methyl)amino]butyl}methylcarbamate

[1020] Potassium carbonate (3.20 g) was added to a solution of tert-butyl N-methyl-N-[4-(methylamino)butyl]carbamate (1.70 g) and 2,6-dichloro-3-nitropyridin-4-amine (1.60 g) in N,N-dimethylformamide (38 mL) at room temperature, and stirred at the same temperature for 6 hours. Water was added to the reaction mixture, and extraction was performed twice with ethyl acetate. The obtained organic layer was washed with water three times, washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (3.00 g).

[1021] (Step 2) tert-butyl {4-[(3,4-diamino-6-chloropyridin-2-yl)(methyl)amino]butyl}methylcarbamate

[1022] A mixture of the compound (3.00 g) obtained in the above step 1, iron powder (2.23 g), ammonium chloride (215 mg), ethanol (39 mL) and water (19 mL) was stirred at 90 ° C for 1.5 hours. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration. Saturated sodium bicarbonate aqueous solution was added to the filtrate, extracted 3 times with ethyl acetate, and the obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (2.85 g).

[1023] (Step 3) Ethyl 4-[{4-[(tert-butoxycarbonyl)(methyl)amino]butyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate

[1024] A mixture of the compound obtained in step 2 (2.80 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (3.10 g), ethanol (20 mL) and acetic acid (4.5 mL) was stirred at 100° C. for 3.5 hours. After the reaction mixture was cooled to room temperature, a saturated sodium bicarbonate aqueous solution was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with water and saturated saline, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.30 g).

[1025] 1 H-NMR (CDCl 3)δ:10.20(1H,br s),6.66(1H,s),4.28(2H,q,J=7.2Hz),4.06-3.98(4H,m),3.37(3H,br s),3.27(2H,br s),2.83(3H,s),1.70-1.62(2H,m),1.62-1.54(2H,m),1.46(9H,s),1.34(3H,t,J=7.2Hz).

[1026] The same operations as steps 1 to 3 of Reference Example 40 were carried out to synthesize the following compounds (Table 5-1).

[1027] [Table 5-1]

[1028]

[1029]

[1030] Reference Example 46

[1031] Production of tert-butyl (3-formyl-2-methylpyridin-4-yl)carbamate

[1032] [Chemical formula 58]

[1033]

[1034] tert-Butyl (3-formyl-2-methylpyridin-4-yl)carbamate

[1035] To a solution of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (4.00 g) in 1,2-dimethoxyethane (30 mL) was added a 50% tetrahydrofuran solution of trimethylboroxine (13.4 mL), potassium carbonate (6.46 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (318 mg) at room temperature, and the mixture was stirred under heating reflux for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite to remove insoluble matter, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (3.26 g).

[1036] 1 H-NMR (CDCl 3 )δ:10.98(1H,br s),10.46(1H,s),8.43(1H,d,J=6.1Hz),8.25(1H,d,J=6.1Hz),2.85(3H,s),1.54(9H,s).

[1037] Reference Example 47

[1038] Production of 4-amino-2,6-dimethylpyridine-3-carboxaldehyde

[1039] [Chemical formula 59]

[1040]

[1041] 4-Amino-2,6-dimethylpyridine-3-carbaldehyde

[1042] The title compound was obtained by the same operation as in Reference Example 46 except that 4-amino-2,6-dichloropyridine-3-carbaldehyde and a 50% tetrahydrofuran solution of trimethylboroxine were used as production raw materials.

[1043] 1 H-NMR (CDCl 3 )δ:10.36(1H,s),6.26(1H,s),2.72(3H,s),2.39(3H,s).

[1044] Reference Example 48

[1045] Production of tert-butyl (2-ethyl-3-formylpyridin-4-yl)carbamate

[1046] [Chemical formula 60]

[1047]

[1048] (Step 1) tert-butyl (2-vinyl-3-formylpyridin-4-yl)carbamate

[1049] Under a nitrogen atmosphere, a mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (2.00 g), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (1.47 mL), cesium carbonate (7.68 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (318 mg), 1,4-dioxane (24 mL) and water (6.0 mL) was stirred for 2.5 hours under heating reflux. The reaction mixture was cooled to room temperature, water was added, and ethyl acetate was used for extraction three times. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.60 g).

[1050] 1 H-NMR (CDCl 3)δ:10.97(1H,br s),10.50(1H,s),8.56(1H,d,J=6.1Hz),8.32(1H,d,J=6.1Hz),7.33(2H,dd,J=17.1 ,10.7Hz),6.27(1H,dd,J=17.1,1.8Hz),5.83(1H,dd,J=10.7,1.8Hz),1.57(9H,s).

[1051] (Step 2) tert-Butyl (2-ethyl-3-formylpyridin-4-yl)carbamate

[1052] To a solution of the compound (2.55 g) obtained in the above step 1 in ethyl acetate (35 mL) was added 10% palladium on carbon (containing 50% water, 273 mg) at room temperature, and stirred at the same temperature for 2 hours under a hydrogen atmosphere. After removing the insoluble matter by filtration through celite, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.30 g).

[1053] 1 H-NMR (CDCl 3 )δ:10.98(1H,br s),10.43(1H,s),8.46(1H,d,J=6.1Hz),8.23(1H,d,J=6.1Hz),3.15(2H,q,J=7.6Hz),1.53(9H,s),1.35(3H,t,J=7.6Hz).

[1054] Reference Example 49

[1055] Production of tert-butyl [3-formyl-2-(1-methylcyclopropyl)pyridin-4-yl]carbamate

[1056] [Chemical formula 61]

[1057]

[1058] (Step 1) Potassium trifluoro(1-methylcyclopropyl)borate (1-)

[1059] Potassium hydrofluoride (510 mg) was added to a mixed solution of 4,4,5,5-tetramethyl-2-(1-methylcyclopropyl)-1,3,2-dioxaborolane (383 mg) in acetonitrile (6.0 mL) / water (0.9 mL) at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, diethyl ether was added to the residue, the precipitated solid was separated by filtration, and the obtained solid was washed with diethyl ether and methanol to obtain a crude title compound (341 mg).

[1060] (Step 2) tert-Butyl [3-formyl-2-(1-methylcyclopropyl)pyridin-4-yl]carbamate

[1061] To a mixed suspension of the compound obtained in the above step 1 (287 mg) and tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (350 mg) in toluene (8.0 mL) / water (2.0 mL) were added cesium carbonate (1.33 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (111 mg) at room temperature, and stirred at 100° C. for 4 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (119 mg).

[1062] 1 H-NMR (CDCl 3 )δ:10.97(1H,br s),10.90(1H,s),8.47(1H,d,J=6.1Hz),8.25(1H,d,J=6.1Hz),1.55(9H,s),1.53(3H,s),1.11(2H,dd,J=6.1,4.3Hz),0.94(2H,dd,J=6.1,4.3Hz).

[1063] Reference Example 50

[1064] Production of tert-butyl [3-formyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate

[1065] [Chemical formula 62]

[1066]

[1067] (Step 1) tert-Butyl [2-(3,6-dihydro-2H-pyran-4-yl)-3-formylpyridin-4-yl]carbamate

[1068] The title compound was obtained by carrying out the same operation as in Step 1 of Reference Example 48 except using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran as a production raw material.

[1069] 1 H-NMR (CDCl 3)δ:10.85(1H,br s),10.15(1H,s),8.53(1H,d,J=6.1Hz),8.28(1H,d,J=6.1Hz),5.79(1H,br s),4.40-4.32(2H,m),3.98(2H,t,J=5.5Hz),2.74-2.65(2H,m),1.55(9H,s).

[1070] (Step 2) tert-Butyl [3-(hydroxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate

[1071] 10%-palladium carbon (containing 50% water, 300 mg) was added to a solution of the compound (660 mg) obtained in the above step 1 in ethanol (20 mL) at room temperature, and stirred at 50°C for 4.5 hours under a hydrogen atmosphere. The reaction mixture was cooled to room temperature, filtered through celite to remove the insoluble matter, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (250 mg).

[1072] 1 H-NMR (CDCl 3 )δ:8.42(1H,d,J=5.5Hz),7.93(1H,br s),7.83(1H,d,J=5.5Hz),4.85(2H,d,J=5.5Hz),4.12-4.06(2H,m),3.55(2H,t,J=11.0Hz), 3.22-3.14(1H,m),2.18-2.07(2H,m),1.97(1H,t,J=5.5Hz),1.63-1.57(2H,m),1.53(9H,s).

[1073] (Step 3) tert-Butyl [3-formyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate

[1074] Manganese dioxide (250 mg) was added to a solution of the compound (250 mg) obtained in step 2 in dichloromethane (10 mL) at room temperature, and stirred at the same temperature for 9.5 hours. Manganese dioxide (500 mg) was then added and stirred at the same temperature for 9.5 hours. Then, manganese dioxide (500 mg) was added to the reaction mixture at room temperature, and stirred at the same temperature for 7 hours. The insoluble matter was removed by filtration through diatomaceous earth, and the residue was washed with dichloromethane. The combined filtrate was concentrated under reduced pressure to obtain the title compound (220 mg).

[1075] 1H-NMR (CDCl 3 )δ:11.02(1H,br s),10.55(1H,s),8.52(1H,d,J=6.1Hz),8.25(1H,d,J=6.1Hz),4.11(2H,dd,J=11 .3,4.0Hz),3.63-3.53(3H,m),2.29-2.18(2H,m),1.74-1.67(2H,m),1.53(9H,s).

[1076] Reference Example 51

[1077] Production of tert-butyl [3-formyl-2-(4-methylpiperazin-1-yl)pyridin-4-yl]carbamate

[1078] [Chemical formula 63]

[1079]

[1080] tert-Butyl [3-formyl-2-(4-methylpiperazin-1-yl)pyridin-4-yl]carbamate

[1081] A mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (200 mg), 1-methylpiperazine (172 μL), potassium carbonate (215 mg) and N,N-dimethylformamide (1.5 mL) was stirred for 7.5 hours at 110° C. The reaction mixture was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (118 mg).

[1082] 1 H-NMR (CDCl 3 )δ:10.76(1H,br s),9.96(1H,s),8.20(1H,d,J=6.1Hz),7.87(1H,d,J=6.1Hz),3.45(4H,t,J=4.9Hz),2.63-2.52(4H,m),2.36(3H,s),1.53(9H,s).

[1083] Reference Example 52

[1084] Production of tert-butyl {2-[4-(dimethylamino)piperidin-1-yl]-3-formylpyridin-4-yl]carbamate

[1085] [Chemical formula 64]

[1086]

[1087] tert-Butyl {2-[4-(dimethylamino)piperidin-1-yl]-3-formylpyridin-4-yl]carbamate

[1088] The title compound was obtained by carrying out the same operation as in Reference Example 51 except using 4-(dimethylamino)piperidine as a raw material.

[1089] 1 H-NMR (CDCl 3 )δ:10.78(1H,br s),9.92(1H,s),8.18(1H,d,J=6.1Hz),7.85(1H,d,J=6.1Hz),3.82-3.72(2H,m),3.1 4-3.04(2H,m),2.38-2.29(7H,m),2.00-1.88(2H,m),1.71-1.61(2H,m),1.53(9H,s).

[1090] Reference Example 53

[1091] {2-[( 2 H 3 Preparation of methyloxyphenylboronic acid

[1092] [Chemical formula 65]

[1093]

[1094] (Step 1) 1-bromo-2-[( 2 H 3 )methyloxy]benzene

[1095] Sodium carbonate (4.66 g) was added to a solution of 2-bromophenol (3.80 g) and iodomethane-d3 (4.78 g) in N,N-dimethylformamide (40 mL) at 0°C, and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted three times with diethyl ether. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / diethyl ether) to obtain the title compound (3.33 g).

[1096] 1 H-NMR (CDCl 3 )δ:7.54(1H,dd,J=7.9,1.8Hz),7.31-7.23(1H,m),6.91(1H,dd,J=8.5,1.2Hz),6.87-6.81(1H,m).

[1097] (Process 2) {2-[( 2 H 3 )methyloxy]phenyl}boronic acid

[1098] To a solution of the compound (3.33 g) obtained in step 1 above in tetrahydrofuran (35 mL) was added a 1.58 M n-butyl lithium n-hexane solution (13.3 mL) at -78°C, stirred at 0°C for 15 minutes, and then triisopropyl borate (5.22 mL) was added at -78°C, and further stirred at 0°C for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed three times with ethyl acetate, and the obtained organic layer was dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (2.44 g).

[1099] Reference Example 54

[1100] {2-fluoro-6-[( 2 H 3 Preparation of methyloxyphenylboronic acid

[1101] [Chemical formula 66]

[1102]

[1103] (Steps 1 and 2) {2-fluoro-6-[( 2 H 3 )methyloxy]phenyl}boronic acid

[1104] The crude title compound was obtained by carrying out the same operations as in Steps 1 and 2 of Reference Example 53 except that 2-bromo-3-fluorophenol was used as a raw material.

[1105] Reference Example 55

[1106] Production of [2-fluoro-6-(methoxymethoxy)phenyl]boric acid

[1107] [Chemical formula 67]

[1108]

[1109] (Step 1) 2-Bromo-1-fluoro-3-(methoxymethoxy)benzene

[1110] Chloro(methoxy)methane (510 μL) and potassium carbonate (1.10 g) were added to a solution of 2-bromo-3-fluorophenol (1.00 g) in acetone (18 mL) at room temperature, and stirred at the same temperature for 15 hours. The insoluble matter was removed by filtration through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.18 g).

[1111] 1 H-NMR (CDCl 3)δ:7.22(1H,td,J=8.4,6.5Hz),6.97-6.93(1H,m),6.85-6.79(1H,m),5.27(2H,s),3.52(3H,s).

[1112] (Step 2) [2-Fluoro-6-(methoxymethoxy)phenyl]boronic acid

[1113] The same operation as in Step 2 of Reference Example 53 was carried out using the compound obtained in Step 1 as a raw material, and the obtained solid was washed with n-hexane and then dried under reduced pressure to obtain the title compound.

[1114] 1 H-NMR (CDCl 3 )δ:7.40(1H,ddd,J=8.5,7.9,7.3Hz),7.00(1H,d,J=7.9Hz),6.81(1H,dd,J=10.4,8.5Hz),6.32-6.26(2H,m),5.31(2H,s),3.52(3H,s).

[1115] Reference Example 56

[1116] Production of 8-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3-oxa-8-azabicyclo[3.2.1]octane

[1117] [Chemical formula 68]

[1118]

[1119] 8-[3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3-oxa-8-azabicyclo[3.2.1]octane

[1120] Potassium carbonate (212 mg) was added to a solution of 2-[3-(bromomethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (151 mg) and 3-oxa-8-azabicyclo[3.2.1]octane hydrochloride (94 mg) in N,N-dimethylformamide (1.5 mL) at room temperature, and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, and extraction was performed twice with ethyl acetate, and the obtained organic layer was dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (167 mg).

[1121] Reference Example 57

[1122] (3-formyl-2-{2-[(2 H 3 Preparation of tert-butyl 1,4-dimethyloxyphenyl)carbamate

[1123] [Chemical formula 69]

[1124]

[1125] (3-formyl-2-{2-[( 2 H 3 tert-Butyl)methyloxy]phenyl}pyridin-4-yl)carbamate

[1126] Under a nitrogen atmosphere, a mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (3.85 g), the compound obtained in step 2 of reference example 53 (2.44 g), sodium carbonate (3.18 g), tetrakis(triphenylphosphine)palladium(0) (867 mg), 1,4-dioxane (38 mL) and water (19 mL) was stirred at 100 ° C for 1 hour. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure. Water was added to the residue, and ethyl acetate was used for extraction three times. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (3.76 g).

[1127] 1 H-NMR (DMSO-D 6 )δ:10.91(1H,br s),9.72(1H,s),8.63(1H,d,J=6.1Hz),8.36(1H,d,J=6.1Hz),7.50-7.43(2H,m),7.14-7.10(1H,m),6.96(1H,d,J=8.5Hz),1.55(9H,s).

[1128] The same operation as in Reference Example 57 was carried out to synthesize the following compounds (Table 6-1).

[1129] [Table 6-1]

[1130]

[1131]

[1132] Reference Example 69

[1133] Production of 4-amino-1'-methyl-1',2',5',6'-tetrahydro[2,3'-bipyridine]-5-carbaldehyde

[1134] [Chemical formula 70]

[1135]

[1136] 4-Amino-1'-methyl-1',2',5',6'-tetrahydro[2,3'-bipyridine]-5-carbaldehyde

[1137] The title compound was obtained by the same operation as in Reference Example 57 using 4-amino-6-chloronicotinaldehyde and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine as raw materials.

[1138] 1 H-NMR (CD 3 OD)δ:9.88(1H,s),8.49(1H,s),8.28(2H,br s),6.84(1H,s),6.83-6.79(1H,m),4.20-4.15(2H,m),3.44-3.35(2H,m),3.01(3H,s),2.74-2.67(2H,m).

[1139] Reference Example 70

[1140] Preparation of methyl 3-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2-methylbenzoate

[1141] [Chemical formula 71]

[1142]

[1143] Methyl 3-{4-[(tert-Butyloxycarbonyl)amino]-3-formylpyridin-2-yl}-2-methylbenzoate

[1144] Under a nitrogen atmosphere, a mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (200 mg), methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (240 mg), cesium carbonate (0.76 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (95 mg), 1,4-dioxane (10 mL) and water (5 mL) was stirred at 100° C. for 1.5 hours. After the reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (240 mg).

[1145] 1 H-NMR (CDCl 3 )δ:10.93(1H,s),9.68(1H,s),8.62(1H,d,J=6.1Hz),8.43(1H,d,J=6.1Hz),7.96 (1H,dd,J=7.4,1.8Hz),7.40-7.35(2H,m),3.92(3H,s),2.33(3H,s),1.56(9H,s).

[1146] The same operation as in Reference Example 70 was carried out to synthesize the following compounds (Table 7-1).

[1147] [Table 7-1]

[1148]

[1149]

[1150] Reference Example 79

[1151] Preparation of tert-butyl [2-(2-cyano-6-fluorophenyl)-3-formylpyridin-4-yl]carbamate

[1152] [Chemical formula 72]

[1153]

[1154] tert-Butyl [2-(2-cyano-6-fluorophenyl)-3-formylpyridin-4-yl]carbamate

[1155] Under a nitrogen atmosphere, a mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (437 mg), 2-cyano-6-fluorophenylboronic acid (312 mg), cesium fluoride (515 mg), copper iodide (67.1 mg), tetrakis(triphenylphosphine)palladium(0) (401 mg) and N,N-dimethylformamide (5.6 mL) was stirred at room temperature for 1 hour. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (200 mg).

[1156] 1 H-NMR (CDCl 3 )δ:10.88(1H,br s),9.78(1H,d,J=3.1Hz),8.71(1H,d,J=6.1Hz),8.55(1H,d,J=6.1Hz),7.68(1H,dd,J=7 .9,1.2Hz),7.61(1H,ddd,J=8.5,7.9,4.9Hz),7.45(1H,td,J=8.5,1.2Hz),1.56(9H,s).

[1157] Reference Example 80

[1158] Production of tert-butyl {2-[2-fluoro-6-(methoxymethoxy)phenyl]-3-formylpyridin-4-yl}carbamate

[1159] [Chemical formula 73]

[1160]

[1161] tert-Butyl {2-[2-fluoro-6-(methoxymethoxy)phenyl]-3-formylpyridin-4-yl}carbamate

[1162] Under a nitrogen atmosphere, a mixture of tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (215 mg), the compound obtained in step 2 of Reference Example 55 (170 mg), cesium carbonate (550 mg), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl) [2-(2'-amino-1,1'-biphenyl)] palladium (II) chloride (66.0 mg), 1,4-dioxane (8.0 mL) and water (2.0 mL) was stirred for 1.5 hours at 100° C. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (225 mg).

[1163] 1 H-NMR (CDCl 3 )δ:10.90(1H,br s),9.81(1H,s),8.66(1H,d,J=6.1Hz),8.43(1H,d,J=6.1Hz),7.39(1H,td,J=8.5,6.7Hz),7.03(1H,d,J =8.5Hz), 6.89(1H,t,J=8.5Hz), 5.13(1H,d,J=7.3Hz), 5.04(1H,d,J=7.3Hz), 3.32(3H,s), 1.55(9H,s).

[1164] Reference Example 81

[1165] Production of tert-butyl {2-[3-(difluoromethoxy)-2-methylphenyl]-3-formylpyridin-4-yl}carbamate

[1166] [Chemical formula 74]

[1167]

[1168] (Step 1) 1-Bromo-3-(difluoromethoxy)-2-methylbenzene

[1169] To a solution of 3-bromo-2-methylphenol (500 mg) in N,N-dimethylformamide (10 mL) was added sodium 2-chloro-2,2-difluoroacetate (820 mg) and cesium carbonate (1.75 g) at room temperature, and the mixture was stirred at 90°C for 9.5 hours. After the reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (400 mg).

[1170] 1 H-NMR (CDCl 3 )δ:7.44-7.41(1H,m),7.07-7.05(2H,m),6.49(1H,t,J=73.9Hz),2.38(3H,s).

[1171] (Step 2) tert-Butyl {2-[3-(difluoromethoxy)-2-methylphenyl]-3-formylpyridin-4-yl}carbamate

[1172] Under a nitrogen atmosphere, a mixture of the compound obtained in the above step 1 (400 mg), bis(pinacolato)diboron (640 mg), potassium acetate (500 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (140 mg) and 1,4-dioxane (20 mL) was stirred at 90°C for 6 hours. The reaction mixture was cooled to room temperature, water (5.0 mL), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (300 mg) and cesium carbonate (1.10 g) were added, and stirred at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (220 mg).

[1173] 1 H-NMR (CDCl 3 )δ:10.93(1H,br s),9.71(1H,s),8.62(1H,d,J=6.1Hz),8.43(1H,d,J=6.1Hz),7.31(1H,t,J=8.5Hz),7.21 (1H,d,J=8.5Hz),7.13(1H,d,J=8.5Hz),6.55(1H,t,J=73.9Hz),2.08(3H,s),1.56(9H,s).

[1174] Reference Example 82

[1175] Production of tert-butyl {2-[2-(difluoromethoxy)phenyl]-3-formylpyridin-4-yl}carbamate

[1176] [Chemical formula 75]

[1177]

[1178] tert-Butyl {2-[2-(difluoromethoxy)phenyl]-3-formylpyridin-4-yl}carbamate

[1179] The title compound was obtained by carrying out the same operation as in Step 2 of Reference Example 81 except that 1-bromo-2-(difluoromethoxy)benzene was used as a raw material.

[1180] 1 H-NMR (CDCl 3)δ:10.93(1H,br s),9.77(1H,s),8.62(1H,d,J=6.1Hz),8.43(1H,d,J=6.1Hz),7.50-7.54(2H,m), 7.39(1H,t,J=7.9Hz), 7.27(1H,d,J=7.9Hz), 6.40(1H,t,J=76.0Hz), 1.56(9H,s).

[1181] Reference Example 83

[1182] Production of tert-butyl (6'-chloro-3-formyl-4'-methoxy[2.3'-bipyridyl]-4-yl)carbamate

[1183] [Chemical formula 76]

[1184]

[1185] (Step 1) 5-Bromo-2-chloro-4-methoxypyridine

[1186] A 1M sodium methoxide methanol solution (200 mL) was added to a solution of 5-bromo-2,4-dichloropyridine (45.0 g) in methanol (250 mL) at 0°C, and the mixture was stirred at room temperature for 24 hours. Ice water (300 mL) was added to the reaction mixture, and the mixture was stirred for 30 minutes. The precipitated solid was separated by filtration, washed once with water and once with cold methanol, and then the operation of removing water by azeotropy with toluene was repeated three times to obtain the title compound (38.0 g).

[1187] 1 H-NMR (CDCl 3 )δ:8.35(1H,s),6.84(1H,s),3.97(3H,s).

[1188] (Step 2) 2-Chloro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[1189] To a tetrahydrofuran (240 mL) solution of the compound (13.0 g) obtained in the above step 1 and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g) was added dropwise a 1.57 M hexane solution of n-butyllithium (52.0 mL) at -78°C, and the mixture was stirred at the same temperature for 2 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture at -78°C, and the mixture was heated to room temperature and then extracted three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure to obtain a crude title compound (15.8 g).

[1190] (Step 3) tert-Butyl (6'-chloro-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl)carbamate

[1191] Under nitrogen atmosphere, a mixture of the compound obtained in step 2 (15.8 g), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (13.0 g), potassium carbonate (14.0 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (825 mg), 1,4-dioxane (120 mL) and water (60 mL) was stirred at 100° C. for 6 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The obtained solid was washed with a mixture of n-hexane / ethyl acetate (6:1) and then dried under reduced pressure to obtain the title compound (11.0 g).

[1192] 1 H-NMR (CDCl 3 )δ:10.84(1H,s),9.69(1H,s),8.63(1H,d,J=6.1Hz),8.44(1H,d,J=6.1Hz),8.39(1H,s),6.94(1H,s),3.84(3H,s),1.55(9H,s).

[1193] Reference Example 84

[1194] Production of tert-butyl (3-formyl-4'-methoxy-6'-methyl[2.3'-bipyridyl]-4-yl)carbamate

[1195] [Chemical formula 77]

[1196]

[1197] tert-Butyl (3-formyl-4'-methoxy-6'-methyl[2,3'-bipyridyl]-4-yl)carbamate

[1198] To a solution of the compound (800 mg) obtained in step 3 of Reference Example 83 in 1,2-dimethoxyethane (12 mL) were added a 50% tetrahydrofuran solution of trimethylboroxine (750 μL), potassium carbonate (610 mg) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (90 mg) at room temperature, and the mixture was stirred for 5 hours under heating reflux. After the reaction mixture was cooled to room temperature, the insoluble matter was removed by diatomaceous earth filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol), and the obtained solid was washed with a mixture of n-hexane / ethyl acetate (5:1), and then dried under reduced pressure to obtain the title compound (623 mg).

[1199] 1 H-NMR (CDCl 3 )δ:10.90(1H,br s),9.73(1H,s),8.66(1H,d,J=5.5Hz),8.50(1H,s),8.42(1H,d,J=5.5Hz),6.79(1H,s),3.83(3H,s),2.65(3H,s),1.58(9H,s).

[1200] Reference Example 85

[1201] Production of tert-butyl (6'-ethyl-3-formyl-4'-methoxy[2.3'-bipyridyl]-4-yl)carbamate

[1202] [Chemical formula 78]

[1203]

[1204] (Steps 1 and 2) tert-butyl (6'-ethyl-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl)carbamate

[1205] The title compound was obtained by using the compound obtained in Step 3 of Reference Example 83 as a raw material and carrying out the same operations as Steps 1 and 2 of Reference Example 48.

[1206] 1 H-NMR (CDCl 3)δ:10.88(1H,br s),9.72(1H,s),8.64(1H,d,J=6.1Hz),8.50(1H,s),8.40(1H,d,J=6.1Hz),6.76 (1H,s),3.82(3H,s),2.88(2H,q,J=7.6Hz),1.55(9H,s),1.35(3H,t,J=7.6Hz).

[1207] Reference Example 86

[1208] Production of tert-butyl (6'-cyclopropyl-3-formyl-4'-methoxy[2.3'-bipyridyl]-4-yl)carbamate

[1209] [Chemical formula 79]

[1210]

[1211] tert-Butyl (6'-cyclopropyl-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl)carbamate

[1212] Under nitrogen atmosphere, a mixture of the compound obtained in step 3 of Reference Example 83 (12.2 g), potassium cyclopropyltrifluoroborate (6.45 g), cesium carbonate (32.8 g), palladium (II) acetate (565 mg), butyl [di (tricyclo [3.3.1.1 ~ 3,7 ~] decane-1-yl)] phosphine (1.80 g), toluene (170 mL) and water (17 mL) was stirred at 100 ° C for 11 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). A mixed solution of ethanol (30 mL) / water (30 mL) was added to the obtained oily substance, and after stirring at 70 ° C for 15 minutes, the mixture was cooled to room temperature. The precipitated solid was separated by filtration, washed with water and a mixed solution of ethanol / water (1:2) in that order, and then dried under reduced pressure to obtain the title compound (10.6 g).

[1213] 1 H-NMR (CDCl 3 )δ:10.87(1H,br s),9.71(1H,s),8.62(1H,d,J=6.1Hz),8.40(1H,s),8.38(1H,d,J=6.1Hz),6 .76(1H,s),3.81(3H,s),2.12-2.01(1H,m),1.55(9H,s),1.21-0.99(4H,m).

[1214] Reference Example 87

[1215] Production of tert-butyl [6'-cyclopropyl-4'-(difluoromethoxy)-3-formyl[2,3'-bipyridyl]-4-yl]carbamate

[1216] [Chemical formula 80]

[1217]

[1218] (Step 1) 5-Bromo-2-chloropyridin-4-ol

[1219] 12M-hydrochloric acid (1 mL) was added to a suspension of 5-bromo-2,4-dichloropyridine (300 mg) in 1,4-dioxane (1 mL) at room temperature, and stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, 1M-sodium hydroxide aqueous solution (12 mL) was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (188 mg).

[1220] 1 H-NMR (DMSO-D 6 )δ:12.27(1H,br s),8.33(1H,s),6.90(1H,s).

[1221] (Step 2) 5-Bromo-2-chloro-4-(difluoromethoxy)pyridine

[1222] To a solution of the compound (185 mg) obtained in the above step 1 in N,N-dimethylformamide (4.4 mL) were added cesium carbonate (578 mL) and sodium bromodifluoroacetate (262 mg) at room temperature, and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled to room temperature and purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (156 mg).

[1223] 1 H-NMR (CDCl 3 )δ:8.53(1H,s),7.19-7.15(1H,m),6.70(1H,t,J=71.1Hz).

[1224] (Steps 3 and 4) tert-Butyl [6'-chloro-4'-(difluoromethoxy)-3-formyl[2,3'-bipyridyl]-4-yl]carbamate

[1225] The title compound was obtained by using the compound obtained in the above step 2 as a raw material and carrying out the same operations as steps 2 and 3 of reference example 83.

[1226] 1 H-NMR (CDCl 3 )δ:10.86(1H,br s),9.76(1H,s),8.64(1H,d,J=6.1Hz),8.52(1H,s),8.50(1H,d,J=6.1Hz),6.57(1H,t,J=71.1Hz),1.56(9H,s).,MS(m / z):400(M+H) + .

[1227] (Step 5) tert-Butyl [6'-cyclopropyl-4'-(difluoromethoxy)-3-formyl[2,3'-bipyridyl]-4-yl]carbamate

[1228] Under a nitrogen atmosphere, a mixture of the compound obtained in step 4 (78.0 mg), potassium cyclopropyltrifluoroborate (86.0 mg), cesium carbonate (127 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (16.0 mg), toluene (2.0 mL) and water (0.5 mL) was stirred for 6 hours at 100° C. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (18.0 mg).

[1229] 1 H-NMR (CDCl 3 )δ:10.89(1H,br s),9.77(1H,s),8.62(1H,d,J=6.1Hz),8.51(1H,s),8.44(1H,d,J=6.1Hz),7.01( 1H,s),6.56(1H,t,J=72.1Hz),2.14-2.03(1H,m),1.55(9H,s),1.22-0.99(4H,m).

[1230] Reference Example 88

[1231] Production of tert-butyl [3-formyl-2-(4-methoxy-2-methylpyrimidin-5-yl)pyridin-4-yl]carbamate

[1232] [Chemical formula 81]

[1233]

[1234] (Steps 1 to 4) tert-Butyl [3-formyl-2-(4-methoxy-2-methylpyrimidin-5-yl)pyridin-4-yl]carbamate

[1235] The title compound was obtained by using 5-bromo-2,4-dichloropyrimidine as a raw material and carrying out the same procedures as steps 1 and 2 of Reference Example 83 and Reference Example 70 and Reference Example 84.

[1236] 1 H-NMR (CDCl 3 )δ:10.88(1H,s),9.76(1H,s),8.64(1H,d,J=6.1Hz),8.60(1H,s),8.45(1H,d,J=6.1Hz),3.97(3H,s),2.73(3H,s),1.57(9H,s).

[1237] Reference Example 89

[1238] Production of tert-butyl [3-formyl-4'-methoxy-6'-(trifluoromethyl)[2,3'-bipyridyl]-4-yl]carbamate

[1239] [Chemical formula 82]

[1240]

[1241] (Step 1) [4-Methoxy-6-(trifluoromethyl)pyridin-3-yl]boronic acid

[1242] 1.56M-n-butyllithium hexane solution (500 μL) was added to a solution of 5-bromo-4-methoxy-2-(trifluoromethyl)pyridine (200 mg) in tetrahydrofuran (4.0 mL) at -78°C, stirred at the same temperature for 30 minutes, triisopropyl borate (270 μL) was added, the temperature was raised to 0°C, and further stirred for 20 minutes. Saturated aqueous ammonium chloride solution was added to the reaction mixture, extracted three times with ethyl acetate, and the obtained organic layer was dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (172 mg).

[1243] (Step 2) tert-Butyl [3-formyl-4'-methoxy-6'-(trifluoromethyl)[2,3'-bipyridyl]-4-yl]carbamate

[1244] Under nitrogen atmosphere, a mixture of the compound obtained in step 1 (171 mg), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (299 mg), cesium carbonate (758 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (129 mg), 1,4-dioxane (4.0 mL) and water (1.5 mL) was stirred at 90°C for 3.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (127 mg).

[1245] 1 H-NMR (CDCl 3 )δ:10.85(1H,s),9.70(1H,s),8.71(1H,s),8.66(1H,d,J=6.1Hz),8.48(1H,d,J=6.1Hz),7.29(1H,s),3.92(3H,s),1.56(9H,s).

[1246] Reference Example 90

[1247] Production of tert-butyl [6'-(1,1-difluoroethyl)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1248] [Chemical formula 83]

[1249]

[1250] (Step 1) 2-(1,1-difluoroethyl)-4-methoxypyridine

[1251] To a solution of 1-(4-methoxypyridin-2-yl)ethanone (1.00 g) in dichloromethane (7.0 mL) was added (diethylamino)sulfur trifluoride (8.60 mL) at 0°C, and the mixture was stirred at room temperature for 9 hours. The reaction mixture was cooled to 0°C, and a saturated aqueous sodium bicarbonate solution was carefully added, followed by extraction twice with dichloromethane, and the obtained organic layer was dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (937 mg).

[1252] 1 H-NMR (CDCl 3)δ: 8.46 (1H, d, J = 5.5Hz), 7.17 (1H, d, J = 2.4Hz), 6.86 (1H, dd, J = 5.5, 2.4Hz), 3.89 (3H, s), 2.00 (3H, t, J = 17.7Hz).

[1253] (Step 2) 5-Bromo-2-(1,1-difluoroethyl)-4-methoxypyridine

[1254] Sulfuric acid (1.7 mL) and N-bromosuccinimide (312 mg) were carefully added to the compound (300 mg) obtained in the above step 1 at 0°C, and the mixture was stirred at 60°C for 1.5 hours. The reaction mixture was cooled to 0°C, and ethyl acetate and 10M-sodium hydroxide aqueous solution were added in small amounts each time, followed by extraction with ethyl acetate three times, and the obtained organic layer was dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (297 mg).

[1255] 1 H-NMR (CDCl 3 )δ:8.60(1H,s),7.19(1H,s),4.03(3H,s),2.03(3H,t,J=17.4Hz).

[1256] (Step 3) [6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]boric acid was added dropwise to a solution of the compound (297 mg) obtained in the above step 2 in tetrahydrofuran (6.0 mL) at -78°C, and triisopropyl borate (540 μL) was added, followed by stirring at the same temperature for 30 minutes. Saturated aqueous ammonium chloride solution and water were added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure to obtain a crude title compound (255 mg).

[1257] (Step 4) tert-Butyl [6'-(1,1-difluoroethyl)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1258] Under nitrogen atmosphere, a mixture of the compound obtained in step 3 (256 mg), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (303 mg), cesium carbonate (1.14 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (193 mg), 1,4-dioxane (6.0 mL) and water (2.0 mL) was stirred at 90°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (181 mg).

[1259] 1 H-NMR (CDCl 3 )δ:10.89(1H,s),9.73(1H,s),8.67(1H,d,J=6.1Hz),8.64(1H,s),8.47(1H,d,J=6.1Hz),3.91(3H,s),2.08(3H,t,J=18.6Hz),1.58(9H,s).

[1260] Reference Example 91

[1261] Production of tert-butyl [6'-(difluoromethyl)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1262] [Chemical formula 84]

[1263]

[1264] (Steps 1 to 3) tert-Butyl [6'-(difluoromethyl)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1265] The title compound was obtained by carrying out the same operation as steps 1 and 2 of Reference Example 90 and step 2 of Reference Example 81 using 4-methoxypyridine-2-carbaldehyde as a manufacturing raw material.

[1266] 1 H-NMR (CDCl 3 )δ:10.88(1H,s),9.72(1H,s),8.68(1H,d,J=6.1Hz),8.65(1H,s),8.48(1 H,d,J=6.1Hz),8.41(1H,s),6.84-6.50(1H,m),3.92(3H,s),1.58(9H,s).

[1267] Reference Example 92

[1268] Production of tert-butyl [3-formyl-4'-methoxy-6'-(propan-2-yl)[2,3'-bipyridyl]-4-yl]carbamate

[1269] [Chemical formula 85]

[1270]

[1271] (Steps 1 to 4) tert-Butyl [3-formyl-4'-methoxy-6'-(propan-2-yl)[2,3'-bipyridyl]-4-yl]carbamate

[1272] The title compound was obtained by using 2-bromo-4-methoxypyridine as a raw material and carrying out the same operations as steps 1 and 2 of Reference Example 48, step 2 of Reference Example 90 and step 2 of Reference Example 81.

[1273] 1 H-NMR (CDCl 3 )δ:10.89(1H,s),9.74(1H,s),8.65(1H,d,J=6.1Hz),8.52(1H,s),8.41(1H ,d,J=6.1Hz),6.77(1H,s),3.84(3H,s),1.56(9H,s),1.36(6H,d,J=6.7Hz).

[1274] Reference Example 93

[1275] Production of tert-butyl [6'-(difluoromethoxy)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1276] [Chemical formula 86]

[1277]

[1278] (Step 1) 5-Bromo-4-chloro-2-(difluoromethoxy)pyridine

[1279] To a mixture of 5-bromo-4-chloro-1H-pyridin-2-one (938 mg), cesium fluoride (752 mg), trimethylsilyl difluoro(fluorosulfonyl)acetate (3.60 mL) and acetonitrile (15 mL) was added 55%-sodium hydride (oil) (241 mg) at 0°C, and stirred at the same temperature for 18 hours. Water and ethyl acetate were added to the reaction mixture, and the insoluble matter was filtered off. The filtrate was extracted 3 times with ethyl acetate, and the obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (578 mg).

[1280] 1 H-NMR (CDCl 3 )δ:8.34(1H,s),7.39(1H,t,J=72.3Hz),7.06(1H,s).

[1281] (Step 2) 5-Bromo-2-(difluoromethoxy)-4-methoxypyridine

[1282] A mixture of the compound obtained in step 1 (533 mg), sodium hydroxide (423 mg) and methanol (4.2 mL) was stirred at 70°C for 1 hour. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (162 mg).

[1283] 1 H-NMR (CD 3 OD)δ:8.18(1H,s),7.52(1H,t,J=72.6Hz),6.68(1H,s),3.99(3H,s).

[1284] (Step 3) tert-Butyl [6'-(difluoromethoxy)-3-formyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1285] Under nitrogen atmosphere, a mixture of the compound obtained in step 2 (162 mg), bis(pinacolato)diboron (199 mg), potassium acetate (189 mg), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (115 mg) and N,N-dimethylformamide (1.6 mL) was stirred at 90°C for 30 minutes. Then, tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (216 mg), sodium carbonate (221 mg), N,N-dimethylformamide (1.6 mL) and water (1.6 mL) were added to the reaction mixture at 90°C, and the mixture was further stirred at the same temperature for 1 hour. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (49.1 mg).

[1286] 1 H-NMR (CDCl 3 )δ:10.85(1H,s),9.71(1H,s),8.63(1H,d,J=6.1Hz),8.43(1H,d,J=6.1Hz), 8.20(1H,s),7.54(1H,t,J=72.9Hz),6.46(1H,s),3.83(3H,s),1.56(9H,s).

[1287] Reference Example 94

[1288] Production of tert-butyl {2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1289] [Chemical formula 87]

[1290]

[1291] (Step 1) 1-(Difluoromethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1292] To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg) in acetonitrile (10 mL) were added sodium 2-chloro-2,2-difluoroacetate (165 mg) and 18-crown-6 (50.0 mg) at room temperature, and the mixture was stirred at 90°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride solution was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (220 mg).

[1293] 1 H-NMR (CDCl 3 )δ:7.13(1H,t,J=59.8Hz),2.57(3H,s),2.33(3H,s),1.31(12H,s).

[1294] (Step 2) tert-Butyl {2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1295] Under nitrogen atmosphere, a mixture of the compound obtained in step 1 (180 mg), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (125 mg), cesium carbonate (0.48 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (60 mg), 1,4-dioxane (4 mL) and water (2 mL) was stirred at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (150 mg).

[1296] 1 H-NMR (CDCl 3 )δ:10.90(1H,s),9.83(1H,s),8.64(1H,d,J=6.1Hz),8.40(1H,d,J=6.1Hz),7.20(1H,t,J=59.2Hz),2.37(3H,s),2.18(3H,s),1.56(9H,s).

[1297] Reference Example 95

[1298] Preparation of tert-butyl {2-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1299] [Chemical formula 88]

[1300]

[1301] (Step 1) tert-Butyl 3-cyclopropyl-4-iodo-5-methyl-1H-pyrazole-1-carboxylate

[1302] To a solution of 3-cyclopropyl-4-iodo-5-methyl-1H-pyrazole (1.00 g, which can be produced by the method described in US20140256706A1, etc.) in tetrahydrofuran (20 mL) was added di-tert-butyl dicarbonate (1.10 g), 4-dimethylaminopyridine (100 mg) and N,N-diisopropylethylamine (1.10 mL) at room temperature, and stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.30 g).

[1303] 1 H-NMR (CDCl 3 )δ:2.53(3H,s),1.86-1.77(1H,m),1.62(9H,s),1.02-0.89(4H,m).

[1304] (Step 2) tert-Butyl 3-cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate

[1305] The title compound was obtained by using the compound obtained in the above step 1 as a raw material and carrying out the same operation as in step 2 of reference example 83.

[1306] 1 H-NMR (CDCl 3 )δ:2.64(3H,s),2.30-2.22(1H,m),1.60(9H,s),1.31(12H,s),1.02-0.97(2H,m),0.89-0.83(2H,m).

[1307] (Step 3) 3-Cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1308] The compound obtained in the above step 2 (370 mg) was heated at 180° C. for 20 minutes. After the reaction mixture was cooled to room temperature, ethyl acetate was added and the solvent was distilled off under reduced pressure to obtain the title compound (260 mg).

[1309] 1 H-NMR (CDCl 3 )δ:2.38(3H,s),2.35-2.28(1H,m),1.31(12H,s),0.96-0.89(2H,m),0.86-0.80(2H,m).

[1310] (Steps 4 and 5) tert-Butyl {2-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1311] The title compound was obtained by using the compound obtained in the above step 3 as a raw material and carrying out the same operations as steps 1 and 2 of reference example 94.

[1312] 1 H-NMR (CDCl 3 )δ:10.95(1H,s),9.93(1H,s),8.65(1H,d,J=6.1Hz),8.39(1H,d,J=6.1Hz),7.14( 1H,t,J=59.2Hz),2.40(3H,s),1.56(9H,s),1.04-0.98(1H,m),0.88-0.77(4H,m).

[1313] Reference Example 96

[1314] Production of 1-(cyclopropylmethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1315] [Chemical formula 89]

[1316]

[1317] 1-(Cyclopropylmethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1318] To a solution of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg) in N,N-dimethylformamide (10 mL) were added (bromomethyl)cyclopropane (360 mg) and cesium carbonate (450 mg) at room temperature, and the mixture was stirred at 90°C for 10 hours. The reaction mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (205 mg).

[1319] 1 H-NMR (CDCl 3 )δ:3.85(2H,d,J=7.3Hz),2.40(3H,s),2.35(3H,s),1.29(12H,s),1.19-1.27(1H,m),0.51-0.57(2H,m),0.31-0.36(2H,m).

[1320] Reference Example 97

[1321] Production of 3-cyclopropyl-1-(2,2-difluoroethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1H-pyrazole

[1322] [Chemical formula 90]

[1323]

[1324] 3-Cyclopropyl-1-(2,2-difluoroethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole

[1325] To a solution of the compound (250 mg) obtained in step 3 of Reference Example 95 in N,N-dimethylformamide (10 mL) was added 55% sodium hydride (oil) (70.0 mg) at 0°C, and stirred at room temperature for 30 minutes. Then, a solution of 1,1-difluoro-2-iodoethane (0.40 g) in N,N-dimethylformamide (2.0 mL) was added at 0°C, and stirred at room temperature for 2 hours. Then, a solution of 55% sodium hydride (oil) (70.0 mg) and 1,1-difluoro-2-iodoethane (0.40 g) in N,N-dimethylformamide (2.0 mL) was added to the reaction mixture at 0°C, and stirred at room temperature for 5 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (160 mg).

[1326] 1 H-NMR (CDCl 3 )δ:6.04(1H,tt,J=55.8,4.6Hz),4.27(2H,td,J=13.3,4.6Hz),2.40(3H,s),2.24-2.33(1H,m),1.30(12H,s),0.82-0.90(4H,m).

[1327] Reference Example 98

[1328] Preparation of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[1329] [Chemical formula 91]

[1330]

[1331] 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine

[1332] To a solution of 3-iodo-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine (620 mg) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (677 μL) in tetrahydrofuran (15 mL) was added a 1.3M tetrahydrofuran solution of isopropylmagnesium chloride lithium chloride complex (2.5 mL) at 0°C, and the mixture was stirred at the same temperature for 2.5 hours. Methanol (3.0 mL) was added to the reaction mixture, and the mixture was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (327 mg).

[1333] 1 H-NMR (CDCl 3 )δ:7.59(1H,s),4.40-4.34(2H,m),4.21-4.12(2H,m),2.31-2.18(2H,m),1.31(12H,s).

[1334] The same operation as in step 2 of Reference Example 94 was carried out to synthesize the following compounds (Table 8-1).

[1335] [Table 8-1]

[1336]

[1337] Reference Example 102

[1338] Production of tert-butyl {2-[1-(difluoromethyl)-1H-pyrazol-3-yl]-3-formylpyridin-4-yl}carbamate

[1339] [Chemical formula 92]

[1340]

[1341] (Steps 1 and 2) tert-Butyl {2-[1-(difluoromethyl)-1H-pyrazol-3-yl]-3-formylpyridin-4-yl}carbamate

[1342] The title compound was obtained by carrying out the same operations as in Steps 1 and 2 of Reference Example 94 except that 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole was used as a raw material.

[1343] 1 H-NMR (CDCl 3)δ:10.99(1H,s),10.51(1H,s),8.61(1H,d,J=6.1Hz),8.41(1H,d,J=6.1Hz),7. 95(1H,d,J=2.4Hz),7.27(1H,t,J=60.4Hz),7.09(1H,d,J=2.4Hz),1.56(9H,s).

[1344] Reference Example 103

[1345] Production of tert-butyl {2-[3-(difluoromethyl)-5-methyl-1-(propane-2-yl)-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1346] [Chemical formula 93]

[1347]

[1348] (Step 1) 3-(Difluoromethyl)-4-iodo-5-methyl-1H-pyrazole

[1349] N-iodosuccinimide (1.70 g) was added to a solution of 3-(difluoromethyl)-5-methyl-1H-pyrazole (1.00 g) in acetonitrile (15 mL) at room temperature, and the mixture was stirred at room temperature for 1 hour. A 5% sodium thiosulfate aqueous solution was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium bicarbonate aqueous solution and saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure to obtain a crude title compound (2.00 g).

[1350] (Steps 2 to 4) tert-Butyl {2-[3-(difluoromethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate

[1351] The title compound was obtained by carrying out the same operation as in Reference Example 97, Step 2 of Reference Example 83 and Step 2 of Reference Example 94 using the compound obtained in the above Step 2 and 2-iodopropane as manufacturing raw materials.

[1352] 1 H-NMR (CDCl 3)δ:10.95(1H,br s),9.87(1H,s),8.61(1H,d,J=6.1Hz),8.39(1H,d,J=6.1Hz),6.70(1H,t,J=54.3Hz),4. 53-4.46(1H,m),2.18(3H,s),1.55(9H,s),1.55(3H,d,J=6.7Hz),1.51(3H,d,J=6.7Hz).

[1353] Reference Example 104

[1354] Production of tert-butyl [2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-formylpyridin-4-yl]carbamate

[1355] [Chemical formula 94]

[1356]

[1357] (Step 1) 5-iodo-1,4-dimethyl-1H-pyrazole

[1358] To a solution of 3-iodo-4-methyl-1H-pyrazole (1.10 g) in tetrahydrofuran (20 mL) was added 55% sodium hydride (oil) (0.46 g) at 0°C, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to 0°C again, iodomethane (1.30 mL) was added, and the mixture was stirred at room temperature for 2 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a 5% aqueous sodium thiosulfate solution and saturated brine, and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (350 mg).

[1359] 1 H-NMR (CDCl 3 )δ:7.05(1H,s),3.87(3H,s),1.98(3H,s).

[1360] (Step 2) tert-Butyl [2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-formylpyridin-4-yl]carbamate

[1361] The title compound was obtained by using the compound obtained in the above step 1 as a raw material and carrying out the same operation as in step 2 of reference example 81.

[1362] 1 H-NMR (CDCl 3)δ:10.89(1H,s),9.75(1H,s),8.68(1H,d,J=5.5Hz),8.45(1H,d,J=5.5Hz),7.40(1H,s),3.84(3H,s),1.93(3H,s),1.56(9H,s).

[1363] Reference Example 105

[1364] Production of tert-butyl [6'-cyclopropyl-3-(isothiocyanatemethyl)-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1365] [Chemical formula 95]

[1366]

[1367] (Step 1) tert-Butyl [6'-cyclopropyl-3-(hydroxymethyl)-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1368] Sodium borohydride (161 mg) was added to a solution of the compound (800 mg) obtained in Reference Example 86 in ethanol (10 mL) at 0°C, and stirred at the same temperature for 1.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed three times with dichloromethane. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (759 mg).

[1369] (Step 2) tert-Butyl [3-(azidomethyl)-6'-cyclopropyl-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1370] To a solution of the compound (390 mg) obtained in step 1 above in tetrahydrofuran (6.0 mL) were added diphenylphosphoryl azide (455 μL) and 1,8-diazabicyclo[5,4,0]-7-undecene (315 μL) at room temperature, and stirred at the same temperature for 15.5 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (276 mg).

[1371] 1 H-NMR (CDCl 3)δ:8.55(1H,d,J=5.5Hz),8.21(1H,s),8.12(1H,d,J=5.5Hz),7.43(1H,br s),6.78(1H,s),4.27(1H,d,J=14.7Hz),4.16(1H,d,J=14.1Hz),3.84(3H,s),2.13-2.01(1H,m),1.56(9H,s),1.18-0.99(4H,m).

[1372] (Step 3) tert-Butyl [6'-cyclopropyl-3-(isothiocyanatemethyl)-4'-methoxy[2,3'-bipyridyl]-4-yl]carbamate

[1373] Triphenylphosphine (161 mg) was added to a tetrahydrofuran (3.0 mL) solution of the compound (236 mg) obtained in the above step 2 at room temperature, and the mixture was stirred at 50°C for 3 hours. The reaction mixture was cooled to room temperature, and the solvent was distilled off under reduced pressure. Acetonitrile (3.0 mL) and carbon disulfide (360 μL) were added to the obtained residue at room temperature, and the mixture was stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed once with acetonitrile (3.0 mL) and dried under reduced pressure to obtain the title compound (200 mg).

[1374] 1 H-NMR (CDCl 3 )δ:8.58(1H,d,J=6.1Hz),8.26(1H,s),7.00(1H,d,J=6.1Hz),6.80(1H,s),6.67(1H,br s),4.52-4.08(2H,m),3.88(3H,s),2.14-2.01(1H,m),1.71(9H,s),1.18-1.03(4H,m).

[1375] Reference Example 106

[1376] Production of tert-butyl [3-(aminomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate

[1377] [Chemical formula 96]

[1378]

[1379] (Steps 1 and 2) tert-Butyl [3-(azidomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate

[1380] The title compound was obtained by using the compound obtained in Reference Example 59 as a raw material and carrying out the same operations as steps 1 and 2 of Reference Example 105.

[1381] 1 H-NMR (CDCl 3 )δ:8.54(1H,d,J=6.1Hz),8.17(1H,d,J=6.1Hz),7.53-7.46(1H,m),7.44- 7.30(4H,m),4.29(1H,d,J=14.0Hz), 4.17(1H,d,J=14.0Hz), 1.57(9H,s).

[1382] (Step 3) tert-Butyl [3-(aminomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate

[1383] Triphenylphosphine (161 mg) was added to a tetrahydrofuran (3.0 mL) / water (3.0 mL) solution of the compound (170 mg) obtained in the above step 2 at room temperature, and stirred at the same temperature for 22 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (152 mg).

[1384] 1 H-NMR (CDCl 3 )δ:10.37(1H,br s),8.48(1H,d,J=6.1Hz),8.12(1H,d,J=6.1Hz),7.51-7.43(1H,m),7.40- 7.31(3H,m),3.86(1H,d,J=13.4Hz), 3.74(1H,d,J=13.4Hz), 1.57(9H,s).

[1385] Reference Example 107

[1386] Production of tert-butyl [3-(aminomethyl)-2-(2-methoxyphenyl)pyridin-4-yl]carbamate

[1387] [Chemical formula 97]

[1388]

[1389] (Steps 1 to 3) tert-Butyl [3-(aminomethyl)-2-(2-methoxyphenyl)pyridin-4-yl]carbamate

[1390] The title compound was obtained by using the compound obtained in Reference Example 60 as a raw material and carrying out the same operation as steps 1 and 2 of Reference Example 105 and step 3 of Reference Example 106.

[1391] 1 H-NMR (CDCl 3 )δ:8.48(1H,d,J=6.1Hz),8.06(1H,d,J=6.1Hz),7.43-7.36(1H,m),7.35-7.31(1H,m),7.08(1H,t,J=7 .9Hz), 6.98(1H,d,J=7.9Hz), 3.86(1H,d,J=13.4Hz), 3.78(3H,s), 3.73(1H,d,J=13.4Hz), 1.57(9H,s).

[1392] Reference Example 108

[1393] Production of tert-butyl [1'-(cyclopropanecarbonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridyl]-4-yl]carbamate

[1394] [Chemical formula 98]

[1395]

[1396] (Step 1) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine trifluoroacetate

[1397] Trifluoroacetic acid (2.50 mL) was added to a solution of tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.00 g) in dichloromethane (7.0 mL) at 0° C., and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and then excess trifluoroacetic acid was removed by azeotropy with toluene to obtain a crude title compound (1.04 g).

[1398] (Step 2) Cyclopropyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]methanone

[1399] Triethylamine (266 μL) and cyclopropanecarbonyl chloride (75.0 μL) were added to a solution of the compound (207 mg) obtained in the above step 1 in dichloromethane (2.0 mL) at 0° C., and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (110 mg).

[1400] 1 H-NMR (CDCl 3 )δ:6.83-6.57(1H,m),4.33-4.14(2H,m),3.80-3.60(2H,m),2.38-2.17(2H,m) ,1.88-1.71(1H,m),1.32-1.22(12H,m),1.03-0.95(2H,m),0.81-0.71(2H,m).

[1401] (Step 3) tert-Butyl [1'-(cyclopropanecarbonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridyl]-4-yl]carbamate

[1402] The title compound was obtained by using the compound obtained in the above step 2 as a raw material and carrying out the same operation as in Reference Example 70.

[1403] 1 H-NMR (CDCl 3 )δ:10.84(1H,br s),10.18-10.06(1H,m),8.58-8.45(1H,m),8.40-8.21(1H,m),6.05-5.79(1H,m),4.73(1H,s),4.58(1H,s),3.96-3.7 6(2H,m),2.55-2.35(2H,m),1.91-1.77(1H,m),1.55(9H,s),1.32-1.18(1H,m),1.12-0.98(2H,m),0.86-0.74(2H,m).

[1404] Reference Example 109

[1405] Production of tert-butyl [1'-(cyclopropylsulfonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridyl]-4-yl]carbamate

[1406] [Chemical formula 99]

[1407]

[1408] (Steps 1 and 2) tert-Butyl [1'-(cyclopropylsulfonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridyl]-4-yl]carbamate

[1409] The title compound was obtained by carrying out the same operation as in Step 2 of Reference Example 108 and Reference Example 57 using the compound obtained in Step 1 of Reference Example 108 and cyclopropanesulfonyl chloride as raw materials.

[1410] 1 H-NMR (CDCl 3 )δ:10.84(1H,br s),10.12(1H,s),8.50(1H,d,J=5.9Hz),8.31(1H,d,J=5.9Hz),5.92-5.88(1H,m),4.38-4.33(2H,m ),3.59-3.53(2H,m),2.57-2.51(2H,m),2.42-2.35(1H,m),1.28-1.19(11H,m),1.05-0.97(2H,m).

[1411] Reference Example 110

[1412] Production of 4-amino-2-[1-(phenylsulfonyl)azepan-3-yl]pyridine-3-carboxaldehyde

[1413] [Chemical formula 100]

[1414]

[1415] (Step 1) 6-{4-[(tert-Butyloxycarbonyl)amino]-3-formylpyridin-2-yl}-2,3,4,7-tetrahydro-1H-azepine -1-tert-Butyl formate

[1416] 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,7-tetrahydro-1H-aza -1-tert-butyl formate [251 mg, positional isomers containing double bonds (6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-aza -1-carboxylic acid tert-butyl ester)] was used as a raw material and the same operation as in Reference Example 57 was carried out to obtain the title compound and a positional isomer of the double bond (6-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2,3,4,5-tetrahydro-1H-azepine -1-carboxylic acid tert-butyl ester) (242 mg).

[1417] 1 H-NMR (CDCl 3 )δ:10.88(0.6H,br s),10.84(0.4H,br s),10.10(0.6H,s),10.06(0.4H,s),8.49(0.6H,d,J=5.9Hz),8.47(0.4H,d,J= 5.9Hz),8.26(0.6H,d,J=5.9Hz),8.22(0.4H,d,J=5.9Hz),5.84-5.78(0.6H,m), 5.76-5.71(0.4H,m),4.43-4.30(2H,m),3.82-3.56(2H,m),2.55-2.43(2H,m),1 .96-1.85(2H,m),1.55(5.4H,s),1.54(3.6H,s),1.45(3.6H,s),1.23(5.4H,s).

[1418] (Step 2) 4-amino-2-(2,5,6,7-tetrahydro-1H-azepine -3-yl)pyridine-3-carboxaldehyde hydrochloride

[1419] A mixture of the compound obtained in step 1 (53 mg), ethyl acetate (1 mL) and a 4M 1,4-dioxane solution (0.3 mL) of hydrogen chloride was stirred at room temperature for 18.5 hours. The reaction mixture was concentrated under reduced pressure to obtain a crude title compound and a positional isomer of the double bond (4-amino-2-(4,5,6,7-tetrahydro-1H-azepine) -3-yl)pyridine-3-carboxaldehyde hydrochloride) (41 mg).

[1420] (Step 3) 4-amino-2-[1-(phenylsulfonyl)-2,5,6,7-tetrahydro-1H-azepine -3-yl]pyridine-3-carboxaldehyde

[1421] The compound obtained in the above step 2 and benzenesulfonyl chloride were used as raw materials, and the same operation as in step 2 of reference example 108 was carried out to obtain the title compound and a positional isomer of the double bond (4-amino-2-[1-(phenylsulfonyl)-4,5,6,7-tetrahydro-1H-azepine -3-yl]pyridine-3-carboxaldehyde).

[1422] 1 H-NMR (CDCl 3)δ:10.04(1H,s),8.13(1H,d,J=5.9Hz),7.78(2H,dd,J=8.2,1.2Hz),7.59-7.42(3H,m),6.42(1H,d,J= 5.9Hz),5.89-5.82(1H,m),4.39-4.26(2H,m),3.59-3.50(2H,m),2.53-2.40(2H,m),2.03-1.94(2H,m).

[1423] (Step 4) 4-amino-2-[1-(phenylsulfonyl)azepan-3-yl]pyridine-3-carbaldehyde

[1424] A mixture of the compound obtained in step 3 (30 mg), 10% palladium carbon (30 mg) and ethyl acetate (2 mL) was stirred at room temperature for 2.5 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration through celite, and the solvent was distilled off under reduced pressure to obtain a crude title compound (25 mg).

[1425] Reference Example 111

[1426] Production of tert-butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate

[1427] [Chemical Formula 101]

[1428]

[1429] (Step 1) 1-(4-bromo-3-methylphenyl)-N-methylmethanamine

[1430] To a 2M tetrahydrofuran solution of methylamine (6.80 mL) was added a solution of 1-bromo-4-(chloromethyl)-2-methylbenzene (1.00 g) in N,N-dimethylformamide (20 mL) at 0°C, and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was removed under reduced pressure to obtain the title compound (1.00 g).

[1431] 1 H-NMR (CDCl 3 )δ:7.47(1H,d,J=7.9Hz),7.20(1H,d,J=1.8Hz),6.99(1H,dd,J=7.9,1.8Hz),3.67(2H,s),2.39(3H,s).

[1432] (Step 2) tert-butyl (4-bromo-3-methylbenzyl)methylcarbamate

[1433] To a solution of the compound (1.00 g) obtained in the above step 1 in ethanol (20 mL) was added di-tert-butyl dicarbonate (1.20 g) at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.00 g).

[1434] 1 H-NMR (CDCl 3 )δ:7.49(1H,d,J=7.9Hz),7.08(1H,br s),6.91(1H,br s),4.34(2H,s),2.85-2.75(3H,m),2.38(3H,s),1.47(9H,s).

[1435] (Step 3) tert-Butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate

[1436] Under a nitrogen atmosphere, a mixture of the compound obtained in the above step 2 (1.00 g), bis(pinacolato)diboron (1.20 g), potassium acetate (0.95 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.26) and 1,4-dioxane (20 mL) was stirred at 90°C for 10 hours. After the reaction mixture was cooled to room temperature, it was diluted with ethyl acetate and the insoluble matter was removed by diatomaceous earth filtration. The obtained filtrate was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.00 g).

[1437] 1 H-NMR (CDCl 3 )δ:7.72(1H,d,J=7.9Hz),7.06-6.98(2H,m),4.38(2H,br s),2.86-2.72(3H,m),2.52(3H,s),1.51-1.43(9H,m),1.34(12H,s).

[1438] Reference Example 112

[1439] Production of tert-butyl [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate

[1440] [Chemical formula 102]

[1441]

[1442] (Step 1) tert-butyl (3-bromo-2-methylphenoxy)acetate

[1443] To a solution of 3-bromo-2-methylphenol (500 mg) in N,N-dimethylformamide (20 mL) was added tert-butyl bromoacetate (0.59 mL) and potassium carbonate (550 mg) at room temperature, and the mixture was stirred at 90°C for 7.5 hours. The reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (0.80 g).

[1444] 1 H-NMR (CDCl 3 )δ: 7.19(1H,d,J=7.9Hz), 6.98(1H,t,J=7.9Hz), 6.64(1H,d,J=7.9Hz), 4.52(2H,s), 2.38(3H,s), 1.48(9H,s).

[1445] (Step 2) tert-Butyl [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate

[1446] The title compound was obtained by using the compound obtained in the above step 1 as a raw material and carrying out the same operation as in step 3 of reference example 111.

[1447] 1 H-NMR (CDCl 3 )δ:7.37(1H,d,J=8.0Hz),7.11(1H,t,J=8.0Hz),6.79(1H,d,J=8.0Hz),4.51(2H,s),2.49(3H,s),1.48(9H,s),1.34(12H,s).

[1448] Reference Example 113

[1449] Production of tert-butyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}acetate

[1450] [Chemical formula 103]

[1451]

[1452] (Step 1) tert-Butyl [(3-bromophenyl)sulfanyl]acetate

[1453] To a solution of 3-bromothiophenol (1.00 g) in N,N-dimethylformamide (20 mL) was added tert-butyl bromoacetate (1.20 mL) and potassium carbonate (1.10 g) at room temperature, and the mixture was stirred at the same temperature for 8 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.60 g).

[1454] 1 H-NMR (CDCl 3 )δ:7.53(1H,t,J=1.8Hz),7.35-7.29(2H,m),7.15(1H,t,J=7.9Hz),3.56(2H,s),1.42(9H,s).

[1455] (Step 2) tert-Butyl [(3-bromophenyl)sulfonyl]acetate

[1456] Water (20 mL) and potassium peroxymonosulfate (9.70 g) were added to a solution of the compound (1.60 g) obtained in step 1 in 1,4-dioxane (20 mL) at 0°C, and stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.10 g).

[1457] 1 H-NMR (CDCl 3)δ: 8.09(1H,t,J=1.8Hz), 7.89(1H,dt,J=7.9,1.8Hz), 7.82(1H,dt,J=7.9,1.8Hz), 7.47(1H,t,J=7.9Hz), 4.05(2H,s), 1.39(9H,s).

[1458] (Step 3) tert-Butyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}acetate

[1459] The title compound was obtained by using the compound obtained in the above step 2 as a raw material and carrying out the same operation as in step 3 of reference example 111.

[1460] 1 H-NMR (CDCl 3 )δ:8.37(1H,br s),8.08(1H,t,J=7.7Hz),8.02(1H,t,J=7.7Hz),7.58(1H,t,J=7.7Hz),4.05(2H,s),1.36(9H,s),1.35(12H,s).

[1461] Reference Example 114

[1462] Production of tert-butyl [3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl] acetate

[1463] [Chemical formula 104]

[1464]

[1465] tert-Butyl [3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate

[1466] To a solution of 3,5-dimethylpyrazole-4-boronic acid pinacol ester (500 mg) in N,N-dimethylformamide (10 mL) was added tert-butyl bromoacetate (0.40 mL) and cesium carbonate (1.10 g) at room temperature, and the mixture was stirred at the same temperature for 8 hours. Water was added to the reaction mixture, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed three times with water, once with saturated brine, and then dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (0.76 g).

[1467] 1H-NMR (CDCl 3 )δ:4.67(2H,s),2.35(3H,s),2.34(3H,s),1.57(9H,s),1.28(12H,s).

[1468] Reference Example 115

[1469] Preparation of tert-butyl 2-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate

[1470] [Chemical formula 105]

[1471]

[1472] Tert-butyl 2-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate

[1473] To a solution of 3,5-dimethylpyrazole-4-boronic acid pinacol ester (400 mg) and tert-butyl 2-bromopropionate (0.9 mL) in N,N-dimethylformamide (9 mL) was added 55% sodium hydride (oil) (91 mg) at room temperature, and stirred at the same temperature for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture, and extraction was performed with ethyl acetate. The obtained organic layer was washed with water 3 times, washed with saturated brine once, and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (596 mg).

[1474] 1 H-NMR (CDCl 3 )δ:4.82-4.71(1H,m),2.37(2.1H,s),2.35(2.1H,s),2.23(0.9H,s),2.21(0.9H,s) ,1.77(2.1H,d,J=7.4Hz),1.75(0.9H,d,J=7.4Hz),1.42(9H,s),1.31-1.24(12H,m).

[1475] Reference Example 116

[1476] Preparation of tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate

[1477] [Chemical formula 106]

[1478]

[1479] Tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate

[1480] To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.00 g) in acetonitrile (20 mL) were added tert-butyl acrylate (1.50 mL) and 1,8-diazabicyclo[5.4.0]-7-undecene (0.38 mL) at room temperature, and the mixture was stirred at the same temperature for 19.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.40 g).

[1481] 1 H-NMR (CDCl 3 )δ:7.78(1H,s),7.72(1H,s),4.38(2H,t,J=6.7Hz),2.81(2H,t,J=6.7Hz),1.41(9H,s),1.31(12H,s).

[1482] The same operation as in Reference Example 70 was carried out to synthesize the following compounds (Table 9-1).

[1483] [Table 9-1]

[1484]

[1485]

[1486] Example 1

[1487] Production of 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one

[1488] [Chemical formula 107]

[1489]

[1490] 3-{6-Chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one

[1491] A mixture of the compound obtained in step 3 of Reference Example 1 (3.60 g), 4-aminopyridine-3-carboxaldehyde (1.30 g), piperidine (2.94 mL) and ethanol (55 mL) was stirred for 9 hours under heating reflux. The reaction mixture was cooled to room temperature and the precipitated solid was separated by filtration. The obtained solid was washed twice with ethanol and dried under reduced pressure to obtain the title compound (3.76 g).

[1492] 1 H-NMR (DMSO-D 6 )δ:12.84(1H,br s),12.73(1H,br s),9.13(1H,s),9.02(1H,s),8.55(1H,d,J=5.5Hz),7.31(1H,d,J=5.5Hz),6.99(1H,s),5.47-5.34(1H,m),4.96-4.75(1H, m),4.04-3.92(1H,m),3.84-3.69(2H,m),3.64-3.52(1H,m),3.43-3.35(1H,m),1.27(3H,d,J=6.7Hz).,MS(m / z):397(M+H) + .

[1493] The same operation as in Example 1 was carried out to synthesize the following compounds (Table 10-1 and Table 10-2).

[1494] [Table 10-1]

[1495]

[1496]

[1497] [Table 10-2]

[1498]

[1499] Example 9

[1500] Production of 3-[4-(5-amino-3,3-difluoropiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one trifluoroacetate

[1501] [Chemical formula 108]

[1502]

[1503] (Step 1) tert-Butyl {1-[6-chloro-2-(2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-1H-imidazo[4,5-c]pyridin-4-yl]-5,5-difluoropiperidin-3-yl}carbamate

[1504] The title compound was obtained by carrying out the same operation as in Step 1 of Example 1 except that the compound obtained in Step 3 of Reference Example 9 and 4-aminopyridine-3-carbaldehyde were used as raw materials.

[1505] 1 H-NMR (DMSO-D 6 )δ:9.03(1H,s),9.00(1H,s),8.54(1H,d,J=6.1Hz),7.33(1H,d,J=6.1Hz),7.06(1H,s),6.84(1H,br s),5.59-5.41(1H,m),5.31-5.18(1H,m),3.88-3.73(1H,m),3.69-3.52(1H,m),2.53-2.34(2H,m),2.31-1.96(1H,m),1.42(9H,s).

[1506] (Step 2) 3-[4-(5-amino-3,3-difluoropiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one trifluoroacetate

[1507] Trifluoroacetic acid (650 μL) was added to the compound (33.8 mg) obtained in the above step 1 at room temperature, and stirred at the same temperature for 2 hours. After the reaction mixture was concentrated under reduced pressure, the excess remaining trifluoroacetic acid was removed by azeotropy with toluene, and ethyl acetate was added to the residue to solidify. The solid was separated by filtration, washed with hexane, and dried under reduced pressure to obtain the title compound (31.5 mg).

[1508] 1 H-NMR (DMSO-D 6 )δ:13.02-12.87(2H,m),9.21(1H,s),9.10(1H,s),8.61(1H,d,J=5.5Hz),8.33-8.16(3H,br s),7.40(1H,d,J=5.5Hz),7.13(1H,s),5.69-5.49(1H,m),5.04-4.89(1H,m), 4.19-4.03(1H,m),3.66-3.43(2H,m),2.45-2.13(2H,m).,MS(m / z):432(M+H) + .

[1509] Example 10

[1510] Production of 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one

[1511] [Chemical formula 109]

[1512]

[1513] 3-{6-Chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one

[1514] A mixture of the compound obtained in Reference Example 19 (60 mg), 4-aminopyridine-3-carboxaldehyde (24 mg), piperidine (50 μL) and ethanol (5.0 mL) was stirred for 6 hours at 90° C. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and a n-hexane / ethyl acetate mixture was added to the residue, followed by filtration to obtain the title compound (48 mg).

[1515] 1 H-NMR (DMSO-D 6 )δ:12.80(2H,br s),9.12(1H,s),9.03(1H,s),8.54(1H,d,J=6.1Hz),7.31(1H,d,J=6.1Hz),6.92(1H,s),5.45(1H,br d,J=54.3Hz),4.84-4.59(2H,m),4.14-3.96(1H,m),2.53-2.42(1H,m),2.11-1.78(1H,m),1.35(3H,d,J=6.1Hz).

[1516] The same operation as in Example 10 was carried out to synthesize the following compounds (Table 11-1 and Table 11-2).

[1517] [Table 11-1]

[1518]

[1519]

[1520] [Table 11-2]

[1521]

[1522]

[1523] Embodiment 17

[1524] Production of 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one

[1525] [Chemical formula 110]

[1526]

[1527] 3-[6-Chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one

[1528] A mixture of the compound (2.00 g) obtained in step 3 of Reference Example 23, the compound (1.46 g) obtained in Reference Example 46, piperidine (1.70 mL) and ethanol (35 mL) was stirred for 4.5 hours under heating reflux. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed twice with ethanol and then dried under reduced pressure to obtain the title compound (2.27 g).

[1529] 1 H-NMR (DMSO-D 6 )δ:13.03(1H,br s),12.78(1H,br s),9.14(1H,s),8.43(1H,d,J=6.1Hz),7.54(1H,s),7.21(1H,d,J=6.1Hz),4.05-4.95(2H,m),3.82-3 .70(1H,m),3.64-3.51(2H,m),2.86(3H,s),2.08-1.93(2H,m),1.86-1.75(2H,m).,MS(m / z):396(M+H) + .

[1530] The same operation as in Example 17 was carried out to synthesize the following compounds (Table 12-1 and Table 12-2).

[1531] [Table 12-1]

[1532]

[1533]

[1534] [Table 12-2]

[1535]

[1536] Embodiment 24

[1537] Preparation of 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one trifluoroacetate

[1538] [Chemical formula 111]

[1539]

[1540] (Steps 1 and 2) 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one trifluoroacetate

[1541] The title compound was obtained by using the compound obtained in step 3 of reference example 25 as a raw material and carrying out the same operation as in step 2 of example 1 and example 9.

[1542] 1 H-NMR (DMSO-D 6 )δ:13.24(2H,br s),9.38(1H,s),9.32(1H,s),8.80-8.70(1H,m),8.67(1H,d,J=5.9Hz),8.51-8.41(1H,m),7.70(1H ,s),7.56(1H,t,J=7.8Hz),7.49(1H,d,J=5.9Hz),7.22(1H,dd,J=7.8,1.2Hz).,MS(m / z):389(M+H) + .

[1543] Embodiment 25

[1544] Production of 3-[6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one

[1545] [Chemical formula 112]

[1546]

[1547] 3-[6-Chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one

[1548] The title compound was obtained by carrying out the same operation as in Example 1 except that the compound obtained in Step 3 of Reference Example 26 was used as a raw material.

[1549] 1H-NMR (DMSO-D 6 )δ:13.16(1H,s),12.79(1H,s),9.15(1H,s),9.08(1H,s),8.54(1H,d,J=6.1Hz),7.79(1H,td,J=7.3, 1.8Hz),7.73(1H,s),7.60-7.56(1H,m),7.41-7.36(2H,m),7.30(1H,d,J=6.1Hz).,MS(m / z):392(M+H) + .

[1550] Embodiment 26

[1551] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 Preparation of 1,6-naphthyridin-2(1H)-one

[1552] [Chemical formula 113]

[1553]

[1554] 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H 3 )methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one

[1555] A mixture of the compound obtained in step 3 of Reference Example 29 (34 mg), the compound obtained in Reference Example 57 (40 mg), piperidine (24 μL) and ethanol (1.5 mL) was stirred at 80° C. for 5 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (48 mg).

[1556] 1 H-NMR (DMSO-D 6 )δ:12.97(1H,s),12.87(1H,s),8.68(1H,s),8.64(1H,d,J=5.5Hz),7.64-7.56(1H,m),7.49(1H,s),7.46-7. 40(1H,m),7.36(1H,d,J=5.5Hz),7.31(1H,d,J=7.9Hz),7.22-7.15(1H,m),2.63(3H,s).,MS(m / z):421(M+H) + .

[1557] The same operation as in Example 26 was carried out to synthesize the following compounds (Table 13-1 and Table 13-2).

[1558] [Table 13-1]

[1559]

[1560]

[1561]

[1562]

[1563]

[1564]

[1565] [Table 13-2]

[1566]

[1567]

[1568]

[1569]

[1570] Embodiment 56

[1571] Preparation of 3-[4-(3-aminopiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one hydrochloride

[1572] [Chemical formula 114]

[1573]

[1574] (Step 1) tert-Butyl (1-{6-chloro-2-[5-(2-methylphenyl)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl]-1H-imidazo[4,5-c]pyridin-4-yl}piperidin-3-yl)carbamate

[1575] A mixture of the compound obtained in step 3 of Reference Example 8 (70.3 mg), the compound obtained in Reference Example 62 (50.2 mg), piperidine (31.8 μL) and ethanol (4.0 mL) was stirred for 12 hours at 90° C. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain a crude title compound (64.1 mg).

[1576] (Step 2) 3-[4-(3-aminopiperidin-1-yl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one hydrochloride

[1577] To a mixture of the compound (64.1 mg) obtained in the above step 1 and a 4M-hydrochloric acid 1,4-dioxane solution (2.0 mL) was added ethanol (0.50 mL) at 80°C, and stirred at the same temperature for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and ethanol (3.0 mL) was added to the obtained residue, and stirred at room temperature for 1 hour. The precipitated solid was separated by filtration, washed with ethanol, and dried under reduced pressure to obtain the title compound (43.2 mg).

[1578] 1 H-NMR (DMSO-D 6 )δ:13.37(1H,br s),12.87(1H,s),8.71(1H,d,J=5.9Hz),8.45(1H,s),8.27-8.05(3H,m),7.70-7.55(2H,m),7.54-7.39(3H,m),6.97(1H,s),5.04-4.92( 1H,m),4.61-4.46(1H,m),3.48-3.34(1H,m),3.26-3.10(2H,m),2.17(3H,s),2.13-2.00(1H,m),1.78-1.43(3H,m).,MS(m / z):486(M+H) + .

[1579] Embodiment 57

[1580] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one

[1581] [Chemical formula 115]

[1582]

[1583] (Step 1) 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-fluoro-6-(methoxymethoxy)phenyl]-1,6-naphthyridin-2(1H)-one

[1584] The crude title compound was obtained by carrying out the same operation as in Example 26 using the compound obtained in Step 3 of Reference Example 30 and the compound obtained in Reference Example 80 as raw materials.

[1585] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one

[1586] To a suspension of the compound (124 mg) obtained in the above step 1 in 1,4-dioxane (2.0 mL) was added 6M hydrochloric acid (0.20 mL) at room temperature, and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to 0° C., 1M aqueous sodium hydroxide solution (1.2 mL) was added, and the precipitated solid was separated by filtration, washed with water, and dried under reduced pressure to obtain the title compound (105 mg).

[1587] 1 H-NMR (DMSO-D 6 )δ:13.00(1H,br s),12.93(1H,br s),10.27(1H,s),8.66(1H,d,J=6.1Hz),8.62(1H,s),7.50(1H,s),7.44(1H,dd,J=12.2,8.5Hz),7.39 (1H,d,J=6.1Hz),6.95-6.83(2H,m),3.02(2H,q,J=7.3Hz),1.28(3H,t,J=7.3Hz).,MS(m / z):436(M+H) + .

[1588] Embodiment 58

[1589] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one

[1590] [Chemical formula 116]

[1591]

[1592] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one

[1593] A mixture of the compound obtained in step 3 of Reference Example 30 (1.00 g), the compound obtained in Reference Example 86 (1.38 g), piperidine (738 μL) and ethanol (10 mL) was stirred at 90° C. for 6 hours. The reaction mixture was cooled to room temperature and the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (1.53 g).

[1594] 1 H-NMR (DMSO-D 6 )δ:13.01-12.78(2H,m),8.69-8.60(1.9H,m),8.52(0.1H,s),8.32(0.9H,s),8.28( 0.1H,s),7.60(0.1H,s),7.50(0.9H,s),7.37(1H,d,J=5.9Hz),7.33(0.9H,s),7.29( 0.1H,s),3.84(2.7H,s),3.80(0.3H,s),3.19-3.11(0.2H,m),3.06(1.8H,q,J=7.4H z),2.32-2.20(1H,m),1.31(3H,t,J=7.4Hz),1.10-0.99(4H,m).,MS(m / z):473(M+H) + .

[1595] The same operation as in Example 58 was carried out to synthesize the following compounds (Table 14-1 and Table 14-2).

[1596] [Table 14-1]

[1597]

[1598]

[1599]

[1600]

[1601]

[1602] [Table 14-2]

[1603]

[1604]

[1605]

[1606] Embodiment 80

[1607] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1608] [Chemical formula 117]

[1609]

[1610] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1611] A mixture of the compound obtained in step 3 of Reference Example 30 (76.0 mg), the compound obtained in step 2 of Reference Example 89 (51.2 mg), piperidine (53 μL) and ethanol (2.0 mL) was stirred at 90° C. for 9 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (40.0 mg).

[1612] 1 H-NMR (DMSO-D 6 )δ:13.00(1H,s),12.98(1H,s),8.71(1H,s),8.71(1H,d,J=6.1Hz),8.59(1H,s),7.89(1H,s),7.50(1H, s),7.45(1H,d,J=6.1Hz),3.98(3H,s),3.04(2H,q,J=7.3Hz),1.29(3H,t,J=7.3Hz).,MS(m / z):501(M+H) + .

[1613] Embodiment 81

[1614] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1615] [Chemical formula 118]

[1616]

[1617] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1618] A mixture of the compound obtained in step 3 of Reference Example 30 (45.3 mg), the compound obtained in step 3 of Reference Example 93 (66.9 mg), piperidine (47 μL) and ethanol (1.1 mL) was stirred at 90° C. for 4 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (43.8 mg).

[1619] 1 H-NMR (DMSO-D 6 )δ:12.96(1H,s),12.91(1H,s),8.64(1H,d,J=5.5Hz),8.61(1H,s),8.22(1H,s),7.84(1H,t,J=72.6Hz),7.48(1H,s ),7.38(1H,d,J=5.5Hz),7.08(1H,s),3.85(3H,s),3.04(2H,q,J=7.5Hz),1.28(3H,t,J=7.5Hz).,MS(m / z):499(M+H) + .

[1620] Embodiment 82

[1621] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1622] [Chemical formula 119]

[1623]

[1624] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1625] A mixture of the compound obtained in step 3 of Reference Example 30 (60.4 mg), the compound obtained in step 4 of Reference Example 90 (82.1 mg), piperidine (58 μL) and ethanol (4.2 mL) was stirred at 90° C. for 5 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (64.6 mg).

[1626] 1 H-NMR (DMSO-D6 )δ:12.99(1H,s),12.96(1H,s),8.69(1H,d,J=5.5Hz),8.61(2H,s),8.60(2H,s),7.62(1H,s),7.50(1H, s),7.43(1H,d,J=5.5Hz),3.93(3H,s),3.04(2H,q,J=7.3Hz),2.11(3H,t,J=7.3Hz).,MS(m / z):497(M+H) + .

[1627] Embodiment 83

[1628] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one

[1629] [Chemical formula 120]

[1630]

[1631] (Step 1) 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one

[1632] A mixture of the compound obtained in step 3 of Reference Example 30 (50 mg), the compound obtained in step 2 of Reference Example 94 (80 mg), piperidine (60 μL) and ethanol (5 mL) was stirred at 90° C. for 16.5 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, and a n-hexane / ethyl acetate mixture was added to the obtained residue. The precipitated solid was separated by filtration and dried under reduced pressure to obtain the title compound (64 mg).

[1633] 1 H-NMR (DMSO-D 6 )δ:12.98(1H,br s),12.91(1H,br s),8.74(1H,s),8.67(1H,d,J=5.5Hz),7.93(1H,t,J=57.7Hz),7.51(1H,s),7.36(1H,d,J=5.5H z),3.07(2H,q,J=7.5Hz),2.35(3H,s),2.18(3H,s),1.32(3H,t,J=7.5Hz).,MS(m / z):470(M+H) + .

[1634] The same operation as in Example 83 was carried out to synthesize the following compounds (Table 15-1 and Table 15-2).

[1635] [Table 15-1]

[1636]

[1637]

[1638]

[1639]

[1640] [Table 15-2]

[1641]

[1642]

[1643]

[1644] Embodiment 101

[1645] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1646] [Chemical formula 121]

[1647]

[1648] (Step 1) tert-Butyl (3-{[(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)amino]methyl}-6'-cyclopropyl-4'-methoxy[2,3'-bipyridyl]-4-yl)carbamate

[1649] A mixture of the compound obtained in step 2 of Reference Example 30 (45.5 mg), the compound obtained in step 3 of Reference Example 105 (100 mg), imidazole (16.5 mg) and N,N-dimethylformamide (1.5 mL) was stirred at 80°C for 9 hours, and then N,N'-diisopropylcarbodiimide (84.0 μL) was added and stirred at the same temperature for 7 hours. After the reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (68.1 mg).

[1650] 1 H-NMR (DMSO-D 6 )δ:12.54(1H,s),10.79(1H,s),8.42(1H,d,J=4.9Hz),8.17(1H,s),7.30(1H,s),7.22(1H,s),6.95(1H,d,J=4.9Hz) ,5.22-4.83(2H,m),3.81(3H,s),2.93(2H,q,J=7.4Hz),2.24-2.16(1H,m),1.26(3H,t,J=7.4Hz),1.04-0.97(4H,m).

[1651] (Step 2) 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1652] To a solution of the compound (68.1 mg) obtained in step 1 above in dichloromethane (1.0 mL) was added a 4.0 M solution of hydrogen chloride in 1,4-dioxane (330 μL) at room temperature, and the mixture was stirred at the same temperature for 17.5 hours. The reaction mixture was concentrated under reduced pressure, and N,N-dimethylformamide (1.0 mL), triethylamine (51.5 μL) and 1,1'-carbonyldiimidazole (40.0 mg) were added to the obtained residue at room temperature, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at 70°C for 4 hours. The reaction mixture was cooled to room temperature, and then water was added, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (34.4 mg).

[1653] 1 H-NMR (DMSO-D 6)δ:12.51(1H,br s),10.76(1H,br s),8.39(1H,d,J=4.9Hz),8.14(1H,s),7.27(1H,s),7.19(1H,s),6.92(1H,d,J=4.9Hz),5.00(2H,br s),3.78(3H,s),2.90(2H,q,J=7.6Hz),2.21-2.13(1H,m),1.22(3H,t,J=7.6Hz),1.01-0.95(4H,m).,MS(m / z):476(M+H) + .

[1654] Embodiment 102

[1655] Production of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1656] [Chemical formula 122]

[1657]

[1658] (Step 1) tert-Butyl [3-{[(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)amino]methyl}-2-(2-chlorophenyl)pyridin-4-yl]carbamate

[1659] 1,1'-Thiocarbonyldiimidazole (96 mg) was added to a solution of the compound (150 mg) obtained in step 3 of Reference Example 106 in acetonitrile (4 mL) at room temperature, and after stirring at the same temperature for 1 hour, N,N-dimethylformamide (1.5 mL) and 6-chloropyridine-3,4-diamine (77.4 mg) were added, and further stirred at 80°C for 2 hours. Next, N,N'-diisopropylcarbodiimide (84 μL) was added to the reaction mixture at 80°C, and stirred at the same temperature for 7 hours. After the reaction mixture was cooled to room temperature, water was added, and extraction was performed three times with ethyl acetate. The obtained organic layer was washed with saturated brine and dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (128 mg).

[1660] 1 H-NMR (CDCl 3)δ:11.06(0.35H,s),10.93(0.65H,s),10.68(0.65H,br s),10.43(0.35H,br s),8.46-8.35(1.35H,m),8.18(0.35H,d,J=6.1Hz),8.15(0.65H,d,J=6.1Hz),7.96(0.65H,s),7.42-6.90(5H,m),5.14(0.65H ,t,J=6.7Hz), 4.89(0.35H,t,J=6.7Hz), 4.44(1.30H,d,J=6.7Hz), 4.41(0.70H,d,J=6.7Hz), 1.63(5.85H,s), 1.59(3.15H,s).

[1661] (Step 2) 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1662] To a solution of the compound (125 mg) obtained in the above step 1 in N,N-dimethylformamide (3 mL) was added 55% sodium hydride (oil) (56 mg) at room temperature, and the mixture was stirred at 70°C for 9 hours. The reaction mixture was cooled to room temperature, and a saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. The obtained organic layer was filtered, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (40.5 mg).

[1663] 1 H-NMR (DMSO-D 6 )δ:12.63(1H,br s),10.90(1H,br s),8.50(1H,s),8.43(1H,d,J=5.5Hz),7.67(1H,dd,J=7.9,1.2Hz),7.62-7.4 1(4H,m),6.98(1H,d,J=5.5Hz),4.98(2H,s),3.33(3H,s).,MS(m / z):411(M+H) + .

[1664] Embodiment 103

[1665] Production of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1666] [Chemical formula 123]

[1667]

[1668] (Steps 1 and 2) 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one

[1669] The title compound was obtained by using the compound obtained in step 3 of reference example 107 as a raw material and carrying out the same operations as steps 1 and 2 of example 102.

[1670] 1 H-NMR (DMSO-D 6 )δ:12.59(1H,br s),10.81(1H,br s),8.48(1H,s),8.39(1H,d,J=5.5Hz),7.57-7.40(2H,m),7.27(1H,dd,J=7.4,1.8Hz),7.20(1H,d,J =8.0Hz),7.10(1H,t,J=7.4Hz),6.93(1H,d,J=5.5Hz),4.98(2H,s),3.72(3H,s).,MS(m / z):407(M+H) + .

[1671] Embodiment 104

[1672] Production of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1673] [Chemical formula 124]

[1674]

[1675] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylsulfonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1676] A mixture of the compound obtained in Reference Example 28 (65 mg), the compound obtained in Step 2 of Reference Example 109 (110 mg), piperidine (49 μL) and ethanol (3 mL) was stirred at 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (58.8 mg).

[1677] 1 H-NMR (DMSO-D 6 )δ:13.20-12.77(2H,m),9.27(1H,s),8.80(1H,s),8.57(1H,d,J=5.9Hz),7.70(1H,br s),7.29(1H,d,J=5.9Hz),6.25-6.20(1H,m),4.35-4.29(2H,m),3.59-3.51(2H, m),2.77-2.70(1H,m),2.60-2.53(2H,m),1.08-0.98(4H,m).,MS(m / z):483(M+H) + .

[1678] Embodiment 105

[1679] Production of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylcarbonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1680] [Chemical formula 125]

[1681]

[1682] 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(cyclopropylcarbonyl)-1,2,5,6-tetrahydropyridin-3-yl]-1,6-naphthyridin-2(1H)-one

[1683] The title compound was obtained by carrying out the same operation as in Example 104 using the compound obtained in Reference Example 28 and the compound obtained in Step 3 of Reference Example 108 as raw materials.

[1684] 1 H-NMR (DMSO-D 6 )δ:9.24(1H,s),8.78(1H,s),8.54(1H,d,J=5.5Hz),7.69(1H,s),7.25(1H,d,J=5.5Hz),6.30-6.15(1H,m),4.72(1H,s),4.4 8(1H,s),3.99-3.88(1H,m),3.80-3.67(1H,m),2.46-2.34(2H,m),2.17-1.93(1H,m),0.82-0.67(4H,m).,MS(m / z):447(M+H) + .

[1685] Embodiment 106

[1686] Production of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one

[1687] [Chemical formula 126]

[1688]

[1689] 3-(6-Chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one

[1690] The title compound was obtained by carrying out the same operation as in Example 104 using the compound obtained in Reference Example 28 and the compound obtained in Step 4 of Reference Example 110 as raw materials.

[1691] 1 H-NMR (DMSO-D 6 )δ:13.21(0.35H,s),13.10(0.65H,s),12.89-12.85(1H,m),9.24(0.35H,s),9.22(0.65H,s),8.90(0. 65H,s),8.81(0.35H,d,J=0.8Hz),8.51(0.35H,d,J=5.5Hz),8.50(0.65H,d,J=5.5Hz),7.87(0.35H,s), 7.82(2H,d,J=7.0Hz),7.71(0.65H,d,J=1.2Hz),7.66-7.59(3H,m),7.24(1H,d,J=5.5Hz),3.84-3.61( 3H,m),3.57-3.47(1H,m),3.23-3.11(1H,m),2.04-1.83(3H,m),1.80-1.58(3H,m).,MS(m / z):535(M+H) + .

[1692] Embodiment 107

[1693] 7-Chloro-18-fluoro-10,14-dimethyl-3,8,10,14,21,25,31-heptaazahexacyclo[18.6.2.2 16,19 .1 2 ,5 .0 4,9 .0 24,28] Preparation of 1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione

[1694] [Chemical formula 127]

[1695]

[1696] (Step 1) Methyl 4-(3-{4-[{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)-3-fluorobenzoate

[1697] A mixture of the compound obtained in step 3 of Reference Example 41 (170 mg), the compound obtained in Reference Example 78 (190 mg), piperidine (0.10 mL) and ethanol (10 mL) was stirred at 90° C. for 21 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, a n-hexane / ethyl acetate mixed solution was added to the residue, and the precipitated solid was separated by filtration to obtain a crude title compound (118 mg).

[1698] (Step 2) 4-(3-{4-[{3-[(tert-butoxycarbonyl)(methyl)amino]propyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl)-3-fluorobenzoic acid

[1699] To a solution of the compound (118 mg) obtained in step 1 above in methanol (2 mL)-tetrahydrofuran (2 mL) was added 1M sodium hydroxide aqueous solution (2 mL) at room temperature, and stirred at the same temperature for 24 hours. 1M hydrochloric acid (2.3 mL) and water were added to the reaction mixture, and extracted three times with ethyl acetate. The obtained organic layer was washed with water and saturated brine, and then dried with anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure to obtain a crude title compound (110 mg).

[1700] (Step 3) 4-[3-(6-Chloro-4-{methyl[3-(methylamino)propyl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-2-oxo-1,2-dihydro-1,6-naphthyridin-5-yl]-3-fluorobenzoic acid

[1701] Trifluoroacetic acid (1 mL) was added to a suspension of the compound (110 mg) obtained in the above step 2 in dichloromethane (5 mL) at room temperature, and the mixture was stirred at the same temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, and the remaining trifluoroacetic acid was removed by azeotropy with toluene to obtain a crude title compound (100 mg).

[1702] (Step 4) 7-chloro-18-fluoro-10,14-dimethyl-3,8,10,14,21,25,31-heptaazahexacyclo[18.6.2.2 16,19 .1 2,5 .0 4,9 .0 24,28 ] Henty-undecene-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione

[1703] To a solution of the compound (100 mg) obtained in the above step 3 in N,N-dimethylformamide (18 mL) were added O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g) and N,N-diisopropylethylamine (0.16 mL) at room temperature, and the mixture was stirred at the same temperature for 13.5 hours. The reaction mixture was diluted with ethyl acetate, and water and a saturated aqueous solution of ammonium chloride were added, stirred, and then separated into an organic layer and an aqueous layer. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layer was washed with water three times, washed once with saturated brine, and dried over anhydrous sodium sulfate. After filtering the obtained organic layer, the solvent was distilled off under reduced pressure, the residue was suspended with a mixed solution of n-hexane / ethyl acetate, and the precipitated solid was separated by filtration to obtain the title compound (73 mg).

[1704] 1 H-NMR (DMSO-D 6 )δ:12.85(1H,s),12.69(1H,s),8.68(1H,d,J=5.5Hz),8.30(1H,d,J=1.8Hz),7.63(1H,t,J=7.3Hz),7.57(1H,dd,J=9.8,1.2Hz),7.44-7.40(2 H,m),6.88(1H,s),4.20-4.09(1H,m),3.73-3.65(1H,m),3.12-3.03(2 H,m),3.11(3H,s),3.03(3H,s),2.06-1.87(2H,m).,MS(m / z):518(M+H) + .

[1705] The same operations as steps 1 to 4 of Example 107 were carried out to synthesize the following compounds (Table 15-3 and Table 15-4).

[1706] [Table 15-3]

[1707]

[1708]

[1709] [Table 15-4]

[1710]

[1711]

[1712]

[1713] Embodiment 117

[1714] Preparation of 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one p-toluenesulfonate

[1715] 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one p-toluenesulfonate

[1716] To a suspension of the compound (3.76 g) obtained in Example 1 in ethanol (53 mL) was added p-toluenesulfonic acid monohydrate (1.80 g) at room temperature, and the mixture was stirred at 90° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (5.01 g).

[1717] 1 H-NMR (DMSO-D 6)δ:13.26(1H,br s),12.90(1H,br s),9.41(1H,br s),9.10(1H,s),8.69-8.63(1H,m),7.59-7.51(1H,m),7.47(2H,d,J=7 .9Hz),7.11(2H,d,J=7.9Hz),6.99(1H,s),5.51-5.37(1H,m),4.91-4.7 6(1H,m),4.04-3.94(1H,m),3.82-3.72(2H,m),3.64-3.54(1H,m),3.4 2-3.32(1H,m),2.29(3H,s),1.28(3H,d,J=6.7Hz).,MS(m / z):397(M+H) + .

[1718] Embodiment 118

[1719] Preparation of 3-{6-chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one methanesulfonate

[1720] 3-{6-Chloro-4-[(2R,4R)-4-fluoro-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one methanesulfonate

[1721] Methanesulfonic acid (8.2 μL) was added to a suspension of the compound (48 mg) obtained in Example 10 in ethanol (2.0 mL) at room temperature, and the mixture was stirred at the same temperature for 8 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated solid was separated by filtration and dried under reduced pressure to obtain the title compound (56 mg).

[1722] 1 H-NMR (DMSO-D 6 )δ:13.34(1H,s),12.83(1H,s),9.45(1H,s),9.14(1H,s),8.69(1H,d,J=6.1Hz),7.60(1H,d,J=6.1Hz),6.91(1H,s),5.45(1H,d,J=53.7Hz),4 .86-4.57(2H,m),4.04(1H,dd,J=36.6,12.8Hz),2.31(3H,s),2.32-2.2 7(1H,m),2.09-1.93(1H,m),1.36(3H,d,J=6.1Hz).,MS(m / z):399(M+H) + .

[1723] The same operations as in Example 118 were carried out to synthesize the following compounds (Table 16).

[1724] [Table 16]

[1725]

[1726]

[1727] Embodiment 125

[1728] Production of 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one methanesulfonate

[1729] 3-[6-Chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-methyl-1,6-naphthyridin-2(1H)-one methanesulfonate

[1730] Methanesulfonic acid (67.0 μL) was added to a suspension of the compound (273 mg) obtained in Example 17 in ethanol (7.0 mL) at room temperature, and the mixture was stirred at 90° C. for 4 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was separated by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (339 mg).

[1731] 1 H-NMR (DMSO-D 6 )δ:13.47(1H,s),9.13(1H,s),8.60(1H,d,J=6.7Hz),7.58-7.50(2H,m),4.06-3.96(2H,m),3.83-3 .72(1H,m),3.61-3.51(2H,m),3.06(3H,s),2.32(3H,s),2.08-1.93(2H,m),1.86-1.75(2H,m).,MS

[1732] (m / z):396(M+H) + .

[1733] The same operations as in Example 125 were carried out to synthesize the following compounds (Table 17).

[1734] [Table 17]

[1735]

[1736]

[1737] Embodiment 138

[1738] Preparation of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate

[1739] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate

[1740] To the compound obtained in Example 58 (30.32 mg) were added a 1.002 mol / L methanesulfonic acid aqueous solution (66 μL) and water (234 μL) at room temperature, and the mixture was stirred at 40° C. for 24 hours. The precipitated solid was separated by filtration and dried at room temperature for 17 hours to obtain the title compound (35.13 mg) in the form of crystals (elemental analysis measured values; C: 48.34%, H: 5.18%, N: 12.95%, Cl: 5.50%, S: 4.97%). 1 H-NMR (DMSO-D 6 )δ:13.05(1H,br s),8.70(1H,d,J=5.9Hz),8.67(1H,br s),8.60(1H,s),7.52(1H,s),7.48(1H,d,J=5.9Hz),7.42(1H,s),4.00(3H,s),3.08(2 H,q,J=7.4Hz),2.46-2.36(1H,m),2.32(3H,s),1.43-1.24(7H,m).,MS(m / z):473(M+H) + .

[1741] The obtained solid was measured using a powder X-ray diffraction apparatus (SmartLab, manufactured by Rigaku Co., Ltd.). The results are shown in FIG. Figure 1 In the diffraction pattern showing powder X-ray diffraction (CuKα, λ=1.54 Å, scanning speed=20° / min) Figure 1 The characteristic peaks of the present crystal are shown in Table 18, and all the peaks are shown in Table 19. In addition, in Table 19, when * is added to the peak number, it means the top 10 with the highest relative intensity among all the peaks.

[1742] [Table 18]

[1743]

[1744] [Table 19]

[1745]

[1746]

[1747]

[1748] The same operations as in Example 138 were carried out to synthesize the following compounds (Table 20).

[1749] [Table 20]

[1750]

[1751] Embodiment 145

[1752] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1753] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1754] Methanesulfonic acid (5.1 μL) was added to a suspension of the compound obtained in Example 80 (40.0 mg) in acetonitrile (2.6 mL) at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. The precipitated solid was separated by filtration, washed with acetonitrile, and dried under reduced pressure to obtain the title compound (46.3 mg).

[1755] 1 H-NMR (DMSO-D 6 )δ:13.01(1H,s),8.72(1H,s),8.71(1H,d,J=6.1Hz),8.58(1H,s),7.89(1H,s),7.51(1H,s),7.46(1H,d ,J=6.1Hz),3.97(3H,s),3.05(2H,q,J=7.5Hz),2.31(3H,s),1.29(3H,t,J=7.5Hz).,MS(m / z):501(M+H) + .

[1756] Embodiment 146

[1757] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1758] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1759] The title compound was obtained by using the compound obtained in Example 81 as a raw material and carrying out the same procedures as in Example 145.

[1760] 1 H-NMR (DMSO-D 6 )δ:13.01(1H,s),8.72(1H,s),8.71(1H,d,J=6.1Hz),8.58(1H,s),7.89(1H,s),7.51(1H,s),7.46(1H,d ,J=6.1Hz),3.97(3H,s),3.05(2H,q,J=7.5Hz),2.31(3H,s),1.29(3H,t,J=7.5Hz).,MS(m / z):499(M+H) + .

[1761] Embodiment 147

[1762] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1763] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1764] The title compound was obtained by carrying out the same procedures as in Example 145 using the compound obtained in Example 82 as a raw material.

[1765] 1 H-NMR (DMSO-D 6)δ:13.04(1H,s),8.71(1H,d,J=5.5Hz),8.63(1H,s),8.59(1H,s),7.63(1H,s),7.51(1H,s),7.47(1H,d,J=5.5Hz), 3.94(3H,s),3.05(2H,q,J=7.5Hz),2.32(3H,s),2.11(3H,t,J=19.2Hz),1.29(3H,t,J=7.5Hz).,MS(m / z):497(M+H) + .

[1766] Embodiment 148

[1767] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1768] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate

[1769] Methanesulfonic acid (5.0 μL) was added to a suspension of the compound (35 mg) obtained in Example 83 in ethanol (2 mL) at room temperature, and the mixture was stirred at 90° C. for 3.5 hours and then at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the precipitated solid was separated by filtration and dried under reduced pressure to obtain the title compound (32 mg).

[1770] 1 H-NMR (DMSO-D 6 )δ:13.13(1H,s),8.69-8.72(2H,m),7.95(1H,t,J=57.7Hz),7.52(1H,s),7.4 6(1H,d,J=6.1Hz),2.38(3H,s),2.31(3H,s),2.19(3H,s).,MS(m / z):470(M+H) + .

[1771] The same operations as in Example 148 were carried out to synthesize the following compounds (Table 21).

[1772] [Table 21]

[1773]

[1774]

[1775] Embodiment 154

[1776] Preparation of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one methanesulfonate

[1777] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one methanesulfonate

[1778] To a suspension of the compound obtained in Example 101 (23.5 mg) in ethanol (3.0 mL) was added a 10% methanesulfonic acid ethanol solution (47.6 μL) at room temperature, and the mixture was stirred at the same temperature for 6 hours. The precipitated solid was separated by filtration, washed with ethanol, and dried under reduced pressure to obtain the title compound (14.2 mg).

[1779] 1 H-NMR (DMSO-D 6 )δ:12.58(1H,br s),11.13(1H,br s),8.51(1H,d,J=5.9Hz),8.39(1H,s),7.38-7.35(2H,m),7.09(1H,d,J=5.9Hz),5.07(2H,br s),3.91(3H,s),3.03-2.85(2H,m),2.35-2.24(3H,m),1.25(3H,t,J=7.4Hz),1.21-1.10(4H,m).,MS(m / z):476(M+H) + .

[1780] Embodiment 155

[1781] Production of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate

[1782] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate

[1783] To the compound obtained in Example 58 (30.30 mg), 1.000 mol / L 1,2-ethanedisulfonic acid aqueous solution (33 μL) and water (267 μL) were added at room temperature, and the mixture was stirred at 40° C. for 24 hours. The precipitated solid was separated by filtration and dried at room temperature for 17 hours to obtain the title compound (29.91 mg) in the form of crystals (elemental analysis measured values; C: 51.53%, H: 4.80%, N: 13.79%, Cl: 5.84%, S: 5.26%). 1 H-NMR (DMSO-D 6 )δ:13.05(1H,br s),8.70(1H,d,J=5.9Hz),8.66(1H,br s),8.60(1H,s),7.51(1H,s),7.48(1H,d,J=5.9Hz),7.42(1H,s),4.00(3H,s),3.08(2H,q ,J=7.4Hz),2.65-2.60(2H,m),2.44-2.35(1H,m),1.40-1.25(7H,m).,MS(m / z):473(M+H) + .

[1784] The obtained solid was measured using a powder X-ray diffraction apparatus (SmartLab, manufactured by Rigaku Co., Ltd.). The results are shown in FIG. Figure 2 In the diffraction pattern showing powder X-ray diffraction (CuKα, λ=1.54 Å, scanning speed=20° / min) Figure 2 The characteristic peaks of the present crystal are shown in Table 22, and all peaks are shown in Table 23. In Table 23, when a peak number is marked with an asterisk (*), it indicates the top 10 peaks with the highest relative intensities among all peaks.

[1785] [Table 22]

[1786]

[1787]

[1788] [Table 23]

[1789]

[1790]

[1791] Embodiment 156

[1792] Preparation of 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one benzenesulfonate

[1793] 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-onebenzenesulfonate

[1794] To the compound obtained in Example 58 (30.82 mg) were added a 1.000 mol / L benzenesulfonic acid aqueous solution (67 μL) and water (233 μL) at room temperature, and the mixture was stirred at 40° C. for 24 hours. The precipitated solid was separated by filtration and dried at room temperature for 17 hours to obtain the title compound (35.92 mg) in the form of crystals (elemental analysis measured values; C: 55.17%, H: 4.75%, N: 12.24%, Cl: 5.24%, S: 4.77%). 1 H-NMR (DMSO-D 6 )δ:13.05(1H,br s),8.70(1H,d,J=5.9Hz),8.67(1H,br s),8.60(1H,s),7.61-7.57(2H,m),7.52(1H,s),7.48(1H,d,J=5.9Hz),7.42(1H,s),7.35-7.27(3H ,m),4.00(3H,s),3.08(2H,q,J=7.4Hz),2.45-2.37(1H,m),1.45-1.26(7H,m).,MS(m / z):473(M+H) + .

[1795] The obtained solid was measured using a powder X-ray diffraction apparatus (SmartLab, manufacture...

Claims

1. A compound represented by formula (1) or a pharmaceutically acceptable salt thereof, [Chemical formula 1] In formula (1), R 1 represents a hydrogen atom, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a hydroxyl group or a halogen atom), a C3-C6 cycloalkyl group, a phenyl group (the phenyl group may be substituted with an amino group or a halogen atom), a 2-tert-butylamino-2-oxoethyl group, a [dimethyl(oxy)-λ6-sulfanylidene]amino group, or a group represented by the following formula (2), or -NR 1d R 1e , [Chemical formula 2] (In formula (2), W a Represents CH2, oxygen atom or NR 1f , W b represents CH, nitrogen atom or C-OH, R 1a , R 1b , R 1c are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted by a halogen atom, an amino group or an oxo group, n represents 0, 1 or 2) R 1d , R 1e are the same or different and each independently represents a hydrogen atom, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a halogen atom or a 4-7 membered heterocyclic group), a 4-7 membered heterocyclic group, or a C3-C6 cycloalkyl group which may be substituted with a hydroxyl group, R 1f represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted by a C1-C6 alkyl group, a 2,4-dimethylpyrazolyl group, or any group selected from the following formula (3), [Chemical formula 3] (In formula (3), Dashed lines represent single or double bonds. V a Represents CR 2f or nitrogen atoms, V b Represents CR 2g or nitrogen atoms, V c Represents CR 2j or nitrogen atoms, V d Represents CR 2k or nitrogen atoms, V g represents CH or nitrogen atom, V h Indicates CHN(CH3)2, NR 2l or oxygen atoms, n 2 Indicates 1 or 2, R 2a , R 2b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted by a hydroxyl group, a halogen atom or a 4-7 membered heterocyclic group), a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted by a halogen atom or deuterium), or a C3-C6 cycloalkyl group, R 2c represents a C3-C6 cycloalkyl group or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted by a C3-C6 cycloalkyl group or a halogen atom), R 2d represents a hydrogen atom, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group or a C3-C6 cycloalkyl group, R 2e represents a C1-C6 alkylsulfonyl group, a C3-C6 cycloalkylsulfonyl group, a benzenesulfonyl group (the benzenesulfonyl group may be substituted with a C1-C6 alkyl group or a halogen atom), a C3-C6 cycloalkylcarbonyl group, a C1-C6 alkylcarbonyl group or a benzoyl group (the benzoyl group may be substituted with a C1-C6 alkyl group or a halogen atom), R 2f , R 2g are the same or different and each independently represents a hydrogen atom, a halogen atom, a C1-C6 alkoxy group which may be substituted by a halogen atom, or a C1-C6 alkyl group which may be substituted by a hydroxyl group, or the following formula (4), [Chemical formula 4] (In formula (4), R 2h , R 2i are the same or different, each independently representing a C1-C6 alkyl group, Or, R 2h , R 2i may be bonded to each other to form a 4-7 membered heterocyclic group which may be substituted by a C1-C6 alkyl group) R 2j , R 2k are the same or different and each independently represents a hydrogen atom, a C1-C6 alkyl group which may be substituted by a halogen atom, or a C3-C6 cycloalkyl group, Or, R 2c With R 2k can be bonded to each other to form the following groups, [Chemical formula 5] R 2l represents C1-C6 alkyl or C3-C6 cycloalkyl) Or, R 1 With R 2 can be bonded to each other to form a group represented by the following formula (5), (The bond at the left end of each group represents the bond between the aromatic ring of the compound represented by formula (1) and R 1 The bond on the right represents the bond between the aromatic ring of the compound represented by formula (1) and R 2 The key between [Chemical formula 6] (In formula (5), A represents an aryl group, a heteroaryl group or a 4-7 membered heterocyclic group, R 6a represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group or a C1-C6 alkoxy group, D stands for -NR 6e CO-, or -CONR 6f -, E stands for -CR 6g R 6h -、-NR 6i -, -O-, -S-, -SO-, or -SO2-. When there are multiple E's, the multiple E's may be the same or different. R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i Each independently represents a hydrogen atom, a C1-C6 alkyl group or a C3-C6 cycloalkyl group, or, R 6b With R 6c , R 6b With R 6e , or R 6c With R 6d can bond to each other to form a ring, m 1 Indicates 0 or 1, m 2 means 1, 2, 3, 4 or 5, m 3 means 0, 1, 2 or 3) R 3 represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group or a 1-methyl-3,6-dihydro-2H-pyrazin-5-yl group, R 4 represents a hydrogen atom or a halogen atom, XY represents C=CH or N-CH2, Z represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group, a cyano group or a C1-C6 alkoxycarbonyl group.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 represents a hydrogen atom, a C1-C6 alkyl group, -NR 11d R 11e or any group selected from the following formula (6), [Chemical formula 7] In formula (6), R 11a , R 11b are the same or different, and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group or a C1-C6 alkyl group, R 11d , R 11e are the same or different and each independently represents a hydrogen atom or a C1-C6 alkyl group which may be substituted by a halogen atom.

3. The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein: R 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group which may be substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7), [Chemical formula 8] In formula (7), V 2a Represents CR 21e or nitrogen atoms, V 2b Represents CR 21f or nitrogen atoms, R 21a , R 21b are the same or different and each independently represents a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group (the C1-C6 alkoxy group may be substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group, R 21c represents a C1-C6 alkyl group which may be substituted by a halogen atom, R 21d represents a hydrogen atom or a C3-C6 cycloalkyl group, R 21e represents a hydrogen atom or a halogen atom, R 21f represents a hydrogen atom or a halogen atom.

4. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein: R 3 represents a hydrogen atom, R 4 represents a hydrogen atom, XY represents C=CH or N-CH2, Z represents a halogen atom.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 represents any group selected from ethyl, 2,2-difluoroethylamino or [(2R)-1,1,1-trifluoropropane-2-yl]amino, R 2 represents 2-methoxypyridin-3-yl, 1,5-dimethyl-1H-pyrazol-4-yl, or a group represented by the following formula (8), [Chemical formula 9] In formula (8), R 22 represents a C1-C6 alkyl group which may be substituted by a halogen atom, a C1-C6 alkoxy group which may be substituted by a halogen atom, or a C3-C6 cycloalkyl group; R 3 represents a hydrogen atom, R 4 represents a hydrogen atom, XY represents C=CH or N-CH2, Z represents a halogen atom.

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the following compounds, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1,5-dimethyl-1H-pyrazol-4-yl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one, 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-(2-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one, or 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one.

7. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one or a pharmaceutically acceptable salt thereof.

8. 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one 1,2-ethanedisulfonate.

9. 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one methanesulfonate.

10. 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridin-2(1H)-one benzenesulfonate.

11. 3-(6-Chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,6-naphthyridine-2(1H)-one adipate. 12 . A SMG1 inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 13 . An NMD inhibitor comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient. 14 . A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient, wherein the pharmaceutical composition may contain a pharmaceutically acceptable carrier.

15. The pharmaceutical composition according to claim 14, which is used for treating cancer.

16. The pharmaceutical composition according to claim 15, wherein The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

17. The pharmaceutical composition according to claim 16, wherein The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are contained in separate preparations as active ingredients, respectively, and are administered simultaneously or at different times.

18. The pharmaceutical composition according to claim 16, wherein The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor are contained as active ingredients in a single preparation.

19. The pharmaceutical composition according to any one of claims 16 to 18, wherein Immune checkpoint inhibitors are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

20. The pharmaceutical composition according to any one of claims 15 to 19, wherein The cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

21. An anticancer agent comprising the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

22. A method for treating cancer, characterized in that: An effective amount of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is administered.

23. A method for treating cancer, characterized in that: The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

24. The method of claim 23, wherein: The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are contained in separate preparations as active ingredients, respectively, and are administered simultaneously or at different times.

25. The method of claim 23, wherein: The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor are contained as active ingredients in a single preparation and administered.

26. The method of treatment according to any one of claims 23 to 25, wherein Immune checkpoint inhibitors are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

27. The method of treatment according to any one of claims 22 to 26, wherein The cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

28. The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, for use in the treatment of cancer.

29. The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, for use in the treatment of cancer, characterized in that: Administered in combination with immune checkpoint inhibitors.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, characterized in that: The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are contained in separate preparations as active ingredients, respectively, and are administered simultaneously or at different times.

31. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, characterized in that: The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor are contained as active ingredients in a single preparation and administered.

32. The compound or pharmaceutically acceptable salt thereof according to any one of claims 29 to 31, wherein: Immune checkpoint inhibitors are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

33. The compound or pharmaceutically acceptable salt thereof according to any one of claims 28 to 32, wherein: The cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

34. Use of the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating cancer.

35. The use according to claim 34, characterized in that The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

36. The use according to claim 35, characterized in that The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor are contained in separate preparations as active ingredients, respectively, and are administered simultaneously or at different times.

37. The use according to claim 35, characterized in that The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor are contained as active ingredients in a single preparation and administered.

38. The use according to any one of claims 35 to 37, wherein Immune checkpoint inhibitors are anti-PD-1 antibodies, anti-PD-L1 antibodies, or anti-CTLA-4 antibodies.

39. The use according to any one of claims 34 to 38, wherein The cancer is a blood cancer selected from the group consisting of leukemia, lymphoma and multiple myeloma, a sarcoma selected from the group consisting of osteosarcoma, chordoma, chondrosarcoma and Ewing sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colorectal cancer, esophageal cancer, head and neck cancer, breast cancer, liver cancer, kidney cancer, tongue cancer, thyroid cancer, uterine cancer, ovarian cancer, prostate cancer, cervical cancer, pancreatic cancer, skin cancer, adrenal cancer, biliary tract cancer, thymic cancer, mesothelioma, bladder cancer and brain tumor.

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