Imidazopyridine derivatives with bicyclic structure

Abstract

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

Description

Imidazopyridine derivatives with bicyclic structures

[0001] The present invention relates to a compound having a specific chemical structure or a pharmaceutically acceptable salt thereof, which has SMG1 inhibitory activity.

[0002] SMG1 is a serine-threonine kinase identified as the human ortholog of C. elegans smg-1. It is classified as a member of the PI3K-related protein kinase (PIKK) family, along with mTOR. SMG1 plays an essential role in nonsense-mediated mRNA decay (NMD), contributing to the degradation of transcripts containing premature termination codons. It has also been reported that SMG1 kinase activity is essential for this function (Non-Patent Document 1). Suppression of SMG1 has been reported to reduce the responsiveness of cancer cells to ER stress and DNA damage, increasing their susceptibility and vulnerability to these conditions (Non-Patent Documents 2-4). Based on these findings, compounds that inhibit SMG1 are expected to be therapeutic agents for malignant tumors. SMG1 inhibitors are also expected to be therapeutic agents for hereditary diseases such as cystic fibrosis and congenital muscular dystrophy (Non-Patent Documents 5 and 6). Recently, it has been suggested that the mechanism by which SMG1 inhibition increases tumor antigen expression may be effective in the treatment of malignant tumors. For example, it has been shown that suppressing the expression of SMG1 or other NMD-related factors in tumors results in antitumor effects in mouse allograft models, and that this effect is mediated by T cell-mediated immunity (Non-Patent Document 7). The mechanism of action is thought to be that SMG1 inhibition increases and accumulates transcripts derived from somatic mutations or aberrant splicing isoforms in tumors, which then become novel antigens and activate tumor immunity (Non-Patent Documents 7 and 8). In addition, there have been reports on the modulation of immune cell activation mechanisms by SMG1 inhibition (Non-Patent Document 9). Furthermore, papers have been published suggesting the importance of NMD in clinical tumor immunity (Non-Patent Document 10) and the importance of novel antigens in the therapeutic effects of immune checkpoint inhibitors, and the involvement of NMD (Non-Patent Documents 11-13). The following compounds are known to have NMD and SMG1 inhibitory activity (Non-Patent Documents 14-17, Patent Documents 1 and 2).

[0003] International Publication No. WO2018 / 152095 Pamphlet International Publication No. WO2017 / 112954 Pamphlet

[0004] A Yamashita, et al., Genes & Dev. 2001,15,2215-2228K M Brumbaugh, et al., Mol Cell. 2004,14(5),585-98S C Gehen, et al., Oncogene 2008,27(29),4065-4074E Gubanova, et al., Clin Cancer Res. 2012,18(5),1257-1267F Usuki, et al., Ann Neurol. 2004,55,740-744D R McHugh, et al., Int J Mol Sci. 2021,22(1),344F Pastor, et al., Nature 2010,465(7295),227-30J El-Bchiri, et al. al., PLoS ONE 2008, 3(7), e2583T Mino, et al., Nucleic Acids Res. 2019,47(16),8838-8859B Zhao, et al., PLoS Comput Biol. 2019,15(10), e1007467R GH Lindeboom, et al., Nat Genetics 2019,51(11),1645-1651K Litchfield, et al., Nat Commun. 2020,11,3800K Litchfield, et al., Cell 2021,184(3),596-614 e14A Gopalsamy, et al., Bioorg. Med. Chem. Lett. 2012,22 (21),6636-6641A Nickless, et al., Cell Biosci. 2017,7,26Cheruiyot, et al., Cancer Res. 2021, 81(17), 4499-4513J P Becker, et al., iScience 2021,24(4),102389

[0005] An objective of the present invention is to provide a novel compound having SMG1 inhibitory activity and anti-cancer activity, or a pharmaceutically acceptable salt thereof.

[0006] In order to solve the above problems, the present inventors synthesized compounds having various structures and searched for compounds that inhibit SMG1 and exhibit anti-cancer activity. As a result, the present inventors discovered the compound of the present invention and its pharmaceutically acceptable salts, etc., and completed the present invention. That is, the present invention is as described below.

[0007] That is, the present invention encompasses the following aspects: [1] A compound represented by formula (1) or a pharmaceutically acceptable salt thereof. 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-tertbutylamino-2-oxo-ethyl group, a [dimethyl(oxide)-λ6-sulfanylidene]amino group, or a group represented by the following formula (2): (In formula (2), W a is CH2, an oxygen atom, or NR 1f indicates W b represents CH, a nitrogen atom, or C—OH, and R 1a , R 1b , R 1c are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a halogen atom, an amino group, or an oxo group, and n represents 0, 1, or 2. 1d R 1e , denotes R 1d , R 1e are each independently the same or different and represent a hydrogen atom, a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a halogen atom or a 4- to 7-membered heterocyclic group), a 4- to 7-membered heterocyclic group, or a C3-C6 cycloalkyl group optionally substituted with a hydroxyl group; R 1f represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, R 2represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group, a 2,4-dimethylpyrazolyl group, or any group selected from the following formula (3): (In formula (3), the dashed line represents a single bond or a double bond, and V a is CR 2f or a nitrogen atom, V b is CR 2g or a nitrogen atom, V c is CR 2j or a nitrogen atom, V d is CR 2k or a nitrogen atom, V g represents CH or a nitrogen atom, V h is CHN(CH3)2, NR 2l , or an oxygen atom, n 2 indicates 1 or 2, R 2a , R 2b are each independently the same or different and represent 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 with a hydroxyl group, a halogen atom, or a 4- to 7-membered heterocyclic group), 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 2c represents a C3-C6 cycloalkyl group or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a C3-C6 cycloalkyl group or a halogen atom), R 2d represents a hydrogen atom, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group, or a C3-C6 cycloalkyl group, and R 2erepresents 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 each independently the same or different and represent a hydrogen atom, a halogen atom, a C1-C6 alkoxy group optionally substituted with a halogen atom, a C1-C6 alkyl group optionally substituted with a hydroxyl group, or a group represented by the following formula (4): (In formula (4), R 2h , R 2i are each independently the same or different and represent a C1-C6 alkyl group, or R 2h , R 2i may be bonded to each other to form a 4- to 7-membered heterocyclic group optionally substituted with a C1-C6 alkyl group. 2j , R 2k are each independently the same or different and represent a hydrogen atom, a C1-C6 alkyl group optionally substituted with a halogen atom, or a C3-C6 cycloalkyl group, or R 2c and R 2k may be bonded to each other to form the group shown below: R 2l represents a C1-C6 alkyl group or a C3-C6 cycloalkyl group.) Or, R 1 and R 2 may be bonded to each other to form a group represented by the following formula (5), (the leftmost bond of each group is connected to the aromatic ring of the compound of formula (1) and R 1 The bond on the right side represents the bond between the aromatic ring of the compound of formula (1) and R 2 represents a bond with (In formula (5), A represents an aryl group, a heteroaryl group, or a 4- to 7-membered heterocyclic group; R 6arepresents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group, and D represents -NR 6e CO- or -CONR 6f - indicates E, -CR 6g R 6h -, -NR 6i represents -, -O-, -S-, -SO-, or -SO2-, and when there are a plurality of E's, the plurality of 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 and R 6c , R 6b and R 6e , or R 6c and R 6d may be bonded to each other to form a ring, m 1 indicates 0 or 1, and m 2 indicates 1, 2, 3, 4, or 5, and m 3 indicates 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, and Z represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group, a cyano group, or a C1-C6 alkoxycarbonyl group. [2] R 1 is a hydrogen atom, a C1-C6 alkyl group, -NR 11d R 11e or any group selected from the following formula (6): [1] The compound according to [1], or a pharmaceutically acceptable salt thereof. (In formula (6), R 11a , R 11bare each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C6 alkyl group. 11d , R 11e are each independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group optionally substituted with a halogen atom. 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7): (In formula (7), V 2a is CR 21e or a nitrogen atom, V 2b is CR 21f or a nitrogen atom, R 21a , R 21b are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group (a C1-C6 alkoxy group optionally substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group; R 21c represents a C1-C6 alkyl group optionally substituted with 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] R 3 indicates a hydrogen atom, and R 4 [5] The compound according to any one of [1] to [3], wherein R represents a hydrogen atom, XY represents C=CH or N-CH2, and Z represents a halogen atom, or a pharmaceutically acceptable salt thereof. 1 represents any group selected from an ethyl group, a 2,2-difluoroethylamino group, or a [(2R)-1,1,1-trifluoropropan-2-yl]amino group, and R 2represents a 2-methoxypyridin-3-yl group, a 1,5-dimethyl-1H-pyrazol-4-yl group, or a group represented by the following formula (8): (In formula (8), R 22 represents a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group optionally substituted with a halogen atom, or a C3-C6 cycloalkyl group. 3 indicates a hydrogen atom, and R 4represents a hydrogen atom, XY represents C=CH or N-CH2, and Z represents a halogen atom, or a pharmaceutically acceptable salt thereof. [6] The compound according to [1], selected from the following compounds, or a pharmaceutically acceptable salt thereof: 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-trifluoropropan-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-naphthyridin-2(1H)-one adipic acid salt.

[12] An SMG1 inhibitor comprising, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[13] An NMD inhibitor comprising, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[14] A pharmaceutical composition comprising, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable carrier.

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

[16] The pharmaceutical composition according to

[10] , wherein the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

[17] The pharmaceutical composition according to

[11] , wherein the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in different preparations, and are administered simultaneously or at different times.

[18] The pharmaceutical composition according to

[16] , wherein the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in a single preparation.

[19] The pharmaceutical composition according to 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.

[20] The pharmaceutical composition according to 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's 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, as an active ingredient, the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[22] A method for treating cancer, comprising administering an effective amount of the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof.

[23] A method for treating cancer, comprising administering the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor.

[24] The method for treating cancer according to

[23] , wherein the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in different formulations, and administered simultaneously or at different times.

[25] The method for treating cancer according to

[23] , wherein the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in a single formulation, and administered.

[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.

[27] The method for treating cancer according to 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's 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 [1] to

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

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

[11] , or a pharmaceutically acceptable salt thereof, for use in cancer treatment, wherein the compound is administered in combination with an immune checkpoint inhibitor.

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

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

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

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in a single preparation and administered simultaneously.

[32] The compound according to any one of

[29] to

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

[33] The compound according to any one of

[28] to

[32] , or a pharmaceutically acceptable salt thereof, 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's sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colon 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 [1] to

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

[35] The use according to

[34] , characterized in that the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof is administered in combination with an immune checkpoint inhibitor.

[36] The use according to

[35] , characterized in that the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in different formulations and administered simultaneously or at different times.

[37] The use according to

[35] , characterized in that the compound according to any one of [1] to

[11] or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor are contained as active ingredients in a single formulation and administered.

[38] The use according to 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.

[39] The use according to 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's sarcoma, or a solid cancer selected from the group consisting of gastric cancer, lung cancer, colon 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.

[0008] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits SMG1 and NMD inhibitory activity, and also exhibits anti-cancer activity when used alone or in combination with an immune checkpoint inhibitor.

[0009]

[0033] Figure 1 shows the powder X-ray diffraction pattern (CuKα, λ = 1.54 Å, scanning speed = 20° / min) of the salt crystals obtained in Example 138. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the diffraction angle 2θ.

[0034] Figure 1 shows the powder X-ray diffraction pattern (CuKα, λ = 1.54 Å, scanning speed = 20° / min) of the salt crystals obtained in Example 155. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the diffraction angle 2θ.

[0035] Figure 1 shows the powder X-ray diffraction pattern (CuKα, λ = 1.54 Å, scanning speed = 20° / min) of the salt crystals obtained in Example 156. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the diffraction angle 2θ. 1 shows the powder X-ray diffraction pattern (CuKα, λ=1.54 Å, scanning rate=20° / min) of the salt crystals obtained in Example 157. The vertical axis of the figure shows the diffraction intensity as relative line intensity, and the horizontal axis shows the diffraction angle 2θ value. This figure shows the antitumor 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 implanted with MC38 mouse colon cancer cell line. The horizontal axis shows the number of days from the first administration, and the vertical axis shows the tumor volume. This figure shows the antitumor effect of the compound of Example 117, administered alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-L1 antibody), on mice subcutaneously implanted with MC38 mouse colon cancer cell line. The horizontal axis shows the number of days from the first administration, and the vertical axis shows the tumor volume. 1 shows the antitumor 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 implanted with MC38 mouse colon cancer cell line. In the figure, the horizontal axis shows the number of days from the first administration, and the vertical axis shows the tumor volume. FIG. 2 shows the antitumor effect of the compound of Example 138, administered alone and in combination with an immune checkpoint inhibitor (anti-mouse PD-1 antibody), on mice subcutaneously implanted with MC38 mouse colon cancer cell line. In the figure, the horizontal axis shows the number of days from the first administration, and the vertical axis shows the tumor volume.1 shows the antitumor 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 implanted with MC38 mouse colon cancer cell line. In the figure, the horizontal axis represents the number of days from the first administration, and the vertical axis represents tumor volume.

[0010] The substituents and terms used in the present invention will be explained below.

[0011] As used herein, the term "C1-C6 alkyl group" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, and examples thereof include a methyl group, an ethyl group, a 1-propyl group, an isopropyl group, a 1-butyl group, a 2-butyl group, a 2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-pentyl group, a 2-pentyl group, a 3-pentyl group, a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a 1-hexyl group, a 2-hexyl group, a 3-hexyl group, a 2-methyl-1-pentyl group, a 3-methyl-1-pentyl group, a 2-ethyl-1-butyl group, a 2,2-dimethyl-1-butyl group, and a 2,3-dimethyl-1-butyl group.

[0012] As used herein, the term "halogen atom" includes, for example, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, and the like.

[0013] As used herein, the term "C3-C6 cycloalkyl group" refers to a cyclic alkyl group having 3 to 6 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.

[0014] As used herein, the term "C3-C8 cycloalkyl group" refers to a cyclic alkyl group having 3 to 8 carbon atoms, and examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

[0015] As used herein, the term "4- to 7-membered heterocyclic group" refers to a 4- to 7-membered heterocyclic group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and the ring may contain one or two unsaturated bonds, and the ring may be bridged by 1 to 3 methylenes, heteroatoms, or a combination thereof. Examples of such heterocyclic groups include azetidyl, pyrrolidyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, piperidinyl, azepanyl, piperazinyl, hexahydropyrimidinyl, morpholyl, thiomorpholyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, thioxanyl, dihydropyridyl, and 3-oxa-8-azabicyclo[3.2.1]octanyl.

[0016] In this specification, the term "aryl group" refers to an aromatic hydrocarbon group having a single benzene ring such as phenyl or naphthyl, or having two condensed benzene rings.

[0017] As used herein, the term "heteroaryl group" refers to a 5- or 6-membered monocyclic heteroaromatic ring group containing 1 to 3 atoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom, and examples thereof include a thienyl group, a pyridyl group, and a pyrazolyl group.

[0018] As used herein, the term "C1-C6 alkylsulfonyl group" refers to 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.

[0019] As used herein, the term "C3-C6 cycloalkylsulfonyl group" refers to a group in which a C3-C6 cycloalkyl is bonded to a sulfonyl group, and examples thereof include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a cyclopentylsulfonyl group, and a cyclohexylsulfonyl group.

[0020] As used herein, the term "C1-C6 alkylcarbonyl group" refers to a group in which a C1-C6 alkyl group is bonded to a carbonyl group, and examples thereof include a methylcarbonyl group, an ethylcarbonyl group, a 1-propylcarbonyl group, an isopropylcarbonyl group, a 1-butylcarbonyl group, a 2-butylcarbonyl group, a 2-methyl-1-propylcarbonyl group, a 2-methyl-2-propylcarbonyl group, a 1-pentylcarbonyl group, a 2-pentylcarbonyl group, a 3- Examples thereof include a pentylcarbonyl group, a 2-methyl-2-butylcarbonyl group, a 3-methyl-2-butylcarbonyl group, a 1-hexylcarbonyl group, a 2-hexylcarbonyl group, a 3-hexylcarbonyl group, a 2-methyl-1-pentylcarbonyl group, a 3-methyl-1-pentylcarbonyl group, a 2-ethyl-1-butylcarbonyl group, a 2,2-dimethyl-1-butylcarbonyl group, and a 2,3-dimethyl-1-butylcarbonyl group.

[0021] As used herein, the term "C3-C6 cycloalkylcarbonyl group" refers to 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.

[0022] The term "a pharmaceutically acceptable salt thereof" refers to a salt that can be used as a medicine. When a compound has an acidic or basic group, it can be converted into a basic salt or an acid salt by reacting it with a base or an acid, and the term "a pharmaceutically acceptable salt thereof" refers to such a salt.

[0023] The pharmaceutically acceptable "basic salt" of the compound is preferably an alkali metal salt such as a sodium salt, a potassium salt, or a lithium salt; an alkaline earth metal salt such as a magnesium salt or a calcium salt; an organic base salt such as an N-methylmorpholine salt, a triethylamine salt, a tributylamine salt, a diisopropylethylamine salt, a dicyclohexylamine salt, an N-methylpiperidine salt, a pyridine salt, a 4-pyrrolidinopyridine salt, or a picoline salt; or an amino acid salt such as a glycine salt, a lysine salt, an arginine salt, an ornithine salt, a glutamic acid salt, or an aspartic acid salt.

[0024] The pharmaceutically acceptable "acid salt" of a compound is preferably an inorganic acid salt such as a hydrohalide salt such as hydrofluoride, hydrochloride, hydrobromide, or hydroiodide, a nitrate, perchlorate, sulfate, or phosphate; a lower alkane sulfonate salt such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, or 1,2-ethanedisulfonate; an arylsulfonate salt such as benzenesulfonate, p-toluenesulfonate, 2-naphthalenesulfonate, or 1,5-naphthalenedisulfonate; an organic acid salt such as acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate, oxalate, maleate, or adipate; or an amino acid salt such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, or aspartate.

[0025] The compound of the present invention or a pharmaceutically acceptable salt thereof may absorb moisture and become hydrated by being left in the air or by being recrystallized, and the present invention also includes such various hydrates, solvates and crystalline polymorphic compounds.

[0026] The compounds of the present invention, their pharmaceutically acceptable salts, or solvates thereof may exist in various isomers, such as geometric isomers such as cis- and trans-isomers, tautomers, rotational isomers, or optical isomers such as d- and l-isomers (including enantiomers and diastereomers), depending on the types and combinations of substituents. Unless otherwise specified, the compounds of the present invention encompass all such isomers, stereoisomers, and mixtures of these isomers and stereoisomers in any ratio. Mixtures of these isomers can be separated by known resolution methods.

[0027] The compounds of the present invention also include labeled compounds, that is, compounds in which one or more atoms of the compound are substituted with isotopes (for example, 2H, 3H, 13C, 14C, 35S, etc.).

[0028] The compounds of the present invention are generally named according to the nomenclature of the International Union of Pure and Applied Chemistry (IUPAC).

[0029] In the names of the compounds of the present invention, when the structure of the compound has an atom that serves as an asymmetric center, the absolute configuration may be indicated by R and S (along with the position number).

[0030] The relative configuration is indicated by adding an asterisk (*) to the configuration indication when the configuration of the first asymmetric center is R or S (R * and S * ) or by placing the prefix (symbol) rel- (meaning relative) before the name.

[0031] Racemic mixtures are usually designated without R and S, but the absolute configuration is not specified. * and S * The symbols RS and SR are used instead, or the name may be indicated by placing the prefix (symbol) rac- (meaning racemic) before it.

[0032] The present invention also encompasses so-called prodrugs. A prodrug is a compound having a group that can be converted into an amino group, a hydroxyl group, a carboxyl group, or the like of a compound by hydrolysis or under physiological conditions. Examples of groups that form such prodrugs include those described in Prog. Med., Vol. 5, pp. 2157-2161, 1985, etc. More specific examples of the prodrug include: (1) when the compound has an amino group, compounds in which the amino group has been acylated, alkylated or phosphorylated (for example, compounds in which the amino group has been eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl-2-oxo-1,3-dioxolen-4-yl)methoxycarbonylated, tetrahydrofuranylated, pyrrolidylmethylated, pivaloyloxymethylated or tert-butylated), etc.; (2) when the compound has a hydroxyl group, compounds in which the hydroxyl group has been acylated, alkylated, phosphorylated or borated (for example, compounds in which the hydroxyl group has been acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated or dimethylaminomethylcarbonylated), etc.; and (3) when the compound has a carboxyl group, Examples thereof include compounds in which the carboxy group is esterified or amidated (for example, compounds in which the carboxy group is ethyl-esterified, phenyl-esterified, carboxymethyl-esterified, dimethylaminomethyl-esterified, pivaloyloxymethyl-esterified, ethoxycarbonyloxyethyl-esterified, amidated or methylamidated).

[0033] The compounds of the present invention may be used as a partial structure of a degradation inducer for target proteins, collectively known as TPD (Targeted Protein Degradation), by taking advantage of their strong binding ability to SMG1 and binding to a ligand of E3 ubiquitin ligase via a linker structure at any site in their chemical structure. TPD to which the compound of the present invention is applied can be prepared by any known method, for example, 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.

[0034] Other aspects of the present invention will be described in detail below. One aspect of the present invention is a compound represented by formula (1) or a pharmaceutically acceptable salt thereof. (In formula (1), R 1 , R 2 , R 3 , R 4 , X, Y, and Z have the same meanings as above.) Other preferred embodiments of the compound represented by formula (1) of the present invention or a pharmaceutically acceptable salt thereof are shown below.

[0035] R 1 is preferably a hydrogen atom, a C1-C6 alkyl group, or —NR 11d R 11e or any group selected from the following formula (6): (In formula (6), R 11a , R 11b are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C6 alkyl group. 11d , R 11eare each independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group optionally substituted with a halogen atom.) More preferably, R 1 is an ethyl group, a 2,2-difluoroethylamino group, or a [(2R)-1,1,1-trifluoropropan-2-yl]amino group.

[0036] R 2 is preferably a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7): (In formula (7), V 2a is CR 21e or a nitrogen atom, V 2b is CR 21f or a nitrogen atom, R 21a , R 21b are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group (a C1-C6 alkoxy group optionally substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group; R 21c represents a C1-C6 alkyl group optionally substituted with 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), and more preferably, R 2 is a 2-methoxypyridin-3-yl group, a 1,5-dimethyl-1H-pyrazol-4-yl group, or a group represented by the following formula (8): (In formula (8), R 22 represents a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group optionally substituted with a halogen atom, or a C3-C6 cycloalkyl group.

[0037] In another embodiment, R 1 and R2 may be bonded to each other to form a group represented by the following formula (5): (In formula (5), R 6a , R 6b , R 6c , R 6d , A, D, E, m 1 , m 2 , m 3 has the same meaning as above.) In a preferred embodiment of the group of formula (5), A is a phenyl group, 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. Further preferred embodiments of the group of formula (5) are any groups selected from the following. (The leftmost bond of each group is between the aromatic ring of the compound represented by formula (1) and R 1 The bond on the right side represents the bond between the aromatic ring of the compound represented by formula (1) and R 2 represents a bond with R 3 is preferably a hydrogen atom. 4 is preferably a hydrogen atom. XY is preferably C=CH or N-CH2. Z is preferably a halogen atom, more preferably a chlorine atom.

[0038] In 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:

[0039] In another preferred embodiment, R 1 is an ethyl group or any group selected from the following: In another preferred embodiment, R 2 is a hydrogen atom, a methyl group, an ethyl group, or any group selected from the following:

[0040] In another preferred embodiment, R 2 is any group selected from the following:

[0041] In another embodiment, preferred combinations of substituents for the compound represented by formula (1) are shown below. 1 represents a hydrogen atom, a C1-C6 alkyl group, -NR 11d R 11e or any group selected from the following formula (6): (In formula (6), R 11a , R 11b are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C6 alkyl group. 11d , R 11e are each independently the same or different and represent a hydrogen atom or a C1-C6 alkyl group optionally substituted with a halogen atom. 2 represents a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group optionally substituted with a C1-C6 alkyl group, a 4-(dimethylamino)piperidin-1-yl group, or any group selected from the following formula (7): (In formula (7), V 2a is CR 21e or a nitrogen atom, V 2b is CR 21f or a nitrogen atom, R 21a , R 21b are each independently the same or different and represent a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group optionally substituted with a halogen atom, a C1-C6 alkoxy group (a C1-C6 alkoxy group optionally substituted with a halogen atom or deuterium), or a C3-C6 cycloalkyl group; R 21c represents a C1-C6 alkyl group optionally substituted with 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. 3 indicates a hydrogen atom, and R 4 represents a hydrogen atom, XY represents C=CH or N-CH2, and Z represents a halogen atom.

[0042] Another aspect of the present invention is a compound selected from the following, or a pharmaceutically acceptable salt thereof: 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one, 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, 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, 3-{6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one, 3-{6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one, 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, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methylpiperazin-1-yl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-(dimethylamino)piperidin-1-yl]-1,6-naphthyridin-2(1H)-one, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 3-(6-chloro-4-propyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-methyl-1,6-naphthyridin-2(1H)-one, 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one, 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, 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, 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one, 3-[6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[(, 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluorophenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one, 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one, 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(difluoromethoxy)-2-methylphenyl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-[6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-cyclopropyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-[6-chloro-4-(1-hydroxyethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-[6-chloro-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, N-tert-butyl-2-[6-chloro-2-(5-{2-[( 2 H3) methyloxy]phenyl}-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-1H-imidazo[4,5-c]pyridin-4-yl]acetamide, 3-[6-chloro-4-(3-oxopiperazin-1-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-{[dimethyl(oxide)-λ6-sulfanylidene]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 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, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[3-(2-hydroxypropan-2-yl)phenyl]-1,6-naphthyridin-2(1H)-one, 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, 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, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-{6-chloro-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 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, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one, 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-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-methyl-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-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(4-methoxy-6-methylpyridin-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-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one, 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, 3-(6-chloro-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-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[6-(difluoromethyl)-4-methoxypyridin-3-yl]-1,6-naphthyridin-2(1H)-one, 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, 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-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxy-6-methylpyridin-3-yl)-1,6-naphthyridin-2(1H)-one, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(1-methyl-1H-pyrrol-3-yl)-1,6-naphthyridin-2(1H)-one, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-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-(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, 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, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-3,4-dihydropyrido[4,3-d]pyrimidin-2(1H)-one, 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, 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, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one, 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 ]hentriaconta-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione, 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 ]Hentriaconta-1(28),2,4,6,8,16(30),17,19,21(29),22,24-undecene-15,27-dione, 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 ]Hentriaconta-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-13,26-dione, 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 ] pentatriaconta-1(30),2,4,6,8,18(32),19,21,23(31),24,26-undecene-15,29-dione, 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]dotriaconta-1(29),2,4,6,8,17(31),18,20,22(30),23,25-undecaene-14,28-dione, 7-chloro-17-thia-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 ]pentatriaconta-1(30),2,4,6,8,18(32),19,21,23(31),24,26-undecene-15,29-dione 17,17-dioxide, 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 ]dotriaconta-1(29),2,4,6,8,19,21(31),22(30),23,25-decaene-16,28-dione, 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 ]hentriaconta-1(28),2,4,6,8,18,20(30),21(29),22,24-decaene-15,27-dione, 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 ]hentriaconta-1(28),2,4,6,8,18,20(30),21(29),22,24-decaene-15,27-dione, or 7-chloro-3,8,10,14,18,19,23,27,34-nonaazaheptacyclo[20.6.2.2 10,14 .1 2,5 .1 18,21 .0 4,9 .0 26,30]tetratriaconta-1(29),2,4,6,8,19,21(31),22(30),23,25-decaene-15,28-dione

[0043] A preferred embodiment of the present invention is a compound selected from the following, or a pharmaceutically acceptable salt thereof: 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-2-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-(dimethylamino)piperidin-1-yl]-1,6-naphthyridin-2(1H)-one, 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, 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, 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, 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, 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, 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one, 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, 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, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-chlorophenyl)-1,6-naphthyridin-2(1H)-one, 5-(2-chloro-6-fluorophenyl)-3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methylphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-[6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-5-{2-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 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, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(5-fluoro-2-methoxyphenyl)-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one, 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-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-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-1H-imidazo[4,5-c]pyridin-2-yl)-5-[4-methoxy-6-(propan-2-yl)pyridin-3-yl]-1,6-naphthyridin-2(1H)-one, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-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-(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 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,

[0044] A more preferred embodiment of the present invention is a compound selected from the following, or a pharmaceutically acceptable salt thereof: 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-trifluoropropan-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

[0045] Another preferred embodiment of the present invention is a salt of a compound selected from the following:3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one trifluoroacetate, 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, 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, 3-[6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one methanesulfonate, 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, 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, 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, 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, 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, 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-[2-(difluoromethoxy)phenyl]-1,6-naphthyridin-2(1H)-one methanesulfonate, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[(. 2H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate, 3-{6-chloro-4-[(3S)-tetrahydrofuran-3-ylamino]-1H-imidazo[4,5-c]pyridin-2-yl}-5-{2-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate, 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2 H3) methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-fluoro-6-[( 2H3)methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one methanesulfonate, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 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, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropan-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, 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, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-3,4-dihydropyridin[4,3-d]pyrimidin-2(1H)-one methanesulfonate, 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, 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, 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, or 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 adipate.

[0046] More preferably, 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, 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, 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, or 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 adipate.

[0047] In yet another preferred embodiment of the present invention, the compound represented by formula (1) or a pharmaceutically acceptable salt thereof is in the form of a crystal. In the present invention, a crystal refers to a solid whose internal structure is one in which atoms, atomic groups, molecules, or ions are spatially arranged in a regular pattern, and is distinguished from an amorphous solid or non-crystalline body which does not have such a regular internal structure.

[0048] In the present invention, the crystalline form of the compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be confirmed by observation with a polarizing microscope, powder X-ray crystallography, single crystal X-ray diffraction measurement, or the like. Furthermore, the type of crystal can be identified by comparing the characteristics of the crystal with data based on each index measured in advance. Therefore, according to a preferred embodiment of the present invention, the crystal according to the present invention can be confirmed to be a crystal using such measurement means. In the present invention, differences in crystal form are particularly distinguished by powder X-ray diffraction.

[0049] In the present invention, not only crystals with perfectly identical diffraction angles in powder X-ray diffraction, but also crystals with diffraction angles that match within a range of ±0.2 are included in the present invention. This is common practice because, in general, even for the same crystal, there is inherent variation in peak values ​​between measurements (each time a sample to be measured is prepared) due to factors such as nonuniformity in particle size (particle diameter) and preferred orientation (see, for example, the Japanese Pharmacopoeia, 18th Edition, "2.58 Powder X-ray Diffraction Measurement Method" and "5. Qualitative Analysis (Phase Identification)"). Because the diffraction angle (2θ) in powder X-ray diffraction can have an error within a range of ±0.2, the above-mentioned diffraction angle value should be understood to include values ​​within a range of approximately ±0.2.

[0050] The crystalline form of the compound of the present invention or a pharmaceutically acceptable salt thereof is preferably a crystalline form 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, which has peaks at at least five diffraction angles (2θ) selected from 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 in powder X-ray diffraction using CuKα radiation; 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, which has peaks at at least five diffraction angles (2θ) selected from 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 in powder X-ray diffraction using CuKα radiation. 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, which has peaks at at least five diffraction angles (2θ) selected from 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 in powder X-ray diffraction using CuKα radiation; or 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(6-cyclopropyl-4-methoxypyridin-3-yl)-1,A crystal of 6-naphthyridin-2(1H)-one adipate salt, which has peaks at at least five diffraction angles (2θ) selected from 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 in powder X-ray diffraction using CuKα radiation.

[0051] More preferably, it is 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, which 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 in powder X-ray diffraction using CuKα radiation. a crystalline form of methanesulfonate salt, which exhibits 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 in powder X-ray diffraction using CuKα radiation; a crystalline form 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, which exhibits 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 in powder X-ray diffraction using CuKα radiation; The crystals are 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 adipate salt, which have 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 in powder X-ray diffraction using CuKα radiation.

[0052] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits SMG1 inhibitory activity, NMD inhibitory activity, anti-cancer activity when used alone, and anti-cancer activity when used in combination with an immune checkpoint inhibitor, and is useful as a pharmaceutical.

[0053] One aspect of the present invention relates to a pharmaceutical composition for treating cancer, which comprises a compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient, and may include a pharmaceutically acceptable carrier.

[0054] Another aspect of the present invention relates to a method for treating cancer, which comprises administering an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

[0055] In the present invention, the type of cancer to be treated is not particularly limited as long as sensitivity to the compound of the present invention is confirmed. Note that, in this specification, "cancer" is synonymous with malignant tumor, and is broadly classified into solid cancers including epithelial cell cancer and sarcoma, or blood cancer, and also includes rare cancers such as mesothelioma.

[0056] "Blood cancers" are cancers of blood cells, including leukemia, lymphoma, and multiple myeloma. "Solid tumors" are a collective term for epithelial cell cancers and sarcomas. "Epithelial cell cancers" are cancers that originate from epithelial cells, including stomach cancer, lung cancer, colon 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, biliary tract cancer, thymus cancer, bladder cancer, and brain tumors. "Sarcomas" are malignant tumors that develop in connective tissues such as bone and soft tissues (fat, muscle, nerves, etc.), including osteosarcoma, chordoma, chondrosarcoma, and Ewing's sarcoma. 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's sarcoma, or a solid cancer selected from the group consisting of stomach cancer, lung cancer, colon 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.

[0057] As used herein, "treat" and its derivatives refer to the remission, alleviation and / or delay of progression of the clinical condition of cancer in a patient suffering from cancer.

[0058] Another aspect of the present invention relates to a pharmaceutical composition for treating cancer, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor.

[0059] Another aspect of the present invention relates to a method for treating cancer, comprising administering a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with an immune checkpoint inhibitor.

[0060] The compound of the present invention or a pharmaceutically acceptable salt thereof and the immune checkpoint inhibitor may be contained as active ingredients in different preparations 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.

[0061] As used herein, the term "immune checkpoint inhibitor" refers to a drug that binds to an immune checkpoint molecule or its ligand, inhibiting the transmission of immunosuppressive signals, thereby relieving the suppression of T cell activation.

[0062] 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 to these.

[0063] Another aspect of the present invention is an SMG1 inhibitor comprising the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient.

[0064] As used herein, the term "SMG1 inhibitor" refers to a drug that inhibits SMG1 kinase activity and exerts a pharmacological effect. Because the kinase activity of SMG1 is essential for nonsense-mediated mRNA decay (NMD), SMG1 inhibitors are drugs that inhibit NMD.

[0065] Another aspect 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.

[0066] As used herein, the term "NMD inhibitor" refers to a drug that exerts a pharmacological effect by inhibiting nonsense-mediated mRNA decay (NMD).

[0067] Nonsense-mediated mRNA decay (NMD) is a quality control mechanism for mRNA. Specifically, NMD recognizes premature stop codons in mRNAs caused by nonsense or frameshift mutations in the genome or by splicing defects, and directs their degradation. Some long non-coding sequences are also subject to NMD.

[0068] A premature stop codon is a stop codon that appears upstream of the original stop codon.

[0069] (Production Method) Representative production methods for 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 methods shown below are only examples, and the present invention should not be construed as being limited to these.

[0070] The compound represented by formula (1) or a pharmaceutically acceptable salt thereof can be produced by various known production methods utilizing characteristics based on the basic skeleton or the type of substituents thereof, such as those described in "ORGANIC FUNCTIONAL GROUP PREPARATIONS," 2nd Edition, Academic Press, Inc., 1989, and "Comprehensive Organic Transformations," VCH Publishers Inc., 1989.

[0071] In this case, depending on the type of functional group present in the compound, it may be effective from the viewpoint of production technology to protect the functional group with an appropriate protecting group at the stage of a raw material or intermediate, or to replace the functional group with a group that can be easily converted into the functional group.

[0072] Examples of such functional groups include an amino group, a hydroxy group, and a carboxy group, and examples of protecting groups for these groups include those described in "Greene's Protective Groups in Organic Synthesis" by T.W. Greene and P.G. Wuts (4th ed., John Wiley & Sons, Inc., 2006).

[0073] The protecting group or the group that can be easily converted into the functional group may be appropriately selected depending on the reaction conditions of the production method for producing the compound.

[0074] According to such a method, after the reaction is carried out by introducing the group, the protecting group can be removed or converted into the desired group as necessary to obtain the desired compound.

[0075] The compound represented by formula (1) can be produced, for example, by the following [Method A1], [Method A2], [Method B1], [Method B2], [Method B3], [Method B4], [Method C1], [Method C2], [Method C3], [Method D1], [Method D2], [Method D3], or [Method E]. These production methods can be used to obtain commercially available compounds or compounds obtained by the production methods shown in the Reference Examples below.

[0076] [Method A1] Method A1 is a method for producing 1a of the compounds represented by formula (1). [In the formula, R 1 , R 2 and R 3has the same meaning as above. Q represents hydrogen or an alkoxycarbonyl group.] (Step A1-1) Step of Constructing a 1,6-naphthyridin-2(1H)-one Structure This step involves reacting Compounds 1b and 1c with a base in a solvent to obtain Compound 1a. Examples of the base include piperidine, pyrrolidine, triethylamine, N,N-diisopropylethylamine, and pyridine. Examples of the solvent include ethanol, n-butanol, 2-propanol, methanol, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, and tetrahydrofuran. The reaction temperature is usually 50°C to 120°C, and the reaction time is usually about 1 hour to 24 hours.

[0077] [Method A2] When the structure of compound 1a is represented by 1a-1, Method A2 is a method for producing compound 1a-1. [In the formula, R 17a is NR 19a or CHR 19a indicates R 18a represents a C1-C6 alkyl group optionally substituted with a C1-C6 alkyl group, or a C3-C8 cycloalkyl group; R 27a represents a phenyl group, a heteroaryl group, or a 4- to 7-membered heterocyclic group, and n 1 indicates 0, 1, or 2, and R 5 is hydrogen, a C1-C6 alkyl group optionally substituted with halogen, or a C3-C8 cycloalkyl group; R 19a represents a hydrogen atom or a C1-C6 alkyl group. 19a and R 5may be bonded to each other to form a ring structure. Boc represents a tert-butoxycarbonyl group, and t-Bu represents a tert-butyl group. (Step A2-1) Deprotection Step This is a step in which compound 1a-3 is obtained by reacting compound 1a-2 with an acid in a solvent. Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid, and hydrogen chloride. Examples of the solvent include dichloromethane, 1,4-dioxane, toluene, and ethyl acetate. The reaction temperature is usually from room temperature to about 100°C, and the reaction time is usually from about 30 minutes to 24 hours. (Step A2-2) Macrocycle Construction Step This is a step in which compound 1a-1 is obtained by reacting compound 1a-3 with a base and a condensing agent in a solvent. Examples of the base include N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and pyridine. 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. Examples of the solvent include N,N-dimethylformamide, N-methylpyrrolidone, dichloromethane, tetrahydrofuran, and acetonitrile. The reaction temperature is usually from room temperature to about 80°C, and the reaction time is usually from about 1 hour to about 3 days.

[0078] [Method B1] Method B1 is a method for producing compound 1b. [In the formula, R 1have the same meanings as above.] (Step B1-1) Step of reducing the nitro group This is a step of obtaining compound 3b by reacting compound 2b with an acid and a reducing metal in a solvent. Examples of the acid include ammonium chloride, hydrochloric acid, and acetic acid. Examples of the metal include iron, tin, and zinc. Examples of the solvent include ethanol, methanol, 2-propanol, tetrahydrofuran, 1,4-dioxane, water, and mixtures thereof. The reaction temperature is usually about 50°C to 120°C, and the reaction time is usually about 1 hour to 2 days. (Step B1-2) Step of constructing an imidazo[4,5-c]pyridine structure This is a step of obtaining compound 1b by reacting compound 3b with ethyl 3-ethoxy-3-iminopropionate hydrochloride in a solvent. Examples of the solvent include ethanol, acetic acid, dimethyl sulfoxide, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, 1,4-dioxane, and mixtures thereof. The reaction temperature is usually from room temperature to about 120° C., and the reaction time is usually from about 1 hour to 2 days.

[0079] [Method B2] When the structure of compound 2b is represented by 2b-1, Method B2 is a method for producing compound 2b-1. [In the formula, R 17b-1 represents a C1-C6 alkyl group optionally substituted with halogen, a hydroxy group, an amino group, an alkoxycarbonyl group, an aminocarbonyl group, a C3-C8 cycloalkyl group, a phenyl group, a heteroaryl group, or a 4- to 7-membered heterocyclic group, and n 2 indicates 0, 1, or 2, and R 17b-2 represents hydrogen or a C1-C6 alkyl group. 17b-1 and R 17b-2may be bonded to each other to form a ring structure.] (Step B2-1) Step of Performing Aromatic Nucleophilic Substitution This is a step of obtaining compound 2b-1 by reacting compound 4b with compound 5b and a base in a solvent. Examples of the base include calcium carbonate, cesium carbonate, sodium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, sodium hydride, 1,8-diazabicyclo[5,4,0]-7-undecene, etc. Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 2-propanol, ethanol, and methanol. The reaction temperature is usually from room temperature to about 120°C, and the reaction time is usually from about 1 hour to about 6 days.

[0080] [Method B3] When the structure of compound 2b is represented by 2b-2, Method B3 is a method for producing compound 2b-2. [In the formula, R 17b-3represents an optionally halogenated C1-C6 alkyl group, a C3-C8 cycloalkyl group, a phenyl group, or a heteroaryl group; and M represents an organoboron group such as dialkoxyboron, an organozinc group such as monoalkylzinc, an organotin group such as zinc halide or trialkyltin, an organoaluminum group such as magnesium halide or dialkylaluminum, or an organozirconium group such as monoalkylzirconium.] (Step B3-1) Cross-Coupling Step This step involves reacting compound 6b with compound 4b and a palladium catalyst, and optionally a base, in a solvent to obtain compound 2b-2. Examples of palladium catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and bis(triphenylphosphine)palladium(II) dichloride. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and triethylamine. Examples of the solvent include 1,4-dioxane, 2,2-dimethoxyethane, tetrahydrofuran, toluene, N,N-dimethylformamide, water, a mixture thereof, etc. The reaction temperature is usually from room temperature to about 120° C., and the reaction time is usually from about 1 hour to 2 days.

[0081] [Method B4] When the structure of compound 3b is represented by 3b-1, Method B4 is a method for producing compound 3b-1. wherein U represents a dihydroxyboryl group or a (pinacolato)boryl group, and J represents an oxygen atom or NR 17b-4 indicates n 3 and n 4 are each independently the same or different and represent 1, 2, or 3; R 17b-4represents hydrogen, a C1-C6 alkyl group, a C3-C8 cycloalkyl group, or a tert-butoxycarbonyl group.] (Step B4-1) Cross-Coupling Step This step involves reacting compound 7b with compound 5b, a palladium catalyst, and a base in a solvent to obtain compound 8b. This step can be carried out using the same palladium catalyst and base as in Step B3-1, at the same reaction temperature and for the same reaction time. (Step B4-2) Reduction of Double Bond and Nitro Group This step involves reacting compound 8b with hydrogen and a platinum catalyst to obtain compound 3b-1. Examples of platinum catalysts include platinum(IV) oxide and platinum (sulfided) carbon. Examples of solvents include ethanol, tetrahydrofuran, ethyl acetate, methanol, or a mixture thereof. The reaction temperature is typically from room temperature to about 80°C, and the reaction time is typically from about 1 hour to 2 days.

[0082] Compounds 6b and 7b are either known or prepared by known methods or analogous methods starting from known compounds. Known compounds can be purchased from commercial sources or readily synthesized by literature methods or analogous methods. Known literature includes, for example, J. Am. Chem. Soc., 132, 50, 17701-17703 (2010), Angew. Chem. Int. Ed., 50, 8230-8232 (2011), WO2010018113, US20100298575, Chem. Commun., (18), 2143-2145 (2008), Adv. Synth. & Catal., 359, 2741-2746 (2017), Heterocycles, 91, 1654-1659 (2015), WO2008156726 A1, WO2009048527 A1, and US20090118284. A1, WO2009058801 A1, US20090197864 A1, Eur. J. Org. Chem., 2021, 6551-6560 (2021), Angew. Chem. Int. Ed., 47, 4851-4854 (2008), J. Am. Chem. Soc., 139, 7741-7744 (2017), Eur. J. Org. Chem., 2016, 83-86 (2016), J. Org. Chem., 65, 5653-5658 (2000), etc.

[0083] [Method C1] When the structure of compound 1c is represented by 1c-1, Method C1 is a method for producing compound 1c-1. [In the formula, R 3 , Q and n 2 has the same meaning as above. 27c-1 represents a C1-C6 alkyl group optionally substituted with halogen, a hydroxy group, an amino group, a halogeno group, an alkoxycarbonyl group, an aminocarbonyl group, a C3-8 cycloalkyl group, a phenyl group, a heteroaryl group, or a 4- to 7-membered heterocyclic group, and R 27c-2 represents hydrogen or a C1-C6 alkyl group. 27c-1 and R 27c-2may be bonded to each other to form a ring structure.] (Step C1-1) Step of Aromatic Nucleophilic Substitution This is a step of obtaining compound 1c-1 by reacting compound 2c with compound 3c and a base in a solvent. Examples of the base include calcium carbonate, cesium carbonate, sodium carbonate, N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, sodium hydride, 1,8-diazabicyclo[5,4,0]-7-undecene, etc. Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, 2-propanol, ethanol, and methanol. The reaction temperature is usually from room temperature to about 120°C, and the reaction time is usually from about 1 hour to about 6 days.

[0084] [Method C2] When the structure of compound 1c is represented by 1c-2, Method C2 is a method for producing compound 1c-2. [In the formula, R 3 , M and Q are as defined 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.] (Step C2-1) Cross-Coupling Step This step involves reacting compound 4c with compound 5c and a palladium catalyst, and optionally a base, in a solvent to obtain compound 1c-2. Examples of palladium catalysts include [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct, tetrakis(triphenylphosphine)palladium(0), and bis(triphenylphosphine)palladium(II) dichloride. Examples of bases include sodium carbonate, potassium carbonate, cesium carbonate, tripotassium phosphate, and triethylamine. Examples of solvents include 1,4-dioxane, 2,2-dimethoxyethane, tetrahydrofuran, toluene, N,N-dimethylformamide, water, and mixtures thereof. The reaction temperature is usually from room temperature to about 120° C., and the reaction time is usually from about 1 hour to 2 days.

[0085] [Method C3] When the structure of compound 1c is represented by 1c-3, Method C3 is a method for producing compound 1c-3. [In the formula, R 3 , G, U, J, Q, n 3 and n 4 are as defined above.] (Step C3-1) Step of Carrying Out Cross-Coupling This is a step of carrying out a reaction from Compound 6c using Compound 5c, a palladium catalyst, and a base in a solvent to obtain Compound 7c. This can be carried out using the same palladium catalyst and base as in Step C2-1, at the same reaction temperature and for the same reaction time. (Step C3-2) Step of Carrying Out Double Bond Reduction This is a step of carrying out a reaction from Compound 7c using hydrogen and a transition metal catalyst in a solvent to obtain Compound 1c-3. Examples of transition metal catalysts include palladium on carbon, platinum(IV) oxide, platinum(sulfided)carbon, and tris(triphenylphosphine)rhodium(I) chloride. Examples of solvents include ethyl acetate, ethanol, tetrahydrofuran, methanol, toluene, or a mixture thereof. The reaction temperature is usually from room temperature to about 80°C, and the reaction time is usually from about 1 hour to 2 days.

[0086] Compounds 4c and 6c are known compounds or can be prepared by known methods or methods analogous thereto using known compounds as starting materials. Known compounds can be purchased from commercial suppliers or can be easily synthesized by methods described in the literature or methods analogous thereto. Examples of known compounds include the same literature as those listed for the preparation of compounds 6b and 7b.

[0087] [Method D1] Method D1 is a method for producing 1e of the compounds represented by formula (1). [In the formula, R 1 , R 2 , R 3and Boc have the same meanings as above.] (Step D1-1) Step of Constructing a 2-aminoimidazo[4,5-c]pyridine Structure This step involves reacting compound 2e with compound 3b, a base, and a diimide compound in a solvent to obtain compound 3e. Examples of the base include imidazole, pyridine, 4-dimethylaminopyridine, etc. Examples of the diimide compound include N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, etc. Examples of the solvent include N,N-dimethylformamide, dimethyl sulfoxide, acetonitrile, etc. The reaction temperature is usually from room temperature to about 120°C, and the reaction time is usually from about 1 hour to about 24 hours. (Step D1-2) Step of Constructing a 3,4-Dihydropyrido[4,3-d]pyrimidine Structure This is a step of obtaining compound 1e by removing the Boc group from compound 3e using an acid, followed by reaction in a solvent using a base and 1,1'-carbonyldiimidazole, or by reaction in a solvent using a base. Examples of acids include hydrogen chloride, trifluoroacetic acid, etc. Examples of bases include triethylamine, sodium hydride, N,N-diisopropylethylamine, N-methylmorpholine, etc. Examples of solvents include dichloromethane, 1,4-dioxane, tetrahydrofuran, ethyl acetate, etc. The reaction temperature is usually from room temperature to about 110°C, and the reaction time is usually from about 1 hour to about 24 hours.

[0088] [Method D2] Method D2 is a method for producing compound 2e. [In the formula, R 2 , R 3and Boc have the same meanings as above.] (Step D2-1) Step of reducing the formyl group This is a step of obtaining compound 4e by reacting compound 1c with a reducing agent in a solvent. Examples of the reducing agent include sodium borohydride. Examples of the solvent include methanol, ethanol, tetrahydrofuran, water, or a mixture thereof. The reaction temperature is usually from room temperature to about 80°C, and the reaction time is usually from about 1 to 10 hours. (Step D2-2) Step of azidation This is a step of obtaining compound 5e by reacting compound 4e with an azidation reagent and, if necessary, a base in a solvent. Examples of the azidation reagent include diphenylphosphorazide 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. Examples of the base include 1,8-diazabicyclo[5,4,0]-7-undecene, imidazole, triethylamine, etc. Examples of the solvent include tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, etc. The reaction temperature is usually from room temperature to about 120°C, and the reaction time is usually from about 1 hour to 24 hours. (Step D2-3) Step of Isothiocyanation This is a step in which compound 5e is reacted with triphenylphosphine and carbon disulfide in a solvent to obtain compound 2e. Examples of the solvent include acetonitrile, tetrahydrofuran, dichloromethane, chloroform, toluene, etc. The reaction temperature is usually from room temperature to about 110°C, and the reaction time is usually from about 1 hour to 2 days.

[0089] [Method D3] Method D3 is an alternative to Method E1 and is a method for producing compound 3e. [In the formula, R 1 , R 2 , R 3and Boc have the same meanings as above.] (Step D3-1) Step of reducing an azide This is a step of obtaining compound 6e by reacting compound 5e with triphenylphosphine in a solvent. Examples of solvents include a mixture of tetrahydrofuran and water, methanol, and the like. The reaction temperature is usually from room temperature to about 60°C, and the reaction time is usually from about 1 hour to 2 days. (Step D3-2) Step of constructing a 2-aminoimidazo[4,5-c]pyridine structure This is a step of obtaining compound 3e by reacting compound 6e with compound 3b, 1,1'-thiocarbonyldiimidazole, and a diimide compound in a solvent. Examples of diimide compounds include N,N'-diisopropylcarbodiimide, N,N'-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and the like. Examples of solvents include acetonitrile, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, and the like. The reaction temperature is usually from room temperature to about 120° C., and the reaction time is usually from about 1 hour to about 24 hours.

[0090] [Method E] Method E is a method for producing a methanesulfonate salt of the compound represented by formula (1). [In the formula, R 1 , R 2 , R 3 , X and Y have the same meanings as above.] (Step E-1) Step of Methanesulfonation This is a step of obtaining a salt of the compound represented by formula (1) by reaction with methanesulfonic acid. Examples of solvents include ethanol, acetonitrile, dichloromethane, and ethyl acetate. The reaction temperature is usually from room temperature to about 90°C, and the reaction time is usually from about 1 hour to about 24 hours.

[0091] The compounds produced by the above methods can be isolated and purified by known methods, such as extraction, precipitation, distillation, chromatography, fractional recrystallization, recrystallization, etc. Furthermore, when a compound or a production intermediate has an asymmetric carbon, optical isomers exist. These optical isomers can be isolated and purified by conventional methods such as fractional recrystallization (salt resolution) in which the compound is recrystallized with an appropriate salt or column chromatography. An example of a reference for methods of resolving optical isomers from a racemate is J. Jacques et al., "Enantiomers, Racemates and Resolution, John Wiley and Sons, Inc."

[0092] The SMG1 kinase inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof can be measured, for example, by the method described below. Using purified human SMG1 protein and a substrate peptide as materials, kinase activity can be measured by ADP-Glo ​​Kinase Assay, and the SMG1 kinase inhibitory activity of the test substance can be evaluated by comparing the kinase activity with and without the addition of the test substance.

[0093] The NMD inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof in cells can be measured, for example, by the following method. EMT6 mouse breast cancer cell line is treated in vitro with a test substance for 6 hours, and the increase in the transcript of Snhg1, a known NMD target gene, is quantified as an index of NMD inhibition. Quantification is performed by real-time PCR.

[0094] The in vivo NMD inhibitory activity of the compound of the present invention or a pharmaceutically acceptable salt thereof can be measured, for example, by the following method: Using mice subcutaneously implanted with EMT6 mouse breast cancer cell line, a test substance is orally administered, and tumor tissue is excised 6 hours later. The increase in Snhg1 transcripts is quantified as an index of NMD inhibition in the tumor, similar to the in vitro method.

[0095] The antitumor effect of the compound of the present invention or a pharmaceutically acceptable salt thereof in an allograft model can be evaluated, for example, by the method described below. MC38 mouse colon cancer cell line is subcutaneously transplanted into C57BL6 / J mice, and tumor volume is measured over time. The inhibition of tumor growth in groups administered with the test substance (single agent), an immune checkpoint inhibitor (single agent), and a test substance in combination with an immune checkpoint inhibitor is quantified as the antitumor effect, thereby evaluating the effect of the test substance alone and in combination with an immune checkpoint inhibitor.

[0096] The compound of the present invention or a pharmaceutically acceptable salt thereof can be used in combination with various therapeutic or preventive agents for diseases for which it is believed to be effective, including but not limited to immune checkpoint inhibitors. The compound of the present invention or a pharmaceutically acceptable salt thereof may be used in combination with other antitumor agents. Examples of other antitumor agents include alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant components, BRMs (biological response regulators), hormones, vitamins, antitumor antibodies, molecularly targeted drugs, and other antitumor agents.

[0097] More specifically, examples of the alkylating agent include alkylating agents such as nitrogen mustard, nitrogen mustard-N-oxide, and chlorambucil; aziridine alkylating agents such as carboquone and thiotepa; epoxide alkylating agents such as dibromomannitol and dibromodalcitol; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozotodin, chlorozotodin, and ranimustine; busulfan, improsulfan tosylate, and dacarbazine.

[0098] Examples of the various antimetabolites include purine antimetabolites such as 6-mercaptopurine, 6-thioguanine, and thioinosine; pyrimidine antimetabolites such as fluorouracil, tegafur, tegafur-uracil, carmofur, doxifluridine, broxuridine, cytarabine, and enocitabine; and folate antimetabolites such as pemetrexed, methotrexate, and trimetrexate.

[0099] Examples of antitumor antibiotics include anthracycline antibiotic antitumor agents such as mitomycin C, bleomycin, peplomycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4'-epidoxorubicin, and epirubicin; chromomycin A3; and actinomycin D.

[0100] Examples of antitumor plant ingredients include vinca alkaloids such as vindesine, vincristine, or vinblastine, taxanes such as paclitaxel or docetaxel, or epipodophyllotoxins such as etoposide or teniposide.

[0101] Examples of BRM include tumor necrosis factor and indomethacin.

[0102] Examples of hormones include hydrocortisone, dexamethasone, methylprednisolone, prednisolone, prasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, methenolone, fosfestrol, ethinylestradiol, chlormadinone, and medroxyprogesterone.

[0103] Examples of vitamins include vitamin C and vitamin A. Examples of anti-tumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib, gefitinib, erlotinib, sunitinib, lapatinib, or sorafenib, dasatinib, nilotinib, vemurafenib, osimertinib, and the like.

[0104] Other antitumor agents include, for example, cisplatin, carboplatin, oxaliplatin, tamoxifen, camptothecin, ifosfamide, cyclophosphamide, melphalan, L-asparaginase, aceclaton, sizofiran, picibanil, procarbazine, pipobroman, neocarzinostatin, hydroxyurea, ubenimex, and krestin.

[0105] The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The formulations for simultaneous administration may be formulated as a combined preparation or as separate formulations.

[0106] The pharmaceutical composition of the present invention comprises the compound of the present invention or a pharmaceutically acceptable salt thereof, and may contain a pharmaceutically acceptable carrier. It can be administered as various injections, such as intravenous injection, intramuscular injection, or subcutaneous injection, or by various methods, such as oral administration or transdermal administration. A pharmaceutically acceptable carrier refers to a pharmaceutically acceptable material (e.g., excipient, diluent, additive, solvent, etc.) that is involved in transporting the compound of the present invention or a composition containing the compound of the present invention from one organ or organ to another. A formulation containing the compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient is prepared using additives such as carriers and excipients commonly used in formulations. The compound of the present invention can be administered orally in the form of tablets, pills, capsules, granules, powders, or liquids, or parenterally in the form of intraarticular, intravenous, or intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, transdermal patches, transmucosal solutions, transmucosal patches, inhalants, etc.

[0107] Solid compositions for oral administration include tablets, powders, granules, etc. Such solid compositions consist of one or more active ingredients and at least one inert excipient, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, and / or magnesium aluminometasilicate. These solid compositions may contain inert additives, such as lubricants such as magnesium stearate, disintegrants such as sodium carboxymethyl starch, stabilizers, and solubilizers, according to conventional methods. Tablets or pills may be coated with a sugar coating or a film of a gastric or enteric substance, if necessary.

[0108] When used as a tablet, carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, and calcium carbonate. Disintegrants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc.; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, etc.; absorption promoters such as quaternary ammonium salts, sodium lauryl sulfate, etc.; humectants such as glycerin, starch, etc.; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, etc.; lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol, etc. If necessary, tablets may be coated with a conventional coating, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layered tablets or multi-layered tablets.

[0109] When used as a pill, carriers that can be used include, for example, excipients such as glucose, lactose, cocoa butter, starch, hardened vegetable oil, kaolin, and talc; binders such as powdered gum arabic, powdered tragacanth, gelatin, and ethanol; and disintegrants such as laminaran and agar.

[0110] Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. Commonly used inert diluents, such as purified water or ethanol, can be added to such liquid compositions. In addition to the inert diluents, the liquid compositions may contain adjuvants such as solubilizers and wetting agents, sweeteners, flavors, fragrances, and preservatives.

[0111] Injectable preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection or physiological saline. Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, or vegetable oils such as olive oil, alcohols such as ethanol, or polysorbate 80. Such injectable compositions may further contain an isotonicity agent, preservative, wetting agent, emulsifier, dispersant, stabilizer, or solubilizer. These injectable compositions can be sterilized, for example, by filtration through a bacteria-retaining filter, addition of a sterilizer, or irradiation. Alternatively, these injectable compositions can be prepared as sterile solid compositions, which can be dissolved or suspended in sterile water or a sterile injectable solvent prior to use.

[0112] When used as an injection, it can be used as a solution, emulsion, or suspension. These solutions, emulsions, or suspensions are preferably sterilized and isotonic with blood. The solvent used to prepare these solutions, emulsions, or suspensions is not particularly limited as long as it can be used as a medical diluent, and examples include water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. In this case, the formulation may contain sufficient amounts of table salt, glucose, or glycerin to prepare an isotonic solution, and may also contain common solubilizers, buffers, soothing agents, etc.

[0113] Furthermore, the above-mentioned preparations may contain coloring agents, preservatives, fragrances, flavorings, sweeteners, etc., as needed, and may further contain other pharmaceuticals. The amount of the compound contained in the above-mentioned preparations is not particularly limited and may be selected appropriately from a wide range, but is usually 0.5 to 70% by weight, preferably 1 to 30% by weight, of the total composition.

[0114] The dosage and frequency of administration of the compound of the present invention are determined appropriately, taking into consideration the symptoms, age, etc. of the patient (warm-blooded animal, especially human). In the case of oral administration, the daily dosage is usually about 0.001-100 mg / kg of body weight, preferably 0.1-30 mg / kg, more preferably 0.1-10 mg / kg, administered once or in two or more divided doses. In the case of intravenous administration, the daily dosage is usually about 0.0001-10 mg / kg of body weight, administered once or in multiple divided doses.

[0115] The present invention will be specifically described below with reference to Reference Examples and Examples, but the present invention is not limited to these and should not be construed as being limited in any way. Furthermore, reagents, solvents, and starting materials not specifically described in this specification are readily available from commercial sources.

[0116] Reference Example 1 Preparation of ethyl {6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) 6-chloro-2-[(3R)-3-methylmorpholin-4-yl]-3-nitropyridin-4-amine. To a solution of (R)-3-methylmorpholin (4.00 mL) and 2,6-dichloro-3-nitropyridin-4-amine (6.00 g) in N,N-dimethylformamide (60 mL) was added potassium carbonate (8.00 g) at room temperature and stirred at the same temperature for 23 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed twice with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (6.93 g). 1H-NMR (CDCl3) 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, 3.1 Hz), 3.72 (1H, d, J = 11.6 Hz), 3.61-3.51 (2H, m), 2.84-2.74 (1H, m), 1.37 (3H, d, J = 6.7 Hz). (Step 2) 6-chloro-2-[(3R)-3-methylmorpholin-4-yl]pyridine-3,4-diamine. The compound obtained in Step 1 (6.93 g) was dissolved in ethanol (100 mL) and water (50 mL). To a solution of 1 mL of ethanol (2.5 mL), iron powder (4.30 g) and ammonium chloride (1.36 g) were added at room temperature, and the mixture was stirred at 80°C for 2.5 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration through Celite, and the residue was washed with ethyl acetate and water. The combined filtrate was concentrated under reduced pressure, and the ethanol was distilled off. The mixture was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was distilled off under reduced pressure, and a mixture of n-hexane / ethyl acetate (1:1) was added to the residue to solidify it. The precipitated solid was filtered off to obtain the title compound (4.47 g). 1H-NMR (CDCl3) δ: 6.49 (1H, s), 3.96 (2H, br s), 3.95-3.85 (2H, m), 3.76 (1H, td, J = 11.0, 2.6 Hz), 3.60 (2H, br s), 3.52-3.44 (1H, m), 3.37 (1H, dd, J = 11.0, 9.2 Hz), 3.02 (1H, ddd, J = 12.2, 9.2, 2.6 Hz), 2.83 (1H, dt, J = 12.2, 2.6 Hz), 0.83 (3H, d, J = 6.1 Hz). (Step 3) Ethyl {6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate. A mixture of the compound obtained in Step 2 above (5.04 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (8.11 g), and ethanol (70 mL) was stirred under reflux for 9 hours. After the reaction mixture was cooled to room temperature, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The resulting oil was solidified with a mixture of n-hexane / ethyl acetate (10:1). The precipitated solid was filtered, washed with n-hexane, and dried under reduced pressure to give the title compound (6.33 g). 1 H-NMR (CDCl3) δ: 10.07 (1H, br s), 6.76 (1H, s), 5.48-5.37 (1H, m), 4.77 (1H, d, J = 13.4 Hz), 4.30 (2H, q, J = 7.3 Hz), 4.06-4.01 (1H, m), 4.00 (2H, s), 3.87 (1H, dd, J = 11.0, 3.1 Hz), 3.80 (1H, d, J = 11.0 Hz), 3.69 (1H, td, J = 11.0, 3.1 Hz), 3.47 (1H, td, J = 12.8, 3.1 Hz), 1.38-1.33 (6H, m).

[0117] Reference Example 2 Preparation of ethyl {6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) (3S)-4-benzylmorpholine-3-carbaldehyde [(3R)-4-benzylmorpholin-3-yl]methanol (300 mg, BLD PHARM) in acetonitrile (15 mL) was added 2-hydroxy-2-azaadamantane (11.1 mg), copper(I) chloride (7.2 mg), 2,2'-bipyridyl (11.3 mg), and 4-dimethylaminopyridine (17.7 mg) at room temperature, followed by stirring at the same temperature for 17 hours. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added to the reaction mixture, which was then extracted three times with dichloromethane. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to afford the crude title compound (297 mg). (Step 2) (3S)-4-benzyl-3-(difluoromethyl)morpholine To a solution of the compound obtained in Step 1 above (297 mg) 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 solution of sodium bicarbonate was added to the reaction mixture, which was extracted three times with dichloromethane. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (71.4 mg). 1H-NMR (CDCl) δ: 7.39-7.22 (5H, m), 6.21 (1H, td, J = 55.5, 5.5 Hz), 3.93 (1H, dd, J = 14.1, 3.1 Hz), 3.90-3.79 (2H, m), 3.78-3.64 (3H, m), 2.90-2.80 (2H, m), 2.45-2.37 (1H, m). (Step 3) (3S)-3-(Difluoromethyl)morpholine hydrochloride To a solution of the compound obtained in Step 2 above (70 mg) in 1,2-dichloroethane (1 mL) was added 1-chloroethyl chloroformate (0.1 mL) at room temperature, and the mixture was stirred under reflux for 8 hours. Subsequently, the reaction mixture was cooled to room temperature, and then methanol (1 mL) was added, followed by stirring under reflux for 1 hour. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure to give the crude title compound (54 mg). (Step 4) 6-chloro-2-[(3S)-3-(difluoromethyl)morpholin-4-yl]-3-nitropyridin-4-amine. To a solution of the compound obtained in Step 3 above (50.1 mg) in 1,4-dioxane (1.5 mL) was 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 cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the crude title compound (64.5 mg). (Step 5) 6-chloro-2-[(3S)-3-(difluoromethyl)morpholin-4-yl]pyridine-3,4-diamine. To a solution of the compound obtained in Step 4 above (64.5 mg) in a mixed solution of ethanol (2 mL) and water (1 mL), iron powder (76 mg) and ammonium chloride (36 mg) were added at room temperature, and the mixture was stirred at 80°C for 1 hour. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration through Celite, and the residue was washed with ethyl acetate and water. The combined filtrate was extracted twice with dichloromethane, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was evaporated under reduced pressure to give the crude title compound (37.9 mg).(Step 6) Ethyl {6-chloro-4-[(3S)-3-(difluoromethyl)morpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate A mixture of the compound obtained in Step 5 above (37.9 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (68 mg), and ethanol (1 mL) was stirred under reflux for 1.5 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (22.3 mg). 1 H-NMR (CDCl3) δ: 10.14 (1H, br s), 6.81 (1H, s), 6.26 (1H, td, J = 56.3, 5.9 Hz), 5.80-5.78 (1H, m), 4.81 (1H, d, J = 14.1 Hz), 4.32-4.22 (3H, m), 4.05 (1H, dd, J = 11.7, 3.1 Hz), 3.99 (2H, d, J = 1.8 Hz), 3.90-3.80 (1H, m), 3.69 (1H, td, J = 11.7, 3.1 Hz), 3.49 (1H, td, J = 13.0, 3.3 Hz), 1.34 (3H, t, J = 7.4 Hz).

[0118] Reference Example 3 Preparation of ethyl {6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) trans-4-[(4-amino-6-chloro-3-nitropyridin-2-yl)(methyl)amino]cyclohexanol To a solution of trans-4-(methylamino)cyclohexanol (155 mg) and 2,6-dichloro-3-nitropyridin-4-amine (208 mg) in N,N-dimethylformamide (3.3 mL) was added potassium carbonate (276 mg) at room temperature and stirred at 40°C for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound. (Steps 2 and 3) Ethyl {6-chloro-4-[(trans-4-hydroxycyclohexyl)(methyl)amino]-1H-imidazo[4,5-c]pyridin-2-yl}acetate The title compound was obtained by using the compound obtained in Step 1 above as a starting material and carrying out the same operations as in Steps 5 and 6 of Reference Example 2. 1 H-NMR (DMSO-D6) δ: 12.57 (1H, s), 6.70 (1H, s), 5.24-5.06 (1H, m), 4.58 (1H, d, J = 4.9 Hz), 4.14 (2H, q, J = 7.0 Hz), 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 = 7.0 Hz).

[0119] Reference Example 4 Preparation of ethyl (6-chloro-4-{[(2R)-1,1,1-trifluoropropan-2-yl)amino]-1H-imidazo[4,5-c]pyridin-2-yl)acetate (Step 1) 6-chloro-3-nitro-N-2-[(2R)-1,1,1-trifluoropropan-2-yl]pyridine-2,4-diamine. A mixture of (R)-1,1,1-trifluoropropan-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. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed twice with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (723 mg). 1 H-NMR (CDCl3) δ: 9.00 (1H, br d, J = 9.4 Hz), 6.07 (1H, s), 5.31-5.17 (1H, m), 2.62 (2H, s), 1.44 (3H, d, J = 7.0 Hz). (Steps 2 and 3) Ethyl (6-chloro-4-{[(2R)-1,1,1-trifluoropropan-2-yl)amino]-1H-imidazo[4,5-c]pyridin-2-yl)acetate Using the compound obtained in Step 1 above as the production starting material, the title compound was obtained by performing the same procedures as in Steps 5 and 6 of Reference Example 2. 1 H-NMR (DMSO-D6) δ: 12.69 (1H, s), 7.56 (1H, d, J = 9.4 Hz), 6.84 (1H, s), 5.31-5.10 (1H, m), 4.13 (2H, q, J = 7.0 Hz), 3.96 (2H, s), 1.38 (3H, d, J = 7.0 Hz), 1.20 (3H, t, J = 7.0 Hz)

[0120] Reference Example 5 Ethyl (6-chloro-4-[dimethyl(oxide)-λ 6 -sulfanylidene]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate (Step 1) 6-chloro-2-{[dimethyl(oxide)-λ6 A mixture of S,S-dimethylsulfoximine (559 mg), 2,6-dichloro-3-nitropyridin-4-amine (416 mg), N,N-diisopropylethylamine (1.05 mL), and 1,4-dioxane (5.0 mL) was heated to reflux and stirred for 128 hours. The reaction mixture was cooled to room temperature, and saturated aqueous sodium bicarbonate and water were added. The mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was solidified with a mixture of ethyl acetate (3 mL) and n-hexane (9 mL). The precipitated solid was filtered, washed with a mixture of n-hexane and ethyl acetate, and dried under reduced pressure to give the title compound (346 mg). 1 H-NMR (DMSO-D6) δ: 6.96 (2H, s), 6.30 (1H, s), 3.39 (6H, s). (Steps 2 and 3) Ethyl (6-chloro-4-[[dimethyl(oxide)-λ 6 -sulfanylidene]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate The title compound was obtained by using the compound obtained in Step 1 above as a production starting material and carrying out the same operations as in Steps 5 and 6 of Reference Example 2. 1 H-NMR (CDCl3) 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).

[0121] The following compounds were synthesized by carrying out the same procedures as in any of the steps of Reference Examples 1 to 5 (Tables 1-1 and 1-2).

[0122]

[0123]

[0124] Reference Example 12: Preparation of tert-butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate (Step 1) 1-tert-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate. To a solution of (4R)-1-(tert-butoxycarbonyl)-4-hydroxy-L-proline (2.0 g) in N,N-dimethylformamide (20 mL) was added potassium carbonate (1.8 g) and iodomethane (1.1 mL) at 0°C, followed by stirring at room temperature for 2 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed once with 5% aqueous sodium thiosulfate, twice with water, and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (2.0 g). 1H-NMR (CDCl) 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). (Step 2) 1-tert-butyl 2-methyl(2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine-1,2-dicarboxylate The compound (2.0) obtained in Step 1 above was To a solution of (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.0 g) in N,N-dimethylformamide (20 mL) was added imidazole (1.1 g) and tert-butyldimethylchlorosilane (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 the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to give the crude title compound (3.0 g). (Step 3) tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-(hydroxymethyl)pyrrolidine-1-carboxylate To a solution of the compound obtained in Step 2 (3.0 g) in ethanol (30 mL) was added sodium borohydride (1.2 g) at 0°C, and the mixture was stirred at room temperature for 5 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (2.5 g). 1H-NMR (CDCl) δ: 4.92 (1H, d, J = 8.0 Hz), 4.28 (1H, br s), 3.73-3.66 (1H, m), 3.58-3.51 (1H, m), 3.43 (1H, d, J = 11.7 Hz), 3.34 (1H, dd, J = 11.7, 3.7 Hz), 1.98-1.93 (1H, m), 1.61-1.54 (1H, m), 1.47 (9H, s), 0.87 (9H, s), 0.06 (6H, s). (Step 4) tert-Butyl (2S,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine-1-carboxylate To a dichloromethane (30 mL) solution of the compound obtained in Step 3 above (2.5 g), triethylamine (3.1 mL) and methanesulfonic anhydride (2.9 g) were added at 0°C, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, and the two layers were separated. The aqueous layer was extracted twice with chloroform. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (2.9 g). (Step 5) tert-Butyl (2R,4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-methylpyrrolidine-1-carboxylate To a solution of the compound obtained in Step 4 above (2.9 g) in tetrahydrofuran (30 mL), 1.01 M lithium triethylborohydride in tetrahydrofuran (35 mL) was added 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 resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (2.5 g). 1H-NMR (CDCl) 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). (Step 6) tert-Butyl (2R,4R)-4-hydroxy-2-methylpyrrolidine-1-carboxylate To a solution of the compound (2.5 g) obtained in Step 5 above in tetrahydrofuran (20 mL) was added 1.0 M tetra-n-butylammonium fluoride 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). 1 H-NMR (CDCl3) 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 = 5.5 Hz)

[0125] The following compounds were synthesized by carrying out the same procedures as in any one of steps 1 to 6 of Reference Example 12 (Tables 2-1 and 2-2).

[0126]

[0127]

[0128] Reference Example 17 Preparation of tert-butyl (2R,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate (Step 1) tert-Butyl (2R,3S)-3-hydroxy-2-({[(4-methylphenyl)sulfonyl]oxy}methyl)pyrrolidine-1-carboxylate. To a solution of the compound obtained in Reference Example 15 (0.50 g) in pyridine (2.0 mL) was added 4-methylbenzenesulfonyl chloride (0.66 g) at room temperature, and the mixture was stirred at the same temperature for 6 hours. Water was added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.55 g). 1 H-NMR (CDCl) δ: 7.77 (2H, d, J = 6.7 Hz), 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). (Step 2) tert-Butyl (2R,3S)-3-hydroxy-2-methylpyrrolidine-1-carboxylate Using the compound obtained in Step 1 above as the starting material, the crude title compound was obtained by the same procedure as in Step 5 of Reference Example 12.

[0129] Reference Example 18 Preparation of ethyl {6-chloro-4-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) (3R,5R)-5-methylpyrrolidin-3-ol hydrochloride: To the compound obtained in Step 6 of Reference Example 12 (1.3 g), 4 M hydrogen chloride in 1,4-dioxane (5 mL) was added at room temperature, and the mixture was stirred at the same temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and toluene was added to the resulting residue, which was then concentrated again under reduced pressure to give the crude title compound (0.90 g). (Step 2) (3R,5R)-1-(4-amino-6-chloro-3-nitropyridin-2-yl)-5-methylpyrrolidin-3-ol: To a solution of the compound obtained in Step 1 (0.90 g) in N,N-dimethylformamide (20 mL), 2,6-dichloro-3-nitropyridin-4-amine (1.0 g) and potassium carbonate (2.0 g) were added at room temperature, and the mixture was stirred at the same temperature for 27 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was removed under reduced pressure to give the crude title compound (1.6 g). (Step 3) (3R,5R)-1-(3,4-Diamino-6-chloropyridin-2-yl)-5-methylpyrrolidin-3-ol. A mixture of the compound obtained in Step 2 above (1.6 g), iron powder (1.3 g), ammonium chloride (0.13 g), ethanol (20 mL), and water (5 mL) was stirred at 90°C for 1.5 hours. After cooling the reaction mixture to room temperature, insoluble material was removed by filtration through Celite, and the residue was washed with ethanol. The combined filtrate was concentrated under reduced pressure, and saturated aqueous sodium bicarbonate was added to the residue. Extraction was performed three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine, then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (1.4 g). (Step 4) Ethyl {6-chloro-4-[(2R,4R)-4-hydroxy-2-methylpyrrolidin-1-yl]-1H-imidazo[4,5-c]pyridin-2-yl}acetate A mixture of the compound obtained in Step 3 above (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, saturated aqueous sodium bicarbonate was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.15 g). 1 H-NMR (CDCl3) 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 = 7.1 Hz), 4.21-4.15 (1H, m), 4.06 (1H, dd, J = 12.2, 4.3 Hz), 3.97 (2H, s), 2.26-2.19 (1H, m), 1.95-1.88 (1H, m), 1.67 (1H, d, J = 4.9 Hz), 1.58 (9H, s), 1.35-1.31 (6H, m).

[0130] The following compounds were synthesized by carrying out the same procedures as in steps 1 to 4 of Reference Example 18 (Table 3-1).

[0131]

[0132] Reference Example 23 Preparation of ethyl [6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate (Step 1) 6-chloro-2-(3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine. 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-nitropyridin-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 under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. Insoluble matter was removed by filtration through Celite. The filtrate was extracted three times with ethyl acetate. The resulting 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 (6.08 g). 1H-NMR (CDCl) δ: 6.66 (1H, s), 5.95-5.88 (1H, m), 5.63 (2H, br s), 4.25 (2H, q, J = 2.7 Hz), 3.91 (2H, t, J = 5.2 Hz), 2.53-2.44 (2H, m). (Step 2) 6-chloro-2-(tetrahydro-2H-pyran-4-yl)pyridine-3,4-diamine. To a solution of the compound obtained in Step 1 (4.00 g) in ethanol (100 mL) was added 5% platinum (sulfided) on carbon (916 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at 50°C for 7 hours. After cooling the reaction mixture to room temperature, insoluble materials were removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. Ethyl acetate (300 mL) was added to the resulting residue, and insoluble material was removed by filtration. The solvent was then evaporated under reduced pressure to yield the crude title compound (2.95 g). (Step 3) Ethyl [6-chloro-4-(tetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate. A mixture of the compound obtained in Step 2 above (3.10 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (5.33 g), ethanol (50 mL), and acetic acid (3.9 mL) was stirred under reflux for 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered and concentrated under reduced pressure. Toluene was added to the residue, and the mixture was again concentrated under reduced pressure. The resulting residue was solidified with diethyl ether. The precipitated solid was collected by filtration, washed with a mixture of n-hexane / ethyl acetate (1:3), and then dried under reduced pressure to obtain the title compound (2.10 g). 1 H-NMR (CD3OD) δ: 7.36 (1H, s), 4.21 (2H, q, J = 7.2 Hz), 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 = 7.2 Hz).

[0133] Reference Example 24 Preparation of ethyl [6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate (Step 1) 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl nonafluorobutane-1-sulfonate To a solution of 2,2-dimethyltetrahydro-4H-pyran-4-one (708 mg) in tetrahydrofuran (15 mL) was added 1.08 M lithium diisopropylamide in n-hexane-tetrahydrofuran (6.2 mL) at -70°C, and the mixture was 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 warmed to 0°C and stirred for an additional 2.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted twice with hexane. The resulting 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 give a mixture (1.60 g) of the title compound and the positional isomer of the double bond (6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl nonafluorobutane-1-sulfonate). 1H-NMR (CDCl) 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 (0.5H, m), 2.42-2.38 (0.5H, m), 2.32-2.28 (1.5H, m), 1.33 (1.5H, m), 1.31-1.27 (4.5H, m). (Step 2) 6-Chloro-2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine. The compound obtained in Step 1 above (1.00 g), bis(pinacolato)diboron (743 mg), potassium acetate (718 mg), and 6-chloro-2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine were prepared by the following procedure: A mixture of 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 1,4-dioxane (12 mL) was stirred at 80°C for 7.5 hours under a nitrogen atmosphere. 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 the mixture was 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 obtained residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give a mixture (299 mg) of the title compound and the positional isomer of the double bond (6-chloro-2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-3-nitropyridin-4-amine). 1H-NMR (CDCl) 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 = 4.9 Hz). (Step 3) 6-chloro-2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridine-3,4-diamine A mixture of the compound obtained in Step 2 above (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. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite. The filtrate was extracted with dichloromethane, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give a mixture of the crude title compound and the double bond regioisomer (6-chloro-2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyridine-3,4-diamine) (262 mg). (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. A mixture of the compound obtained in Step 3 above (260 mg), ethyl 3-ethoxy-3-iminopropionate hydrochloride (400 mg), ethanol (14 mL), and acetic acid (0.50 mL) was stirred under reflux for 3 hours. After cooling the reaction mixture to room temperature, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give a mixture of the title compound and the double bond regioisomer (ethyl [6-chloro-4-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate) (223 mg). 1H-NMR (CDCl3) 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 = 13.4 Hz), 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). (Step 5) Ethyl [6-chloro-4-(4-hydroxy-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate. To a solution of the compound obtained in Step 4 above (88.0 mg) in 2-propanol (2.8 mL) / dichloromethane (0.40 mL) was added tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (15 mg) at 0°C, and the mixture was stirred at room temperature under an oxygen atmosphere for 3 hours. Ethyl acetate and saturated aqueous sodium thiosulfate were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (31.7 mg). 1 H-NMR (CDCl3) 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), 2.82-2.67 (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).

[0134] Reference Example 25 Preparation of ethyl 2-{4-[3-(tert-butoxycarbonylamino)phenyl]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) tert-Butyl N-[3-(4-amino-6-chloro-3-nitro-2-pyridyl)phenyl]carbamate A mixture of 3-(N-tert-butoxycarbonylamino)phenylboronic acid (228 mg), 2,6-dichloro-3-nitropyridin-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 under a nitrogen atmosphere for 5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted twice with ethyl acetate. The resulting 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 (138 mg). 1H-NMR (CDCl) δ: 7.59 (1H, br s), 7.41-7.36 (1H, m), 7.31 (1H, t, J = 7.8 Hz), 7.12-7.08 (1H, m), 6.71 (1H, s), 6.61 (1H, br s), 5.81 (2H, s), 1.52 (9H, s). (Step 2) tert-Butyl N-[3-(3,4-diamino-6-chloro-2-pyridyl)phenyl]carbamate To a mixture of the compound obtained in Step 1 above (138 mg), ammonium chloride (20 mg), ethanol (4 mL), and water (2 mL) was added iron powder (211 mg) at 80°C, and the mixture was stirred at the same temperature for 2 hours. After the reaction mixture was cooled to room temperature, insoluble material was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (120 mg). (Step 3) Ethyl 2-{4-[3-(tert-butoxycarbonylamino)phenyl]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate A mixture of the compound obtained in Step 2 above (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, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (114 mg). 1 H-NMR (DMSO-D6) 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 = 7.0 Hz), 4.12 (2H, s), 1.54 (9H, s), 1.34 (3H, t, J = 7.0 Hz).

[0135] Reference Example 26 Preparation of ethyl [6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate (Steps 1 to 3) Ethyl [6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate Using 2-fluorophenylboronic acid as a raw material, the title compound was obtained by performing the same operations as in Steps 1 to 3 of Reference Example 25. 1 H-NMR (CDCl3) 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 = 6.1 Hz), 4.14 (2H, s), 1.36-1.34 (3H, m).

[0136] Reference Example 27 Preparation of ethyl (6-chloro-4-{[(3S)-tetrahydrofuran-3-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate (Steps 1 to 3) Ethyl (6-chloro-4-{[(3S)-tetrahydrofuran-3-yl]amino}-1H-imidazo[4,5-c]pyridin-2-yl)acetate Using (S)-3-aminotetrahydrofuran as a raw material, the title compound was obtained by performing the same operations as in Step 1 of Reference Example 1 and Steps 2 and 3 of Reference Example 25. 1 H-NMR (CDCl3) δ: 10.19 (1H, br s), 6.72 (1H, s), 5.52 (1H, d, J = 8.0 Hz), 4.92-4.85 (1H, m), 4.28 (2H, q, J = 7.2 Hz), 3.99 (2H, s), 4.07-3.96 (2H, m), 3.90-3.82 (1H, m), 3.77 (1H, dd, J = 9.2, 3.7 Hz), 2.42-2.33 (1H, m), 1.98-1.88 (1H, m), 1.33 (3H, t, J = 7.2 Hz).

[0137] Reference Example 28 Preparation of ethyl (6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate A mixture of ethyl (6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate 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 the mixture was cooled to 0°C. The precipitated solid was collected 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 crude product, and the mixture was stirred at 60°C for 20 minutes. After that, insoluble matter was removed by filtration while still warm. The filtrate was cooled to 0°C, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to obtain the title compound (14.9 g). 1 H-NMR (DMSO-D6) δ: 13.25-12.83 (1H, m), 8.67 (1H, s), 7.64 (1H, br s), 4.15 (2H, q, J = 7.0 Hz), 4.07 (2H, s), 1.21 (3H, t, J = 7.0 Hz).

[0138] Reference Example 29 Preparation of ethyl (6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate (Step 1) 6-chloro-2-methyl-3-nitropyridin-4-amine. 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 dropwise 2.0 M trimethylaluminum in toluene (6.0 mL) at room temperature, followed by stirring at 70°C for 3 hours. The reaction mixture was cooled to room temperature, and ice water and ethyl acetate were added. Insoluble matter was removed by filtration. The resulting filtrate was extracted twice with ethyl acetate. Saturated aqueous sodium bicarbonate solution was then added to the aqueous layer, followed by further extraction twice with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (855 mg). 1H-NMR (CDCl3) δ: 6.64 (1H, s), 5.94 (2H, br s), 2.71 (3H, s). (Step 2) 6-chloro-2-methylpyridine-3,4-diamine. A mixture of the compound obtained in Step 1 above (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. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite. A saturated aqueous solution of sodium bicarbonate was added to the filtrate, which was then extracted four times with dichloromethane, twice with ethyl acetate, and twice with a 4:1 ethyl acetate / tetrahydrofuran mixture. The combined organic layer was dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was removed under reduced pressure to give the crude title compound (629 mg). (Step 3) Ethyl (6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate A mixture of the compound obtained in Step 2 above (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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The resulting 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). 1 H-NMR (DMSO-D6) δ: 12.89 (1H, br s), 7.45 (1H, s), 4.14 (2H, q, J = 7.0 Hz), 4.04 (2H, s), 2.64 (3H, s), 1.21 (3H, t, J = 7.0 Hz).

[0139] Reference Example 30 Preparation of ethyl (6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate (Step 1) 6-chloro-2-ethyl-3-nitropyridin-4-amine. To a mixture of 2,6-dichloro-3-nitropyridin-4-amine (4.00 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (785 mg), and 1,4-dioxane (40 mL) was added 1.12 M diethylzinc in n-hexane (21.0 mL) at room temperature, and the mixture was stirred at 70°C for 3 hours. After the reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was stirred at room temperature for 10 minutes. Insoluble matter was removed by filtration, and the filtrate was extracted with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.87 g). 1H-NMR (CDCl) δ: 6.61 (1H, s), 5.75 (2H, br s), 2.93 (2H, q, J = 7.4 Hz), 1.33 (3H, t, J = 7.4 Hz). (Step 2) 6-Chloro-2-ethylpyridine-3,4-diamine. To a solution of the compound obtained in Step 1 above (1.87 g) in a tetrahydrofuran (20 mL), ethanol (10 mL), and water (5.0 mL) mixture, iron powder (1.55 g) was added at room temperature, and the mixture was heated to 70 °C. Ammonium chloride (51.2 mg) was then added, and the mixture was stirred at the same temperature for 3 hours. After cooling the reaction mixture to room temperature, insoluble matter was removed by filtration through Celite. The filtrate was concentrated under reduced pressure and dried to give the crude title compound (1.61 g). (Step 3) Ethyl (6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)acetate A mixture of the compound obtained in Step 2 above (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, 10% aqueous citric acid was added and the mixture was stirred at room temperature for several minutes. Subsequently, saturated aqueous sodium bicarbonate was added to the mixture, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was distilled off under reduced pressure, and the resulting 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), then filtered, 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). 1 H-NMR (DMSO-D6) δ: 13.21-12.74 (1H, m), 7.44 (1H, br s), 4.15 (2H, q, J = 7.0 Hz), 4.05 (2H, s), 3.09-2.92 (2H, m), 1.28 (3H, t, J = 7.4 Hz), 1.21 (3H, t, J = 7.0 Hz).

[0140] Reference Example 31 Preparation of ethyl [6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate (Step 1) A mixture of 6-chloro-3-nitro-2-(prop-1-en-2-yl)pyridin-4-amine isopropenylboronic acid pinacol ester (677 μL), 2,6-dichloro-3-nitropyridin-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 under a nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite. The filtrate was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (356 mg). 1 H-NMR (CDCl) δ: 6.65 (1H, s), 5.64 (2H, s), 5.21 (1H, s), 5.06 (1H, s), 2.16 (3H, s). (Step 2) 6-chloro-2-(propan-2-yl)pyridine-3,4-diamine A mixture of the compound obtained in Step 1 above (354 mg), platinum(IV) oxide (56 mg), and ethanol (17 mL) was stirred under a hydrogen atmosphere at 50°C for 6 hours. After cooling the reaction mixture to room temperature, insoluble matter was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the crude title compound. (Step 3) Ethyl [6-chloro-4-(propan-2-yl)-1H-imidazo[4,5-c]pyridin-2-yl]acetate Using the compound obtained in Step 2 above as a raw material, the title compound (338 mg) was obtained by the same procedure as in Step 3 of Reference Example 25. 1H-NMR (DMSO-D6) δ: 12.87 (1H, s), 7.43 (1H, s), 4.15 (2H, q, J = 7.3 Hz), 4.05 (2H, s), 3.71-3.57 (1H, m), 1.29 (6H, d, J = 7.3 Hz), 1.21 (3H, t, J = 7.3 Hz).

[0141] Reference Example 32: Preparation of 6-chloro-3-nitro-2-propylpyridin-4-amine 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 0.5 M propylzinc bromide in tetrahydrofuran (12 mL) at room temperature, and the mixture was stirred at 70°C under a nitrogen atmosphere for 5.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) and (n-hexane / dichloromethane) to give the title compound (395 mg). 1 H-NMR (CDCl3) 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 = 7.3 Hz).

[0142] Reference Example 33 Preparation of 6-chloro-2-cyclopropyl-3-nitropyridin-4-amine 6-Chloro-2-cyclopropyl-3-nitropyridin-4-amine Using 0.5M cyclopropylzinc bromide tetrahydrofuran solution as a raw material, the title compound was obtained by the same procedure as in Reference Example 32. 1 H-NMR (CDCl3) 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).

[0143] Reference Example 34: Preparation of 2-(4-amino-6-chloro-3-nitropyridin-2-yl)-N-tert-butylacetamide (Step 1) tert-Butyl (4-amino-6-chloro-3-nitropyridin-2-yl)(cyano)acetate. To a solution of 2,6-dichloro-3-nitropyridin-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, 1 M hydrochloric acid was added, and the mixture was extracted twice with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (752 mg). (Step 2) 2-(4-amino-6-chloro-3-nitropyridin-2-yl)-N-tert-butylacetamide To a solution of the compound obtained in Step 1 above (752 mg) in dichloromethane (5.0 mL) was added trifluoroacetic acid (2.50 mL) at room temperature, and the mixture was stirred at the same temperature for 20 hours. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (132 mg). 1 H-NMR (CDCl3) δ: 6.67 (1H, s), 6.29 (2H, br s), 5.64 (1H, br s), 3.97 (2H, s), 1.39 (9H, s).

[0144] The following compounds were synthesized by the same procedures as in Steps 2 and 3 of Reference Example 25 (Table 4-1).

[0145]

[0146] Reference Example 38 Preparation of ethyl [6-chloro-4-(1-hydroxyethyl)-1H-benzimidazol-2-yl]acetate (Step 1) 1-(4-amino-6-chloro-3-nitropyridin-2-yl)ethanone. To a solution of 2,6-dichloro-3-nitropyridin-4-amine (2.75 g) in N,N-dimethylformamide (25 mL) was added tributyl(1-ethoxyvinyl)tin (4.60 mL) and bis(triphenylphosphine)palladium(II) chloride (232 mg) at room temperature, followed by stirring at 90°C for 3.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed twice with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. 1,4-dioxane (25 mL) and 2M hydrochloric acid (30 mL) were added to the resulting residue, followed by stirring at room temperature for 1 hour. To the reaction mixture was added 1M aqueous sodium hydroxide solution (60 mL) at 0°C, followed by extraction three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was removed under reduced pressure, and the resulting residue was solidified with a mixture of n-hexane / ethyl acetate / dichloromethane (10:1:1). The precipitated solid was filtered, washed with a mixture of n-hexane / ethyl acetate / dichloromethane (10:1:1), and dried under reduced pressure to yield the crude title compound (2.24 g). (Step 2) 1-(3,4-Diamino-6-chloropyridin-2-yl)ethanol. To a solution of the compound obtained in Step 1 (2.24 g) in ethanol (40 mL) was added sodium borohydride (1.18 g) at 0°C and stirred at room temperature for 1 hour. Sodium borohydride (590 mg) was then added again, and the mixture was stirred at the same temperature for an additional 1 hour. Water was added to the reaction mixture, and insoluble material was removed by filtration through Celite. The filtrate was extracted three times with ethyl acetate, and the resulting organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (1.55 g).(Step 3) 2-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-chloropyridine-3,4-diamine To a solution of the compound obtained in Step 2 above (1.55 g) in N,N-dimethylformamide (21 mL) were added imidazole (1.55 g) and tert-butyldimethylchlorosilane (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 collected by filtration, washed twice with water and twice with hexane, and then dried under reduced pressure to give the crude title compound (1.64 g). (Step 4) Ethyl [4-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)acetate A mixture of the compound obtained in Step 3 above (1.64 g), ethyl 3-ethoxy-3-iminopropionate hydrochloride (2.13 g), and ethanol (14 mL) was stirred under reflux for 2.5 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.47 g). 1H-NMR (CDCl3) δ: 10.86 (1H, br s), 7.50 (1H, s), 5.23 (1H, q, J = 6.1 Hz), 4.30 (2H, q, J = 7.3 Hz), 4.09 (2H, s), 1.57-1.51 (3H, m), 1.34 (3H, t, J = 7.3 Hz), 0.92 (9H, s), 0.18 (3H, s), 0.10 (3H, s). (Step 5) Ethyl [6-chloro-4-(1-hydroxyethyl)-1H-benzimidazol-2-yl]acetate. To a solution of the compound obtained in Step 4 above (1.47 g) in 1,4-dioxane (12 mL) was added 6 M hydrochloric acid (3.0 mL) at room temperature. mL) was added and stirred at the same temperature for 2.5 hours. 1M aqueous sodium hydroxide solution (19 mL) was added to the reaction mixture at 0°C, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting 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 filtered off. The resulting solid was suspended in ethyl acetate, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to obtain the title compound (836 mg). 1 H-NMR (CDCl3) 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).

[0147] Reference Example 39 Preparation of tert-butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate (Step 1) tert-Butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-hydroxyethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate. To a solution of the compound obtained in Step 5 of Reference Example 38 (60.0 mg) in tetrahydrofuran (1.0 mL) were added di-tert-butyl dicarbonate (51.0 mg) and 4-dimethylaminopyridine (5.0 mg) 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (71.9 mg). 1 H-NMR (CDCl3) δ: 7.76 (1H, s), 5.43-5.31 (1H, m), 4.27 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 1.69 (9H, s), 1.64 (3H, d, J = 6.7 Hz), 1.27 (3H, t, J = 7.1 Hz). (Step 2) tert-Butyl 6-chloro-2-(2-ethoxy-2-oxoethyl)-4-(1-fluoroethyl)-1H-imidazo[4,5-c]pyridine-1-carboxylate To a solution of the compound obtained in Step 1 (71 mg) in dichloromethane (1 mL), bis(2-methoxyethyl)aminosulfur trifluoride (80 The reaction mixture was then 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). 1 H-NMR (CDCl3) δ: 7.83 (1H, d, J = 1.2 Hz), 6.20 (1H, dq, J = 47.3, 6.7 Hz), 4.29 (2H, s), 4.21 (2H, q, J = 7.1 Hz), 1.84 (3H, dd, J = 23.8, 6.7 Hz), 1.69 (9H, s), 1.27 (3H, t, J = 7.1 Hz).

[0148] Reference Example 40 Preparation of ethyl {4-[{4-[(tert-butoxycarbonyl)(methyl)amino]butyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate (Step 1) tert-Butyl {4-[(4-amino-6-chloro-3-nitropyridin-2-yl)(methyl)amino]butyl}methylcarbamate. 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) was added potassium carbonate (3.20 g) at room temperature and stirred at the same temperature for 6 hours. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (3.00 g). (Step 2) tert-Butyl {4-[(3,4-diamino-6-chloropyridin-2-yl)(methyl)amino]butyl}methylcarbamate A mixture of the compound obtained in Step 1 above (3.00 g), 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. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite. A saturated aqueous solution of sodium bicarbonate was added to the filtrate, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (2.85 g). (Step 3) Ethyl {4-[{4-[(tert-butoxycarbonyl)(methyl)amino]butyl}(methyl)amino]-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl}acetate A mixture of the compound obtained in Step 2 above (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. The reaction mixture was cooled to room temperature, and then saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and 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 residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.30 g). 1 H-NMR (CDCl3) δ: 10.20 (1H, br s), 6.66 (1H, s), 4.28 (2H, q, J = 7.2 Hz), 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 = 7.2 Hz).

[0149] The following compounds were synthesized by carrying out the same procedures as in steps 1 to 3 of Reference Example 40 (Table 5-1).

[0150]

[0151] Reference Example 46: Preparation of tert-butyl (3-formyl-2-methylpyridin-4-yl)carbamate To a solution of tert-butyl (3-formyl-2-methylpyridin-4-yl)carbamate (4.00 g) in 1,2-dimethoxyethane (30 mL), 50% trimethylboroxine in tetrahydrofuran (13.4 mL), potassium carbonate (6.46 g), and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (318 mg) were added at room temperature, and the mixture was stirred under reflux for 3 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and insoluble material was removed by filtration through Celite. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to afford the title compound (3.26 g). 1H-NMR (CDCl3) δ: 10.98 (1H, br s), 10.46 (1H, s), 8.43 (1H, d, J = 6.1 Hz), 8.25 (1H, d, J = 6.1 Hz), 2.85 (3H, s), 1.54 (9H, s).

[0152] Reference Example 47: Preparation of 4-amino-2,6-dimethylpyridine-3-carbaldehyde 4-Amino-2,6-dimethylpyridine-3-carbaldehyde 4-amino-2,6-dichloropyridine-3-carbaldehyde and 50% trimethylboroxine tetrahydrofuran solution were used as raw materials and the same procedure as in Reference Example 46 was carried out to obtain the title compound. 1 H-NMR (CDCl3) δ: 10.36 (1H, s), 6.26 (1H, s), 2.72 (3H, s), 2.39 (3H, s).

[0153] Reference Example 48: Preparation of tert-butyl (2-ethyl-3-formylpyridin-4-yl)carbamate (Step 1) tert-Butyl (2-ethenyl-3-formylpyridin-4-yl)carbamate: 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 under reflux for 2.5 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting 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 (1.60 g). 1H-NMR (CDCl3) δ: 10.97 (1H, br s), 10.50 (1H, s), 8.56 (1H, d, J = 6.1 Hz), 8.32 (1H, d, J = 6.1 Hz), 7.33 (2H, dd, J = 17.1, 10.7 Hz), 6.27 (1H, dd, J = 17.1, 1.8 Hz), 5.83 (1H, dd, J = 10.7, 1.8 Hz), 1.57 (9H, s). (Step 2) tert-Butyl (2-ethyl-3-formylpyridin-4-yl)carbamate The compound obtained in Step 1 (2.55 g) was dissolved in ethyl acetate (35 To the solution (mL) was added 10% palladium on carbon (50% water content, 273 mg) at room temperature, and the mixture was stirred under a hydrogen atmosphere at the same temperature for 2 hours. After removing insoluble matter by filtration through Celite, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (2.30 g). 1 H-NMR (CDCl3) δ: 10.98 (1H, br s), 10.43 (1H, s), 8.46 (1H, d, J = 6.1 Hz), 8.23 ​​(1H, d, J = 6.1 Hz), 3.15 (2H, q, J = 7.6 Hz), 1.53 (9H, s), 1.35 (3H, t, J = 7.6 Hz).

[0154] Reference Example 49: Preparation of tert-butyl [3-formyl-2-(1-methylcyclopropyl)pyridin-4-yl]carbamate (Step 1) Potassium trifluoro(1-methylcyclopropyl)borate (1-) To a solution of 4,4,5,5-tetramethyl-2-(1-methylcyclopropyl)-1,3,2-dioxaborolane (383 mg) in a mixed solution of acetonitrile (6.0 mL) and water (0.9 mL) was added potassium hydrofluoride (510 mg) at room temperature, and the mixture was stirred at the same temperature for 4.5 hours. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The precipitated solid was filtered off, and the resulting solid was washed with diethyl ether and methanol to give the crude title compound (341 mg). (Step 2) tert-Butyl [3-formyl-2-(1-methylcyclopropyl)pyridin-4-yl]carbamate To a suspension of the compound obtained in Step 1 above (287 mg) and tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (350 mg) in toluene (8.0 mL) / water (2.0 mL), cesium carbonate (1.33 g) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (111 mg) were added at room temperature, and the mixture was stirred at 100°C for 4 hours under a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (119 mg). 1 H-NMR (CDCl3) δ: 10.97 (1H, br s), 10.90 (1H, s), 8.47 (1H, d, J = 6.1 Hz), 8.25 (1H, d, J = 6.1 Hz), 1.55 (9H, s), 1.53 (3H, s), 1.11 (2H, dd, J = 6.1, 4.3 Hz), 0.94 (2H, dd, J = 6.1, 4.3 Hz).

[0155] Reference Example 50: Preparation of tert-butyl [3-formyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate (Step 1) tert-Butyl [2-(3,6-dihydro-2H-pyran-4-yl)-3-formylpyridin-4-yl]carbamate The title compound was obtained using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran as a raw material and by performing the same operation as in Step 1 of Reference Example 48. 1 H-NMR (CDCl3) δ: 10.85 (1H, br s), 10.15 (1H, s), 8.53 (1H, d, J = 6.1 Hz), 8.28 (1H, d, J = 6.1 Hz), 5.79 (1H, br s), 4.40-4.32 (2H, m), 3.98 (2H, t, J = 5.5 Hz), 2.74-2.65 (2H, m), 1.55 (9H, s). (Step 2) tert-Butyl [3-(hydroxymethyl)-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate. The compound obtained in Step 1 (660 mg) was dissolved in ethanol (20 To the solution of 1 mL of 10% palladium on carbon (50% water content, 300 mg) was added at room temperature, and the mixture was stirred at 50°C under a hydrogen atmosphere for 4.5 hours. The reaction mixture was cooled to room temperature, and insoluble matter was removed by filtration through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (250 mg). 1H-NMR (CDCl3) δ: 8.42 (1H, d, J = 5.5 Hz), 7.93 (1H, br s), 7.83 (1H, d, J = 5.5 Hz), 4.85 (2H, d, J = 5.5 Hz), 4.12-4.06 (2H, m), 3.55 (2H, t, J = 11.0 Hz), 3.22-3.14 (1H, m), 2.18-2.07 (2H, m), 1.97 (1H, t, J = 5.5 Hz), 1.63-1.57 (2H, m), 1.53 (9H, s). (Step 3) tert-butyl [3-Formyl-2-(tetrahydro-2H-pyran-4-yl)pyridin-4-yl]carbamate To a solution of the compound obtained in Step 2 above (250 mg) in dichloromethane (10 mL) was added manganese dioxide (250 mg) 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. Subsequently, manganese dioxide (500 mg) was added to the reaction mixture at room temperature and stirred at the same temperature for an additional 7 hours. Insoluble matter was removed by filtration through Celite, and the residue was washed with dichloromethane. The combined filtrate was concentrated under reduced pressure to give the title compound (220 mg). 1 H-NMR (CDCl3) δ: 11.02 (1H, br s), 10.55 (1H, s), 8.52 (1H, d, J = 6.1 Hz), 8.25 (1H, d, J = 6.1 Hz), 4.11 (2H, dd, J = 11.3, 4.0 Hz), 3.63-3.53 (3H, m), 2.29-2.18 (2H, m), 1.74-1.67 (2H, m), 1.53 (9H, s).

[0156] Reference Example 51 Preparation of tert-butyl [3-formyl-2-(4-methylpiperazin-1-yl)pyridin-4-yl]carbamate A mixture of tert-butyl [3-formyl-2-(4-methylpiperazin-1-yl)pyridin-4-yl]carbamate 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). 1 H-NMR (CDCl3) δ: 10.76 (1H, br s), 9.96 (1H, s), 8.20 (1H, d, J = 6.1 Hz), 7.87 (1H, d, J = 6.1 Hz), 3.45 (4H, t, J = 4.9 Hz), 2.63-2.52 (4H, m), 2.36 (3H, s), 1.53 (9H, s).

[0157] Reference Example 52 Preparation of tert-butyl {2-[4-(dimethylamino)piperidin-1-yl]-3-formylpyridin-4-yl]carbamate tert-Butyl {2-[4-(dimethylamino)piperidin-1-yl]-3-formylpyridin-4-yl]carbamate 4-(dimethylamino)piperidine was used as a raw material and the title compound was obtained by the same procedure as in Reference Example 51. 1 H-NMR (CDCl3) δ: 10.78 (1H, br s), 9.92 (1H, s), 8.18 (1H, d, J = 6.1 Hz), 7.85 (1H, d, J = 6.1 Hz), 3.82-3.72 (2H, m), 3.14-3.04 (2H, m), 2.38-2.29 (7H, m), 2.00-1.88 (2H, m), 1.71-1.61 (2H, m), 1.53 (9H, s).

[0158] Reference example 53 {2-[( 2 H3) Preparation of {methyloxy}phenyl}boronic acid (Step 1) 1-bromo-2-[( 2To a solution of 2-bromophenol (3.80 g) and iodomethane-d3 (4.78 g) in N,N-dimethylformamide (40 mL), sodium carbonate (4.66 g) was added at 0°C, and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted three times with diethyl ether. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / diethyl ether) to give the title compound (3.33 g). 1 H-NMR (CDCl3) δ: 7.54 (1H, dd, J = 7.9, 1.8 Hz), 7.31-7.23 (1H, m), 6.91 (1H, dd, J = 8.5, 1.2 Hz), 6.87-6.81 (1H, m). (Step 2) {2-[( 2 To a solution of the compound obtained in Step 1 (3.33 g) in tetrahydrofuran (35 mL), 1.58 M n-butyllithium n-hexane solution (13.3 mL) was added dropwise at −78°C, and the mixture was stirred at 0°C for 15 minutes. Then, triisopropyl borate (5.22 mL) was added dropwise at −78°C, and the mixture was stirred at 0°C for an additional 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was extracted three times with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (2.44 g).

[0159] Reference Example 54 {2-fluoro-6-[( 2 H3) Preparation of {methyloxy}phenyl}boronic acid (Steps 1 and 2) {2-fluoro-6-[( 2 H3) Methyloxy]phenyl}boronic acid Using 2-bromo-3-fluorophenol as the starting material, the crude title compound was obtained by the same procedures as in Steps 1 and 2 of Reference Example 53.

[0160] Reference Example 55: Preparation of [2-fluoro-6-(methoxymethoxy)phenyl]boronic acid (Step 1) 2-Bromo-1-fluoro-3-(methoxymethoxy)benzene. To a solution of 2-bromo-3-fluorophenol (1.00 g) in acetone (18 mL), chloro(methoxy)methane (510 μL) and potassium carbonate (1.10 g) were added at room temperature, and the mixture was stirred at the same temperature for 15 hours. Insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.18 g). 1 H-NMR (CDCl) δ: 7.22 (1H, td, J = 8.4, 6.5 Hz), 6.97-6.93 (1H, m), 6.85-6.79 (1H, m), 5.27 (2H, s), 3.52 (3H, s). (Step 2) [2-Fluoro-6-(methoxymethoxy)phenyl]boronic acid Using the compound obtained in Step 1 above as the starting material, the same procedure as in Step 2 of Reference Example 53 was carried out. The resulting solid was washed with n-hexane and then dried under reduced pressure to obtain the title compound. 1 H-NMR (CDCl3) δ: 7.40 (1H, ddd, J = 8.5, 7.9, 7.3 Hz), 7.00 (1H, d, J = 7.9 Hz), 6.81 (1H, dd, J = 10.4, 8.5 Hz), 6.32-6.26 (2H, m), 5.31 (2H, s), 3.52 (3H, s).

[0161] Reference Example 56: Preparation of 8-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3-oxa-8-azabicyclo[3.2.1]octane 8-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-3-oxa-8-azabicyclo[3.2.1]octane. 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) was added potassium carbonate (212 mg) at room temperature and stirred at the same temperature for 30 minutes. Water was added to the reaction mixture, which was then extracted twice with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (167 mg).

[0162] Reference Example 57 tert-butyl (3-formyl-2-{2-[( 2 H3) Preparation of (methyloxy)phenyl}pyridin-4-yl)carbamate tert-Butyl (3-formyl-2-{2-[( 2 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 under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (3.76 g). 1H-NMR (DMSO-D6) δ: 10.91 (1H, br s), 9.72 (1H, s), 8.63 (1H, d, J = 6.1 Hz), 8.36 (1H, d, J = 6.1 Hz), 7.50-7.43 (2H, m), 7.14-7.10 (1H, m), 6.96 (1H, d, J = 8.5 Hz), 1.55 (9H, s).

[0163] The following compounds were synthesized by the same procedure as in Reference Example 57 (Table 6-1).

[0164]

[0165] Reference Example 69 Preparation of 4-amino-1'-methyl-1',2',5',6'-tetrahydro[2,3'-bipyridine]-5-carbaldehyde 4-amino-1'-methyl-1',2',5',6'-tetrahydro[2,3'-bipyridine]-5-carbaldehyde 4-amino-6-chloronicotinaldehyde and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine were used as raw materials and the title compound was obtained by the same operation as in Reference Example 57. 1 H-NMR (CD3OD) 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).

[0166] Reference Example 70 Preparation of methyl 3-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2-methylbenzoate A mixture of methyl 3-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2-methylbenzoate 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 under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water was added. The mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and 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 (240 mg). 1 H-NMR (CDCl3) δ: 10.93 (1H, s), 9.68 (1H, s), 8.62 (1H, d, J = 6.1 Hz), 8.43 (1H, d, J = 6.1 Hz), 7.96 (1H, dd, J = 7.4, 1.8 Hz), 7.40-7.35 (2H, m), 3.92 (3H, s), 2.33 (3H, s), 1.56 (9H, s).

[0167] The following compounds were synthesized by the same procedure as in Reference Example 70 (Table 7-1).

[0168]

[0169] Reference Example 79: Preparation of tert-butyl [2-(2-cyano-6-fluorophenyl)-3-formylpyridin-4-yl]carbamate A mixture of tert-butyl [2-(2-cyano-6-fluorophenyl)-3-formylpyridin-4-yl]carbamate (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 under a nitrogen atmosphere for 1 hour. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (200 mg). 1 H-NMR (CDCl3) δ: 10.88 (1H, br s), 9.78 (1H, d, J = 3.1 Hz), 8.71 (1H, d, J = 6.1 Hz), 8.55 (1H, d, J = 6.1 Hz), 7.68 (1H, dd, J = 7.9, 1.2 Hz), 7.61 (1H, ddd, J = 8.5, 7.9, 4.9 Hz), 7.45 (1H, td, J = 8.5, 1.2 Hz), 1.56 (9H, s).

[0170] Reference Example 80 Preparation of tert-butyl {2-[2-fluoro-6-(methoxymethoxy)phenyl]-3-formylpyridin-4-yl}carbamate A mixture of tert-butyl {2-[2-fluoro-6-(methoxymethoxy)phenyl]-3-formylpyridin-4-yl}carbamate 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), chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) (66.0 mg), 1,4-dioxane (8.0 mL), and water (2.0 mL) was stirred under a nitrogen atmosphere at 100°C for 1.5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (225 mg). 1 H-NMR (CDCl3) δ: 10.90 (1H, br s), 9.81 (1H, s), 8.66 (1H, d, J = 6.1 Hz), 8.43 (1H, d, J = 6.1 Hz), 7.39 (1H, td, J = 8.5, 6.7 Hz), 7.03 (1H, d, J = 8.5 Hz), 6.89 (1H, t, J = 8.5 Hz), 5.13 (1H, d, J = 7.3 Hz), 5.04 (1H, d, J = 7.3 Hz), 3.32 (3H, s), 1.55 (9H, s).

[0171] Reference Example 81 Preparation of tert-butyl {2-[3-(difluoromethoxy)-2-methylphenyl]-3-formylpyridin-4-yl}carbamate (Step 1) 1-Bromo-3-(difluoromethoxy)-2-methylbenzene. To a solution of 3-bromo-2-methylphenol (500 mg) in N,N-dimethylformamide (10 mL) was added 2-chloro-2,2-difluoroacetic acid, sodium salt (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 the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. After filtering the resulting organic layer, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (400 mg). 1 H-NMR (CDCl3) δ: 7.44-7.41 (1H, m), 7.07-7.05 (2H, m), 6.49 (1H, t, J = 73.9 Hz), 2.38 (3H, s). (Step 2) tert-Butyl {2-[3-(difluoromethoxy)-2-methylphenyl]-3-formylpyridin-4-yl}carbamate A mixture of the compound obtained in Step 1 above (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 under a nitrogen atmosphere for 6 hours. The reaction mixture was cooled to room temperature, and water (5.0 mL), tert-butyl 2-chloro-3-formylpyridin-4-ylcarbamate (300 mg), and cesium carbonate (1.10 g) were added, followed by stirring at 90°C for 2 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (220 mg). 1H-NMR (CDCl3) δ: 10.93 (1H, br s), 9.71 (1H, s), 8.62 (1H, d, J = 6.1 Hz), 8.43 (1H, d, J = 6.1 Hz), 7.31 (1H, t, J = 8.5 Hz), 7.21 (1H, d, J = 8.5 Hz), 7.13 (1H, d, J = 8.5 Hz), 6.55 (1H, t, J = 73.9 Hz), 2.08 (3H, s), 1.56 (9H, s).

[0172] Reference Example 82: Preparation of tert-butyl {2-[2-(difluoromethoxy)phenyl]-3-formylpyridin-4-yl}carbamate tert-Butyl {2-[2-(difluoromethoxy)phenyl]-3-formylpyridin-4-yl}carbamate The title compound was obtained using 1-bromo-2-(difluoromethoxy)benzene as a raw material and by performing the same operation as in Step 2 of Reference Example 81. 1 H-NMR (CDCl3) δ: 10.93 (1H, br s), 9.77 (1H, s), 8.62 (1H, d, J = 6.1 Hz), 8.43 (1H, d, J = 6.1 Hz), 7.50-7.54 (2H, m), 7.39 (1H, t, J = 7.9 Hz), 7.27 (1H, d, J = 7.9 Hz), 6.40 (1H, t, J = 76.0 Hz), 1.56 (9H, s).

[0173] Reference Example 83 Preparation of tert-butyl (6'-chloro-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl)carbamate (Step 1) 5-Bromo-2-chloro-4-methoxypyridine To a solution of 5-bromo-2,4-dichloropyridine (45.0 g) in methanol (250 mL) was added 1 M sodium methoxide in methanol (200 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 filtered off, washed once with water and once with cold methanol, and then the water was removed by azeotropy with toluene three times to give the title compound (38.0 g). 1H-NMR (CDCl3) δ: 8.35 (1H, s), 6.84 (1H, s), 3.97 (3H, s). (Step 2) 2-chloro-4-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine. To a solution of the compound obtained in Step 1 (13.0 g) and 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (13.1 g) in tetrahydrofuran (240 mL) was added dropwise 1.57 M n-butyllithium in hexane (52.0 mL) at −78°C and stirred at the same temperature for 2 hours. Saturated aqueous ammonium chloride was added to the reaction mixture at −78°C, and the mixture was warmed to room temperature. It was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (15.8 g). (Step 3) tert-butyl (6'-chloro-3-formyl-4'-methoxy[2.3'-bipyridin]-4-yl)carbamate. 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 under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The organic layer was filtered, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). The solid was washed with a 6:1 mixture of n-hexane / ethyl acetate and then dried under reduced pressure to give the title compound (11.0 g). 1H-NMR (CDCl3) δ: 10.84 (1H, s), 9.69 (1H, s), 8.63 (1H, d, J = 6.1 Hz), 8.44 (1H, d, J = 6.1 Hz), 8.39 (1H, s), 6.94 (1H, s), 3.84 (3H, s), 1.55 (9H, s).

[0174] Reference Example 84: Preparation of tert-butyl (3-formyl-4'-methoxy-6'-methyl[2,3'-bipyridin]-4-yl)carbamate tert-Butyl (3-formyl-4'-methoxy-6'-methyl[2,3'-bipyridin]-4-yl)carbamate. To a solution of the compound obtained in Step 3 of Reference Example 83 (800 mg) in 1,2-dimethoxyethane (12 mL) was added 50% trimethylboroxine in tetrahydrofuran (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 under reflux for 5 hours. After the reaction mixture was cooled to room temperature, insoluble matter was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane / methanol). The resulting solid was washed with a mixture of n-hexane / ethyl acetate (5:1) and then dried under reduced pressure to yield the title compound (623 mg). 1 H-NMR (CDCl3) δ: 10.90 (1H, br s), 9.73 (1H, s), 8.66 (1H, d, J = 5.5 Hz), 8.50 (1H, s), 8.42 (1H, d, J = 5.5 Hz), 6.79 (1H, s), 3.83 (3H, s), 2.65 (3H, s), 1.58 (9H, s).

[0175] Reference Example 85: Preparation of tert-butyl (6'-ethyl-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl)carbamate (Steps 1 and 2) tert-butyl (6'-ethyl-3-formyl-4'-methoxy[2.3'-bipyridin]-4-yl)carbamate The title compound was obtained by using the compound obtained in Step 3 of Reference Example 83 as a manufacturing raw material and performing the same operations as in Steps 1 and 2 of Reference Example 48. 1 H-NMR (CDCl3) δ: 10.88 (1H, br s), 9.72 (1H, s), 8.64 (1H, d, J = 6.1 Hz), 8.50 (1H, s), 8.40 (1H, d, J = 6.1 Hz), 6.76 (1H, s), 3.82 (3H, s), 2.88 (2H, q, J = 7.6 Hz), 1.55 (9H, s), 1.35 (3H, t, J = 7.6 Hz).

[0176] Reference Example 86: Preparation of tert-butyl (6'-cyclopropyl-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl)carbamate 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-]decan-1-yl)]phosphane (1.80 g), toluene (170 mL), and water (17 mL) was stirred at 100°C for 11 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate). To the resulting oily substance was added a mixture of ethanol (30 mL) and water (30 mL), and the mixture was stirred at 70° C. for 15 minutes, and then cooled to room temperature. The precipitated solid was collected by filtration, washed successively with water and a mixture of ethanol and water (1:2), and then dried under reduced pressure to obtain the title compound (10.6 g). 1H-NMR (CDCl3) δ: 10.87 (1H, br s), 9.71 (1H, s), 8.62 (1H, d, J = 6.1 Hz), 8.40 (1H, s), 8.38 (1H, d, J = 6.1 Hz), 6.76 (1H, s), 3.81 (3H, s), 2.12-2.01 (1H, m), 1.55 (9H, s), 1.21-0.99 (4H, m).

[0177] Reference Example 87 Preparation of tert-butyl [6'-cyclopropyl-4'-(difluoromethoxy)-3-formyl[2,3'-bipyridin]-4-yl]carbamate (Step 1) 5-Bromo-2-chloropyridin-4-ol. To a suspension of 5-bromo-2,4-dichloropyridine (300 mg) in 1,4-dioxane (1 mL) was added 12 M hydrochloric acid (1 mL) at room temperature, and the mixture was stirred at 100°C for 5 hours. The reaction mixture was cooled to room temperature, and 1 M aqueous sodium hydroxide solution (12 mL) was added. The mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (188 mg). 1 H-NMR (DMSO-D6) δ: 12.27 (1H, br s), 8.33 (1H, s), 6.90 (1H, s). (Step 2) 5-Bromo-2-chloro-4-(difluoromethoxy)pyridine. To a solution of the compound obtained in Step 1 above (185 mg) 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 give the title compound (156 mg). 1H-NMR (CDCl3) δ: 8.53 (1H, s), 7.19-7.15 (1H, m), 6.70 (1H, t, J = 71.1 Hz). (Steps 3 and 4) tert-butyl [6'-chloro-4'-(difluoromethoxy)-3-formyl[2.3'-bipyridin]-4-yl]carbamate Using the compound obtained in Step 2 above as the starting material, the title compound was obtained by performing the same operations as in Steps 2 and 3 of Reference Example 83. 1 H-NMR (CDCl3) δ: 10.86 (1H, br s), 9.76 (1H, s), 8.64 (1H, d, J = 6.1 Hz), 8.52 (1H, s), 8.50 (1H, d, J = 6.1 Hz), 6.57 (1H, t, J = 71.1 Hz), 1.56 (9H, s)., MS (m / z): 400 (M+H) + (Step 5) tert-Butyl [6'-cyclopropyl-4'-(difluoromethoxy)-3-formyl[2,3'-bipyridin]-4-yl]carbamate. A mixture of the compound obtained in Step 4 above (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 under a nitrogen atmosphere at 100°C for 6 hours. After cooling the reaction mixture to room temperature, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (18.0 mg). 1 H-NMR (CDCl3) δ: 10.89 (1H, br s), 9.77 (1H, s), 8.62 (1H, d, J = 6.1 Hz), 8.51 (1H, s), 8.44 (1H, d, J = 6.1 Hz), 7.01 (1H, s), 6.56 (1H, t, J = 72.1 Hz), 2.14-2.03 (1H, m), 1.55 (9H, s), 1.22-0.99 (4H, m).

[0178] Reference Example 88 Preparation of tert-butyl [3-formyl-2-(4-methoxy-2-methylpyrimidin-5-yl)pyridin-4-yl]carbamate (Steps 1 to 4) tert-butyl [3-formyl-2-(4-methoxy-2-methylpyrimidin-5-yl)pyridin-4-yl]carbamate The title compound was obtained by using 5-bromo-2,4-dichloropyrimidine as a raw material and performing the same operations as in Steps 1 and 2 of Reference Example 83, Reference Example 70, and Reference Example 84. 1 H-NMR (CDCl3) δ: 10.88 (1H, s), 9.76 (1H, s), 8.64 (1H, d, J = 6.1 Hz), 8.60 (1H, s), 8.45 (1H, d, J = 6.1 Hz), 3.97 (3H, s), 2.73 (3H, s), 1.57 (9H, s).

[0179] Reference Example 89: Preparation of tert-butyl [3-formyl-4'-methoxy-6'-(trifluoromethyl)[2,3'-bipyridin]-4-yl]carbamate (Step 1) [4-Methoxy-6-(trifluoromethyl)pyridin-3-yl]boronic acid. To a solution of 5-bromo-4-methoxy-2-(trifluoromethyl)pyridine (200 mg) in tetrahydrofuran (4.0 mL), 1.56 M n-butyllithium hexane solution (500 μL) was added at −78°C. The mixture was stirred at the same temperature for 30 minutes, and then triisopropyl borate (270 μL) was added. The mixture was warmed to 0°C and stirred for an additional 20 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (172 mg). (Step 2) tert-butyl [3-formyl-4'-methoxy-6'-(trifluoromethyl)[2,3'-bipyridin]-4-yl]carbamate. A mixture of the compound obtained in Step 1 above (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 under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (127 mg). 1 H-NMR (CDCl3) δ: 10.85 (1H, s), 9.70 (1H, s), 8.71 (1H, s), 8.66 (1H, d, J = 6.1 Hz), 8.48 (1H, d, J = 6.1 Hz), 7.29 (1H, s), 3.92 (3H, s), 1.56 (9H, s).

[0180] Reference Example 90 Preparation of tert-butyl [6'-(1,1-difluoroethyl)-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate (Step 1) 2-(1,1-Difluoroethyl)-4-methoxypyridine. 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 saturated aqueous sodium bicarbonate solution was carefully added. The mixture was then extracted twice with dichloromethane, and the resulting organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (937 mg). 1 H-NMR (CDCl3) δ: 8.46 (1H, d, J = 5.5 Hz), 7.17 (1H, d, J = 2.4 Hz), 6.86 (1H, dd, J = 5.5, 2.4 Hz), 3.89 (3H, s), 2.00 (3H, t, J = 17.7 Hz). (Step 2) 5-Bromo-2-(1,1-difluoroethyl)-4-methoxypyridine. To the compound obtained in Step 1 (300 mg) above, sulfuric acid (1.7 mL) and N-bromosuccinimide (312 mg) were carefully added 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 10 M aqueous sodium hydroxide solution were added in small portions. The mixture was then extracted three times with ethyl acetate. The resulting organic layer was 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 (297 mg). 1H-NMR (CDCl3) δ: 8.60 (1H, s), 7.19 (1H, s), 4.03 (3H, s), 2.03 (3H, t, J = 17.4 Hz). (Step 3) [6-(1,1-Difluoroethyl)-4-methoxypyridin-3-yl]boronic acid. To a solution of the compound obtained in Step 2 (297 mg) in tetrahydrofuran (6.0 mL), 1.56 M n-butyllithium n-hexane solution (760 μL) was added dropwise at −78°C, followed by triisopropyl borate (540 μL) and stirring at the same temperature for 30 minutes. Saturated aqueous ammonium chloride and water were added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to afford the crude title compound (255 mg). (Step 4) tert-Butyl [6'-(1,1-difluoroethyl)-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate A mixture of the compound obtained in Step 3 above (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 under a nitrogen atmosphere for 2 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting 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 (181 mg). 1 H-NMR (CDCl3) δ: 10.89 (1H, s), 9.73 (1H, s), 8.67 (1H, d, J = 6.1 Hz), 8.64 (1H, s), 8.47 (1H, d, J = 6.1 Hz), 3.91 (3H, s), 2.08 (3H, t, J = 18.6 Hz), 1.58 (9H, s).

[0181] Reference Example 91 Preparation of tert-butyl [6'-(difluoromethyl)-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate (Steps 1 to 3) tert-butyl [6'-(difluoromethyl)-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate The title compound was obtained using 4-methoxypyridine-2-carbaldehyde as a raw material and by carrying out the same operations as in Steps 1 and 2 of Reference Example 90 and Step 2 of Reference Example 81. 1 H-NMR (CDCl3) δ: 10.88 (1H, s), 9.72 (1H, s), 8.68 (1H, d, J = 6.1 Hz), 8.65 (1H, s), 8.48 (1H, d, J = 6.1 Hz), 8.41 (1H, s), 6.84-6.50 (1H, m), 3.92 (3H, s), 1.58 (9H, s).

[0182] Reference Example 92 Preparation of tert-butyl [3-formyl-4'-methoxy-6'-(propan-2-yl)[2,3'-bipyridin]-4-yl]carbamate (Steps 1 to 4) tert-butyl [3-formyl-4'-methoxy-6'-(propan-2-yl)[2,3'-bipyridin]-4-yl]carbamate Using 2-bromo-4-methoxypyridine as a raw material, the title compound was obtained by performing the same operations as in Steps 1 and 2 of Reference Example 48, Step 2 of Reference Example 90, and Step 2 of Reference Example 81. 1 H-NMR (CDCl3) δ: 10.89 (1H, s), 9.74 (1H, s), 8.65 (1H, d, J = 6.1 Hz), 8.52 (1H, s), 8.41 (1H, d, J = 6.1 Hz), 6.77 (1H, s), 3.84 (3H, s), 1.56 (9H, s), 1.36 (6H, d, J = 6.7 Hz).

[0183] Reference Example 93 Preparation of tert-butyl [6'-(difluoromethoxy)-3-formyl-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate (Step 1) 5-Bromo-4-chloro-2-(difluoromethoxy)pyridine 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 in 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 insoluble material was removed by filtration. The filtrate was extracted three times with ethyl acetate, and the resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (578 mg). 1 H-NMR (CDCl3) δ: 8.34 (1H, s), 7.39 (1H, t, J = 72.3 Hz), 7.06 (1H, s). (Step 2) 5-Bromo-2-(difluoromethoxy)-4-methoxypyridine. A mixture of the compound obtained in Step 1 above (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 the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (162 mg). 1H-NMR (CD3OD) δ: 8.18 (1H, s), 7.52 (1H, t, J = 72.6 Hz), 6.68 (1H, s), 3.99 (3H, s). (Step 3) tert-butyl [6'-(difluoromethoxy)-3-formyl-4'-methoxy[2,3'-bipyridine]-4-yl]carbamate A mixture of the compound obtained in Step 2 above (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 under a nitrogen atmosphere for 30 minutes. Subsequently, 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 stirred at the same temperature for an additional 1 hour. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (49.1 mg). 1 H-NMR (CDCl3) δ: 10.85 (1H, s), 9.71 (1H, s), 8.63 (1H, d, J = 6.1 Hz), 8.43 (1H, d, J = 6.1 Hz), 8.20 (1H, s), 7.54 (1H, t, J = 72.9 Hz), 6.46 (1H, s), 3.83 (3H, s), 1.56 (9H, s).

[0184] Reference Example 94 Preparation of tert-butyl {2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate (Step 1) 1-(Difluoromethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 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) was added 2-chloro-2,2-difluoroacetic acid, sodium salt (165 mg) and 18-crown-6 (50.0 mg) at room temperature, followed by stirring at 90°C for 3 hours. The reaction mixture was cooled to room temperature, saturated aqueous ammonium chloride was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (220 mg). 1 H-NMR (CDCl3) δ: 7.13 (1H, t, J = 59.8 Hz), 2.57 (3H, s), 2.33 (3H, s), 1.31 (12H, s). (Step 2) tert-Butyl {2-[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate The compound obtained in Step 1 above (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) were dissolved in 100 ml of toluene. A mixture of these (mL) was stirred at 100°C under a nitrogen atmosphere for 1.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (150 mg). 1H-NMR (CDCl3) δ: 10.90 (1H, s), 9.83 (1H, s), 8.64 (1H, d, J = 6.1 Hz), 8.40 (1H, d, J = 6.1 Hz), 7.20 (1H, t, J = 59.2 Hz), 2.37 (3H, s), 2.18 (3H, s), 1.56 (9H, s).

[0185] Reference Example 95 Preparation of tert-butyl {2-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate (Step 1) tert-Butyl 3-cyclopropyl-4-iodo-5-methyl-1H-pyrazole-1-carboxylate. To a solution of 3-cyclopropyl-4-iodo-5-methyl-1H-pyrazole (1.00 g, which can be prepared by a method described in US20140256706A1 or the like) 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 the mixture was stirred at the same temperature for 2 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 give the title compound (1.30 g). 1 H-NMR (CDCl3) δ: 2.53 (3H, s), 1.86-1.77 (1H, m), 1.62 (9H, s), 1.02-0.89 (4H, m). (Step 2) tert-Butyl 3-cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate Using the compound obtained in Step 1 above as the starting material, the title compound was obtained by performing the same procedure as in Step 2 of Reference Example 83. 1H-NMR (CDCl3) 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). (Step 3) 3-Cyclopropyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. The compound obtained in Step 2 above (370 mg) was heated at 180°C for 20 minutes. The reaction mixture was cooled to room temperature, and then ethyl acetate was added. The solvent was evaporated under reduced pressure to give the title compound (260 mg). 1 H-NMR (CDCl3) 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). (Steps 4 and 5) tert-Butyl {2-[3-cyclopropyl-1-(difluoromethyl)-5-methyl-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate Using the compound obtained in Step 3 above as the starting material, the title compound was obtained by performing the same procedures as in Steps 1 and 2 of Reference Example 94. 1 H-NMR (CDCl3) δ: 10.95 (1H, s), 9.93 (1H, s), 8.65 (1H, d, J = 6.1 Hz), 8.39 (1H, d, J = 6.1 Hz), 7.14 (1H, t, J = 59.2 Hz), 2.40 (3H, s), 1.56 (9H, s), 1.04-0.98 (1H, m), 0.88-0.77 (4H, m).

[0186] Reference Example 96 Preparation of 1-(cyclopropylmethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 1-(Cyclopropylmethyl)-3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole. 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) was added (bromomethyl)cyclopropane (360 mg) and cesium carbonate (450 mg) at room temperature, followed by stirring at 90°C for 10 hours. The reaction mixture was cooled to room temperature, saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (205 mg). 1 H-NMR (CDCl3) δ: 3.85 (2H, d, J = 7.3 Hz), 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).

[0187] Reference Example 97 Preparation of 3-cyclopropyl-1-(2,2-difluoroethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole 3-Cyclopropyl-1-(2,2-difluoroethyl)-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole To a solution of the compound obtained in Step 3 of Reference Example 95 (250 mg) in N,N-dimethylformamide (10 mL) was added 55% sodium hydride in oil (70.0 mg) at 0°C and stirred at room temperature for 30 minutes, followed by addition of a solution of 1,1-difluoro-2-iodoethane (0.40 g) in N,N-dimethylformamide (2.0 mL) at 0°C and stirring at room temperature for an additional 2 hours. Subsequently, to the reaction mixture was added a solution of 55% sodium hydride in oil (70.0 mg) and 1,1-difluoro-2-iodoethane (0.40 g) in N,N-dimethylformamide (2.0 mL) at 0°C and stirring at room temperature for 5 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (160 mg). 1 H-NMR (CDCl3) δ: 6.04 (1H, tt, J = 55.8, 4.6 Hz), 4.27 (2H, td, J = 13.3, 4.6 Hz), 2.40 (3H, s), 2.24-2.33 (1H, m), 1.30 (12H, s), 0.82-0.90 (4H, m).

[0188] Reference Example 98: 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 3-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine. 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 1.3 M isopropylmagnesium chloride lithium chloride complex solution in tetrahydrofuran (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, which was then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to afford the title compound (327 mg). 1 H-NMR (CDCl3) 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).

[0189] The following compounds were synthesized by the same procedure as in Step 2 of Reference Example 94 (Table 8-1).

[0190]

[0191] Reference Example 102 Preparation of tert-butyl {2-[1-(difluoromethyl)-1H-pyrazol-3-yl]-3-formylpyridin-4-yl}carbamate (Steps 1 and 2) tert-Butyl {2-[1-(difluoromethyl)-1H-pyrazol-3-yl]-3-formylpyridin-4-yl}carbamate The title compound was obtained using 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as a raw material and by carrying out the same operations as in Steps 1 and 2 of Reference Example 94. 1H-NMR (CDCl3) δ: 10.99 (1H, s), 10.51 (1H, s), 8.61 (1H, d, J = 6.1 Hz), 8.41 (1H, d, J = 6.1 Hz), 7.95 (1H, d, J = 2.4 Hz), 7.27 (1H, t, J = 60.4 Hz), 7.09 (1H, d, J = 2.4 Hz), 1.56 (9H, s).

[0192] Reference Example 103 Preparation of tert-butyl {2-[3-(difluoromethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate (Step 1) 3-(difluoromethyl)-4-iodo-5-methyl-1H-pyrazole. 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% aqueous solution of sodium thiosulfate was added to the reaction mixture, which was extracted three times with ethyl acetate. The resulting organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (2.00 g). (Steps 2 to 4) tert-Butyl {2-[3-(difluoromethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-4-yl]-3-formylpyridin-4-yl}carbamate The title compound was obtained by using the compound obtained in Step 2 above and 2-iodopropane as starting materials and carrying out the same operations as in Reference Example 97, Step 2 of Reference Example 83, and Step 2 of Reference Example 94. 1H-NMR (CDCl3) δ: 10.95 (1H, br s), 9.87 (1H, s), 8.61 (1H, d, J = 6.1 Hz), 8.39 (1H, d, J = 6.1 Hz), 6.70 (1H, t, J = 54.3 Hz), 4.53-4.46 (1H, m), 2.18 (3H, s), 1.55 (9H, s), 1.55 (3H, d, J = 6.7 Hz), 1.51 (3H, d, J = 6.7 Hz).

[0193] Reference Example 104: Preparation of tert-butyl [2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-formylpyridin-4-yl]carbamate (Step 1) 5-iodo-1,4-dimethyl-1H-pyrazole. To a solution of 3-iodo-4-methyl-1H-pyrazole (1.10 g) in tetrahydrofuran (20 mL) was added 55% sodium hydride in oil (0.46 g) at 0°C and stirred at room temperature for 30 minutes. The reaction mixture was cooled again to 0°C, and iodomethane (1.30 mL) was added, followed by stirring at room temperature for 2 hours. A saturated aqueous solution of sodium bicarbonate was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed with a 5% aqueous solution of sodium thiosulfate and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (350 mg). 1 H-NMR (CDCl3) δ: 7.05 (1H, s), 3.87 (3H, s), 1.98 (3H, s). (Step 2) tert-butyl [2-(1,4-dimethyl-1H-pyrazol-5-yl)-3-formylpyridin-4-yl]carbamate The title compound was obtained by using the compound obtained in Step 1 above as a starting material and performing the same procedure as in Step 2 of Reference Example 81. 1H-NMR (CDCl3) δ: 10.89 (1H, s), 9.75 (1H, s), 8.68 (1H, d, J = 5.5 Hz), 8.45 (1H, d, J = 5.5 Hz), 7.40 (1H, s), 3.84 (3H, s), 1.93 (3H, s), 1.56 (9H, s).

[0194] Reference Example 105 Preparation of tert-butyl [6'-cyclopropyl-3-(isothiocyanatomethyl)-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate (Step 1) tert-Butyl [6'-cyclopropyl-3-(hydroxymethyl)-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate. To a solution of the compound obtained in Reference Example 86 (800 mg) in ethanol (10 mL) was added sodium borohydride (161 mg) at 0°C, and the mixture was stirred at the same temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture, which was then extracted three times with dichloromethane. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (759 mg). (Step 2) tert-Butyl [3-(azidomethyl)-6'-cyclopropyl-4'-methoxy[2.3'-bipyridin]-4-yl]carbamate To a solution of the compound obtained in Step 1 above (390 mg) in tetrahydrofuran (6.0 mL), diphenylphosphoryl azide (455 μL) and 1,8-diazabicyclo[5.4.0]-7-undecene (315 μL) were added at room temperature, and the mixture was stirred at the same temperature for 15.5 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (276 mg). 1H-NMR (CDCl3) δ: 8.55 (1H, d, J = 5.5 Hz), 8.21 (1H, s), 8.12 (1H, d, J = 5.5 Hz), 7.43 (1H, br s), 6.78 (1H, s), 4.27 (1H, d, J = 14.7 Hz), 4.16 (1H, d, J = 14.1 Hz), 3.84 (3H, s), 2.13-2.01 (1H, m), 1.56 (9H, s), 1.18-0.99 (4H, m). (Step 3) tert-Butyl [6'-cyclopropyl-3-(isothiocyanatomethyl)-4'-methoxy[2,3'-bipyridin]-4-yl]carbamate To a solution of the compound obtained in Step 2 (236 mg) in tetrahydrofuran (3.0 mL) was added triphenylphosphine (161 mg) 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. To the resulting residue, acetonitrile (3.0 mL) and carbon disulfide (360 μL) were added 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 filtered off. The resulting solid was washed once with acetonitrile (3.0 mL) and dried under reduced pressure to give the title compound (200 mg). 1 H-NMR (CDCl3) δ: 8.58 (1H, d, J = 6.1 Hz), 8.26 (1H, s), 7.00 (1H, d, J = 6.1 Hz), 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).

[0195] Reference Example 106: Preparation of tert-butyl [3-(aminomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate (Steps 1 and 2) tert-butyl [3-(azidomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate The title compound was obtained by using the compound obtained in Reference Example 59 as a raw material and performing the same operations as in Steps 1 and 2 of Reference Example 105. 1 H-NMR (CDCl) δ: 8.54 (1H, d, J = 6.1 Hz), 8.17 (1H, d, J = 6.1 Hz), 7.53-7.46 (1H, m), 7.44-7.30 (4H, m), 4.29 (1H, d, J = 14.0 Hz), 4.17 (1H, d, J = 14.0 Hz), 1.57 (9H, s). (Step 3) tert-Butyl [3-(aminomethyl)-2-(2-chlorophenyl)pyridin-4-yl]carbamate To a solution of the compound obtained in Step 2 above (170 mg) in tetrahydrofuran (3.0 mL) / water (3.0 mL) was added triphenylphosphine (161 mg) at room temperature, and the mixture was stirred at the same temperature for 22 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (152 mg). 1 H-NMR (CDCl3) δ: 10.37 (1H, br s), 8.48 (1H, d, J = 6.1 Hz), 8.12 (1H, d, J = 6.1 Hz), 7.51-7.43 (1H, m), 7.40-7.31 (3H, m), 3.86 (1H, d, J = 13.4 Hz), 3.74 (1H, d, J = 13.4 Hz), 1.57 (9H, s).

[0196] Reference Example 107 Preparation of tert-butyl [3-(aminomethyl)-2-(2-methoxyphenyl)pyridin-4-yl]carbamate (Steps 1 to 3) tert-Butyl [3-(aminomethyl)-2-(2-methoxyphenyl)pyridin-4-yl]carbamate The title compound was obtained by using the compound obtained in Reference Example 60 as a raw material and performing operations similar to those in Steps 1 and 2 of Reference Example 105 and Step 3 of Reference Example 106. 1 H-NMR (CDCl3) δ: 8.48 (1H, d, J = 6.1 Hz), 8.06 (1H, d, J = 6.1 Hz), 7.43-7.36 (1H, m), 7.35-7.31 (1H, m), 7.08 (1H, t, J = 7.9 Hz), 6.98 (1H, d, J = 7.9 Hz), 3.86 (1H, d, J = 13.4 Hz), 3.78 (3H, s), 3.73 (1H, d, J = 13.4 Hz), 1.57 (9H, s).

[0197] Reference Example 108 Preparation of tert-butyl [1'-(cyclopropanecarbonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridin]-4-yl]carbamate (Step 1) 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine trifluoroacetate: 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) was added trifluoroacetic acid (2.50 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 azeotropically with toluene to give the crude title compound (1.04 g). (Step 2) Cyclopropyl[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridin-1(2H)-yl]methanone. To a solution of the compound obtained in Step 1 above (207 mg) in dichloromethane (2.0 mL) were added triethylamine (266 μL) and cyclopropanecarbonyl chloride (75.0 μL) 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). 1 H-NMR (CDCl3) 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). (Step 3) tert-Butyl [1'-(cyclopropanecarbonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridin]-4-yl]carbamate Using the compound obtained in Step 2 above as a starting material, the title compound was obtained by the same procedure as in Reference Example 70. 1H-NMR (CDCl3) 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), 3.96-3.76 (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).

[0198] Reference Example 109: Preparation of tert-butyl [1'-(cyclopropylsulfonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridin]-4-yl]carbamate (Steps 1 and 2) tert-butyl [1'-(cyclopropylsulfonyl)-3-formyl-1',2',5',6'-tetrahydro[2,3'-bipyridin]-4-yl]carbamate The title compound was obtained by using the compound obtained in Step 1 of Reference Example 108 and cyclopropanesulfonyl chloride as raw materials and performing the same operations as in Step 2 of Reference Example 108 and Reference Example 57. 1 H-NMR (CDCl3) δ: 10.84 (1H, br s), 10.12 (1H, s), 8.50 (1H, d, J = 5.9 Hz), 8.31 (1H, d, J = 5.9 Hz), 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).

[0199] Reference Example 110 Preparation of 4-amino-2-[1-(phenylsulfonyl)azepan-3-yl]pyridine-3-carbaldehyde (Step 1) tert-butyl 6-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)2,3,4,7-tetrahydro-1H-azepine-1-carboxylate [251 mg, containing the double bond positional isomer (tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate)] was used as a raw material and the same procedure as in Reference Example 57 was carried out to obtain the title compound and the double bond positional isomer (tert-butyl A mixture (242 mg) of 6-{4-[(tert-butoxycarbonyl)amino]-3-formylpyridin-2-yl}-2,3,4,5-tetrahydro-1H-azepine-1-carboxylate) was obtained. 1H-NMR (CDCl3) 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 = 5.9 Hz), 8.47 (0.4H, d, J = 5.9 Hz), 8.26 (0.6H, d, J = 5.9 Hz), 8.22 (0.4H, d, J = 5.9 Hz),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). (Step 2) 4-amino-2-(2,5,6,7-tetrahydro-1H-azepin-3-yl)pyridine-3-carbaldehyde hydrochloride A mixture of the compound obtained in Step 1 above (53 mg), ethyl acetate (1 mL) and 4 M hydrogen chloride in 1,4-dioxane (0.3 mL) was stirred at room temperature for 18.5 hours. The reaction mixture was concentrated under reduced pressure to give a mixture (41 mg) of the crude title compound and the double bond regioisomer (4-amino-2-(4,5,6,7-tetrahydro-1H-azepin-3-yl)pyridine-3-carbaldehyde hydrochloride). (Step 3) 4-Amino-2-[1-(benzenesulfonyl)-2,5,6,7-tetrahydro-1H-azepin-3-yl]pyridine-3-carbaldehyde. Using the compound obtained in Step 2 above and benzenesulfonyl chloride as raw materials, and carrying out the same procedure as in Step 2 of Reference Example 108, a mixture of the title compound and the double bond regioisomer (4-amino-2-[1-(benzenesulfonyl)-4,5,6,7-tetrahydro-1H-azepin-3-yl]pyridine-3-carbaldehyde) was obtained. 1H-NMR (CDCl3) δ: 10.04 (1H, s), 8.13 (1H, d, J = 5.9 Hz), 7.78 (2H, dd, J = 8.2, 1.2 Hz), 7.59-7.42 (3H, m), 6.42 (1H, d, J = 5.9 Hz), 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). (Step 4) 4-Amino-2-[1-(phenylsulfonyl)azepan-3-yl]pyridine-3-carbaldehyde The compound (30) obtained in Step 3 above was obtained. A mixture of 10% palladium-carbon (30 mg), 10% palladium-carbon (30 mg), and ethyl acetate (2 mL) was stirred under a hydrogen atmosphere at room temperature for 2.5 hours. Insoluble matter was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the crude title compound (25 mg).

[0200] Reference Example 111 Preparation of tert-butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate (Step 1) 1-(4-bromo-3-methylphenyl)-N-methylmethanamine. A solution of 1-bromo-4-(chloromethyl)-2-methylbenzene (1.00 g) in N,N-dimethylformamide (20 mL) was added to a 2 M solution of methylamine in tetrahydrofuran (6.80 mL) at 0°C, and the mixture was stirred at room temperature for 4.5 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the title compound (1.00 g). 1H-NMR (CDCl) δ: 7.47 (1H, d, J = 7.9 Hz), 7.20 (1H, d, J = 1.8 Hz), 6.99 (1H, dd, J = 7.9, 1.8 Hz), 3.67 (2H, s), 2.39 (3H, s). (Step 2) tert-Butyl (4-bromo-3-methylbenzyl)methylcarbamate. To a solution of the compound obtained in Step 1 above (1.00 g) 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.00 g). 1 H-NMR (CDCl3) δ: 7.49 (1H, d, J = 7.9 Hz), 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). (Step 3) tert-Butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate The compound obtained in Step 2 above (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 g), methyl tert-butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate (1.0 ... methyl tert-butyl methyl[3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]carbamate (1.00 g), potassium acetate (0.95 g), [1,1'-bis(diphenylphosphino)ferrocene]dichloropallad A mixture of 1,4-dioxane (20 mL) and 1,4-dioxane (20 mL) was stirred at 90°C for 10 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and insoluble matter was removed by filtration through Celite. The filtrate was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (1.00 g). 1H-NMR (CDCl3) δ: 7.72 (1H, d, J = 7.9 Hz), 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).

[0201] Reference Example 112 Preparation of tert-butyl [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate (Step 1) tert-Butyl (3-bromo-2-methylphenoxy)acetate. 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, followed by stirring at 90°C for 7.5 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to give the title compound (0.80 g). 1 H-NMR (CDCl3) δ: 7.19 (1H, d, J = 7.9 Hz), 6.98 (1H, t, J = 7.9 Hz), 6.64 (1H, d, J = 7.9 Hz), 4.52 (2H, s), 2.38 (3H, s), 1.48 (9H, s). (Step 2) tert-Butyl [2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetate Using the compound obtained in Step 1 above as the starting material, the title compound was obtained by the same procedure as in Step 3 of Reference Example 111. 1H-NMR (CDCl3) δ: 7.37 (1H, d, J = 8.0 Hz), 7.11 (1H, t, J = 8.0 Hz), 6.79 (1H, d, J = 8.0 Hz), 4.51 (2H, s), 2.49 (3H, s), 1.48 (9H, s), 1.34 (12H, s).

[0202] Reference Example 113 Preparation of tert-butyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}acetate (Step 1) tert-Butyl [(3-bromophenyl)sulfanyl]acetate. To a solution of 3-bromobenzenethiol (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, followed by stirring at the same temperature for 8 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (1.60 g). 1 H-NMR (CDCl3) δ: 7.53 (1H, t, J = 1.8 Hz), 7.35-7.29 (2H, m), 7.15 (1H, t, J = 7.9 Hz), 3.56 (2H, s), 1.42 (9H, s). (Step 2) tert-Butyl [(3-bromophenyl)sulfonyl]acetate. To a solution of the compound obtained in Step 1 (1.60 g) in 1,4-dioxane (20 mL) was added water (20 mL) and potassium peroxymonosulfate (9.70 g) at 0 °C, and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting 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 (1.10 g). 1H-NMR (CDCl) δ: 8.09 (1H, t, J = 1.8 Hz), 7.89 (1H, dt, J = 7.9, 1.8 Hz), 7.82 (1H, dt, J = 7.9, 1.8 Hz), 7.47 (1H, t, J = 7.9 Hz), 4.05 (2H, s), 1.39 (9H, s). (Step 3) tert-Butyl {[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]sulfonyl}acetate Using the compound obtained in Step 2 above as the starting material, the title compound was obtained by the same procedure as in Step 3 of Reference Example 111. 1 H-NMR (CDCl3) δ: 8.37 (1H, br s), 8.08 (1H, t, J = 7.7 Hz), 8.02 (1H, t, J = 7.7 Hz), 7.58 (1H, t, J = 7.7 Hz), 4.05 (2H, s), 1.36 (9H, s), 1.35 (12H, s).

[0203] Reference Example 114 Preparation of tert-butyl [3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate tert-Butyl [3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]acetate. 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, followed by stirring at the same temperature for 8 hours. Water was added to the reaction mixture, which was then extracted three times with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (0.76 g). 1H-NMR (CDCl3) δ: 4.67 (2H, s), 2.35 (3H, s), 2.34 (3H, s), 1.57 (9H, s), 1.28 (12H, s).

[0204] Reference Example 115 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 tert-Butyl 2-[3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate. 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 in oil (91 mg) at room temperature and stirred at the same temperature for 1 hour. Saturated aqueous ammonium chloride was added to the reaction mixture, which was then extracted with ethyl acetate. The resulting organic layer was washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to yield the title compound (596 mg). 1 H-NMR (CDCl3) 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 = 7.4 Hz), 1.75 (0.9H, d, J = 7.4 Hz), 1.42 (9H, s), 1.31-1.24 (12H, m).

[0205] Reference Example 116 Preparation of tert-butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate tert-Butyl 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propanoate. 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) was 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 resulting residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (1.40 g). 1 H-NMR (CDCl3) δ: 7.78 (1H, s), 7.72 (1H, s), 4.38 (2H, t, J = 6.7 Hz), 2.81 (2H, t, J = 6.7 Hz), 1.41 (9H, s), 1.31 (12H, s).

[0206] The following compounds were synthesized by the same procedure as in Reference Example 70 (Table 9-1).

[0207]

[0208] Example 1 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 3-{6-chloro-4-[(3R)-3-methylmorpholin-4-yl]-1H-imidazo[4,5-c]pyridin-2-yl}-1,6-naphthyridin-2(1H)-one. A mixture of the compound obtained in Step 3 of Reference Example 1 (3.60 g), 4-aminopyridine-3-carbaldehyde (1.30 g), piperidine (2.94 mL), and ethanol (55 mL) was stirred under reflux for 9 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered off. The resulting solid was washed twice with ethanol and dried under reduced pressure to give the title compound (3.76 g). 1H-NMR (DMSO-D6) δ: 12.84 (1H, br s), 12.73 (1H, br s), 9.13 (1H, s), 9.02 (1H, s), 8.55 (1H, d, J = 5.5 Hz), 7.31 (1H, d, J = 5.5 Hz), 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 = 6.7 Hz)., MS (m / z): 397 (M+H) + .

[0209] The following compounds were synthesized by the same procedure as in Example 1 (Tables 10-1 and 10-2).

[0210]

[0211] Example 9 Preparation 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 (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 The title compound was obtained by the same procedure as in Step 1 of Example 1 using the compound obtained in Step 3 of Reference Example 9 and 4-aminopyridine-3-carbaldehyde as starting materials. 1H-NMR (DMSO-D6) δ: 9.03 (1H, s), 9.00 (1H, s), 8.54 (1H, d, J = 6.1 Hz), 7.33 (1H, d, J = 6.1 Hz), 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). (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 salt. Trifluoroacetic acid (650 μL) was added to the compound obtained in Step 1 (33.8 mg) at room temperature, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then excess trifluoroacetic acid was removed by azeotropy with toluene. Ethyl acetate was added to the residue to solidify it. The solid was filtered off, washed with hexane, and dried under reduced pressure to give the title compound (31.5 mg). 1 H-NMR (DMSO-D6) δ: 13.02-12.87 (2H, m), 9.21 (1H, s), 9.10 (1H, s), 8.61 (1H, d, J = 5.5 Hz), 8.33-8.16 (3H, br s), 7.40 (1H, d, J = MS (m / z): 432 (M+H) + .

[0212] Example 10 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 A mixture of the compound obtained in Reference Example 19 (60 mg), 4-aminopyridine-3-carbaldehyde (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 evaporated under reduced pressure, and a mixture of n-hexane / ethyl acetate was added to the residue, followed by filtration to obtain the title compound (48 mg). 1 H-NMR (DMSO-D6) δ: 12.80 (2H, br s), 9.12 (1H, s), 9.03 (1H, s), 8.54 (1H, d, J = 6.1 Hz), 7.31 (1H, d, J = 6.1 Hz), 6.92 (1H, s), 5.45 (1H, br d, J = 54.3 Hz), 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 = 6.1 Hz).

[0213] The following compounds were synthesized by the same procedure as in Example 10 (Tables 11-1 and 11-2).

[0214]

[0215]

[0216] Example 17 Preparation 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 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. A mixture of the compound obtained in Step 3 of Reference Example 23 (2.00 g), the compound obtained in Reference Example 46 (1.46 g), piperidine (1.70 mL), and ethanol (35 mL) was stirred under reflux for 4.5 hours. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered off. The obtained solid was washed twice with ethanol and then dried under reduced pressure to give the title compound (2.27 g). 1 H-NMR (DMSO-D6) δ: 13.03 (1H, br s), 12.78 (1H, br s), 9.14 (1H, s), 8.43 (1H, d, J = 6.1 Hz), 7.54 (1H, s), 7.21 (1H, d, J = 6.1 Hz), 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) + .

[0217] The following compounds were synthesized by the same procedure as in Example 17 (Tables 12-1 and 12-2).

[0218]

[0219]

[0220] Example 24 Preparation of 3-[4-(3-aminophenyl)-6-chloro-1H-imidazo[4,5-c]pyridin-2-yl]-1H-1,6-naphthyridin-2-one trifluoroacetate (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 Using the compound obtained in Step 3 of Reference Example 25 as a starting material, the title compound was obtained by performing the same operations as in Step 2 of Example 1 and Example 9. 1H-NMR (DMSO-D6) 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 = 5.9 Hz), 8.51-8.41 (1H, m), 7.70 (1H, s), 7.56 (1H, t, J = 7.8 Hz), 7.49 (1H, d, J = 5.9 Hz), 7.22 (1H, dd, J = 7.8, 1.2 Hz)., MS (m / z): 389 (M+H) + .

[0221] Example 25 Preparation of 3-[6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one 3-[6-chloro-4-(2-fluorophenyl)-1H-imidazo[4,5-c]pyridin-2-yl]-1,6-naphthyridin-2(1H)-one The title compound was obtained by using the compound obtained in Step 3 of Reference Example 26 as a manufacturing raw material and performing the same operation as in Example 1. 1 H-NMR (DMSO-D6) δ: 13.16 (1H, s), 12.79 (1H, s), 9.15 (1H, s), 9.08 (1H, s), 8.54 (1H, d, J = 6.1 Hz), 7.79 (1H, td, J = 7.3, 1.8 Hz), 7.73 (1H, s), 7.60-7.56 (1H, m), 7.41-7.36 (2H, m), 7.30 (1H, d, J = 6.1 Hz)., MS (m / z): 392 (M+H) + .

[0222] Example 26 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2 H3) Preparation of methyloxy]phenyl}-1,6-naphthyridin-2(1H)-one 3-(6-chloro-4-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-{2-[( 2A 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. 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 (48 mg). 1 H-NMR (DMSO-D6) δ: 12.97 (1H, s), 12.87 (1H, s), 8.68 (1H, s), 8.64 (1H, d, J = 5.5 Hz), 7.64-7.56 (1H, m), 7.49 (1H, s), 7.46-7.40 (1H, m), 7.36 (1H, d, J = 5.5 Hz), 7.31 (1H, d, J = 7.9 Hz), 7.22-7.15 (1H, m), 2.63 (3H, s)., MS (m / z): 421 (M+H) + .

[0223] The following compounds were synthesized by the same procedure as in Example 26 (Tables 13-1 and 13-2).

[0224]

[0225]

[0226] Example 56 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 (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 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 at 90° C. for 12 hours. After the reaction mixture was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (n-hexane / ethyl acetate) to obtain the crude title compound (64.1 mg). (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. To a mixture of the compound obtained in Step 1 above (64.1 mg) and 4 M hydrogen chloride in 1,4-dioxane (2.0 mL), ethanol (0.50 mL) was added at 80°C and the mixture was stirred at the same temperature for 8 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. Ethanol (3.0 mL) was added to the resulting residue and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with ethanol, and then dried under reduced pressure to give the title compound (43.2 mg). 1 H-NMR (DMSO-D6) δ: 13.37 (1H, br s), 12.87 (1H, s), 8.71 (1H, d, J = 5.9 Hz), 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) + .

[0227] Example 57 Preparation 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 (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 The compound obtained in Step 3 of Reference Example 30 and the compound obtained in Reference Example 80 were used as starting materials to obtain the crude title compound by the same procedure as in Example 26. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridin-2-yl)-5-(2-fluoro-6-hydroxyphenyl)-1,6-naphthyridin-2(1H)-one To a suspension of the compound obtained in Step 1 above (124 mg) in 1,4-dioxane (2.0 mL) was added 6 M 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, and 1M aqueous sodium hydroxide solution (1.2 mL) was added. The precipitated solid was filtered off, washed with water, and then dried under reduced pressure to obtain the title compound (105 mg). 1 H-NMR (DMSO-D6) δ: 13.00 (1H, br s), 12.93 (1H, br s), 10.27 (1H, s), 8.66 (1H, d, J = 6.1 Hz), 8.62 (1H, s), 7.50 (1H, s), 7.44 (1H, MS (m / z): 436 (M+H) + .

[0228] Example 58 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 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 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). 1 H-NMR (DMSO-D6) 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 = 5.9 Hz), 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 = 7.4 Hz), 2.32-2.20 (1H, m), 1.31 (3H, t, J = 7.4 Hz), 1.10-0.99 (4H, m)., MS (m / z): 473 (M+H) + .

[0229] The following compounds were synthesized by the same procedure as in Example 58 (Tables 14-1 and 14-2).

[0230]

[0231]

[0232] Example 80 Preparation 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 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 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. 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 (40.0 mg). 1 H-NMR (DMSO-D6) δ: 13.00 (1H, s), 12.98 (1H, s), 8.71 (1H, s), 8.71 (1H, d, J = 6.1 Hz), 8.59 (1H, s), 7.89 (1H, s), 7.50 (1H, s), 7.45 (1H, d, J = 6.1 Hz), 3.98 (3H, s), 3.04 (2H, q, J = 7.3 Hz), 1.29 (3H, t, J = 7.3 Hz)., MS (m / z): 501 (M+H) + .

[0233] Example 81 Preparation 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 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 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. 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 (43.8 mg). 1 H-NMR (DMSO-D6) δ: 12.96 (1H, s), 12.91 (1H, s), 8.64 (1H, d, J = 5.5 Hz), 8.61 (1H, s), 8.22 (1H, s), 7.84 (1H, t, J = 72.6 Hz), 7.48 (1H, s), 7.38 (1H, d, J = 5.5 Hz), 7.08 (1H, s), 3.85 (3H, s), 3.04 (2H, q, J = 7.5 Hz), 1.28 (3H, t, J = 7.5 Hz)., MS (m / z): 499 (M+H) + .

[0234] Example 82 Preparation 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 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 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. The reaction mixture was cooled to room temperature, and the precipitated solid was filtered off. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (64.6 mg).1 H-NMR (DMSO-D6) δ: 12.99 (1H, s), 12.96 (1H, s), 8.69 (1H, d, J = 5.5 Hz), 8.61 (2H, s), 8.60 (2H, s), 7.62 (1H, s), 7.50 (1H, s), 7.43 (1H, d, J = 5.5 Hz), 3.93 (3H, s), 3.04 (2H, q, J = 7.3 Hz), 2.11 (3H, t, J = 7.3 Hz)., MS (m / z): 497 (M+H) + .

[0235] Example 83 Preparation 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 (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. 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 mixture of n-hexane and ethyl acetate was added to the resulting residue. The precipitated solid was filtered off and dried under reduced pressure to give the title compound (64 mg). 1 H-NMR (DMSO-D6) δ: 12.98 (1H, br s), 12.91 (1H, br s), 8.74 (1H, s), 8.67 (1H, d, J = 5.5 Hz), 7.93 (1H, t, J = 57.7 Hz), 7.51 (1H, s), 7.36 (1H, d, J = 5.5 Hz), 3.07 (2H, q, J = 7.5 Hz), 2.35 (3H, s), 2.18 (3H, s), 1.32 (3H, t, J = 7.5 Hz)., MS (m / z): 470 (M+H) +.

[0236] The following compounds were synthesized by the same procedure as in Example 83 (Tables 15-1 and 15-2).

[0237]

[0238]

[0239] Example 101 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 (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'-bipyridin]-4-yl)carbamate 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 the mixture was stirred at the same temperature for an additional 7 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / methanol) to obtain the title compound (68.1 mg). 1H-NMR (DMSO-D6) δ: 12.54 (1H, s), 10.79 (1H, s), 8.42 (1H, d, J = 4.9 Hz), 8.17 (1H, s), 7.30 (1H, s), 7.22 (1H, s), 6.95 (1H, d, J = 4.9 Hz), 5.22-4.83 (2H, m), 3.81 (3H, s), 2.93 (2H, q, J = 7.4 Hz), 2.24-2.16 (1H, m), 1.26 (3H, t, J = 7.4 Hz), 1.04-0.97 (4H, m). (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. To a solution of the compound obtained in Step 1 (68.1 mg) in dichloromethane (1.0 mL) was added 4.0 M 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 to the resulting residue were added N,N-dimethylformamide (1.0 mL), triethylamine (51.5 μL), and 1,1'-carbonyldiimidazole (40.0 mg) at room temperature. The mixture was stirred at the same temperature for 30 minutes, followed by stirring at 70°C for an additional 4 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The organic layer was filtered, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to give the title compound (34.4 mg). 1H-NMR (DMSO-D6) δ: 12.51 (1H, br s), 10.76 (1H, br s), 8.39 (1H, d, J = 4.9 Hz), 8.14 (1H, s), 7.27 (1H, s), 7.19 (1H, s), 6.92 (1H, d, J = 4.9 Hz), 5.00 (2H, br s), 3.78 (3H, s), 2.90 (2H, q, J = 7.6 Hz), 2.21-2.13 (1H, m), 1.22 (3H, t, J = 7.6 Hz), 1.01-0.95 (4H, m)., MS (m / z): 476 (M+H) + .

[0240] Example 102 Preparation 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 (Step 1) tert-Butyl [3-{[(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)amino]methyl}-2-(2-chlorophenyl)pyridin-4-yl]carbamate To a solution of the compound obtained in Step 3 of Reference Example 106 (150 mg) in acetonitrile (4 mL) was added 1,1'-thiocarbonyldiimidazole (96 mg) at room temperature and stirred at the same temperature for 1 hour. After stirring at the same temperature, N,N-dimethylformamide (1.5 mL) and 6-chloropyridine-3,4-diamine (77.4 mg) were added and the mixture was stirred at 80°C for an additional 2 hours. Subsequently, N,N'-diisopropylcarbodiimide (84 μL) was added to the reaction mixture at 80°C and the mixture was stirred at the same temperature for 7 hours. After cooling the reaction mixture to room temperature, water was added, and the mixture was extracted three times with ethyl acetate. The resulting 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 residue was purified by silica gel column chromatography (n-hexane / ethyl acetate) to obtain the title compound (128 mg). 1H-NMR (CDCl3) 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 = 6.1 Hz), 8.15 (0.65H, d, J = 6.1 Hz), 7.96 (0.65H, s), 7.42-6.90 (5H, m), 5.14 (0.65H, t, J = 6.7 Hz), 4.89 (0.35H, t, J = 6.7 Hz), 4.44 (1.30H, d, J = 6.7 Hz), 4.41 (0.70H, d, J = 6.7 Hz), 1.63 (5.85H, s), 1.59 (3.15H, s). (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. To a solution of the compound obtained in Step 1 (125 mg) in N,N-dimethylformamide (3 mL) was added 55% sodium hydride in 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, saturated aqueous ammonium chloride solution was added, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol) to obtain the title compound (40.5 mg). 1 H-NMR (DMSO-D6) δ: 12.63 (1H, br s), 10.90 (1H, br s), 8.50 (1H, s), 8.43 (1H, d, J = 5.5 Hz), 7.67 (1H, dd, J = 7.9, 1.2 Hz), 7.62-7.41 (4H, m), 6.98 (1H, d, J = 5.5 Hz), 4.98 (2H, s), 3.33 (3H, s)., MS (m / z): 411 (M+H) + .

[0241] Example 103 Preparation 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 (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 The title compound was obtained by using the compound obtained in Step 3 of Reference Example 107 as a manufacturing raw material and performing the same operations as in Steps 1 and 2 of Example 102. 1 H-NMR (DMSO-D6) δ: 12.59 (1H, br s), 10.81 (1H, br s), 8.48 (1H, s), 8.39 (1H, d, J = 5.5 Hz), 7.57-7.40 (2H, m), 7.27 (1H, dd, J = 7.4, MS (m / z): 407 (M+H) + .

[0242] Example 104 Preparation 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 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 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 collected by filtration. The obtained solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (58.8 mg). 1H-NMR (DMSO-D6) δ: 13.20-12.77 (2H, m), 9.27 (1H, s), 8.80 (1H, s), 8.57 (1H, d, J = 5.9 Hz), 7.70 (1H, br s), 7.29 (1H, d, J = 5.9 MS (m / z): 483 (M+H) + .

[0243] Example 105 Preparation 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 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 The title compound was obtained by using the compound obtained in Reference Example 28 and the compound obtained in Step 3 of Reference Example 108 as raw materials and performing the same operation as in Example 104. 1 H-NMR (DMSO-D6) δ: 9.24 (1H, s), 8.78 (1H, s), 8.54 (1H, d, J = 5.5 Hz), 7.69 (1H, s), 7.25 (1H, d, J = 5.5 Hz), 6.30-6.15 (1H, m), 4.72 (1H, s), 4.48 (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) + .

[0244] Example 106 Preparation of 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one 3-(6-chloro-1H-imidazo[4,5-c]pyridin-2-yl)-5-[1-(phenylsulfonyl)azepan-3-yl]-1,6-naphthyridin-2(1H)-one The title compound was obtained by using the compound obtained in Reference Example 28 and the compound obtained in Step 4 of Reference Example 110 as starting materials and performing the same operation as in Example 104. 1 H-NMR (DMSO-D6) 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 = 0.8 Hz), 8.51 (0.35H, d, J = 5.5 Hz), 8.50 (0.65H, d, J = 5.5 Hz), 7.87 (0.35H, s), 7.82 (2H, d, J = 7.0 Hz), 7.71 (0.65H, d, J = 1.2 Hz), 7.66-7.59 (3H, m), 7.24 (1H, d, J = 5.5 Hz), 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) + .

[0245] Example 107 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 Hentriaconta-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione (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 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 evaporated under reduced pressure, and a mixture of n-hexane / ethyl acetate was added to the residue. The precipitated solid was filtered off to give the crude title compound (118 mg). (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. To a solution of the compound obtained in Step 1 above (118 mg) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide solution (2 mL) at room temperature, and the mixture was stirred at the same temperature for 24 hours. 1M hydrochloric acid (2.3 mL) and water were added to the reaction mixture, and the mixture was extracted three times with ethyl acetate. The resulting organic layer was washed with water and saturated brine and then dried over anhydrous sodium sulfate. The resulting organic layer was filtered, and the solvent was evaporated under reduced pressure to give the crude title compound (110 mg). (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 To a suspension of the compound obtained in Step 2 above (110 mg) in dichloromethane (5 mL) was added trifluoroacetic acid (1 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 give the crude title compound (100 mg).(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 ]Hentriaconta-1(27),2,4,6,8,16,18,20(28),21,23,29-undecene-15,26-dione To a solution of the compound obtained in Step 3 (100 mg) in N,N-dimethylformamide (18 mL) at room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.14 g) and N,N-diisopropylethylamine (0.16 mL) were added and stirred at the same temperature for 13.5 hours. The reaction mixture was diluted with ethyl acetate, and water and saturated aqueous ammonium chloride were added and stirred. The organic and aqueous layers were separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed three times with water and once with saturated brine and then dried over anhydrous sodium sulfate. The obtained organic layer was filtered, and then the solvent was evaporated under reduced pressure. The residue was suspended in a mixed solution of n-hexane / ethyl acetate, and the precipitated solid was filtered off to obtain the title compound (73 mg). 1 H-NMR (DMSO-D6) δ: 12.85 (1H, s), 12.69 (1H, s), 8.68 (1H, d, J = 5.5 Hz), 8.30 (1H, d, J = 1.8 Hz), 7.63 (1H, t, J = 7.3 Hz), 7.57 (1H, dd. (3H, s), 2.06-1.87 (2H, m)., MS (m / z): 518 (M+H) + .

[0246] The following compounds were synthesized by performing the same procedures as in steps 1 to 4 of Example 107 (Tables 15-3 and 15-4).

[0247]

[0248]

[0249] Example 117 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 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 To a suspension of the compound obtained in Example 1 (3.76 g) in ethanol (53 mL), p-toluenesulfonic acid monohydrate (1.80 g) was added 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 collected by filtration. The resulting solid was washed with ethanol and then dried under reduced pressure to obtain the title compound (5.01 g). 1 H-NMR (DMSO-D6) 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 = 7.9 Hz), 7.11 (2H, d, J = 7.9 Hz), 6.99 (1H, s), 5.51-5.37 (1H, m), 4.91-4.76 (1H, m), 4.04-3.94 (1H, m), 3.82-3.72 (2H, m), 3.64-3.54 (1H, m), 3.42-3.32 (1H, m), 2.29 (3H, s), 1.28 (3H, d, J = 6.7 Hz)., MS (m / z): 397 (M+H) + .

[0250] Example 118 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 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 To a suspension of the compound obtained in Example 10 (48 mg) in ethanol (2.0 mL), methanesulfonic acid (8.2 μL) was added 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 collected by filtration and dried under reduced pressure to obtain the title compound (56 mg). 1 H-NMR (DMSO-D6) δ: 13.34 (1H, s), 12.83 (1H, s), 9.45 (1H, s), 9.14 (1H, s), 8.69 (1H, d, J = 6.1 Hz), 7.60 (1H, d, J = 6.1 Hz), 6.91 (1H, s), 5.45 (1H, d, J = 53.7 Hz), 4.86-4.57 (2H, m), 4.04 (1H, dd, J = 36.6, 12.8 Hz), 2.31 (3H, s), 2.32-2.27 (1H, m), 2.09-1.93 (1H, m), 1.36 (3H, d, J = 6.1 Hz)., MS (m / z): 399 (M+H) + .

[0251] The following compounds were synthesized by the same procedure as in Example 118 (Table 16).

[0252]

[0253] Example 125 Preparation 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 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 To a suspension of the compound obtained in Example 17 (273 mg) in ethanol (7.0 mL), methanesulfonic acid (67.0 μL) was added 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). 1 H-NMR (DMSO-D6) δ: 13.47 (1H, s), 9.13 (1H, s), 8.60 (1H, d, J = 6.7 Hz), 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 (m / z): 396 (M+H) + .

[0254] The following compounds were synthesized by the same procedure as in Example 125 (Table 17).

[0255]

[0256] Example 138 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 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 To the compound obtained in Example 58 (30.32 mg) were added 1.002 mol / L aqueous methanesulfonic acid 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 filtered off and dried at room temperature for 17 hours to obtain the title compound (35.13 mg) as crystals (actual elemental analysis values: C: 48.34%, H: 5.18%, N: 12.95%, Cl: 5.50%, S: 4.97%). 1 H-NMR (DMSO-D6) δ: 13.05 (1H, br s), 8.70 (1H, d, J = 5.9 Hz), 8.67 (1H, br s), 8.60 (1H, s), 7.52 (1H, s), 7.48 (1H, d, J = 5.9 Hz), 7.42 (1H, s), 4.00 (3H, s), 3.08 (2H, q, J = 7.4 Hz), 2.46-2.36 (1H, m), 2.32 (3H, s), 1.43-1.24 (7H, m)., MS (m / z): 473 (M+H) + The resulting solid was analyzed using a powder X-ray diffractometer (SmartLab, manufactured by Rigaku Corporation), and the results are shown in Figure 1. In Figure 1, which shows the diffraction pattern of powder X-ray diffraction (CuKα, λ = 1.54 Å, scan rate = 20° / min), characteristic peaks of this crystal are shown in Table 18, and all peaks are shown in Table 19. In Table 19, peak numbers marked with an asterisk indicate the top 10 peaks with the highest relative intensity.

[0257]

[0258]

[0259] The following compounds were synthesized by the same procedure as in Example 138 (Table 20).

[0260]

[0261] Example 145 Preparation 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 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 To a suspension of the compound obtained in Example 80 (40.0 mg) in acetonitrile (2.6 mL), methanesulfonic acid (5.1 μL) was added at room temperature, and the mixture was stirred at the same temperature for 2.5 hours. The precipitated solid was collected by filtration, washed with acetonitrile, and then dried under reduced pressure to obtain the title compound (46.3 mg). 1 H-NMR (DMSO-D6) δ: 13.01 (1H, s), 8.72 (1H, s), 8.71 (1H, d, J = 6.1 Hz), 8.58 (1H, s), 7.89 (1H, s), 7.51 (1H, s), 7.46 (1H, d, J = MS (m / z): 501 (M+H) + .

[0262] Example 146 Preparation 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 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 Using the compound obtained in Example 81 as the starting material, the title compound was obtained by performing the same operation as in Example 145. 1 H-NMR (DMSO-D6) δ: 13.01 (1H, s), 8.72 (1H, s), 8.71 (1H, d, J = 6.1 Hz), 8.58 (1H, s), 7.89 (1H, s), 7.51 (1H, s), 7.46 (1H, d, J = MS (m / z): 499 (M+H) + .

[0263] Example 147 Preparation 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 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 Using the compound obtained in Example 82 as the starting material, the title compound was obtained by performing the same operation as in Example 145. 1H-NMR (DMSO-D6) δ: 13.04 (1H, s), 8.71 (1H, d, J = 5.5 Hz), 8.63 (1H, s), 8.59 (1H, s), 7.63 (1H, s), 7.51 (1H, s), 7.47 (1H, d, J = MS (m / z): 497 (M+H) + .

[0264] Example 148 Preparation 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 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 To a suspension of the compound obtained in Example 83 (35 mg) in ethanol (2 mL), methanesulfonic acid (5.0 μL) was added 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 collected by filtration and dried under reduced pressure to obtain the title compound (32 mg). 1 H-NMR (DMSO-D6) δ: 13.13 (1H, s), 8.69-8.72 (2H, m), 7.95 (1H, t, J = 57.7 Hz), 7.52 (1H, s), 7.46 (1H, d, J = 6.1 Hz), 2.38 (3H, s), 2.31 (3H, s), 2.19 (3H, s)., MS (m / z): 470 (M+H) + .

[0265] The following compounds were synthesized by the same procedure as in Example 148 (Table 21).

[0266]

[0267] Example 154 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 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 To a suspension of the compound obtained in Example 101 (23.5 mg) in ethanol (3.0 mL), a 10% methanesulfonic acid, ethanol solution (47.6 μL) was added at room temperature, and the mixture was stirred at the same temperature for 6 hours. The precipitated solid was collected by filtration, washed with ethanol, and then dried under reduced pressure to obtain the title compound (14.2 mg). 1 H-NMR (DMSO-D6) δ: 12.58 (1H, br s), 11.13 (1H, br s), 8.51 (1H, d, J = 5.9 Hz), 8.39 (1H, s), 7.38-7.35 (2H, m), 7.09 (1H, d, J = 5.9 MS (m / z): 476 (M+H) + .

[0268] Example 155 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 1,2-ethanedisulfonate 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 To the compound obtained in Example 58 (30.30 mg) were added a 1.000 mol / L aqueous 1,2-ethanedisulfonic acid solution (33 μL) and water (267 μL) at room temperature, followed by stirring at 40° C. for 24 hours. The precipitated solid was filtered off and dried at room temperature for 17 hours to obtain the title compound (29.91 mg) as crystals (actual elemental analysis values: C: 51.53%, H: 4.80%, N: 13.79%, Cl: 5.84%, S: 5.26%). 1 H-NMR (DMSO-D6) δ: 13.05 (1H, br s), 8.70 (1H, d, J = 5.9 Hz), 8.66 (1H, br s), 8.60 (1H, s), 7.51 (1H, s), 7.48 (1H, d, J = 5.9 Hz), 7.42 (1H, s), 4.00 (3H, s), 3.08 (2H, q, J = 7.4 Hz), 2.65-2.60 (2H, m), 2.44-2.35 (1H, m), 1.40-1.25 (7H, m)., MS (m / z): 473 (M+H) + The resulting solid was analyzed using a powder X-ray diffractometer (SmartLab, manufactured by Rigaku Corporation), and the results are shown in Figure 2. In Figure 2, which shows the diffraction pattern of powder X-ray diffraction (CuKα, λ = 1.54 Å, scan rate = 20° / min), characteristic peaks of this crystal are shown in Table 22, and all peaks are shown in Table 23. In Table 23, peak numbers marked with an asterisk indicate the top 10 peaks with the highest relative intensity.

[0269]

[0270]

[0271] Example 156 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 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 To the compound obtained in Example 58 (30.82 mg) were added 1.000 mol / L aqueous benzenesulfonic acid solution (67 μL) and water (233 μL) at room temperature, followed by stirring at 40° C. for 24 hours. The precipitated solid was filtered off and dried at room temperature for 17 hours to obtain the title compound (35.92 mg) as crystals (actual elemental analysis values: C: 55.17%, H: 4.75%, N: 12.24%, Cl: 5.24%, S: 4.77%). 1 H-NMR (DMSO-D6) δ: 13.05 (1H, br s), 8.70 (1H, d, J = 5.9 Hz), 8.67 (1H, br s), 8.60 (1H, s), 7.61-7.57 (2H, m), 7.52 (1H, s), 7.48 (1H, d, J = 5.9 Hz), 7.42 (1H, s), 7.35-7.27 (3H, m), 4.00 (3H, s), 3.08 (2H, q, J = 7.4 Hz), 2.45-2.37 (1H, m), 1.45-1.26 (7H, m)., MS (m / z): 473 (M+H) + The resulting solid was analyzed using a powder X-ray diffractometer (SmartLab, manufactured by Rigaku Corporation), and the results are shown in Figure 3. In Figure 3, which shows the diffraction pattern of powder X-ray diffraction (CuKα, λ = 1.54 Å, scan rate = 20° / min), characteristic peaks of this crystal are shown in Table 24, and all peaks are shown in Table 25. In Table 25, peak numbers marked with an asterisk indicate the top 10 peaks with the highest relative intensity.

[0272]

[0273]

[0274] Example 157 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 adipate 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 adipate To the compound obtained in Example 58 (29.52 mg) were added 1.000 mol / L aqueous benzenesulfonic acid solution (67 μL) and water (233 μL) at room temperature, followed by stirring at 40° C. for 24 hours. The precipitated solid was collected by filtration and dried at room temperature for 17 hours to obtain the title compound (29.96 mg) as crystals (actual elemental analysis: 60.89%, H: 4.91%, N: 14.98%, Cl: 6.39%, S: 0.00%). 1 H-NMR (DMSO-D6) δ: 12.97 (1H, s), 12.86 (0.6H, br s), 12.04 (0.4H, br s), 8.67-8.60 (2H, m), 8.32 (1H, s), 7.50 (1H, s), 7.37 (1H, d, J = 5.9 Hz), 7.33 (1H, s), 4.84 (3H, s), 3.06 (2H, q, J = 7.4 Hz), 2.31-2.15 (3H, m), 1.54-1.45 (2H, m), 1.31 (3H, t, J = 7.4 Hz), 1.10-0.98 (4H, m)., MS (m / z): 473 (M+H) +The resulting solid was analyzed using a powder X-ray diffractometer (SmartLab, manufactured by Rigaku Corporation), and the results are shown in Figure 4. In Figure 4, which shows the diffraction pattern of powder X-ray diffraction (CuKα, λ = 1.54 Å, scan rate = 20° / min), characteristic peaks of this crystal are shown in Table 26, and all peaks are shown in Table 27. In Table 27, peak numbers marked with an asterisk indicate the top 10 peaks with the highest relative intensity.

[0275]

[0276]

[0277] (Test Examples) The pharmacological activities of the compounds of the present invention were confirmed by the following tests.

[0278] Test Example 1: Measurement of SMG1 kinase activity The reaction was carried out using a 384-well plate with ADP-Glo ​​Kinase Assay (Promega, catalog number V9102) in assay buffer (100 mM HEPES (pH 7.5), 50 mM NaCl, 10 mM MnCl, 0.01% BSA, 0.1% Tween 20, 5 mM TCEP). The test substance (DMSO solution; final DMSO concentration: 1%) and purified human SMG1 enzyme (Genes Dev. 2011 Jan 15; 25(2): 153-164, prepared by Daiichi Sankyo RD Novare Co., Ltd., final concentration: 5 nM) were incubated at room temperature for 15 minutes, followed by the addition of the substrate Upf1 peptide (Biotin-(PEG8) QIDVALSQDSTYQG, prepared by Eurofins genomics, final concentration: 8 μg / mL) and ATP (Promega; 4 μM) for 60 minutes at room temperature (for details of the Upf1 peptide, see R. Melero, et al., Structure Volume 22, Issue 8, 5 August 2014, Pages 1105-1119). ADP-Glo ​​Reagent was added, followed by a 40-minute incubation at room temperature. Kinase Detection Reagent was added, followed by an additional 30 minutes of incubation. Luminescence intensity was measured using an EnVision (PerkinElmer) system. The activity value (%) of the wells containing the test substance was calculated using the following formula, where the average luminescence intensity of the wells containing DMSO was set to 0% and the average luminescence intensity of the wells without SMG1 enzyme was set to -100%. Activity value (%) of the wells containing the test substance = [(luminescence intensity of each well - average luminescence intensity of wells without SMG1) / (average luminescence intensity of wells with DMSO - average luminescence intensity of wells without SMG1)] × 100 - 100. The qAC50 (compound concentration showing 50% inhibition, synonymous with IC50) of the test substance was calculated using the activity value (%) at each concentration using Smartfit in Screener (Genedata). Smartfit is a common four-parameter logistic regression model. The IC50 values ​​are shown in Table 28.

[0279] Test Example 2: Measurement of NMD inhibitory activity in cells NMD inhibitory activity was measured by treating EMT6 mouse breast cancer cell line (ATCC) with the test substance and quantifying the increase in the transcriptional product of Snhg1, an NMD target gene (for details of NMD target genes, see F. Usui, et al., Scientific Reports volume 9, Article number: 1279 (2019)). Specifically, EMT6 cells were suspended in Waymouth's medium (Gibco, 15% FBS) and plated at 2 x 10 cells per well in a 96-well plate. 4Cells were seeded at 1000 cells / well and cultured for one day. The next day, serially diluted test substances (DMSO solution, final DMSO concentration: 2%) were added and cultured for 6 hours. The supernatant was removed, and RNA was extracted using an RNeasy® 96 kit (QIAGEN, 74182). cDNA was synthesized using a High Capacity cDNA Reverse Transcription kit (Applied Biosystems, 4368813). The cDNA, PrimeTime® Gene Expression Master Mix (Integrated DNA Technologies), and various probes were mixed, and gene expression was quantified using a QantStudio® 6 Flex (Thermo Fisher Scientific Inc.). The probe for the NMD target Snhg1 gene was Mm.PT.58.44039547 (FAM) (Integrated DNA Technologies), and the probe for the endogenous control Tbp gene was Mm00446973_m1 Tbp (VIC-PL) (Applied Biosystems). Relative quantification of Snhg1 transcripts was calculated using the ΔΔCT method, with Tbp as the endogenous control and the expression level of Snhg1 in untreated wells set at 1. A known NMD inhibitor (pyrimidine derivative Example 11i, Bioorg Med Chem Lett. 2012, 22(21), 6636-41) was used as a positive control for NMD inhibition. The NMD inhibitory activity of the test substance-treated wells was determined by the maximum fold change in Sngh1 expression in the positive control wells relative to the untreated wells. The EC50 (compound concentration showing 50% activity) of the test substance showing half of this change was calculated using the GROWTH function in Microsoft Excel. The calculated EC50 values ​​for each test substance are shown in Table 28.

[0280]

[0281] Test Example 3: Evaluation of NMD Inhibitory Activity in Vivo In this test, the NMD inhibitory activity in tumor tissue following oral administration of a test substance was evaluated using mice subcutaneously transplanted with the EMT6 mouse breast cancer cell line. The increase in the transcriptional activity of the NMD target gene, Snhg1, was quantified as an index of NMD inhibitory activity. First, EMT6 cells (ATCC) were subcutaneously transplanted into BALB / c mice, and engraftment was confirmed 7 days later. A 0.5% methylcellulose suspension of the test substance was prepared and orally administered at the doses shown in Table 22. Six hours after administration of the test substance, the mice were euthanized, and the collected tumor tissue was cryopreserved. RNA from tumor tissue was extracted using the illustra® RNAspin Mini RNA Isolation kit (GE Healthcare Life Sciences), and cDNA was synthesized using High-Capacity cDNA Reverse Transcription Kits (Applied Biosystems, 4368813). The cDNA and Prime Time® gene Expression Master Mix (Integrated DNA Technologies) were mixed with various probes, and gene expression was quantified using a QantStudio® 6 Flex (Thermo Fisher Scientific Inc.). The probe for the NMD target Snhg1 gene was Mm.PT.58.44039547 (FAM) (Integrated DNA Technologies), and the probe for the endogenous control Gapdh gene was Mm99999915_g2 (VIC-PL) (Applied Biosystems). The relative quantification of Snhg1 transcripts in each sample was calculated by the ΔΔCT method using Gapdh as an endogenous control, and the expression level of Snhg1 in each test substance administration group was calculated by setting the expression level in the vehicle group (0.5% methylcellulose administration group) to 1. The results are shown in Table 29.

[0282] Test Example 4: Antitumor Test in an Allograft Model In this test, the antitumor effects of the test substance in combination with an immune checkpoint inhibitor were examined using mice subcutaneously implanted with the MC38 mouse colon cancer cell line. MC38 mouse colon cancer cell line (NCI) was implanted at 3 x 10 5 The test substances were crushed in an agate mortar and then suspended in 0.5% methylcellulose solution (Fujifilm Wako Pure Chemical Industries, Ltd., #133-17815). These suspensions were administered orally once daily starting the day after subcutaneous implantation at the doses shown in Figures 5 to 9. Anti-mouse PD-1 antibody (Bio X cell, BE0146, clone: ​​RMP1-14) or anti-mouse PD-L1 antibody (Bio X cell, BE0101, clone: ​​10F.9G2) was diluted to the specified concentration with PBS and administered intraperitoneally at 10 mg / kg every 3–4 days starting 3 days after subcutaneous implantation (four times total), or every 3–4 days starting 7 days after subcutaneous implantation (three times total). The diameter of the tumor in each group was measured over time using a vernier caliper (Mitutoyo, CD-15AX), and the tumor volume was calculated using the SMAD2 system (Jmacsoft Co., Ltd.) according to the following formula: Tumor volume (mm 3 ) = major axis (mm) x [minor axis (mm)] 2 The antitumor effect was evaluated by comparing the tumor volume of each group with that of the vehicle group (0.5% methylcellulose administration group). The results are shown in Figures 5 to 9.

[0283] The compound of the present invention or a pharmaceutically acceptable salt thereof exhibits SMG1 and NMD inhibitory activity, and also exhibits anti-cancer activity when used alone or in combination with an immune checkpoint inhibitor.

Claims

1. A compound represented by formula (1), or a pharmaceutically acceptable salt thereof. 【Chemistry 1】 In formula (1), R 1 This includes 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-oxo-ethyl group, a [dimethyl(oxide)-λ6-sulfanylidene]amino group, or a group represented by the following formula (2). 【Chemistry 2】 (In formula (2), W a CH 2 , oxygen atom, or NR 1f Show, W b This represents CH, a nitrogen atom, or C-OH. R 1a , R 1b , R 1c Each of these independently represents, identical or different, a hydrogen atom, a halogen atom, a hydroxyl group, a C1-C6 alkyl group which may be substituted with a halogen atom, an amino group, or an oxo group. n represents 0, 1, or 2. or -NR 1d R 1e and R 1d , R 1e Each of these independently represents the same or different 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 This represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group. R 2 This 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 2,4-dimethylpyrazolyl group, or any group selected from the following formula (3): 【Transformation 3】 (In formula (3), The dashed line indicates a single or double bond. V a CR 2f , or indicates a nitrogen atom. V b CR 2g , or indicates a nitrogen atom. V c CR 2j , or indicates a nitrogen atom. V d CR 2k , or indicates a nitrogen atom. V g This represents CH or a nitrogen atom. V h CHN(CH 3 ) 2 , NR 2l , or, representing an oxygen atom, n 2 This indicates 1 or 2. R 2a , R 2b Each of these independently represents, identically or differently, 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 with 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 with a halogen atom or deuterium), or a C3-C6 cycloalkyl group. R 2c This represents a C3-C6 cycloalkyl group or a C1-C6 alkyl group (the C1-C6 alkyl group may be substituted with a C3-C6 cycloalkyl group or a halogen atom), R 2d This represents a C1-C6 alkyl group, a C1-C6 alkoxy group, or a C3-C6 cycloalkyl group, which may be substituted with a hydrogen atom or a halogen atom. R 2e This 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 Each of these independently represents, identically or differently, a hydrogen atom, a halogen atom, a C1-C6 alkoxy group which may be substituted with a halogen atom, or a C1-C6 alkyl group which may be substituted with a hydroxyl group, or the following formula (4): 【Chemistry 4】 (In formula (4), R 2h , R 2i Each of these independently represents the same or different C1-C6 alkyl group, Alternatively, R 2h , R 2i These may bond to each other to form a 4-7 membered heterocyclic group which may be substituted with a C1-C6 alkyl group. R 2j , R 2k Each of these independently represents the same or different C1-C6 alkyl group, or C3-C6 cycloalkyl group, which may be substituted with a hydrogen atom or a halogen atom. Alternatively, R 2c and R 2k These may combine with each other to form the following groups: 【Transformation 5】 R 2l (This represents a C1-C6 alkyl group or a C3-C6 cycloalkyl group.) Alternatively, R 1 and R 2 These may combine with each other to form a group shown in formula (5) below. (The leftmost bond of each group is the aromatic ring and R of the compound represented by formula (1) 1 This represents a bond between the two, and the bond at the far right is between the aromatic ring and R of the compound represented by formula (1). 2 (This represents a combination with.) 【Transformation 6】 (In formula (5), A represents an aryl group, a heteroaryl group, or a 4-7 membered heterocyclic group. R 6a This represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, or a C1-C6 alkoxy group. D is -NR 6e CO-, or -CONR 6f - indicates, E is -CR 6g R 6h -, -NR 6i -, -O-, -S-, -SO-, or -SO 2 - indicates that if there are multiple E's, then each E may be the same or different. R 6b , R 6c , R 6d , R 6e , R 6f , R 6g , R 6h , R 6i Each of these independently represents a hydrogen atom, a C1-C6 alkyl group, or a C3-C6 cycloalkyl group, or R 6b and R 6c , R 6b and R 6e , or R 6c and R 6d They may be joined to each other to form a ring. m 1 This indicates 0 or 1. m 2 This indicates 1, 2, 3, 4, or 5. m 3 (This represents 0, 1, 2, or 3.) R 3 This represents a hydrogen atom, a halogen atom, a C1-C6 alkyl group, or a 1-methyl-3,6-dihydro-2H-pyrazine-5-yl group. R 4 This represents a hydrogen atom or a halogen atom. XY is C=CH or N-CH 2 Show, 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. R 1 However, hydrogen atoms, C1-C6 alkyl groups, -NR 11d R 11e , or the compound according to claim 1, or a pharmaceutically acceptable salt thereof, which represents any group selected from the following formula (6). 【Transformation 7】 (In formula (6), R 11a , R 11b Each of these independently represents, either identically or distinctly, a hydrogen atom, a halogen atom, a hydroxyl group, or a C1-C6 alkyl group. R 11d , R 11e Each of these independently represents a C1-C6 alkyl group which may be substituted with a hydrogen atom or a halogen atom, either identically or differently.

3. R 2 The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound 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)piperidine-1-yl group, or any group selected from the following formula (7). 【Transformation 8】 (In formula (7), V 2a CR 21e , or indicates a nitrogen atom. V 2b CR 21f , or indicates a nitrogen atom. R 21a , R 21b Each of these independently represents, identical or different, 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 which may be substituted with a halogen atom or deuterium, or a C3-C6 cycloalkyl group. R 21c represents a C1-C6 alkyl group optionally substituted by a halogen atom, R 21d This represents a hydrogen atom or a C3-C6 cycloalkyl group. R 21e This represents a hydrogen atom or a halogen atom. R 21f (This represents a hydrogen atom or a halogen atom.)

4. R 3 However, it shows a hydrogen atom. R 4 However, it shows a hydrogen atom. XY is C=CH or N-CH 2 Show, The compound according to claim 1, wherein Z represents a halogen atom, or a pharmaceutically acceptable salt thereof.

5. R 1 represents any group selected from an ethyl group, a 2,2-difluoroethylamino group, or a [(2R)-1,1,1-trifluoropropan-2-yl]amino group, R 2 However, it represents a 2-methoxypyridine-3-yl group, a 1,5-dimethyl-1H-pyrazole-4-yl group, or a group represented by the following formula (8), 【Chemistry 9】 (In formula (8), R 22 This represents a C1-C6 alkyl group which may be substituted with a halogen atom, a C1-C6 alkoxy group which may be substituted with a halogen atom, or a C3-C6 cycloalkyl group. R 3 However, it shows a hydrogen atom. R 4 However, it shows a hydrogen atom. XY is C=CH or N-CH 2 Show, The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z represents a halogen atom.

6. A compound selected from the following compounds, or a pharmaceutically acceptable salt thereof. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-(6-cyclopropyl-4-methoxypyridine-3-yl)-1,6-naphthyridine-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-[4-methoxy-6-(trifluoromethyl)pyridine-3-yl]-1,6-naphthyridine-2(1H)-one, 3-(6-chloro-4-{[(2R)-1,1,1-trifluoropropane-2-yl]amino}-1H-imidazo[4,5-c]pyridine-2-yl)-5-(1,5-dimethyl-1H-pyrazole-4-yl)-1,6-naphthyridine-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-[6-(1,1-difluoroethyl)-4-methoxypyridine-3-yl]-1,6-naphthyridine-2(1H)-one, 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-[6-(difluoromethoxy)-4-methoxypyridine-3-yl]-1,6-naphthyridine-2(1H)-one, 3-{6-chloro-4-[(2,2-difluoroethyl)amino]-1H-imidazo[4,5-c]pyridine-2-yl}-5-(2-methoxypyridine-3-yl)-1,6-naphthyridine-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]pyrimidine-2(1H)-one.

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

8. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-(6-cyclopropyl-4-methoxypyridine-3-yl)-1,6-naphthyridine-2(1H)-one 1,2-ethanedisulfonate.

9. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-(6-cyclopropyl-4-methoxypyridine-3-yl)-1,6-naphthyridine-2(1H)-one methanesulfonate.

10. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-(6-cyclopropyl-4-methoxypyridine-3-yl)-1,6-naphthyridine-2(1H)-one benzenesulfonate.

11. 3-(6-chloro-4-ethyl-1H-imidazo[4,5-c]pyridine-2-yl)-5-(6-cyclopropyl-4-methoxypyridine-3-yl)-1,6-naphthyridine-2(1H)-one adipate.

12. An SMG1 inhibitor comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient.

13. An NMD inhibitor comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient.

14. A pharmaceutical composition containing a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient, and which may also contain a pharmaceutically acceptable carrier.

15. A pharmaceutical composition according to claim 14 for treating cancer.

16. The pharmaceutical composition according to claim 15, characterized in that a 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, characterized in that a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor are each contained as active ingredients in different formulations and administered simultaneously or at different times.

18. The pharmaceutical composition according to claim 16, characterized in that a 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 formulation.

19. The pharmaceutical composition according to claim 16, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

20. The pharmaceutical composition according to claim 15, wherein the cancer is a hematological 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's sarcoma, or a solid tumor selected from the group consisting of stomach 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 a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, as an active ingredient.

22. Use of a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a pharmaceutical for the treatment of cancer.

23. The use according to claim 22, 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 use according to claim 23, characterized in that a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor are each contained as active ingredients in different formulations and administered simultaneously or at different times.

25. The use according to claim 23, characterized in that a 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 formulation and administered.

26. The use according to claim 23, wherein the immune checkpoint inhibitor is an anti-PD-1 antibody, an anti-PD-L1 antibody, or an anti-CTLA-4 antibody.

27. The use according to claim 22, wherein the cancer is a hematological 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's sarcoma, or a solid tumor selected from the group consisting of stomach 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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