Antitumor drugs used in combination with immune checkpoint inhibitors

Abstract

The present invention pertains to an agent that is for prevention and / or treatment of cancer, that contains an mPGES-1 inhibitor as an active ingredient, and that is for use in combination with an immune checkpoint inhibitor. The present invention is industrially applicable.

Description

[Technical Field]

[0001] The present invention relates to a cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor as an active ingredient for use in combination with an immune checkpoint inhibitor, and to a cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. [Background technology]

[0002] It is known that PGE2 synthase (PGES) has three subtypes: membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2, and cytosolic PGES (cPGES) (Non-Patent Documents 1 to 3). mPGES-1, like COX-2, is induced primarily during inflammation and is involved in PGE2 production in inflammatory lesions. In addition, mPGES-1 is known to be involved in malignant tumors (e.g., colon cancer, breast cancer, lung cancer, prostate cancer, etc.) (see Non-Patent Documents 1, 2, and 3).

[0003] Patent Document 1 describes that a heterocyclic derivative represented by the general formula [1], or a tautomer thereof, or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity.

[0004] Non-Patent Document 4 describes the combined use of immune checkpoint inhibitors and the combined use of immune checkpoint inhibitors with other anticancer drugs.

[0005] However, there have been no reports to date of cancer prevention and / or treatment using an mPGES-1 inhibitor in combination with an immune checkpoint inhibitor. [Prior art documents] [Patent documents]

[0006] Patent Document 1: WO2013 / 024898 [Non-patent literature]

[0007] Non-patent document 1: J.Biol.Chem., 2003, 278(21), 19396-19405 Non-patent document 2: Oncogene, 2012, 31(24), 2943-2952 Non-patent document 3: Cancer Res., 2008, 68(9), 3251-3259 Non-patent document 4: Front Immunol.2018 Jul 27;9:1739. Summary of the Invention [Problem to be solved by the invention]

[0008] The problem to be solved by the present invention is to provide a novel agent for preventing and / or treating cancer. [Means for solving the problem]

[0009] The present inventors discovered that the combined use of an mPGES-1 inhibitor and an immune checkpoint inhibitor synergistically enhances antitumor activity, and thus completed the present invention.

[0010] The present invention relates to the following:

[0011] (1) A cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor as an active ingredient for use in combination with an immune checkpoint inhibitor. (2) The agent for preventing and / or treating cancer according to (1), wherein the mPGES-1 inhibitor is a compound of formula [1] (hereinafter also referred to as the present compound) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula [1] is as follows: Formula [1]: [ka] [In the formula, Ring A is represented by formula [2], [3], or [4]: [ka] (In the formula, X 1 is NH, N-alkyl, or O, A 1 is hydrogen or alkyl, A 2 teeth, i) hydrogen, ii) halogens, iii) an alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy; iv) cycloalkyl optionally substituted with alkyl, the alkyl being optionally substituted with 1 to 3 halogen atoms; v) alkoxy, vi) a saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo; vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) Formula [5]: [ka] (In the formula, R 3 , R 4 are the same or different, a) hydrogen, b) an alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, saturated heterocyclic group optionally substituted with alkyl, alkoxy, hydroxycarbonyl, hydroxyl, alkyloxycarbonyl, and alkylthio, or c) cycloalkyl or ix) saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl is a group represented by R 1 is phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl, 1,2-dihydrocyclobutabenzen-4-yl, or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are i) halogens, ii) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and phenyl; iii) alkoxy, iv) hydroxy, and v) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of R 2 is phenyl or pyridyl, and the phenyl or pyridyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with 1 to 3 halogen or alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkoxyalkoxy, cycloalkyl, phenyl, and halogen; and optionally substituted with 1 to 3 groups selected from the group consisting of As follows. (3) Ring A is a group represented by formula [4], and X 1 The agent for preventing and / or treating cancer according to (2), wherein is NH. (4) R1 is phenyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl, or 1,2-dihydrocyclobutabenzen-4-yl, and the phenyl is i) halogens, ii) alkyl optionally substituted with 1 to 3 halogens; iii) alkoxy, and iv) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of A preventive and / or therapeutic agent for cancer according to (2) or (3). (5) R 2 is phenyl, The phenyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl; and optionally substituted with 1 to 3 groups selected from the group consisting of The agent for preventing and / or treating cancer according to any one of (2) to (4). (6) Ring A is a group represented by the general formula [4], and X 1 But NH, A 2 but, i) hydrogen, ii) an alkyl optionally substituted with a group selected from the group consisting of halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy; iii) cycloalkyl optionally substituted by alkyl optionally substituted by 1 to 3 halogens; iv) Alkoxy v) a saturated heterocyclic group optionally substituted with alkyl or alkyloxycarbonyl, vi) alkylthio, vii) alkylsulfonyl, viii) alkylsulfinyl, ix) amino substituted with alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl, hydroxyl, and alkylthio; x) amino substituted with cycloalkyl, or xi) saturated cyclic amino optionally substituted with alkyl, dialkylamino, alkoxy, or hydroxyl; R 1 but, i) phenyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl optionally substituted with 1 to 3 halogens, alkoxy, and cyano; ii) 1,2,3,4-tetrahydronaphthalen-5-yl, iii) 2,3-dihydro-1H-inden-5-yl, iv) benzyl optionally substituted with halogen or alkyl optionally substituted with 1 to 3 halogens; v) cycloalkyl, vi) cycloalkylmethyl, vii) naphthyl, viii) pyridylmethyl optionally substituted by alkyl optionally substituted by 1 to 3 halogens, ix) thienyl, x) thienylmethyl, xi) benzothiazolyl, xii) benzothiadiazolyl, xiii) indolyl, or xiv) alkyl; R 2 represents phenyl or pyridyl, The phenyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl; and optionally substituted with 1 to 3 groups selected from the group consisting of The pyridyl may be substituted with halogen. The agent for preventing and / or treating cancer according to any one of (2) to (5). (7) Ring A is a group represented by the general formula [4], and X 1 But NH, A 2 is alkyl substituted by alkoxy, dialkylamino, tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino, or cycloalkyl optionally substituted by unsubstituted or 1 to 3 halogen-substituted alkyl, R 1 is phenyl substituted with one halogen and one methyl; R 2 is phenyl optionally substituted with one trifluoromethyl or two halogens; The agent for preventing and / or treating cancer according to any one of (2) to (6). (8) mPGES-1 inhibitors (1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (4) N-[(1-hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzofuran-7-carboxamide (6) N-Cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide (7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide (8) N-Cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide (9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (11) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (12) N-Cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (14) N-Cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (15) N-Cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (17) N-Cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (18) 2-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (19) N-Cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (20) 2-(Methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (21) 2-(Methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (22) 2-(Methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (24) 2-(Methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27) 2-(Methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (32) N-(2,3-Dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (33) 2-(Methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (35) 2-(Methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (36) 2-(Methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (41) 2-(Methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (43) 2-(2-amino-2-oxoethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (44) 2-(2-amino-2-oxoethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (46) N-Cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (47) 1-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (49) N-Cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (50) 1-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (52) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (55) 2-Ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (59) 2-(2-Methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (60) tert-Butyl 3-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}azetidine-1-carboxylate (61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (62) {4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}methyl acetate (63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (64) 2-[(2R)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (66) 2-[(2S)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (67) 2-(1-acetylazetidin-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (68) tert-Butyl (2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (69) tert-Butyl (2R)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (70) N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (72) 2-[(2S)-1-Acetylpyrrolidin-2-yl]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (73) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethoxy)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (74) N-(3-chloro-2-methylphenyl)-2-(1-methoxy-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (75) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (76) 2-tert-butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (79) 2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (85) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (86) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (87) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzimidazole-4-carboxamide (93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (101) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (102) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (106) 6-{[(2-bromo-5-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (113) N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yloxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (114) 6-({[2-chloro-5-(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (116) 6-({[5-(3-tert-butoxyprop-1-yn-1-yl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole-4-carboxamide (126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (131) N-(3-chloro-2-methylphenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (134) 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperazin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (143) 2-[bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (145) N-(3-chloro-2-methylphenyl)-2-{[2-(morpholin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (146) N-(3-chloro-2-methylphenyl)-2-{[2-(dimethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (147) N-(3-chloro-2-methylphenyl)-2-(3-hydroxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (150) N-(3-chloro-2-methylphenyl)-2-{[2-(diethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (151) N-(3-chloro-2-methylphenyl)-2-{[2-(pyrrolidin-1-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (152) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)propyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (153) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (154) N-(3-chloro-2-methylphenyl)-2-{[2-(dipropan-2-ylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (155) N-(3-chloro-2-methylphenyl)-2-(morpholin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (156) 2-Amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (158) N-(3-chloro-2-methylphenyl)-2-{[(3-methyloxetan-3-yl)methyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (159) tert-Butyl N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycinate (160) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (161) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (162) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (163) N-(3-chloro-2-methylphenyl)-2-(pyrrolidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (164) 2-(Azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (169) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (170) N-(3-chloro-2-methylphenyl)-2-{[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (171) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (172) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (173) N-(3-chloro-2-methylphenyl)-2-[(3-methoxypropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (174) N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (175) 2-[(2-tert-butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylsulfanyl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (178) N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (180) N-(3-chloro-2-methylphenyl)-2-(methylsulfinyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (185) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (186) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-hydroxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (194) 2-[(2-tert-butoxyethyl)amino]-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide (195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide (198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide (199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (200) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutan-2-yl]amino}-1H-benzimidazole-4-carboxamide (201) N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (203) N-(2,3-Dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide (210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide (211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)-1H-benzimidazole-4-carboxamide (213) 2-(Methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (214) 2-(Methoxymethyl)-N-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (215) 2-(Methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (216) N-Benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (218) 2-(Methoxymethyl)-N-(naphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (219) 2-(Methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (220) N-(2,1,3-benzothiadiazol-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (221) N-(1,1-dioxide-1-benzothiophen-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (222) 2-(Methoxymethyl)-N-(thiophen-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (224) N-(1,3-Benzothiazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (226) 2-(Methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (227) N-(5-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (229) 2-(Methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (230) N-(cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (231) N-(1,3-Benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (232) N-(6-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (237) 6-{[(5-butoxy-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide, and (239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide The agent for preventing and / or treating cancer according to any one of (2) to (7), which is a compound selected from the group consisting of: or a tautomer thereof, or a pharmaceutically acceptable salt thereof. (9) mPGES-1 inhibitors N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfate The agent for preventing and / or treating cancer according to any one of (2) to (8), which is a compound selected from the group consisting of: or a tautomer thereof, or a pharmaceutically acceptable salt thereof. (10) Immune checkpoint inhibitors include adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-5'-nucleotidase (anti-NT5E, anti-CD73), anti-CD134 (antibody OX40), anti-CD154 (anti-CD40L), anti-CD223 (anti-LAG-3: Lymphocyte Activation Gene 3 Protein), anti-CD27, anti-CD276 antigen (anti-B7-H3), anti-CD70, anti-CTLA4: Cytotoxic T-Lymphocyte Protein 4 (anti-CD152), anti-DLL1: delta-like protein 1, anti-ENTPD1 (anti-CD39), anti-ILDR2: Immunoglobulin-Like Domain-Containing Receptor 2 (anti-C1orf32), anti-PD-1, anti-PD-L1 (anti-CD274), and anti-PVRIG: Transmembrane protein The cancer preventive and / or therapeutic agent according to any one of (1) to (9), having an effect selected from the group consisting of PVRIG, anti-TGFβ2: Transforming Growth Factor beta-2, anti-TIM3: Hepatitis A Virus Cellular Receptor 2, anti-VISTA: V-Type Immunoglobulin Domain-Containing Suppressor of T-cell Activation, antibody VTCN1 (anti-B7-H4, anti-Ovr110), CD47 / SIRPalpha interaction inhibition (Tyrosine-Protein Phosphatase Non-receptor Type Substrate 1), tryptophan-2,3-dioxygenase: TDO inhibition, and tubulin polymerization inhibition. (11) Immunity to the immune systemノシンA2A receptor アンタゴニスト, アデノシンA2B receptor アンタゴニスト, anti-CD73 antibody, anti-CTLA-4 / OX40 dual-specific antibody, anti-CD40L PEGylated Fab antibody フラグメント(pegylated Fab antibody fragment against the CD40 ligand), anti-CD40L Fc fusion protein (anti-CD40L Fc-fusion protein), anti-CD40L Tn3 fusion protein (anti-CD40 This list includes: ligand-Tn3 fusion protein, anti-CD40L antibody, anti-LAG-3 antibody, anti-CD27 antibody, anti-B7-H3 antibody, anti-CD70 antibody, anti-CTLA-4 antibody, CTLA-4 targeting probody, anti-CTLA-4 / LAG-3 dual-specific antibody, anti-PD-L1 / CTLA-4 dual-specific antibody, anti-DLL1 antibody, anti-CD39 antibody, anti-ILDR2 antibody, anti-PD-1 antibody, B7-DC and antibody Fc fusion tank (a fusion protein of B7-DC and an antibody Fc portion), and anti-PD-1 / anti-LAG-3 dual-affinity re-targeting (DART). protein, anti-PD-1 / CTLA-4 dual-specific antibody, anti-PD-1 / CTLA-4 dual-specific antibody, anti-PD-1 / ICOS dual-specific antibody, anti-PD-1 / TIM-3 dual-specific antibody, anti-PD-1 / PD-L1 dual-specific antibody, anti-PD-L1 antibody, protease-activated anti-PD-L1 antibody (protease-activated anti-PD-L1 antibody) (prodrug), anti-PD-L1 / CD137 bispecific antibody, anti-LAG-3 / PD-L1 bispecific antibody, anti-PD-L1 / TIM3 bispecific antibody, DuoBody-PD-L1x4-1BB (GEN-1046), anti-PVRIG antibody, anti-PD-L1 / TGFβ2 trap fusion protein, anti-TIM-3 antibody (a fully human Fc-engineered)The agent for preventing and / or treating cancer according to any one of (1) to (9), which is at least one selected from the group consisting of an IgG1κ antibody targeting co-inhibitory receptor T-cell immunoglobulin and mucin, an anti-VISTA antibody, an anti-B7-H4 antibody, an anti-SIRPα antibody, a drug-conjugated antibody, an agonist redirected checkpoint (ARC) fusion protein consisting of the extracellular domains of human programmed cell death 1 (PD-1; PDCD1; CD279) and tumor necrosis factor ligand superfamily member 4 (TNFSF4; OX40 ligand; OX40L; CD252), linked by a central Fc domain (PD1-Fc-OX40L), an IDO-1 inhibitor, a PD-L1 inhibitor, a PD-L1 / PD-L2 / VISTA antagonist, and a JAK2 / STAT3 inhibitor. (12) The preventive and / or therapeutic agent for cancer according to any one of (1) to (9) above, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulva cancer, kidney cancer, renal pelvis and ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, or cancer of unknown primary origin. (13) A preventive and / or therapeutic agent for cancer, comprising an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. (14) A pharmaceutical composition for the prevention and / or treatment of cancer, comprising an mPGES-1 inhibitor and a pharmaceutically acceptable carrier, for use in combination with an immune checkpoint inhibitor. (15) A pharmaceutical composition for the prevention and / or treatment of cancer, comprising an mPGES-1 inhibitor, an immune checkpoint inhibitor, and a pharmaceutically acceptable carrier. (16) An mPGES-1 inhibitor for use in combination with an immune checkpoint inhibitor in the prevention and / or treatment of cancer. (17) Use of an mPGES-1 inhibitor in the manufacture of a medicament for use in combination with an immune checkpoint inhibitor in the prevention and / or treatment of cancer. (18) A method for preventing and / or treating cancer, comprising administering a combination of an mPGES-1 inhibitor and an immune checkpoint inhibitor to a subject in need thereof.

[0012] The above-mentioned configurations can be arbitrarily selected and combined. [Effects of the Invention]

[0013] According to the present invention, it is possible to provide a cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor as an active ingredient, for use in combination with an immune checkpoint inhibitor, and a cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. [Brief explanation of the drawings]

[0014] [Figure 1] Figure 1 shows the combined effect of Compound 1 and an anti-mouse PD-1 antibody in an allograft model of the mouse colon cancer cell line CT26. In the figure, "Combination" refers to the group in which Compound 1 and an anti-mouse PD-1 antibody were used in combination. [Figure 2] Figure 2 shows the combined effect of Compound 2 and an anti-mouse PD-1 antibody in an allograft model of the mouse colon cancer cell line CT26. In the figure, "Combination" refers to the group in which Compound 2 was combined with an anti-mouse PD-1 antibody. [Figure 3]3 shows the combined effects of Compound 1, Compound 2, and anti-mouse CTLA-4 antibody in an allograft model of the mouse colon cancer cell line CT26. In the figure, the combinations shown are a combination group of Compound 1 and anti-mouse CTLA-4 antibody and a combination group of Compound 2 and anti-mouse CTLA-4 antibody. DETAILED DESCRIPTION OF THE INVENTION

[0015] An embodiment of the present invention will be described.

[0016] In one aspect of the present invention, there is provided an agent for preventing and / or treating chronic prostatitis / pelvic pain syndrome, which comprises an mPGES-1 inhibitor as an active ingredient.

[0017] In one embodiment of the present invention, mPGES-1 inhibitors that can be used are commercially available and / or can be prepared according to conventional methods in the field of synthetic organic chemistry.

[0018] In one embodiment of the present invention, the mPGES-1 inhibitor can be used as a pharmaceutical directly, or can be prepared into a pharmaceutically acceptable salt by a known method. Examples of such salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. For example, the hydrochloride salt of an mPGES-1 inhibitor can be obtained by dissolving the mPGES-1 inhibitor in an alcoholic, ethyl acetate, or diethyl ether solution of hydrogen chloride.

[0019] In one embodiment of the present invention, the mPGES-1 inhibitor may have an asymmetric carbon, and each optical isomer and a mixture thereof can be used in the preventive and / or therapeutic agent of the present invention. Optical isomers can be produced, for example, by optical resolution of a racemate obtained as in the Examples described below using an optically active acid (e.g., tartaric acid, dibenzoyltartaric acid, mandelic acid, or 10-camphorsulfonic acid) by a known method, taking advantage of its basicity, or by using a pre-prepared optically active compound as a starting material. Alternatively, optical isomers can be produced by optical resolution using a chiral column or asymmetric synthesis. Furthermore, among mPGES-1 inhibitors, those that can form tautomers can be used in the preventive and / or therapeutic agent of the present invention, either as individual tautomers or as a mixture thereof.

[0020] In one embodiment of the present invention, the mPGES-1 inhibitor is, for example, a compound of formula [I] (the present compound) or a pharmaceutically acceptable salt thereof. The present compound can be produced from known compounds and / or easily synthesized intermediates by the method described in WO2013 / 024898 and / or by known methods.

[0021] In the compound of the formula [I] (the present compound), each substituent is exemplified as follows. "Halogen" includes, for example, fluorine, chlorine, bromine, and iodine. Examples of "alkyl" include linear or branched alkyls having 1 to 8 carbon atoms, specifically, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. Of these, alkyls having 1 to 6 carbon atoms are preferred, and alkyls having 1 to 3 carbon atoms are more preferred. The alkyl portion of "monoalkylamino," "dialkylamino," "monoalkylaminocarbonyl," "dialkylaminocarbonyl," "alkylcarbonyloxy," "alkyloxycarbonyl," "alkylcarbonyl," "alkylthio," "alkylsulfonyl," "alkylsulfinyl," "alkoxyalkyl," and "alkoxyalkylamino" can be similar to the "alkyl" described above. The alkoxy portion of "alkoxy" includes, for example, straight-chain or branched-chain alkoxy groups having 1 to 8 carbon atoms, specifically, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, t-butoxy, n-pentyloxy, n-hexyloxy, n-heptyloxy, and n-octyloxy. The alkoxy moiety of "alkoxyalkoxy", "alkoxyalkyl", and "alkoxyalkylamino" can be the same as the "alkoxy" mentioned above. Examples of "heteroaryl" include mono- or bicyclic aromatic rings having 1 to 3 heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom, and a sulfur atom. Specific examples include furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl, 3-thienyl), pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), imidazolyl (e.g., 1-imidazolyl, 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl), triazolyl (e.g., 1,2,4-triazolyl), and the like. azolyl (e.g., 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl), oxazolyl (e.g., 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), isoxazolyl (e.g., 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxadiazolyl (e.g., , 1,3,4-oxadiazol-2-yl), thiazolyl (e.g., 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,3-thiadiazolyl), isothiazolyl (e.g., 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4 -pyridyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzothiadiazolyl (e.g., 1,2,3-benzothiadiazol-4-yl, 1,2,3-benzothiadiazol-5-yl, 2,1,3-benzothiadiazol-4-yl, 2,1,3-benzothiadiazol-5-yl), benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl), indolyl (e.g., indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl), benzothiophenyl (e.g., 1-benzothiophen-2-yl, 1-benzothiophen-3-yl, 1-benzothiophen-4-yl, 1-benzothiophen-5-yl, 1-benzothiophen-6-yl, 1-benzothiophen-7-yl), ), 1,1-dioxo-1-benzothiophenyl (for example, 1,1-dioxo-1-benzothiophen-2-yl, 1,1-dioxo-1-benzothiophen-3-yl, 1,1-dioxo-1-benzothiophen-4-yl, 1,1-dioxo-1-benzothiophen-5-yl, 1,1-dioxo-1-benzothiophen-6-yl, 1,1-dioxo-1-benzothiophen-7-yl), quinolyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), 1,3-benzoxazol-2-yl. The heteroaryl part of "heteroarylmethyl" can be the same as the above-mentioned "heteroaryl". Examples of the "saturated cyclic amino" include a 4- to 7-membered saturated cyclic amino group having one or two N atoms, which may have one O or S atom as a ring-constituting atom and may be substituted with oxo, and specific examples include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, 1-homopiperazinyl, and 2-oxooxazolidin-3-yl. The saturated cyclic amino moiety of the "saturated cyclic aminocarbonyl" can be the same as the above-mentioned "saturated cyclic amino". Examples of the "saturated heterocyclic group" include 4- to 6-membered saturated heterocyclic groups having one N or O ring-constituting atom, specifically, for example, 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanyl, 3-oxetanyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl. Examples of "cycloalkyl" include those having 3 to 8 carbon atoms, specifically, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The cycloalkyl portion of "cycloalkylmethyl" can be the same as the above-mentioned "cycloalkyl". "Naphthyl" includes, for example, 1-naphthyl and 2-naphthyl. Examples of "pyridyl" include 2-pyridyl, 3-pyridyl, and 4-pyridyl. Examples of "alkynyl" include straight-chain or branched-chain alkynyl having 2 to 6 carbon atoms. Specific examples include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 2-propynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl.

[0022] In one aspect of the present invention, the mPGES-1 inhibitor is, for example, the above-mentioned compounds (1) to (239) or tautomers thereof, or pharmaceutically acceptable salts thereof, and preferably, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide or a pharmaceutically acceptable salt thereof, more preferably N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, or N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride.

[0023] When the present compound or a pharmaceutically acceptable salt thereof is administered as a medicine, it is administered to mammals, including humans, as is or as a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, of the present compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable, non-toxic, and inert carrier.

[0024] The carrier may be one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. Of course, the pharmaceutical composition may be administered in a dosage form suitable for these administration methods.

[0025] The pharmaceutical dosage is preferably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether it is a salt, and the type of salt. Generally, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult is in the range of 0.01 mg to 5 g per adult, preferably 1 mg to 1000 mg per adult, per day when administered orally. In some cases, a lower dose may be sufficient, or a higher dose may be required. Generally, the compound is administered once a day or in divided doses. In the case of intravenous administration, the compound may be administered as a rapid or continuous dose within 24 hours.

[0026] In one embodiment of the present invention, the immune checkpoint inhibitor is not particularly limited as long as it is a substance capable of suppressing the function (signal) of an immune checkpoint molecule, or an inhibitor of an immune checkpoint molecule.

[0027] In one aspect of the present invention, an immune checkpoint molecule refers to a molecule that exerts an immunosuppressive function by transmitting an inhibitory co-signal.

[0028] In one embodiment of the present invention, the immune checkpoint molecule is, for example, an adenosine A2A receptor, an adenosine A2B receptor, 5'-nucleotidase (NT5E, CD73), CD134 (OX40), CD154 (CD40L), CD223 (LAG-3: Lymphocyte Activation Gene 3 Protein), anti-CD27, anti-CD276 antigen (anti-B7-H3), anti-CD70, CTLA-4: Cytotoxic T-Lymphocyte Protein 4 (anti-CD152), DLL1: delta-Like Protein 1, ENTPD1 (CD39), ILDR2: Immunoglobulin-Like Domain-Containing Receptor 2 (C1orf32), PD-1, PD-L1 (CD274), PVRIG: Transmembrane protein PVRIG, or TGFβ2: Transforming Growth Factor beta-2, TIM3: Hepatitis A Virus Cellular Receptor 2, VISTA: V-Type Immunoglobulin Domain-Containing Suppressor of T-cell Activation, VTCN1 (anti-B7-H4, Ovr110), CD47 / SIRPalpha (Tyrosine-Protein Phosphatase Non-receptor Type Substrate 1), tryptophan-2,Examples of such immunosuppressants include 3-dioxygenase, TDO, and tubulin, and preferably CTLA-4, PD-1, PD-L1 (programmed cell death-ligand 1), PD-L2 (programmed cell death-ligand 2), LAG-3 (lymphocyte activation gene 3), TIM3 (T cell immunoglobulin and mucin-3), BTLA (B and T lymphocyte attenuator), B7H3, B7H4, CD160, CD39, CD73, A2aR (adenosine A2a receptor), KIR (killer inhibitory receptor), VISTA (V-domain Ig-containing suppressor of T cell activation), IDO1 (indoleamine 2,3-dioxygenase), Arginase I, TIGIT (T cell immunoglobulin and ITIM domain), and CD115, but are not particularly limited as long as they are equivalent to molecules that exert immunosuppressive function by transmitting inhibitory co-signals.

[0029] In one embodiment of the present invention, examples of immune checkpoint inhibitors include adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-5'-nucleotidase (anti-NT5E, anti-CD73), anti-CD134 (anti-OX40), anti-CD154 (anti-CD40L), anti-CD223 (anti-LAG-3), anti-CD27, anti-CD276 antigen (anti-B7-H3), anti-CD70, anti-CTLA4 (anti-CD152), anti-DLL1, anti-ENTPD1 (anti-CD39), anti-ILDR2 (anti-C1orf32), anti-PD-1, anti-PD-L1 (anti-CD274), anti-PVRIG, anti-TGFβ2, anti-TIM3, anti-VISTA, antibody VTCN1 (anti-B7 -H4, anti-Ovr110), CD47 / SIRPalpha interaction inhibition, tryptophan-2,3-dioxygenase:TDO inhibition, and tubulin polymerization inhibition, and preferably includes immune checkpoint inhibitors having an activity selected from the group consisting of anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2, anti-LAG-3, anti-TIM3, anti-BTLA, anti-B7H3, anti-B7H4, anti-CD160, anti-CD39, anti-CD73, anti-A2aR, anti-KIR, anti-VISTA, anti-IDO1, anti-Arginase I, anti-TIGIT, and anti-CD115.

[0030] In one aspect of the present invention, the immune checkpoint inhibitor is, for example, an inhibitor of a human immune checkpoint molecule, and preferably includes a neutralizing antibody against a human immune checkpoint molecule.

[0031] In one embodiment of the present invention, neutralizing antibodies against human immune checkpoint molecules include, for example, mab (whole monoclonal antibody), Fab (antigen-binding region fragment, one arm), F(ab')2 (antigen-binding region fragment including hinge region, both arms), Fab' (antigen-binding region fragment including hinge region, one arm), scFv (single-chain variable region fragment), di-scFv (dimeric single-chain variable region fragment), sdAb (single-domain antibody, nanobody), and bispecific monoclonal antibody.

[0032] In one embodiment of the present invention, the neutralizing antibody against a human immune checkpoint molecule is a bispecific monoclonal antibody, which is an artificial protein composed of fragments of two different monoclonal antibodies and binds to two different types of antigens, such as F(ab')2, BiIE, IgG-IgG, Bi-sdAb, CrossMab, TandAb, DART, DVD-Ig, TrioMab, and Triplebody.

[0033] Examples of immune checkpoint inhibitors include, but are not limited to, the following:

[0034] In one embodiment of the present invention, examples of immune checkpoint inhibitors that are 5'-nucleotidase (CD73) inhibitors include MCI-186; MT-1186; TW-001; 5798V6YJRP (UNII code); SIM-071201; Y-2; AB-680.

[0035] In one embodiment of the present invention, examples of immune checkpoint inhibitors that are adenosine A2A receptor antagonists include CPI-444; V-81444; 8KFO2187CP (UNII code); NIR-178; PBF-509; AZD-4635; and HTL-1071.

[0036] In one embodiment of the present invention, an example of an immune checkpoint inhibitor that is an adenosine A2B receptor antagonist is AB-928.

[0037] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-5'-nucleotidase (NT5E, CD73) activity include MEDI-9447; 5CRY01URYQ (UNII code); BMS-986179; CPI-006; CPX-006; NZV-930; SRF-373; TJ-004309; TJ-4309; and TJD-5.

[0038] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-CD154 (anti-CD40L) activity include CDP-7657; BMS-986004; 449MIE2SD6 (UNII code); MEDI-4920; VIB-4920; INX-021; SAR-441344; and AT-1501.

[0039] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-CD223 (anti-LAG-3) activity include IMP-701; ImmuTune IMP-701; LAG-525; BMS-986016; ONO-4482; AF75XOF6W3 (UNII code); 2831781; GSK-2831781; TSR-033; MK-4280; BI-754111; REGN-3767; OX5LRQ5H6K (UNII code); Sym-022; INCAGN-02385; INCAGN-2385.

[0040] In one embodiment of the present invention, an example of an immune checkpoint inhibitor having anti-CD27 activity is CDX-1127.

[0041] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-CD276 antigen (B7-H3) activity include 8H9; MAb8H9; 131I-8H9; MGA-271; M6030H73N9 (UNII code); 124I-8H9; and MGD-009.

[0042] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-CD70 activity include ARGX-110 and JNJ-4550.

[0043] In one embodiment of the present invention, examples of immune checkpoint inhibitors having antibody CTLA-4 (anti-CD152) activity include 0D1; BMS-734016; MAb10D14; MDX-010; MDX-CTLA4; MDX-101 (formerly); 4.1.1; CP-642570; CP-675206; CT-4.1.1; MEDI-1123; PF-06753388; AGEN-1884; BMS-986218; ADU-1604; BMS-986249; CS-1002; XmAb-22841; BCD-145; REGN-4659; KN-046; IBI-310; AGEN-1181.

[0044] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-DLL1 activity include CT-011 and MDV-9300.

[0045] In one embodiment of the present invention, an example of an immune checkpoint inhibitor having anti-ENTPD1 (anti-CD39) activity is TTX-030.

[0046] In one embodiment of the present invention, an example of an immune checkpoint inhibitor having anti-ILDR2 (anti-C1orf32) activity is BAY-1905254.

[0047] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-PD-1 activity include BMS-936558; MDX-1106; ONO-4538; MK-3475; SCH-900475; h409A11; 2661380; AMP-224; B7-DCIg; ANB-011; TSR-042; WBP-285; P0GVQ9A4S5 (UNII code); BGB-A317; hu31 7-1 / IgG4mt2;0KVO411B3N(UNIIcode);REGN-2810;SAR-439684;6QVL057INT(UNIIcode);PDR-001;HR-30121 0;INCSHR-01210;SHR-1210;MGD-013;PF-06801591;RN-888;LZZ0IC2EWP(UNIIcode);BCD-100;XmAb-20717;J S-001;TAB-001;APL-501;CBT-501;GB-226;IBI-308;JNJ-3283;JNJ-63723283;LYK98WP91F(UNIIcode);BI- 754091;CC-90006;NCMGA-00012;INCMGA-0012;MGA-012;ABBV-181;AGEN-2034w;GLS-010;WBP-3055;AK-104; Examples include LZM-009; Sym-021; AB-122; Pd-1-pik; AK-105; CS-1003; mAb-23104; JTX-4014; HLX-10; MEDI-5752; F-520; BMS-986213; RG-7769; RO-7121661; HX-008; IBI-318; BAT-1306; AMG-404; LY-3434172; 609-A; and ONO-4685.

[0048] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-PD-L1 (anti-CD274) activity include, for example, MPDL-3280A; RG-7446; RO-5541267; 52CMI0WC3Y (UNII code); 28X28X9OKV (UNII code); MEDI-4736; 451238; MSB-0010682; MSB-0010718C; PF-06834635; KXG2PJ551I (UNII code); STI-1014; STI-A1014; ZKAB-001; CK-301; TG-1501; CX-072; MCLA-145; LY-3300 054; NR4MAD6PPB (UNII code); 3D-025; ASC-22; KN-035; APL-502; CBT-502; TQB-2450; CS-1001; WBP-3155; FAZ-053; FS-118; FS118mAb2; LAG-3 / PD-L1mAb2; HTI-1088; SHR-1316; MSB-2311; IMC-001; STI-3031; STI-A-1015; STI-A1015; HLX-20; PL2#3; A-167; KL-A167; LY-3415244; DuoBody-PD-L1x4-1BB; GEN-1046.

[0049] In one embodiment of the present invention, an example of an immune checkpoint inhibitor having anti-PVRIG activity is COM-701.

[0050] In one embodiment of the present invention, examples of immune checkpoint inhibitors that are anti-TGFbeta2 include M-7824; MSB-0011359C.

[0051] In one embodiment of the present invention, examples of immune checkpoint inhibitors having anti-TIM3 activity include MBG-453; APE-5137; TSR-022; WBP-296A; 3K5H4TX2KP (UNII code); LY-3321367; BGB-A425; BMS-986258; ONO-7807; Sym-023; INCAGN-02390; and INCAGN-2390.

[0052] In one embodiment of the present invention, an immune checkpoint inhibitor having anti-VISTA (anti-VSIR) activity includes, for example, JNJ-61610588;1UI8F5IIZ4 (UNII code).

[0053] In one embodiment of the present invention, an example of an immune checkpoint inhibitor having anti-VTCN1 (anti-B7-H4; anti-Ovr110) activity is FPA-150.

[0054] In one embodiment of the present invention, immune checkpoint inhibitors that are CD47 / SIRPalpha interaction inhibitors include, for example, BI-765063; Effi-DEM; and OSE-172.

[0055] In one embodiment of the present invention, an immune checkpoint inhibitor that is a cytotoxic T-cell protein 4 inhibitor includes, for example, MK-1308.

[0056] In one embodiment of the present invention, an example of an immune checkpoint inhibitor that is a DNA alkylating agent is MGC-018.

[0057] In one embodiment of the present invention, examples of immune checkpoint inhibitors that act on Tumor Necrosis Factor Receptor Superfamily Member 4 (OX40, CD134) include PD-1-Fc-OX40L; SL-279252; and TAK-252.

[0058] In one embodiment of the present invention, examples of immune checkpoint inhibitors that target Programmed Cell Death 1 Ligand 1 (PD-L1; CD274) include ES-101; INBRX-105; INBRX-105-1; and GS-4224.

[0059] In one embodiment of the present invention, immune checkpoint inhibitors that are indoleamine 2,3-dioxygenase 1 (IDO1; IDO) inhibitors include, for example, D-1MT; NLG-8189; NSC-721782; INCB-024360; INCB-24360; 71596A9R13 (UNII code); BMS-986205; F-001287; ONO-7701; 0A7729F42K (as hydrochloride salt); EOS-200271; PF-06840003; KHK-2455; NLG-802; and LY-3381916.

[0060] In one embodiment of the present invention, an immune checkpoint inhibitor that is an inhibitor of Programmed Cell Death 1 (PDCD1; PD-1; CD279) / PD-1 Ligand 1 (PD-L1; CD274) interaction includes, for example, INCB-086550.

[0061] In one embodiment of the present invention, an immune checkpoint inhibitor that is a Programmed Cell Death 1 Ligand 1 (PD-L1; CD274) antagonist includes, for example, AUPM-170; CA-170.

[0062] In one embodiment of the present invention, an immune checkpoint inhibitor that is a Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor includes, for example, WP-1066.

[0063] In one embodiment of the present invention, immune checkpoint inhibitors that are tryptophan-2,3-dioxygenase (TDO) inhibitors include, for example, HTI-1090; SHR-9146; M-4112; DN-1406131; LPM-3480226; and LY-01013.

[0064] In one embodiment of the present invention, an example of an immune checkpoint inhibitor that is a tubulin polymerization inhibitor is SGN-CD48A.

[0065] In one embodiment of the present invention, examples of immune checkpoint inhibitors include anti-CTLA-4 antibodies (e.g., ipilimumab (Yervoy®), Tremelimumab), anti-PD-1 antibodies (e.g., human anti-human PD-1 monoclonal (neutralizing) antibodies (e.g., nivolumab (Opdivo®), REGN-2810), humanized anti-human PD-1 monoclonal (neutralizing) antibodies (e.g., pembrolizumab (KEYTRUDA®), PDR-001, BGB-A317, AMP-514 (MEDI0680)), )), anti-PD-L1 antibodies (e.g., Atezolizumab (RG7446, MPDL3280A), Avelumab (PF-06834635, MSB0010718C), Durvalumab (MEDI4736), BMS-936559), anti-PD-L2 antibodies, PD-L1 fusion proteins, PD-L2 fusion proteins (e.g., AMP-224), anti-Tim-3 antibodies (e.g., MBG453), anti-LAG-3 antibodies (e.g., BMS-986016, LAG525), anti-KIR antibodies (e.g., Lirilumab), etc.

[0066] In one embodiment of the present invention, the immune checkpoint inhibitors used in the combination of the present invention are preferably anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-L1 fusion proteins, and PD-L2 fusion proteins. More preferably, they are anti-CTLA-4 antibodies, anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, PD-L1 fusion proteins, and PD-L2 fusion proteins. Particularly preferably, they are anti-CTLA-4 antibodies and anti-PD-1 antibodies.

[0067] In one embodiment of the present invention, any one or more of these immune checkpoint inhibitors can be used in combination with the compounds used in the present invention.

[0068] In one aspect of the present invention, the dosage of the immune checkpoint inhibitor used in the combination of the present invention varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is adjusted to achieve the optimal desired effect.

[0069] In one embodiment of the present invention, for example, when an anti-PD-1 antibody is used, one embodiment of the dosage is 0.1 to 20 mg / kg body weight. For example, when nivolumab is used, one embodiment of the dosage is 0.3 to 10 mg / kg body weight, preferably 2 mg / kg, 3 mg / kg, or 6 mg / kg body weight.

[0070] In one embodiment of the present invention, for example, when an anti-CTLA-4 antibody is used, one embodiment of the dosage is 0.1 to 20 mg / kg body weight, preferably 0.1 to 10 mg / kg body weight, and more preferably 3 mg / kg or 10 mg / kg body weight.

[0071] In one aspect of the present invention, the combination of the present invention is expected to maximize its antitumor effect, particularly in cancer patients for whom the therapeutic effect of an immune checkpoint inhibitor alone is insufficient. Furthermore, the combination of the present invention also makes it possible to administer each drug at a lower dose, which is expected to reduce side effects. [Example]

[0072] The present invention will be explained in more detail below with reference to Reference Examples, Examples, Test Examples and Formulation Examples, but the present invention is not limited to these examples.

[0073] The test compounds used in Test Examples 1 and 2 are as follows. The compounds used in Test Examples 1 and 2 were prepared and used according to the descriptions in Examples 1 to 249 of WO2013 / 024898. Activity data for the compounds used in Test Examples 1 and 2 are as shown in Tables 1 to 17 of WO2013 / 024898.

[0074] Test Example 1 mPGES-1 inhibitory activity test mPGES-1 microsomes were prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. The mPGES-1 microsomes were diluted in potassium phosphate buffer (pH 7.4) containing reduced glutathione, and either a DMSO solution of the test compound or DMSO (final DMSO concentration of 1% in both cases) was added and incubated for 20 minutes at 4°C. The enzyme reaction was then initiated by adding a PGH2 substrate solution adjusted to a final concentration of 1 μM, followed by incubation at 4°C for 60 seconds. The reaction was terminated by adding ferric chloride and citrate solutions (final concentrations of 1 mg / mL and 50 mM, respectively). The amount of PGE2 formed was quantified using an HTRF kit (Cisbio International product catalog #62P2APEC). A solution without test compound served as a positive control, and a solution without test compound and microsomes served as a negative control. 100% activity was defined as the PGE2 production in the positive control minus the PGE2 production in the negative control. IC50 values ​​were then determined using standard methods.

[0075] Test Example 2: Inhibition of PGE2 and PGF2α production using A549 cells 2 x 10 human A549 cells 4Cells were seeded at 100 μL / well in a 96-well plate and incubated overnight. The medium was then removed and washed with phosphate-buffered saline, followed by replacement with RPMI medium containing 3% FBS and either a DMSO solution of the test compound or DMSO (final DMSO concentration: 0.1% in both cases). After 60 minutes of incubation, IL-1β (5 ng / well) was added and incubated for 24 hours at 37°C. PGE2 in the medium was then quantified using an HTRF kit (Cisbio International product catalog #62P2APEC), and PGF2α was quantified using an EIA kit (Cayman Chemical Company product catalog #516011). A solution without test compound served as a positive control, and a solution without test compound and IL-1β served as a negative control. 100% activity was defined as the PGE2 and PGF2α production in the positive control minus the PGE2 and PGF2α production in the negative control. IC50 values ​​were then determined using standard methods.

[0076] The compounds used in Test Example 3 are as follows.

[0077] Compound 1 and Compound 2 Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate and Compound 2: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide were prepared and used according to the description in Example 239 and Example 89 of WO2013 / 024898 (hereinafter also referred to as Compound 1 and Compound 2).

[0078] Test Example 3: Effect of combined use of mPGES-1 inhibitor and immune checkpoint inhibitor in an allograft model of mouse colon cancer cell line CT26 The combined effect of mPGES-1 inhibitors (compounds 1 and 2) and immune checkpoint inhibitors (anti-mouse PD-1 antibodies) was evaluated in an allograft model of the mouse colon cancer cell line CT26 (Cancer Res. (2013), 73(12), p3591-603). 1. Test drug Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, Compound 2: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide Anti-mouse PD-1 antibody: InVivoMAb anti-mouse PD-1 (CD279) (Bio X Cell, Inc. (West Lebanon, NH, USA)) 2. Preparation of Cells for Transplantation CT26 cells were cultured in a CO2 incubator using RPMI-1640 medium containing 10 vol% FBS and 1 vol% penicillin-streptomycin. On the day of transplantation, the culture supernatant was removed, and the CT26 cells were washed with HBSS and collected. The collected CT26 cells were suspended in HBSS and used as transplantation cells. 3. Creation of Allograft Model Under anesthesia, female BALB / c mice were injected with 3.0x10 5 The cells for transplantation were subcutaneously transplanted. On the seventh day after transplantation, the mice were assigned to four groups (4 to 6 mice each): a control group, a group treated with mPGES-1 inhibitors (compounds 1 and 2) alone, a group treated with anti-mouse PD-1 antibody alone, and a group treated with the combination of compound 1 or 2 and anti-mouse PD-1 antibody. 4. Measurement of Antitumor Activity Compound 1 or 2 was orally administered at 100 mg / kg (as free form) twice a day from day 7 to day 20 after transplantation to mice in the compound 1 or 2 single-use and combination-use groups. Anti-mouse PD-1 antibody was intraperitoneally administered at a dose of 100 μg / animal to mice in the anti-mouse PD-1 antibody alone and combination groups twice a week from day 7 to day 20 after transplantation. Mice in the vehicle group and the anti-mouse PD-1 antibody alone group were orally administered 5% methylcellulose repeatedly for the same period as Compound 1 or 2. Furthermore, D-PBS was intraperitoneally administered to mice in the vehicle group and the compound 1 or 2 alone group at the same time as the anti-mouse PD-1 antibody. Tumor volume (mm 3 ) was calculated using the following formula by measuring the length and width of the tumor using an electronic caliper.

[0079]

number

[0080] The above compounds 1 and 2 alone did not inhibit tumor growth, but they did so when used in combination with an anti-mouse PD-1 antibody.

[0081] Test Example 4: Effect of combined use of mPGES-1 inhibitor and immune checkpoint inhibitor in an allograft model of mouse colon cancer cell line CT26 The combined effect of mPGES-1 inhibitors (compounds 1 and 2) and immune checkpoint inhibitors (anti-mouse CTLA-4 antibodies) was evaluated in an allograft model of the mouse colon cancer cell line CT26 (Cancer Res. (2013), 73(12), p3591-603). 1. Test drug Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, Compound 2: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide Anti-mouse CTLA-4 antibody: InVivoMAb anti-mouse CTLA-4 (CD152) (Bio X Cell, Inc. (West Lebanon, NH, USA)) 2. Preparation of Cells for Transplantation CT26 cells were cultured in a CO2 incubator using RPMI-1640 medium containing 10 vol% FBS and 1 vol% penicillin-streptomycin. On the day of transplantation, the culture supernatant was removed, and the CT26 cells were washed with HBSS and collected. The collected CT26 cells were suspended in HBSS and used as transplantation cells. 3. Creation of Allograft Model Under anesthesia, 3.0 × 10 cells were subcutaneously transplanted into the right flank of female BALB / c mice. On the seventh day after transplantation, the mice were assigned to six groups (three mice per group): a control group, a group treated with mPGES-1 inhibitors (compounds 1 and 2) alone, a group treated with anti-mouse CTLA-4 antibody alone, and a group treated with the combination of compound 1 or 2 and anti-mouse CTLA-4 antibody. 4. Measurement of Antitumor Activity Compound 1 or 2 was orally administered at 100 mg / kg (as free form) twice a day from day 8 to day 20 of transplantation to mice in the compound 1 or 2 single-use and combination-use groups. Anti-mouse CTLA-4 antibody was intraperitoneally administered at a dose of 100 μg / animal to mice in the anti-mouse CTLA-4 antibody alone and combination groups twice a week from day 8 to day 20 after transplantation. To the mice in the vehicle group and the anti-mouse CTLA-4 antibody alone group, 5% methylcellulose was repeatedly orally administered for the same period as Compound 1 or 2. Furthermore, D-PBS was intraperitoneally administered to mice in the vehicle group and the compound 1 or 2 alone group at the same time as the anti-mouse CTLA-4 antibody. Tumor volume (mm 3 ) was calculated using the following formula by measuring the length and width of the tumor using an electronic caliper.

[0082]

number

[0083] The above compounds 1 and 2 alone did not inhibit tumor growth, but they did so when used in combination with an anti-mouse CTLA-4 antibody.

[0084] Formulation Example 1 Tablets (oral tablets) Prescription 1 tablet 80mg This compound 5.0mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg The mixed powder in this ratio is tableted by a conventional method to form oral tablets. [Industrial Applicability]

[0085] The present invention relates to a cancer preventive and / or therapeutic agent containing an mPGES-1 inhibitor as an active ingredient for use in combination with an immune checkpoint inhibitor, and has industrial applicability.

Claims

1. A preventive and / or therapeutic agent for cancer, which contains an mPGES-1 inhibitor as an active ingredient, for use in combination with an immune checkpoint inhibitor, wherein the mPGES-1 inhibitor is (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) A prophylactic and / or therapeutic agent for cancer, which is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

2. A preventive and / or therapeutic agent for cancer, which contains an mPGES-1 inhibitor as an active ingredient, for use in combination with an immune checkpoint inhibitor, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

3. A preventive and / or therapeutic agent for cancer, which contains an mPGES-1 inhibitor as an active ingredient for use in combination with an immune checkpoint inhibitor, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

4. The preventive and / or therapeutic agent for cancer according to any one of claims 1 to 3, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulva cancer, kidney cancer, renal pelvis and ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, or cancer of unknown primary origin.

5. A preventive and / or therapeutic agent for cancer, which contains an immune checkpoint inhibitor as an active ingredient, for use in combination with an mPGES-1 inhibitor, wherein the mPGES-1 inhibitor is (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) A prophylactic and / or therapeutic agent for cancer, which is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

6. A preventive and / or therapeutic agent for cancer, which contains an immune checkpoint inhibitor as an active ingredient, for use in combination with an mPGES-1 inhibitor, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

7. A preventive and / or therapeutic agent for cancer, which contains an immune checkpoint inhibitor as an active ingredient, for use in combination with an mPGES-1 inhibitor, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

8. The preventive and / or therapeutic agent for cancer according to any one of claims 5 to 7, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulva cancer, kidney cancer, renal pelvis and ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, or cancer of unknown primary origin.

9. A preventive and / or therapeutic agent for cancer, comprising an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients, wherein the mPGES-1 inhibitor is (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) A prophylactic and / or therapeutic agent for cancer, which is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, a tautomer thereof, or a pharmaceutically acceptable salt thereof, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

10. A preventive and / or therapeutic agent for cancer, comprising an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

11. A preventive and / or therapeutic agent for cancer, comprising an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients, wherein the mPGES-1 inhibitor is N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and the immune checkpoint inhibitor is an anti-PD-1 antibody or an anti-CTLA-4 antibody.

12. The preventive and / or therapeutic agent for cancer according to any one of claims 9 to 11, wherein the cancer is leukemia, malignant lymphoma, multiple myeloma, myelodysplastic syndrome, head and neck cancer, esophageal cancer, esophageal adenocarcinoma, gastric cancer, duodenal cancer, colorectal cancer, colon cancer, rectal cancer, liver cancer, gallbladder and bile duct cancer, biliary tract cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine cancer, endometrial cancer, vaginal cancer, vulva cancer, kidney cancer, renal pelvis and ureter cancer, urothelial cancer, penile cancer, prostate cancer, testicular tumor, bone and soft tissue sarcoma, malignant bone tumor, skin cancer, thymoma, mesothelioma, or cancer of unknown primary origin.

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