Anti-tumor drug used in combination with immune checkpoint inhibitor

Abstract

The present invention relates to a prophylactic 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, and which has industrial utility.

Description

[0001] This application is a divisional application of Chinese invention application No. 202080090360.9, filed on December 24, 2020, entitled "Antitumor Drug Used in Combination with Immune Checkpoint Inhibitors". Technical Field

[0002] This invention relates to a cancer prevention and / or treatment agent containing an mPGES-1 inhibitor as an active ingredient for use in combination with an immune checkpoint inhibitor, and a cancer prevention and / or treatment agent containing both an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. Background Technology

[0003] Three subtypes of PGE2 synthase (PGES) are known to exist: membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2, and cytoplasmic PGES (cPGES) (Non-Patent Literature 1-3). Like COX-2, mPGES-1 is primarily induced during inflammation and participates in PGE2 production during inflammatory lesions. Furthermore, mPGES-1 is known to be associated with malignant tumors (e.g., colon cancer, breast cancer, lung cancer, prostate cancer, etc.) (see Non-Patent Literature 1, Non-Patent Literature 2, Non-Patent Literature 3).

[0004] Patent document 1 describes that heterocyclic derivatives represented by general formula [1], or their tautomers or their pharmaceutically permissible salts, have mPGES-1 inhibitory activity.

[0005] Non-patent literature 4 describes the combined use of immune checkpoint inhibitors, and the combined use of immune checkpoint inhibitors and other anticancer agents.

[0006] However, to date, there have been no reports of cancer prevention and / or treatment using the combined use of mPGES-1 inhibitors and immune checkpoint inhibitors.

[0007] Existing technical documents

[0008] Patent documents

[0009] Patent Document 1: WO2013 / 024898

[0010] Non-patent literature

[0011] Non-patent literature 1: J. Biol. Chem., 2003, 278(21), 19396-19405

[0012] Non-patent literature 2: Oncogene, 2012, 31(24), 2943-2952

[0013] Non-patent literature 3: Cancer Res., 2008, 68(9), 3251-3259

[0014] Non-patent literature 4: Front Immunol. 2018 Jul 27; 9: 1739. Summary of the Invention

[0015] The problem that the invention aims to solve

[0016] The problem to be solved by this invention is to provide novel cancer prevention and / or treatment agents.

[0017] Methods for solving problems

[0018] The inventors discovered that by using mPGES-1 inhibitors and immune checkpoint inhibitors in combination, anti-tumor activity can be synergistically enhanced, thus completing this invention.

[0019] The present invention relates to the following methods. (1)

[0021] A cancer prevention and / or treatment agent for use in combination with an immune checkpoint inhibitor, comprising an mPGES-1 inhibitor as the active ingredient. (2)

[0023] According to the cancer prevention and / or treatment agents described in (1),

[0024] mPGES-1 inhibitors are compounds of formula [1] (hereinafter also referred to as the compound), or their tautomers or pharmaceutically permissible salts thereof, wherein,

[0025] The compounds of formula [1] are shown in the following formula [1],

[0026] Equation [1]:

[0027] [Chemical Formula 1]

[0028]

[0029] In formula [1],

[0030] Ring A is a group represented by formula [2], [3] or [4].

[0031] [Chemical Formula 2]

[0032]

[0033] (in the formula,

[0034] X 1 It is NH, N-alkyl, or O.

[0035] A1 It is hydrogen or alkyl.

[0036] A 2 for:

[0037] i) Hydrogen;

[0038] ii) Halogens;

[0039] iii) An alkyl group optionally substituted with one to three groups selected from halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy.

[0040] iv) A cycloalkyl group optionally substituted with an alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 halogens;

[0041] v) Alkoxy;

[0042] vi) Saturated heterocyclic groups optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxygen;

[0043] vii) alkylthio group;

[0044] viii)alkylsulfonyl group;

[0045] ix) alkyl sulfinyl group;

[0046] The group represented by formula [5] x)

[0047] [Chemical Formula 3]

[0048]

[0049] (where R is in the formula) 3 R 4 Same or different, as follows:

[0050] a) Hydrogen;

[0051] b) An alkyl group optionally substituted with a group selected from the following: monoalkylamino, dialkylamino, saturated cyclic amino group optionally substituted with an alkyl group, saturated heterocyclic group optionally substituted with an alkyl group, alkoxy, hydroxycarbonyl, hydroxy, alkyloxycarbonyl, and alkylthio; or

[0052] c) cycloalkyl); or

[0053] ix) optional saturated cyclic amino groups substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl groups.

[0054] R 1The phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutanyl-3-yl, 1,2-dihydrocyclobutanyl-4-yl, or alkyl, wherein the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are optionally selected from...

[0055] i) Halogen,

[0056] ii) Alkyl groups optionally substituted with 1 to 3 groups selected from halogens, hydroxyl groups, and phenyl groups.

[0057] iii) Alkoxy groups,

[0058] iv) hydroxyl groups, and

[0059] v) Cyano

[0060] Substitution of 1 to 3 groups,

[0061] R 2 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally selected from...

[0062] i) Halogen,

[0063] ii) Alkyl sulfonyl,

[0064] iii) Alkoxy groups optionally substituted with 1 to 3 halogen or alkoxy groups,

[0065] iv) Alkynes optionally substituted with alkoxyalkyl or cycloalkyl groups, and,

[0066] v) Alkyl groups optionally substituted with 1 to 3 groups selected from alkoxy, alkoxyalkoxy, cycloalkyl, phenyl, and halogen.

[0067] (1 to 3 groups are substituted). (3)

[0069] According to the cancer prevention and / or treatment agent described in (2), wherein,

[0070] Ring A is a group represented by formula [4], X 1 It is NH. (4)

[0072] According to (2) or (3), the cancer prevention and / or treatment agent, wherein,

[0073] R 1The phenyl group is phenyl, 1,2,3,4-tetrahydronaphth-5-yl, 1,2,3,4-tetrahydronaphth-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutanyl-3-yl, or 1,2-dihydrocyclobutanyl-4-yl, wherein the phenyl group is optionally selected from...

[0074] i) Halogen,

[0075] ii) Alkyl groups optionally substituted with 1 to 3 halogens,

[0076] iii) Alkoxy groups, and

[0077] iv) Cyano

[0078] One to three groups are substituted. (5)

[0080] A cancer prevention and / or treatment agent according to any one of (2) to (4), wherein,

[0081] R 2 It is a phenyl group.

[0082] The phenyl group is optionally selected from...

[0083] i) Halogen,

[0084] ii) Alkyl sulfonyl,

[0085] iii) Alkoxy groups optionally substituted with alkoxy groups,

[0086] iv) Alkynes optionally substituted with alkoxyalkyl or cycloalkyl groups, and

[0087] v) Alkyl groups optionally substituted with 1 to 3 groups selected from halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl.

[0088] One to three groups are substituted. (6)

[0090] A cancer prevention and / or treatment agent according to any one of (2) to (5), wherein,

[0091] Ring A is a group represented by general formula [4], X 1 For NH,

[0092] A 2 for:

[0093] i) Hydrogen;

[0094] ii) Alkyl groups optionally substituted with groups selected from halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy groups;

[0095] iii) A cycloalkyl group optionally substituted with an alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 halogens;

[0096] iv) Alkoxy groups;

[0097] v) Saturated heterocyclic groups optionally substituted with alkyl or alkyloxycarbonyl groups;

[0098] vi) Alkylthio group;

[0099] vii)alkylsulfonyl group;

[0100] viii)alkylsulfinyl group;

[0101] ix) An amino group optionally substituted with an alkyl group, wherein the alkyl group is optionally substituted with a group selected from monoalkylamino, dialkylamino, saturated cyclic amino group optionally substituted with an alkyl group, tetrahydrofuranyl, morpholinyl, alkoxy, hydroxycarbonyl, hydroxy, and alkylthio.

[0102] x) An amino group optionally substituted with a cycloalkyl group; or

[0103] xi) Saturated cyclic amino groups optionally substituted with alkyl, dialkylamino, alkoxy, or hydroxyl groups,

[0104] R 1 for:

[0105] i) Phenyl groups optionally substituted with 1 to 3 groups selected from halogens, alkyl groups optionally substituted with 1 to 3 halogens, alkoxy groups, and cyano groups;

[0106] ii) 1,2,3,4-Tetrahydronaphth-5-yl;

[0107] iii) 2,3-Dihydro-1H-inden-5-yl;

[0108] iv) Benzyl group optionally substituted with halogen or alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 halogens;

[0109] v) Cycloalkyl;

[0110] vi) Cycloalkylmethyl;

[0111] vii) Naphthyl;

[0112] viii) Pyridylmethyl group optionally substituted with an alkyl group, wherein the alkyl group is optionally substituted with 1 to 3 halogens;

[0113] ix) Thiophene group;

[0114] x) Thiopheneylmethyl;

[0115] xi) benzothiazolyl;

[0116] xii) Benzothiadiazole group;

[0117] xiii) Indole group; or

[0118] xiv)alkyl,

[0119] R 2 Indicates phenyl or pyridyl.

[0120] The phenyl group is optionally selected from...

[0121] i) Halogen,

[0122] ii) Alkyl sulfonyl,

[0123] iii) Alkoxy groups optionally substituted with alkoxy groups,

[0124] iv) Alkynes optionally substituted with alkoxyalkyl or cycloalkyl groups, and

[0125] v) Alkyl groups optionally substituted with 1 to 3 groups selected from halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl.

[0126] Substitution of 1 to 3 groups,

[0127] The pyridyl group can optionally be replaced by a halogen. (7)

[0129] A cancer prevention and / or treatment agent according to any one of (2) to (6), wherein,

[0130] Ring A is a group represented by general formula [4], X 1 For NH,

[0131] A 2 It is an alkyl group substituted with an alkoxy group, a dialkylamino group, a tetrahydrofuranyl group, a tetrahydrofuranylmethyl group, an alkoxyalkylamino group, or a cycloalkyl group that is unsubstituted or optionally substituted with 1 to 3 halogen-substituted alkyl groups.

[0132] R 1 A phenyl group substituted with one halogen and one methyl group.

[0133] R 2 The phenyl group is optionally substituted with one trifluoromethyl group or two halogens. (8)

[0135] A cancer prevention and / or treatment agent according to any one of (2) to (7), wherein,

[0136] mPGES-1 inhibitors are compounds selected from the following, or their tautomers or pharmaceutically permissible salts.

[0137] (1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0138] (2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0139] (3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0140] (4) N-[(1-hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0141] (5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzofuran-7-carboxamide

[0142] (6) N-Cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide

[0143] (7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide

[0144] (8) N-cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide

[0145] (9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide

[0146] (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0147] (11) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0148] (12) N-cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0149] (13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0150] (14) N-Cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0151] (15) N-Cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0152] (16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0153] (17) N-Cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0154] (18) 2-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0155] (19) N-Cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0156] (20) 2-(methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0157] (21) 2-(methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0158] (22) 2-(methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0159] (23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0160] (24) 2-(methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0161] (25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0162] (26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0163] (27) 2-(methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0164] (28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0165] (29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0166] (30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0167] (31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0168] (32) N-(2,3-dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0169] (33) 2-(methoxymethyl)-N-(5,6,7,8-tetrahydronaphth-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0170] (34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0171] (35) 2-(methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0172] (36) 2-(methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0173] (37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0174] (38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0175] (39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0176] (40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0177] (41) 2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0178] (42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0179] (43) 2-(2-amino-2-oxoethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0180] (44) 2-(2-amino-2-oxoethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0181] (45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0182] (46) N-cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0183] (47) 1-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0184] (48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0185] (49) N-Cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0186] (50) 1-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0187] (51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzo[ 4-Formamide

[0188] (52) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3- 4-Formamide

[0189] (53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzo[ 4-Formamide

[0190] (54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0191] (55) 2-Ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0192] (56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0193] (57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0194] (58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0195] (59) 2-(2-methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0196] (60) 3-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}azacyclobutane-1-carboxylic acid tert-butyl ester

[0197] (61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0198] (62) methyl acetate {4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}acetate

[0199] (63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0200] (64) 2-[(2R)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0201] (65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2―(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0202] (66) 2-[(2S)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0203] (67) 2-(1-acetylazetane-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0204] (68) (2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl ester

[0205] (69) (2R)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylic acid tert-butyl ester

[0206] (70) N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolid-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0207] (71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0208] (72) 2-[(2S)-1-acetylpyrrolidone-2-yl]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0209] (73) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethoxy)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0210] (74) N-(3-chloro-2-methylphenyl)-2-(1-methoxy-2-methylpropane-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0211] (75) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0212] (76) 2-tert-butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0213] (77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0214] (78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0215] (79) 2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide

[0216] (80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0217] (81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0218] (82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0219] (83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0220] (84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0221] (85) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0222] (86) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0223] (87) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0224] (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0225] (89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0226] (90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0227] (91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0228] (92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzimidazole-4-carboxamide

[0229] (93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0230] (94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0231] (95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0232] (96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0233] (97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0234] (98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0235] (99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0236] (100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0237] (101) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0238] (102) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0239] (103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0240] (104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0241] (105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0242] (106) 6-{[(2-bromo-5-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0243] (107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0244] (108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0245] (109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0246] (110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0247] (111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0248] (112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0249] (113) N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propane-2-yloxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0250] (114) 6-({[2-chloro-5-(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0251] (115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0252] (116) 6-({[5-(3-tert-butoxypropyl-1-yn-1-yl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0253] (117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0254] (118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0255] (119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0256] (120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0257] (121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0258] (122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0259] (123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0260] (124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0261] (125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole-4-carboxamide

[0262] (126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0263] (127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0264] (128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide

[0265] (129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-oxopyrrolid-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0266] (130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-oxopyrrolid-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0267] (131) N-(3-chloro-2-methylphenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0268] (132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0269] (133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0270] (134) 2-Chloro-N-(3-Chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0271] (135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0272] (136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0273] (137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0274] (138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0275] (139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0276] (140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0277] (141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0278] (142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperazin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0279] (143) 2-[bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0280] (144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0281] (145) N-(3-chloro-2-methylphenyl)-2-{[2-(morpholin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0282] (146) N-(3-chloro-2-methylphenyl)-2-{[2-(dimethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0283] (147) N-(3-chloro-2-methylphenyl)-2-(3-hydroxyazacyclobutane-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0284] (148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0285] (149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0286] (150) N-(3-chloro-2-methylphenyl)-2-{[2-(diethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0287] (151) N-(3-chloro-2-methylphenyl)-2-{[2-(pyrrolidin-1-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0288] (152) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)propyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0289] (153) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0290] (154) N-(3-chloro-2-methylphenyl)-2-{[2-(dipropane-2-ylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0291] (155) N-(3-chloro-2-methylphenyl)-2-(morpholin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0292] (156) 2-Amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0293] (157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0294] (158) N-(3-chloro-2-methylphenyl)-2-{[(3-methyloxetane-3-yl)methyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0295] (159) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine tert-butyl ester

[0296] (160) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine

[0297] (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

[0298] (162) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0299] (163) N-(3-chloro-2-methylphenyl)-2-(pyrrolid-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0300] (164) 2-(azacyclobutane-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0301] (165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazacyclobutane-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0302] (166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0303] (167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0304] (168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0305] (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

[0306] (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

[0307] (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

[0308] (172) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0309] (173) N-(3-chloro-2-methylphenyl)-2-[(3-methoxypropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0310] (174) N-(3-chloro-2-methylphenyl)-2-{[2-(propane-2-yloxy)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0311] (175) 2-[(2-tert-butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0312] (176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0313] (177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylthio)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0314] (178) N-(3-chloro-2-methylphenyl)-2-(methylthio)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0315] (179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0316] (180) N-(3-chloro-2-methylphenyl)-2-(methylsulfinyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0317] (181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0318] (182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0319] (183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0320] (184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0321] (185) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0322] (186) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0323] (187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0324] (188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0325] (189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0326] (190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-hydroxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0327] (191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0328] (192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-{[2-(propane-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide

[0329] (193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propane-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide

[0330] (194) 2-[(2-tert-butoxyethyl)amino]-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide

[0331] (195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0332] (196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0333] (197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide

[0334] (198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide

[0335] (199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide

[0336] (200) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutane-2-yl]amino}-1H-benzimidazole-4-carboxamide

[0337] (201) N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0338] (202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0339] (203) N-(2,3-dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0340] (204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0341] (205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0342] (206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide

[0343] (207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0344] (208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide

[0345] (209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide

[0346] (210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide

[0347] (211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0348] (212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)-1H-benzimidazole-4-carboxamide

[0349] (213) 2-(methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0350] (214) 2-(methoxymethyl)-n-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0351] (215) 2-(methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0352] (216) N-Benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0353] (217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0354] (218) 2-(methoxymethyl)-N-(naphth-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0355] (219) 2-(methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0356] (220) N-(2,1,3-benzothiadiazol-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0357] (221) N-(1,1-dioxide-1-benzothiophene-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0358] (222) 2-(methoxymethyl)-N-(thiophene-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0359] (223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0360] (224) N-(1,3-benzothiazo-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0361] (225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0362] (226) 2-(methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0363] (227) N-(5-chloro-1,3-benzo[] -2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0364] (228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0365] (229) 2-(methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0366] (230) N-(cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0367] (231) N-(1,3-benzo[] -2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0368] (232) N-(6-chloro-1,3-benzo[] -2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0369] (233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0370] (234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0371] (235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0372] (236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0373] (237) 6-{[(5-butoxy-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0374] (238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide, and

[0375] (239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide. (9)

[0377] A cancer prevention and / or treatment agent according to any one of (2) to (8), wherein,

[0378] mPGES-1 inhibitors are compounds selected from the following, or their tautomers or pharmaceutically permissible salts:

[0379] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0380] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride

[0381] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0382] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate,

[0383] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate,

[0384] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0385] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride

[0386] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0387] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate,

[0388] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate,

[0389] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide,

[0390] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride

[0391] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate,

[0392] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate, and

[0393] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfate. (10)

[0395] The cancer prevention and / or treatment agent according to any one of (1) to (9) above, wherein,

[0396] Immune checkpoint inhibitors are selected from adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-5'-nucleotidases (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-associated 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. 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 microtubule polymerization inhibition. (11)

[0398] The cancer prevention and / or treatment agent according to any one of (1) to (9) above, wherein,

[0399] Immune checkpoint inhibitors are selected from 5'-nucleotidase inhibitors, adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-CD73 antibodies, anti-CTLA-4 / OX40 bispecific antibodies, pegylated Fab antibody fragments against the CD40 ligand, anti-CD40L Fc fusion protein, anti-CD40L Tn3 fusion protein, anti-CD40L antibodies, anti-LAG-3 antibodies, anti-CD27 antibodies, anti-B7-H3 antibodies, anti-CD70 antibodies, anti-CTLA-4 antibodies, and CTLA-4 targeting antibodies. Probody), and anti-CTLA-4 / LAG-3 bispecific antibody, anti-PD-L1 / CTLA-4 bispecific antibody, anti-PD-1 antibody with anti-DLL1 activity, anti-CD39 antibody, anti-ILDR2 antibody, anti-PD-1 antibody, B7-DC and antibody Fc fusion protein (a fusion protein of B7-DC and an antibody Fc portion), anti-PD-1 / anti-LAG-3 DART protein: anti-PD-1 / anti-LAG-3 dual-affinity re-targeting (DART) protein, anti-PD-1 / CTLA-4 bispecific antibody, anti-PD-1 / CTLA-4 bispecific antibody, anti-PD-1 / ICOS bispecific antibody, anti-PD-1 / TIM-3 bispecific antibody, anti-PD-1 / PD-L1 bispecific antibody, anti-PD-L1 antibody, protease-activated anti-PD-L1 antibody prodrug. 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 (bifunctional anti-PD-L1 / TGFβ Trap fusion protein), anti-TIM-3 antibody (a fully human Fc-engineered IgG1κ antibody targeting co-inhibitory receptor T-cell)At least one of the following: immunoglobulin and mucin, anti-VISTA antibody, anti-B7-H4 antibody, anti-SIRPa antibody, drug-binding 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), IDO-1 inhibitor, PD-L1 inhibitor, PD-L1 / PD-L2 / VISTA antagonist, and JAK2 / STAT3 inhibitor. (12)

[0401] The cancer prevention and / or treatment agent according to any one of (1) to (9) above, wherein,

[0402] Cancers include 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 / choleduct cancer, bile duct cancer, pancreatic cancer, thyroid cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, uterine endometrial cancer, vaginal cancer, vulvar cancer, kidney cancer, renal pelvis / ureter cancer, urothelial carcinoma, penile cancer, prostate cancer, testicular tumors, bone / soft tissue sarcoma, malignant bone tumors, skin cancer, thymoma, mesothelioma, and cancers of unknown primary origin. (13)

[0404] A cancer prevention and / or treatment agent containing an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. (14)

[0406] A pharmaceutical composition for the prevention and / or treatment of cancer, used in combination with an immune checkpoint inhibitor, comprising an mPGES-1 inhibitor and a pharmaceutically permissible carrier. (15)

[0408] A pharmaceutical composition for the prevention and / or treatment of cancer, comprising an mPGES-1 inhibitor, an immune checkpoint inhibitor, and a pharmaceutically permissible carrier. (16)

[0410] An mPGES-1 inhibitor for use in combination with immune checkpoint inhibitors in the prevention and / or treatment of cancer. (17)

[0412] Use of mPGES-1 inhibitors in the manufacture of pharmaceutical products for use in combination with immune checkpoint inhibitors in the prevention and / or treatment of cancer. (18)

[0414] A method for the prevention and / or treatment of cancer, comprising:

[0415] The mPGES-1 inhibitor was combined with an immune checkpoint inhibitor and administered to the desired recipient.

[0416] The above components can be chosen and combined arbitrarily.

[0417] The effects of the invention

[0418] According to the present invention, preventive and / or therapeutic agents for cancer containing an mPGES-1 inhibitor as an active ingredient for use in combination with immune checkpoint inhibitors, and preventive and / or therapeutic agents for cancer containing both an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients can be provided. Attached Figure Description

[0419] Figure 1 The combined effects of compound 1 and anti-mouse PD-1 antibody in an allogeneic model of mouse colorectal cancer cell line CT26 are shown. In the figure, the combined use indicates the group using compound 1 and anti-mouse PD-1 antibody together.

[0420] Figure 2 The combined effects of compound 2 and anti-mouse PD-1 antibody in an allogeneic model of the mouse colorectal cancer cell line CT26 are shown. In the figure, the combined use indicates the group using compound 2 and anti-mouse PD-1 antibody together.

[0421] Figure 3 The combined effects of compounds 1, 2, and anti-mouse CTLA-4 antibody in an allogeneic model of the mouse colorectal cancer cell line CT26 are shown. In the figure, "combined use" indicates the group using compound 1 and anti-mouse CTLA-4 antibody, and the group using compound 2 and anti-mouse CTLA-4 antibody. Detailed Implementation

[0422] The embodiments of the present invention will be described.

[0423] In one aspect of the invention, a preventive and / or therapeutic agent for chronic prostatitis / pelvic pain syndrome is provided, which contains an mPGES-1 inhibitor as an active ingredient.

[0424] In one aspect of the invention, the mPGES-1 inhibitor may be a commercially available inhibitor and / or an inhibitor that can be manufactured according to conventional methods in the field of organic synthetic chemistry.

[0425] In one aspect of the present invention, the mPGES-1 inhibitor can be used directly as a pharmaceutical product, or it can be prepared into a pharmaceutically permissible salt form using known methods. Examples of such salts include salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and salts of organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid.

[0426] For example, the hydrochloride salt of mPGES-1 inhibitor can be obtained by dissolving the mPGES-1 inhibitor in an alcoholic solution, an ethyl acetate solution, or a diethyl ether solution of hydrogen chloride.

[0427] In one embodiment of the invention, the mPGES-1 inhibitor may have a chiral carbon, and various optical isomers and mixtures thereof can be used as preventive and / or therapeutic agents of the invention. For example, the optical isomers can be optically resolved from racemates obtained as described in the examples below using known methods, utilizing their basicity and optically active acids (tartaric acid, dibenzoyltartaric acid, mandelic acid, 10-camphorsulfonic acid, etc.), or they can be manufactured using pre-prepared optically active compounds as raw materials. Furthermore, they can also be manufactured using optical resolution of chiral columns or asymmetric synthesis.

[0428] In addition, among mPGES-1 inhibitors, for inhibitors that can form tautomers, each tautomer and mixtures thereof can be used as the preventive and / or therapeutic agents of the present invention.

[0429] In one aspect of the invention, the mPGES-1 inhibitor is, for example, a compound of formula [I] above (this compound) or a pharmaceutically permissible salt thereof. This compound can be manufactured from known compounds and / or readily synthesizable intermediates based on the methods described in WO2013 / 024898 and / or known methods.

[0430] Examples of substituents in the compound of formula [I] (this compound) are as follows.

[0431] Examples of "halogens" include fluorine, chlorine, bromine, and iodine.

[0432] The term "alkyl" refers to a linear or branched alkyl group having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. Preferably, the alkyl group has 1 to 6 carbon atoms, and more preferably, it has 1 to 3 carbon atoms.

[0433] As for the alkyl portion of "monoalkylamino", "dialkylamino", "monoalkylaminocarbonyl", "dialkylaminocarbonyl", "alkylcarbonyloxy", "alkyloxycarbonyl", "alkylcarbonyl", "alkylthio", "alkylsulfonyl", "alkylsulfinyl", "alkoxyalkyl", and "alkoxyalkylamino", groups that are the same as the "alkyl" mentioned above can be cited.

[0434] The alkoxy group, as a "alkoxy group", is, for example, a linear or branched alkoxy group with 1 to 8 carbon atoms. Examples include: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, n-heptoxy, and n-octoxy.

[0435] As for the alkoxy moiety in "alkoxyalkoxy", "alkoxyalkyl", and "alkoxyalkylamino", examples can be of groups that are the same as the "alkoxy" mentioned above.

[0436] As a "heteroaryl" group, examples include aromatic rings with one to two rings and having one to three heteroatoms selected from nitrogen, oxygen, and sulfur atoms as constituent atoms. Specific examples include: furanyl (e.g., 2-furanyl, 3-furanyl), 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-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl), and tetrazolyl (e.g., 1-tetrazolyl, 2-tetrazolyl, 5-tetrazolyl). Base (e.g., 2- basal, 4- Base, 5- (base), (different) Base (e.g., 3-iso) 4-iso 5-iso base), Bases (e.g., 1,3,4-) -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), pyridinyl (e.g., 2-pyridinyl, 3-pyridinyl, 4-pyridinyl), pyridazinyl (e.g., 3-pyridazinyl, 4-pyridazinyl), pyrimidinyl (e.g., 2-yl), thiazolyl ...thiazolyl), thiazolyl (e.g., thiazolyl), thiazolyl (e.g., thiazo -pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyrazinyl (e.g., 2-pyrazinyl), benzothiadiazoleyl (e.g., 1,2,3-benzothiadiazole-4-yl, 1,2,3-benzothiadiazole-5-yl, 2,1,3-benzothiadiazole-4-yl, 2,1,3-benzothiadiazole-5-yl), benzothiazolyl (e.g., benzothiazol-2-yl, benzothiazol-4-yl, benzothiazol-5-yl, benzothiazol-6-yl, benzothiazol-7-yl), -yl), indoleyl (e.g., indole-3-yl, indole-4-yl, indole-5-yl, indole-6-yl, indole-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 (e.g., 1,1-dioxo-1-benzothiophen-2-yl), -yl, 1,1-dioxo-1-benzothiophene-3-yl, 1,1-dioxo-1-benzothiophene-4-yl, 1,1-dioxo-1-benzothiophene-5-yl, 1,1-dioxo-1-benzothiophene-6-yl, 1,1-dioxo-1-benzothiophene-7-yl), quinolinyl (quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl), 1,3-benzo[…] -2-base.

[0437] As the heteroaryl moiety of "heteroarylmethyl", the same group as the "heteroaryl" mentioned above can be cited.

[0438] As a "saturated cyclic amino group," it can be, for example, a 4- to 7-membered saturated cyclic amino group that optionally has one O or S as a cyclic atom and optionally has one or two N atoms that are substituted with oxygen. Specific examples include: 1-azacyclobutane, 1-pyrrolidinyl, 1-imidazolyl, piperidinyl, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholinyl, 4-thiomorpholinyl, 1-homoperazinyl, 2-oxo Alkyl-3-yl.

[0439] As the saturated cyclic amino group of a "saturated cyclic amino carbonyl", the same group as the "saturated cyclic amino group" mentioned above can be cited.

[0440] As a "saturated heterocyclic group", it is a 4- to 6-membered saturated heterocyclic group having one N or O as a cyclic atom. Specific examples include: 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2-oxetanebutyl, 3-oxetanebutyl, 2-tetrahydrofuranyl, and 3-tetrahydrofuranyl.

[0441] As a "cycloalkyl", it is a group with 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0442] The cycloalkyl moiety of "cycloalkylmethyl" can be an example of a group that is the same as the "cycloalkyl" mentioned above.

[0443] Examples of "naphthyl" groups include 1-naphthyl and 2-naphthyl.

[0444] Examples of "pyridyl" include 2-pyridyl, 3-pyridyl, and 4-pyridyl.

[0445] Examples of "alkynyl" groups include those with 2 to 6 carbon atoms, either linear or branched. 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.

[0446] In one aspect of the invention, the mPGES-1 inhibitor is, for example, the compounds (1) to (239) described above, or their tautomers or pharmaceutically permissible salts thereof, preferably.

[0447] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0448] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or

[0449] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide or a pharmaceutically permissible salt thereof.

[0450] Further preferred

[0451] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide,

[0452] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride

[0453] N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate,

[0454] N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, or

[0455] N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride.

[0456] When administering this compound or its pharmaceutically permitted salt in the form of a pharmaceutical product, the compound or its pharmaceutically permitted salt may be administered to mammals, including humans, directly or in a pharmaceutically permitted nontoxic and inactive carrier containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%.

[0457] As a carrier, one or more of solid, semi-solid, or liquid diluents, fillers, and other prescription adjuvants may be used. The pharmaceutical composition of the present invention is preferably administered in the form of a dosing unit. The pharmaceutical composition can be administered intra-tissuely, orally, intravenously, topically (transdermal, ophthalmic, intraperitoneal, intrapleural, etc.), or rectally. Of course, it can also be administered in dosage forms suitable for these methods of administration.

[0458] The dosage of the pharmaceutical product is preferably adjusted based on considerations such as the patient's condition (age, weight, type and severity of disease), route of administration, type of compound of the present invention, whether it is a salt, and type of salt. Generally, the effective amount of the compound of the present invention or its pharmaceutically permissible salt for adults is, in the case of oral administration, an average of 0.01 mg to 5 g / ad per adult per day, preferably 1 mg to 1000 mg / adult per day. Depending on the circumstances, sometimes dosages below the above range are sufficient, and sometimes dosages above the above range are required. Generally, it can be administered once a day or divided into several doses, or in the case of intravenous administration, it can be administered rapidly or continuously for up to 24 hours.

[0459] In one aspect of the present invention, the immune checkpoint inhibitor is any substance capable of inhibiting the function (signal) of immune checkpoint molecules, and is not particularly limited.

[0460] In one aspect of the present invention, immune checkpoint molecules refer to molecules that exert immunosuppressive functions by transmitting inhibitory co-signals.

[0461] In one embodiment of the invention, immune checkpoint molecules may include, for example: adenosine A2A receptor, 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, TGFβ2: Transforming Growth Factor beta-2, TIM3: Hepatitis A Virus Cellular Receptor 2. VISTA: V-TypeImmunoglobulin Domain-Containing Suppressor of T-cell Activation, VTCN1 (anti-B7-H4, Ovr110), CD47 / SIRPalpha (Tyrosine-Protein Phosphatase Non-receptor TypeSubstrate 1), Tryptophan-2,3-Dioxygenases: TDO and microtubules, preferably including: 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 A2areceptor), 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), CD115. Any molecule equivalent to these that exerts immunosuppressive function by transmitting inhibitory co-signals is acceptable; there are no particular limitations.

[0462] In one aspect of the present invention, examples of immune checkpoint inhibitors include those selected from adenosine A2A receptor antagonists, adenosine A2B receptor antagonists, anti-5'-nucleotidases (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, and anti-TIM. 3. Immune checkpoint inhibitors with anti-VISTA, anti-VTCN1 (anti-B7-H4, anti-Ovr110), CD47 / SIRPalpha interaction inhibition, tryptophan-2,3-dioxygenase: TDO inhibition, and microtubule polymerization inhibition effects, preferably immune checkpoint inhibitors selected from 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 effects.

[0463] In one aspect of the invention, the immune checkpoint inhibitor is, for example, an inhibitor of human immune checkpoint molecules, preferably a neutralizing antibody against human immune checkpoint molecules.

[0464] In one aspect of the present invention, neutralizing antibodies against human immune checkpoint molecules may include, for example: mab (complete monoclonal antibody), Fab (antigen-binding region fragment, one arm), F(ab')2 (antigen-binding region fragment containing a hinge region, both arm), Fab' (antigen-binding region fragment containing a 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.

[0465] In one aspect of the present invention, the neutralizing antibody against human immune checkpoint molecules is a bispecific monoclonal antibody, which is an artificial protein composed of fragments of two different monoclonal antibodies and binding to two different types of antigens. Examples include: F(ab')2, BiIE, IgG-IgG, Bi-sdAb, CrossMab, TandAb, DART, DVD-Ig, TrioMab, and Triplebody.

[0466] The following are examples of immune checkpoint inhibitors, but immune checkpoint inhibitors are not limited to these.

[0467] In one aspect of the invention, examples of 5'-nucleotidase (CD73) inhibitors, i.e. immune checkpoint inhibitors, include: MCI-186; MT-1186; TW-001; 5798V6YJRP (UNII code); SIM-071201; Y-2; AB-680.

[0468] In one aspect of the invention, examples of adenosine A2A receptor antagonists, i.e. immune checkpoint inhibitors, include: CPI-444; V-81444; 8KFO2187CP (UNII code); NIR-178; PBF-509; AZD-4635; HTL-1071.

[0469] In one aspect of the invention, AB-928 can be cited as an example of an adenosine A2B receptor antagonist, i.e., an immune checkpoint inhibitor.

[0470] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-5'-nucleotidase (NT5E, CD73) activity include: MEDI-9447; 5CRY01URYQ (UNIIcode); BMS-986179; CPI-006; CPX-006; NZV-930; SRF-373; TJ-004309; TJ-4309; TJD-5.

[0471] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-CD154 (anti-CD40L) activity include: CDP-7657; BMS-986004; 449MIE2SD6 (UNII code); MEDI-4920; VIB-4920; INX-021; SAR-441344; AT-1501.

[0472] In one aspect of the present invention, examples of immune checkpoint inhibitors with 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.

[0473] In one aspect of the invention, CDX-1127 can be cited as an example of an immune checkpoint inhibitor with anti-CD27 activity.

[0474] In one aspect 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; MGD-009.

[0475] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-CD70 activity include: ARGX-110 and JNJ-4550.

[0476] In one aspect of the present invention, examples of immune checkpoint inhibitors having antibody CTLA-4 (anti-CD152) activity include: OD1; 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.

[0477] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-DLL1 activity include CT-011 and MDV-9300.

[0478] In one aspect of the invention, TTX-030 can be cited as an example of an immune checkpoint inhibitor with anti-ENTPD1 (anti-CD39) activity.

[0479] In one aspect of the invention, BAY-1905254 can be cited as an example of an immune checkpoint inhibitor with anti-ILDR2 (anti-C1orf32) activity.

[0480] In one aspect of the present invention, examples of immune checkpoint inhibitors with 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; hu317-1 / IgG4mt2; OKVO411B3N (UNIIcode); REGN-2810; SAR-439684; 6QVL057INT (UNIIcode); PDR-001; HR-301210; INCSHR-01210; SHR-1210; MGD-013; PF-06801591; RN-888; LZZ0IC2EWP (UNIIcode); BCD-100; C-90006; NCMGA-00012; INCMGA-0012; MGA-012; ABBV-181; AGEN-2034w; GLS-010; WBP-3055; AK-104; 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; ONO-4685.

[0481] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-PD-L1 (anti-CD274) activity include: 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(UNIIcode);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;H TI-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.

[0482] In one aspect of the present invention, COM-701 can be cited as an example of an immune checkpoint inhibitor with anti-PVRIG activity.

[0483] In one aspect of the present invention, examples of immune checkpoint inhibitors against TGFbeta2 include: M-7824; MSB-0011359C.

[0484] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-TIM3 activity include: MBG-453; APE-5137; TSR-022; WBP-296A; 3K5H4TX2KP (UNIIcode); LY-3321367; BGB-A425; BMS-986258; ONO-7807; Sym-023; INCAGN-02390; INCAGN-2390.

[0485] In one aspect of the present invention, examples of immune checkpoint inhibitors with anti-VISTA (anti-VSIR) activity include: JNJ-61610588; 1UI8F5IIZ4 (UNII code).

[0486] In one aspect of the invention, FPA-150 can be cited as an example of an immune checkpoint inhibitor having anti-VTCN1 (anti-B7-H4; anti-Ovr110) activity.

[0487] In one aspect of the invention, examples of CD47 / SIRPalpha interaction inhibitors, i.e., immune checkpoint inhibitors, include BI-765063, Effi-DEM, and OSE-172.

[0488] In one aspect of the present invention, MK-1308 can be cited as an example of a cytotoxic T-cell protein 4 inhibitor, i.e., an immune checkpoint inhibitor.

[0489] In one aspect of the invention, MGC-018 can be cited as an example of a DNA alkylating agent, i.e., an immune checkpoint inhibitor.

[0490] In one aspect of the invention, examples of immune checkpoint inhibitors that interact with Tumor Necrosis Factor Receptor SuperfamilyMember 4 (OX40, CD134) include: PD-1-Fc-OX40L; SL-279252; TAK-252.

[0491] In one aspect of the present invention, examples of immune checkpoint inhibitors targeting Programmed Cell Death 1 Ligand 1 (PD-L1;CD274) include: ES-101; INBRX-105; INBRX-105-1; GS-4224.

[0492] In one aspect of the present invention, examples of indoleamine 2,3-diaddition oxidase 1 (IDO1; IDO) inhibitors, i.e. immune checkpoint inhibitors, include: D-1MT; NLG-8189; NSC-721782; INCB-024360; INCB-24360; 71596A9R13 (UNII code); BMS-986205; F-001287; ONO-7701; 0A7729F42K (in hydrochloride form); EOS-200271; PF-06840003; KHK-2455; NLG-802; LY-3381916.

[0493] In one aspect of the invention, INCB-086550 can be cited as an example of an inhibitor of the Programmed Cell Death 1 (PDCD1; PD-1; CD279) / PD-1 Ligand 1 (PD-L1; CD274) interaction, i.e., an immune checkpoint inhibitor.

[0494] In one aspect of the invention, examples of Programmed Cell Death 1 Ligand 1 (PD-L1;CD274) antagonists, i.e. immune checkpoint inhibitors, include, for example, AUPM-170 and CA-170.

[0495] In one aspect of the invention, WP-1066 can be cited as an example of a Signal Transducer and Activator of Transcription 3 (STAT3) inhibitor, i.e., an immune checkpoint inhibitor.

[0496] In one aspect of the invention, examples of tryptophan-2,3-dioxygenase (TDO) inhibitors, i.e. immune checkpoint inhibitors, include: HTI-1090; SHR-9146; M-4112; DN-1406131; LPM-3480226; LY-01013.

[0497] In one aspect of the invention, SGN-CD48A can be cited as an example of a microtubule polymerization inhibitor, i.e., an immune checkpoint inhibitor.

[0498] In one aspect of the invention, the immune checkpoint inhibitor is, for example, an anti-CTLA-4 antibody (e.g., Ipilimumab (YERVOY (registered trademark)), Tremelimumab), an anti-PD-1 antibody (e.g., human anti-human PD-1 monoclonal (neutralizing) antibody (e.g., Nivolumab (OPDIVO (registered trademark)), REGN-2810), a humanized anti-human PD-1 monoclonal (neutralizing) antibody (e.g., Pembrolizumab (KEYTRUDA (registered trademark)), PDR-001, BGB-A317, AMP-514 (MEDI0680)), an anti-PD-L1 antibody (e.g., Atezolizumab (RG7446, MPDL3280A), Avelumab (PF-06834635, MSB0010718C), Durvalumab). (MEDI4736), BMS-936559), anti-PD-L2 antibody, PD-L1 fusion protein, PD-L2 fusion protein (e.g., AMP-224), anti-Tim-3 antibody (e.g., MBG453), anti-LAG-3 antibody (e.g., BMS-986016, LAG525), anti-KIR antibody (e.g., Lirilumab), etc.

[0499] In one embodiment of the invention, the immune checkpoint inhibitor used in the combination of the invention is preferably an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, a PD-L1 fusion protein, or a PD-L2 fusion protein. More preferably, it is an anti-CTLA-4 antibody, an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-PD-L2 antibody, a PD-L1 fusion protein, or a PD-L2 fusion protein. Particularly preferred are anti-CTLA-4 antibodies and anti-PD-1 antibodies.

[0500] In one aspect of the invention, any one or more of these immune checkpoint inhibitors may be used in combination with the compounds used in the invention.

[0501] In one aspect of the invention, the dosage of the immune checkpoint inhibitor used in the combination of the invention varies depending on age, weight, symptoms, treatment effect, method of administration, treatment time, etc., and can be adjusted in a way that brings about the optimal desired effect.

[0502] In one embodiment of the invention, for example, when using an anti-PD-1 antibody, the dosage is 0.1 to 20 mg / kg body weight. For example, when using nivolumab, the dosage is 0.3 to 10 mg / kg body weight, preferably 2 mg / kg, 3 mg / kg, or 6 mg / kg body weight.

[0503] In one embodiment of the invention, for example, when using an anti-CTLA-4 antibody, the dosage is typically 0.1 to 20 mg / kg body weight. Preferably, it is 0.1 to 10 mg / kg body weight, more preferably 3 mg / kg or 10 mg / kg body weight.

[0504] In one aspect of the invention, for example, for cancer patients whose treatment with immune checkpoint inhibitors alone is not satisfactory, the combination of the present invention is particularly expected to maximize its anti-tumor effect. Furthermore, the combination of the present invention can also reduce the dosage of each agent, and is expected to reduce side effects.

[0505] Example

[0506] The present invention will be described in more detail below with reference examples, examples, test examples and formulation examples, but the present invention is not limited thereto.

[0507] The test compounds used in Test Examples 1 and 2 are described below.

[0508] The compounds used in Test Examples 1 and 2 were prepared and used according to Examples 1 to 249 of WO2013 / 024898. The activity data of the compounds used in Test Examples 1 and 2 are shown in Tables 1 to 17 of WO2013 / 024898.

[0509] Experimental Example 1: mPGES-1 Inhibitory Activity Assay

[0510] mPGES-1 microsomal samples were prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. The mPGES-1 microsomal samples were diluted in potassium phosphate buffer (pH 7.4) containing reduced glutathione, and then incubated at 4°C for 20 minutes with either DMSO solution containing the test compound or DMSO (final concentration of 1%). The enzyme reaction was then initiated by adding a solution to adjust the PGH2 substrate to a final concentration of 1 μM and incubated 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 PGE2 produced was quantified using an HTRF kit (Cisbio International catalog #62P2APEC). A solution without the test compound served as a positive control, and a solution without both the test compound and the microsomal sample served as a negative control. 100% activity was defined as the amount of PGE2 produced in the positive control after subtracting the amount produced in the negative control. Next, the IC50 value was determined using standard methods.

[0511] Experiment 2: Inhibition of PGE2 and PGF2α production using A549 cells.

[0512] Human A549 cells were seeded at 100 μL / well (96-well plate) for 2 × 10⁶ cells. 4 The culture medium was incubated overnight. Then, the medium was removed, washed with phosphate-buffered saline, and replaced with DMSO solution containing the test compound, or RPMI medium containing 3% FBS and DMSO (final DMSO concentration 0.1%). After 60 minutes of incubation, IL-1β (5 ng / well) was added, and the medium was incubated at 37°C for 24 hours. PGE2 in the medium was then quantified using an HTRF kit (Cisbio International catalog #62P2APEC) and PGF2α was quantified using an EIA kit (Cayman Chemical Company catalog #516011). A solution without the test compound was used as a positive control, and a solution without the test compound and IL-1β was used as a negative control. 100% activity was defined as the amount of PGE2 and PGF2α produced in the positive control after subtracting the amount produced in the negative control. The IC50 value was then determined using standard methods.

[0513] The compounds used in Experimental Example 3 are described below.

[0514] Compound 1 and Compound 2:

[0515] 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 (hereinafter also referred to as Compound 1 and Compound 2) were prepared and used according to Examples 239 and 89 of WO2013 / 024898.

[0516] Experimental Example 3: The combined effect of mPGES-1 inhibitors and immune checkpoint inhibitors in a mouse allogeneic model of CT26 colorectal cancer cells.

[0517] In an allogeneic transplantation model of the mouse colorectal cancer cell line CT26 (Cancer Res. (2013), 73(12), p3591-603), the combined effects of mPGES-1 inhibitors (compounds 1 and 2) and immune checkpoint inhibitors (anti-mouse PD-1 antibody) were evaluated.

[0518] 1. Test drug

[0519] Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate,

[0520] Compound 2: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0521] Anti-mouse PD-1 antibody: InVivoMAb anti-mouse PD-1 (CD279) (Bio X Cell, Inc. (West Lebanon, NH, USA))

[0522] 2. Preparation of cells for transplantation

[0523] 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, after removing the culture supernatant, the CT26 cells were washed with HBSS and recovered. The recovered CT26 cells were then resuspended in HBSS to prepare cells for transplantation.

[0524] 3. Preparation of allogeneic transplantation models

[0525] Under anesthesia, 3.0 × 10⁻⁶ slits were subcutaneously transplanted into the right abdomen of female BALB / c mice. 5 Cells for transplantation. On day 7 after transplantation, the mice were divided into four groups of 4-6 mice each: control group, mPGES-1 inhibitor (compounds 1 and 2) group alone, anti-mouse PD-1 antibody group alone, and combination group (compound 1 or 2 and anti-mouse PD-1 antibody).

[0526] 4. Determination of antitumor activity

[0527] From day 7 to day 20 after transplantation, mice in the single and combined groups of compound 1 or 2 were repeatedly orally administered compound 1 or 2 at 100 mg / kg (based on free bodies) twice a day.

[0528] From day 7 to day 20 after transplantation, mice were administered anti-mouse PD-1 antibody intraperitoneally twice a week after transplantation at a dose of 100 μg / individual in both the single and combined groups.

[0529] It should be noted that mice in the mediator group and the anti-mouse PD-1 antibody group were repeatedly orally administered 5% methylcellulose and compound 1 or 2 during the same period.

[0530] In addition, mice in the mediator group and the compound 1 or 2 group alone were administered D-PBS and anti-mouse PD-1 antibody intraperitoneally at the same time.

[0531] The length and width of the tumor were measured using an electronic micrometer, and the tumor volume (mm) was calculated using the following formula. 3 ).

[0532] [Mathematical Expression 1]

[0533] Tumor volume = major axis × (minor axis) 2 / 2

[0534] Figure 1 and 2 The tumor volume of each group on day 21 after transplantation is shown in the figure.

[0535] Compound 1 or 2 alone did not inhibit tumor proliferation, but when used in combination with an anti-mouse PD-1 antibody, tumor proliferation was inhibited.

[0536] Experimental Example 4: The effect of combined use of mPGES-1 inhibitors and immune checkpoint inhibitors in a mouse allogeneic model of CT26 colorectal cancer cell line

[0537] In an allogeneic transplantation model of the mouse colorectal cancer cell line CT26 (Cancer Res. (2013), 73(12), p3591-603), the combined efficacy of mPGES-1 inhibitors (compounds 1 and 2) and immune checkpoint inhibitors (anti-mouse CTLA-4 antibody) was evaluated.

[0538] 1. Test drug

[0539] Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide-4-methylbenzenesulfonate,

[0540] Compound 2: N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide

[0541] Anti-mouse CTLA-4 antibody: InVivoMAb anti-mouse CTLA-4 (CD152) (Bio X Cell, Inc. (West Lebanon, NH, USA))

[0542] 2. Preparation of cells for transplantation

[0543] 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, after removing the culture supernatant, the CT26 cells were washed with HBSS and recovered. The recovered CT26 cells were then resuspended in HBSS to prepare cells for transplantation.

[0544] 3. Preparation of allogeneic transplantation models

[0545] Under anesthesia, 3.0 × 10⁻⁶ slits were subcutaneously transplanted into the right abdomen of female BALB / c mice. 5 Cells for transplantation. On day 7 after transplantation, the mice were divided into six groups of three: control group, mPGES-1 inhibitor (compounds 1 and 2) alone group, anti-mouse CTLA-4 antibody alone group, and combination group (compound 1 or 2 and anti-mouse CTLA-4 antibody).

[0546] 4. Determination of antitumor activity

[0547] From day 8 to day 20 after transplantation, mice in the single and combined groups of compound 1 or 2 were repeatedly orally administered compound 1 or 2 at 100 mg / kg (based on free bodies) twice a day.

[0548] From day 8 to day 20 after transplantation, mice were administered anti-mouse CTLA-4 antibody intraperitoneally twice a week at a dose of 100 μg / individual in both the single and combined groups.

[0549] It should be noted that mice in the mediator group and the anti-mouse CTLA-4 antibody group were repeatedly orally administered 5% methylcellulose and compound 1 or 2 during the same period.

[0550] In addition, mice in the mediator group and the compound 1 or 2 group alone were administered D-PBS and anti-mouse CTLA-4 antibody intraperitoneally at the same time.

[0551] The length and width of the tumor were measured using an electronic micrometer, and the tumor volume (mm) was calculated using the following formula. 3 ).

[0552] [Mathematical Expression 2]

[0553] Tumor volume = major axis × (minor axis) 2 / 2

[0554] Neither compound 1 nor compound 2 alone inhibited tumor proliferation, but when used in combination with an anti-mouse CTLA-4 antibody, tumor proliferation was inhibited.

[0555] Formulation Example 1

[0556] Tablets (for oral administration)

[0557] In one 80mg tablet of the prescription

[0558] 5.0 mg of this compound

[0559] Corn starch 46.6mg

[0560] Crystalline cellulose 24.0mg

[0561] Methylcellulose 4.0mg

[0562] Magnesium stearate 0.4 mg

[0563] The mixed powder in this proportion is compressed into tablets using conventional methods to produce oral tablets.

[0564] Industrial applicability

[0565] This invention relates to a cancer prevention and / or treatment agent containing an mPGES-1 inhibitor as an active ingredient for use in combination with immune checkpoint inhibitors, and has industrial applicability.

Claims

1. A cancer prevention and / or treatment agent comprising an mPGES-1 inhibitor and an immune checkpoint inhibitor as active ingredients. The mPGES-1 inhibitor is selected from the following compounds, or their tautomers or pharmaceutically permissible salts: (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, The immune checkpoint inhibitor is an anti-PD-1 antibody and / or an anti-CTLA-4 antibody.

2. The use of mPGES-1 inhibitors in the manufacture of cancer prevention and / or therapeutic agents. The cancer prevention and / or treatment agents use immune checkpoint inhibitors. The mPGES-1 inhibitor is selected from the following compounds, or their tautomers or pharmaceutically permissible salts: (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, The immune checkpoint inhibitor is an anti-PD-1 antibody and / or an anti-CTLA-4 antibody.

3. Use of immune checkpoint inhibitors in the manufacture of cancer prevention and / or therapeutic agents, wherein the cancer prevention and / or therapeutic agents utilize mPGES-1 inhibitors. The mPGES-1 inhibitor is selected from the following compounds, or their tautomers or pharmaceutically permissible salts: (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, The immune checkpoint inhibitor is an anti-PD-1 antibody and / or an anti-CTLA-4 antibody.

4. The use of a combination of mPGES-1 inhibitors and immune checkpoint inhibitors in the manufacture of pharmaceuticals for the prevention and / or treatment of cancer. The mPGES-1 inhibitor is selected from the following compounds, or their tautomers or pharmaceutically permissible salts: (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, The immune checkpoint inhibitor is an anti-PD-1 antibody and / or an anti-CTLA-4 antibody.

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