Prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome

Abstract

The present invention pertains to a prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome, said agent comprising an mPGES-1 inhibitor as an active ingredient.

Description

Preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome

[0001] The present invention relates to an agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, which contains an mPGES-1 inhibitor as an active ingredient.

[0002] Prostatitis is classified by the US National Institutes of Health (NIH) into four categories (acute bacterial prostatitis, chronic bacterial prostatitis, chronic prostatitis / chronic pelvic pain syndrome, and asymptomatic inflammatory prostatitis) (Non-Patent Document 1). Category I is acute bacterial prostatitis, which is caused by bacterial infection and is accompanied by systemic symptoms such as urinary symptoms, pain, and fever. Category II is chronic bacterial prostatitis, which is a chronic version of Category I and is characterized by symptoms of recurrent bacterial infection. Category III is chronic prostatitis / chronic pelvic pain syndrome, which is classified as a disease characterized by pain / discomfort in the perineum, testicles, penis, and lower abdomen, as well as urinary symptoms such as a feeling of incomplete urination and frequent urination. Category IV asymptomatic inflammatory prostatitis is asymptomatic, but inflammatory findings are observed in prostate biopsy tissue specimens, expressed prostatic fluid, and semen. It has also been reported that the expression of IL-1β is significantly increased in the seminal plasma of patients with chronic prostatitis, and that the expression of MIP-1α and MCP-1 is significantly increased in the expressed prostatic fluid of patients with chronic prostatitis (Non-Patent Documents 2 and 3).

[0003] However, unlike acute bacterial prostatitis of category I and chronic bacterial prostatitis of category II, the cause of chronic prostatitis / chronic pelvic pain syndrome of category III is unknown, and no effective treatment has been found.

[0004] It is known that there are three subtypes of PGE2 synthase (PGES): membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2, and cytosolic PGES (cPGES) (Non-Patent Documents 4 to 6). Like COX-2, mPGES-1 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 7, 8, and 9).

[0005] Patent Document 1 describes that a heterocyclic derivative represented by general formula [1], a tautomer thereof, or a pharmaceutically acceptable salt thereof has mPGES-1 inhibitory activity. Patent Documents 2 and 3 describe low molecular weight compounds having mPGES-1 inhibitory activity. Non-Patent Document 10 describes that Kanefron (registered trademark) N contains plant-derived components and has mPGES-1 inhibitory activity.

[0006] However, the relationship between chronic prostatitis and the mPGES-1 pathway has not been reported so far.

[0007] Patent Document 1: WO2013 / 024898 Patent Document 2: WO2011 / 023812 Patent Document 3: WO2017 / 073709

[0008] Non-patent document 1: JAMA. 1999 Jul. 21;282(3):236-7. Non-patent document 2: Int. J. Urol. 2001 Sep;8(9):495-499 Non-patent document 3: J. Urol. 2008 May; 179(5):1857-1862. Non-Patent Document 4: Jakobsson et al., Proc. Natl. Acad. Sci. USA, 1999, 96, 7220-7225 Non-patent document 5: Biochem. Biophys. Res. Commun. , 2002, 291, 884-889 Non-patent document 6: J. Biol. Chem. , 2000, 275, 32775-32782 Non-patent document 7: J. Biol. Chem. , 2003, 278 (21), 19396-19405 Non-patent document 8: Oncogene, 2012, 31 (24), 2943-2952 Non-patent document 9: Cancer Res. , 2008, 68(9), 3251-3259 Non-patent document 10: j. phymed. 2019,60,152987

[0009] The problem to be solved by the present invention is to provide an agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome.

[0010] The present inventors began elucidating the pathology of chronic prostatitis / chronic pelvic pain syndrome and found that the mPGES-1 pathway is involved in chronic prostatitis / chronic pelvic pain syndrome. Furthermore, the present inventors discovered that the use of an mPGES-1 inhibitor can reduce pain and inflammation in an animal model of chronic prostatitis, leading to the completion of the present invention.

[0011] The present invention relates to

[0012] (1) A prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor as an active ingredient. (2) The prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome 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 represented by the following formula [1]: [Wherein, ring A is represented by formula [2], [3], or [4]: (In the formula, X １ is NH, N-alkyl, or O; １ is hydrogen or alkyl; ２ is i) hydrogen, ii) halogen, iii) 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, wherein the alkyl is optionally substituted with 1 to 3 halogen, v) alkoxy, vi) saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo, vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the formula [5]: (In the formula, R ３ , R ４are the same or different and are a) hydrogen, b) 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), and 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 said phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are optionally substituted with 1 to 3 groups selected from the group consisting of i) halogen, 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; R ２ is phenyl or pyridyl, and the phenyl or pyridyl may be substituted with 1 to 3 groups selected from the group consisting of i) halogen, 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.１ (4) The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to (2) above, wherein R is NH. １ (5) The prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to (2) or (3), wherein R 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-dihydrocyclobutabenzene-3-yl, or 1,2-dihydrocyclobutabenzene-4-yl, and the phenyl is optionally substituted with 1 to 3 groups selected from the group consisting of i) halogen, ii) alkyl optionally substituted with 1 to 3 halogens, iii) alkoxy, and iv) cyano. ２ (6) The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (4), wherein X is phenyl, and the phenyl is optionally substituted with 1 to 3 groups selected from the group consisting of i) halogen, 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. １ is NH, and A ２is i) hydrogen, ii) 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 with alkyl optionally substituted with 1 to 3 halogens, iv) alkoxy, v) 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, and R １ is i) phenyl optionally substituted by 1 to 3 groups selected from the group consisting of halogen, alkyl optionally substituted by 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 by halogen or alkyl optionally substituted by 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; and R ２(7) The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (5), wherein ring A is a group represented by general formula [4], and X represents phenyl or pyridyl, and the phenyl is optionally substituted with 1 to 3 groups selected from the group consisting of i) halogen, 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 the pyridyl is optionally substituted with halogen. １ is NH, and A ２ is alkyl substituted with alkoxy, dialkylamino, tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino, or cycloalkyl which may be unsubstituted or substituted with 1 to 3 halogen-substituted alkyl, and R １ is phenyl substituted with one halogen and one methyl, R ２is phenyl optionally substituted with one trifluoromethyl or two halogens. (8) The mPGES-1 inhibitor is selected from the group consisting of: (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; and (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-benzimidazole-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) The prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (7), which is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. (9) The mPGES-1 inhibitor is selected from the group consisting of 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,The preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (8), which is a compound selected from the group consisting of 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, or a tautomer thereof, or a pharmaceutically acceptable salt thereof. (10) A pharmaceutical composition for the prevention and / or treatment of chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor and a pharmaceutically acceptable carrier. (11) An mPGES-1 inhibitor for use in the prevention and / or treatment of chronic prostatitis / chronic pelvic pain syndrome. (12) Use of an mPGES-1 inhibitor in the manufacture of a medicament for the prevention and / or treatment of chronic prostatitis / chronic pelvic pain syndrome. (13) A method for the prevention and / or treatment of chronic prostatitis / chronic pelvic pain syndrome, comprising administering an mPGES-1 inhibitor to a subject in need thereof.

[0013] The above-mentioned configurations can be arbitrarily selected and combined.

[0014] The therapeutic and / or therapeutic agent of the present invention exhibits therapeutic and / or preventive effects on chronic prostatitis / chronic pelvic pain syndrome, and is therefore useful for treating and / or preventing chronic prostatitis / chronic pelvic pain syndrome.

[0015] The results of evaluation of the analgesic effect of test compounds 1 to 5 in a chronic autoimmune prostatitis model are shown below.

[0016] An embodiment of the present invention will be described.

[0017] In one aspect of the present invention, there is provided an agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, which comprises an mPGES-1 inhibitor as an active ingredient.

[0018] 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 organic synthetic chemistry.

[0019] In one embodiment of the present invention, the mPGES-1 inhibitor can be used as a pharmaceutical directly, or can be used in the form of a pharmaceutically acceptable salt by a known method. Examples of such salts include salts of mineral 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. For example, the hydrochloride salt of the 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.

[0020] 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 optically resolving 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, the mPGES-1 inhibitor can be produced by optical resolution using a chiral column or asymmetric synthesis. Furthermore, for mPGES-1 inhibitors that can form tautomers, each tautomer and a mixture thereof can be used in the preventive and / or therapeutic agent of the present invention.

[0021] 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.

[0022] In the compound of formula [I] (the present compound), each substituent is exemplified as follows. Examples of "halogen" include fluorine, chlorine, bromine, and iodine. Examples of "alkyl" include linear or branched alkyls having 1 to 8 carbon atoms, specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, and n-octyl. Among these, alkyls having 1 to 6 carbon atoms are preferred, and alkyls having 1 to 3 carbon atoms are more preferred. Examples of the alkyl moiety of "monoalkylamino," "dialkylamino," "monoalkylaminocarbonyl," "dialkylaminocarbonyl," "alkylcarbonyloxy," "alkyloxycarbonyl," "alkylcarbonyl," "alkylthio," "alkylsulfonyl," "alkylsulfinyl," "alkoxyalkyl," and "alkoxyalkylamino" include the same as those described above for "alkyl." Examples of the alkoxy moiety of "alkoxy" include linear or branched 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. Examples of the alkoxy moiety of "alkoxyalkoxy," "alkoxyalkyl," and "alkoxyalkylamino" include the same as those described above for "alkoxy." Examples of "heteroaryl" include mono- or bicyclic aromatic rings having 1 to 3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms. 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-triazol-1-yl, 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-benzothiophene 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, 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. Examples of the heteroaryl moiety of "heteroarylmethyl" include those similar to those described above for "heteroaryl." Examples of "saturated cyclic amino" include, for example, 4- to 7-membered saturated cyclic amino groups 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, specifically 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, 1-homopiperazinyl, and 2-oxooxazolidin-3-yl. Examples of the saturated cyclic amino moiety of "saturated cyclic aminocarbonyl" include those similar to those described above for "saturated cyclic amino." Examples of "saturated heterocyclic groups" include 4- to 6-membered saturated heterocyclic groups having one N or O ring atom, specifically 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 cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of the cycloalkyl moiety of "cycloalkylmethyl" include the same as those described above for "cycloalkyl." Examples of "naphthyl" include 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.

[0023] In one embodiment 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 is 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, and 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.

[0024] When the present compound or a pharmaceutically acceptable salt thereof is administered as a medicine, it is administered to mammals including humans as it 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.

[0025] The carrier may be one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliary agents. 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.

[0026] The pharmaceutical dose is desirably 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 or not it is a salt, and the type of salt, but typically, in the case of oral administration to an adult, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof is within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Typically, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a bolus or continuously for up to 24 hours.

[0027] 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.

[0028] 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.

[0029] Test Example 1: mPGES-1 Inhibitory Activity Test. mPGES-1 microsome preparations were prepared from CHO-K1 cells transiently transfected with a plasmid encoding human mPGES-1 cDNA. The mPGES-1 microsome preparations were diluted in potassium phosphate buffer (pH 7.4) containing reduced glutathione, and 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 solution of PGH2 substrate 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 the test compound was used as a positive control, and a solution without the test compound and microsome preparation was used 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.

[0030] Test Example 2: Inhibition of PGE2 and PGF2α production using A549 cells Human A549 cells 2 x 10 ４Cells were seeded at 100 μL / well (96-well plate) and incubated overnight. The medium was then removed and washed with phosphate-buffered saline, and replaced with a DMSO solution of the test compound or RPMI medium containing 3% FBS containing DMSO (final DMSO concentration: 0.1% in both cases). After 60 minutes of incubation, IL-1β (5 ng / well) was added and incubated at 37°C for 24 hours. 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 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 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.

[0031] The test compounds used in Test Examples 3 to 8 are as follows:

[0032] Test Compound 1 and Test Compound 2: Test Compound 1: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and Test 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 Test Compound 1 and Test Compound 2). Test compound 3: Test compound 3: N-cyclopentyl-1-(1-isopropyl-5,6-dimethyl-1H-benzo[d]imidazol-2-yl)piperidine-4-carboxamide was prepared and used as described in Example 9 of WO 2011 / 023812. Test compound 4: Test compound 4: N-[4-chloro-3-(5-cyano-6-oxo-4-thiophen-3-yl-1,6-dihydropyrimidin-2-yl)benzyl]-2,2-dimethylpropionamide was prepared and used as described in Example 2 of WO 2017 / 073709. Kanefron (registered trademark) N was purchased commercially and used.

[0033] Test Example 3: Evaluation of analgesic effect in an autoimmune chronic prostatitis model The analgesic effect of test compounds 1 to 4 was evaluated by the following method using an experimental autoimmune prostatitis (EAP) model, which is a commonly used model for chronic prostatitis. Prostates were excised from 14-week-old male Wistar rats (Japan SLC Co., Ltd.) and homogenized in ice-cooled PBS (Cat. No. 045-29795, Fujifilm Wako Pure Chemical Industries, Ltd.) supplemented with cComplete™ Mini, EDTA-free (Cat. No. 11836170001, Roche Diagnostics GmbH) using a handy microhomogenizer (NS-310E, Microtec Nichion Corporation). The mixture was then centrifuged at 10,000 x g for 30 minutes at 4°C using a centrifuge (Allegra X-30R, Beckman Coulter) to recover the supernatant. The protein concentration was quantified using a DC™ protein assay kit (Cat. No. 500-0112, BIO-RAD Laboratories) and a microplate reader SpectraMax® M5 (Molecular Devices), and then stored at -20°C. 2. Method for preparing EAP models Equal amounts of PAg and Complete Freund's adjuvant (Cat. No. 263810, Becton Dickinson) were mixed to prepare an emulsion with a PAg protein concentration of 5 mg / 250 μL. Male Wistar rats (Japan SLC, Inc.), aged 9 weeks, were anesthetized with isoflurane and administered 250 μL of the emulsion intradermally into the soles of both hind paws and the base of the tail as a primary immunization. A similar treatment was administered 28 days after the primary immunization as a booster immunization. The sham-treated group received an emulsion of equal amounts of saline (Cat. No. 35081517, Otsuka Pharmaceutical Factory) and Complete Freund's adjuvant (Reference: Prostate. 2018 Nov;78(15):1157-1165).3. Grouping Method 37 days after the initial immunization, pre-values ​​were measured using the pain assessment method described below, and the animals were divided into groups so that there were no significant differences in the pain response rate or AUC at each stimulation intensity. Grouping was performed by stratified randomization using SAS version 9.3 and EXSUS version 8.1. 4. Pain Assessment Method 42 days after the initial immunization, the test substance was prepared in a 0.5% methylcellulose aqueous solution as a vehicle at 100 mg / kg (free form equivalent) and orally administered at 10 mL / kg. Pain assessment was performed 4 hours after administration. Rats were placed on a wire mesh for 30 minutes prior to assessment to allow for acclimation. Three types of von Frey filaments (Touch Test (registered trademark), Cat. Nos. NC12775-06, NC12775-08, NC12775-11, manufactured by North Coast Medical) weighing 0.4, 1, and 4 g with different stimulation intensities were pressed against the lower abdomen of the rats from beneath the wire mesh for 1 to 2 seconds, and the presence or absence of an escape response (e.g., running away, licking the stimulated area) was observed. Stimulation was performed five times at each stimulation intensity, beginning with the weakest filament, and the percentage of animals that showed an escape response was calculated to obtain the escape response rate (%). The area under the curve (AUC) was calculated from a line graph created from the stimulation intensity and the escape response rate. Statistical Analysis Summary statistics calculation and statistical analysis were performed using Microsoft Office Excel 2016 (registered trademark), SAS version 9.3, and EXSUS version 8.1. The mean and standard error of AUC for each group were calculated, and Student's t-tests were performed between the sham group and the EAP model-vehicle administration group, and between the EAP model-vehicle administration group and the EAP model-drug administration group. 6. Test Results The analgesic effects of test compounds 1 to 5 in the EAP model are shown in Figure 1.

[0034] Test Example 4: Evaluation of anti-inflammatory effect in normal human prostatic stromal cells 1. Cell culture Normal human prostatic stromal cells (WPMY-1 cells, Cat. No. CRL-2854™) purchased from ATCC (registered trademark) were subcultured using a growth medium at 37°C and 5% CO2. The growth medium used was DMEM (Cat. No. 08458-45, manufactured by Nacalai Tesque, Inc.) containing a final concentration of 5% inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare), a final concentration of 20 U / mL penicillin, and 20 μg / mL streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, manufactured by Nacalai Tesque, Inc.). 2. Cell seeding and drug treatment: On the day before each test compound treatment, WPMY-1 cells were suspended in growth medium and seeded into a Falcon® Cell Culture 12-well multiwell plate (Cat. No. 353043, Corning) at 57,000 cells / well. The WPMY-1 cells seeded in the 12-well plate were incubated at 37°C and 5% CO ２ The cells were cultured overnight under these conditions. The test substances were treated the day after seeding. First, a 10 mM DMSO solution was prepared using DMSO (Cat. No. 13445-74, manufactured by Nacalai Tesque, Inc.) and diluted to 10 μM using assay medium. However, for Canephron, a 1000 mg / mL DMSO solution was prepared and diluted to 1000 μg / mL using assay medium. DMEM (Cat. No. 08458-45, manufactured by Nacalai Tesque, Inc.) containing a final concentration of 2% heat-inactivated fetal bovine serum (Cat. No. SH30910, manufactured by GE Healthcare), a final concentration of 20 U / mL penicillin, and a final concentration of 20 μg / mL streptomycin (penicillin-streptomycin mixed solution, Cat. No. 26253-84, manufactured by Nacalai Tesque, Inc.) was used as the assay medium. The growth medium was removed and replaced with assay medium containing each test substance, and then the cells were incubated at 37°C, 5% CO ２The cells were cultured for 24 hours under the conditions of 3. Cytokine stimulation. Cytokine stimulation was performed 24 hours after treatment with each test substance. An assay medium containing 1 ng / mL each of IL-17 (Cat. No. 200-17, Pepro Tech), TNF-α (Cat. No. 300-01A, Pepro Tech), and IFN-γ (Cat. No. 300-02, Pepro Tech) was prepared as the cytokine stimulation medium. Each test substance was diluted using the cytokine stimulation medium in the same manner as the previous day, and the cells were treated with each test substance and cytokine. The incubation temperature was 37°C, 5% CO ２The cells were cultured under these conditions for 5 hours and then harvested. 4. Gene Expression Analysis Total RNA was extracted from the cells using the RNeasy® Mini Kit (Cat. No. 74106, Qiagen) according to the manufacturer's protocol, and the RNA concentration was measured using NanoDrop™ ONE (Cat. No. ND-ONE-W, Thermo Scientific). 500 ng of RNA was reverse transcribed using ReverTra Ace® qPCR RT Master Mix (Cat. No. FSQ-201, Toyobo) and a Biometra Advanced 96SG (BM Instruments). CCL2 gene expression levels were assessed using reverse-transcribed cDNA and TB Green® Premix Ex Taq II (Cat. No. RR820, Takara Bio Inc.) with a LightCycler® 480 Real-Time PCR System (Roche Diagnostics GmbH). The CCL2 primers used were Fw: AGCAGCAAGTGTCCCAAAGA, Rv: GGTGGTCCATGGAATCCTGA. The Δ threshold cycle (Ct) method (2-ΔΔCt) was used to calculate the ratio of mRNA levels in each treatment group to those in the NT (non-treated) group, thereby calculating the percent change. All data were normalized for GAPDH. The PCR conditions were 95°C for 10 minutes, followed by 45 cycles of 95°C for 15 seconds and 60°C for 1 minute. 5. Test Results The test compound suppressed the expression of inflammatory cytokine / chemokine (CCL2) in normal human prostate stromal cells (WPMY-1 cells), demonstrating anti-inflammatory effects (Table 1).

[0035] Test Example 5: Evaluation of anti-inflammatory effect in an autoimmune chronic prostatitis model 1. Preparation of protein solution EAP model rats were prepared in the same manner as in Test Example 1, and the test substance was administered for 42 days after the initial immunization. 42 days after the initial immunization, the ventral prostate lobe was collected, placed in a 2 mL tube, frozen in liquid nitrogen, and stored at -80°C. To a 2 mL tube containing the prostate, 1 mL of T-PER (Cat. No. 78510, Thermo Scientific) containing cComplete™ Mini, EDTA-free was added per 100 mg of prostate tissue. The tissue was homogenized using a handy microhomogenizer (NS-310E, Microtec Nichion Corporation). The homogenized tissue was then centrifuged at 14,000 x g and 4°C for 30 minutes using a himac™ CT15RE (Koiki Holdings Co., Ltd.). The supernatant was collected to prepare a protein solution. 2. Measurement of cytokine / chemokine levels: The levels of 23 cytokines / chemokines were measured using a cytokine assay kit (Rat 23-plex panel) and a Bio-Plex system (Bio-Rad) according to the manufacturer's protocol. In addition, the total protein amount was quantified using a DC™ protein assay kit (Cat. No. 500-0112, BIO-RAD Laboratories) and a microplate reader SpectraMax® M5 (BIO-RAD Laboratories Molecular Devices), and the cytokine / chemokine concentration per mg of total protein was calculated. 2. Test Results The test compound suppressed the expression of inflammatory cytokines / chemokines (IL-1β, CCL2, CCL3, CCL5) in the EAP model, demonstrating anti-inflammatory effects.

[0036] Test Example 6: Evaluation of analgesic effect in a hormone-induced chronic prostatitis (hormone / castration-induced prostatitis; HCP) model 1. Method for preparing an HCP model Male Wistar retired rats (Charles River Japan, Inc.) were castrated under isoflurane anesthesia, and 17β-estradiol (Cat. No. 14541-61, Nacalai Tesque, Inc.) was administered subcutaneously at 2 mL / kg using sesame oil (Cat. No. S3547, Sigma-Aldrich) as a vehicle once daily for 30 days from the day of surgery. The sham treatment group underwent a sham operation and received the vehicle sesame oil in the same manner (Reference: Prostate. 2019 Apr; 79(5): 446-453.). 2. Drug treatment: The test substance was administered for 30 days starting from the day of surgery. 3. Pain evaluation method: Evaluation was performed using the same method as in Test Example 3. 4. Statistical analysis: Evaluation was performed using the same method as in Test Example 3. 5. Test results: The test compound exhibited analgesic effects in the HCP model.

[0037] Test Example 7 Evaluation of Analgesic Effect in Formalin-Induced Prostatitis Model 1. Method for Producing Formalin-Induced Prostatitis Model Under isoflurane anesthesia, a midline incision was made in the lower abdomen of 7-week-old male SD rats (manufactured by Japan SLC, Inc.) to expose the prostate, and 25 μL of 5% formalin solution prepared by mixing equal volumes of 10% neutral buffered formalin solution (Cat. No. 062-01661, Fujifilm Wako Pure Chemical Industries, Ltd.) and physiological saline solution (Cat. No. 35081517, Otsuka Pharmaceutical Factory) was injected into each of the left and right ventral lobes of the prostate. The rats were then sutured, and the antibiotic cephalexin (Cat. No. 034-11052, Fujifilm Wako Pure Chemical Industries, Ltd.) was administered subcutaneously at 15 mg / kg. In the sham treatment group, 25 μL of saline was injected into the left and right ventral lobes of the prostate (Reference: Int Neurourol J. 2018 Jun;22(2):90-98.). 2. Drug treatment: The test substance was administered twice daily for seven days starting from the day the model was created. 3. Pain evaluation method: Pain was evaluated using the same method as in Test Example 1 seven days after model creation. 4. Statistical analysis: Pain was evaluated using the same method as in Test Example 3. 5. Test results: The test compound exhibited analgesic effects in the formalin-induced prostatitis model.

[0038] Test Example 8: Evaluation of PGE2 production in prostate epithelial cells derived from patients with benign prostatic hyperplasia 1. Cell culture Prostate epithelial cells derived from patients with benign prostatic hyperplasia (BPH-1 cells, Cat. No. ACC143) purchased from DSMZ were subcultured using a growth medium under conditions of 37°C and 5% CO2. The growth medium used was RPMI-1640 (Cat. No. 189-02025, Fujifilm Wako Pure Chemical Industries, Ltd.) containing a final concentration of 20% heat-inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), a final concentration of 20 ng / mL testosterone (Cat. No. 32811-61, Nacalai Tesque, Inc.), a final concentration of 4.2 μg / mL recombinant human insulin, a final concentration of 3.8 μg / mL human transferrin, and a final concentration of 5 ng / mL sodium selenite (insulin-transferrin-sodium selenite medium supplement, Cat. No. 11884, Sigma-Aldrich). Cell seeding and drug treatment: On the day before each test compound treatment, BPH-1 cells were suspended in growth medium and seeded into a Falcon® Cell Culture 96-well multiwell plate (Cat. No. 353072, Corning) at 9,600 cells / well. However, control wells were seeded with cells in control medium. As a control medium, RPMI-1640 (Cat. No. 189-02025, Fujifilm Wako Pure Chemical Industries, Ltd.) containing heat-inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare) at a final concentration of 2%, testosterone (Cat. No. 32811-61, Nacalai Tesque, Inc.) at a final concentration of 20 ng / mL, recombinant human insulin (Cat. No. 4.2 μg / mL), human transferrin (Cat. No. 11884, Sigma-Aldrich) at a final concentration of 4.2 μg / mL, and sodium selenite (Insulin-Transferrin-Sodium Selenite Medium Supplement, Cat. No. 11884, Sigma-Aldrich) at a final concentration of 5 ng / mL was used. BPH-1 cells seeded in a 96-well plate were incubated at 37°C and 5% CO. ２The cells were cultured overnight under the conditions of 0.1 μM each. The day after seeding, the cells were treated with each test substance. First, a 10 mM DMSO solution was prepared using DMSO (Cat. No. 13445-74, manufactured by Nacalai Tesque, Inc.), and diluted to 10, 1, or 0.1 μM using growth medium. The growth medium or control medium was removed, and the growth medium containing each test substance or the control well was replaced with control medium not containing the test substance. After that, the cells were incubated at 37°C, 5% CO ２ The cells were cultured for 48 hours under the conditions above, and the supernatant was collected. 3. Measurement of PGE2 Amount The amount of PGE2 in the cell culture supernatant was measured using Prostaglandin E2 kits (Cat. No. 62P2APEG, Cisbio) and a microplate reader SpectraMax® M5 (Molecular Devices) according to the manufacturer's protocol. 4. Test Results The test compound inhibited PGE2 production in BPH-1 cells.

[0039] Formulation Example 1 Tablet (oral tablet) Formulation per 80 mg tablet: Test compound 5.0 mg Corn starch 46.6 mg Microcrystalline cellulose 24.0 mg Methylcellulose 4.0 mg Magnesium stearate 0.4 mg The powder mixture in this proportion is compressed into tablets by a conventional method to give oral tablets.

[0040] INDUSTRIAL APPLICABILITY The present invention relates to an agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome, which contains an mPGES-1 inhibitor as an active ingredient, and has industrial applicability.

Claims

1. A prophylactic, therapeutic , or prophylactic and therapeutic pharmaceutical composition for chronic prostatitis / chronic pelvic pain syndrome, comprising a pharmaceutically effective amount of an mPGES-1 inhibitor as an active ingredient . wherein the mPGES-1 inhibitor is a compound selected from the group consisting of N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide; and N -(3-chloro-2-methylphenyl)-2-[1 -(trifluoromethyl)cyclopropyl]-6-({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or a tautomer thereof, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1, 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.

3. The pharmaceutical composition according to claim 1, 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.

4. A process for manufacturing a medicament for the prevention, treatment, or prevention and treatment of chronic prostatitis / chronic pelvic pain syndrome, comprising the step of incorporating an mPGES-1 inhibitor selected from the group consisting of: N-(3-chloro-2-methylphenyl)-2- (methoxymethyl)-6-({[2- (trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, and N-(3-chloro-2-methylphenyl)-2 -[1-(trifluoromethyl)cyclopropyl] -6-({[2(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or a tautomer of the compound, or a pharmaceutically acceptable salt thereof.

5. The process for manufacturing according to claim 4, 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.

6. The process for manufacturing according to claim 4 , 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 .

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