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

Abstract

To provide a prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome.SOLUTION: A prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor as an active ingredient.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[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. [Background technology]

[0002] Prostatitis is classified by the US 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 pelvic region, including the lower abdomen, and urinary symptoms such as a feeling of incomplete urination and frequent urination. Category IV, asymptomatic inflammatory prostatitis, is asymptomatic, but inflammatory findings are found 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 in category I and chronic bacterial prostatitis in category II, the cause of chronic prostatitis / chronic pelvic pain syndrome in category III is unknown, and no effective treatment has been found.

[0004] It is known that PGE2 synthase (PGES) has three subtypes: membrane-bound prostaglandin E synthase-1 (mPGES-1), mPGES-2, and cytosolic PGES (cPGES) (Non-Patent Documents 4 to 6). Like COX-2, mPGES-1 is induced primarily during inflammation and is involved in PGE2 production in inflammatory lesions. It is also 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], or 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 ingredients and has mPGES-1 inhibitory activity.

[0006] However, the relationship between chronic prostatitis and the mPGES-1 pathway has not been reported to date. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2013 / 024898 [Patent Document 2] WO2011 / 023812 [Patent Document 3] WO2017 / 073709 [Non-patent literature]

[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 Summary of the Invention [Problem to be solved by the invention]

[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. [Means for solving the problem]

[0010] The present inventors have begun to elucidate the pathogenesis of chronic prostatitis / chronic pelvic pain syndrome and have found that the mPGES-1 pathway is involved in chronic prostatitis / chronic pelvic pain syndrome. Furthermore, the present inventors have found that the use of an mPGES-1 inhibitor can reduce pain and inflammation in an animal model of chronic prostatitis, thereby completing the present invention.

[0011] The present invention relates to

[0012] (1) A preventive and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome, comprising an mPGES-1 inhibitor as an active ingredient. (2) The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to (1) above, wherein the mPGES-1 inhibitor is a compound of formula [1] (hereinafter also referred to as the present compound) or a tautomer thereof, or a pharmaceutically acceptable salt thereof, wherein the compound of formula [1] is as follows: Formula [1]: [ka] [In the formula, Ring A is represented by formula [2], [3], or [4]: [ka] (In the formula, X 1 is NH, N-alkyl, or O, A 1 is hydrogen or alkyl, A 2 teeth, i) hydrogen, ii) halogens, iii) an alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy; iv) cycloalkyl optionally substituted with alkyl, the alkyl being optionally substituted with 1 to 3 halogen atoms; v) alkoxy, vi) a saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo; vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) Formula [5]: [ka] (In the formula, R 3 , R 4 are the same or different, a) hydrogen, b) an alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, saturated heterocyclic group optionally substituted with alkyl, alkoxy, hydroxycarbonyl, hydroxyl, alkyloxycarbonyl, and alkylthio, or c) cycloalkyl or ix) saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl is a group represented by R 1 is phenyl, benzyl, naphthyl, cycloalkyl, cycloalkylmethyl, heteroaryl, heteroarylmethyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl, 1,2-dihydrocyclobutabenzen-4-yl, or alkyl, and the phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are i) halogens, ii) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and phenyl; iii) alkoxy, iv) hydroxy, and v) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of R 2is phenyl or pyridyl, and the phenyl or pyridyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with 1 to 3 halogen or alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, alkoxyalkoxy, cycloalkyl, phenyl, and halogen; and optionally substituted with 1 to 3 groups selected from the group consisting of As follows. (3) Ring A is a group represented by formula [4], and X 1 The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to (2) above, wherein is NH. (4) R 1 is phenyl, 1,2,3,4-tetrahydronaphthalen-5-yl, 1,2,3,4-tetrahydronaphthalen-6-yl, 2,3-dihydro-1H-inden-4-yl, 2,3-dihydro-1H-inden-5-yl, 1,2-dihydrocyclobutabenzen-3-yl, or 1,2-dihydrocyclobutabenzen-4-yl, and the phenyl is i) halogens, ii) alkyl optionally substituted with 1 to 3 halogens; iii) alkoxy, and iv) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to (2) or (3) above. (5) R 2 is phenyl, The phenyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl; and optionally substituted with 1 to 3 groups selected from the group consisting of The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (4) above. (6) Ring A is a group represented by the general formula [4], and X 1 But NH, A 2 but, i) hydrogen, ii) an alkyl optionally substituted with a group selected from the group consisting of halogen, monoalkylamino, dialkylamino, monoalkylaminocarbonyl, dialkylaminocarbonyl, saturated cyclic aminocarbonyl, alkoxy, alkoxyalkoxy, and alkylcarbonyloxy; iii) cycloalkyl optionally substituted by alkyl optionally substituted by 1 to 3 halogens; iv) Alkoxy v) a saturated heterocyclic group optionally substituted with alkyl or alkyloxycarbonyl, vi) alkylthio, vii) alkylsulfonyl, viii) alkylsulfinyl, ix) amino substituted with alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl, hydroxyl, and alkylthio; x) amino substituted with cycloalkyl, or xi) saturated cyclic amino optionally substituted with alkyl, dialkylamino, alkoxy, or hydroxyl; R1 but, i) phenyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl optionally substituted with 1 to 3 halogens, alkoxy, and cyano; ii) 1,2,3,4-tetrahydronaphthalen-5-yl, iii) 2,3-dihydro-1H-inden-5-yl, iv) benzyl optionally substituted with halogen or alkyl optionally substituted with 1 to 3 halogens; v) cycloalkyl, vi) cycloalkylmethyl, vii) naphthyl, viii) pyridylmethyl optionally substituted by alkyl optionally substituted by 1 to 3 halogens, ix) thienyl, x) thienylmethyl, xi) benzothiazolyl, xii) benzothiadiazolyl, xiii) indolyl, or xiv) alkyl; R 2 represents phenyl or pyridyl, The phenyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy; iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl, and v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl; and optionally substituted with 1 to 3 groups selected from the group consisting of The pyridyl may be substituted with halogen. The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (5) above. (7) Ring A is a group represented by the general formula [4], and X 1 But NH, A 2 is alkyl substituted by alkoxy, dialkylamino, tetrahydrofuryl, tetrahydrofurylmethyl, alkoxyalkylamino, or cycloalkyl optionally substituted by unsubstituted or 1 to 3 halogen-substituted alkyl, R 1 is phenyl substituted with one halogen and one methyl; R 2 is phenyl optionally substituted with one trifluoromethyl or two halogens; The agent for preventing and / or treating chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (6) above. (8) mPGES-1 inhibitors (1) N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (2) N-cyclohexyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (3) N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (4) N-[(1-hydroxycyclohexyl)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (5) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino}-2,3-dihydro-1-benzofuran-7-carboxamide (6) N-Cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide (7) N-(3-chloro-2-methylphenyl)-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxamide (8) N-Cyclohexyl-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide (9) N-[2-(trifluoromethyl)benzyl]-5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-indazole-7-carboxamide (10) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (11) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (12) N-Cyclohexyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (13) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (14) N-Cyclopentyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (15) N-Cyclobutyl-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (16) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (17) N-Cyclohexyl-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (18) 2-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (19) N-Cyclohexyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (20) 2-(Methoxymethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (21) 2-(Methoxymethyl)-N-(2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (22) 2-(Methoxymethyl)-N-(4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (23) N-(2-chlorobenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (24) 2-(Methoxymethyl)-N-(4-methylbenzyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (25) N-(4,4-difluorocyclohexyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (26) N-(4-tert-butylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (27) 2-(Methoxymethyl)-N-[4-(trifluoromethyl)phenyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (28) N-(2,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (29) N-(2-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (30) N-(3,4-dimethylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (31) N-(3-chloro-4-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (32) N-(2,3-Dihydro-1H-inden-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (33) 2-(Methoxymethyl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (34) N-(2-fluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (35) 2-(Methoxymethyl)-N-(2-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (36) 2-(Methoxymethyl)-N-(4-methoxyphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (37) N-(3-bromo-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (38) N-(3-chloro-2-methylbenzyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (39) N-(2,6-difluorophenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (40) N-(3-cyano-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (41) 2-(Methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (42) N-(2-chloro-6-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (43) 2-(2-amino-2-oxoethyl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (44) 2-(2-amino-2-oxoethyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (45) N-(3-chloro-2-methylphenyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (46) N-Cyclohexyl-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (47) 1-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (48) N-(3-chloro-2-methylphenyl)-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (49) N-Cyclohexyl-1-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (50) 1-Ethyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (51) N-(3-chloro-2-methylphenyl)-2-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (52) 2-Methyl-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (53) N-(3-chloro-2-methylphenyl)-2-ethyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1,3-benzoxazole-4-carboxamide (54) N-(3-chloro-2-methylphenyl)-2-ethoxy-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (55) 2-Ethoxy-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (56) N-(3-chloro-2-methylphenyl)-2-(1-chloro-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (57) N-(3-chloro-2-methylphenyl)-2-[(dimethylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (58) N-(3-chloro-2-methylphenyl)-2-(2-methylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (59) 2-(2-Methylpropyl)-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (60) tert-Butyl 3-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}azetidine-1-carboxylate (61) N-(3-chloro-2-methylphenyl)-2-[(methylamino)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (62) {4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}methyl acetate (63) N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (64) 2-[(2R)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (65) N-(3-chloro-2-methylphenyl)-2-[(2S)-tetrahydrofuran-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (66) 2-[(2S)-tetrahydrofuran-2-yl]-N-[2-(trifluoromethyl)benzyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (67) 2-(1-acetylazetidin-3-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (68) tert-Butyl (2S)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (69) tert-Butyl (2R)-2-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}pyrrolidine-1-carboxylate (70) N-(3-chloro-2-methylphenyl)-2-[(2S)-pyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (71) N-(3-chloro-2-methylphenyl)-2-[(2S)-1-methylpyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (72) 2-[(2S)-1-Acetylpyrrolidin-2-yl]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (73) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethoxy)methyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (74) N-(3-chloro-2-methylphenyl)-2-(1-methoxy-2-methylpropan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (75) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (76) 2-tert-butyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (77) N-(3-chloro-2-methylphenyl)-2-(2-ethoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (78) N-(3-chloro-2-methylphenyl)-2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (79) 2-(ethoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-benzimidazole-4-carboxamide (80) N-(3-chloro-2-methylphenyl)-2-(2-methoxyethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (81) N-(3-chloro-2-methylphenyl)-2-(2,2-dimethylpropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (82) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (83) N-(3-chloro-2-methylphenyl)-2-(2-methylpentan-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (84) N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (85) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (86) 2-tert-butyl-N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (87) 2-tert-butyl-N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (88) N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (89) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (90) N-(2-chlorobenzyl)-2-(methoxymethyl)-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (91) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (92) 6-{[(2-chloro-4-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-methoxymethyl-1H-benzimidazole-4-carboxamide (93) 6-{[(2-chloro-5-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (94) N-(3-chloro-2-methylphenyl)-6-{[(2-chlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (95) N-(3-chloro-2-methylphenyl)-6-{[(2-chloropyridin-3-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (96) 6-{[(2-bromophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (97) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (98) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (99) 6-{[(2-chloro-3-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (100) 6-{[(2-chloro-3,6-difluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (101) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (102) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (103) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-6-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (104) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-4-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (105) 6-{[(5-bromo-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (106) 6-{[(2-bromo-5-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (107) N-(3-chloro-2-methylphenyl)-6-{[(2-chloro-5-methylphenyl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (108) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[5-methyl-2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (109) 6-({[2,5-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (110) 6-({[2,4-bis(trifluoromethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (111) N-(3-chloro-2-methylphenyl)-6-({[5-fluoro-2-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (112) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-6-(trifluoromethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (113) N-(3-chloro-2-methylphenyl)-6-[({2-chloro-5-[2-(propan-2-yloxy)ethoxy]phenyl}carbonyl)amino]-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (114) 6-({[2-chloro-5-(2-ethoxyethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (115) 6-({[2-chloro-5-(3-methoxypropyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (116) 6-({[5-(3-tert-butoxyprop-1-yn-1-yl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (117) 6-({[5-(3-tert-butoxypropyl)-2-chlorophenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (118) 6-({[2-chloro-5-(3-hydroxy-3-methylbutyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (119) 6-({[2-chloro-5-(ethoxymethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (120) 6-[({2-chloro-5-[(2-ethoxyethoxy)methyl]phenyl}carbonyl)amino]-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (121) 6-({[2-chloro-5-(2-cyclopropylethyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (122) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(2-phenylethyl)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (123) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (124) N-(3-chloro-2-methylphenyl)-2-cyclopentyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (125) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-cyclopentyl-1H-benzimidazole-4-carboxamide (126) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (127) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (128) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2R)-tetrahydrofuran-2-yl]-1H-benzimidazole-4-carboxamide (129) N-(3-chloro-2-methylphenyl)-2-[(2S)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (130) N-(3-chloro-2-methylphenyl)-2-[(2R)-5-oxopyrrolidin-2-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (131) N-(3-chloro-2-methylphenyl)-2-[2-oxo-2-(pyrrolidin-1-yl)ethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (132) N-(3-chloro-2-methylphenyl)-2-[2-(dimethylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (133) N-(3-chloro-2-methylphenyl)-2-[2-(methylamino)-2-oxoethyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (134) 2-chloro-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (135) N-(3-chloro-2-methylphenyl)-2-[(2-methoxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (136) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxyethyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (137) N-(3-chloro-2-methylphenyl)-2-(methylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (138) N-(3-chloro-2-methylphenyl)-2-(ethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (139) N-(3-chloro-2-methylphenyl)-2-[(2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (140) N-(3-chloro-2-methylphenyl)-2-(cyclopentylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (141) N-(3-chloro-2-methylphenyl)-2-(piperidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (142) N-(3-chloro-2-methylphenyl)-2-(4-methylpiperazin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (143) 2-[bis(2-hydroxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (144) N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (145) N-(3-chloro-2-methylphenyl)-2-{[2-(morpholin-4-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (146) N-(3-chloro-2-methylphenyl)-2-{[2-(dimethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (147) N-(3-chloro-2-methylphenyl)-2-(3-hydroxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (148) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-(dimethylamino)pyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (149) N-(3-chloro-2-methylphenyl)-2-[(3S)-3-hydroxypyrrolidin-1-yl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (150) N-(3-chloro-2-methylphenyl)-2-{[2-(diethylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (151) N-(3-chloro-2-methylphenyl)-2-{[2-(pyrrolidin-1-yl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (152) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)propyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (153) N-(3-chloro-2-methylphenyl)-2-{[3-(dimethylamino)-2,2-dimethylpropyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (154) N-(3-chloro-2-methylphenyl)-2-{[2-(dipropan-2-ylamino)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (155) N-(3-chloro-2-methylphenyl)-2-(morpholin-4-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (156) 2-Amino-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (157) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (158) N-(3-chloro-2-methylphenyl)-2-{[(3-methyloxetan-3-yl)methyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (159) tert-Butyl N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycinate (160) N-{4-[(3-chloro-2-methylphenyl)carbamoyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazol-2-yl}glycine (161) N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1-methyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (162) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (163) N-(3-chloro-2-methylphenyl)-2-(pyrrolidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (164) 2-(Azetidin-1-yl)-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (165) N-(3-chloro-2-methylphenyl)-2-(3-methoxyazetidin-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (166) N-(3-chloro-2-methylphenyl)-2-[(2-hydroxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (167) N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (168) N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (169) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (170) N-(3-chloro-2-methylphenyl)-2-{[(2R)-1-hydroxy-3-methylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (171) N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3,3-dimethylbutan-2-yl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (172) N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)(methyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (173) N-(3-chloro-2-methylphenyl)-2-[(3-methoxypropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (174) N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (175) 2-[(2-tert-butoxyethyl)amino]-N-(3-chloro-2-methylphenyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (176) N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (177) N-(3-chloro-2-methylphenyl)-2-{[2-(methylsulfanyl)ethyl]amino}-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (178) N-(3-chloro-2-methylphenyl)-2-(methylsulfanyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (179) N-(3-chloro-2-methylphenyl)-2-(methylsulfonyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (180) N-(3-chloro-2-methylphenyl)-2-(methylsulfinyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (181) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (182) N-(3-chloro-2-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (183) N-(3-chloro-2-methylphenyl)-6-{[(2,4-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (184) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (185) 6-{[(2-bromo-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (186) 6-{[(2-bromo-6-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (187) 6-({[2-chloro-5-(cyclopropylethynyl)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (188) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (189) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (190) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-hydroxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (191) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (192) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (193) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[2-(propan-2-yloxy)ethyl]amino}-1H-benzimidazole-4-carboxamide (194) 2-[(2-tert-butoxyethyl)amino]-6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-1H-benzimidazole-4-carboxamide (195) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-methoxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (196) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(2-methoxy-2-methylpropyl)amino]-1H-benzimidazole-4-carboxamide (197) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide (198) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2R)-tetrahydrofuran-2-ylmethyl]amino}-1H-benzimidazole-4-carboxamide (199) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-[(3-hydroxy-2,2-dimethylpropyl)amino]-1H-benzimidazole-4-carboxamide (200) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-{[(2S)-1-hydroxy-3-methylbutan-2-yl]amino}-1H-benzimidazole-4-carboxamide (201) N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (202) N-(4-tert-butylphenyl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (203) N-(2,3-Dihydro-1H-inden-5-yl)-2-(dimethylamino)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (204) 6-{[(2-chloro-6-fluorophenyl)carbonyl]amino}-N-(3-chloro-4-methylphenyl)-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (205) N-(3-chloro-4-methylphenyl)-6-{[(2,6-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (206) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide (207) N-(3-chloro-2-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (208) N-(3-chloro-4-methylphenyl)-2-cyclopropyl-6-{[(2,5-dichlorophenyl)carbonyl]amino}-1H-benzimidazole-4-carboxamide (209) N-(3-chloro-2-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide (210) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(1-methylcyclopropyl)-1H-benzimidazole-4-carboxamide (211) N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(methylsulfonyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (212) N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(2-methoxyethyl)-1H-benzimidazole-4-carboxamide (213) 2-(Methoxymethyl)-N-phenyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (214) 2-(Methoxymethyl)-N-propyl-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (215) 2-(Methoxymethyl)-N-(pyridin-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (216) N-Benzyl-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (217) N-(cyclohexylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (218) 2-(Methoxymethyl)-N-(naphthalen-1-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (219) 2-(Methoxymethyl)-N-(thiophen-3-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (220) N-(2,1,3-benzothiadiazol-4-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (221) N-(1,1-dioxide-1-benzothiophen-6-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (222) 2-(Methoxymethyl)-N-(thiophen-2-ylmethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (223) N-(1H-indol-5-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (224) N-(1,3-Benzothiazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (225) N-(2,2-dimethylpropyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (226) 2-(Methoxymethyl)-N-(thiophen-2-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (227) N-(5-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (228) N-(2-benzylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (229) 2-(Methoxymethyl)-N-(quinolin-8-yl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (230) N-(cycloheptylmethyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (231) N-(1,3-Benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (232) N-(6-chloro-1,3-benzoxazol-2-yl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (233) N-[3-chloro-2-(hydroxymethyl)phenyl]-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide (234) N-(3-chloro-2-methylphenyl)-6-{[(3-fluoropyridin-2-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (235) N-(3-chloro-2-methylphenyl)-6-{[(3-chloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (236) N-(3-chloro-2-methylphenyl)-6-{[(3,5-dichloropyridin-4-yl)carbonyl]amino}-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (237) 6-{[(5-butoxy-2-chlorophenyl)carbonyl]amino}-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide (238) 6-({[2-chloro-5-(2,2-difluoroethoxy)phenyl]carbonyl}amino)-N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide, and (239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide The prophylactic and / or therapeutic agent for chronic prostatitis / chronic pelvic pain syndrome according to any one of (2) to (7) above, which is a compound selected from the group consisting of: (9) mPGES-1 inhibitors N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide sulfate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide methanesulfonate, N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide sulfate The prophylactic 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: (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 preventing and / or treating 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. [Effects of the Invention]

[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. [Brief explanation of the drawings]

[0015] [Figure 1] 1 shows the results of evaluation of the analgesic effect of test compounds 1 to 5 in an autoimmune chronic prostatitis model. DETAILED DESCRIPTION OF THE INVENTION

[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 synthetic organic chemistry.

[0019] In one embodiment of the present invention, the mPGES-1 inhibitor can be used as a pharmaceutical directly, or can be prepared into a pharmaceutically acceptable salt by a known method. Examples of such salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and salts with organic acids such as acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid. For example, the hydrochloride salt of an mPGES-1 inhibitor can be obtained by dissolving the mPGES-1 inhibitor in an alcoholic, ethyl acetate, or diethyl ether solution of hydrogen chloride.

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

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

[0023] In one aspect of the present invention, the mPGES-1 inhibitor is, for example, the above-mentioned compounds (1) to (239) or tautomers thereof, or pharmaceutically acceptable salts thereof, and preferably, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, or N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide or a pharmaceutically acceptable salt thereof, more preferably N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, N-(3-chloro-2-methylphenyl)-2-(1-methylcyclopropyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide hydrochloride, or N-(3-chloro-4-methylphenyl)-6-{[(2,5-dichlorophenyl)carbonyl]amino}-2-(dimethylamino)-1H-benzimidazole-4-carboxamide hydrochloride.

[0024] When the present compound or a pharmaceutically acceptable salt thereof is administered as a medicine, it is administered to mammals, including humans, as is or as a pharmaceutical composition containing, for example, 0.001% to 99.5%, preferably 0.1% to 90%, of the present compound or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable, non-toxic, and inert carrier.

[0025] The carrier may be one or more solid, semi-solid, or liquid diluents, fillers, and other formulation auxiliaries. The pharmaceutical composition of the present invention is preferably administered in a dosage unit form. The pharmaceutical composition may be administered intramuscularly, orally, intravenously, topically (transdermally, by eye drop, intraperitoneally, intrapleurally, etc.), or rectally. Of course, the pharmaceutical composition may be administered in a dosage form suitable for these administration methods.

[0026] The pharmaceutical dosage is preferably adjusted taking into consideration the patient's condition, such as age, body weight, type and severity of disease, the route of administration, the type of compound of the present invention, whether or not it is a salt, and the type of salt. However, the amount of the active ingredient of the compound of the present invention or a pharmaceutically acceptable salt thereof for an adult is usually within the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, when administered orally. In some cases, a lower dose may be sufficient, or conversely, a higher dose may be required. Usually, the compound is administered once a day or in divided doses, or in the case of intravenous administration, it can be administered as a rapid administration or continuously for up to 24 hours. [Example]

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

[0030] Test Example 2: Inhibition of PGE2 and PGF2α production using A549 cells 2 x 10 human A549 cells 4Cells were seeded at 100 μL / well in a 96-well plate and incubated overnight. The medium was then removed and washed with phosphate-buffered saline, followed by replacement with RPMI medium containing 3% FBS and either a DMSO solution of the test compound or DMSO (final DMSO concentration: 0.1% in both cases). After 60 minutes of incubation, IL-1β (5 ng / well) was added and incubated for 24 hours at 37°C. PGE2 in the medium was then quantified using an HTRF kit (Cisbio International product catalog #62P2APEC), and PGF2α was quantified using an EIA kit (Cayman Chemical Company product catalog #516011). A solution without test compound served as a positive control, and a solution without test compound and IL-1β served as a negative control. 100% activity was defined as the PGE2 and PGF2α production in the positive control minus the PGE2 and PGF2α production in the negative control. IC50 values ​​were then determined using standard methods.

[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 WO2011 / 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 WO2017 / 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 effects of test compounds 1 to 4 were evaluated by the following method using an experimental autoimmune prostatitis (EAP) model, which is a commonly used model for chronic prostatitis. 1. Prostate-specific antigen (PAg) preparation method Prostates were excised from 14-week-old male Wistar rats (Japan SLC Co., Ltd.) and homogenized in ice-cold PBS (Cat. No. 045-29795, Fujifilm Wako Pure Chemical Industries, Ltd.) supplemented with cOmplete™ Mini, EDTA-free (Cat. No. 11836170001, Roche Diagnostics GmbH) using a handy microhomogenizer (NS-310E, Microtec Nichion Corporation). The homogenized samples were then centrifuged at 10,000 × g for 30 minutes at 4°C using a centrifuge (Allegra X-30R, Beckman Coulter). The protein concentration was quantified using a DC™ protein assay kit (Cat. No. 500-0112, BIO-RAD Laboratories) and a SpectraMax® M5 microplate reader (Molecular Devices) and then stored at -20°C. 2. EAP model preparation method Equal volumes 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 to the soles of both hind paws and the base of the tail as the primary immunization. The same treatment was repeated 28 days after the primary immunization as a booster immunization. The sham-treated group received an emulsion of equal volumes of saline (Cat. No. 35081517, Otsuka Pharmaceutical Factory) and Complete Freund's adjuvant (Reference: Prostate. 2018 Nov; 78(15):1157-1165.). 3. Grouping method Thirty-seven days after the first immunization, the pre-value was measured using the pain assessment method described below, and the subjects were divided into groups so that there were no significant differences in the pain response rate or AUC at each stimulation intensity. Group division was performed by stratified random allocation using SAS version 9.3 and EXSUS version 8.1. 4. Pain assessment method Forty-two days after the initial immunization, the test substance was orally administered at 10 mL / kg in 0.5% methylcellulose solution at a concentration of 100 mg / kg (free form equivalent). Pain assessment was performed 4 hours after administration. Prior to assessment, rats were placed on a wire mesh for 30 minutes to allow for habituation. Three von Frey filaments (Touch Test®, Cat. Nos. NC12775-06, NC12775-08, and NC12775-11, North Coast Medical) with different stimulation intensities of 0.4, 1, and 4 g were applied to the rat's lower abdomen from below the wire mesh for 1–2 seconds, and the rats were observed for escape responses (e.g., escape, licking of the stimulated area). Starting with the weakest filament, five stimulations were administered at each intensity. The percentage of animals that exhibited an escape response was calculated as the escape response rate (%). The area under the curve (AUC) was calculated from a line graph plotting the stimulation intensity and escape response rate. 5.Statistical analysis Summary statistics were calculated and statistical analysis was 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 FIG.

[0034] <Test Example 4: Evaluation of anti-inflammatory effect in normal human prostate stromal cells> 1.Cell culture Normal human prostate stromal cells (WPMY-1 cells, Cat. No. CRL-2854™) purchased from ATCC (registered trademark) were subcultured in growth medium at 37°C and 5% CO. The growth medium used was DMEM (Cat. No. 08458-45, manufactured by Nacalai Tesque, Inc.) containing a final concentration of 5% heat-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 The day before treatment with each test compound, 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 cultured overnight at 37°C in 5% CO. The test substances were treated the day after seeding. First, a 10 mM DMSO solution was prepared using DMSO (Cat. No. 13445-74, Nacalai Tesque, Inc.) and diluted to 10 μM using assay medium. However, a 1000 mg / mL DMSO solution of Canephron was prepared and diluted to 1000 μg / mL using assay medium. DMEM (Cat. No. 08458-45, Nacalai Tesque, Inc.) containing a final concentration of 2% heat-inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), penicillin at a final concentration of 20 U / mL, and streptomycin at a final concentration of 20 μg / mL (penicillin-streptomycin mixed solution, Cat. No. 26253-84, Nacalai Tesque, Inc.) was used as the assay medium. The growth medium was removed and replaced with an assay medium containing each test substance, and then the cells were cultured at 37°C in 5% CO2 for 24 hours. 3. Cytokine Stimulation Twenty-four hours after treatment with each test substance, cytokine stimulation was performed. 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 in the cytokine stimulation medium in the same manner as the previous day, and the cells were treated with each test substance and cytokine. The cells were cultured at 37°C and 5% CO2 for 5 hours, and then harvested. 4. Gene Expression Analysis Total RNA was extracted from cells using the RNeasy® Mini Kit (Cat. No. 74106, Qiagen) according to the manufacturer's protocol, and RNA concentration was measured using a 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 the reverse-transcribed cDNA and TB Green® Premix Ex Taq II (Cat. No. RR820, Takara Bio Inc.) on 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 the value in the untreated (NT) group. All data were normalized using GAPDH. PCR conditions included a 10-minute incubation at 95°C, followed by 45 cycles of 15 seconds at 95°C and 1 minute at 60°C. 5. Test Results The test compound suppressed the expression of inflammatory cytokines / chemokines (CCL2) in normal human prostate stromal cells (WPMY-1 cells), demonstrating anti-inflammatory effects (Table 1). [Table 1]

[0035] <Test Example 5: Evaluation of anti-inflammatory effect in an autoimmune chronic prostatitis model> 1. Protein Solution Preparation 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 first immunization. 42 days after the first immunization, the ventral prostate lobe was collected, placed in a 2 mL tube, frozen in liquid nitrogen, and stored at -80°C. To the 2 mL tube containing the prostate, 1 mL of T-PER (Cat. No. 78510, Thermo Scientific) containing cOmplete™ Mini, EDTA-free was added for every 100 mg of prostate tissue weight, and the tissue was homogenized using a handy microhomogenizer (NS-310E, Microtech Nichion Corporation). The tissue was then centrifuged at 14,000 × g and 4°C for 30 minutes using a himac™ CT15RE (Koiki Holdings Co., Ltd.), and the supernatant was collected to prepare a protein solution. 2. Cytokine / chemokine level measurement The levels of 23 cytokines / chemokines were measured using a cytokine assay kit (Rat 23-plex panel) and the Bio-Plex system (Bio-Rad Laboratories) according to the manufacturer's protocol. Total protein was quantified using a DC™ protein assay kit (Cat. No. 500-0112, BIO-RAD Laboratories) and a SpectraMax® M5 microplate reader (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 / castration-induced prostatitis (HCP) model> 1. HCP model preparation method Male Wistar retired rats (Charles River Japan) were castrated under isoflurane anesthesia and administered 17β-estradiol (Cat. No. 14541-61, Nacalai Tesque, Inc.) at 0.25 mg / kg subcutaneously at 2 mL / kg once daily for 30 days, using sesame oil (Cat. No. S3547, Sigma-Aldrich). Sham-operated rats were administered sesame oil (Prostate. 2019 Apr;79(5):446-453). 2. Drug Treatment The test substance was administered for 30 days from the day of surgery. 3. Pain assessment method Evaluation was carried out in the same manner as in Test Example 3. 4.Statistical analysis Evaluation was carried out in the same manner as in Test Example 3. 5. Test Results The test compounds exhibited analgesic activity in the HCP model.

[0037] <Test Example 7: Evaluation of analgesic effect in a formalin-induced prostatitis model> 1. Method for producing formalin-induced prostatitis model Under isoflurane anesthesia, 7-week-old male SD rats (Japan SLC, Inc.) underwent a midline abdominal incision to expose the prostate. A 5% formalin solution (25 μL each) was prepared by mixing equal parts 10% neutral buffered formalin (Cat. No. 062-01661, Fujifilm Wako Pure Chemical Industries, Ltd.) and saline (Cat. No. 35081517, Otsuka Pharmaceutical Factory) into the left and right ventral prostate lobes. The rats were then sutured and treated with the antibiotic cephalexin (Cat. No. 034-11052, Fujifilm Wako Pure Chemical Industries, Ltd.) at a dose of 15 mg / kg subcutaneously. In the sham-treated group, saline was injected into the left and right ventral prostate lobes at a dose of 25 μL each (Reference: Int Neurourol J. 2018Jun;22(2):90-98). 2. Drug Treatment The test substance was administered twice a day for 7 days from the day the model was created. 3. Pain assessment method Seven days after the model was produced, it was evaluated in the same manner as in Test Example 1. 4.Statistical analysis Evaluation was carried out in the same manner as in Test Example 3. 5. Test Results The test compound exhibited analgesic activity in a 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 (BPH-1 cells, Cat. No. ACC143) derived from patients with benign prostatic hyperplasia (DSMZ) were subcultured at 37°C in 5% CO2 using growth medium (RPMI-1640, Cat. No. 189-02025, Fujifilm Wako Pure Chemical Industries, Ltd.) containing 20% ​​heat-inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), 20 ng / mL testosterone (Cat. No. 32811-61, Nacalai Tesque, Inc.), 4.2 μg / mL recombinant human insulin, 3.8 μg / mL human transferrin, and 5 ng / mL sodium selenite (Insulin-Transferrin-Sodium Selenite Medium Supplement, Cat. No. 11884, Sigma-Aldrich). 2. Cell Seeding and Drug Treatment On the day before treatment with each test compound, 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, except for control wells, where cells were seeded using control medium. Control medium consisted of RPMI-1640 (Cat. No. 189-02025, Fujifilm Wako Pure Chemical Industries, Ltd.) containing 2% heat-inactivated fetal bovine serum (Cat. No. SH30910, GE Healthcare), 20 ng / mL testosterone (Cat. No. 32811-61, Nacalai Tesque, Inc.), 4.2 μg / mL recombinant human insulin, 3.8 μg / mL human transferrin, and 5 ng / mL sodium selenite (Insulin-Transferrin-Sodium Selenite Medium Supplement, Cat. No. 11884, Sigma-Aldrich). BPH-1 cells seeded in a 96-well plate were cultured overnight at 37°C in 5% CO. The day after seeding, cells were treated with each test substance. First, a 10 mM DMSO solution (Cat. No. 13445-74, Nacalai Tesque, Inc.) was prepared and diluted to 10, 1, or 0.1 μM with 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 without the test substance. After incubation at 37°C and 5% CO for 48 hours, the supernatant was collected. 3.PGE2 amount measurement The amount of PGE2 in the cell culture supernatant was measured using Prostaglandin E2 kits (Cat. No. 62P2APEG, manufactured by Cisbio) and a microplate reader SpectraMax® M5 (manufactured by 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 Tablets (oral tablets) Prescription 1 tablet 80mg Test compound 5.0 mg Corn starch 46.6mg Crystalline cellulose 24.0mg Methylcellulose 4.0mg Magnesium stearate 0.4mg The mixed powder in this ratio is tableted by a conventional method to form oral tablets. [Industrial Applicability]

[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. The following formula [A]: 【Chemistry 1】 [In the formula, R represents methyl which may be substituted with a methoxy group or an ethoxy group, or cycloalkyl which may be unsubstituted or substituted with 1 to 3 halogen-substituted alkyl groups.] An anti-inflammatory agent comprising, as an active ingredient, a compound represented by the following formula:

2. The anti-inflammatory agent according to claim 1, which suppresses the expression of inflammatory cytokines and / or chemokines.

3. 3. The anti-inflammatory agent according to claim 2, wherein the inflammatory cytokine and / or chemokine is at least one selected from the group consisting of IL-1β, CCL2, CCL3 and CCL5.

4. The anti-inflammatory agent according to claim 2, wherein the inflammatory cytokine and / or chemokine is CCL2.

5. An anti-inflammatory agent comprising, as an active ingredient, 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.

6. An anti-inflammatory agent containing N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate as an active ingredient.

7. An anti-inflammatory agent containing N-(3-chloro-2-methylphenyl)-2-[1-(trifluoromethyl)cyclopropyl]-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide as an active ingredient.

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