Solid dispersion, pharmaceutical preparation containing solid dispersion, and methods for producing the same

Abstract

To provide a solid dispersion useful as a pharmaceutical containing a compound having mPGES-1 inhibitory activity, a preparation useful as a pharmaceutical containing the solid dispersion, and methods for producing the solid dispersion and the preparation.SOLUTION: A solid dispersion comprises at least one compound selected from the group consisting of a hetero ring derivative represented by general formula [1], a tautomer thereof, and a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable polymer. A preparation containing the solid dispersion is also provided.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a solid dispersion, a formulation containing the solid dispersion, and a method for producing the same. [Background technology]

[0002] Membrane-bound prostaglandin E synthase-1 (mPGES-1) has been suggested to be involved in the progression of various inflammatory conditions. Furthermore, mPGES-1 inhibitors are expected to be highly safe anti-inflammatory agents because they inhibit only cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2) production (see, for example, Patent Document 1). Patent Document 1 discloses novel heterocyclic derivatives and pharmaceutically acceptable salts thereof, as well as formulation examples, as compounds with mPGES-1 inhibitory activity.

[0003] However, Patent Document 1 does not describe the solubility of the heterocyclic derivatives and pharmaceutically acceptable salts thereof, nor does it describe the oral absorbability of the heterocyclic derivatives and pharmaceutically acceptable salts thereof. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2013 / 024898 Summary of the Invention [Problem to be solved by the invention]

[0005] An object of the present invention is to provide a solid dispersion useful as a pharmaceutical containing a compound having mPGES-1 inhibitory activity, a formulation useful as a pharmaceutical containing the solid dispersion, and methods for producing them. [Means for solving the problem]

[0006] The present inventors have discovered that a compound represented by the general formula [1]: [ka] It has been found that at least one compound selected from the group consisting of heterocyclic derivatives represented by the following formula (I): and tautomers thereof, and pharmaceutically acceptable salts thereof, has a problem in terms of administrability. The present inventors have also found that a solid dispersion containing at least one compound selected from the group consisting of the heterocyclic derivatives represented by the above general formula, tautomers thereof, and pharmaceutically acceptable salts thereof in an amorphous state, obtained using a pharmaceutically acceptable polymer, can solve the above-mentioned problems, and further found that a formulation using the solid dispersion is excellent as a pharmaceutical.

[0007] The present invention is based on this novel finding, and relates to, for example, the following inventions described in (Item 1) to (Item 11).

[0008] (Section 1) A solid dispersion comprising at least one compound selected from the group consisting of heterocyclic derivatives represented by the following general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable polymer: [ka] In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4]. [ka] [In the general formulas [2], [3] and [4], X 1 represents NH, N-alkyl, or O. 1 represents hydrogen or alkyl. 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 halogens; v) alkoxy, vi) a saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo; vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5]: [ka] (In general formula [5], R 3 and 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) represents a saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl. R 1represents 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 such phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are i) halogens, ii) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and phenyl; iii) alkoxy, iv) hydroxy, and v) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of: R 2 represents phenyl or pyridyl, and such 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: (Section 2) The compound is 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, 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 solid dispersion according to (Item 1), wherein the solid dispersion is at least one selected from the group consisting of: (Section 3) The solid dispersion according to (Item 1) or (Item 2), wherein the solubility of the solid dispersion in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomer, and its pharmaceutically acceptable salt. (Section 4) The solid dispersion according to any one of (Item 1) to (Item 3), wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of a cellulose-based polymer, an acrylic-based polymer, and a vinyl-based polymer. (Section 5) The solid dispersion according to any one of (Item 1) to (Item 4), wherein the pharmaceutically acceptable polymer is soluble in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, and has a solubility of, for example, 1 mg / mL or more, preferably 1 to 3 mg / mL. (Section 6) The solid dispersion according to (Item 4) or (Item 5), wherein the compound accounts for 1 to 98% by mass relative to the total mass of the solid dispersion. (Section 7) A formulation comprising the solid dispersion according to any one of (Item 1) to (Item 6). (Section 8) The formulation according to (Item 7), wherein the solubility of the formulation in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomer, and its pharmaceutically acceptable salt. (Section 9) The formulation according to (Item 7) or (Item 8), which is for oral administration. (Section 10) The formulation according to any one of (Item 7) to (Item 9), which is in the form of a tablet. (Section 11) A method for producing a solid dispersion, comprising: A production method comprising a step of spray-drying a solution obtained by dissolving at least one compound selected from the group consisting of heterocyclic derivatives represented by the general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable polymer in a solvent, by a spray-drying method. [Effects of the Invention]

[0009] According to the present invention, there are provided a solid dispersion useful as a pharmaceutical containing a compound having mPGES-1 inhibitory activity, a pharmaceutical preparation containing the solid dispersion useful as a pharmaceutical, and methods for producing them. Furthermore, according to the present invention, the solubility and / or oral absorbability of a compound having mPGES-1 inhibitory activity can be improved. [Brief explanation of the drawings]

[0010] [Figure 1] 1 is a powder X-ray diffraction spectrum of the solid dispersion of Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0011] Hereinafter, embodiments of the present invention will be described in detail, but the present invention is not limited to the following embodiments.

[0012] (compound) The compound according to this embodiment is selected from the group consisting of heterocyclic derivatives represented by the following general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof (hereinafter also referred to as the compound, etc.). [ka]

[0013] In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4]. [ka] [In the general formulas [2], [3] and [4], X 1 represents NH, N-alkyl, or O. 1 represents hydrogen or alkyl. 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 halogens; v) alkoxy, vi) a saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo; vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5]: [ka] (In general formula [5], R 3 and 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) represents a saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl. R 1 represents 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 such phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are i) halogens, ii) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and phenyl; iii) alkoxy, iv) hydroxy, and v) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of: R 2 represents phenyl or pyridyl, and such 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:

[0014] "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. Examples of "alkoxy" include linear or branched alkoxy 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 one S atom as a ring-constituting atom, and specific examples thereof include 1-azetidinyl, 1-pyrrolidinyl, 1-imidazolidinyl, piperidino, 1-piperazinyl, 1-tetrahydropyrimidinyl, 4-morpholino, 4-thiomorpholino, 1-homopiperazinyl, and oxazolidin-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.

[0015] The compound according to this embodiment is preferably a compound described in the following (A), (B) or (C). (A) In the general formula [1], ring A is a group represented by the general formula [4], and X 1 Heterocyclic derivatives in which is NH, and tautomers thereof, and pharmaceutically acceptable salts thereof. (B) In general formula [1], 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 tautomers thereof, and pharmaceutically acceptable salts thereof. (C)R 2 is phenyl, and the phenyl is i) halogens, ii) alkylsulfonyl, iii) alkoxy optionally substituted with alkoxy, and iv) alkynyl optionally substituted with alkoxyalkyl or cycloalkyl; v) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkoxy, alkoxyalkoxy, cycloalkyl, and phenyl; and tautomers thereof, and pharmaceutically acceptable salts thereof.

[0016] In addition, the compound according to this embodiment may be a compound in which ring A is a group represented by 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 with alkyl, the alkyl being optionally substituted with 1 to 3 halogens; iv) alkoxy, v) a saturated heterocyclic group optionally substituted with alkyl or alkyloxycarbonyl, vi) alkylthio, vii) alkylsulfonyl, viii) alkylsulfinyl, ix) amino substituted with alkyl optionally substituted with a group selected from the group consisting of monoalkylamino, dialkylamino, saturated cyclic amino optionally substituted with alkyl, tetrahydrofuryl, morpholino, alkoxy, hydroxycarbonyl, hydroxyl, and alkylthio; x) amino substituted with cycloalkyl, or xi) saturated cyclic amino optionally substituted with alkyl, dialkylamino, alkoxy, or hydroxyl; R 1 but, i) phenyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, alkyl optionally substituted with 1 to 3 halogens, alkoxy, and cyano; ii) 1,2,3,4-tetrahydronaphthalen-5-yl, iii) 2,3-dihydro-1H-inden-5-yl, iv) benzyl optionally substituted with halogen or alkyl optionally substituted with 1 to 3 halogens; v) cycloalkyl, vi) cycloalkylmethyl, vii) naphthyl, viii) pyridylmethyl optionally substituted by alkyl optionally substituted by 1 to 3 halogens, ix) thienyl, x) thienylmethyl, xi) benzothiazolyl, xii) benzothiadiazolyl, xiii) indolyl, or xiv) alkyl; R 2 represents phenyl or pyridyl, and 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. Heterocyclic derivatives, and tautomers thereof, and pharmaceutically acceptable salts thereof are more preferred.

[0017] Furthermore, in the compound according to this embodiment, ring A is a group represented by 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 Further preferred are heterocyclic derivatives in which R is phenyl optionally substituted with one trifluoromethyl or two halogens, and tautomers thereof, and pharmaceutically acceptable salts thereof.

[0018] Furthermore, as the compound according to this embodiment, the heterocyclic derivatives described in any one of the following (1) to (239), and tautomers thereof, and pharmaceutically acceptable salts thereof are particularly preferred. (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 (239) N-(3-chloro-2-methylphenyl)-6-({[2-chloro-5-(4,4,4-trifluorobutoxy)phenyl]carbonyl}amino)-2-(methoxymethyl)-1H-benzimidazole-4-carboxamide

[0019] Some of the compounds according to this embodiment have asymmetric carbon atoms, and all of the optical isomers and mixtures thereof are included in the compounds according to this embodiment.

[0020] Among the heterocyclic derivatives according to this embodiment, those which can form tautomers include both the individual tautomers and mixtures thereof. For example, when ring A is a group represented by general formula [4], X 1 A heterocyclic derivative represented by the general formula [1] in which is NH (that is, a heterocyclic derivative represented by the following general formula (1X)) can form a heterocyclic derivative represented by the general formula [1XA]. [ka] In the general formulas [1X] and [1XA], R 1 , R 2 , A 2 has the same meaning as in general formula [1].

[0021] Examples of pharmaceutically acceptable salts of the heterocyclic derivatives and tautomers thereof according to this embodiment 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.

[0022] The compound according to this embodiment can be produced by the production method described in Patent Document 1, for example.

[0023] The compound according to this embodiment is 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, 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 It may be at least one selected from the group consisting of:

[0024] The compounds according to this embodiment may be used singly or in combination of two or more.

[0025] Pharmaceutically acceptable polymers The pharmaceutically acceptable polymer according to this embodiment may be dissolved, for example, at a pH of 6.0 or higher, preferably at a concentration of 1 mg / mL or higher, and more preferably at a concentration of 1 to 3 mg / mL. The pharmaceutically acceptable polymer according to this embodiment may be dissolved in the second fluid of the Japanese Pharmacopoeia, 18th Edition dissolution test, preferably after stirring at room temperature of 25°C for 12 hours.

[0026] The pharmaceutically acceptable polymer in this embodiment is, for example, at least one selected from the group consisting of acrylic polymers, vinyl polymers, cellulose polymers, and polyethylene glycol, and preferably at least one selected from the group consisting of methacrylic acid copolymer L, dry methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer E, polyvinylpyrrolidone, and hypromellose.

[0027] The pharmaceutically acceptable polymer according to this embodiment is an acrylic polymer, for example, at least one selected from the group consisting of methacrylic acid copolymer L (e.g., Eudragit® L100 (manufactured by EVONIK)), dry methacrylic acid copolymer LD (e.g., Eudragit® L100-55 (manufactured by EVONIK)), methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E (Eudragit® EPO (manufactured by EVONIK)), ammonioalkyl methacrylate copolymer, and ethyl acrylate-methyl methacrylate copolymer, preferably at least one selected from the group consisting of methacrylic acid copolymer L, dry methacrylic acid copolymer LD, and aminoalkyl methacrylate copolymer E, more preferably methacrylic acid copolymer L.

[0028] The pharmaceutically acceptable polymer in this embodiment is a vinyl polymer, for example, at least one selected from the group consisting of polyvinylpyrrolidone, carboxyvinyl polymer, and polyvinyl alcohol-polyethylene glycol graft copolymer, and is preferably polyvinylpyrrolidone.

[0029] The pharmaceutically acceptable polymer according to this embodiment is a cellulose-based polymer, and is, for example, at least one selected from the group consisting of hypromellose (e.g., HPMC E3LV), hypromellose acetate succinate (e.g., HPMCAS-M, HPMCAS-H, HPMCAS-L), hypromellose phthalate (e.g., HPMCP-HP55, HPMCP-HP55S, HPMCP-HP50), hydroxypropyl cellulose, ethyl cellulose, and hydroxyethyl cellulose, preferably at least one selected from the group consisting of hypromellose, hypromellose acetate succinate, and hypromellose phthalate, and more preferably hypromellose.

[0030] An example of a pharmaceutically acceptable polymer according to this embodiment is a methacrylic acid / methyl methacrylate copolymer.

[0031] In the methacrylic acid / methyl methacrylate copolymer according to this embodiment, the ratio of structural units derived from methacrylic acid to structural units derived from methyl methacrylate (structural units derived from methacrylic acid:structural units derived from methyl methacrylate) may be 30:70 to 70:30, 35:65 to 65:35, 40:60 to 60:40, or 45:55 to 55:45.

[0032] The methacrylic acid / methyl methacrylate copolymer according to the present embodiment dissolves, for example, at 1 mg / mL or more, preferably at 1 to 3 mg / mL. The methacrylic acid / methyl methacrylate copolymer according to the present embodiment dissolves, for example, in the second fluid of the Japanese Pharmacopoeia, 18th Edition dissolution test, preferably after stirring at room temperature of 25°C for 12 hours.

[0033] Examples of the methacrylic acid / methyl methacrylate copolymer that can be used in this embodiment include methacrylic acid copolymer L, dry methacrylic acid copolymer LD, methacrylic acid copolymer LD, and methacrylic acid copolymer S, with methacrylic acid copolymer L being preferred. Examples of the methacrylic acid / methyl methacrylate copolymer that can be used include the commercially available Eudragit (registered trademark) series (manufactured by EVONIK).

[0034] The pharmaceutically acceptable polymer according to this embodiment may be used alone or in combination of two or more.

[0035] The pharmaceutically acceptable polymer according to this embodiment may optionally be used in combination with a surfactant, for example, sodium lauryl sulfate.

[0036] [Solid dispersion] The solid dispersion according to this embodiment contains at least one compound selected from the group consisting of heterocyclic derivatives represented by the general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, and the pharmaceutically acceptable polymer. The solid dispersion according to this embodiment contains the compound in an amorphous state, and the amorphous compound is dispersed in the polymer.

[0037] The solid dispersion according to this embodiment may be used in a dissolution test as defined in the Japanese Pharmacopoeia, 18th Edition, as long as its dissolution concentration in the second fluid is greater than the dissolution concentration of at least one compound selected from the group consisting of heterocyclic derivatives represented by the general formula [1], their tautomers, and pharmaceutically acceptable salts thereof (e.g., the compound). For example, 100 mg of the solid dispersion (compound A) is added to 250 mL of the second fluid of the Japanese Pharmacopoeia, 18th Edition. The mixture is physically mixed in a weight ratio of solid dispersion:L-HPC:sorbitol = 1:2:2 and used for the test. When the mixture is stirred at 37°C with a paddle rotation speed of 200 rpm, the maximum dissolution concentration from 0 to 90 minutes into the test is compared with the dissolution concentration at 120 minutes into the test, and the decrease in dissolution concentration is 70% or less.

[0038] (Weight ratio of compound to pharmaceutically acceptable polymer) The ratio of the compound to the pharmaceutically acceptable polymer in the solid dispersion according to this embodiment is, for example, 1 to 98% by mass, preferably 10 to 98% by mass, more preferably 20 to 40% by mass, even more preferably 25 to 35% by mass, and even more preferably 30% by mass, relative to the total mass of the solid dispersion.

[0039] (Method of producing solid dispersion) The solid dispersion according to the present invention can be produced, for example, by a spray-drying method or a melting method.

[0040] That is, the method for producing the solid dispersion according to this embodiment includes a step of spray-drying a solution in which the compound according to this embodiment (at least one compound selected from the group consisting of heterocyclic derivatives represented by general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof) and the polymer according to this embodiment (for example, a pharmaceutically acceptable methacrylic acid / methyl methacrylate copolymer) are dissolved in a solvent by a spray-drying method.

[0041] The solvent may be any solvent capable of dissolving the compound and polymer according to this embodiment, for example, methanol, dichloromethane, acetone and tetrahydrofuran, a mixed solvent of two or more of these, and a mixed solvent of these with water. Since the solid dispersion according to this embodiment can be efficiently obtained, the solvent is preferably methanol, dichloromethane and tetrahydrofuran, a mixed solvent of two or more of these, or a mixed solvent of these with water, more preferably a mixed solvent of methanol and dichloromethane, and a mixed solvent of tetrahydrofuran and water, more preferably a mixed solvent of dichloromethane and methanol (dichloromethane / methanol=9 / 1 to 7 / 3), and a mixed solvent of tetrahydrofuran and water (tetrahydrofuran / water=90 / 10 to 99 / 1), and particularly preferably a mixed solvent of dichloromethane and methanol (dichloromethane / methanol=8 / 2), and a mixed solvent of tetrahydrofuran and water (tetrahydrofuran / water=95 / 5).

[0042] Spray drying by the spray drying method can be carried out according to a conventional method, specifically, for example, using a commercially available spray drying apparatus (for example, Spray Dryer B-290, manufactured by BUCHI).

[0043] The temperature during spray drying may be, for example, 40 to 140° C., 60 to 120° C., or 80 to 110° C. The time during spray drying may be, for example, 30 minutes to 72 hours, or 18 to 50 hours.

[0044] Furthermore, if the sample obtained by spray drying contains residual solvent, post-treatment may include a step of removing the solvent, such as drying under reduced pressure.

[0045] 〔formulation〕 The formulation according to this embodiment contains the solid dispersion according to the present invention. The formulation according to this embodiment may contain only the solid dispersion according to this embodiment, or may contain the solid dispersion according to this embodiment together with other pharmaceutically acceptable ingredients.

[0046] (Other ingredients) Examples of other ingredients include excipients, binders, disintegrants, lubricants, flow agents, colorants, and the like.

[0047] Examples of excipients include D-mannitol, potato starch, lactose hydrate, corn starch, calcium hydrogen phosphate hydrate, magnesium carbonate, and calcium carbonate.

[0048] Examples of binders include hydroxypropylmethylcellulose (hypromellose), hydroxypropylcellulose, polyvinyl alcohol, and methylcellulose.

[0049] Examples of disintegrants include crystalline cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, light anhydrous silicic acid, calcium silicate, low-substituted hydroxypropyl cellulose, agar powder, crospovidone, and lactose (milk sugar) hydrate.

[0050] Examples of lubricants include magnesium stearate, calcium stearate, sucrose fatty acid ester, sodium stearyl fumarate, and stearic acid.

[0051] Examples of the fluidizing agent include light anhydrous silicic acid, titanium oxide, stearic acid, colloidal silica, talc, starch, and magnesium aluminum silicate.

[0052] Examples of colorants include titanium oxide, yellow ferric oxide, and ferric oxide.

[0053] (Polymer content in formulation) The content of the polymer in the formulation according to this embodiment can be set arbitrarily depending on the dosage form and dosage regime of the formulation, and may be, for example, 10% by mass to 90% by mass, 20% by mass to 80% by mass, or 30% by mass to 60% by mass relative to the total mass of the entire formulation.

[0054] In the formulation of this embodiment, the dissolution concentration of at least one compound selected from the group consisting of heterocyclic derivatives represented by the general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, is, for example, 1 μg / mL or more, and preferably, when 100 mg of the compound etc. is added to 250 mL of the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, at 37°C and the dissolution concentration is measured at a paddle rotation speed of 200 rpm, the formulation shows a dissolution concentration of 1 μg / mL or more.

[0055] (Dosage form) The dosage form of the preparation according to this embodiment is not particularly limited, and may be, for example, tablets, capsules, powders, granules, or fine granules.

[0056] (Preparation manufacturing method) The formulation according to this embodiment can be manufactured according to a conventional method depending on the dosage form, etc. For example, when the formulation according to this embodiment is a tablet, it can be manufactured by carrying out steps such as granulation, crushing (e.g., dry crushing, wet crushing), sizing, tableting, and film coating.

[0057] (Dosage and dosage) The formulation according to this embodiment may be administered orally or parenterally. Therefore, the formulation according to this embodiment may be for oral administration or parenteral administration. It is desirable to adjust the dosage of the formulation according to this embodiment taking into consideration the patient's condition, such as age, weight, type and severity of disease, the route of administration, the type of compound according to this embodiment, and the like. Generally, the amount of the active ingredient of the compound according to this embodiment for an adult is in the range of 0.01 mg to 5 g per adult, preferably 1 mg to 500 mg per adult, per day when administered orally. In some cases, a lower dosage may be sufficient, or a higher dosage may be required. Generally, the formulation according to this embodiment is administered once a day or in divided doses, or in the case of intravenous administration, it may be administered as a rapid or continuous administration within 24 hours.

[0058] (Medicinal use) The compound according to this embodiment exhibits mPGES-1 inhibitory activity. Therefore, the formulation according to this embodiment is effective in treating, for example, inflammatory bowel disease, irritable bowel syndrome, migraine, headache, lower back pain, lumbar spinal stenosis, herniated disc, temporomandibular joint disorder, cervicobrachial syndrome, cervical spondylosis, endometriosis, adenomyosis, premature labor, threatened premature labor, dysmenorrhea, overactive bladder, nocturia, interstitial cystitis, neurodegenerative diseases (e.g., Alzheimer's disease, multiple sclerosis), psoriasis, rheumatoid arthritis, rheumatic fever, fibromyalgia, neuralgia, complex regional pain syndrome, myofascial disorders, viral infections (e.g., influenza, cold, shingles, AIDS), bacterial infections, and fungal infections. It can be used as a preventive or therapeutic agent for pain in burns, inflammation and pain after surgery, trauma and tooth extraction, malignant tumors (e.g., colon cancer, breast cancer, lung cancer, prostate cancer, etc.), atherosclerosis, stroke, gout, arthritis, osteoarthritis, juvenile arthritis, ankylosing spondylitis, tenosynovitis, ossification of the ligaments, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, conjunctivitis, iritis, scleritis, uveitis, wound treatment, dermatitis, eczema, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic diseases, familial adenomatous polyposis, scleroderma, bursitis, uterine fibroids and cancer. [Example]

[0059] The present invention will be described in more detail below with reference to examples, although the present invention is not limited to the following examples.

[0060] Test Example 1: Preparation of Compound A and Compound B Compound A: N-(3-chloro-2-methylphenyl)-2-(methoxymethyl)-6-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-1H-benzimidazole-4-carboxamide 4-methylbenzenesulfonate, and Compound B: 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 WO 2013 / 024898 (hereinafter also referred to as Compound A and Compound B).

[0061] Test Example 2: Preparation of solid dispersion by spray drying method Example 1 12 parts by weight of Compound A prepared in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) L100 (manufactured by EVONIK, methacrylic acid copolymer L) (weight ratio 30:70) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane / methanol = 8 / 2). The resulting solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was carried out under the conditions of an inlet temperature of 75-90°C and a spray rate of 12-20 mL / min. After spray drying, the solution was further dried using a dryer at 40°C for 24 hours and then at 50°C for an additional 21 hours to obtain the solid dispersion of Example 1.

[0062] Example 2 12 parts by weight of Compound A prepared in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) L100-55 (EVONIK, dry methacrylic acid copolymer LD) (weight ratio 30:70) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane / methanol = 8 / 2). The resulting solution was spray-dried using a spray dryer (B-290, BUCHI). Spray drying was carried out under the conditions of an inlet temperature of 75-90°C and a spray rate of 12-20 mL / min. After spray drying, the solution was further dried for 12 hours at 40°C using a dryer to obtain the solid dispersion of Example 2.

[0063] Example 3 12 parts by weight of Compound A prepared in Test Example 1 and 28 parts by weight of Eudragit (registered trademark) EPO (manufactured by EVONIK, aminoalkyl methacrylate copolymer E) (weight ratio 30:70) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane / methanol = 8 / 2). The resulting solution was spray-dried using a spray dryer (B-290, manufactured by BUCHI). Spray drying was carried out under the conditions of an inlet temperature of 75-90°C and a spray rate of 12-20 mL / min. After spray drying, the solution was further dried at 40°C for 12 hours using a dryer to obtain the solid dispersion of Example 3.

[0064] Example 4 12 parts by weight of Compound A produced in Test Example 1 and 28 parts by weight (weight ratio 30:70) of PVP / VA64 (BASF, copolymer of vinylpyridone and vinyl acetate) were dissolved in a mixed solvent of dichloromethane and methanol (dichloromethane / methanol = 8 / 2). The resulting solution was spray-dried using a spray dryer (B-290, BUCHI). Spray drying was carried out under the conditions of an inlet temperature of 81-84°C and a spray rate of 18-20 mL / min. After spray drying, the solution was further dried at 40°C for 24 hours using a dryer to obtain the solid dispersion of Example 4.

[0065] Example 5 Eight parts by weight of Compound A prepared in Test Example 1 and 32 parts by weight of hydroxypropylmethylcellulose (HPMC, manufactured by DuPont) (weight ratio 20:80) were dissolved in a mixed solvent of tetrahydrofuran and water (tetrahydrofuran / water = 95 / 5). The resulting solution was spray-dried using a spray dryer (B-290, manufactured by Buchi). Spray drying was carried out under the conditions of an inlet temperature of 102-104°C and a spray rate of 18-20 mL / min. After spray drying, the solution was further dried at 40°C for 24 hours using a dryer to obtain the solid dispersion of Example 5.

[0066] (Reference example 1) Tablets of Compound A were prepared according to the recipe in the table below. Each ingredient was listed in or conforms to the Japanese Pharmacopoeia (18th Edition), Pharmaceutical Excipients Standards, European Pharmacopoeia 9.0, The United States Pharmacopeia 41, and The National Formulary 36. [Table 1]

[0067] Compound A produced in Test Example 1, lactose hydrate, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crospovidone, and light anhydrous silicic acid were mixed, and then wet-granulated using a hydroxypropyl cellulose binding solution, followed by crushing, drying, and sieving. The resulting granules were mixed with magnesium stearate to form tablet granules. The tablet granules were compressed to obtain uncoated tablets. A coating solution prepared using hypromellose, titanium oxide, yellow ferric oxide, ferric oxide, and purified water was sprayed onto the uncoated tablets, which were then film-coated to obtain the tablets of Reference Example 1.

[0068] Test Example 3: Evaluation of solid dispersion (Powder X-ray diffraction) The crystalline state of the solid dispersions of Examples 1 to 5 immediately after production was evaluated using a powder X-ray diffractometer. The measurement conditions for powder X-ray diffractometry were as follows: Measuring device: SmartLab 9kW (Rigaku) Tube voltage: 45V Tube current: 200mA Measurement range: 5 to 40 degrees

[0069] As a result of powder X-ray diffraction, the crystalline peak derived from Compound A disappeared and a halo pattern was observed in all of the solid dispersions of Examples 1 to 5 (FIG. 1: Example 1), confirming that Compound A was contained in an amorphous state.

[0070] A dissolution test was carried out using the first dissolution test fluid of the 18th edition of the Japanese Pharmacopoeia at 37°C. The test fluid volume was 250 mL, the paddle rotation speed was 200 rpm, and the amount added was 100 mg of Compound A. The results are shown in Table 2. [Table 2]

[0071] A dissolution test was carried out using the second dissolution test fluid of the 18th edition of the Japanese Pharmacopoeia at 37°C. The test fluid volume was 250 mL, the paddle rotation speed was 200 rpm, and the amount added was 100 mg of Compound A. The results are shown in Table 3. [Table 3]

[0072] (PK study in dogs (satiation conditions)) Using the administration samples of Example 1 and Reference Example 1, the administration dose was changed to a dose giving 100 mg of Compound A, and a PK test in dogs was carried out under the following conditions. One of the samples was orally administered to beagle dogs (5-6 dogs, body weight 9-14 kg) under fasted conditions at a dose of 100 mg of compound A. At 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 hours after administration, blood (approximately 0.6 mL) was collected from the cephalic vein under unanesthetized conditions, and heparin sodium (6 μL) was added and then cooled on ice. The collected blood was centrifuged (3,000 × g, 10 minutes, 4°C) to collect plasma. The plasma concentration of compound A was measured by LC-MS / MS. The maximum plasma concentration (C max ), time to reach maximum plasma concentration (T max ) and the area under the plasma concentration-time curve from 0 to 24 hours (AUC last The results are shown in Table 4. [Table 4]

[0073] [Formulation Example 1] In Formulation Example 1, additives listed in or equivalent to the Japanese Pharmacopoeia (18th Edition), Pharmaceutical Excipients Standards, European Pharmacopoeia 9.0, The United States Pharmacopeia 41, and The National Formulary 36 were used. The solid dispersion of Example 1, corn starch, D-mannitol, croscarmellose sodium, light anhydrous silicic acid, crospovidone, mannitol, and magnesium stearate were tableted at a tableting load of 500 kgf using a 16 x 8 mm punch to a mass of 660 mg in the formulation ratios shown in Table 5. The obtained tablets can be film-coated as needed.

[0074] [Table 5]

[0075] [Formulation Example 2] In Formulation Example 2, additives listed in or equivalent to the Japanese Pharmacopoeia (18th Edition), Pharmaceutical Excipients Standards, European Pharmacopoeia 9.0, The United States Pharmacopeia 41, and The National Formulary 36 were used. The solid dispersion of Example 1, corn starch, D-mannitol, croscarmellose sodium, light anhydrous silicic acid, crospovidone, mannitol, and magnesium stearate were tableted at a tableting load of 500 kgf using a 16 x 8 mm punch to a mass of 660 mg in the formulation ratios shown in Table 6. The obtained tablets can be film-coated as needed.

[0076] [Table 6]

[0077] Test method: 18th edition Japanese Pharmacopoeia dissolution test (paddle method), One tablet of Compound A (100 mg) or Formulation Examples 1 and 2 was added to 250 mL of the second dissolution test fluid of the Japanese Pharmacopoeia, 18th Edition, at 37°C, and the test was carried out at a paddle rotation speed of 200 rpm to measure the dissolution concentration. The results are shown in Table 7.

[0078] [Table 7]

Claims

1. A solid dispersion comprising at least one compound selected from the group consisting of heterocyclic derivatives represented by the following general formula [1], tautomers thereof, and pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable polymer: 【Chemical 1】 In the general formula [1], ring A represents a group represented by the following general formula [2], [3] or [4]. 【Chemistry 2】 [In the general formulas [2], [3] and [4], X １ represents NH, N-alkyl, or O. １ represents hydrogen or alkyl. 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 halogens; v) alkoxy, vi) a saturated heterocyclic group optionally substituted with alkyl, alkyloxycarbonyl, alkylcarbonyl, or oxo; vii) alkylthio, viii) alkylsulfonyl, ix) alkylsulfinyl, x) a group represented by the following general formula [5]: 【Chemistry 3】 (In general formula [5], R ３ and 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) represents a saturated cyclic amino optionally substituted with alkyl, amino, monoalkylamino, dialkylamino, alkoxy, or hydroxyl. R １ represents 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 such phenyl, benzyl, cycloalkyl, cycloalkylmethyl, heteroaryl, and heteroarylmethyl are i) halogens, ii) alkyl optionally substituted with 1 to 3 groups selected from the group consisting of halogen, hydroxy, and phenyl; iii) alkoxy, iv) hydroxy, and v) Cyano and optionally substituted with 1 to 3 groups selected from the group consisting of: R ２ represents phenyl or pyridyl, and such 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:

2. The compound is 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, 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 solid dispersion according to claim 1, wherein the solid dispersion is at least one selected from the group consisting of:

3. 3. The solid dispersion according to claim 1, wherein the solubility of the solid dispersion in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomer, and its pharmaceutically acceptable salt.

4. 4. The solid dispersion according to claim 3, wherein the pharmaceutically acceptable polymer is at least one selected from the group consisting of a cellulose-based polymer, an acrylic-based polymer, and a vinyl-based polymer.

5. 4. The solid dispersion according to claim 3, wherein the pharmaceutically acceptable polymer is soluble in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition.

6. 6. The solid dispersion according to claim 4, wherein the compound is present in an amount of 1 to 98% by mass relative to the total mass of the solid dispersion.

7. A formulation comprising the solid dispersion according to any one of claims 1 to 6.

8. The formulation according to claim 7, wherein the solubility of the formulation in the second fluid of the dissolution test of the Japanese Pharmacopoeia, 18th Edition, is greater than the solubility of the heterocyclic derivative represented by the general formula [1], its tautomer, and its pharmaceutically acceptable salt.

9. The formulation of claim 8, which is for oral administration.

10. 10. The formulation of claim 9 in the form of a tablet.

Images