Pharmaceutical composition for the treatment or prevention of cell proliferation disorders containing arylamide derivatives

Abstract

To provide a novel pharmaceutical composition for the treatment or prevention of cell proliferation disorders, particularly cancer, containing a compound having RAF / MEK complex stabilizing activity and / or MEK inhibitory activity as an active ingredient. [Solution] A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, comprising, for example, a compound represented by the following general formula (6) [wherein X1, X2, X3, and X4 are each independently -CR2= or -N=] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, as an active ingredient. TIFF2026102816000348.tif52149

Claims

1. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, comprising as an active ingredient a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. 【Chemistry 1】 [In the formula, Ring A is given by the following general formulas (2), (3), (4), or (5) (where the bonds marked with *, **, and *** are -NH-, -CONH-, and -CH, respectively). ２ It is a group that is bonded to (-). 【Chemistry 2】 X １ , X ２ , X ３ , X ４ , X ５ and X ６ Each is independently -CR ２ = or -N = R ２ is a hydrogen atom, a halogen atom or a C1-6 alkyl group, R １ ha -S (=O) ２ -NH-R ８ or -S (=O) ２ -R ８ And, R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, a C1-6 alkoxy group, a C3-6 cycloalkyl group, or a C3-6 heterocycloalkyl group), a monocyclic or bicyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group or a C1-6 alkoxy group), or a monocyclic or bicyclic C3-6 heterocycloalkyl group. R ３ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), a C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a halogen atom or a C1-6 alkyl group), or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), R ５ is a halogen atom or a C1-6 alkyl group, R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ is a hydrogen atom, a halogen atom, a C1-6 alkyl group, a C2-7 alkenyl group, a C2-7 alkynyl group, a C3-6 cycloalkyl group or a C1-6 alkylthio group, or R ６ and R ４ These, together with the carbon atoms to which they are bonded, form an unsaturated hetero 5-membered ring. R ７ is a hydrogen atom or a C1-6 alkyl group, R ９ [These are hydrogen atoms, halogen atoms, or C1-6 alkyl groups.]

2. Ring A is a group represented by general formula (2) or (4), R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R ３ These are a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ is a halogen atom or a cyclopropyl group, R ７ is a hydrogen atom or a methyl group. The pharmaceutical composition according to claim 1.

3. The pharmaceutical composition according to claim 1, wherein the compound represented by general formula (1) is the compound represented by the following general formula (6). 【Transformation 3】 [In the formula, X １ , X ２ , X ３ and X ４ Each is independently -CR ２ = or -N = R ２ is a hydrogen atom, a halogen atom, or a C1-6 alkyl group. R １ ha -S (=O) ２ -NH-R ８ or -S (=O) ２ -R ８ And, R ８ These are a hydrogen atom, a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom, a hydroxyl group, or a C1-6 alkoxy group), or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R ３ These are a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), R ５ is a halogen atom or a C1-6 alkyl group, R ６ R is a hydrogen atom, a halogen atom, or a C1-6 alkyl group, ４ [This is a halogen atom or a cyclopropyl group.]

4. R ２ is a hydrogen atom or a halogen atom, R ８ This is a C1-6 alkyl group (the C1-6 alkyl group may be substituted with a halogen atom or a C1-6 alkoxy group) or a monocyclic C3-6 cycloalkyl group (the C3-6 cycloalkyl group may be substituted with a C1-6 alkyl group), R ３ These are a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group (the C1-6 alkoxy group may be substituted with a hydroxyl group), R ５ It is a halogen atom, R ６ is a hydrogen atom, R ４ is a halogen atom or a cyclopropyl group. A pharmaceutical composition according to any one of claims 1 to 3.

5. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide, 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide, 2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 2-(2-chloro-4-iodoanilino)-5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(oxan-4-ylsulfonylamino)phenyl]methyl]benzamide, 2-[4-(difluoromethylsulfanyl)-2-fluoroanilino]-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]oxybenzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxy-1-methyl-6-oxopyridine-3-carboxamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-N-[(2-methylpropan-2-yl)oxy]-6-oxopyridine-3-carboxamide, 5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)-1-methyl-6-oxopyridine-3-carboxamide, 5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]pyridine-4-carboxamide, 5-(2-fluoro-4-iodoanilino)-8-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]imidazo[1,5-a]pyridine-6-carboxamide, 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide, 5-Fluoro-4-(2-Fluoro-4-iodoanilino)-1-[[3-Fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]-6-oxopyridine-3-carboxamide, 4-(2-fluoro-4-iodoanilino)-1-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-5-methyl-6-oxopyridine-3-carboxamide, and 1-[[2-(ethylsulfonylamino)-3-fluoropyridine-4-yl]methyl]-4-(2-fluoro-4-iodoanilino)-5-methyl-6-oxopyridine-3-carboxamide A pharmaceutical composition containing a compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, as an active ingredient.

6. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridine-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridine-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propan-2-ylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide, 5-[[3-(ethylsulfonylamino)-2-fluorophenyl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-N-methoxybenzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methylsulfamoylamino)phenyl]methyl]benzamide, 3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[2-fluoro-3-(methanesulfonamide)phenyl]methyl]benzamide, 4-Fluoro-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, and N-Cyclopropyl-2-(2-Fluoro-4-iodoanilino)-5-[[3-Fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide A pharmaceutical composition containing a compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, as an active ingredient.

7. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide, 2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]-1-methyl-6-oxopyridine-3-carboxamide, and 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide A pharmaceutical composition containing a compound selected from or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, as an active ingredient.

8. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, A pharmaceutical composition containing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt, as an active ingredient.

9. A pharmaceutical composition for the treatment or prevention of cell proliferation disorders, A pharmaceutical composition containing 2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridine-4-yl]methyl]benzamide or its sodium or potassium salt, or a pharmaceutically acceptable solvate of the said compound or salt, as an active ingredient.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the cell proliferation disorder is cancer.

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