Arylamide derivative having antitumor activity

Patent metadata

Field	Value
Publication number	US-11964950-B2
Application number	US-202217869226-A
Country	US
Kind code	B2
Filing date	Jul 20, 2022
Priority date	Jan 22, 2020
Publication date	Apr 23, 2024
Grant date	Apr 23, 2024

Abstract

The present disclosure provides, for example, a compound represented by the general formula below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt:

wherein X 1 , X 2 , X 3 and X 4 are each independently —CR 2 ═ or N═, R 2 is, for example, a halogen atom, R 1 is, for example, —S(═O) 2 —NH—R 8 , R 8 is, for example, a C 1-6 alkyl group, R 3 is, for example, a hydrogen atom, R 5 is, for example, a halogen atom, R 6 is, for example, a hydrogen atom, and R 4 is, for example, a cyclopropyl group. The compounds, salts or solvates provided by the present disclosure exhibit high RAF/MEK complex-stabilizing activity and can be used for the treatment or prevention of cell proliferative disorders, particularly cancers.

First claim

The invention claimed is:

1. A compound represented by general formula (6) below or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt:

wherein:
X 1 , X 2 , X 3 and X 4 are each independently —CR 2 ═ or —N═;
R 2 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group;
R 1 is —S(═O) 2 —NH—R 8 or —S(═O) 2 —R 8 ;
R 8 is a hydrogen atom, a C1-6 alkyl group, or a monocyclic C3-6 cycloalkyl group, the C1-6 alkyl group being optionally substituted with a halogen atom, a hydroxy group or a C1-6 alkoxy group, and the C3-6 cycloalkyl group being optionally substituted with a C1-6 alkyl group;
R 3 is a hydrogen atom, a C1-6 alkyl group, a C3-6 cycloalkyl group, or a C1-6 alkoxy group, the C1-6 alkoxy group being optionally substituted with a hydroxy group;
R 5 is a halogen atom or a C1-6 alkyl group;
R 6 is a hydrogen atom, a halogen atom, or a C1-6 alkyl group; and
R 4 is a halogen atom or a cyclopropyl group.

2. The compound, salt or solvate according to claim 1 , wherein:
R 2 is a hydrogen atom or a halogen atom;
R 8 is a C1-6 alkyl group or a monocyclic C3-6 cycloalkyl group, the C1-6 alkyl group being optionally substituted with a halogen atom or a C1-6 alkoxy group, and the C3-6 cycloalkyl group being optionally substituted with a C1-6 alkyl group;
R 5 is a halogen atom;
R 6 is a hydrogen atom; and
R 4 is a halogen atom or a cyclopropyl group.

3. The compound, salt or solvate according to claim 1 , wherein:
R 2 is a hydrogen atom or a fluorine atom;
R 8 is a C1-4 alkyl group or a cyclopropyl group, the C1-4 alkyl group being optionally substituted with a fluorine atom or a C1-4 alkoxy group, and the cyclopropyl group being optionally substituted with a C1-4 alkyl group;
R 3 is a hydrogen atom, a C1-4 alkyl group, a cyclopropyl group, or a C1-4 alkoxy group, the C1-4 alkoxy group being optionally substituted with a hydroxy group;
R 5 is a fluorine atom;
R 6 is a hydrogen atom; and
R 4 is an iodine atom or a cyclopropyl group.

4. The compound, salt or solvate according to claim 1 , wherein:
R 2 is a fluorine atom;
R 1 is —S(═O) 2 —NH—R 8 ;
R 8 is a C1-4 alkyl group;
R 3 is a hydrogen atom or a cyclopropyl group;
R 5 is a fluorine atom;
R 6 is a hydrogen atom; and
R 4 is an iodine atom or a cyclopropyl group.

5. A compound or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, said compound being selected from the group consisting of:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]-N-methoxybenzamide,
3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-methylsulfanylanilino)benzamide,
2-(4-ethynyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(4-bromo-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-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)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-[(4-fluoro-1-benzothiophen-5-yl)amino]-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide, and
5-(2-fluoro-4-iodoanilino)-2-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]pyridine-4-carboxamide.

6. The compound, salt or solvate according to claim 1 , wherein said compound is selected from the group consisting of:
N-cyclopropyl-3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
2-(4-cyclopropyl-2-fluoroanilino)-3,4-difluoro-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
N-cyclopropyl-5-[[2-(ethylsulfamoylamino)-3-fluoropyridin-4-yl]methyl]-3,4-difluoro-2-(2-fluoro-4-iodoanilino)benzamide,
N-cyclopropyl-3,4-difluoro-5-[[3-fluoro-2-(2-fluoroethylsulfamoylamino)pyridin-4-yl]methyl]-2-(2-fluoro-4-iodoanilino)benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-[(2-methylpropan-2-yl)oxy]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-methoxybenzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
5-[[2-(cyclopropylsulfamoylamino)-3-fluoropyridin-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)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methoxyethylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(2-methylpropylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-[(1-methylcyclobutyl)sulfamoylamino]pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(propylsulfamoylamino)pyridin-4-yl]methyl]benzamide,
3,4-difluoro-2-(2-fluoro-4-iodoanilino)-5-[[3-fluoro-2-(methylsulfamoylamino)pyridin-4-yl]methyl]-N-(2-hydroxyethoxy)benzamide,
5-[[3-(ethylsulfonylamino)-2-flu

Assignees

• Chugai Pharmaceutical Co Ltd

Inventors

• Isshiki Yoshiaki
• Watanabe Fumio
• Tomizawa Masaki
• Hada Kihito
• Hattori Kazuo
• Kawasaki Kenichi
• Hyodo Ikumi
• Aoki Toshihiro

Classifications

• C07D265/02 Primary

  1,2-Oxazines; Hydrogenated 1,2-oxazines · CPC title

• C07C39/26

  monocyclic monohydroxylic containing halogen bound to ring carbon atoms · CPC title

• C07C69/76

  Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring · CPC title

• C07C211/55

  Diphenylamines · CPC title

• C07C307/02

  Monoamides of sulfuric acids or esters thereof, e.g. sulfamic acids · CPC title