N-Methylbenzimidazoles as mIDH1 inhibitors

Patent metadata

Field	Value
Publication number	US-10370339-B2
Application number	US-201615580372-A
Country	US
Kind code	B2
Filing date	Jun 3, 2016
Priority date	Jun 8, 2015
Publication date	Aug 6, 2019
Grant date	Aug 6, 2019

Abstract

The present invention relates to benzimidazol-2-amines of general formula (I), in which R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

First claim

The invention claimed is:

1. A compound of formula (I)

wherein:
R 1 is a halogen atom or a group selected from the group consisting of:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl,
C 1 -C 6 -haloalkoxy, cyano, (C 1 -C 6 -alkyl)-S—, (C 1 -C 6 -alkyl)-S(═O)—, (C 1 -C 6 -alkyl)-S(═O) 2 —, (C 1 -C 6 -haloalkyl)-S—, (C 1 -C 6 -haloalkyl)-S(═O)—, (C 1 -C 6 -haloalkyl)-S(═O) 2 —, —C(═O)OR 9 , —C(═O)N(R 10 )R 11 and N(R 10 )R 11 ;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom or a halogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 , R 9 OC(═O)—(C 1 -C 6 -alkyl)-, R 9 OC(═O)—(C 2 -C 6 -alkenyl)-, R 9 OC(═O)—(C 1 -C 6 -alkoxy)-, —C(═O)N(R 10 )R 11 , R 10 (R 11 )NC(═O)—(C 1 -C 6 -alkyl)-, R 10 (R 11 )NC(═O)—(C 2 -C 6 -alkenyl)- and R 10 (R 11 )NC(═O)—(C 1 -C 6 -alkoxy)-;

R 6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy and cyano;

R 7 is a hydrogen atom;
R 8 is a hydrogen atom;
R 9 is a hydrogen atom or a group selected from the group consisting of:
C 1 -C 6 -alkyl and C 3 -C 6 -cycloalkyl; and

R 10 and R 11
are independently selected from the group consisting of:
hydrogen and C 1 -C 6 -alkyl;

or
R 10 and R 11
are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycloalkyl,
wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with one substituent selected from the group consisting of: C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, amino, hydroxy, halogen and cyano,
or wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with two halogen atoms,

or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

2. The compound according to claim 1 , wherein:
R 1 is a halogen atom or a group selected from the group consisting of:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl and C 1 -C 6 -haloalkoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom or a halogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 6 -alkyl)-;

R 6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl and C 1 -C 6 -haloalkoxy;

R 7 is a hydrogen atom;
R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a C 1 -C 6 -alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

3. The compound according to claim 1 , wherein:
R 1 is a halogen atom or a group selected from the group consisting of:
C 1 -C 3 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 1 -C 3 -haloalkyl and C 1 -C 3 -haloalkoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom or a halogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 3 -alkyl)-;

R 6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, C 1 -C 3 -haloalkyl and C 1 -C 3 -haloalkoxy;

R 7 is a hydrogen atom;
R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a C 1 -C 3 -alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

4. The compound according to claim 1 , wherein:
R 1 is a group selected from the group consisting of:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and C 1 -C 3 -haloalkoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 2 -alkyl)-;

R 6 is a hydrogen atom or a group selected from the group consisting of:
C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy;

R 7 is a hydrogen atom;
R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a C 1 -C 3 -alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

5. The compound according to claim 1 , wherein:
R 1 is a group selected from the group consisting of:
isopropyl, isopropoxy and trifluoromethoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 2 -alkyl)-;

R 6 is a hydrogen atom or a group selected from the group consisting of:
methyl and methoxy,

R 7 is a hydrogen atom;
R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a methyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

6. The compound according to claim 1 , having a structural formula (I-a):

wherein:
R 1 is a group selected from the group consisting of:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy and C 1 -C 3 -haloalkoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 2 -alkyl)-;

R 6 is a hydrogen atom or a group selected from the group consisting of:
C 1 -C 3 -alkyl and C 1 -C 3 -alkoxy, R 7 is a hydrogen atom;

R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a C 1 -C 3 -alkyl group,
or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

7. The compound according to claim 6 , wherein:
R 1 is a group selected from the group consisting of:
isopropyl, isopropoxy and trifluoromethoxy;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a group selected from the group consisting of:
C(═O)OR 9 and R 9 OC(═O)—(C 1 -C 2 -alkyl)-;

R 6 is a hydrogen atom or a group selected from the group consisting of:
methyl and methoxy,

R 7 is a hydrogen atom;
R 8 is a hydrogen atom; and
R 9 is a hydrogen atom or a methyl group,
or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

8. The compound according to claim 1 , which is selected from the group consisting of:
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazole-5-carboxylate;
methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazole-5-carboxylate;
methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyc

Assignees

• Bayer Pharma AG

Inventors

• Ring Sven
• Panknin Olaf
• Zimmermann Katja
• Günther Judith
• Bärfacker Lars

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D235/30 Primary

  Nitrogen atoms not forming part of a nitro radical · CPC title