Benzimidazol-2-amines as MIDH1 inhibitors

Patent metadata

Field	Value
Publication number	US-9951027-B2
Application number	US-201515118157-A
Country	US
Kind code	B2
Filing date	Feb 10, 2015
Priority date	Feb 11, 2014
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

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 , R 8 , R 9 , R 10 , R 11 and R 12 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:
C 1 -C 6 -alkyl, C 3 -C 6 -cyclo alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-, cyano, nitro, (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 13 , —N(R 14 )R 15 , —N(R 14 )C(═O)R 16 , aryl-O—, aryl-(C 1 -C 3 -alkyl)-, heteroaryl-O—, and heteroaryl-(C 1 -C 3 -alkyl)-,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)N(R 14 )R 15 ;

R 2 and R 3
are independently selected from:
a hydrogen atom, 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, halogen, cyano, nitro, (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(═O)OR 13 , —C(═O)N(R 14 )R 15 , —N(R 14 )R 15 , and —N(R 14 )C(═O)R 16 ;

R 4 is a hydrogen atom, a halogen atom or a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cyclo alkyl, C 1 -C 6 -alkoxy, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, cyano, nitro, (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(═O)OR 13 , —C(═O)N(R 14 )R 15 , aryl-O—, heteroaryl-O—, —N(R 14 )R 15 , and —N(R 14 )C(═O)R 16 ,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)N(R 14 )R 15 ;

R 5 is a hydrogen atom, a halogen atom or a group selected from:
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, nitro, (C 1 -C 6 -alkyl)-S—, (C 1 -C 6 -alkyl)-S(═O)—, (C 1 -C 6 -alkyl)-S(═O) 2 —, aryl-S—, aryl-S(═O)—, aryl-S(═O) 2 —, heteroaryl-S—, heteroaryl-S(═O)—, heteroaryl-S(═O) 2 —, aryl-(C 1 -C 6 -alkyl)-S(═O)—, aryl-(C 1 -C 6 -alkyl)-S(═O) 2 —, heteroaryl-(C 1 -C 6 -alkyl)-S(═O)—, heteroaryl-(C 1 -C 6 -alkyl)-S(═O) 2 —, (C 1 -C 6 -haloalkyl)-S—, aryl-O—, heteroaryl-O—, —C(═O)OR 13 , —C(═O)N(R 14 )R 15 , —C(═O)N(R 14 )S(═O) 2 R 16 , —N(R 14 )R 15 , —N(R 14 )C(═O)R 16 , —N(R 14 )C(═O)R 17 , —N(R 14 )S(═O) 2 R 16 , —S(═O) 2 OR 13 , and —S(═O) 2 N(R 14 )R 15 ,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)N(R 14 )R 15 ;

R 6 is a hydrogen atom, a halogen atom or group selected from:
C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, (C 1 -C 3 -alkoxy)-(C 1 -C 3 -alkyl)-, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, cyano, nitro, (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—, —N(R 14 )R 15 , and —N(R 14 )C(═O)R 16 ;

R 7 is a hydrogen atom, a halogen atom or a C 1 -C 3 -alkyl group;
R 8 is a C 1 -C 3 -alkyl group;
R 9 , R 10 , and R 11
are independently selected from a hydrogen atom and C 1 -C 3 -alkyl;

R 12 is a hydrogen atom;
R 13 is a hydrogen atom or a group selected from:
C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, HO—(C 2 -C 6 -alkyl)-, and (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-;

R 14 and R 15
are independently selected from:
a hydrogen atom, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, HO—(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkoxy)-(C 2 -C 6 -alkyl)-, C 1 -C 6 -haloalkyl, H 2 N—(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl)N(H)(C 2 -C 6 -alkyl)-, (C 1 -C 3 -alkyl) 2 N(C 2 -C 6 -alkyl)-, R 13 OC(═O)—(C 1 -C 6 -alkyl)-, 4- to 6-membered heterocycloalkyl, aryl, heteroaryl, aryl-(C 1 -C 6 -alkyl)-, and heteroaryl-(C 1 -C 6 -alkyl)-,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)NH 2 ;

or
R 14 and R 15
are taken together with the nitrogen atom to which they are attached to form a 4-6-membered heterocycloalkyl,
wherein said 4-6-membered heterocycloalkyl is optionally substituted with one substituent selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -haloalkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkoxy, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, amino, hydroxy, halogen, and cyano,
or
wherein said 4-6-membered heterocycloalkyl is optionally substituted with two halogen atoms;

R 16 is a hydrogen atom or a group selected from:
C 1 -C 6 -alkyl, HO—(C 1 -C 6 -alkyl)-, C 3 -C 6 -cycloalkyl, HO—(C 3 -C 6 -cycloalkyl)-, C 1 -C 6 -haloalkyl, (C 1 -C 3 -alkoxy)-(C 1 -C 6 -alkyl)-, aryl, heteroaryl, and 4- to 6-membered heterocycloalkyl,
wherein said aryl and heteroaryl groups are optionally substituted with one or two substituents, which are independently selected from:
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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)N(R 14 )R 15 ; and

R 17 is a group selected from —N(R 14 )R 15 and C 1 -C 6 -alkoxy,
or a stereoisomer, a tautomer, 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 group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, cyano, nitro, (C 1 -C 3 -alkyl)-S(═O) 2 —, (C 1 -C 3 -haloalkyl)-S—, —C(═O)OR 13 , —N(R 14 )R 15 , and —N(R 14 )C(═O)R 16 ,

or a stereoisomer, a tautomer, 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 2 is a hydrogen atom; and
R 3 is a hydrogen atom or a C 1 -C 3 -alkyl- group,
or a stereoisomer, a tautomer, 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 4 is a hydrogen atom, a halogen atom or a group selected from:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, and —C(═O)OR 13 ,

or a stereoisomer, a tautomer, 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 5 is a group selected from:
—C(═O)OR 13 , —C(═O)N(R 14 )R 15 , and C(═O)N(R 14 )S(═O) 2 R 16 ,

or a stereoisomer, a tautomer, 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 , wherein:
R 5 is a group selected from:
—N(R 14 )R 15 , —N(R 14 )C(═O)R 16 , —N(R 14 )C(═O)R 17 , and —N(R 14 )S(═O) 2 R 16 ,

or a stereoisomer, a tautomer, 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 1 , wherein:
R 5 is a group selected from:
(C 1 -C 3 -alkyl)-S(═O) 2 —, —S(

Assignees

• Bayer Pharma AG

Inventors

• Rehwinkel Hartmut
• Siebeneicher Holger
• Anlauf Sonja
• Nguyen Duy
• Panknin Olaf
• Ring Sven
• Schwede Wolfgang
• Bauser Marcus
• Zimmermann Katja
• Kaulfuss Stefan
• Neuhaus Roland

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

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

• A61P35/00

  Antineoplastic agents · CPC title