Benzimidazol-2-amines as MIDH1 inhibitors

Patent metadata

Field	Value
Publication number	US-10138226-B2
Application number	US-201515520385-A
Country	US
Kind code	B2
Filing date	Oct 20, 2015
Priority date	Oct 23, 2014
Publication date	Nov 27, 2018
Grant date	Nov 27, 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 is selected from the group consisting of:
C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, cyano, (C 1 -C 6 -alkyl)-S—, and (C 1 -C 6 -haloalkyl)-S—;

R 2 is a hydrogen atom;
R 3 is a hydrogen atom;
R 4 is a hydrogen atom;
R 5 is a hydrogen atom;
R 6 is selected from the group consisting of:
R 13 OC(═O)—(C 1 -C 6 -alkyl)-, R 13 OC(═O)—(C 2 -C 6 -alkenyl)-, R 13 OC(═O)—(C 1 -C 6 -alkoxy)-, R 14 (R 15 )NC(═O)—(C 1 -C 6 -alkyl)-, R 14 (R 15 )NC(═O)—(C 2 -C 6 -alkenyl)-, R 14 (R 15 )NC(═O)—(C 1 -C 6 -alkoxy)-, —C(═O)OR 13 , —C(═O)N(R 14 )R 15 , and —C(═O)N(R 14 )S(═O) 2 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 the group consisting of: hydrogen and C 1 -C 3 -alkyl;

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

R 14 and R 15
are independently selected from the group consisting of: hydrogen, 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, phenyl, heteroaryl, phenyl-(C 1 -C 6 -alkyl)-, and heteroaryl-(C 1 -C 6 -alkyl)-;
wherein the phenyl and heteroaryl groups are optionally substituted with one or two substituents, which are independently 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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)NH 2 ;
and wherein the 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, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, amino, hydroxy, halogen, and cyano;
or wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted with one or two halogen atoms;

or
R 14 and R 15
are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycloalkyl;
wherein the 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, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyloxy, amino, hydroxy, halogen, and cyano;
or wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted with one or two halogen atoms; and

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

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 selected from the group consisting of:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, and (C 1 -C 3 -haloalkyl)-S—,
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 1 is a C 1 -C 3 -haloalkoxy 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 6 is selected from the group consisting of: R 13 OC(═O)—(C 1 -C 6 -alkyl)-, R 13 OC(═O)—(C 1 -C 6 -alkoxy)-, R 14 (R 15 )NC(═O)—(C 1 -C 6 -alkyl)-, R 14 (R 15 )NC(═O)—(C 1 -C 6 -alkoxy)-, —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.

5. The compound according to claim 1 , wherein:
R 6 is selected from the group consisting of: —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 6 is selected from the group consisting of: —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.

7. The compound according to claim 1 , wherein:
R 6 is a —C(═O)OR 13 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.

8. The compound according to claim 1 , wherein:
R 7 is a hydrogen atom,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

9. The compound according to claim 1 , wherein:
R 8 is a methyl group;
R 9 is a methyl group;
R 10 is a methyl group; and
R 11 is a methyl 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.

10. The compound according to claim 1 , wherein:
R 8 is a methyl group;
R 9 is a hydrogen atom;
R 10 is a methyl group; and
R 11 is a methyl 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.

11. The compound according to claim 1 , wherein:
R 13 is a hydrogen atom or is selected from the group consisting of:
C 1 -C 4 -alkyl and (C 1 -C 3 -alkoxy)-(C 2 -C 3 -alkyl)-,
or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

12. The compound according to claim 1 , wherein:
R 14 and R 15 are independently selected from the group consisting of:
hydrogen, 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, phenyl, heteroaryl, phenyl-(C 1 -C 6 -alkyl)-, and heteroaryl-(C 1 -C 6 -alkyl)-;
wherein the phenyl and heteroaryl groups are optionally substituted with one or two substituents, which are independently 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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)NH 2 ;
and wherein the 4- to 6-membered heterocycloalkyl group is optionally substituted with one substituent selected from the group consisting of: C 1 -C 3 -al

Assignees

• Bayer Pharma AG

Inventors

• Rehwinkel Hartmut
• Bauser Marcus
• Zimmermann Katja
• Kaulfuss Stefan
• Neuhaus Roland

Classifications

• A61P35/04

  specific for metastasis · CPC title

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P35/00

  Antineoplastic agents · CPC title