Benzimidazol-2-amines as mIDH1 inhibitors

Patent metadata

Field	Value
Publication number	US-9957235-B2
Application number	US-201515118154-A
Country	US
Kind code	B2
Filing date	Feb 10, 2015
Priority date	Feb 11, 2014
Publication date	May 1, 2018
Grant date	May 1, 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 -cycloalkyl, 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 , —C(═O)N(R 14 )R 15 , —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 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:
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)-, and R 14 (R 15 )NC(═O)—(C 1 -C 6 -alkoxy)-;

R 6 is a hydrogen atom, a halogen atom or a 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;
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 -halo alkyl, 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 ,

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 , —C(═O)N(R 14 )R 15 , 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 1 is a group selected from:
—CF 3 , —O—CF 3 , —S—CF 3 , —O—CH 2 —CH 3 , —O—C(H)(CH 3 ) 2 , —CN, —C(H)(CH 3 ) 2 , and —C(═O)OH,

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 5 is a group selected from:
R 13 OC(═O)—(C 1 -C 3 -alkyl)- and R 14 (R 15 )NC(═O)—(C 1 -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.

5. The compound according to claim 1 , wherein:
R 5 is a group selected from:
R 13 OC(═O)—(C 2 -C 4 -alkenyl)- and R 14 (R 15 )NC(═O)—(C 2 -C 4 -alkenyl)-,

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:
R 13 OC(═O)—(C 1 -C 3 -alkoxy)- and R 14 (R 15 )NC(═O)—(C 1 -C 3 -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.

7. The compound according to claim 1 , wherein:
R 5 is a group selected from:
R 13 OC(═O)—CH 2 —CH 2 —CH 2 —, R 13 OC(═O)—CH 2 —CH 2 —, R 13 OC(═O)—CH 2 —, R 14 (R 15 )NC(═O)—CH 2 —CH 2 —, R 14 (R 15 )NC(═O)—CH 2 —, R 13 OC(═O)—CH 2 —O—, R 14 (R 15 )NC(═O)—CH 2 —O—,

wherein * indicates the point of attachment of said groups to the rest of the molecule,

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 5 is a group selected from:
—O—CH 2 —C(═O)—O—C(CH 3 ) 3 , —O—CH 2 —C(═O)—OH, —O—CH 2 —CH 2 —CH 2 —C(═O)—OH, —O—CH 2 —C(═O)—N(H)-cyclopropyl, —O—CH 2 —C(═O)—N(H)—CH 2 —C(═O)—O—CH 3 , —O—CH 2 —C(═O)—N(CH 3 )—CH 2 —C(═O)—O—CH 3 , —O—CH 2 —C(═O)—N(H)—CH 2 —C(═O)—OH, —O—CH 2 —C(═O)—N(CH 3 )—CH 2 —C(═O)—OH, —CH 2 —CH 2 —C(═O)—O—CH 3 , —CH 2 —CH 2 —C(═O)—OH, —CH 2 —C(═O)—O—CH 3 , —CH 2 —C(═O)—OH, —CH 2 —CH 2 —C(═O)—NH 2 , —CH 2 —CH 2 —C(═O)—N(CH 3 ) 2 , —C(H)═C(H)—C(═O)—OH, —C(H)═C(H)—C(═O)—O—CH 3 , —C(H)═C(H)—C(═O)—NH 2 , and —C(H)═C(H)—C(═O)—N(CH 3 ) 2 ,

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 6 is a hydrogen atom, a fluorine atom, a —CH 3 group, a —O—CH 3 group or a —CH 2 —O—CH 3 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 or 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.

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

Assignees

• Bayer Pharma AG

Inventors

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

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/4439

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465) · CPC title