Benzimidazol-2-amines as mIDH1 inhibitors

Patent metadata

Field	Value
Publication number	US-10442772-B2
Application number	US-201815923895-A
Country	US
Kind code	B2
Filing date	Mar 16, 2018
Priority date	Feb 11, 2014
Publication date	Oct 15, 2019
Grant date	Oct 15, 2019

Abstract

The present invention relates to benzimidazol-2-amines of general formula (I), in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 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 method of treatment of a disease responsive to inhibition of mIDH1 activity, comprising administering to a patient in need thereof a therapeutically effect amount of 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, (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 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, C 1 -C 3 -haloalkoxy, halogen, cyano, —C(═O)OR 13 , and —C(═O)N(R 14 )R 5 ;

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:
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 the group consisting of:
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 the group consisting of 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 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 1 -C 6 -alkyl)-;

R 14 and R 15
are independently selected from the group consisting of:
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 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 ;

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 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 said 4-6-membered heterocycloalkyl is optionally substituted with two halogen atoms; and

R 16 is a hydrogen atom or a group 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)-, 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 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 method of claim 1 , wherein:
R 1 is a group 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, 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 .

3. The method of claim 1 , wherein:
R 1 is a group selected from the group consisting of:
—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.

4. The method of claim 1 , wherein:
R 5 is a group selected from the group consisting of:
R 13 OC(═O)—(C 1 -C 3 -alkyl)-, R 14 (R 15 )NC(═O)—(C 1 -C 3 -alkyl)-,
R 13 OC(═O)—(C 2 -C 4 -alkenyl)-, R 14 (R 15 )NC(═O)—(C 2 -C 4 -alkenyl)-,
R 13 OC(═O)—(C 1 -C 3 -alkoxy)-, and R 14 (R 15 )NC(═O)—(C 1 -C 3 -alkoxy)-.

5. The method of claim 1 , wherein:
R 5 is a group selected from the group consisting of:
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.

6. The method of claim 1 , wherein:
R 5 is a group selected from the group consisting of:
—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 .

7. The method of 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.

8. The method of 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.

9. The method of claim 1 , wherein:
R 13 is a hydrogen atom, a —CH 3 group or a —C(CH 3 ) 3 group.

10. The method of claim 1 , wherein:
R 14 is a hydrogen atom or a —CH 3 group.

11. The method of claim 1 , wherein:
R 15 is a hydrogen atom or a group selected from the group consisting of:
—CH 3 , cyclopropyl, —CH 2 —C(═O)—OH, —CH 2 —C(═O)—O—CH 3 , phenyl and pyridinyl,
wherein said phenyl and pyridinyl groups are optionally substituted with one or two substituents, which are independently selected from the group consisting of:
F, Cl, —CH 3 , —CHF 2 , —CF 3 , —OCHF 2 , —OCF 3 , and —C(═O)OCH 3 .

12. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:
(±) methyl (2E)-3-(2-{[4-(trifluorome

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

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/4184

  condensed with carbocyclic rings, e.g. benzimidazoles · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title