1-cyclohexyl-2-phenylaminobenzimidazoles as mIDH1 inhibitors for the treatment of tumors

Patent metadata

Field	Value
Publication number	US-10137110-B2
Application number	US-201515520384-A
Country	US
Kind code	B2
Filing date	Oct 21, 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 a group 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 phenyl or heteroaryl group,
wherein said phenyl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
halo-, cyano, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, nitro, R 13 O—, R 13 S—, 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 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 , —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 ;

R 6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of C 1 -C 6 -alkyl and C 1 -C 6 -alkoxy;
R 7 is a hydrogen atom;
R 8 is C 1 -C 3 -alkyl;
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 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 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)-, 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 said phenyl and heteroaryl groups are optionally substituted with one or two substituents independently selected from the group consisting of:
C 3 -C 6 -cycloalkyl, C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkyloxy, 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 one or two halogen atoms;

R 16 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 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 said phenyl and heteroaryl groups are optionally substituted with one or two substituents 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 ; and

R 17 is a group selected from the group consisting of —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 the group consisting of:
C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -haloalkyl, C 1 -C 3 -haloalkoxy, (C 1 -C 3 -alkyl)-S—, 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 group selected from the group consisting of:
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.

4. The compound according to claim 1 , wherein:
R 5 is a phenyl or heteroaryl group,
wherein said phenyl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
halo-, cyano, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, nitro, R 13 O—, R 13 S—, 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 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(═)OR 13 , —C(═O)N(R 14 )R 15 , —C(═O)N(R 14 )S(═O) 2 R 16 , —N(R 4 )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 , and
wherein said heteroaryl group is selected from the group consisting of:
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl,

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 phenyl or heteroaryl group,
wherein said phenyl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
halo-, cyano, C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -haloalkoxy, nitro, R 13 O—, R 13 S—, 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 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(═)OR 13 , —C(═O)N(R 14 )R 15 , —C(═O)N(R 14 )S(═O) 2 R 16 , —N(R 4 )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 , and
wherein said heteroaryl group is selected from the group consisting of:
oxazolyl, pyrazolyl, oxadiazolyl, triazolyl, tetrazolyl, and pyridinyl,

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 phenyl or heteroaryl group,
wherein said phenyl or heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of:
halo-, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, R 13 O—, —C(═O)OR 13 , and —C(═O)N(R 14 )R 15 , and
wherein said heteroaryl group is selected from the group consisting of:
thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, thia-4H-pyrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl,

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a s

Assignees

• Bayer Pharma AG

Inventors

• Rehwinkel Hartmut
• Anlauf Sonja
• Nguyen Duy
• Panknin Olaf
• Bauser Marcus
• Zimmermann Katja
• Kaulfuss Stefan
• Neuhaus Roland
• Blaney Paul Matthew
• Toschi Gianna

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P35/02

  specific for leukemia · CPC title

• A61P43/00

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

• A61P37/02

  Immunomodulators · CPC title