# US 10,370,339 B2 · N-Methylbenzimidazoles as mIDH1 inhibitors

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- Number: US 10,370,339 B2
- Document ID: US10370339B2
- Status: Granted
- Kind: B2
- Application number: 15/580,372
- Filed: 2016-06-03
- Published: 2018-06-21
- Granted: 2019-08-06
- Earliest claimed: 2015-06-08
- Assignees: Bayer Pharma Aktiengesellschaft
- Applicants: Bayer Pharma Aktiengesellschaft
- Inventors: Sven Ring; Olaf Panknin; Katja Zimmermann; Judith Günther; Lars Bärfacker
- Web page: https://patentgrep.com/patent/US10370339B2

## CPC

- C07D 235/30: Nitrogen atoms not forming part of a nitro radical
- A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 235/24: with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
- C07C 229/42: with carboxyl groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by saturated carbon chains
- C07C 229/60: with amino and carboxyl groups bound in meta- or para- positions
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present invention relates to benzimidazol-2-amines of general formula (I), in which R1, R2, R3, R4, R5, R6, R7 and R8 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.

## Claims

### Claim 1

A compound of formula (I)
wherein:
R1 is a halogen atom or a group selected from the group consisting of:
C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyloxy, C1-C6-haloalkyl,
C1-C6-haloalkoxy, cyano, (C1-C6-alkyl)-S—, (C1-C6-alkyl)-S(═O)—, (C1-C6-alkyl)-S(═O)2—, (C1-C6-haloalkyl)-S—, (C1-C6-haloalkyl)-S(═O)—, (C1-C6-haloalkyl)-S(═O)2—, —C(═O)OR9, —C(═O)N(R10)R11 and N(R10)R11;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom or a halogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9, R9OC(═O)—(C1-C6-alkyl)-, R9OC(═O)—(C2-C6-alkenyl)-, R9OC(═O)—(C1-C6-alkoxy)-, —C(═O)N(R10)R11, R10(R11)NC(═O)—(C1-C6-alkyl)-, R10(R11)NC(═O)—(C2-C6-alkenyl)- and R10(R11)NC(═O)—(C1-C6-alkoxy)-;
R6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyloxy, C1-C6-haloalkyl, C1-C6-haloalkoxy and cyano;
R7 is a hydrogen atom;
R8 is a hydrogen atom;
R9 is a hydrogen atom or a group selected from the group consisting of:
C1-C6-alkyl and C3-C6-cycloalkyl; and
R10 and R11
are independently selected from the group consisting of:
hydrogen and C1-C6-alkyl;
or
R10 and R11
are taken together with the nitrogen atom to which they are attached to form a 4- to 6-membered heterocycloalkyl,
wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with one substituent selected from the group consisting of: C1-C3-alkyl, C1-C3-haloalkyl, C1-C3-alkoxy, C1-C3-haloalkoxy, amino, hydroxy, halogen and cyano,
or wherein said 4- to 6-membered heterocycloalkyl group is optionally substituted with two halogen atoms,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
R1 is a halogen atom or a group selected from the group consisting of:
C1-C6-alkyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C3-C6-cycloalkyloxy, C1-C6-haloalkyl and C1-C6-haloalkoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom or a halogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C6-alkyl)-;
R6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C1-C6-alkyl, C1-C6-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyloxy, C1-C6-haloalkyl and C1-C6-haloalkoxy;
R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a C1-C6-alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein:
R1 is a halogen atom or a group selected from the group consisting of:
C1-C3-alkyl, C3-C6-cycloalkyl, C1-C3-alkoxy, C3-C6-cycloalkyloxy, C1-C3-haloalkyl and C1-C3-haloalkoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom or a halogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C3-alkyl)-;
R6 is a hydrogen atom, a halogen atom, or a group selected from the group consisting of:
C1-C3-alkyl, C1-C3-alkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkyloxy, C1-C3-haloalkyl and C1-C3-haloalkoxy;
R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a C1-C3-alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein:
R1 is a group selected from the group consisting of:
C1-C3-alkyl, C1-C3-alkoxy and C1-C3-haloalkoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C2-alkyl)-;
R6 is a hydrogen atom or a group selected from the group consisting of:
C1-C3-alkyl and C1-C3-alkoxy;
R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a C1-C3-alkyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein:
R1 is a group selected from the group consisting of:
isopropyl, isopropoxy and trifluoromethoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C2-alkyl)-;
R6 is a hydrogen atom or a group selected from the group consisting of:
methyl and methoxy,
R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a methyl group,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 6 (depends on 1)

The compound according to claim 1, having a structural formula (I-a):
wherein:
R1 is a group selected from the group consisting of:
C1-C3-alkyl, C1-C3-alkoxy and C1-C3-haloalkoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C2-alkyl)-;
R6 is a hydrogen atom or a group selected from the group consisting of:
C1-C3-alkyl and C1-C3-alkoxy, R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a C1-C3-alkyl group,
or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein:
R1 is a group selected from the group consisting of:
isopropyl, isopropoxy and trifluoromethoxy;
R2 is a hydrogen atom;
R3 is a hydrogen atom;
R4 is a hydrogen atom;
R5 is a group selected from the group consisting of:
C(═O)OR9 and R9OC(═O)—(C1-C2-alkyl)-;
R6 is a hydrogen atom or a group selected from the group consisting of:
methyl and methoxy,
R7 is a hydrogen atom;
R8 is a hydrogen atom; and
R9 is a hydrogen atom or a methyl group,
or an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 8 (depends on 1)

The compound according to claim 1, which is selected from the group consisting of:
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)-phenyl]amino}-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazole-5-carboxylate;
methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazole-5-carboxylate;
methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylate;
methyl 1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazole-5-carboxylate;
methyl 2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazole-5-carboxylate;
methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate;
methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}acetate;
methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}acetate;
methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate;
methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazol-5-yl}acetate;
methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazol-5-yl}acetate;
methyl (1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetate;
methyl {1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazol-5-yl}acetate;
methyl {2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}acetate;
methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;
methyl 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}propanoate;
methyl 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}propanoate;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazole-5-carboxylic acid;
2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazole-5-carboxylic acid;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazole-5-carboxylic acid;
2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazole-5-carboxylic acid;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazole-5-carboxylic acid;
1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazole-5-carboxylic acid;
2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazole-5-carboxylic acid;
(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid;
{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}acetic acid;
{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-1H-benzimidazol-5-yl}acetic acid;
(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid;
{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methyl-1H-benzimidazol-5-yl}acetic acid;
{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methyl-1H-benzimidazol-5-yl}acetic acid;
(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)acetic acid;
{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-6-methoxy-1H-benzimidazol-5-yl}acetic acid;
{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}acetic acid;
3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid;
3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]-1H-benzimidazol-5-yl}propanoic acid;
3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 1H-benzimidazol-5-yl}propanoic acid;
methyl 3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;
methyl 3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}propanoate;
methyl 3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)-amino]-6-methoxy-1H-benzimidazol-5-yl}propanoate;
3-(1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid;
3-{2-[(4-isopropoxyphenyl)amino]-1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-6-methoxy-1H-benzimidazol-5-yl}propanoic acid; and
3-{1-[(1R,2S,5R)-2-isopropyl-5-methylcyclohexyl]-2-[(4-isopropylphenyl)amino]methoxy-1H-benzimidazol-5-yl}propanoic acid,
or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing.

### Claim 9 (depends on 1)

A method of preparing the compound of formula (I) according to claim 1, comprising reacting an intermediate compound of formula (III):
wherein R4, R5, R6 and R7 are as defined for the compound of formula (I),
with a compound of formula (IV):
wherein R1, R2 and R3 are as defined for the compound of formula (I),
to provide the compound of formula (I):
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (I).

### Claim 10 (depends on 1)

A method of preparing the compound of formula (I) according to claim 1, comprising reacting an intermediate compound of formula (V):
wherein R4, R5, R6 and R7 are as defined for the compound of formula (I),
with a compound of formula (VI):
wherein R1, R2, R3 and R8 are as defined for the compound of formula (I),
to provide the compound of formula (I):
wherein R1, R2, R3, R4, R5, R6, R7 and R8 are as defined for the compound of formula (I).

### Claim 11 (depends on 1)

A pharmaceutical composition comprising the compound of formula (I) according to claim 1, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing, and a pharmaceutically acceptable diluent or carrier.

### Claim 12 (depends on 1)

A pharmaceutical combination comprising:
one or more first active ingredients selected from the compound of formula (I) according to claim 1, or a stereoisomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture of any of the foregoing; and
one or more second active ingredients selected from chemotherapeutic anti-cancer agents.

### Claim 13 (depends on 1)

The compound of claim 1 or a salt thereof.

### Claim 14 (depends on 8)

The compound of claim 8 or a salt thereof.

### Claim 15 (depends on 12)

The pharmaceutical combination of claim 12, comprising the compound of formula (I) or a salt thereof.