# US 2010/0168181 A1 · Benzimidazole amido derivatives, their manufacture and use as pharmaceutical agents

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- Number: US 2010/0168181 A1
- Document ID: US20100168181A1
- Status: Published application
- Kind: A1
- Application number: 12/600,662
- Filed: 2008-06-23
- Published: 2010-07-01
- Earliest claimed: 2007-06-25
- Assignees: Hoffmann-La Roche Inc.
- Inventors: Guy Georges; Eike Hoffmann; Klaus Kaluza; Matthias Koerner; Ulrike Reiff; Stefan Weigand
- Web page: https://patentgrep.com/patent/US20100168181A1

## CPC

- C07D 401/14: containing three or more hetero rings
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/18: for pancreatic disorders, e.g. pancreatic enzymes
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/06: Antiasthmatics
- A61P 13/08: of the prostate
- A61P 13/10: of the bladder
- A61P 13/12: of the kidneys
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Objects of the present invention are the compounds of formula (I) their pharmaceutically acceptable salts, enantiomeric forms, diastereoisomers and racemates, the preparation of the above-mentioned compounds, medicaments containing them and their manufacture, as well as the use of the above-mentioned compounds in the control or prevention of illnesses such as cancer.

## Claims

### Claim 1

A compound of formula I,
wherein
R1 is selected from the group consisting of: —R3, —O—R3 and —NR—R3;
R2 is —X—R4;
R3 is selected from the group consisting of:
a) —(CH2)n—(O)m-phenyl, wherein the phenyl is optionally substituted one to three times with the substitutents being each independently selected from the group consisting of: alkyl, —O-alkyl, halogen, cyano, —N(alkyl)2, trifluoromethyl, and trifluoromethoxy; with the proviso that, if R1 is —O—R3 or —NR—R3 and n is 0, m is also 0.
b) alkyl, wherein the alkyl is optionally substituted one to three times with the substituents being each independently selected from the group consisting of: —O-alkyl and halogen;
c) alkenyl;
d) heteroaryl; and
e) (C3-C6) cycloalkyl;
R4 is
a) phenyl, wherein the phenyl is optionally substituted one to three times with the substitutents being each independently selected from the group consisting of: halogen, alkyl, —O-alkyl, —N(alkyl)2, trifluoromethyl and trifluoromethoxy; or
b) pyridyl.
X is (C1-C3)alkylene, wherein the alkylene is optionally substituted once or twice with the substitutents being each independently selected from the group consisting of: hydroxy, alkyl and halogen;
R is hydrogen or (C1-C3)alkyl;
m is 0 or 1; and
n is 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1 characterized in that
R3 is selected from the group consisting of:
a) —(CH2)n—(O)m-phenyl, wherein the phenyl is optionally substituted one or two times with the substitutents being each independently selected from the group consisting of: —O—CH3, cyano, fluorine, chlorine, trifluoromethyl and trifluoromethoxy; with the proviso that, if R1 is —O—R3, or —NR—R3 and n is 0, m is also 0.
b) alkyl, wherein the alkyl is optionally substituted one to three times with the substitutents being each independently selected from the group consisting of: —O—CH3 and chlorine;
c) allyl;
d) furanyl; and
e) cyclopropyl;
R4 is
a) phenyl, wherein the phenyl is optionally substituted once by chlorine; or
b) pyridyl;
X is (C1-C3)alkylene, wherein the alkylene is optionally substituted once by hydroxy;
R is hydrogen; and
n is 0 or 1.

### Claim 3 (depends on 1)

A compound according to claim 1 characterized in that
R1 is —R3 or —NR—R3; and
R3 is selected from the group consisting of:
a) —(CH2)n—(O)m-phenyl, wherein the phenyl is optionally substituted one or two times with the substitutents being each independently selected from the group consisting of: —O—CH3, cyano, chlorine, trifluoromethyl and trifluoromethoxy; with the proviso that, if R1 is —O—R3, or —NR—R3 and n is 0, m is also 0.
b) alkyl, wherein the alkyl is substituted once by —O—CH3;
c) furanyl; and
d) cyclopropyl.

### Claim 4 (depends on 1)

A compound according to claim 1 characterized in that
R1 is —R3.

### Claim 5 (depends on 4)

A compound according to claim 4, selected from the group consisting of:
3-Cyano-N-(2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl)-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]-2,4-difluoro-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]-4-methoxy-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]-benzamide; compound with hydrochloric acid;
N-(2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl)-benzamide; compound with hydrochloric acid;
4-Methoxy-N-(2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl)-benzamide; compound with hydrochloric acid;
4-Chloro-N-(2-{2-oxo-4-[(pyridin-2-ylmethyl)-amino]-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl)-benzamide; compound with hydrochloric acid;
N-{2-[4-(3-Chloro-benzylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-4-methoxy-benzamide; compound with hydrochloric acid;
4-Chloro N-{2-[4-(3 chloro-benzylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide; compound with hydrochloric acid;
N-{2-[4-(3-Chloro-benzylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-2,4-difluoro-benzamide; compound with hydrochloric acid;
3-Chloro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl]-benzamide; compound with hydrochloric acid;
4-Fluoro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl]-benzamide; compound with hydrochloric acid;
3,4-Dichloro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide; compound with hydrochloric acid;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-phenyl-propionamide; compound with hydrochloric acid;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-4-trifluoromethyl-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]2-methoxy-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]-2-chloro-benzamide; compound with hydrochloric acid;
N-[2-(4-Benzylamino-2-oxo-1,2-dihydro-pyridin-3-yl)-3H-benzoimidazol-4-yl]-4-chloro-benzamide; compound with hydrochloric acid;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-2-phenyl-acetamide;
N-{2-[4-(3-Chloro-b enzylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-2,2-dimethyl-propionamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-4-methoxy-benzamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzo imidazol-4-yl}-3-trifluoromethyl-benzamide;
N-[2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl]-2-phenoxy-acetamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3,3-dimethyl-butyramide;
Cyclopropanecarboxylic acid {2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzo imidazol-4-yl}-amide;
2-Fluoro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
2-Chloro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
2-(4-Chloro-phenoxy)-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-acetamide;
3-Cyano-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-2-methoxy-acetamide;
2,4-Difluoro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
3-Fluoro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
2,4-Dichloro-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-benzamide;
N-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-methoxy-benzamide;
4-Cyano-N-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl}-3H-benzoimidazol-4-yl]-benzamide; and
Furan-2-carboxylic acid {2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-amide.

### Claim 6 (depends on 1)

A compound according to claim 1 characterized in that
R1 is —O—R3.

### Claim 7 (depends on 6)

A compound according to claim 6, selected from the group consisting of:
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid 4-methoxy-phenyl ester;
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid 2-methoxy-ethyl ester;
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid 2,2,2-trichloro-1,1-dimethyl-ethyl ester;
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid phenyl ester;
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid allyl ester;
{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-carbamic acid isopropyl ester; and
(2-{4-[(S)-2-(3-Chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-1H-benzoimidazol-4-yl)-carbamic acid methylester.

### Claim 8 (depends on 1)

A compound according to claim 1 characterized in that
R1 is —NR—R3.

### Claim 9 (depends on 8)

A compound according to claim 8, selected from the group consisting of:
1-(3-Fluoro-phenyl)-3-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-urea;
1-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-(4-methoxy-phenyl)-urea;
1-(4-Fluoro-phenyl)-3-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-urea;
1-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-(4-trifluoromethoxy-phenyl)-urea;
1-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-phenyl-urea;
1-{2-[4-((S)-2-Hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-3-(3-methoxy-phenyl)-urea;
1-Benzyl-3-{2-[4-((S)-2-hydroxy-2-phenyl-ethylamino)-2-oxo-1,2-dihydro-pyridin-3-yl]-3H-benzoimidazol-4-yl}-urea; and
1-(2-Chloro-phenyl)-3-(2-{4-[(S)-2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-1H-benzoimidazol-4-yl)-urea.

### Claim 10

(canceled)

### Claim 11 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

### Claim at position 12

12-14. (canceled)