# US 7,608,723 B2 · Indole and benzimidazole derivatives

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- Number: US 7,608,723 B2
- Document ID: US7608723B2
- Status: Granted
- Kind: B2
- Application number: 11/251,440
- Filed: 2005-10-14
- Published: 2006-04-20
- Granted: 2009-10-27
- Earliest claimed: 2004-10-19
- Assignees: Novartis Vaccines and Diagnostics, Inc.
- Inventors: Rustum S. Boyce; Yi Xia; Hongyan Guo; Kris G. Mendenhull; Annette O. Walter; Weibo Wang
- Web page: https://patentgrep.com/patent/US7608723B2

## CPC

- C07D 403/12: linked by a chain containing hetero atoms as chain links
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/14: Radicals substituted by nitrogen atoms, not forming part of a nitro radical
- C07D 235/14: Radicals substituted by nitrogen atoms (by nitro radicals C07D235/10)
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/14: containing three or more hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to new indole and benzimidazole compounds and pharmaceutically acceptable salts, esters or prodrugs thereof, compositions of the new compounds together with pharmaceutically acceptable carriers, and uses of the new compounds. The compounds of the invention have the following general formula:

## Claims

### Claim 1

A compound of formula IC:
wherein
W is ═CH— or ═N—;
p is equal to 0, 1, 2 or 3;
R9 is alkyl or substituted alkyl;
R11 is —X1-A2, wherein X1 is —C(O)— and A2 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R12 is selected from the group consisting of -alkylene-amino, -alkylene-substituted amino, -alkylene-aryl, -alkylene-substituted aryl, -alkylene-nitrogen containing heterocyclic, -alkylene-heteroaryl, and -alkylene-substituted heteroaryl wherein the alkylene is optionally substituted;
or R9 and R12 together with the carbon atom attached to R9 and the nitrogen atom attached to R12 form a group selected from the group consisting of heterocyclic, substituted heterocyclic, heteroaryl, and substituted heteroaryl;
R13 is -L1-A3, wherein L1 is —S(O)r— where r is 1 or 2 or C1 to C2 straight chain alkylene, and A3 is selected from the group consisting of aryl optionally substituted with 1-2 groups independently selected from the group consisting of hydroxy, alkyl, halo, and acylamino, heteroaryl, and substituted heteroaryl;
each R14 is independently selected from the group consisting of halo, C2 to C3 alkynyl, C2 to C3 alkenyl, C1 to C5 alkyl optionally substituted with halo, C1 to C3 alkoxy, and phenyl;
or a pharmaceutically acceptable salt or ester thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R9 is selected from the group consisting of ethyl, isopropyl, and t-butyl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein A2 is aryl or heteroaryl optionally substituted with a substituent selected from the group consisting of halo, alkyl, acylamino, nitro, and hydroxy.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R11 is selected from the group consisting of (2-chloro-6-methylpyridin-4-yl)carbonyl; (5-methylimidazol-4-yl)carbonyl; (dimethylamino)methyl carbonyl; (naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl; 1,5-dimethylpyrazol-3-ylcarbonyl; 1-methyl-5-trifluoromethylpyrazol-4-ylcarbonyl; 1-methyl-5-chloropyrazol-4-ylcarbonyl; 2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl; 2,4-dimethylthiazol-5-ylcarbonyl; 2,6-difluorobenzoyl; 2-aminoethylcarbonyl; 2-aminothiazol-4-ylcarbonyl; 2-chlorobenzoyl; 2-chloropyridin-5-ylcarbonyl; 2-fluorobenzoyl; 2methoxybenzoyl; 2-methylpyridin-5-ylcarbonyl; 3 ,4-dichlorobenzoyl; 3 ,4-dimethylbenzoyl; 3-chlorobenzoyl; 3-fluoro-4-methylbenzoyl; 3-hydroxypyridin-4-ylcarbonyl; 4-aminopyridin-3-ylcarbonyl; 4-bromobenzoyl; 4-chlorobenzoyl; 4-chloropyridin-3-ylcarbonyl; 4-dimethylaminobenzoyl; 4-hydroxybenzoyl; 4-hydroxypyridin-3-ylcarbonyl; 4-methoxybenzoyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl; 4-methylbenzoyl; 4-methylisoxazol-3-ylcarbonyl; 4-methylpyridin-3-ylcarbonyl; 4-morpholino-N-ylpyridin-3-ylcarbonyl; 4-nitrobenzoyl; 4-t-butylbenzoyl; 4-trifluoromethylbenzoyl; 4-trifluoromethylpyridin-3-ylcarbonyl; 5-chloropyridin-3-ylcarbonyl; 5-methylpyrazol-3-ylcarbonyl; 6-chloropyridin-3-ylcarbonyl; benzoyl; cyclohexylcarbonyl; furan-3-ylcarbonyl; isoxazol-3-ylcarbonyl; piperidin-4-ylcarbonyl; pyrazin-2-ylcarbonyl; pyridazin-3-ylcarbonyl; pyridazin-4-ylcarbonyl; tetrahydrofuran-2-ylcarbonyl; tetrahydrofuran-3-ylcarbonyl; and thiazol-4-ylcarbonyl.

### Claim 5 (depends on 1)

The compound of claim 1, wherein R11 is selected from the group consisting of:

### Claim 6 (depends on 4)

The compound of claim 4, wherein R11 is selected from the group consisting of 2-aminoethylcarbonyl; 4-methyl-2-(aminoethylcarbonylamino)benzoyl; (naphth-2-yl)carbonyl; (pyridin-3-yl)carbonyl; (pyridin-4-yl)carbonyl; 2-(2-aminoethylamido)-4-methylbenzoyl; 2,4-difluorobenzoyl; 2,6-difluorobenzoyl; 2-fluorobenzoyl; 3,4-dimethylbenzoyl; 3-fluoro-4-methylbenzoyl; 4-bromobenzoyl; 4-chlorobenzoyl; 4-hydroxybenzoyl; 4-methylbenzoyl; 4-nitrobenzoyl; and benzoyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R9 and R12, together with the carbon atom attached to R9 and the nitrogen atom attached to R12 form a heterocyclic or substituted heterocyclic group.

### Claim 8 (depends on 7)

The compound of claim 7, wherein the substituted heterocyclic group is 3-hydroxy-pyrrolidinyl.

### Claim 9 (depends on 1)

The compound of claim 1, wherein R12 is selected from the group consisting of (aminomethylcarbonyl)aminoethyl; 2,2-dimethyl-3-(4-methylpiperazin-1-yl)propyl; 2,2-dimethyl-3-dimethylaminopropyl; 2-aminoethyl; 2-hydroxyethyl-3-aminopropyl; 2-hydroxypyridin-4-ylmethyl; 2-hydroxypyridin-5-ylmethyl; 3-(1-cyanourea)propyl; 3-(benzylamino)propyl; 3-(cyclobutylamino)propyl; 3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl; 3-(isopropylamino)propyl; 3-[(3-trifluoromethylpyridin-6-yl)amino]propyl; 3-[(5-pyridin-3-yloxyindazol-3-yl)methylamino]propyl; 3-[(6-fluoroindazol-3-yl)methylamino]propyl; 3-[(aminomethyl-carbonyl)amino]propyl; 3-[5-cyanopyridin-2-yl]propyl; 3-[[5-(pyridin-3-yloxy)indazol-3-yl]methylamino]propyl; 3-amino-3-(aminopropyl-methyl)propyl; 3-aminopropyl; 3-methylsulfonylaminopropyl; 3-ureapropyl; 5-methoxyindazol-3-ylmethyl; piperidin-3-ylmethyl; and pyrrolidin-2-ylmethyl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R12 is selected from the group consisting of:

### Claim 11 (depends on 1)

The compound of claim 1, wherein R12 is selected from the group consisting of 3-(1-cyanourea)propyl; 3-(benzylamino)propyl; 3-(cyclobutylamino)propyl; 3-(cyclohexylmethylamino)propyl; 3-(diethylamino)propyl; 3-(isopropylamino)propyl; 3-aminopropyl; 3-ureapropyl; 4-methylbenzyl; and imidazol-4-ylmethyl.

### Claim 12 (depends on 1)

The compound of claim 1, wherein L1 is —SO2— or —CH2— and A3 is optionally substituted aryl.

### Claim 13 (depends on 1)

The compound of claim 1, wherein R13 is selected from the group consisting of 2,4-difluorobenzyl; 2-methylbenzyl; 3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl; 3-methylbenzyl; 4-chlorobenzyl; 4-methylbenzyl; benzyl; and thiazol-4-ylmethyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R13 groups are selected from the group consisting of: 3-(methylamido)benzyl; 3,5-difluorobenzyl; 3-chlorobenzyl; 3-fluorobenzyl; 3-hydroxybenzyl; 4-chlorobenzyl; and benzyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein p is 1.

### Claim 16 (depends on 15)

The compound of claim 15, wherein R14 is selected from the group consisting of propargyl; bromo; —CF3; chloro; ethyl; ethynyl; fluoro; methoxy; methyl; phenyl; and vinyl.

### Claim 17 (depends on 1)

The compound of claim 1, wherein R14 is selected from the group consisting of bromo; chloro; ethyl; methoxy; methyl; propargyl; vinyl; fluoro; and phenyl.

### Claim 18 (depends on 1)

The compound of claim 1, wherein p is 0.

### Claim 19

A compound selected from the group consisting of:
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-chlorobenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(4-chlorobenzyl)-6-fluoro-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-bromobenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]benzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-hydroxybenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[5-ethyl-1-(3-fluorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-1-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-N-1-(4-methylbenzyl)-beta-alaninamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-vinyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-methoxy-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-phenyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
2-(beta-alanylamino)-N-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
(3R,5R)-5-[1-(3-hydroxybenzyl)-5-methyl-1H-benzimidazol-2-yl]-1-(4-methylbenzoyl)pyrrolidin-3-ol;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-5-ethynyl-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
2-(2-aminoethyl)-3-[(1R)-1-(1-benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methylpropyl]-7-methylquinazolin-4(3H)-one;
N-(3-aminopropyl)-3-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-2,4-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-3,4-dimethylbenzamide;
N-((1R)-1-{1-[3-(acetylamino)benzyl]-5-bromo-1H-benzimidazol-2-yl}-2-methylpropyl)-N-(3-aminopropyl)-4-methylbenzamide;
N-(3-aminopropyl)-2,6-difluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-2-fluoro-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3-chlorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-nitrobenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}nicotinamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}isonicotinamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-2-naphthamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2,2-dimethylpropyl}benzamide;
N-(3-aminopropyl)-N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-4-hydroxybenzamide;
N-[3-(benzylamino)propyl]-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-{3-[(cyclohexylmethyl)amino]propyl}-4-methylbenzamide;
N-(3-aminopropyl)-N-[(1R)-1-(1-benzyl-1H-benzimidazol-2-yl)-2,2-dimethylpropyl]benzamide;
N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(isopropylamino)propyl]-4-methylbenzamide;
N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(diethylamino)propyl]-4-methylbenzamide;
N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-N-[3-(cyclobutylamino)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-{(1R)-1-[5-bromo-1-(3,5-difluorobenzyl)-1H-benzimidazol-2-yl]-2-methylpropyl}benzamide;
N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]benzamide;
N-(3-aminopropyl)-N-[1-(1-benzyl-5-chloro-1H-indol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-{1-[5-chloro-1-(phenylsulfonyl)-1H-indol-2-yl]-2-methylpropyl}-4-methylbenzamide;
N-{3-[(aminocarbonyl)(cyano)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro- 1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide;
N-{3-[(aminocarbonyl)amino]propyl}-N-[(1R)-1-(1-benzyl-5-chloro-1H-benzimidazol-2-yl)-2-methylpropyl]-4-methylbenzamide; and
N-{(1R)-1-[1-(3-fluorobenzyl)-5-methyl-1H-benzimidazol-2-yl]-2-methylpropyl}-N-(1H-imidazol-4-ylmethyl)benzamide;
or a pharmaceutically acceptable salt or ester thereof.

### Claim 20 (depends on 1)

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

### Claim 21 (depends on 20)

The composition of claim 20 further comprising at least one additional agent for the treatment of cancer.

### Claim 22 (depends on 21)

The composition of claim 21, wherein the additional agent for the treatment of cancer is selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib, trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel, tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and trastuzumab.