# US 7,608,622 B2 · Imidazo[4,5-b]pyrazinone inhibitors of protein kinases

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- Number: US 7,608,622 B2
- Document ID: US7608622B2
- Status: Granted
- Kind: B2
- Application number: 11/233,725
- Filed: 2005-09-23
- Published: 2006-05-18
- Granted: 2009-10-27
- Earliest claimed: 2004-09-24
- Assignees: Janssen Pharmaceutica NV
- Inventors: Jian Liu; Raymond J. Patch; Mark R. Player; Huaping Hu
- Web page: https://patentgrep.com/patent/US7608622B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention is directed to compounds of Formula I: wherein Q, Y, A are set forth in the specification, as well as solvates, hydrates, tautomers or pharmaceutically acceptable salts thereof, that inhibit protein kinases, especially Aurora-1, Aurora-2 and Aurora-3 kinases.

## Claims

### Claim 1

A compound of Formula I:
a stereoisomeric or tautomeric form thereof or a pharmaceutically acceptable salt thereof, wherein
Q is a direct link or C1-6alkylene;
Y is phenyl, naphthyl, indanyl, thienyl, pyridinyl, or benzofuranyl, each of which may be optionally substituted with one, two, or three substituents selected from the group consisting of C1-4alkyl, nitro, amino, halogen, cyano and metboxy;
A is phenyl, pyridinyl, indolyl, isoxazolyl or thienyl, each of which may be optionally substituted with one to three substituents selected from the group consisting of C1-6alkyl, halogen, hydroxy, hydroxyC1-6alkyl, C1-6alkoxy and carboxyl.

### Claim 2 (depends on 1)

A compound of claim 1 wherein Q is mechylene or ethylene;
wherein Y is phenyl, indanyl, thienyl or pyridinyl; wherein A is phenyl optionally substituted with up to three substituents each independently selected from the group consisting of methyl, chioro, finoro, hydroxyrnethyl, hyciroxy, methoxy, and carboxyl.

### Claim 3 (depends on 1)

A compound of claim 1 wherein the compound is 1 -((S)-(−)-1 -Phenylerhyl)-6-(3,4,5-trimethoxyphenyl)- 1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
j-((R)-(+)- I -Phenylethyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(3,4,5-trimethoxyphenyl)- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one; 6-( 1H-Indol-5-yI)-1((S)-(−)-1-phenylethyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
6-(3,5-Dimethylisoxazal-4-yl)-1-((S)-(−)-1-phenylethyl)-1,3-dihydroimidazo[4,5b]pyrazin-2-one;
3-[2-Oxo-3-((S)-(−)-1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl]-benzonitrile;
6-(3-Hydroxymethylphenyl)-1-((S)-(−)-1-phenylethyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
6-(1H-Indo-2-yI)-1 -((S)-(−)-1 -phenylethyl)- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-pyridia-3-yI- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -Benzyl-6-(3,4-dimnethoxyphenyl )-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(6-methoxypyridin-3-yl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(3.methoxymethylphenyl)- 1,3-dihydroimidazol[4,5-b]pyrazin-2-one;
6-(3-Acetylphenyl)-1-benzyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(2,4-dimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-thiophen-3-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-thiophen-2-yl-1,3-dihydroimidazo[4,5-b]pyraz.in-2-one;
1 -Benzyl-6-(3-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
3-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-benzoic acid;
1-Pyridin-2-ylmethyl-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -Pyridin-3-ylmethyl-6-(3,4,5-trimethoxyphenyl)- I ,3-dihydro-imidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(3,5-dimethoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one;
5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzoic acid;
1-Benzyl-6-(3-hydroxymethyl-4-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-hydroxybenzoic acid;
1-(3-Nitrobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -(4-Chlorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(3-Chlorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-One;
1-(3-Methylbenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one; 1-(3-Fluorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(3-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Naphthalen-1-ylmethyl-6-(3 ,4,5-trimethoxyphenyl)-1, 3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzo[1,3]dioxol-5-ylmethyl-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Indan-1-yI-6-(3 ,4,5-trinaethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2one;
1-Thiophen-2-ylmethyl-6-(3.4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(2-Chlorobenzyl)-6-(3,4,5trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(4-Aminobenzyl)-6-(3,4,5-trimethoxypheflyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one,
1-(3-Aminobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one; or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 1)

A compound of claim 1 wherein the compound is 1-Benzyl-6-(3,4,5-trimethoxyphenyl)- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one; 6-( 1H-Indol-5-yI)-1((S)-(−)-1-phenylethyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
6-(3,5-Dimethylisoxazal-4-yl)-1-((S)-(−)-1-phenylethyl)-1,3-dihydroimidazo[4,5b]pyrazin-2-one;
3-[2-Oxo-3-((S)-(−)-1-phenylethyl)-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl]-benzonitrile; 6-(3-Hydroxymethylphenyl)-1-((S)-(−)-1-phenylethyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
6-(1H-Indo-2-yI)-1 -((S)-(−)-1 -phenylethyl)- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-pyridia-3-yI- 1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -Benzyl-6-(3,4-dimnethoxyphenyl )-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(6-methoxypyridin-3-yl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(3.methoxymethylphenyl)- 1,3-dihydroimidazol[4,5-b]pyrazin-2-one;
6-(3-Acetylphenyl)-1-benzyl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(2,4-dimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-thiophen-3-yl-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-thiophen-2-yl-1,3-dihydroimidazo[4,5-b]pyraz.in-2-one;
1 -Benzyl-6-(3-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
3-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-benzoic acid;
1-Pyridin-2-ylmethyl-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -Pyridin-3-ylmethyl-6-(3,4,5-trimethoxyphenyl)- I ,3-dihydro-imidazo[4,5-b]pyrazin-2-one;
1-Benzyl-6-(3,5-dimethoxyphenyl)-1,3-dihydro-imidazo[4,5-b]pyrazin-2-one;
5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-methoxybenzoic acid;
1-Benzyl-6-(3-hydroxymethyl-4-methoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
5-(3-Benzyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyrazin-5-yl)-2-hydroxybenzoic acid;
1-(3-Nitrobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1 -(4-Chlorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(3-Chlorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1 ,3-dihydroimidazo[4,5-b]pyrazin-2-One;
1-(3-Methylbenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(3-Fluorobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(3-Methoxybenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Naphthalen-1-ylmethyl-6-(3 ,4,5-trimethoxyphenyl)-1, 3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Benzo[1,3]dioxol-5-ylmethyl-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-Indan-1-yI-6-(3 ,4,5-trinaethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2one;
1-(2-Chlorobenzyl)-6-(3,4,5trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one;
1-(4-Aminobenzyl)-6-(3,4,5-trimethoxypheflyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one,
1-(3-Aminobenzyl)-6-(3,4,5-trimethoxyphenyl)-1,3-dihydroimidazo[4,5-b]pyrazin-2-one; or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 1)

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

### Claim 6 (depends on 1)

A pharmaceutical dosage form comprising a pharmaceutically acceptable carrier and from about 0.5 mg to about 10 g of at least one compound of claim 1.