Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors

• US 7,186,832 B2
• Filed: 05/14/2004
• Issued: 03/06/2007
• Est. Priority Date: 02/20/2003
• Status: Expired due to Fees

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Liang, Congxin, Huang, Ping, Guan, Huiping, Harris, G. Davis Jr., Sun, Connie Li
• Primary Examiner(s): TUCKER, ZACHARY C
• Application Number:
  US10/845,586
• Publication Number:
  US 20050009832A1
• Time in Patent Office: 1,026 Days
• Field of Search: None
• US Class Current: 544/350
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

Abstract

The present invention relates to substituted imidazopyrazines of the general Formula I

which modulate the activity of protein kinases (“PKs”). The compounds of this invention are therefore useful in treating disorders related to abnormal PK activity. Pharmaceutical compositions comprising these compounds, methods of treating diseases utilizing pharmaceutical compositions comprising these compounds and methods of preparing them are also disclosed.

Claims

1. A compound of the formula I:

2. The compound of claim 1, wherein R₃ is H.

3. A compound selected from the group consisting of:

2-(4-Chloro-benzylamino)-ethanesulfonic acid [4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-amide;

2-(2-Chloro-benzylamino)-ethanesulfonic acid [4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-amide;

1-(2,6-Difluoro-benzyl)-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-pyridin-4-ylmethyl-urea;

1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-pyridin-2-ylmethyl-urea;

1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(2-pyridin-3-yl-ethyl)-urea;

1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-3-(2-pyridin-2-yl-ethyl)-urea;

N-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-2-(2*-phenyl-cyclo-propylamino)-acetamide;

2-[1-(4-Chloro-phenyl)-ethylamino]-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-carbamic acid 2-(4-fluoro-phenyl)-propyl ester;

[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-carbamic acid 2-(2-chloro-phenyl)-ethyl ester;

N-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-2-phenoxy-acetamide;

2-(2,6-Difluoro-benzyloxy)-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

2-[2-(2-Fluoro-phenyl)-ethoxy]-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

2-[2-(2,6-Difluoro-phenyl)-ethoxy]-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

1-(3-Hydroxy-benzyl)-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

2-(2-Fluoro-benzylamino)-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

N-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-2-(pyridin-3-ylmethoxy)-acetamide;

2-[2-(5-Chloro-2-fluoro-phenyl)-ethoxy]-N-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-acetamide;

1-(2-Chloro-4-fluoro-benzyl)-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

1-(2,4-Dichloro-phenyl)-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

1-Indan-1-yl-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

1-[2-(2,6-Dichloro-phenyl)-ethyl]-3-[4-(8-methylamino-imidazo[1,2-a]pyrazin-3-yl)-phenyl]-urea;

Ethyl-(3-thiophen-3-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

Methyl-(3-pyridin-4-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

[3-(6-Methoxy-pyridin-3-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

(3-Furan-3-yl-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine;

3-Thiophen-3-yl-imidazo[1,2-a]pyrazin-8-ylamine;

Methyl-(3-thiophen-3-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

(3-Benzo[b]thiophen-2-yl-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine;

(3-Benzo[b]thiophen-3-yl-imidazo[1,2-a]pyrazin-8-yl)-methyl-amine;

Cyclopropyl-(3-thiophen-3-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

Cyclopropyl-(3-furan-3-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

Cyclopropyl-[3-(6-methoxy-pyridin-3-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-pyridin-2-one;

Thiophen-2-yl-imidazo[1,2-a]pyrazin-8-ylamine;

(6-Methoxy-pyridin-3-yl)-imidazo[1,2-a]pyrazin-8-ylamine;

Methyl-(3-thiophen-2-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

3-(1H-Indol-4-yl)-imidazo[1,2-a]pyrazin-8-ylamine;

[3-(1H-Indol-5-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

Cyclopropyl-[3-(1H-indol-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine;

[3-(1H-Indol-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

Methyl-(3-pyridin-2-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

Methyl-(3-thiazol-2-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

1-[4-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-ethanone;

1-[4-(8-Cyclopropylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-ethanone;

[3-(6-Amino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

[3-(2-Amino-pyrimidin-5-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

Methyl-(3-thiophen-2-yl-imidazo[1,2-a]pyrazin-8-yl)-amine;

[3-(5-Chloro-thiophen-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

2-[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indol-3-yl]-acetamide;

[3-(3-Dimethylaminomethyl-1H-indol-5-yl)-imidazo[1,2-a]pyrazin-8-yl]-methyl-amine;

and a pharmaceutically acceptable salt thereof.

4. A compound selected from the group consisting of:

5-(Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indole-2-carboxylic acid (3-morpholine-4-yl-propyl)-amide;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indole-2-carboxylic acid (3-morpholin-4-yl-propyl)-amide;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indole-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indole-2-carboxylic acid (2-diethylamino-ethyl)-amide;

[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-1H-indol-2-yl]-morpholin-4-yl-methanone;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophene-2-carboxylic acid methyl ester;

[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-(4-methyl-piperazin-1-yl)-methanone;

[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;

[5-(8-Methyl amino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone;

[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-(3-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophene-2-carboxylic acid (2-diethylamino-ethyl)-amide;

5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophene-2-carboxylic acid (2-morpholin-4-yl-ethyl)-amide;

[5-(8-Methylamino-imidazo[1,2-a]pyrazin-3-yl)-thiophen-2-yl]-morpholin-4-yl-methanone;

{3-[1-(2-Diethylamino-ethyl)-1H-indol-5-yl]-imidazo[1,2-a]pyrazin-8-yl}-methyl-amine;

Methyl-{3-[1-(3-morpholin-4-yl-propyl)-1H-indol-5-yl]-imidazo[1,2-a]pyrazin-8-yl}-amine;

and a pharmaceutically acceptable salt thereof.