BTK inhibitors

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Quick Facts

Patent No.: US 9,446,130
App. No.: 14/762,929
Granted: Sep 20, 2016
Kind: B2

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Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula I or pharmaceutically acceptable salts thereof. Formula I or a pharmaceutically acceptable salt thereof or to pharmaceutical compositions comprising these compounds and to their use in therapy. In particular, the present invention relates to the use of Btk inhibitor compounds in the treatment of Btk mediated disorders.

Claims (60)

1. A compound according to Formula I, or a pharmaceutically acceptable salt thereof

wherein:

bicyclic ring system E-G is selected from the group consisting of:

R 5 is H, cyano, (1-4C)alkyl, or (1-5C)alkoxy; any alkyl or alkoxy group of R 5 may optionally be substituted with one, two or three halogen;

ring system M is selected from the group consisting of:

R 1 is H or OH;

R 2 is H, (1-3C)alkyl, cyclopropyl, or CF 3 ; and

R 3 and R 4 are each independently selected from H, (1-3C) alkyl, (1-3C)alkoxy, and hydroxyl(1-3C)alkyl.

2. The compound of claim 1 , wherein R 5 is selected from the group consisting of CF 3 , CN and

3. The compound of claim 1 , wherein bicyclic ring system E-G is

4. The compound of claim 1 , wherein bicyclic ring system E-G is

5. The compound of claim 1 selected from the group consisting of:

4-[8-amino-3-(4-hydroxy-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4S)-4-hydroxy-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4R)-4-hydroxy-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-[8-amino-3-(1-ethyl-4-hydroxy-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazin-1-yl]-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-2-methyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-1-ethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-2-ethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-1-ethyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-2-ethyl-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4S)-2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-1-(2-hydroxyethyl)-4,5,6,7-tetrahydro-1H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{4-amino-1-[(4R)-2-(2-hydroxyethyl)-4,5,6,7-tetrahydro-2H-indazol-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(8R)-3-cyclopropyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(8S)-3-cyclopropyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-8-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7S)-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(7R)-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyridin-7-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4R)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide;

4-{8-amino-3-[(4S)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(trifluoromethyl)pyridin-2-yl]benzamide; and

4-{8-amino-3-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]imidazo[1,5-a]pyrazin-1-yl}-N-[4-(1-methylethoxyl)pyridin-2-yl]benzamide.

6. The compound of claim 1 having Formula Ia