IP Library › Granted Patent US 10,087,188
Granted Patent B2
US 10,087,188 · App. 15/538,902 · Granted Oct 2, 2018

Benzamide imidazopyrazine Btk inhibitors

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Quick Facts
Patent No.
US 10,087,188
App. No.
15/538,902
Granted
Oct 2, 2018
Kind
B2
Abstract

The present invention provides Bruton's Tyrosine Kinase (Btk) inhibitor compounds according to Formula (I), or pharmaceutically acceptable salts 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 of Formula (I) in the treatment of Btk mediated disorders.

Claims (176)

1. A compound selected from the group consisting of:

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid;

(1R,3S)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid

(1S,3R)-3-(8-amino-1-{4-[(4-ethylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(cyclopropyloxy)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentanecarboxylic acid;

1-[({S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}carbonyl)amino]cyclopropanecarboxylic acid;

1-({(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}carbonyl)-L-proline;

1-({(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}carbonyl)-D-proline;

(3R)-1-({(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}carbonyl)pyrrolidine-3-carboxylic acid;

4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2-dimethylcyclohexanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]benzoic acid;

5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-fluorobenzoic acid;

4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-fluorobenzoic acid;

4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]benzoic acid;

5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1H-pyrrole-2-carboxylic acid;

5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]furan-2-carboxylic acid;

5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]pyridine-2-carboxylic acid;

4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

(2R,4S)-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]piperidine-2-carboxylic acid;

(2S,4R)-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]piperidine-2-carboxylic acid;

(2R,4R)-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]piperidine-2-carboxylic acid;

(3R)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]pyrrolidine-3-carboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclopentanecarboxylic acid;

(3S)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]pyrrolidine-3-carboxylic acid;

(3R)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methylpiperidine-3-carboxylic acid;

(3S)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methylpiperidine-3-carboxylic acid;

(3R)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methylpyrrolidine-3-carboxylic acid;

(3S)-1-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methylpyrrolidine-3-carboxylic acid;

(1R, 3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

{(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}acetic acid;

{(1S,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}acetic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-ethoxy-4-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl] carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

{(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}acetic acid;

{(1R, 3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}acetic acid;

(1R,3S)-3-[8-amino-1-(2-ethoxy-4-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3R)-3-[8-amino-1-(2-ethoxy-4-{[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl] carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

4-(8-amino-1-(2-fluoro-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)cubane-1-carboxylic acid;

4-(8-amino-1-(2-ethoxy-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)cubane-1-carboxylic acid;

(1R,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

4-(8-amino-1-(4-((4-cyclopropylpyridin-2-yl)carbamoyl)-2-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl)cubane-1-carboxylic acid;

4-(8-amino-1-(2-methoxy-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)cubane-1-carboxylic acid;

4-(8-amino-1-(2-methoxy-4-((4-(trifluoromethyl)pyridin-2-yl)carbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)cubane-1-carboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

4-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(2S,4R)-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylpiperidine-2-carboxylic acid;

(2R,4S)-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylpiperidine-2-carboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclohexanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-chloro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

6-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]spiro[3.3]heptane-2-carboxylic acid;

2-{3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}-2-methylpropanoic acid;

2-{3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}-2-methylpropanoic acid;

2-{3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}-2-methylpropanoic acid;

2-{3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopentyl}-2-methylpropanoic acid;

(1R,2R, 5R)-5-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;

(1R,2R, 5R)-5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;

5-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]tricyclo[3.2.2.0˜2,4˜]nonane-1-carboxylic acid;

(1S,2S,5S)-5-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;

(1S,2S,5S)-5-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2-(1-methylethyl)cyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-5-chloro-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-5-chloro-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3S)-3-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1R,3R)-3-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-6-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-5-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-fluoro-6-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

(2S,5S)-5-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]tetrahydrofuran-2-carboxylic acid;

(2S,5S)-5-[8-amino-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]tetrahydrofuran-2-carboxylic acid;

(1S,3R)-3-[8-amino-1-(2-ethoxy-6-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)-5-fluoroimidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

trans-4-[8-amino-1-(2-ethoxy-6-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

4-[8-amino-1-(2-ethoxy-5-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-ethoxy-6-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1,2,2-trimethylcyclopentanecarboxylic acid;

(1S,3S)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-ethoxy-6-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-ethoxy-6-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

4-[8-amino-1-(2-fluoro-6-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(2-ethoxy-5-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(2-chloro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,2,2-trimethylcyclopentanecarboxylic acid;

4-[8-amino-1-(2-ethoxy-6-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)-5-fluoroimidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

4-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-ethoxy-6-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1,4-dimethylcyclohexanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(2-chloro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

4-[8-amino-1-(2-chloro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

4-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,4-dimethylcyclohexanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclopentanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclohexanecarboxylic acid;

(1R, 3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1,3-dimethylcyclohexanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2,3-trimethylcyclopentanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2,3-trimethylcyclopentanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methyl-1-(1-methylethyl)cyclopentanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methyl-1-(1-methylethyl)cyclopentanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methyl-1-(1-methylethyl)cyclopentanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-3-methyl-1-(1-methylethyl)cyclopentanecarboxylic acid;

(1S,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2,3-trimethylcyclopentanecarboxylic acid;

(1R,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-2,2,3-trimethylcyclopentanecarboxylic acid;

2-({(3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}carbonyl)cyclopropanecarboxylic acid;

3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

(1S,3R)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

(1S,3R)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

(1R,3S)-3-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

cis-4-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclohexanecarboxylic acid;

(1R,3S)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]phenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

(1R,3S)-3-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

4-[8-amino-5-chloro-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

4-[8-amino-5-chloro-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

4-(8-amino-5-chloro-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-1-methylcyclohexanecarboxylic acid;

4-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

4-[8-amino-5-chloro-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-1-methylcyclohexanecarboxylic acid;

(1S,2R)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]cyclopropanecarboxylic acid;

4-{(2R)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

3-({(2R,5S)-2-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}carbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid;

1-({(2R)-2-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo [1,5-a]pyrazin-3-yl]morpholin-4-yl}carbonyl)cyclobutanecarboxylic acid;

3-{(2R)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}cyclobutanecarboxylic acid;

4-{(2R)-2-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

4-{(2R,5S)-2-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

4-{(3R)-3-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}-1-methylcyclohexanecarboxylic acid;

2-{(2R)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-2-methylpropanoic acid;

2-{(2R)-2-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-2-methylpropanoic acid;

3-{(2R,5S)-2-[8-amino-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}cyclobutanecarboxylic acid;

2-{(3R)-3-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}-2-methylpropanoic acid;

1-{(3R)-3-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]piperidin-1-yl}cyclopropanecarboxylic acid;

1-{(2R)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}cyclopropanecarboxylic acid;

4-{(2R,5S)-2-[8-amino-5-chloro-1-(2-ethoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

4-{(2R,5S)-2-[8-amino-5-chloro-1-(2-methoxy-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

cis-4-{(2R,5S)-2-[8-amino-1-(4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

cis-4-{(2R,5S)-2-[8-amino-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R)-2-[8-amino-5-chloro-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R)-2-[8-amino-5-chloro-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]morpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-[(2R)-2-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)morpholin-4-yl]-1-methylcyclohexanecarboxylic acid;

cis-4-[(2R)-2-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)morpholin-4-yl]-1-methylcyclohexanecarboxylic acid;

trans-4-[(2R)-2-{8-amino-5-methyl-1-[4-(pyridin-2-ylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}morpholin-4-yl]-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-5-chloro-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl] carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexane carboxylic acid;

cis-4-{(2R,5S)-2-[8-amino-5-chloro-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

(1R,3R)-3-{(2R,5S)-2-[8-amino-5-chloro-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl] carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-(1-methylethyl) cyclopentanecarboxylic acid;

(1R,3S)-3-{(2R,5S)-2-[8-amino-5-chloro-1-(2-fluoro-4-{[4-(trifluoromethyl)pyridin-2-yl]carbamoyl}phenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-(1-methylethyl) cyclopentanecarboxylic acid;

trans-4-[(2R)-2-{8-amino-5-chloro-1-[4-(pyridin-2-ylcarbamoyl)phenyl]imidazo[1,5-a]pyrazin-3-yl}morpholin-4-yl]-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-5-chloro-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}phenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-5-chloro-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}-2-fluorophenyl)imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexane carboxylic acid;

trans-4-{(2R,5S)-2-[8-amino-1-(4-{[4-(difluoromethyl)pyridin-2-yl]carbamoyl}-2-fluorophenyl) imidazo[1,5-a]pyrazin-3-yl]-5-methylmorpholin-4-yl}-1-methylcyclohexanecarboxylic acid;

trans-4-[(2R,5S)-2-(8-amino-5-chloro-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-5-methylmorpholin-4-yl]-1-methylcyclohexanecarboxylic acid; and

trans-4-[(2R,5S)-2-(8-amino-1-{4-[(4-cyclopropylpyridin-2-yl)carbamoyl]-2-fluorophenyl}imidazo[1,5-a]pyrazin-3-yl)-5-methylmorpholin-4-yl]-1-methylcyclohexanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition which comprises a compound of claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

Assignments (4)
MERGER Recorded Aug 8, 2022
From: MERCK SHARP & DOHME CORP.
To: MERCK SHARP & DOHME LLC
Reel/Frame 061102/0145 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2017
From: LIU, JIAN; KOZLOWSKI, JOSEPH A.; ALHASSAN, ABDUL-BASIT; BOGA, SOBHANA BABU; GAO, XIAOLEI; GUIADEEN, DEODIAL GUY; WANG, JYHSHING; YU, WENSHENG
To: MERCK SHARP & DOHME CORP.
Reel/Frame 043494/0633 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2017
From: CAI, JIAQIANG; LIU, SHILAN; WANG, DAHAI; WU, HAO; YANG, CHUNDAO
To: WUXI APPTEC (SHANGHAI) CO., LTD.
Reel/Frame 043494/0864 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 6, 2017
From: WUXI APPTEC (SHANGHAI) CO., LTD.
To: MERCK SHARP & DOHME CORP.
Reel/Frame 043495/0747 →