IP Library › Granted Patent US 8,614,206
Granted Patent B2
US 8,614,206 · App. 13/627,262 · Granted Dec 24, 2013

Pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use

Inventors: Alastair James Hodges (Saffron Walden, GB); Mizio Matteucci (Saffron Walden, GB); Andrew Sharpe (Saffron Walden, GB); Minghua Sun (Burlingame, CA); Xiaojing Wang (Foster City, CA); Vickie H. Tsui (Burlingame, CA)
Assignee: F. Hoffmann-La Roche AG
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Quick Facts
Patent No.
US 8,614,206
App. No.
13/627,262
Granted
Dec 24, 2013
Kind
B2
Abstract

Pyrazol-4-yl-heterocyclyl-carboxamide compounds of Formula I, including stereoisomers, geometric isomers, tautomers, and pharmaceutically acceptable salts thereof, wherein X is thiazolyl, pyrazinyl, pyridinyl, or pyrimidinyl, are useful for inhibiting Pim kinase, and for treating disorders such as cancer mediated by Pim kinase. Methods of using compounds of Formula I for in vitro, in situ, and in vivo diagnosis, prevention or treatment of such disorders in mammalian cells, or associated pathological conditions, are disclosed.

Claims (442)

1. A compound selected from

5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-((methylamino)methyl)piperidin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(3-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-ethylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-ethylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-cyclopropyl-2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluoro-3-methylphenyl)thiazole-4-carboxamide;

(S)-5-Amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-(methylamino)azepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5S)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2,8-diazaspiro[4.5]decan-8-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5R)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5R)-3-amino-5-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-(5-(1,4-diazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-(5-(1,4-diazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-5-amino-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

N-(5-(1,4-diazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-2-(2-fluorophenyl)-N-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2-fluorophenyl)-N-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(6-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(6-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2,4-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2,4-dimethylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(1-cyclopropyl-5-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(1-cyclopropyl-5-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(1-cyclopropyl-5-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(4-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-fluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5R)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5S)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,4S)-4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,4R)-4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,4R)-4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,4S)-4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5R)-3-amino-5-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2-fluoro-5-methylphenyl)-N-(5-(4-hydroxyazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-fluoro-1,4-diazepan-1-yl)-1-(oxetan-3-ylmethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-(trifluoromethyl)piperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-N-(1-(2,2-difluoroethyl)-5-(3-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(1-(2,2-difluoroethyl)-5-(3-hydroxyazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(1-(2,2-difluoroethyl)-5-(6-hydroxy-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-methylpiperazin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(2-ethyl-4-methylpiperazin-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2-fluoro-5-methylphenyl)-N-(5-(4-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(1-(2,2-difluoroethyl)-5-(6-fluoro-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-3-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(3,3-difluoro-5-(methylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5S)-3-amino-5-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-(5-(1,4-diazepan-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5S)-3-amino-5-fluoropiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-fluoro-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-methoxy-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(6-methoxy-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(4-(2,2,2-trifluoroethylamino)azepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

3-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxy-3-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(4-(2,2-difluoroethylamino)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(6-fluoro-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(6-hydroxy-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(6-fluoro-6-methyl-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

3-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-(5-(dimethylamino)-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(5-methyl-1,4-diazepan-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxy-3-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-hydroxy-3-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(3-methylpiperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide;

5-amino-N-(5-(6,6-difluoro-1,4-diazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)pyrimidine-4-carboxamide;

5-Amino-2-(2-fluoro-phenyl)-pyrimidine-4-carboxylic acid[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(3-(trifluoromethyl)piperidin-1-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[1-methyl-5-(3-trifluoromethyl-piperidin-1-yl)-1H-pyrazol-4-yl]-amide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

3-amino-N-(5-(4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

(S)-3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

(R)-3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

(S)-3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

(R)-3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid (1-oxetan-3-ylmethyl-5-piperazin-1-yl-1H-pyrazol-4-yl)-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-hydroxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-hydroxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-fluoro-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(3-fluoro-5-hydroxy-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[1-methyl-5-(3-trifluoromethyl-piperidin-1-yl)-1H-pyrazol-4-yl]-amide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

5-Amino-2-(2,6-difluoro-3-iodo-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl]-amide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

((R)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-Amino-2-(2-fluoro-phenyl)-thiazole-4-carboxylic acid[5-((R)-5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(5-(5-(dimethylamino)-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(5-(5-(dimethylamino)-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)picolinamide;

3-amino-N-(5-(5-amino-3,3-difluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-6-(2-fluorophenyl)pyrazine-2-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluoro-5-methylphenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

5-Amino-2-(3-fluoro-pyridin-2-yl)-thiazole-4-carboxylic acid[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-Amino-2-pyridin-2-yl-thiazole-4-carboxylic acid[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

(S)-5-Amino-2-(2,6-difluorophenyl)-N-(5-(3-methylpiperazin-1-yl)-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(3-amino-azepan-1-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(3-amino-azepan-1-yl)-1-(2,2,2-trifluoro-ethyl)-1H-pyrazol-4-yl]-amide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(3,3-difluoro-5-hydroxy-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide;

5-amino-N-(5-((4S,5R)-4-amino-5-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5R)-5-amino-3-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5S)-5-amino-3-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,5R)-5-amino-3-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5S)-5-amino-3-fluoroazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-hydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide; and

5-Amino-2-(2,6-difluoro-phenyl)-thiazole-4-carboxylic acid[5-(5-amino-3-hydroxy-3-methyl-azepan-1-yl)-1-methyl-1H-pyrazol-4-yl]-amide.

2. A compound 1 selected from

5-amino-N-[5-(5,8-diazaspiro[2.6]nonan-8-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(2-oxoazepan-1-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(7-oxo-1,4-diazepan-1-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3-fluoro-2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-fluoro-5-methyl-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2-fluoro-5-methyl-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2-fluoro-5-methyl-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-[(4S)-4-[(3-methyloxetan-3-yl)methylamino]azepan-1-yl]pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[5-[(4S)-4-(2-hydroxyethylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-[bis(2-hydroxyethyl)amino]azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,5-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(5-oxo-1,4-oxazepan-4-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-[(4S)-4-(oxetan-3-ylmethylamino)azepan-1-yl]pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-[bis(oxetan-3-ylmethyl)amino]azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5S)-5-amino-3,3-difluoro-azepan-1-yl]-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluoro-3-iodo-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5S)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluoro-3-iodo-phenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[5-(1,1-dioxo-1,4-thiazepan-4-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(1,9-diazaspiro[4.6]undecan-9-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(9-oxa-3,7-diazabicyclo[3.3.1]nonan-3-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[5-[6-(hydroxymethyl)-1,4-diazepan-1-yl]-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[5-[6-(hydroxymethyl)-1,4-diazepan-1-yl]-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(2,6-diazaspiro[3.4]octan-6-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(1-oxo-2,8-diazaspiro[4.5]decan-8-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(2,7-diazaspiro[3.4]octan-2-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N[5-[4-(azetidin-3-yl)-1,4-diazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(3,3-difluorocycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(3,3-difluorocycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(2-oxo-1,8-diazaspiro[4.6]undecan-8-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(2-oxo-1,9-diazaspiro[4.6]undecan-9-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(3,3-difluoro-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(3,3-difluoro-5-hydroxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-fluoro-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-hydroxyazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-methoxyazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-[5-(4-acetamido-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5R)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4R,5S)-4-amino-5-fluorocycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(6-cyano-1,4-diazepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-cycloheptyl-1-methyl-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-[5-(4-acetamido-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-5-amino-2-(3-fluoro-2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-ethoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-methoxyazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(pyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-2-yl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(6-hydroxy-2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-(2-aminoacetyl)-1,4-diazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-(2-aminoethyl)-1,4-diazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-[5-(3,4,4a,5,6,8,9,9a-octahydro-2H-[1,4]oxazino[2,3-d]azepin-7-yl)-1-methyl-pyrazol-4-yl]-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-[5-(3,4,4a,5,6,8,9,9a-octahydro-2H-[1,4]oxazino[2,3-d]azepin-7-yl)-1-methyl-pyrazol-4-yl]-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-(2,2-difluoroethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-hydroxy-azepan-1-yl)-1-(2,2-difluoroethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-3-fluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-cyclopropyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[5-[4-hydroxy-4-(trifluoromethyl)azepan-1-yl]-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-azepan-1-yl)-1-ethyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[3,3-difluoro-5-(methylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[3,3-difluoro-5-(methylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-5-amino-4-methoxycyclohept-1-enyl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxycycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxycycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxycycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxycycloheptyl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-methoxy-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(1-methylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(5-fluoro-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3,5-dimethylisoxazol-4-yl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3-fluoropyridin-4-yl)thiazole-4-carboxamide;

5-amino-2-(2-fluorophenyl)-N-[5-(2-methoxy-8-azabicyclo[3.2.1]octan-5-yl)-1-methyl-pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-hydroxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-fluoro-5-methyl-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S)-4-aminoazepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-methoxy-4-methyl-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(4-methyl-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(1,5-dimethylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-methyl-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-methyl-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(6-cyano-2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(1,3-dimethylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(3,5-difluoropyridin-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(5-cyano-2-fluoro-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-dimethyl-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(5-cyano-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,5-dimethyl-3-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5S)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(6-amino-1-oxa-9-azaspiro[3.6]decan-9-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3-methylene-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S,5S)-4-amino-5-fluoro-azepan-1-yl]-1-(trideuteriomethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-(trideuteriomethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(6-amino-1-oxa-9-azaspiro[3.6]decan-9-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5S)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(5-((4R,5S)-4,5-dihydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[4-(aminomethyl)-4-methoxy-1-piperidyl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluoro-4-methoxy-phenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3,3-difluoro-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(1,5-dimethylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(6-cyano-2-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(1,3-dimethylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(1,5-dimethylpyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-methyl-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-hydroxy-3-methyl-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4S,5S)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-[(4R,5R)-4-amino-5-fluoro-azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3,5-difluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3-methoxy-3-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(3-fluoro-4-pyridyl)thiazole-4-carboxamide;

5-amino-2-(2-fluorophenyl)-N-[1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-[4-(aminomethyl)-4-hydroxy-1-piperidyl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-2-(2-fluorophenyl)-N-(1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2-fluorophenyl)-N-(1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(R)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

(S)-5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-(1-oxa-6,9-diazaspiro[3.6]decan-6-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-[1-methyl-5-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)pyrazol-4-yl]thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-4-methoxy-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

N-[5-[(3aR,8aS)-2-oxo-3a,4,5,7,8,8a-hexahydro-3H-oxazolo[4,5-d]azepin-6-yl]-1-methyl-pyrazol-4-yl]-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

[(4S,5R)-5-amino-1-[4-[[5-amino-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]azepan-4-yl]acetate;

N-[5-[(3aS,8aR)-2-oxo-3a,4,5,7,8,8a-hexahydro-3H-oxazolo[4,5-d]azepin-6-yl]-1-methyl-pyrazol-4-yl]-5-amino-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

[(4R,5S)-5-amino-1-[4-[[5-amino-2-(2,6-difluorophenyl)thiazole-4-carbonyl]amino]-2-methyl-pyrazol-3-yl]azepan-4-yl]acetate;

5-amino-2-(2,6-difluorophenyl)-N-(5-((4R,5R)-4,5-dihydroxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-[4-amino-5-(trideuteriomethoxy)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-amino-5-(trideuteriomethoxy)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5S)-5-amino-3,3-difluoro-azepan-1-yl]-1-(trideuteriomethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[(5R)-5-amino-3,3-difluoro-azepan-1-yl]-1-(trideuteriomethyl)pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-3,3-difluoro-5-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,4R)-4-(aminomethyl)-3-ethyl-4-methoxypiperidin-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-1-oxa-8-azaspiro[3.6]decan-8-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-1-oxa-8-azaspiro[3.6]decan-8-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((1R,5R,6S)-6-amino-8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[5-amino-4-hydroxy-4-(2-hydroxyethyl)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-1-oxa-8-azaspiro[3.6]decan-8-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-4-methoxy-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-4-methoxy-4-methyl-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-methoxy-cycloheptyl)-1-methyl-pyrazol-4-yl]-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(2,6-diazaspiro[3.5]nonan-6-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-2-(2,6-difluorophenyl)-N-(1-methyl-5-((3aR,8aS)- 3 a-methyl-2-oxotetrahydro-2H-oxazolo[5,4-d]azepin-6(7H,8H,8aH)-yl)-1H-pyrazol-4-yl)thiazole-4-carboxamide;

5-amino-N-[5-(5-amino-1-oxa-8-azaspiro[3.6]decan-8-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-amino-5-(difluoromethyl)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-amino-5-(difluoromethyl)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-[4-amino-5-(hydroxymethyl)azepan-1-yl]-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-ethoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-[5-(4-amino-5-ethoxy-azepan-1-yl)-1-methyl-pyrazol-4-yl]-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((8R,9S)-8-amino-9-methoxy-5-azaspiro[2.6]nonan-5-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((8R,9S)-9-amino-8-methoxy-5-azaspiro[2.6]nonan-5-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(R)-5-amino-N-(5-(5-amino-3,3-difluoro-5-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-fluoro-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(8-amino-9-methoxy-5-azaspiro[2.6]nonan-5-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(8-amino-9-methoxy-5-azaspiro[2.6]nonan-5-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-(aminomethyl)-4-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-(aminomethyl)-4-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-(aminomethyl)-4-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-(aminomethyl)-4-methoxyazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

(S)-5-amino-N-(5-(5-amino-3,3-difluoro-5-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-(difluoromethoxy)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-(4-amino-5-methoxy-4-methylazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide; and

5-amino-N-(5-(4-amino-5-(difluoromethoxy)azepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2-fluorophenyl)thiazole-4-carboxamide.

3. A pharmaceutical composition comprised of a compound of claim 1 or 2 , and a pharmaceutically acceptable carrier, glidant, diluent, or excipient.

4. The pharmaceutical composition according to claim 3 , further comprising a chemotherapeutic agent.

5. The pharmaceutical composition of claim 3 for use in treating a disease or disorder selected from cancer, immune disorders, cardiovascular disease, viral infection, inflammation, metabolism/endocrine function disorders and neurological disorders, and mediated by Pim kinase.

6. A kit for treating a condition mediated by Pim kinase, comprising:

a) a pharmaceutical composition of claim 3 ; and

b) instructions for use.

7. A compound selected from

5-amino-N-(5-((4R,5R)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-ethyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazo le-4-carboxamide; and

5-amino-N-(5-((4S,5S)-4-amino-5-methoxyazepan-1-yl)-1-cyclopropyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide.

8. A compound selected from

5-amino-N-(5-((3S,5S)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3R,5S)-5-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide;

5-amino-N-(5-((3S,4S)-4-amino-3-fluoroazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,6-difluorophenyl)thiazole-4-carboxamide; and

(R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-(2,2-difluoroethyl)-1H-pyrazol-4-yl)-2-(2,5-difluorophenyl)thiazole-4-carboxamide.

Assignments (7)
CORRECTIVE ASSIGNMENT TO CORRECT THE ASSIGNEE PREVIOUSLY RECORDED AT REEL: 029373 FRAME: 0489. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 3, 2016
From: GENENTECH, INC.
To: GENENTECH, INC.
Reel/Frame 038601/0943 →
CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY'S DATA PREVIOUSLY RECORDED AT REEL: 029373 FRAME: 0460. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Recorded May 2, 2016
From: GENENTECH, INC.
To: GENENTECH, INC.
Reel/Frame 038592/0674 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 29, 2012
From: GENENTECH, INC.
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 029373/0460 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Nov 29, 2012
From: GENENTECH, INC.
To: F. HOFFMANN-LA ROCHE AG
Reel/Frame 029373/0489 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 17, 2012
From: HODGES, ALASTAIR JAMES; MATTEUCCI, MIZIO; SHARPE, ANDREW
To: BIOFOCUS
Reel/Frame 029144/0952 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 17, 2012
From: SUN, MINGHUA; WANG, XIAOJING; TSUI, VICKIE H.
To: GENENTECH, INC.
Reel/Frame 029144/0834 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 17, 2012
From: BIOFOCUS
To: GENENTECH, INC.
Reel/Frame 029145/0135 →
Continuity (2)
Provisional Application 61539634 · Sep 27, 2011
Related Publication 20130079321A1 · Mar 28, 2013