Aminopyrazoles as janus kinase inhibitors
View Patent ↗The instant invention provides compounds which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.
1. A compound selected from:
3-((4-Chloro-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-chloro-3-(methylthio)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide; and
1-(4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , selected from:
3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-chloro-3-(methylthio)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide;
3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide; and
1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 which is 3-((4-Chloro-3-methoxyphenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 2 , which is 3-((4-Chloro-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 , which is 3-((4-chloro-3-(methylthio)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 2 , which is 3-((4-chloro-3-(methylthio)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , which is 3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-(4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 2 , which is 3-((4-cyano-3-methoxyphenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 2 , which is 3-((4-cyano-3-(2-fluoropropan-2-yl)phenyl)amino)-1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-1H-pyrazole-4-carboxamide, or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 2 , which is 1-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-3-((3-methylbenzo[d]isoxazol-5-yl)amino)-1H-pyrazole-4-carboxamide or a pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof and a pharmaceutically acceptable carrier.
12. A method for the treatment of a JAK-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 or a stereoisomer, or a pharmaceutically acceptable thereof.
13. A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2 and JAK 3 which condition is selected from, arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof.
14. A method according to claim 13 , wherein said condition is arthritis.
15. A method according to claim 14 , wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
16. A method according to claim 13 , wherein said condition is asthma or obstructive airways diseases.
17. A method according to claim 13 , wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease (COPD), and emphysema.
18. A method according to claim 13 , wherein said condition is autoimmune diseases or disorders.
19. A method of treating asthma in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or a stereoisomer, thereof.
20. A method of treating arthritis in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt or stereoisomer, thereof.