3,5-diaminopyrazole kinase inhibitors
Provided herein are 3,5-diaminopyrazoles, for example, compounds of Formula I, that are useful for modulating regulated-in-COPD kinase activity, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, preventing, or ameliorating one or more symptoms of a RC kinase-mediated disorder, disease, or condition.
1. A compound of Formula I:
or a stereoisomer, enantiomer, mixture of enantiomers, or mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof; wherein:
R 1 is C 6-14 aryl, heteroaryl, or heterocyclyl;
R 2 and R 3 are each independently C 1-6 alkyl or C 3-10 cycloalkyl;
wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from halo, C 1-6 alkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more C 1-6 alkyl;
with the proviso that the compound is not 3-((3-chlorophenyl)amino)-5-((4-hydroxy -3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.
2. The compound of claim 1 , wherein R 1 is C 6-14 aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q.
3. The compound of claim 1 , wherein R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q.
4. The compound of claim 1 , wherein R 1 is phenyl, optionally substituted with one or more substituents Q.
5. The compound of claim 4 , wherein Q is independently selected from fluoro, chloro, bromo, iodo, methyl, morpholinyl, dimethylmorpholinyl, pyrrolyl, isopropylpiperazinyl, methylpiperazinyl, pyridinyl, and benzylpiperazinyl.
6. The compound of claim 3 , wherein R 1 is 3-methyl-4-morpholinophenyl, 3-chloro-4-morpholinophenyl, 4-morpholinophenyl, 4-(2,6-dimethylmorpholino)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(4-isopropylpiperazin-l-yl)phenyl, 4-(pyridin-2-yl)phenyl, 4-(4-methylpiperazin-l-yl)phenyl, 3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl, or 3-chloro-4-(4-isopropylpiperazin-l -yl)phenyl.
7. The compound of claim 1 , wherein R 1 is heteroaryl, optionally substituted with one or more substituents Q.
8. The compound of claim 7 , wherein R 1 is 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q.
9. The compound of claim 8 , wherein R 1 is pyridinyl, optionally substituted with one or more substituents Q.
10. The compound of claim 9 , wherein R 1 is 2-morpholino-3-chloropyridin-5-yl, 2-morpholinopyridin-5-yl, 5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl, 2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl, or 2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl.
11. The compound of claim 1 , wherein R 2 is C 1-6 alkyl.
12. The compound of claim 1 , wherein R 2 is methyl.
13. The compound of claim 1 , wherein R 3 is C 1-6 alkyl.
14. The compound of claim 1 , wherein R 3 is methyl.
15. The compound of claim 1 selected from the group consisting of:
and stereoisomers, enantiomers, mixtures of enantiomers, and mixtures of diastereomers thereof; and pharmaceutically acceptable salts thereof.
16. A pharmaceutical composition comprising the compound of claim 1 , and one or more pharmaceutically acceptable excipients.
17. The pharmaceutical composition of claim 16 , wherein the composition is formulated for single dose administration.
18. The pharmaceutical composition of claim 16 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
19. The pharmaceutical composition of claim 18 , wherein the oral dosage form is a tablet or capsule.
20. The pharmaceutical composition of claim 16 , further comprising a second therapeutic agent.
21. A compound of Formula I:
or a stereoisomer, enantiomer, mixture of enantiomers, or mixture of diastereomers thereof; or a pharmaceutically acceptable salt thereof; wherein:
R 1 is C 6-14 aryl, heteroaryl, or heterocyclyl;
R 2 and R 3 are each independently C 1-6 alkyl or C 3-10 cycloalkyl;
wherein each alkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl is optionally substituted with one or more substituents Q, where each Q is independently selected from halo, C 1-6 alkyl, C 1-6 alkoxy, aryl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more C 1-6 alkyl, halo, aralkyl, dialkylamino, heterocyclyl, heterocyclylalkyl, and heterocyclylcarbonyl;
with the proviso that the compound is not 3-((3-chlorophenyl)amino)-5-((4-hydroxy-3,5-dimethylbenzyl)amino)-1H-pyrazole-4-carboxamide.
22. The compound of claim 21 , wherein R 1 is C 6-14 aryl or heteroaryl, each of which is optionally substituted with one or more substituents Q.
23. The compound of claim 21 , wherein R 1 is C 6-14 aryl, optionally substituted with one or more substituents Q.
24. The compound of claim 21 , wherein R 1 is phenyl, optionally substituted with one or more substituents Q.
25. The compound of claim 24 , wherein Q is independently selected from fluoro, chloro, bromo, iodo, methyl, morpholinyl, dimethylmorpholinyl, pyrrolyl, isopropylpiperazinyl, methylpiperazinyl, pyridinyl, benzylpiperazinyl, phenyl, imidazolyl, methoxy, tert-butyl, indazolyl, methylpipiperidinyl, (pyrrolidinecarbonyl)piperazinyl, flouropiperidinyl, dimethylpyranyl, piperidinyl, benzyl, 1,1-dioxidothiomorpholino, pyrrolidinylmethyl, dimethylamino, oxazolyl, (piperidinecarbonyl)piperazinyl, acetamido, (pyrimidinyl)piperizinyl, piperidinylmethyl, thiomorpholinyl fluorophenylamido, methoxyphenylamido, isopropylpiperidinyl, cyanomethyl, (trifluoromethyl)phenylamido, and oxomorpholinyl.
26. The compound of claim 23 , wherein R 1 is 3-methyl-4-morpholinophenyl, 3-chloro-4-morpholinophenyl, 4-morpholinophenyl, 4-(2,6-dimethylmorpholino)phenyl, 4-(1H-pyrrol-1-yl)phenyl, 4-(4- isopropylpiperazin-1-yl)phenyl, 4-(pyridin- 2-yl)phenyl, 4-(4-methylpiperazin-1-yl)phenyl, 3-chloro-4-(2,6-dimethylmorpholino)phenyl, 4-(pyridin-3-yl)phenyl, 3-chloro-4-(4-isopropylpiperazin-1-yl)phenyl, 1,1′-biphenyl, 4-(1H-imidazol-1-yl)phenyl, 4-methoxyphenyl, 4-tert-butylphenyl, 4-(4-methyl-[1,4′-bipiperidin]-1′-yl)phenyl, 4-(4-(morpholine-4-carbonyl)piperazin-l-yl)phenyl, 4-(4-fluoropiperidin-1-yl)phenyl, 4-(piperidin-1-yl)phenyl. 3-chloro-4-(2,6-dimethylmorpholino)phenyl, 3-methyl-4-(4-methylpiperazin-1-yl)phenyl, 3-methyl-4-(piperidin -1-yl)phenyl, 4-(4-benzylpiperazin-1-yl)-3-methylphenyl, 4-(1,1-dioxidothiomorpholino)phenyl, (5-(piperidin-1-yl)pyridine-2-yl)phenyl, 4-(4-chloropiperidin-1-yl)phenyl, 4-(pyrrolidin-l -ylmethyl)phenyl, 4-(4-(dimethylamino)piperidin-1-yl)phenyl, 3-fluoro-4-morpholinophenyl, 4-(oxazol-5-yl)phenyl, 4-(4-(piperidine-1-carbonyl)piperazin-1-yl)phenyl, 3-acetamidophenyl, 3-chloro-4-(4-methylpiperazin-l-yl)phenyl, 4-fluorophenyl, 3-cyanophenyl, 4-(4-(pyrimidin-2-yl)piperazin-l-yl)phenyl, 4-(piperidin-l-ylmethyl)phenyl, 4-thiomorpholinophenyl, 4-aminophenyl, 4-(aminosulfonyl)phenyl, 4-(dimethylamino)phenyl, 4-(morpholinomethyl)phenyl, 2-methoxyphenyl, 4-(4-fluorophenylamido)phenyl, 4-(4,5-dihydro-1H-pyrazol-3-yl)phenyl, 4-(2-methoxyphenylamido)phenyl, 4-(3-methoxyphenylamido)phenyl, 4-(4-methoxyphenylamido)phenyl, 4-(4-isopropylpiperidin-1-yl)phenyl 4-(3-oxomorpholinyl)phenyl, 4-(2-cyanomethyl)phenyl, 4((4-trifluoromethyl)phenylamido)phenyl, or 4-(4-methylpiperidin-1-yl)phenyl.
27. The compound of claim 21 , wherein R 1 is heteroaryl, optionally substituted with one or more sub substituents Q.
28. The compound of claim 27 , wherein R 1 is 5- or 6-membered heteroaryl, each of which is optionally substituted with one or more substituents Q.
29. The compound of claim 27 , wherein R 1 is indazolyl, optionally substituted with one or more substituents Q.
30. The compound of claim 28 , wherein R 1 is pyridinyl, optionally substituted with one or more substituents Q.
31. The compound of claim 30 , wherein R 1 is 2-morpholino-3-chloropyridin-5-yl, 2-morpholinopyridin-5-yl, 5-morpholinopyridin-2-yl, 2-morpholino-3-methylpyridin-5-yl, 2-(4-isopropylpiperazin-1-yl)-3-methylpyridin-5-yl, 2-(4-methylpiperazin-1-yl)-3-methylpyridin-5-yl, 6-(2,6-dimethyltetrahydro-2H-pyran-4-yl)pyridin-3-yl, or 2-(4-(pyrrolidin-1-yl)piperidin-1-yl)pyridin-5-yl.
32. The compound of claim 21 , wherein R 2 is C 1-6 alkyl.
33. The compound of claim 21 , wherein R 2 is methyl.
34. The compound of claim 21 , wherein R 3 is C 1-6 alkyl.
35. The compound of claim 21 , wherein R 3 is methyl.
36. The compound of claim 21 selected from the group consisting of:
and stereoisomers, enantiomers, mixtures of enantiomers, and mixtures of diastereomers thereof; and pharmaceutically acceptable salts thereof.
37. A pharmaceutical composition comprising the compound of claim 21 , and one or more pharmaceutically acceptable excipients.
38. The pharmaceutical composition of claim 37 , wherein the composition is formulated for single dose administration.
39. The pharmaceutical composition of claim 37 , wherein the composition is formulated as oral, parenteral, or intravenous dosage form.
40. The pharmaceutical composition of claim 39 , wherein the oral dosage form is a tablet or capsule.
41. The pharmaceutical composition of claim 37 , further comprising a second therapeutic agent.