p-38 kinase inhibitors
Compounds and compositions for modulating the activity of p38 kinases are provided, including p38α and p38β kinase. Methods for treating, preventing or ameliorating one or more symptoms of a p38 kinase mediated disease or disorder are also provided.
1. A compound having formula (I):
or a pharmaceutically acceptable salt thereof, wherein X is
R 2 is attached to any available carbon atom of the phenyl ring A and at each occurrence is independently selected from the group consisting of hydrogen, alkyl, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —OMe, —CN, —NMe 2 ; —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 4 , —NHSO 2 alkyl, —CO 2 R 4 , —CONH 2 , —SO 3 H, —S(O)alkyl, —S(O)aryl, —SO 2 NHR 4 , and —NHC(═O)NHR 4 ;
R 3 is hydrogen, alkyl, —OR 4 , substituted alkyl, cycloalkyl, —CR 4 cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclyl or substituted heterocyclyl;
V is -M-R 10 or R 14 ,
M is —NR 4 (C═O)—, —NR 4 (C═O)NR 4 —, —NR 4 SO 2 —, or —C(═O)—;
R 14 is aryl or heteroaryl optionally substituted with up to three R 12 ;
R 4 is hydrogen, lower alkyl or lower cycloalkyl;
R 6 at each occurrence is independently hydrogen, alkyl, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —OMe, —CN, —NH 2 , —NMe 2 ; —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 4 , —NHSO 2 alkyl, —CO 2 R 4 , —CONH 2 , —SO 3 H, —S(O)alkyl, —S(O)aryl, —SO 2 NHR 4 , —NHC(═O)R 4 , or —NHC(═O)NHR 4 ;
R 10 is alkyl, substituted alkyl, aryl, alkoxyaralkyl or —(CH 2 ) t -D-(CH 2 ) e —R 13 ;
t is selected from 0, 1, 2 and 3; e is selected from 0, 1, 2 and 3;
D is selected from a bond, an optionally substituted heterocyclyl, an optionally substituted aryl, —O—, —S—, —(C═O)—, —NR 4 (C═O)—, —(C═O)NR 4 —, —S(O)—, SO 2 NR 4 —, SO 2 —, and —NR 4 —;
R 12 is selected from R 10 , NO 2 , CN, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —OMe, —CN, —NMe 2 ; —S(═O)alkyl, —S(═O)aryl, —NHSO 2 -aryl-R 4 , —NHSO 2 alkyl, —CO 2 R 4 , —CONH 2 , —SO 3 H, —S(O)alkyl, —S(O)aryl, —SO 2 NHR 4 , and —NHC(═O)NHR 4 ; and
R 13 is selected from an optionally substituted five- to seven-membered heterocyclic ring, an optionally substituted five- to seven-membered heteroaryl ring and an optionally substituted fused bicyclic ring.
2. The compound of claim 1 having formula (III):
3. The compound of claim 1 having formula (IV):
wherein R 3 is selected from lower alkyl, lower cycloakyl, heteroaryl, and substituted heteroaryl.
4. The compound of claim 1 having formula (V):
5. The compound of claim 1 , wherein R 6 is lower alkyl or hydrogen.
6. The compound of claim 1 , wherein R 6 is methyl or hydrogen.
7. The compound of claim 1 , wherein R 6 is methyl.
8. The compound of claim 1 , wherein R 6 is hydrogen.
9. The compound of claim 1 , wherein V is -M-R 10 or R 14 .
10. The compound of claim 1 , wherein R 10 is methoxybenzyl.
11. The compound of claim 1 , wherein R 14 is aryl or heteroaryl optionally substituted with up to three R 12 .
12. The compound of claim 1 , wherein R 14 is heteroaryl optionally substituted with lower alkyl.
13. The compound of claim 1 , wherein R 14 is oxadiazolyl, optionally substituted with methyl.
14. The compound of claim 1 , wherein R 2 is selected from lower alkyl, lower cycloalkyl and halogen.
15. The compound of claim 1 , wherein R 3 is selected from lower alkyl lower cycloalkyl, heteroaryl, substituted heteroaryl.
16. The compound of claim 1 , wherein R 3 is lower cycloalkyl
17. The compound of claim 1 , wherein R 3 is cyclopropyl.
18. The compound of claim 1 is
N-Cyclopropy-4-methyl-3-(5-[1,3,4]oxadiazol-2-yl-pyridin-2-yl)-benzamide; or
N-Cyclopropy-4-methyl-3-[5(5-methyl-[1,3,4]oxadiazol-2-yl)-pyridin-2-yl]benzamide.
19. A pharmaceutical composition, comprising the compound of claim 1 and a pharmaceutically acceptable carrier.