P-38 Kinase Inhibitors

Abstract

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 1  is selected from halogen, hydroxyl, lower alkyl, lower cycloalkyl, alkynyl, trifluoromethyl, methoxy, trifluoromethoxy, cyano, —NH 2 , —NR 4 R 5  and —OR 4 ; 
       R 2  is attached to any available carbon atom of the phenyl ring A and at each occurrence is independently selected from 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 ; 
       n is 0 or 1 
       Y is -L-R 3  or R 11 ; 
       R 3  is selected from hydrogen, alkyl, —OR 4 , substituted alkyl, cycloalkyl, —CR 4 cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle and substituted heterocycle 
       L is —C(═O)NH—, —NH(C═O)—, —SO 2 NH—, —NHSO 2 —, or —C(O)—; 
       R 11  is an optionally substituted 5-membered heteroaryl; 
       V is -M-R 10  or R 14 ; 
       M is —C(O)NR 4 —, —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 ; 
       P is -Q-R 10  or R 15 ; 
       Q is —NR 4 (C═O)—, —NR 4 (C═O)NR 4 —, —SO 2 NR 4 —, —NR 4 SO 2 —, or —C(═O)—, 
       R 15  is aryl or heteroaryl optionally substituted with up to three R 12 , 
       R 4  and R 5  are each selected independently from hydrogen, lower alkyl and lower cycloalkyl; 
       R 6  is attached to any available carbon atom of the phenyl ring B and at each occurrence is independently selected from hydrogen, alkyl, lower cycloalkyl, halo, trifluoromethyl, trifluoromethoxy, —OMe, —CN, —NH 2 , or —NMe 2 ; —NHSO 2 -aryl-R 4 , —NHSO 2 alkyl, —CO 2 R 4 , —CONH 2 , —S(O)alkyl, —S(O)aryl, —SO 2 NHR 4 , —NHC(═O)R 4 , and —NHC(═O)NHR 4 ; 
       R 7  and R 8  are each independently selected from hydrogen, alkyl, substituted alkyl, aryl and cycloalkyl; 
       R 9  is hydrogen, alkyl, substituted alkyl or cycloalkyl; 
       R 10  is alkyl, substituted alkyl, aryl, or —(CH 2 ) t -D-(CH 2 ) e —R 13 ; 
       t is selected from 0, 1, 2 and 3; a is selected from 0, 1, 2 and 3; 
       D is selected from a bond, an optionally substituted heterocycle, an optionally substituted aryl, —O—, —S—, —(CO)—, —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, 
       with the proviso that when Q is CO then Y is not oxadiazolyl and L is not —C(O)NH— or —NHC(═O). 
     
   
   
       2 . The compound of  claim 1 , having formula (II): 
     
       
         
         
             
             
         
       
       where R 2  is selected from hydrogen, methyl end halogen; and 
       R 3  is selected from alkyl, —OR 4 , substituted alkyl, cycloakyl, heteroaryl and substituted heteroaryl, or a pharmaceutically acceptable salt thereof. 
     
   
   
       3 - 4 . (canceled) 
   
   
       5 . The compound of  claim 1  having formula (V): 
     
       
         
         
             
             
         
       
     
     , or a pharmaceutically acceptable salt thereof. 
   
   
       6 . The comp  claim 1  having formula (VI): 
     
       
         
         
             
             
         
       
       where R 1  is selected from methyl, cyclopropyl and halogen; and 
       R 2  is selected from hydrogen, methyl and halogen, or a pharmaceutically acceptable salt thereof. 
     
   
   
       7 . The compound  claim 1  having formula (VII): 
     
       
         
         
             
             
         
       
     
     , or pharmaceutically acceptable salt thereof. 
   
   
       8 . The compound of  claim 1 , having formula (VII): 
     
       
         
         
             
             
         
       
       wherein 
       R 1  is selected from methyl, cyclopropyl and halogen; 
       R 2  is selected from hydrogen, methyl and halogen; and 
       R 15  is selected from hydrogen, lower alkyl and lower cycloalkyl, or pharmaceutically acceptable salt thereof. 
     
   
   
       9 - 10 . (canceled) 
   
   
       11 . The compound of  claim 1 , wherein X is selected from 
     
       
         
         
             
             
         
       
     
     , and 
     , or a pharmaceutically acceptable salt thereof. 
   
   
       12 . The compound of  claim 1 , wherein R 6  is lower alkyl or hydrogen, or a pharmaceutically acceptable salt thereof. 
   
   
       13 - 18 . (canceled) 
   
   
       19 . The compound of  claim 1  wherein V is MR 10  or R 14 , or a pharmaceutically acceptable salt thereof. 
   
   
       20 . The compound of  claim 1 , wherein M is —C(═O)NR 4 —, or a pharmaceutically acceptable salt thereof. 
   
   
       21 - 22 . (canceled) 
   
   
       23 . The compound of  claim 1 , wherein R 10  is methoxybenzyl, or a pharmaceutically acceptable salt thereof. 
   
   
       24 . The compound of  claim 1 , wherein R 14  is aryl or heteroaryl optionally substituted with up to three R 12 , or a pharmaceutically acceptable salt thereof. 
   
   
       25 . The compound of  claim 1  wherein R 14  is heteroaryl optionally substituted with lower alkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       26 . The compound of  claim 1  wherein R 14  is oxadiazolyl, optionally substituted with methyl, or a pharmaceutically acceptable salt thereof. 
   
   
       27 . The compound of  claim 1 , wherein P is —C(═O)—R 10  or R 15 , where R 10  is aryl and R 15  is aryl or heteroaryl optionally substituted with up to three R 12 . 
   
   
       28 - 33 . (canceled) 
   
   
       34 . The compound of  claim 1 , wherein R 3  is selected from lower alkyl, lower cycloalkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       35 . The compound of  claim 1 , wherein R 3  is lower cycloalkyl, or a pharmaceutically acceptable salt thereof. 
   
   
       36 . The compound of  claim 1 , wherein R 3  is cyclopropyl, or a pharmaceutically acceptable salt thereof. 
   
   
       37 . The compound of  claim 1 : selected from:
 6-Methyl-4′-[1,3,4]oxadiazol-2-yl-biphenyl-3-carboxylic acid cyclopropylamide;   6-Methyl-4-(5-methyl-[1,3,4]oxediazol-2-yl)-biphenyl-3-carboxylic acid cyclopropylamide;   6-Methyl-4′-(4H-[1,2,4]triazol-3-yl)-biphenyl-3-carboxylic acid cyclopropylamide;   3-(3-Benzyl-4-oxo-3,4-dihydro-quinazolin-7-yl)-N-cyclopropyl-4-methyl-benzamide;   N-cyclopropyl-3-[3-(2,6-dichloro-benzyl)-4-oxo-3,4-dihydro-quinazolin-7-yl]-4-methyl-benzamide;   N-cyclopropyl-3-[3-(3,4-dichloro-benzyl)-4-oxo-3,4-dihydro-quinazolin-7-yl]-4-methyl-benzamide;   N-cyclopropyl-3-[3-(4-methoxy-benzyl)-4-oxo-3,4-dihydro-quinazolin-7-yl]-4-methyl-benzamide;   N-cyclopropyl-4-methyl-3-(4-oxo-3,4-dihydro-quinazolin-7-yl)-benzamide;   4′-Benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide;   6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-(4-methoxy-benzyl)-nicotinamide;   3′-Amino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide;   N-cyclopropyl-4-methyl-3-(2-oxo-4-phenyl-1,2-dihydro-quinazolin-7-yl)-benzamide;   N-cyclopropyl-4-methyl-3-(4-phenyl-quinazolin-7-yl)-benzamide; and   3′-Acetylamino-4′-benzoyl-6-methyl-biphenyl-3-carboxylic acid cyclopropylamide,   
     or a pharmaceutically acceptable salt thereof. 
   
   
       38 . A method of treating, preventing, or ameliorating one or more symptoms of p38 kinase-mediated diseases or disorders, comprising administering to a subject in need thereof a compound of  claim 1 - 37 . 
   
   
       39 . The method of  claim 38 , wherein the disease or disorder is selected from inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, angiogenic disorders, infectious diseases, neurodegenerative diseases, and viral diseases. 
   
   
       40 - 53 . (canceled) 
   
   
       54 . A pharmaceutical composition, comprising a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
   
   
       55 - 61 . (canceled)