Kinase Antagonists

Abstract

The present invention provides novel compounds that are antagonists of PI3 kinase, PI3 kinase and tyrosine kinase, PI3 kinase and mTOR, or PI33 kinase, mTOR and tyrosine kinase.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 X is ═C(H)—; 
 R 1  is hydrogen, R 3 -substituted or unsubstituted alkyl, R 3 -substituted or unsubstituted heteroalkyl, R 3 -substituted or unsubstituted cycloalkyl, R 3 -substituted or unsubstituted heterocycloalkyl, R 3 -substituted or unsubstituted aryl, or R 3 -substituted or unsubstituted heteroaryl; 
 R 2  is R 4 -substituted heteroaryl; 
 R 3  is halogen, —CN, —OR 5 , —S(O) n R 6 , —NR 7 R 8 , —C(O)R 9 , ═N—NH 2 , —NR 10 —C(O)R 11 , —NR 12 —C(O)—OR 13 , —C(O)NR 14 R 15 , —NR 16 S(O) 2 NR 17 , —S(O) 2 NR 18 , R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted heteroalkyl, R 19 -substituted or unsubstituted cycloalkyl, R 19 -substituted or unsubstituted heterocycloalkyl, R 19 -substituted or unsubstituted aryl, or R 19 -substituted or unsubstituted heteroaryl, wherein n is an integer from 0 to 2; 
 R 36  is —NR 37 R 38 ; 
 R 4  is halogen, —OR 20 , or —NR 22 R 23 ; 
 R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  are independently hydrogen, R 35 -substituted or unsubstituted alkyl, R 35 -substituted or unsubstituted heteroalkyl, unsubstituted cycloalkyl, R 35 -substituted or unsubstituted heterocycloalkyl, R 35 -substituted or unsubstituted aryl, or R 35 -substituted or unsubstituted heteroaryl; 
 R 20 , R 22  and R 23  are hydrogen; 
 R 19  and R 35  are independently hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl; and 
 R 37 and R 38  are hydrogen. 
 
     
     
         2 . The compound of  claim 1 , wherein R 2  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 W 1 , W 2 , W 3 , and W 4  are independently ═CH—, ═CR 4 —, or ═N—; and 
 ring A is a partially or fully unsaturated 6- or 7- membered ring. 
 
     
     
         3 . The compound of  claim 1 , wherein R 2  is R 4 -substituted pyridinyl, R 4 -substituted pyrimidinyl, R 4 -substituted thiophenyl, R 4 -substituted furanyl, R 4 -substituted indolyl, R 4 -substituted benzoxadiazolyl, R 4 -substituted benzodioxolyl, R 4 -substituted benzodioxanyl, R 4 -substituted thianaphthanyl, R 4 -substituted pyrrolopyridinyl, R 4 -substituted indazolyl, R 4 -substituted quinolinyl, R 4 -substituted quinoxalinyl, R 4 -substituted pyridopyrazinyl, R 4 -substituted quinazolinonyl, R 4 -substituted chromenonyl, R 4 -substituted benzoisoxazolyl, R 4 -substituted imidazopyridinyl, R 4 -substituted benzofuranyl, R 4 -substituted dihydro-benzofuranyl, R 4 -substituted dihydro-benzodioxinyl, R 4 -substituted benzoimidazolonyl, or R 4 -substituted benzothiophenyl. 
     
     
         4 . The compound of  claim 1 , wherein R 2  is R 4 -substituted pyrrolpyridinyl, R 4 -substituted quinolinyl, R 4 -substituted indazolyl, or R 4 -substituted indolyl. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is R 4 -substituted indolyl. 
     
     
         6 . The compound of  claim 5 , wherein R 2  is 5-hydroxyindol-2-yl. 
     
     
         7 . The compound of  claim 6 , wherein R 1  is isopropyl. 
     
     
         8 . Thecompound of  claim 1 , wherein R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , and R 18  are independently hydrogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. 
     
     
         9 . The compound of  claim 1 , wherein R 1  is R 3 -substituted or unsubstituted alkyl, R 3 -substituted or unsubstituted cycloalkyl, or R 3 -substituted or unsubstituted aryl. 
     
     
         10 . The compound of  claim 1 , wherein R 1  is R 3 -substituted or unsubstituted C 1 -C 4  alkyl, or R 3 -substituted or unsubstituted C 3 -C 6  cycloalkyl. 
     
     
         11 . The compound of  claim 1 , wherein R 1  is methyl or unsubstituted C 3 -C 6  branched alkyl. 
     
     
         12 . The compound of  claim 1 , wherein R 1  is isopropyl. 
     
     
         13 . The compound of  claim 1 , wherein R 3  is R 19 -substituted or unsubstituted alkyl, R 19 -substituted or unsubstituted cycloalkyl, or R 19 -substituted or unsubstituted aryl. 
     
     
         14 . The compound of  claim 1 , wherein R 3  is R 19 -substituted or unsubstituted alkyl or R 19 -substituted or unsubstituted cycloalkyl. 
     
     
         15 . The compound of  claim 1 , wherein R 19  is unsubstituted alkyl or unsubstituted cycloalkyl. 
     
     
         16 . The compound of  claim 16 , wherein R 19  is unsubstituted C 1 -C 4  alkyl or unsubstituted cyclopentyl. 
     
     
         17 . A pharmaceutical composition comprising the compound of  claim 1  and a pharmaceutically acceptable excipient.