Substituted quinoxalines as b-raf kinase inhibitors

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

1 - 52 . (canceled) 
     
     
         53 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted thiazolyl, optionally substituted thiadiazolyl, optionally substituted tetrazolyl, optionally substituted thienyl, optionally substituted furanyl, optionally substituted pyrrolyl, optionally substituted pyridazinyl, optionally substituted triazolyl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or optionally substituted alkynyl; 
         R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and R 10  are independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or optionally substituted alkynyl; 
         R 6  is hydrogen, cyano, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or optionally substituted alkynyl; and 
         R 9  is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or phosphato. 
       
     
     
         54 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 1  is hydrogen, cyano, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted tetrazolyl, optionally substituted pyridazinyl, or optionally substituted triazolyl. 
     
     
         55 . The compound or pharmaceutically acceptable salt of  claim 54 , wherein R 1  is optionally substituted aryl, optionally substituted heterocycloalkyl, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidinyl, optionally substituted imidazolyl, optionally substituted isoxazolyl, optionally substituted oxazolyl, optionally substituted tetrazolyl, or optionally substituted triazolyl. 
     
     
         56 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 2 , R 3 , R 4 , and R 5  are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl. 
     
     
         57 . The compound or pharmaceutically acceptable salt of  claim 56 , wherein R 2 , R 3 , R 4 , and R 5  are independently hydrogen or halo. 
     
     
         58 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 6  is hydrogen, cyano, or optionally substituted alkyl. 
     
     
         59 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 7 , R 8 , and R 10  are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl and R 6  is independently cyano, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl. 
     
     
         60 . The compound or pharmaceutically acceptable salt of  claim 59 , wherein R 7 , R 8 , and R 10  are independently hydrogen, methyl, cyano, or halo and R 6  is hydrogen, methyl or cyano. 
     
     
         61 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 7  is hydrogen or halo. 
     
     
         62 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 8  is hydrogen. 
     
     
         63 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 10  is hydrogen, halo or methyl. 
     
     
         64 . The compound or pharmaceutically acceptable salt of  claim 53 , wherein R 9  is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl. 
     
     
         65 . The compound or pharmaceutically acceptable salt of  claim 64 , wherein R 9  is hydrogen or optionally substituted lower alkyl. 
     
     
         66 . The compound or pharmaceutically acceptable salt of  claim 64 , wherein R 9  is optionally substituted benzyl. 
     
     
         67 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of  claim 53 . 
     
     
         68 . A method of inhibiting B-raf kinase activity in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of  claim 53 . 
     
     
         69 . A method of inhibiting B-raf kinase activity in a subject in need thereof, comprising:
 a. determining the presence or absence of a B-raf mutation in a biological sample isolated from the subject; and   b. if a B-raf mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of  claim 53 .   
     
     
         70 . The method of  claim 69 , wherein the B-raf mutation is in codon 600. 
     
     
         71 . The method of  claim 68 , further comprising administering an additional anti-cancer agent. 
     
     
         72 . The method of  claim 69 , further comprising administering an additional anti-cancer agent.