C-Met Modulators and Method of Use

Abstract

The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. More specifically, the invention provides quinazolines and quinolines which inhibit, regulate, and/or modulate kinase receptor, particularly c-Met, KDF, c-Kit, flt-3 and flt-4, signal transduction pathways related to the changes in cellular activities as mentioned above, compositions which contain these compounds, and methods of using them to treat kinase-dependent diseases and conditions. The present invention also provides methods for making compounds as mentioned above, and compositions which contain these compounds.

1 - 52 . (canceled) 
     
     
         52 . A compound according to formula XIVa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein:
 Q is selected from ═N— or ═C(H)—; 
 R 2  is halogen, trihalomethyl, —CN, —NH 2 , —NO 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3  and optionally substituted lower alkyl; 
 R 3  is independently selected from —H, or R 4 ; 
 R 4  is independently selected from optionally substituted C 1-6  alkyl, optionally substituted aryl, optionally substituted aryl C 1-6  alkyl, optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6  alkyl; 
 R 20  is selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3  and optionally substituted lower alkyl; 
 R 30  is independently selected from halogen, trihalomethyl, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 3 , —S(O) 0-2 R 3 , —SO 2 NR 3 R 3 , —CO 2 R 3 , —C(O)NR 3 R 3 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , —C(O)R 3 , and optionally substituted C 1-6  alkyl; and 
 R 50  is lower alkyl. 
 
     
     
         53 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein Q is —N═. 
     
     
         54 . The compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, wherein Q is —CH═. 
     
     
         55 . The compound according to  claim 54 , or a pharmaceutically acceptable salt thereof, wherein (R 30 ) 0-4  is (R 30 ) 0 , or methyl. 
     
     
         56 . The compound according to  claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from C 1-6  alkyl, perfluoro C 1-6  alkyl, hydrogen, and halogen. 
     
     
         57 . The compound according to  claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2  is halogen. 
     
     
         58 . The compound according to  claim 54 , or a pharmaceutically acceptable salt thereof, wherein R 2  is hydrogen. 
     
     
         59 . The compound according to  claim 53 , or a pharmaceutically acceptable salt thereof, wherein R 20  is selected from halogen, —CN, —NO 2 , —NH 2 , —OR 3 , —NR 3 R 4 , —N(R 3 )SO 2 R 3 , —N(R 3 )C(O)R 3 , —N(R 3 )CO 2 R 3 , optionally substituted heterocyclyl, and optionally substituted heterocyclyl C 1-6  alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, form an optionally substituted three- to six-membered heteroalicyclic, said optionally substituted three- to six-membered heteroalicyclic fused to the phenyl as in formula XIVa. 
     
     
         60 . The compound according to  claim 59 , or a pharmaceutically acceptable salt thereof, wherein R 20  is selected from halogen, —NR 3 R 4 , optionally substituted heterocyclyl and optionally substituted heterocyclyl C 1-6  alkyl, and (two of R 20 ) together with the atom or atoms to which they are attached, form an optionally substituted five- to six-membered heteroalicyclic, said optionally substituted five- to six-membered heteroalicyclic fused to the phenyl as in XIVa. 
     
     
         61 . The compound according to  claim 60 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from C 1-6  alkyl, perfluoro C 1-6  alkyl, and halogen. 
     
     
         62 . The compound according to  claim 61 , or a pharmaceutically acceptable salt thereof, wherein R 2  is selected from perfluoro C 1-3  alkyl, and halogen. 
     
     
         63 . The compound according to  claim 52  selected from the following: 
       
         
           
                 
                 
                 
               
                     
                 
                     
                   Name 
                   Structure 
                 
                     
                 
                    4 
                   N-(6-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-chloropyridin- 3-yl)-N′- phenylcyclopropane-1,1- dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   12 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   13 
                   N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}phenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   14 
                   N-(4-{[6,7- bis(methyloxy)quinazolin- 4-yl]oxy}-3- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   22 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-methylphenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   24 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3-fluorophenyl)- N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   27 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-3,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   28 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,5- difluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   33 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2,3,5- trifluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   34 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-5-fluoro-2- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   35 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- methylphenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   43 
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}-2-chloro-5- fluorophenyl)-N′-(4- fluorophenyl)cyclopropane- 1,1-dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   104  
                   N-(4-{[6,7- bis(methyloxy)quinolin-4- yl]oxy}phenyl)-N′- phenylcyclopropane-1,1- dicarboxamide 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         64 . A pharmaceutical composition comprising a compound according to  claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         65 . The pharmaceutical composition comprising a compound according to  claim 63 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.