Antimetastatic compounds

Abstract

Screening methods for identifying compounds and compounds and pharmaceutical compositions for treating and preventing cancer are disclosed. The compounds affect signal transduction downstream of the MET receptor.

1 . A method of inhibiting cellular responses to MET receptor signaling by administering a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein each of R 1 , R 2 , R 3 , R 4 , and R 5  is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxy, carboxy, hydroxy, halo, cyano, or together with another R group form a fused ring; 
         and wherein each of R 6 , R 7 , R 8 , R 9 , and R 10  is selected from the group consisting of: H, alkyl, alkenyl, alkynyl, alkoxy, carboxy, carboxyalkyl, hydroxy, halo, cyano, nitro, or together with another R group form a fused ring; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         2 - 28 . (canceled) 
     
     
         29 . A method of inhibiting cellular responses to MET receptor signaling by administering a compound of formula A-I: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, phenyl, and benzyl; 
         R 2  is absent or H; 
         R 3  is H, absent, or together with R 4  forms a carbocyclic ring; 
         R 4  is H, absent or together with R 3  forms a carbocyclic ring; 
         X is N, S, or together with W completes a phenyl ring; 
         W is C, N, or together with X completes a phenyl ring; 
         A is absent or selected from S and NH; 
         B is absent or selected from alkyl and alkenyl; 
         n is 0 or 1; 
         Y is selected from alkyl, alkenyl, alkoxy, hydroxy, unsubstituted aryl, substituted aryl, and heterocycle; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         30 . The method of  claim 29 , wherein the compound is of formula A-II: 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof. 
       
     
     
         31 . The method of  claim 30 , wherein the compound is selected from one of formula A-IIa and A-IIb: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, phenyl, and benzyl; 
         A is absent or selected from S and NH; 
         B is absent or selected from alkyl and alkenyl; 
         n is 0 or 1; 
         Y is selected from alkyl, alkenyl, alkoxy, hydroxy, unsubstituted aryl, substituted aryl, and heterocycle; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         32 . The method of  claim 30 , wherein the compound is of formula A-III: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, phenyl, and benzyl; 
         A is absent selected from S and NH; 
         B is absent or selected from alkyl and alkenyl; 
         n is 0 or 1; 
         Y is selected from alkyl, alkenyl, alkoxy, hydroxy, unsubstituted aryl, unsubstituted heteroaryl, substituted aryl, and substituted heteroaryl; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         33 . A method of inhibiting cellular responses to MET receptor signaling by administering a compound of formula A-IV: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from H, phenyl, and benzyl; 
         A is absent selected from S and NH; 
         B is absent or selected from alkyl and alkenyl; 
         n is 0 or 1; 
         Y is selected from alkyl, alkenyl, alkoxy, hydroxy, unsubstituted aryl, substituted aryl, and heterocycle; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         34 . The method according to  claim 29 , wherein A is S and B is CH 2 . 
     
     
         35 . The method according to  claim 29 , wherein A is NH and B is CH 2 . 
     
     
         36 . The method according to  claim 29 , wherein A is absent and B is CH 2 —CH 2 . 
     
     
         37 . The method according to  claim 29 , wherein A is absent and B is CH═CH. 
     
     
         38 . The method according to  claim 29 , wherein A is S and B is CH 2 CH═CH. 
     
     
         39 . The method according to  claim 29 , wherein A is absent and B is CH 2 —CH 2 —CH 2 . 
     
     
         40 . The method according to  claim 29 , wherein n is 0. 
     
     
         41 . The method according to  claim 29 , wherein n is 1. 
     
     
         42 . The method according to  claim 29 , wherein R is H. 
     
     
         43 . The method according to  claim 29 , wherein R is phenyl. 
     
     
         44 . The method according to  claim 29 , wherein R is benzyl. 
     
     
         45 . The method according to  claim 29 , wherein Y is alkyl. 
     
     
         46 . The method according to  claim 29 , wherein Y is alkenyl. 
     
     
         47 . The method according to  claim 29 , wherein Y is alkoxy. 
     
     
         48 . The method according to  claim 29 , wherein Y is hydroxy. 
     
     
         49 . The method according to  claim 29 , wherein Y is unsubstituted aryl. 
     
     
         50 . The method according to  claim 29 , wherein Y is substituted aryl. 
     
     
         51 . The method according to  claim 29 , wherein Y is heterocycle. 
     
     
         52 . The method according to  claim 29 , wherein Y is selected from 1H-benzo[de]isoquinoline-1,3-(2H)-dione, 3,5-dimethylisoazole, 2-methylthiazole, pyrrolidine, and 3,5-dimethylisoxazole. 
     
     
         53 . The method according to  claim 29 , wherein R 3  and R 4  when present, form a carbocyclic ring. 
     
     
         54 . The method according to  claim 29 , wherein R 3  and R 4  when present, form a carbocyclic ring selected from fused cyclohexene, fused cyclopentene, and fused dihydronaphthalene. 
     
     
         55 - 77 . (canceled)