Pyrrolidinyl urea, pyrrolidinyl thiourea and pyrrolidinyl guanidine compounds as trka kinase inhibitors

Abstract

Compounds of Formula I: or stereoisomers, tautomers, or pharmaceutically acceptable salts, or solvates or prodrugs thereof, where R 1 , R 2 , R a , R b , R c , R d , X, Y, B, and Ring C are as defined herein, and wherein the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration, are inhibitors of TrkA kinase and are useful in the treatment of diseases which can be treated with a TrkA kinase inhibitor such as pain, cancer, inflammation, neurodegenerative diseases and certain infectious diseases.

1 - 37 . (canceled) 
     
     
         38 . A method for treating interstitial cystitis in a mammal, which comprises administering to said mammal a therapeutically effective amount of a compound of Formula I 
       
         
           
           
               
               
           
         
         or stereoisomers, tautomers, or pharmaceutically acceptable salts wherein:
 the Y—B moiety and the NH—C(═X)—NH moiety are in the trans configuration; 
 R a , R b , R c  and R d  are H; 
 X is O; 
 R 1  is (1-3C alkoxy)(1-6C)alkyl, difluoro(1-6C)alkyl or trifluoro(1-6C)alkyl; 
 R 2  is hydrogen; 
 Y is a bond; 
 B is Ar 1 ; 
 Ar 1  is phenyl optionally substituted with one or more substituents independently selected from halogen, CF 3 , CF 3 O—, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; 
 Ring C is formula C-1 
 
       
       
         
           
           
               
               
           
         
         
           R 3  is Ar 2 , hetAr 2  or (1-6C)alkyl; 
           Ar 2  is phenyl optionally substituted with one or more groups independently selected from halogen, (1-6C)alkyl and hydroxymethyl; 
           hetAr 2  is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O and S and optionally substituted with one or more groups independently selected from (1-6C)alkyl and halogen; 
           R 4  is hetAr 4  or Ar 4 ; and 
           R 5  is (1-6C)alkyl. 
         
       
     
     
         39 . The method of  claim 38 , where Ar 1  is phenyl optionally substituted with one or m ore halogens. 
     
     
         40 . The method of  claim 39 , where hetAr 4  is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, S and O and optionally substituted with 1-2 substituents independently selected from (1-6C)alkyl. 
     
     
         41 . The method of  claim 40 , wherein the Y—B moiety and the —NH—C(═X)—NH— moiety of Formula I are trans in the absolute configuration shown in formula C: 
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 41 , wherein said compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         43 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         44 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         45 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         46 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         47 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         49 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         50 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         51 . The method of  claim 42 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof.