P70 s6 kinase inhibitors

Abstract

The present invention provides p70 S6 kinase inhibitors of the formula: pharmaceutical formulations comprising them, and methods for their use.

We claim: 
     
         1 . A compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is N or CR 6 ; 
 Z 1  and Z 2  are independently CR 3  or N, provided that Z 1  and Z 2  are not both N; 
 R 1  is H or C 1 -C 4  alkyl; 
 R 2  is phenyl optionally substituted with a first substituent selected from C 1 -C 4  alkyloxy, cyano, NO 2 , halo, trifluoromethyl, and trifluoromethoxy and optionally further substituted with a second substituent selected from the group consisting of halo; 
 R 3  is hydrogen, halo, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, or C 2 -C 6  alkynyl, wherein C 2 -C 6  alkynyl is optionally substituted with hydroxy; 
 R 4  and R 5  are independently hydrogen or C 1 -C 4  alkyl; 
 R 6  is hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . A compound of  claim 1  of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is N or CR 6 ; 
 Z 1  and Z 2  are independently CR 3  or N, provided that Z 1  and Z 2  are not both N; 
 R 1  is H or C 1 -C 4  alkyl; 
 R 2  is phenyl optionally substituted with a first substituent selected from C 1 -C 4  alkyloxy, cyano, NO 2 , halo, trifluoromethyl, and trifluoromethoxy and optionally further substituted with a second substituent selected from the group consisting of halo; 
 R 3  is hydrogen, halo, or C 3 -C 6  cycloalkyl; 
 R 4  and R 5  are independently hydrogen or C 1 -C 4  alkyl; 
 R 6  is hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof. 
 
     
     
         3 . A compound of  claim 1  where Y is CR 6  or a pharmaceutically acceptable salt thereof. 
     
     
         4 . A compound of  claim 1  where Z 2  is N a pharmaceutically acceptable salt thereof. 
     
     
         5 . A pharmaceutical formulation comprising a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is N or CR 6 ; 
 Z 1  and Z 2  are independently CR 3  or N, provided that Z 1  and Z 2  are not both N; 
 R 1  is H or C 1 -C 4  alkyl; 
 R 2  is phenyl optionally substituted with a first substituent selected from C 1 -C 4  alkyloxy, cyano, NO 2 , halo, trifluoromethyl, and trifluoromethoxy and optionally further substituted with a second substituent selected from the group consisting of halo; 
 R 3  is hydrogen, halo, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, or C 2 -C 6  alkynyl, wherein 
 C 2 -C 6  alkynyl is optionally substituted with hydroxy; 
 R 4  and R 5  are independently hydrogen or C 1 -C 4  alkyl; 
 R 6  is hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier, diluent or excipient. 
 
     
     
         6 . A method for treating adenocarcinomas of the colon in a mammal comprising administering to a mammal in need of such treatment an effective amount of a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein:
 Y is N or CR 6 ; 
 Z 1  and Z 2  are independently CR 3  or N, provided that Z 1  and Z 2  are not both N; 
 R 1  is H or C 1 -C 4  alkyl; 
 R 2  is phenyl optionally substituted with a first substituent selected from C 1 -C 4  alkyloxy, cyano, NO 2 , halo, trifluoromethyl, and trifluoromethoxy and optionally further substituted with a second substituent selected from the group consisting of halo; 
 R 3  is hydrogen, halo, C 1 -C 4  alkyl, C 3 -C 6  cycloalkyl, or C 2 -C 6  alkynyl, wherein 
 C 2 -C 6  alkynyl is optionally substituted with hydroxy; 
 R 4  and R 5  are independently hydrogen or C 1 -C 4  alkyl; 
 R 6  is hydrogen or hydroxy; or a pharmaceutically acceptable salt thereof.