SH2 domain binding inhibitors

Abstract

Disclosed are compounds represented by the formula: or a pharmaceutically acceptable salt or isomer thereof, wherein R 1 -R 6 are as defined in the specification. These compounds are targeted for use as inhibitors of SH2 domain binding with a phosphoprotein, and are contemplated for use in a number of diseases including cancer. Also disclosed are pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable carrier.

1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is C 6 -C 14  aryl heterocyclyl C 1 -C 6  alkyl, whose aryl moiety is substituted with one or more groups selected from the group consisting of C 1 -C 6  alkyl, halo, hydroxy, amino, C 1 -C 6  alkoxy, and hydroxy C 1 -C 6  alkyl; 
 R 2  is carboxy C 1 -C 6  alkyl, carboxy C 1 -C 6  alkylamino, oxalylamino, carboxy C 1 -C 6  alkoxy, dicarboxy C 1 -C 6  alkyl, dicarboxy C 1 -C 6  alkyloxy, dicarboxyhalo C 1 -C 6  alkyl, dicarboxyhalo C 1 -C 6  alkyloxy, RSO 2 NH— wherein R is C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, C 6 -C 14  aryl, C 6 -C 14  aryl C 1 -C 6  alkyl, or trifluoro C 1 -C 6  alkyl, phosphono, phosphono C 1 -C 6  alkyl, phosphonohalo C 1 -C 6  alkyl, C 6 -C 14  aryl C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl, C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl, phosphoryl, phosphoryl C 1 -C 6  alkyl, phosphoryl C 1 -C 6  alkoxy, C 6 -C 14  aryl, or C 6 -C 14  aryl C 1 -C 6  alkyl, wherein the aryl and alkyl moieties may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino C 1 -C 6  alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and keto;  
 R 3  is hydrogen, azido, amino, carboxy C 1 -C 6  alkyl, C 1 -C 6  alkoxycarbonyl C 1 -C 6  alkyl, aminocarbonyl C 1 -C 6  alkyl, or C 1 -C 6  alkylcarbonylamino, wherein the alkyl portion of R 3  may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino C 1 -C 6  alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and keto;  
 R 4  and R 5 , are independently selected from the group consisting of hydrogen, C 1 -C 6  alkyl, C 3 -C 8  cycloalkyl, and heterocyclyl, or R 4  and R 5  together form a C 3 -C 8  cycloalkyl or heterocyclyl; and  
 R 6  is a linker;  
 said heterocyclyl is a 4-7 membered ring comprising at least one hetero atom selected from the group consisting of O, N, and S;  
 or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.  
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is C 6 -C 14  aryl heterocyclyl C 1 -C 6  alkyl, whose aryl moiety is substituted with C 1 -C 6  alkyl.  
     
     
         3 . The compound of  claim 2 , wherein R 1  is a phenyl heterocyclyl C 1 -C 6  alkyl whose aryl moiety is substituted with C 1 -C 6  alkyl.  
     
     
         4 . The compound of  claim 3 , wherein R 1  is a phenyl heterocyclyl methyl whose aryl moiety is substituted with C 1 -C 6  alkyl.  
     
     
         5 . The compound of  claim 4 , wherein R 1  is methyl indolyl methyl.  
     
     
         6 . The compound of  claim 1 , wherein R 2  is carboxy C 1 -C 6  alkyl, oxalylamino, dicarboxy C 1 -C 6  alkyl, RSO 2 NH— wherein R is C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, C 6 -C 14  aryl, C 6 -C 14  aryl C 1 -C 6  alkyl, or trifluoro C 1 -C 6  alkyl, phosphono C 1 -C 6  alkyl, phosphonohalo C 1 -C 6  alkyl, C 6 -C 14  aryl C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl, C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl, C 6 -C 14  aryl, or C 6 -C 14  aryl C 1 -C 6  alkyl, wherein the aryl and alkyl moieties may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino C 1 -C 6  alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and keto.  
     
     
         7 . The compound of  claim 6 , wherein R 2  is carboxy C 1 -C 6  alkyl, oxalylamino, dicarboxy C 1 -C 6  alkyl, RSO 2 NH— wherein R is C 1 -C 6  alkyl, halo C 1 -C 6  alkyl, C 6 -C 14  aryl, C 6 -C 14  aryl C 1 -C 6  alkyl, or trifluoro C 1 -C 6  alkyl, phosphono C 1 -C 6  alkyl, phosphonohalo C 1 -C 6  alkyl, C 6 -C 14  aryl C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl, or C 1 -C 6  alkyl phosphino C 1 -C 6  alkyl.  
     
     
         8 . The compound of  claim 7 , wherein R 2  is carboxy methyl, oxalylamino, dicarboxy methyl, phosphono methyl, benzyl phosphino methyl, or methyl phosphinomethyl.  
     
     
         9 . The compound of  claim 1 , wherein R 3  is carboxy C 1 -C 6  alkyl, wherein the alkyl portion may be optionally substituted with a substituent selected from the group consisting of halo, hydroxy, carboxyl, amino, amino C 1 -C 6  alkyl, C 1 -C 6  alkyl, C 1 -C 6  alkoxy, and keto.  
     
     
         10 . The compound of  claim 9 , wherein R 3  is carboxy C 1 -C 6  alkyl, wherein the alkyl portion may be optionally substituted with hydroxy.  
     
     
         11 . The compound of  claim 10 , wherein R 3  is carboxy methyl or carboxy hydroxymethyl.  
     
     
         12 . The compound of  claim 1 , wherein R 4  and R 5  together form a C 3 -C 8  cycloalkyl.  
     
     
         13 . The compound of  claim 12 , wherein R 4  and R 5  together form cyclohexyl.  
     
     
         14 . The compound of  claim 1 , wherein R 6  is a C 2 -C 4  alkylenyl, C 2 -C 4  alkenylenyl, or C 2 -C 4  alkynylenyl, which may optionally substituted.  
     
     
         15 . The compound of  claim 14 , wherein R 6  is a C 2 -C 4  alkenylenyl.  
     
     
         16 . The compound of  claim 15 , wherein R 6  is C 3  alkenylenyl.  
     
     
         17 . The compound of  claim 1 , which is  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof.  
     
     
         18 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         19 . A method for inhibiting an SH2 domain from binding with a phosphoprotein comprising contacting an SH2 domain with a compound of  claim 1 .  
     
     
         20 . A method for preventing or treating a disease mediated by the binding of an SH2 domain containing protein with a phosphoprotein in a mammal comprising administering to the mammal an effective amount of a compound of  claim 1.