Kinesin inhibitors

Abstract

The present invention provides for compounds, compositions, methods and systems for inhibiting cell growth. More specifically, the present invention provides for methods, compounds and compositions which are capable of inhibiting mitosis in metabolically active cells. Compounds, compositions and methods of the present invention inhibit the activity of a protein involved in the assembly and maintenance of the mitotic spindle. One class of proteins which acts on the mitotic spindle is the family of mitotic kinesins, a subset of the kinesin superfamily.

1 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein R 1-4, 8-10 , as valency and stability permit are each independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, heteroalkyl, OH, OR A , C(═O)R A , CO 2 H, CO 2 R A , CN, halogen, SH, SR A , SOR A , SO 2 R A , NO 2 , NH 2 , NHR A , N(R A ) 2 , hydrogen and NHC(O)R A , wherein each occurrence of R A  as valency and stability permit is independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, and hydrogen, and 
 wherein R 5-7, 11  as valency and stability permit are each independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, heteroalkyl, hydrogen, —(C═O)R B , and —(SO 2 )R B , wherein each occurrence of R B  as valency and stability permit is independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, hydrogen, and —(C═O)R C , wherein R C  as valency and stability permit is selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, and hydrogen.  
 
     
     
         2 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is H, O, halogen, CF 3 , or carbon; and wherein R and R′ as valency and stability permit are each independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, heteroalkyl, hydrogen, —(C═O)R D , and —(SO 2 )R D , wherein each occurrence of R C  as valency and stability permit is independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, hydrogen, and —(C═O)R E , wherein R E  as valency and stability permit is selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, and hydrogen.  
     
     
         3 . (Canceled)  
     
     
         4 . The compound of  claim 1  having the structure:  
       
         
           
           
               
               
           
         
       
       wherein Ar is phenyl, p-hydroxyphenyl, m-hydroxyphenyl, m-methoxyphenyl or m-fluorophenyl and R is as valency and stability permit are each independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, heteroalkyl, hydrogen, —(C═O)R H , and —(SO 2 )R H , wherein each occurrence of R H  as valency and stability permit is independently selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, hydrogen, and —(C═O)R I , wherein R I  as valency and stability permit is selected from the group consisting of substituted or unsubstituted, branched or unbranched alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalkyl, heterocycle, alkoxy, aryloxy, alkylthio, arylthio, heteroaryloxy, heteroarylthio, and hydrogen.  
     
     
         5 . A pharmaceutical composition comprising at least one of the compounds of claims  1 ,  2  or  4  and further comprising a pharmaceutically acceptable carrier.  
     
     
         6 . The composition of  claim 5  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         7 . (Canceled)  
     
     
         8 . (Canceled)  
     
     
         9 . The composition of  claim 6  wherein the compound has the stereochemistry:  
       
         
           
           
               
               
           
         
       
     
     
         10 . A method of treating cancer in a subject comprising administering to a subject in need thereof a therapeutically effective amount of at least one of any of the compounds of claims  1 ,  2  or  4  and a suitable pharmaceutically acceptable carrier.  
     
     
         11 . The method of  claim 10  wherein the compound has the structure:  
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11  wherein the compound has the stereochemistry: