Compounds, compositions, and methods

Abstract

Compounds, compositions and methods useful for treating cellular proliferative diseases and disorders, for example, by modulating the activity of KSP, are disclosed.

1 . A compound selected from the group represented by Formula I:  
       
         
           
           
               
               
           
         
       
       where: 
 V is a covalent bond,  
 R 1 , R 2 , R 3  and R 4  are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, halogen or cyano;  
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl;  
 R 6  to R 9  are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted alkylamino, and  
 R 10  is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl,  
 or a pharmaceutically acceptable salt or thereof.  
 
     
     
         2 . The compound of  claim 1  wherein 
 R 1 , R 2 , R 3  and R 4  are independently hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy or cyano.    
     
     
         3 . The compound of  claim 2  wherein 
 R 1 , R 2 , R 3  and R 4  are independently hydrogen, chloro, fluoro, methyl, methoxy, or cyano.    
     
     
         4 . The compound of  claim 2  where R 1 , R 2 , R 3  and R 4  are hydrogen, or three of R 1 , R 2 , R 3  and R 4  are hydrogen and the fourth is halo, methoxy, methyl or cyano.  
     
     
         5 - 10 . (canceled)  
     
     
         11 . A pharmaceutical formulation comprising a pharmaceutically acceptable excipient and an effective amount of a compound of  claim 1 .  
     
     
         12 - 15 . (canceled)  
     
     
         16 . A compound of the group represented by Formula II:  
       
         
           
           
               
               
           
         
       
       where: 
 T is a covalent bond or optionally substituted lower alkylene;  
 V is a covalent bond;  
 W, X, Y and Z are independently N, C, O, S or absent, provided that: no more than one of W, X, Y or Z is absent, no more than two of W, X, Y and Z are —N═, and W, X, Y or Z can be O or S only when one of W, X, Y or Z is absent;  
 R 1 , R 2 , R 3  and R 4  are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, halogen or cyano, provided that R 1 , R 2 , R 3  or R 4  is absent where W, X, Y or Z, respectively, is —N═, O, S or is absent;  
 R 5  is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, and optionally substituted heteroaralkyl;  
 R 6  to R 9  are independently hydrogen, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl or optionally substituted alkylamino, and  
 R 10  is hydrogen, optionally substituted alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroaralkyl,  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         17 . The compound of  claim 16  wherein 
 T is optionally substituted lower alkylene.    
     
     
         18 . The compound of  claim 17  wherein 
 T is methylene.    
     
     
         19 - 23 . (canceled)  
     
     
         24 . The compound of  claim 1  wherein R 5  is aralkyl or substituted aralkyl.  
     
     
         25 . The compound of  claim 24  wherein R 5  is benzyl or substituted benzyl.  
     
     
         26 . The compound of  claim 1  wherein R 6  to R 9  are independently hydrogen or optionally substituted lower alkyl.  
     
     
         27 . The compound of  claim 26  wherein R 6  to R 9  are hydrogen.  
     
     
         28 . The compound of  claim 1  wherein R 10  is optionally substituted benzyl or optionally substituted phenyl.  
     
     
         29 . The compound of  claim 28  wherein R 10  is benzyl or p-methyl-benzyl.  
     
     
         30 . The compound of  claim 16  wherein R 1 , R 2 , R 3  and R 4  are independently selected from hydrogen, halo, lower alkyl, substituted lower alkyl, lower alkoxy, and cyano.  
     
     
         31 . The compound of  claim 30  wherein R 1 , R 2 , R 3  and R 4  are independently selected from hydrogen, chloro, fluoro, methyl, methoxy, and cyano.  
     
     
         32 . The compound of  claim 30  wherein R 1 , R 2 , R 3  and R 4  are hydrogen, or three of R 1 , R 2 , R 3  and R 4  are hydrogen and the fourth is halo, methoxy, methyl or cyano.  
     
     
         33 . The compound of  claim 16  wherein R 5  is aralkyl or substituted aralkyl.  
     
     
         34 . The compound of  claim 33  wherein R 5  is benzyl or substituted benzyl.  
     
     
         35 . The compound of  claim 16  wherein R 6  to R 9  are independently hydrogen or optionally substituted lower alkyl.  
     
     
         36 . The compound of  claim 35  wherein R 6  to R 9  are hydrogen.  
     
     
         37 . The compound of  claim 16  wherein R 10  is optionally substituted benzyl or optionally substituted phenyl.  
     
     
         38 . The compound of  claim 37  wherein R 10  is benzyl or p-methyl-benzyl.