Certain chemical entities, compositions, and methods

Abstract

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.

What is claimed is: 
     
         1 . At least one chemical entity chosen from compounds of Formula I 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein
 Z is chosen from OR 9  and NR 10 R 11 ; where 
 R 9  is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 10  is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 11  is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 or R 10  and R 11  may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring. 
 
     
     
         2 . At least one chemical entity of  claim 1  wherein Z is OR 9 . 
     
     
         3 . At least one chemical entity of  claim 2  wherein R 9  is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 
     
     
         4 . At least one chemical entity of  claim 1  wherein Z is NR 10 R 11 . 
     
     
         5 . At least one chemical entity of  claim 4  wherein R 10  is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl, and R 11  is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl. 
     
     
         6 . At least one chemical entity of  claim 5  wherein R 10  is hydrogen and R 11  is chosen from optionally substituted alkyl. 
     
     
         7 . At least one chemical entity of  claim 4  wherein R 10  and R 11  are joined together to form a 5- to 7-membered heterocycloalkyl ring. 
     
     
         8 . At least one chemical entity chosen from compounds I-a-I-f and pharmaceutically acceptable salts thereof. 
     
     
         9 . At least one chemical entity chosen from compounds of Formula II 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein
 R 1  and R 2  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 1  and R 2  may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; 
 for each occurrence, R 3  and R 4  are independently chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; or R 3  and R 4  may optionally be joined together with any intervening atoms to form an optionally substituted cycloalkyl ring or optionally substituted heterocycloalkyl ring; 
 or R 1  and one occurrence of R 3  may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring; and 
 n is selected from 1, 2, 3, 4, 5 and 6. 
 
     
     
         10 . At least one chemical entity of  claim 9  wherein R 1  and R 2  are each independently chosen from hydrogen and optionally substituted lower alkyl. 
     
     
         11 . At least one chemical entity of  claim 10  wherein R 1  and R 2  are both hydrogen. 
     
     
         12 . At least one chemical entity of  claim 9  wherein R 1  and R 2  are joined together to form a 5- to 7-membered heterocycloalkyl ring. 
     
     
         13 . At least one chemical entity of any one of  claims 9  to  12  wherein R 3  and R 4  are each independently chosen from hydrogen and optionally substituted lower alkyl. 
     
     
         14 . At least one chemical entity of any one of  claims 9  to  13  wherein n is chosen from 1, 2, and 3. 
     
     
         15 . At least one chemical entity of  claim 9  wherein n is 1, and R 1  and R 3  are joined together to form a 5- to 7-membered heterocycloalkyl ring. 
     
     
         16 . At least one chemical entity chosen from compounds II-a-II-h and pharmaceutically acceptable salts thereof. 
     
     
         17 . At least one chemical entity chosen from compounds of Formula III 
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof, wherein
 R 5  is chosen from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 6  is chosen from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted alkoxycarbonyl, and —P(═O)(OR 7 )(OR 8 ), where R 7  and R 8  are independently chosen from hydrogen and optionally substituted alkyl. 
 
     
     
         18 . At least one chemical entity of  claim 17  wherein R 5  is chosen from hydrogen and optionally substituted lower alkyl. 
     
     
         19 . At least one chemical entity of  claim 18  wherein R 5  is chosen from hydrogen and methyl. 
     
     
         20 . At least one chemical entity of any one of  claims 17  to  19  wherein R 6  is chosen from optionally substituted alkyl. 
     
     
         21 . At least one chemical entity of any one of  claims 17  to  19  wherein R 6  is chosen from optionally substituted acyl. 
     
     
         22 . At least one chemical entity of  claim 21  wherein R 6  is chosen from acetyl, propionyl, isobutyryl, and pivaloyl. 
     
     
         23 . At least one chemical entity of any one of  claims 17  to  19  wherein R 6  is chosen from optionally substituted alkoxycarbonyl. 
     
     
         24 . At least one chemical entity of  claim 23  wherein R 6  is chosen from optionally substituted methoxycarbonyl, ethoxycarbonyl, and isopropoxycarbonyl, 
     
     
         25 . At least one chemical entity of any one of  claims 17  to  19  wherein R 6  is chosen from —P(═O)(OR 7 )(OR), where R 7  and R 8  are independently chosen from hydrogen and optionally substituted alkyl. 
     
     
         26 . At least one chemical entity of  claim 25  wherein R 6  is —P(═O)(OH)(OH). 
     
     
         27 . At least one chemical entity chosen from compounds III-a-III-f and pharmaceutically acceptable salts thereof. 
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one chemical entity of any one of  claims 1  to  27 . 
     
     
         29 . A pharmaceutical composition of  claim 28  wherein the composition is formulated in a form chosen from tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols. 
     
     
         30 . A packaged pharmaceutical composition comprising a pharmaceutical composition of  claim 28  or  29  and instructions for using the composition to treat a subject suffering from cancer. 
     
     
         31 . A method of treating cancer in a subject which comprises administering to a subject in need thereof a therapeutically effective amount of at least one chemical entity of any one of  claims 1  to  27 .