Compounds for treating proliferative disorders

Abstract

Disclosed are compounds and methods of using compounds of the invention for treating a subject with a proliferative disorder, such as cancer, and methods for treating disorders responsive to Hsp70 induction and/or natural killer induction. Also, disclosed are pharmaceutical compositions comprising compounds of the invention and a pharmaceutically acceptable carrier.

What is claimed is: 
     
         1 . A compound represented by formula (VI): 
       
         
           
           
               
               
           
         
         or a tautomer or pharmaceutically acceptable salt-thereof, wherein: 
         X 7  and X 8  are —N(R 5 )— and X 9  and X 10  are each independently an optionally substituted C1-C2 alkylene group, or X 7  and X 8  are each independently an optionally substituted C1-C2 alkylene group and X 9  and X 10  are —N(R 5 )—, provided that the C1-C2 alkylene group is not substituted with ═O or ═S; 
         Z 1 , Z 2 , Z 3 , and Z 4  are each independently O or S, provided that either Z 1  and Z 2  are both S or Z 3  and Z 4  are both S; 
         R 1  and R 2  are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, halo, nitro, cyano, guanidino, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 , provided that when either Z 3  or Z 4  is S and X 7  and X 8  are —C(R 5 ) 2 C(R 5 ) 2 —, then R 1  or R 2  is not —OR 17 , and provided that when R 13  is a covalent bond, then one of R 1  or R 2  is not —SMe or —NR 19 R 20 ; 
         each R 5  is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         R 13  is a covalent bond, or a substituted or unsubstituted C1-C6 alkylene group; 
         R 17  and R 18 , for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; 
         R 19  and R 20 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R 19  and R 20 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; and 
         p is 1 or 2. 
       
     
     
         2 . The compound of  claim 1 , wherein X 9  and X 10  are each an optionally substituted ethylene group. 
     
     
         3 . The compound of  claim 1 , wherein X 7  and X 8  are each an optionally substituted ethylene group. 
     
     
         4 . The compound of  claim 1 , wherein the compound is represented by formula (VII): 
       
         
           
           
               
               
           
         
         or a tautomer or pharmaceutically acceptable salt thereof, wherein: 
         R 3  and R 4  are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; and 
         R 6  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl. 
       
     
     
         5 . The compound of  claim 4 , wherein:
 R 1  and R 2  are each an optionally substituted aryl or an optionally substituted heteroaryl;   R 5  is —H and R 6  is —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl; and   R 3  and R 4  are each an alkyl group.   
     
     
         6 . The compound of  claim 4 , wherein
 R 1  and R 2  are both an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl;   R 5  is —H; and   R 6  is —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl.   
     
     
         7 . The compound of  claim 4 , wherein
 R 13  is —C(R 7 )(R 8 )—;   R 7  and R 8  are each independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, or R 7  is —H and R 8  is an optionally substituted aryl or an optionally substituted heteroaryl.   
     
     
         8 . A compound represented by formula (XIX): 
       
         
           
           
               
               
           
         
         (XIX) 
         or a tautomer or pharmaceutically acceptable salt thereof, wherein: 
         Z 1 , Z 2 , Z 3 , and Z 4  are each independently O or S; 
         R 3  and R 4  are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; 
         R 13  is a covalent bond, or a substituted or unsubstituted C1-C6 alkylene group; and 
         R 40  and R 41  are each independently a substituted or unsubstituted C1-C4 alkylene group. 
       
     
     
         9 . The compound of  claim 8 , wherein R 3  and R 4  are each an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl. 
     
     
         10 . The compound of  claim 8 , wherein
 R 13  is —C(R 7 )(R 8 )—;   R 7  and R 8  are each independently —H or an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, or R 7  is —H and R 8  is an optionally substituted aryl or an optionally substituted heteroaryl.   
     
     
         11 . A compound represented by formula (XXV): 
       
         
           
           
               
               
           
         
         or a tautomer or pharmaceutically acceptable salt thereof, wherein: 
         Z 1 , Z 2 , Z 3 , and Z 4  are each independently O or S, provided that either Z 1  and Z 2  are both S or Z 3  and Z 4  are both S; 
         X 13  and X 14  are each independently an optionally substituted C2-C3 alkylene group; 
         R 1  and R 2  are independently an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, halo, nitro, cyano, guanidino, —OR 17 , —NR 19 R 20 , —C(O)R 17 , —C(O)OR 17 , —OC(O)R 17 , —C(O)NR 19 R 20 , —NR 18 C(O)R 17 , —OP(O)(OR 17 ) 2 , —SP(O)(OR 17 ) 2 , —SR 17 , —S(O) p R 17 , —OS(O) p R 17 , —S(O) p OR 17 , —NR 18 S(O) p R 17 , or —S(O) p NR 19 R 20 ; 
         R 17  and R 18 , for each occurrence, are, independently, —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; 
         R 19  and R 20 , for each occurrence, are independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteroaralkyl; or R 19  and R 20 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 
         R 31  is independently —H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl or an optionally substituted heteroaryl; and 
         p is 1 or 2. 
       
     
     
         12 . The compound of  claim 11 , wherein R 31  is —H, an optionally substituted alkyl, or an optionally substituted phenyl. 
     
     
         13 . The compound of  claim 11 , wherein X 13  and X 14  are each an optionally substituted C2 alkylene group. 
     
     
         14 . The compound of  claim 11 , wherein X 13  and X 14  are each an optionally substituted C3 alkylene group. 
     
     
         15 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 1 . 
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 8 . 
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier or diluent and a compound of  claim 11 . 
     
     
         18 . A method of treating a subject with a cancer, said method comprising administering to the subject an effective amount of a compound of  claim 1 . 
     
     
         19 . A method of treating a subject with a cancer, said method comprising administering to the subject an effective amount of a compound of  claim 8 . 
     
     
         20 . A method of treating a subject with a cancer, said method comprising administering to the subject an effective amount of a compound of  claim 11 .