Triazinone and diazinone derivatives useful as hsp90 inhibitors

Abstract

The present invention relates to compounds according to formulae (IA) to (ID) and compositions that inhibit the activity of Hsp90. The invention further relates to methods of inhibiting the activity of Hsp90 in a subject in need thereof and methods for preventing or treating hyperproliferative disorders, such as cancer, in a subject in need thereof comprising administering to the subject a compound of the invention, or a composition comprising such a compound.

What is claimed is: 
     
         1 . A compound represented by a structural formula selected from: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, or a prodrug thereof, wherein: 
         R 2  and R 3  are each independently —NR 7 H, —OR 7 , —SR 7 , —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O) p R 7 , —SS(O) p R 7 , —S(O) p OR 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O) p OR 7 , —SS(O) p OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; 
         R 4  is 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 heteraralkyl; 
         R 7  and R 8 , 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 heteraralkyl; 
         R 10  and R 11 , 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 heteraralkyl; or R 10  and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 
         R 14  and R 15 , for each occurrence, are independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , —C(O)OR 7 , 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 heteraralkyl; or R 14  and R 15  taken together form an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloakyl, or an optionally substituted cycloalkenyl; 
         p, for each occurrence, is independently, 1 or 2; 
         m for each occurrence, is independently 1, 2, 3, or 4; and 
         provided that when R 14  is —C(O)OEt, R 15  is methyl, and R 3  is —OMe or —OEt, then R 2  is not —OMe, —OEt or —O(optionally substituted heterocycle). 
       
     
     
         2 . The compound of  claim 1 , wherein R 2  and R 3  are each independently —OH, —SH, or —NHR 7 . 
     
     
         3 . The compound of  claim 1 , wherein R 4  is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. 
     
     
         4 . The compound of  claim 1 , wherein R 14  and R 15 , for each occurrence, are independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , —C(O)OR 7 , 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 heteraralkyl. 
     
     
         5 . The compound of  claim 4 , wherein R 14  is independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , or —C(O)OR 7 . 
     
     
         6 . The compound of  claim 5 , wherein, R 15 , is —H or lower alkyl. 
     
     
         7 . The compound of  claim 1 , wherein
 R 2  and R 3  are each independently —OH or —SH;   R 4  is a C1-C6 alkyl or a C3-C6 cycloalkyl;   R 14  is independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , or —C(O)OR 7 ; and R 15 , is —H or lower alkyl.   
     
     
         8 . The compound of  claim 1 , wherein R 14  and R 15  taken together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. 
     
     
         9 . The compound of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound of  claim 9 , wherein
 R 2  and R 3  are each independently —OH or —SH; and   R 4  is a C1-C6 alkyl or a C3-C6 cycloalkyl.   
     
     
         11 . The compound of  claim 10 , wherein R 7  and R 8 , for each occurrence, are independently, —H or lower alkyl. 
     
     
         12 . A compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, or a prodrug thereof, wherein: 
         R 2  and R 3  are each independently —NR 7 H, —OR 7 , —SR 7 , —O(CH 2 ) m OH, —O(CH 2 ) m SH, —O(CH 2 ) m NR 7 H, —S(CH 2 ) m OH, —S(CH 2 ) m SH, —S(CH 2 ) m NR 7 H, —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —NR 7 C(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —NR 7 C(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —NR 7 C(O)OR 7 , —OCH 2 C(O)R 7 , —SCH 2 C(O)R 7 , —NR 7 CH 2 C(O)R 7 , —OCH 2 C(O)OR 7 , —SCH 2 C(O)OR 7 , —NR 7 CH 2 C(O)OR 7 , —OCH 2 C(O)NR 10 R 11 , —SCH 2 C(O)NR 10 R 11 , —NR 7 CH 2 C(O)NR 10 R 11 , —OS(O) p R 7 , —SS(O) p R 7 , —S(O) p OR 7 , —NR 7 S(O) p R 7 , —OS(O) p NR 10 R 11 , —SS(O) p NR 10 R 11 , —NR 7 S(O) p NR 10 R 11 , —OS(O) p OR 7 , —SS(O) p OR 7 , —NR 7 S(O) p OR 7 , —OC(S)R 7 , —SC(S)R 7 , —NR 7 C(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —NR 7 C(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —NR 7 C(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —NR 7 C(NR 8 )OR 7 , —OC(NR 8 )NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; 
         R 4  is 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 heteraralkyl; 
         R 7  and R 8 , 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 heteraralkyl; 
         R 10  and R 11 , 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 heteraralkyl; or R 10  and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl or an optionally substituted heteroaryl; 
         R 14  and R 15 , for each occurrence, are independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , —C(O)OR 7 , 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 heteraralkyl; or R 14  and R 15  taken together form an optionally substituted heterocyclyl, an optionally substituted heteroaryl, an optionally substituted aryl, an optionally substituted cycloakyl, or an optionally substituted cycloalkenyl; 
         p, for each occurrence, is independently, 1 or 2; 
         m for each occurrence, is independently 1, 2, 3, or 4; and 
         provided that when R 15  is —H or methyl, R 3  is —OH or —OAc, and R 2  is —OH or —OMe, then R 4  is not ethyl, n-propyl, or n-hexyl; and 
         provided that when R 14  is —H, R 3  is —OH, and R 2  is cyclopropylmethoxy, then R 4  is not ethyl. 
       
     
     
         13 . The compound of  claim 12 , wherein R 2  and R 3  are each independently —OH, —SH, or —NHR 7 . 
     
     
         14 . The compound of  claim 12 , wherein R 4  is a C1-C6 alkyl, a C1-C6 haloalkyl, a C1-C6 alkoxy, a C1-C6 haloalkoxy, a C1-C6 alkyl sulfanyl or a C3-C6 cycloalkyl. 
     
     
         15 . The compound of  claim 12 , wherein R 14  and R 15 , for each occurrence, are independently —H, —C(O)R 7 , —C(O)NR 10 R 11 , —C(O)OR 7 , 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 heteraralkyl. 
     
     
         16 . The compound of  claim 12 , wherein R 14  and R 15  taken together form an optionally substituted heterocyclyl or an optionally substituted heteroaryl. 
     
     
         17 . A pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a compound of  claims 1 .