Purine analogs having HSP90-inhibiting activity

Abstract

Novel purine compounds and tautomers and pharmaceutically acceptable salts thereof are described, as are pharmaceutical compositions comprising the same, complexes comprising the same, e.g., HSP90 complexes, and methods of using the same.

1 . A compound of formula 
       
         
           
           
               
               
           
         
         or tautomer or pharmaceutically acceptable salt thereof, 
         wherein A is selected from H, halogen, CN, N 3 , NR 1   2 , NR 1 S(O) 2 R 2 , OR 3 , SR 3 , lower alkyl, C(O)N(R 4 ) 2 , guanidine, amidine, NR 1 NR 1   2 , NR 1 OR 4 , and perhaloalkyl; 
         wherein Q is selected from alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl, and heterocyclic, all optionally substituted; e.g., 
       
       
         
           
           
               
               
           
         
         wherein X is selected from the group S, S(O), and S(O) 2 ; 
         wherein Y is selected from the group consisting of H, C(O)R 2 , S(O) 2 R 2 , C(O)NR 4   2 , and C(O)OR 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl) optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl) optionally substituted heterocyclic alkylaminoalkyl, optionally substituted alkylcarbonylaminoalkyl, (—(CH 2 ) n —C(O)—NR 4 —(CH 2 ) n ), optionally substituted alkylcarbonyloxyalkyl (—(CH 2 ) n —C(O)—O—(CH 2 ) n ), hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R 2 , S(O) 2 R 2 , C(O)NR 4   2 , and C(O)OR 2 ; 
         wherein Y is selected from the group consisting of H, optionally substituted alkyl) optionally substituted alkenyl) optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, alkylaminoalkyl, allylcarbonylaminoalkyl (—(CH 2 ) n —C(O)—NR 4 —(CH 2 ) n ), alkylcarbonyloxyalkyl (—(CH 2 ) n —C(O)—O—(CH 2 ) n ), optionally substituted heterocyclic, hydroxyalkyl, haloalkyl, perhaloalkyl, C(O)R 2 , S(O) 2 R 2 , C(O)NR 4   2 ) and C(O)OR 2 ; 
         wherein Z is selected from the group consisting of H, halogen, CN)OR 3 , SR 3 , 7perhaloalkyl, optionally substituted alkyl) optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted alicyclic, optionally substituted araalkyl, optionally substituted aryloxyalkyl, optionally substituted alkoxyalkyl, optionally substituted heterocyclic C(O)R 2 , S(O) 2 R 2 , guanidine, amidine, and C(O)NR 4   2 ; 
         wherein R 1  is independently selected from H, optionally substituted alkyl) optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R 2 , —C(O)OR 2 , C(O)NR 4   2 , C(S)OR 2 , C(S)NR 2   2 , PO 3 R 4 , SO 2 R 2 ; 
         wherein R 2  is independently selected from alkyl, heteroalkyl, cycloalkyl, heterocyclic, heteroaryl, and aryl, all optionally substituted; 
         wherein R 3  is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4   2 ; 
         wherein R 4  is independently selected from the group consisting of H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, and optionally substituted heterocyclic; 
         wherein R 5  is selected from H, OH, and optionally substituted alkyl; and 
         wherein R 6  is independently selected from H, optionally substituted alkyl, OR 3 , SR 3 , NHR 3 , C(O)NR 4   2 , (O)R 5 , NO 2 , CN, halogen, and S(O) 2 R 2 , and wherein n is from 1 to 3. 
       
     
     
         2 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein A is further selected from the group consisting of H, halogen, NR 1   2 , OR 3 , SR 3 , optionally substituted lower alkyl, and C(O)N(R 4 ) 2 . 
     
     
         3 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein Z is further selected from the group consisting of H, halogen, CN, OR 3 , SR 3 , optionally substituted lower perhaloalkyl, optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, and optionally substituted lower aryl; 
     
     
         4 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein X is further selected from S and S(O) (sulfoxide). 
     
     
         5 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein Y is further selected from the group consisting of optionally substituted lower alkyl, optionally substituted lower alkenyl, optionally substituted lower alkynyl, optionally substituted lower aryl, and optionally substituted lower alicyclic. 
     
     
         6 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein Q is further selected from optionally substituted aryl and optionally substituted heteroaryl. 
     
     
         7 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 1  wherein X is S;
 wherein A is selected from the group consisting of Cl, NH 2 , and CH 3 ;   wherein Z is selected from the group consisting of H, F, Cl, Br and CF 3 ;   wherein Y is selected from the group consisting of optionally substituted C3-C8 alkyl, optionally substituted C3-C8 alkenyl, optionally substituted C3-C8 alkynyl, optionally substituted C1-C10 lower aryl, and optionally substituted C3-C10 alicyclic; and   wherein Q is selected from the group consisting of optionally substituted aryl optionally substituted heterocyclic, and optionally substituted heteroaryl, e.g.,   
       
         
           
           
               
               
           
         
         wherein R 1  is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic, C(O)R2, —C(O)OR2, C(O)NR42, C(S)OR2, C(S)NR42, SO2R2, PO3R4; 
         wherein R 5  is selected from H, OH, and optionally substituted alkyl; 
         wherein R 6  is independently selected from H, optionally substituted alkyl, aryl, OR 3 ; SR 3 , NR 3   2 , C(O)R 5 , NO 2 , CN, and halogen, and 
         wherein R 3  is independently selected from H, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heteroalkyl, optionally substituted aryl, optionally substituted heterocyclic and C(O)NR 4   2 . 
       
     
     
         8 . The compound, tautomer, or pharmaceutically acceptable salt of  claim 7 , wherein A is NH 2 ; Z is selected from H, Cl and F; Y is selected from —(CH 2 ) 2 CH═C(CH 3 ) 2 , —(CH 2 ) 3 CCH, —(CH 2 ) 4 Br, —(CH 2 ) 4 Cl, —(CH 2 ) 4 OAc, —(CH 2 ) 4 NHEt, —(CH 2 ) 4 OH, —(CH 2 ) 5 Br, —(CH 2 ) 5 Cl, —(CH 2 )OAc, —(CH 2 ) 2 —O i Pr, and —(CH 2 ) 5 OH; and Q is selected from 2,5-dimethoxyphenyl, 2-iodo-5-methoxyphenyl, 4-iodo-5-methoxyphenyl, 2-iodo-4-fluoro-5-methoxyphenyl, 2-bromo-5-methoxyphenyl, 2-chloro-5-methoxyphenyl, 2-iodo-4-iodo-5-methoxyphenyl, 2-iodo-4-bromo-5-methoxyphenyl, 2-iodo-4-chloro-5-methoxyphenyl, and 2-chloro-3,4,5-trimethoxyphenyl. 
     
     
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         19 . A pharmaceutical composition comprising the compound, tautomer, or pharmaceutically acceptable salt of  claim 1  and one or more pharmaceutical carriers or excipients. 
     
     
         20 . A method of inhibiting an HSP90, comprising:
 contacting a cell having an HSP90 with a compound, tautomer or pharmaceutically acceptable salt or pharmaceutical composition according to  claim 1 .   
     
     
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         50 . A complex comprising the compound, tautomer, or pharmaceutically acceptable salt of  claim 1  and at least one other compound. 
     
     
         51 . The complex of  claim 50  wherein one of said at least one other compound is an HSP90. 
     
     
         52 . The complex of  claim 51  wherein said HSP90 is human. 
     
     
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