Imidazole compounds that modulate hsp90 activity

Abstract

Compounds of formula (I), pharmaceutical compositions comprising compounds of formula (I) and methods of inhibiting Hsp90 in a cell, treating or preventing a proliferation disorder in a mammal and treating cancer in a mammal comprising administering a compound of formula (I) to a patient or a cell. Variable R 5 is an optionally substituted heteroaryl; an optionally substituted 6 to 14-membered aryl; a bicyclic 9-member heterocycle optionally substituted at any substitutable nitrogen or carbon atoms; or a substituent R 18 , defined herein. Ring A is an aryl or a heteroaryl optionally further substituted with one or more substituents in addition to R 3 . Substituent R 3 is defined herein.

1 - 79 . (canceled) 
     
     
         80 . A method of treating breast cancer or lung cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, solvate, or a prodrug thereof, wherein:
 R 1 , R 3  and R 25  are each, independently, —SH or —OH; 
 R 6  is cyclopropyl or isopropyl; 
 R 10  and R 11  are each, independently, selected from hydrogen, methyl, ethyl, propyl and isopropyl, or taken together with the nitrogen to which they are attached, form a ring selected from: 
 
       
       
         
           
           
               
               
           
         
         R 30 , for each occurrence, is 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, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanidino, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 8 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 8 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR 8 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 8 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 8 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —SR 7 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) P OR 7 , —OS(O) P NR 10 R 11 , —S(O) P OR 7 , —NR 8 S(O) P R 7 , —NR 7 S(O) P NR 10 R 11 , —NR 7 S(O) P R 7 , —S(O) P NR 10 R 11 , —SS(O) P R 7 , —SS(O) P OR 7 , —SS(O) P NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; 
         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 heteroaralkyl; 
         R 35  is —H, a C1-C4 alkyl or a C1-C4 acyl; and 
         p, for each occurrence, is independently, 0, 1 or 2. 
       
     
     
         81 . A method of treating breast cancer or lung cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
       
       or a tautomer, pharmaceutically acceptable salt, solvate, or a prodrug thereof, wherein:
 R 1 , R 3  or R 25  are each, independently, selected from —OH, —SH, —NHR 7 , —OC(O)NR 10 R 11 , —SC(O)NR 10 R 11 , —OC(O)R 7 , —SC(O)R 7 , —OC(O)OR 7 , —SC(O)OR 7 , —OS(O) P R 7 , —S(O) P OR 7 , —SS(O) P R 7 , —OS(O) P OR 7 , —SS(O) P OR 7 , —OC(S)R 7 , —SC(S)R 7 , —OC(S)OR 7 , —SC(S)OR 7 , —OC(S)NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —OC(NR 8 )OR 7 , —SC(NR 8 )OR 7 , —OP(O)(OR 7 ) 2  or —SP(O)(OR 7 ) 2 ; 
 R 6  is a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkylsulfanyl or a C3-C6 cycloalkyl; 
 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 heteroaralkyl; 
 R 10  and R 11  are each, independently, hydrogen, a C1-C6 straight or branched alkyl, optionally substituted by —OH, —CN, —SH, amino, a C1-C6 alkoxy, alkylsulfanyl, alkylamino, dialkylamino or a cycloalkyl; or R 10  and R 11 , taken together with the nitrogen to which they are attached, form a substituted or unsubstituted non-aromatic nitrogen-containing heterocyclyl; 
 R 30 , for each occurrence, is 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, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanidino, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 8 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 8 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , OC(NR 8 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 8 )OR 7 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 8 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 8 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —SR 7 , —S(O) P R 7 , —OS(O) P R 7 , —OS(O) P OR 7 , —OS(O) P NR 10 R 11 , —S(O) P OR 7 , —NR 8 S(O) P R 7 , —NR 7 S(O) P NR 10 R 11 —NR 7 S(O) P OR 7 , —S(O) P NR 10 R 11 , —SS(O) P R 7 , —SS(O) P OR 7 , —SS(O) P NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; and 
 p, for each occurrence, is independently, 0, 1 or 2. 
 
     
     
         82 . The method of  claim 81 , wherein:
 R 1  and R 3  are each, independently, —OH, —SH, or —NHR 7 ; and   R 30  is —OH, —SH, halogen, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy or C1-C6 alkylsulfanyl.   
     
     
         83 . The method of  claim 81 , wherein the compound is selected from any one of the following structural formulas: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . A method of treating breast cancer or lung cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, solvate, or a prodrug thereof, wherein:
 R 1  is —SH or —OH; 
 R 2  is an optionally substituted phenyl group; 
 R 3  and R 25  are each —OH; 
 R 6  is an optionally substituted alkyl or cycloalkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, alkoxy, haloalkoxy, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR 7 , —SR 7 , —NR 10 R 11 , —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 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —C(O)SR 7 , —C(S)R 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(S)SR 7 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —S(O) p OR 7 , —S(O) p NR 10 R 11  or S(O) p R 7 ; 
 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 heteroaralkyl; 
 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 heteroaralkyl; 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; and 
 p, for each occurrence, is independently, 0, 1 or 2. 
 
       
     
     
         85 . The method of  claim 84 , wherein the compound is selected from any one of the following structural formulas: 
       
         
           
           
               
               
           
         
       
     
     
         86 . A method of treating breast cancer or lung cancer in a subject, comprising administering to the subject an effective amount of a compound represented by the following structural formula: 
       
         
           
           
               
               
           
         
         or a tautomer, pharmaceutically acceptable salt, solvate, or a prodrug thereof, wherein:
 R 1  and R 3  are each, independently, —SH or OH; 
 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 heteroaralkyl; 
 R 10  and R 11  are each, independently, selected from hydrogen, methyl, ethyl, propyl, isopropyl; or taken together with the nitrogen to which they are attached, form a ring selected from: 
 
       
       
         
           
           
               
               
           
         
         
           
             R 35  is —H, a C1-C4 alkyl or a C1-C4 acyl; 
           
           X 3  and X 4  are each, independently, N, N(O), N + (R 17 ), CH or CR 6 ; 
           X 5  is O, S, NR 17 , CH 2 , CH(R 6 ), C(R 6 ) 2 , CH═CH, CH═CR 6 , CR 6 ═CH, CR 6 ═CR 6 , CH═N, CR 6 ═N, CH═N(O), CR 6 ═N(O), N═CH, N═CR 6 , N(O)═CH, N(O)═CR 6 , N + (R 17 )═CH, N + (R 17 )═CR 6 , CH═N + (R 17 ), CR 6 ═N + (R 17 ), or N═N, provided that at least one of X 3 , X 4  or X 5  is a heteroatom; 
           R 6  is cyclopropyl or isopropyl; 
           R 17 , for each occurrence, is independently an alkyl or an aralkyl; 
           R 30  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, an optionally substituted heteroaralkyl, halo, cyano, nitro, guanidino, haloalkyl, heteroalkyl, alkoxy, haloalkoxy, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , —C(S)R 7 , —C(O)SR 7 , —C(S)SR 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —OC(O)R 7 , —OC(O)OR 7 , —OC(S)OR 7 , —OC(NR 8 )OR 7 , —SC(O)R 7 , —SC(O)OR 7 , —SC(NR 8 )OR 7 , —OC(S)R 7 , —SC(S)R 7 , —SC(S)OR 7 , —OC(O)NR 10 R 11 , —OC(S)NR 10 R 11 , —OC(NR 8 )NR 10 R 11 , —SC(O)NR 10 R 11 , —SC(NR 8 )NR 10 R 11 , —SC(S)NR 10 R 11 , —OC(NR 8 )R 7 , —SC(NR 8 )R 7 , —C(O)NR 10 R 11 , —NR 8 C(O)R 7 , —NR 7 C(S)R 7 , —NR 7 C(S)OR 7 , —NR 7 C(NR 8 )R 7 , —NR 7 C(O)OR 7 , —NR 7 C(NR 8 )OR 7 , —NR 7 C(O)NR 10 R 11 , —NR 7 C(S)NR 10 R 11 , —NR 7 C(NR 8 )NR 10 R 11 , —SR 7 , —S(O) p R 7 , —OS(O) p R 7 , —OS(O) p OR 7 , —OS(O) p NR 10 R 11 , —S(O) p OR 7 , —NR 8 S(O) p R 7 , —NR 7 S(O) p NR 10 R 11 , —NR 7 S(O) p OR 7 , —S(O) p NR 10 R 11 , —SS(O) p R 7 , —SS(O) p OR 7 , —SS(O) p NR 10 R 11 , —OP(O)(OR 7 ) 2 , or —SP(O)(OR 7 ) 2 ; and 
           p, for each occurrence, is independently, 0, 1 or 2. 
         
       
     
     
         87 . The method of  claim 86 , wherein R 30  is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteroaralkyl, —OR 7 , —SR 7 , —NR 10 R 11 , —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 , —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 , —C(O)R 7 , —C(O)OR 7 , —C(O)NR 10 R 11 , —C(O)SR 7 , —C(S)R 7 , —C(S)OR 7 , —C(S)NR 10 R 11 , —C(S)SR 7 , —C(NR 8 )OR 7 , —C(NR 8 )R 7 , —C(NR 8 )NR 10 R 11 , —C(NR 8 )SR 7 , —S(O) p OR 7 , —S(O) p NR 10 R 11 , or —S(O) p R 7 . 
     
     
         88 . The method of  claim 87 , wherein the compound is selected from any one of the following structural formulas: