Novel HSP90 Inhibitor

Abstract

Disclosed is a triazole derivative(s) represented by the general formula (1) below or a pharmacologically acceptable salt(s) thereof. Also disclosed are a prodrug(s) of such a triazole derivative(s) and an HSP90 inhibitor(s) containing any one of them as an active constituent. (1) (In the formula, X represents a halogen atom, an optionally substituted alkyl group, an optionally substituted alkynyl group or the like; Y represents a mercapto group, a hydroxyl group, an optionally substituted sulfonyl group, an optionally substituted amino group or the like; and R represents an optionally substituted aryl or alkyl group or the like.)

1 . A compound represented by the following structural formula (1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or a prodrug thereof, wherein: 
         R is an optionally substituted heterocyclic aryl or an optionally substituted carbocyclic aryl group; 
         R 1  and R 2  are —H, an acyl group, a carbamoyl group, an alkoxycarbonyl group, or an alkoxymethyl group; 
         X is an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted alkynyl group, cyano group, halogen atom, nitro group, an optionally substituted cyclic alkyl group, an optionally substituted carbocyclic aryl group, an optionally substituted heterocyclic aryl group, hydroxyl group, an optionally substituted alkoxyl group, an optionally substituted aryloxy group, mercapto group, an optionally substituted alkylthio group, an optionally substituted arylthio group, an optionally substituted amino group, an optionally substituted carbamoyloxy group, an optionally substituted ureido group, an optionally substituted acyloxy group, an optionally substituted acylamino group, an optionally substituted alkoxycarbonyloxy group, an optionally substituted alkoxycarbonylamino group, an optionally substituted sulfonylamino group, an optionally substituted sulfamoylamino group, an optionally substituted acyl group, an optionally substituted carboxyl group, an optionally substituted alkoxycarbonyl group, an optionally substituted carbamoyl group, an optionally substituted sulfamoyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group, an optionally substituted alkylsulfinyl group, or an optionally substituted arylsulfinyl group; and 
         Y is —OH, —SH, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, or an optionally substituted carbamoyloxy group; provided that when Y is —OH or —SH at least one of R 1  and R 2  is not hydrogen. 
       
     
     
         2 . The compound of  claim 1 , wherein the compound is not
 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2-Hydroxy-4-ethoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-hydroxy-[1,2,4]triazole;   3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5-hydroxy-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(naphthalin-2-yl)-5-hydroxy-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-chloro-phenyl]-4-(quinolin-5-yl)-5-mercapto-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro-phenyl)-5-mercapto-[1,2,4]triazole; or   3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-benzo-imidazol-4-yl)-5-hydroxy-[1,2,4]triazole.   
     
     
         3 . The compound of  claim 1 , wherein when Y is —OH or —SH, R 1  and R 2  are selected from the group consisting of an acyl group, a carbamoyl group, an alkoxycarbonyl group, and an alkoxymethyl group. 
     
     
         4 . The compound of  claim 1 , wherein R 1  and R 2  are the same. 
     
     
         5 . The compound of  claim 1 , wherein R is an optionally substituted carbocyclic aryl group. 
     
     
         6 . The compound of  claim 1 , wherein R is an optionally substituted heterocyclic aryl group. 
     
     
         7 . The compound of  claim 1 , wherein R has the following general formula: 
       
         
           
           
               
               
           
         
         m is an integer from 0 to 5; and 
         A is an optionally substituted cyclic or non-cyclic amino group, an optionally substituted cyclic or non-cyclic acylamino group, or an optionally substituted cyclic or non-cyclic sulfonylamino group. 
       
     
     
         8 . The compound of  claim 1 , wherein R has the following general formula: 
       
         
           
           
               
               
           
         
         m is an integer from 0 to 5; and 
         A is an optionally substituted cyclic or non-cyclic amino group, an acylamino group, or a sulfonylamino group. 
       
     
     
         9 . The compound of  claim 1 , wherein X is an optionally substituted C 1-8  alkyl group, an optionally substituted C 1-8  alkoxyl group, or an optionally substituted C 1-8  alkylthio group. 
     
     
         10 . The compound of  claim 1 , wherein Y is an acyloxy group, an alkoxycarbonyloxy group, or a carbamoyloxy group. 
     
     
         11 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier and   a compound according to  claim 1 .   
     
     
         12 . A compound represented by the following structural formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, or a prodrug thereof, wherein: 
         R is an optionally substituted heteroaryl or an optionally substituted aryl; 
         X is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, cyano, halo, nitro, an optionally substituted cycloalkyl, haloalkyl, 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   a R 11   a , —NR 7 C(O)NR 10   a R 11   a , OC(O)R 7   a , NR 7   b C(O)R 7   b′ , —OC(O)OR 7   c , —NR 7   b C(O)OR 7   b′ , —OCH 2 C(O)NH 2 , SCH 2 C(O)NH 2 , NR 7   b S(O) 2 R 7   b′ , —NR 7   b S(O) 2 NR 10   a R 11   a , —C(O)R 7   d , —C(O)OH, —C(O)OR 7   e , —C(O)NR 10   a R 11   a , —S(O) 2 NR 10   a R 11   a , or —S(O) p R 7   f ; 
         R 1  and R 2  are —H, an acyl group, a carbamoyl group, an alkoxycarbonyl group, or an alkoxymethyl group; 
         R 7  is —H, an optionally substituted alkyl, alkenyl, alkynyl, an optionally substituted cycloalkyl, cycloalkenyl, an optionally substituted aryl, heteroaryl, an aralkyl, or an heteraralkyl; 
         R 7   a  is an optionally substituted alkyl, alkenyl, alkynyl, an optionally substituted cycloalkyl, cycloalkenyl, aryl, an aralkyl, or a heteraralkyl; 
         R 7   b  is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl; 
         R 7   b′  is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or heteraralkyl; 
         R 7   c  is an optionally substituted alkyl, alkenyl, alkynyl, an optionally substituted cycloalkyl, cycloalkenyl, an aralkyl, or a heteraralkyl; 
         R 7   d  is alkyl, aryl, or heteroaryl; 
         R 7   e  is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, an aralkyl, or a heteraralkyl; 
         R 7   f  is an optionally substituted alkyl, alkenyl, alkynyl, an optionally substituted cycloalkyl, cycloalkenyl, an optionally substituted aryl, heteroaryl, an aralkyl, or a heteraralkyl; 
         R 10  and R 11 , for each occurrence, is independently —H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl; or R 10  and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl; 
         R 10   a  and R 11   a , for each occurrence, is independently —H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heteroaryl; 
         Y is —OH, —SH, an optionally substituted acyloxy group, an optionally substituted alkoxycarbonyloxy group, or an optionally substituted carbamoyloxy group; provided that when Y is —OH or —SH at least one of R 1  and R 2  is not hydrogen; and 
         p, for each occurrence, is independently 1 or 2. 
       
     
     
         13 . The compound of  claim 12 , wherein the compound is not
 3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(3-trifluoromethyl-phenyl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2,4-Dihydroxy-5-ethyl-phenyl)-4-(1-methyl-indol-4-yl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2,4-Dihydroxy-5-methoxy-phenyl)-4-(8-methoxy-quinolin-5-yl)-5-carbamoyloxy-[1,2,4]triazole;   3-(2-Hydroxy-4-ethoxycarbonyoxy-5-methoxy-phenyl)-4-(1-isopropyl-benzoimidazol-4-yl)-5-hydroxy-[1,2,4]triazole;   3-(2-Hydroxy-4-ethoxycarbonyoxy-5-ethyl-phenyl)-4-(naphthalin-2-yl)-5-hydroxy-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(naphthalin-2-yl)-5-hydroxy-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-chloro-phenyl]-4-(quinolin-5-yl)-5-mercapto-[1,2,4]triazole;   3-[2-Hydroxy-4-(dimethyl-carbamoyoxy)-5-ethyl-phenyl]-4-(2,3-difluoro-phenyl)-5-mercapto-[1,2,4]triazole; or   3-[2-Hydroxy-4-isobutyryloxy-5-ethyl-phenyl]-4-(1-methyl-benzo-imidazol-4-yl)-5-hydroxy-[1,2,4]triazole.   
     
     
         14 . The compound of  claim 12 , wherein when Y is —OH or —SH, R 1  and R 2  are selected from the group consisting of an acyl group, a carbamoyl group, an alkoxycarbonyl group, and an alkoxymethyl group. 
     
     
         15 . The compound of  claim 12 , wherein R 1  and R 2  are the same. 
     
     
         16 . The compound of  claim 12 , wherein X is —OR 7  or —SR 7  with R 7  being pyridyl. 
     
     
         17 . The compound of  claim 12 , wherein X is OC(O)R 7   a  with R 7   a  being phenyl. 
     
     
         18 . The compound of  claim 12 , wherein X is C(O)R 7   d  with R 7   d  being methyl, ethyl, tert-butyl, phenyl, or pyridyl. 
     
     
         19 . The compound of  claim 12 , wherein X is S(O) p R 7   f  with R 7   f  being pyridyl. 
     
     
         20 . The compound of  claim 12 , wherein X is morpholino group, piperidinyl group, or 4-methylpiperazine-1-yl group. 
     
     
         21 . The compound of  claim 12 , wherein X is —OR 7  or —SR 7  with R 7  being alkyl substituted with an acyl group or an alkoxycarbonyl group. 
     
     
         22 . The compound of  claim 12 , wherein R 10  and R 11 , taken together with the nitrogen to which they are attached, form an optionally substituted heterocyclyl selected from the group consisting of morpholino, piperidinyl, and 4-methylpiperazine-1-yl. 
     
     
         23 . The compound of  claim 12 , wherein R is an optionally substituted naphthyl group. 
     
     
         24 . The compound of  claim 12 , wherein R is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 3 , for each occurrence, is independently a substituent selected from the group consisting of alkyl, alkenyl, an alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, halo, cyano, nitro, —NR 10 R 11 , —OR 7 , —C(O)R 7 , —C(O)OR 7 , OC(O)R 7 , —C(O)NH 2 , —NHC(O)R 7 , —SR 7 , —S(O) p R 7 , —NHS(O) 2 R 7 , or —S(O) 2 NH 2 . 
       
     
     
         25 . The compound of  claim 12 , wherein R is an optionally substituted indolyl. 
     
     
         26 . The compound of  claim 12 , wherein R is represented by the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         R 4  is H, a halo, alkyl, alkoxy, or alkyl sulfanyl; and 
         R 5  is H, alkyl, or alkylcarbonyl. 
       
     
     
         27 . The compound of  claim 12 , wherein X 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. 
     
     
         28 . A pharmaceutical composition comprising:
 a pharmaceutically acceptable carrier and   a compound according to  claim 12 .