2-Aminopurine Analogs Having HSP90-Inhibiting Activity

Abstract

2-Aminopurine analogs are described and demonstrated or predicted to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Method of synthesis and use of such compounds are also described and claimed.

1 . A compound represented by Formula I, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is halogen or lower alkyl;  
 R 2  is —NR 8 R 10 ;  
 R 4  is —CHR 12 —;  
 R 3 is hydrogen, halogen, or —CN;  
 R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, wherein: 
 the aryl group is substituted with 3 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,  
 the alicyclic group is substituted with 3 to 5 substituents,  
 the heterocyclic group is substituted with 3 to 5 substituents, and  
 the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , —NR 8 R 10 , phosphonate and phosphonic acid;  
 
 R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;  
 R 9  is lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10  or —OR 11 ;  
 R 10  is independently hydrogen or lower alkyl;  
 R 11  is lower alkyl, lower aryl or lower heteroaryl;  
 R 12  is hydrogen or lower alkyl;  
 provided that  
 when R 5  is aryl, R 5  is not an organo-metallic cyclopentadiene;  
 when R 5  is phenyl, the substituents are not 3,5 di-halo;  
 when R 5  is alicyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons; and  
 when R 5  is heterocyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons or the ring system is not a tetra-substituted pyrrolidine.  
 
     
     
         2 . The compound of  claim 1 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen or methyl; and    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 .    
     
     
         3 . The compound of  claim 1 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen;    R 2  is —NH 2 ;    R 3  is hydrogen; and    R 5  is aryl or heteroaryl, wherein 
 each of said aryl and heteroaryl groups is monocyclic or bicyclic,  
 the aryl group is substituted with 4 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.  
   
     
     
         4 . The compound of  claim 1 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen;    R 2  is —NH 2 ;    R 4  is lower alkyl;    R 3  is hydrogen; and    R 5  is aryl or heteroaryl, wherein 
 each of said aryl and heteroaryl groups is monocyclic or bicyclic,  
 the aryl group is substituted with 4 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.  
   
     
     
         5 . The compound of  claim 1 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein 
 R 1  is chloro or bromo,    R 2  is —NH 2 , and    R 5  is a phenyl having 3 to 5 substituents, a pyridyl having 3 to 5 substituents or an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.    
     
     
         6 . A compound represented by Formula II, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is halogen or lower alkyl;  
 R 2  is —NR 8 R 10 ;  
 R 3  is hydrogen, halogen, or —CN;  
 R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, wherein 
 the aryl group is substituted with 3 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,  
 the alicyclic group is substituted with 3 to 5 substituents,  
 the heterocyclic group is substituted with 3 to 5 substituents, and  
 the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , —NR 8 R 10 , phosphonate and phosphonic acid;  
 
 R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;  
 R 9  is lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10  or —OR 11 ;  
 R 10  is independently hydrogen or lower alkyl; and  
 R 11  is lower alkyl, lower aryl or lower heteroaryl;  
 provided that  
 when R 5  is aryl, R 5  is not an organo-metallic cyclopentadiene;  
 when R 5  is phenyl, the substituents are not 3,5 di-halo;  
 when R 5  is alicyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons;  
 when R 5  is heterocyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons or the ring system is not a tetra-substituted pyrrolidine.  
 
     
     
         7 . The compound of  claim 6 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein each of said aryl, heteroaryl, alicyclic or heterocyclic group is monocyclic or bicyclic.  
     
     
         8 . The compound of  claim 6 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen or methyl; and    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 .    
     
     
         9 . The compound of  claim 8 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1  is halogen.  
     
     
         10 . The compound of  claim 9 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 2  is —NH 2  and R 3  is hydrogen.  
     
     
         11 . The compound of  claim 6 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen;    R 2  is —NH 2 ;    R 3  is hydrogen; and    R 5  is aryl or heteroaryl, wherein 
 each of the aryl and heteroaryl groups is monocyclic or bicyclic,  
 the aryl group is substituted with 4 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.  
   
     
     
         12 . The compound of  claim 6 , or a polymorph, solvate , ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is a phenyl having 3 to 5 substituents.  
     
     
         13 . The compound of  claim 6 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is a pyridyl having 3 to 5 substituents.  
     
     
         14 . The compound of  claim 6 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.  
     
     
         15 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         16 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 11 , wherein the compound is a member selected from the group of compounds below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         23 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         27 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         29 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         30 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         31 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         32 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         33 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         34 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         35 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         36 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         37 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         38 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         41 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         42 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         43 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         44 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         45 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         46 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         47 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         48 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         49 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         50 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         51 . The compound of  claim 11 , wherein said compound is represented by the formula below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         52 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         53 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         54 . The compound of  claim 11 , wherein said compound is a member selected from the group below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
     
     
         55 . A pharmaceutical composition comprising one or more pharmaceutical acceptable excipients and at least one compound represented by Formula I below, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is halogen or lower alkyl;  
 R 2  is —NR 8 R 10 ;  
 R 4  is —CHR 12 —;  
 R 3  is hydrogen, halogen, or —CN;  
 R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, wherein 
 the aryl group is substituted with 3 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,  
 the alicyclic group is substituted with 3 to 5 substituents,  
 the heterocyclic group is substituted with 3 to 5 substituents, and  
 the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , —NR 8 R 10 , phosphonate and phosphonic acid;  
 
 R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;  
 R 9  is lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10  or —OR 11 ;  
 R 10  is independently hydrogen or lower alkyl;  
 R 11  is lower alkyl, lower aryl or lower heteroaryl;  
 R 12  is hydrogen or lower alkyl; and  
 provided that  
 when R 5  is aryl, R 5  is not an organo-metallic cyclopentadiene;  
 when R 5  is phenyl, the substituents are not 3,5 di-halo;  
 when R 5  is alicyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons; and  
 when R 5  is heterocyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons or the ring system is not a tetra-substituted pyrrolidine.  
 
     
     
         56 . The pharmaceutical composition of  claim 55  wherein R 4  is —CH 2 —.  
     
     
         57 . The pharmaceutical composition of  claim 55 , wherein: 
 R 1  is halogen;    R 2  is —NH 2 ;    R 3  is hydrogen; and    R 5  is aryl or heteroaryl, wherein 
 each of the aryl and heteroaryl groups is monocyclic or bicyclic,  
 the aryl group is substituted with 4 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring.  
   
     
     
         58 . The pharmaceutical composition of  claim 56  wherein, wherein 
 R 1  is chloro or bromo;    R 2  is —NH 2 ; and    R 5  is selected from a phenyl having 3 to 5 substituents, a pyridyl having 3 to 5 substituents and an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.    
     
     
         59 . A method of treating an gingival having an HSP90 mediated disorder comprising administering to said individual a pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Formula I:  
       
         
           
           
               
               
           
         
       
       or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen, —OR 11 , SR 11 , —NHR 8 , hydrogen, or lower alkyl;  
 R 2  is —NR 8 R 10 ;  
 R 3  is hydrogen, halogen, —N 3  or —CN;  
 R 1  is —(CHR 12 ) n — where n=0, 1 or 2, —C(O)—, —C(S)—, or —S(O)—;  
 R 5  is alkyl, aryl, heteroaryl, alicyclic, or heterocyclic, all optionally substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , or —NR 8 R 10 ;  
 R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;  
 R 9  is lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 ;  
 R 10  is independently hydrogen or lower alkyl;  
 R 11  is lower alkyl, lower aryl or lower heteroaryl;  
 R 12  is hydrogen or lower alkyl; and  
 provided that:  
 —R 4 R 5  is not a ribose or derivative thereof, or a sugar or derivative thereof;  
 —R 4 R 5  is not a phosphonate or phosphonic acid, or substituted with phosphonate or phosphonic acid; and  
 when R 4  is —(CH 2 ) n — where n=1 or 2, then R 4  and R 5  are not connected through an ether linkage.  
 
     
     
         60 . The method of  claim 59 , wherein: 
 R 3  is hydrogen, halogen or —CN; and    R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally substituted with halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , or —NR 8 R 10 .    
     
     
         61 . The method of  claim 59 , wherein: 
 R 1  is halogen;    R is —NH 2 ;    R 3  is hydrogen;    R 4  is —CH 2 ; and    R 5  is aryl or heteroaryl, wherein: 
 the aryl and heteroaryl groups are monocyclic or bicyclic,  
 the aryl group is substituted with 4 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when  
 the heteroaryl is substituted with two substituents, the two substituents must form part of an optionally substituted fused ring.  
   
     
     
         62 . The method of  claim 60 , wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is a phenyl having 3 to 5 substituents, a pyridyl having 3 to 5 substituents or an 1-oxy-pyridyl (N-oxy-pyridyl) having 3 to 5 substituents.  
     
     
         63 . The method of  claim 60 , wherein the HSP90 mediated disorder is selected from the group of inflammatory diseases, infections, autoimmune disorders, stroke, ischemia, cardiac disorders, neurological disorders, fibrogenetic disorders, proliferative disorders, tumors, leukemias, neoplasms, cancers, carcinomas, metabolic diseases, and malignant disease.  
     
     
         64 . The method of  claim 63  wherein the fibrogenetic disorder is further selected from the group of scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.  
     
     
         65 . The method of  claim 60 , further comprising administering at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.  
     
     
         66 . The method of  claim 65 , wherein the at least one anti-neoplastic agents is selected from the group of alkylating agents, anti-metabolites, epidophyllotoxins, antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal/anti-hormonal therapeutic agents, and haematopoietic growth factors.  
     
     
         67 . A compound, or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, prepared by the process comprising: 
 reacting a compound of formula Y and a compound of formula Z, wherein:    Y is represented by any of the following formulae, respectively:                          and    Z is L 1 —R 4 —R 5 ; wherein: 
 L 1  is halogen, NR 8 R 10 , triflate, tosylate, or mesylate;  
 R 4  is —CHR 2 —,  
 R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, wherein: 
 the aryl group is substituted with 3 to 5 substituents,  
 the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with only two substituents, the two substituents must form part of an optionally substituted fused ring,  
 the alicyclic group is substituted with 3 to 5 substituents,  
 the heterocyclic group is substituted with 3 to 5 substituents, and  
 the substituents are selected from the group of halogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower alicyclic, arylalkyl, aryloxy, aryloxyalkyl, alkoxyalkyl, perhaloalkyl, perhaloalkyloxy, perhaloacyl, —N 3 , —SR 8 , —OR 8 , —CN, —C(O)R 9 , —NO 2 , —NR R 8 R 10 , phosphonate and phosphonic acid;  
 
 R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;  
 R 9  is lower alkyl, lower aryl, lower heteroaryl, —NR 10 R 10  or —OR 11 ;  
 R 10  is independently hydrogen or lower alkyl;  
 R 11  is lower alkyl, lower aryl or lower heteroaryl;  
 R 12  is hydrogen or lower alkyl;  
 R 21  is halogen, lower alkyl or —OH;  
 R 22  is —NR 8 R 10 ;  
 R 23  is hydrogen, halogen, or —CN;  
 R 24  is —NH 2 , —NO 2 , or —NO;  
 R 25  is halogen or —OH;  
 R 26  is —C(O)NH 2  or C(O)OEt; and  
 R 27  is —NH 2 , —OH or halogen;  
 provided that:  
   when R 5  is aryl, R 5  is not an organo-metallic cyclopentadiene;    when R 5  is phenyl, the substituents are not 3, 5 di-halo;    when R 5  is alicyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons; or    when R 5  is heterocyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons or the ring system is not a tetra-substituted pyrrolidine.    
     
     
         68 . The compound of  claim 67  wherein R 4  is —CH 2 —.  
     
     
         69 . The compound of  claim 68 , wherein: 
 L 1  is —Cl, —Br or NH 2 ; and    R 5  is aryl or heteroaryl, wherein the aryl group is substituted with 4 to 5 substituents, the heteroaryl group is substituted with 2 to 5 substituents, wherein when the heteroaryl is substituted with two substituents, the two substituents must form part of an optionally substituted fused ring.    
     
     
         70 . The compound of  claim 69 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein Y is a substituted purine.  
     
     
         71 . The compound of  claim 68 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein said reaction is performed in a solvent comprising a member selected from the group of DMF, THF, and DMSO.  
     
     
         72 . The compound of  claim 70 , or a polymorph, solvate, ester, tautomer, pharmaceutically acceptable salt or prodrug thereof, wherein said reaction is performed in a solvent that comprises DMF.