Triazolopyrimidines and related analogs as HSP90-inhibitors

Abstract

Triazolopyrimidines and related compounds 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.

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         22 . A method of treating an individual 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, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen, —OR 11 , —SR 11  or lower alkyl;  
 R 2  is —NHR 8 ;  
 R 4  is —CHR 12 —, —C(O)—, —C(S)—, —S(O)— or —SO 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,  
 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 consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)OH, —C(O)R 9 , —NO 2 , —NR 8 R 10  lower aryl, heteroaryl, alicyclic, lower heterocyclic, arylalkyl, heteroarylalkyl, amino, alkylamino, dialkylamino, diarylalkylamino, oxo, oxa, perhaloalkyl, perhaloalkoxy, perhaloacyl, guanidine, pyridinyl, thiophene, furanyl, indole, indazole, phosphonates, phosphates, phosphoramides, sulfonates, sulfones, sulfates, sulphonamides, carbamates, ureas, thioureas and thioamides, wherein R 8  and R 10  taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;  
 
 R 8  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, or —C(O)R 9 ;  
 R 9  is H, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl, —NR 10 R 10 , or —OR 11 , wherein R 10  and R 10  taken together optionally form a ring of 3-7 ring atoms and optionally 1-3 of the ring atoms are heteroatoms selected from the group of O, S and N;  
 R 10  is hydrogen, lower alkyl, lower heteroaryl, lower aryl, lower alkenyl, or lower alkynyl,  
 R 11  is lower alkyl, lower alkenyl, lower alkynyl, lower heteroaryl or lower aryl; and  
 R 12  is hydrogen or lower alkyl;  
 provided that when R 5  is alicyclic, the ring system does not contain any tetra-substituted sp 3  ring carbons.  
 
     
     
         23 . The method of  claim 22 , wherein: 
 R 1  is halogen;    R 2  is —NH 2 ,    R 4  is —CH 2 —; and    R 5  is aryl or heteroaryl, wherein each of the aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.    
     
     
         24 . The method of  claim 22 , wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is a phenyl having at least three substituents.  
     
     
         25 . The method of  claim 22 , wherein R 1  is chloro or bromo, R 2  is —NH 2  and R 5  is a pyridyl having at least two substituents.  
     
     
         26 . The method of  claim 22 , wherein R 1  is chloro or bromo, R 2  is —NH 2 , and R 5  is an 
 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.    
     
     
         27 . The method of  claim 22 , 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.  
     
     
         28 . The method of  claim 27  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.  
     
     
         29 . The method of  claim 22 , further comprising administering at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.  
     
     
         30 . The method of  claim 29 , wherein the at least one anti-neoplastic agent 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.  
     
     
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