Pyrazolopyrimidines and related analogs as HSP90-inhibitors

Abstract

Pyrazolopyrimidines and related 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.

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         44 . 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, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen, —OR 11 , —SR 11  or lower alkyl;  
 R 2  is —NHR 8 ;  
 R 3  is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —CO 2 H, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic and heterocyclic, all optionally substituted, wherein: 
 the aryl, heteroaryl, alicyclic and heterocyclic groups are optionally mono-, bi- or tri-cyclic;  
 R 8  and R 10  taken together optionally form a ring of 3-7 ring atoms and optionally 1-2 of the ring atoms are heteroatoms selected from the group of O, S and N, and  
 the optional substituents on R 3  are selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OOH, —NO 2 , —NR 8 R 10 , lower aryl, lower heteroaryl, lower 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 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 on R 5  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  and —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 hydrogen, 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 alkenyl, lower alkynyl, lower aryl or lower heteroaryl;  
 R 11  is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl; and  
 R 12  is hydrogen or lower alkyl.  
 
     
     
         45 . The method of  claim 44 , wherein: 
 R 1  is halogen or lower alkyl;    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 ; and    R 5  is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.    
     
     
         46 . The method of  claim 44 , wherein: 
 R 2  is —NH 2 ;    R 3  is selected from hydrogen, halogen, —SR 1 , —OR 8 , —CN, —NR 8 R 10 , lower alkyl lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lower heteroaryl, lower alicyclic, and lower heterocyclic, wherein R 8  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl, and 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; and    R 5  is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.    
     
     
         47 . The method of  claim 44 , wherein: 
 R 1  is halogen or lower alkyl;    R 2  is —NH 2 ;    R 4  is —(CH 2 )—; and    R 5  is aryl, heteroaryl, alicyclic or heterocyclic, wherein each of said aryl, heteroaryl alicyclic or heterocyclic groups is monocyclic or bicyclic.    
     
     
         48 . The method of  claim 44 , wherein: 
 R 1  is halogen;    R 2  is —NH 2 ;    R 3  is hydrogen, halogen, —SR 8 , —OR 8 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, lower heteroaryl, or —NR 8 R 10  wherein R 8  and R 10  when 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 4  is —CH 2 —; and    R 5  is aryl or heteroaryl, wherein each of said aryl and heteroaryl groups is monocyclic or bicyclic.    
     
     
         49 . The method of  claim 48 , wherein R 1  is chloro or bromo; and R 5  is a phenyl having 3 to 5 substituents.  
     
     
         50 . The method of  claim 48 , wherein R 1  is chloro or bromo; and R 5  is a pyridyl having 3 to 5 substituents.  
     
     
         51 . The method of  claim 48 , wherein R 1  is chloro or bromo; and R 5  is a 1-oxy-pyridyl(N-oxy-pyridyl) having 3 to 5 substituents.  
     
     
         52 . The method of  claim 44 , 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.  
     
     
         53 . The method of  claim 52  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.  
     
     
         54 . The method of  claim 44  further comprising administering at least one therapeutic agent selected from the group of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.  
     
     
         55 . The method of  claim 54  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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         64 . 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 II:  
       
         
           
           
               
               
           
         
       
       or a polymorph, solvate, ester, tautomer, 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 on R 5  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 9  is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower aryl, lower heteroaryl or —C(O)R 9 ;  
 R 9  is hydrogen, 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 alkenyl, lower alkynyl, lower aryl or lower heteroaryl;  
 R 11  is lower alkyl, lower alkenyl, lower alkynyl, lower aryl or lower heteroaryl;  
 R 12  is hydrogen or lower alkyl; and  
 R 15  is hydrogen, lower alkyl, lower alkenyl or lower alkynyl.  
 
     
     
         65 . The method of  claim 64 , wherein: 
 R 1  is halogen or lower alkyl;    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 ;    R 4  is —(CH 2 )—; and    R 5  is aryl, heteroaryl, alicyclic, or heterocyclic, all optionally mono-, bi- or tri-cyclic.    
     
     
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