Pyrrolopyrimidines and Related Analogs as HSP90-Inhibitors

Abstract

Pyrrolopyrimidines and related analogs are described and demonstrated to have utility as Heat Shock Protein 90 (HSP90) inhibiting agents used in the treatment and prevention of various HSP90 mediated disorders, e.g., proliferative disorders. Methods of synthesis and use of such compounds are also described and claimed.

1 - 48 . (canceled)  
     
     
         49 . 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 0  is selected from hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN, and —NHR 8 ,  
 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 , —C(O)OH, —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 1-3 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)OH, —C(O)R 9 , —NO2, —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 0  or R 3  is —OH or —SH, the compound may exist as the corresponding (thio)keto tautomer or a mixture of keto-enol tautomers;  
 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, —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, or 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 alkenyl, lower alkynyl, lower aryl or lower heteroaryl;  
 R 11  is lower alkyl, lower alkenyl, or lower alkynyl, lower heteroaryl or lower aryl; and  
 R 12  is hydrogen or lower alkyl.  
 
     
     
         50 . The method of  claim 49 , wherein: 
 R 0  is hydrogen, halogen, —SH, —OH, or —CN,    R 1  is halogen; and    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 .    
     
     
         51 . The method of  claim 49 , wherein: 
 R 1  is chloro or bromo,    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 ,    R 3  is hydrogen, halogen, —OR 8 , —SR 8 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl.    
     
     
         52 . The method of  claim 49 , wherein: 
 R 0  is hydrogen, halogen or —CN,    R 2  is —NHR 8 , where R 8  is hydrogen or —C(O)R 9 ; and    R 4  is —CH 2 —.    
     
     
         53 . The method of  claim 49 , wherein: 
 R 0  is hydrogen, halogen, —SH, —OH or —CN;    R 1  is halogen;    R 2  is —NH 2 ;    R 3  is hydrogen, halogen, —OR 8 , —SR 8 , —NR 8 R 8 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, lower aryl, or lower heteroaryl, wherein R 8  is hydrogen, lower alkyl, lower aryl, or —C(O)R 9 ;    R 4  is —CH 2 —; and    R 5  is aryl or heteroaryl, wherein each of said aryl and heteroaryl is monocyclic or bicyclic and is substituted with 3 to 5 substituents.    
     
     
         54 . The method of  claim 53 , wherein: 
 R 1  is chloro or bromo;    R 2  is —NH 2 ; and    R 5  is a phenyl having at least three substituents, a pyridyl having at least two substituents, or 1-oxy-pyridyl (N-oxy-pyridyl) having at least two substituents.    
     
     
         55 . The method of  claim 49 , wherein the HSP90 mediated disorder is selected from the group consisting 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 diseases.  
     
     
         56 . The method of  claim 55 , wherein the fibrogenetic disorder is further selected from the group consisting of scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis and pulmonary fibrosis.  
     
     
         57 . The method of  claim 49 , further comprising administering at least one therapeutic agent selected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti-neoplastic agents.  
     
     
         58 . The method of  claim 57 , wherein the at least one anti-neoplastic agent is selected from the group consisting 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.  
     
     
         59 - 68 . (canceled)  
     
     
         69 . 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:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 0  is hydrogen, halogen, lower alkyl, —SR 8 , —OR 8 , —CN or —NHR 8 ;  
 R 1  is halogen, —OR 11 , —SR 11  or lower alkyl;  
 R 2  is —NH 2 ;  
 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 H, lower alkyl, 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;  
 R 12  is hydrogen or lower alkyl; and  
 R 0  and R 10  taken together optionally form an exocyclic double bond which is optionally substituted, or 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.  
 
     
     
         70 - 75 . (canceled)  
     
     
         76 . 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 III:  
       
         
           
           
               
               
           
         
       
       or a polymorph, solvate, ester, tantomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen, —OR 11 , —SR 11  or lower alkyl;  
 R 2  is —NH 2 ;  
 R 3  is selected from the group consisting of hydrogen, halogen, —SR 8 , —OR 8 , —CN, —C(O)R 9 , —C(O)OH, —NO 2 , —NR 8 R 10 , lower alkyl, lower alkenyl, lower alkynyl, lower perhaloalkyl, aryl, heteroaryl, alicyclic, 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 1-3 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)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 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, firanyl, 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 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;  
 R 12  is hydrogen or lower alkyl; and  
 R 3  and R 10  taken together optionally form an exocyclic double bond which is optionally substituted, or 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.  
 
     
     
         77 - 80 . (canceled)  
     
     
         81 . 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 IV:  
       
         
           
           
               
               
           
         
       
       or a polymorph, solvate, ester, tantomer, enantiomer, pharmaceutically acceptable salt or prodrug thereof, wherein: 
 R 1  is halogen, —OR 11 , —SR 11  or lower alkyl;  
 R 2  is —NH 2 ;  
 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 H, lower alkyl, 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.