Compounds and methods for inhibition of HIV and related viruses

Abstract

The present invention is directed to compounds, compositions and methods of inhibiting and treating HIV and related viruses, and methods for cocrystallizing reverse transcriptase in vitro, inhibition of the replication of HIV and related viruses thereof.

1 . A method for treating HIV which comprises administering to a patient in need thereof, an effective anti-HIV amount of a compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein A is  
       
         
           
           
               
               
           
         
         where Z i  is O,  
         R 1  is isothiazolyl, substituted isothiazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl;  
         R 2  is a group of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein R 5  is a stable, saturated or unsaturated, substituted or unsubstituted 3 to 8 member organic monocyclic ring having 0 to 4 heteroatoms selected from S, O and N; or R 5  is a stable, saturated or unsaturated, substituted or unsubstituted 7 to 10 membered organic bicyclic ring having 0 to 5 heteroatoms selected from S, O or N; and  
         are;  
         R 3  and R 4  are hydrogen; or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The method of  claim 1  wherein R 5  is cyclo(C 3 -C 8 )alkyl, cyclo (C 3 -C 8 ) alkenyl; isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, substituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted thienyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, substituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl.  
     
     
         3 . The method of  claim 1 , wherein R 1  is, thiazolyl or substituted thiazolyl  
     
     
         4 . The method of  claim 1  wherein; 
 R 1  is thiazolyl, (4-methyl)thiazolyl, (4,5-dimethyl)thiazolyl, (4-cyano)thiazolyl, (4-ethyl)thiazolyl, 4-(3-pyridyl)thiazolyl, 4-(3-nitrophenyl)thiazolyl, 1,3,4-thiadiazolyl,;  
                     
 R 5  is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl, 2-fluoro-6-ethoxyphenyl, 2,3,5,6-tetrafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 1-cyclohexenyl, 2-naphthyl, 2,5-dimethoxyphenyl, 2-azidophenyl, 2,3,4-trifluorophenyl, 2-fluoro-6-chlorophenyl, 2,6-dimethoxyphenyl, 2,3,6-trichlorophenyl, 2,6-dichlorophenyl, 2,3,5-trichlorophenyl, 3,5-dichlorophenyl, 3-fluorophenyl, 2,4-dimethoxyphenyl, 2-pyridyl, 2-(6-methoxy)pyridyl, 2-(6-ethoxy)pyridyl, 2-(6-fluoro)pyridyl, 2-(5-fluoro)pyridyl, 2-(4-fluoro)pyridyl, 2-(3-fluoro)pyridyl, 2-(6-chloro)pyridyl, 2-(5-chloro)pyridyl, 2-(4-chloro)pyridyl, 2-(3-chloro)pyridyl, 2-(5-methoxy-6-fluoro)pyridyl, 2-(3-methoxy-6-fluoro)pyridyl, 2-(6-methoxy-3-fluoro)pyridyl, 2-(5-ethoxy-6-fluoro)pyridyl, 2-(3-ethoxy-6-fluoro)pyridyl, 2-(6-ethoxy-3-fluoro)pyridyl, 2-(5,6-difluoro)pyridyl, 2-(3,6-difluoro)pyridyl, 2-(5,6-dichloro)pyridyl, 2-(3,6-dichloro)pyridyl, 2-(6-methoxy)pyridyl, 2-(6-ethoxy)pyridyl, 2-(1,3-pyrimidyl), 2-pyrazinyl, 3-pyridazinyl, 2,6-difluoro-3-methoxyphenyl, 2,6-difluoro-3-ethoxyphenyl, 2,6-difluoro-4-methoxyphenyl, 2,6-difluoro-4-ethoxyphenyl, 2-(3-ethoxy)pyridyl, 2-(3-methoxy)pyridyl, 2,6-difluorophenyl, 2,6-difluoro-3-N-methylcarboxamidephenyl, 2-fluoro-6-chlorophenyl, 3-bromo-6-methoxyphenyl, 3-ethoxyphenyl, 3-bromo-6-ethoxyphenyl, 3-(2-fluoro)pyridyl, (2-vinyl)phenyl, (3-vinyl)phenyl, (3-methoxycarbonyl)phenyl, 5,6-dimethylbenzotriazolyl, 2,3-difluoro-6-methoxyphenyl, 2,6-difluoro-3-cyanophenyl, 3-ethynylphenyl, and 2,5-diethoxyphenyl.  
 
     
     
         5 . The method as recited in  claim 1  further comprising administering at least one other anti-HIV agent to said patient.  
     
     
         6 . The method as recited in  claim 5  wherein said agent is selected from ddI, ddC, or AZT.  
     
     
         7 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein A is  
       
         
           
           
               
               
           
         
         Z i  is O;  
         R 1  is isothiazolyl, substituted isothiazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl,  
         R 2  is a group of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein R 5  is a stable, unsaturated, substituted or unsubstituted i) 3 to 8 membered monocyclic ring having 0 to 4 hetero atoms or ii) a 7 to 10 membered bicyclic ring having 0 to 5 hetero atoms, said hetero atoms being selected from S, O and N; and  
         R 3  and R 4  are hydrogen; or a pharmaceutically acceptable salt thereof.  
       
     
     
         8 . The compound of  claim 7  wherein the substituted R 1  and/or R 5  groups have single or multiple substituents independently selected from halo, C 1 -C 6  alkyl, C 1 -C 5  alkoxy, C 2 -C 6  alkenyl, C 2 -C 8  alkynyl, C 2 -C 8  alkenoxy, amino, nitro, cyano, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, hydroxy, C 1 -C 4  alkanoyloxy, carbamoyl, halo-substituted C 1 -C 6  alkyl, C 1 -C 6  alkoxy-substituted C 1 -C 6  alkyl, a group of the formula 
       —SO 2 R x   
       wherein R x  is C 1 -C 6  alkyl or amino; or a group of the formula  
       
         
           
           
               
               
           
         
       
       wherein R x  is C 1 -C 6  alkyl.  
     
     
         9 . The compound of  claim 7  wherein R 1  is thiazolyl, (4-methyl)thiazolyl, (4,5-dimethyl)thiazolyl, (4-cyano)thiazolyl, (4-ethyl)thiazolyl, 4-(3-pyridyl)thiazolyl, 4-(3-nitrophenyl)thiazolyl, or 1,3,4-thiadiazolyl.  
     
     
         10 . The compound of  claim 7 , wherein R 5  is cyclo(C3-C-8)alkenyl, thiazolyl, substituted thiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substituted pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, naphthyl, sustituted naphthyl, benzoxazolyl, substituted benzoxazolyl, benzimidazolyl, substituted benzimidazolyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, benzothiazolyl, substituted benzothiazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadaizolyl, substituted thadiazolyl, benzotriazolyl, substituted benzotriazolyl, pyrrolyl, substituted pyrrolyl, indolyl, substituted indolyl, benzothienyl, substituted benzothienyl, thienyl, substituted theinyl, benzofuryl, substituted benzofuryl, furyl, substituted furyl, quinolinyl, substituted quinolinyl, isoquinolinyl, subsituted isoquinolinyl, pyrazolyl, and substituted pyrazolyl.  
     
     
         11 . The compound of  claim 10 , wherein R 5  is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-ethoxyphenyl, 2-methylphenyl, 3-methylphenyl, 2-fluorophenyl, 2,6-difluorophenyl, 2-fluoro-6-methoxyphenyl, 2-fluoro-6-ethoxyphenyl, 2,3,5,6-tetrafluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 1-cyclohexenyl, 2-naphthyl, 2,5-dimethoxyphenyl, 2-azidophenyl, 2,3,4-trifluorophenyl, 2-fluoro-67-chlorophenyl, 2,6-dimethoxyphenyl, 2,3,6-trichlorophenyl, 2,6-dichlorophenyl, 2,3,5-trichlorophenyl, 3,5-dichlorophenyl, 3-fluorophenyl, 2,4-dimethoxyphenyl, 2-pyridyl, 2-(6-methoxy)pyridyl, 2-(6-ethoxy)pyridyl, 2-(6-fluoro)pyridyl, 2-(5-fluoro)pyridyl, 2-(4-fluoro)pyridyl, 2-(3-fluoro)pyridyl, 2-(6-chloro)pyridyl, 2-(5-chloro)pyridyl, 2-(4-chloro)pyridyl, 2-(3-chloro)pyridyl, 2-(5-methoxy-6-fluoro)pyridyl, 2-(3-methoxy-6-fluoro)pyridyl, 2-(6-methoxy-3-fluoro)pyridyl, 2-(5-ethoxy-6-fluoro)pyridyl, 2-(3-ethoxyl-6-fluoro)pyridyl, 2-(6-ethoxy-3-fluoro)pyridyl, 2-(5, 6-difluoro)pyridyl, 2-(3,6-difluoro)pyridyl, 2-(5,6-dichloro)pyridyl, 2-(3,6-dichloro)pyridyl, 2-(6-methoxy)pyridyl, 2-(6-ethoxy)pyridyl, 2-(1,3-pyrimidyl), 2-pyrizinyl, 3-pyridazinyl, 2,6-difluoro-3-methoxyphenyl, 2,6-difluoro-3-ethoxylphenyl, 2,6-difluoro-4-methoxyphenyl, 2,6-difluoro-4-ethoxyphenyl, 2-(3-ethoxy)pyridyl, 2-(3-methoxy)pyridyl, 2,6-difluorophenyl, 2,6-difluoro-4-ethoxyphenyl, 2-(3-ethoxy)pyridyl, 2-(3-methoxy)pyridyl, 2,6-difluorophenyl, 2,6-difluoro-3-N-methylcarboxamidephenyl. 2-fluoro-6-chlorphenyl, 3-bromo-6-methoxyphenyl, 3-ethoxyphenyl, 3-bromo-6-ethoxyphenyl, 3-(2-fluoro)pyridyl, (2-vinyl)phenyl, (3-vinyl)phenyl, (3-methoxycarbonyl)phenyl, 5,6-dimethylbenzotriazolyl, 2,3-difluoro-6-methoxyphenyl, 2,6-difluoro-3-cyanophenyl, 3-ethynylphenyl or 2,5-diethoxyphenyl.  
     
     
         12 . The compound of  claim 7 , wherein the N′ linkage to R 1  is at the 2 position relative to a heteroatom in said isothiazolyl, substituted isothiazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl.  
     
     
         13 . A pharmaceutical formulation comprising an effective amount of a compound as defined in  claim 7;  and a pharmaceutically acceptable carrier or diluent therefor.  
     
     
         14 . A pharmaceutical formulation according to  claim 13 , wherein said agent is selected from ddI, ddC or AZT.  
     
     
         15 . A method for treating or inhibiting HIV, comprising administering to a patient suffering from HIV infection an amount of a compound of  claim 7  effective for treating or inhibiting HIV.