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.

We claim:  
     
         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  
                     
  and 
 Z i  is O, Se, NR a  or C(R a ) 2 , and  
 Z ii  is —O or (═O) 2 ; 
 and wherein R a  is H, OR b , CN, NO 2 , N(R b ) 2 , SR b , SO 2 R b , SO 2 N(R b ) 2 , COR b , CO 2 R b , CON(R b ) 2 , PO(R b ) 2 , PO(OR b ) 2 , PO(NR b)   2 , wherein R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 2 -C 8  alkynyl, C 2 -C 8  substituted alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, C 4-10  aralkyl, C 1-10  alkaryl, C 1-10  alkylthio, C 4-10  aralkylthio, C 1-10  alkylsulfinyl, C 4-10  aralkylsulfinyl, C 1-10  alkylsulfonyl, C 4-10  aralkylsulfonyl, carboxy, C 1-10  alkylthiocarbonyl, C 4-10  aralkylcarbonyl, C 4-10  aralkylthiocarbonyl, C 4-10  aralkoxycarbonyl, C 4-10  aralkoxycarbonyl, C 1-4  alkyl, C 4-10  aralkoxy, C 1-12  dialkylamino-C 1-6  aralkanoylamino C 4-10  aralkylamino or C 1 -C 4  alkanoyloxy;  
 
 
 R 1  is isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, imidazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, theinyl, substituted thienyl, pyrazolyl or substituted pyrazolyl;  
 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;  
 R 6 , R 7 , R 8 , and R 9  are independently C 3 -C 8  cycloalkyl, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, C 1 -C 6  substituted alkoxy, halo, amino, nitro, cyano, C 1 -C 5  alkoxy, hydroxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, carbamoyl, or a halo substituted C 1 -C 6  alkyl; or two of which, along with the carbons to which they are attached, combine to form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, O, or N;  
 
 R 3  and R 4  are independently hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, substituted alkoxy, amino, cyano, nitro, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, halo-substituted (C 1 -C 6 )alkyl, or carbamoyl; 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 isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, imidazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, theinyl, substituted thienyl, substituted furyl, pyrazolyl and substituted pyrazolyl.  
     
     
         4 . The method of claim I wherein R 3  and R 4  are hydrogen; 
 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; imidazolyl,    R 2  is   R 5 —CH 2 CH 2 —    or                           and 
 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-tetrafluuorophenyl, 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 of  claim 1 , wherein Z i  is O.  
     
     
         6 . The method as recited in  claim 1  further comprising administering at least one other anti-HIV agent to said patient.  
     
     
         7 . The method as recited in  claim 6  wherein said agent is selected from ddl, ddC, or AZT.  
     
     
         8 . A compound having the formula  
       
         
           
           
               
               
           
         
       
       wherein 
 A is  
                     
  and 
 Z i  is O, Se, NR a  or C(R a ) 2 , and  
 Z ii  is —O or (═O) 2 ; 
 and wherein R a  is H, OR b , CN, NO 2 , N(R b ) 2 , SR b , SO 2 R b , SO 2 N(R b ) 2 , COR b , CO 2 R b , CON(R b ) 2 , PO(R b ) 2 , PO(OR b ) 2 , PO(NR b ) 2 , wherein R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 2 -C 8  alkynyl, C 2 -C 8  substituted alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, C 4-10  aralkyl, C 1-10  alkaryl, C 1-10  alkylthio, C 4-10  aralkylthio, C 1-10  alkylsulfinyl, C 4-10  aralkylsulfinyl, C 1-10  alkylsulfonyl, C 4-10  aralkylsulfonyl, carboxy, C 1-10  alkylthiocarbonyl, C 4-10  aralkylcarbonyl, C 4-10  aralkylthiocarbonyl, C 4-10  aralkoxycarbonyl, C 4-10  aralkoxycarbonyl, C 1-4  alkyl, C 4-10  aralkoxy, C 1-12  dialkylamino-C 1-6  aralkanoylamino C 4-10  aralkylamino or C 1 -C 4  alkanoyloxy;  
 
 
 and wherein R 1  is isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, imidazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, thienyl, substituted thienyl, pyrazolyl or substituted pyrazolyl and;  
 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    two of R 6 , R 7 , R 8  and R 9  are independently C 3 -C 8  cycloalkyl, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, C 1 -C 6  substituted alkoxy, halo, amino, nitro, cyano, C 1 -C 5  alkoxy, hydroxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, carbamoyl, or a halo substituted C 1 -C 6  alkyl; and the other two of which, along with the carbons to which they are attached, combine to form a stable, saturated or unsaturated, substituted or unsubstituted, 3 to 7 membered organic monocylic ring having 0 to 4 hetero atoms selected from S, O, or N;    
 R 3  and R 4  are independently hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, substituted alkoxy, amino, cyano, nitro, C 1 -C 6  alkoxy, C 1 -C 6  sustituted alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -4 alkylthio, C 1 -C 4  alkanoyloxy, halo-substituted (C 1 -C 6 ) alkyl, or carbamoyl; or a pharmaceutically acceptable salt thereof.  
 
     
     
         9 . The compound of  claim 8  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.  
     
     
         10 . The compound of  claim 8  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 or imidazolyl.  
     
     
         11 . The compound of  claim 8 , wherein R5 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.  
     
     
         12 . The compound of  claim 11 , 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.  
     
     
         13 . The compound of  claim 8 , wherein R 3  and R 4  are hydrogen.  
     
     
         14 . The compound of  claim 8 , wherein R 2  is R 5 -(cis)-cyclopropyl.  
     
     
         15 . The compound of  claim 8 , wherein Z i  is O.  
     
     
         16 . The compound of  claim 8 , wherein the N′ linkage to R 1  is at the 2 position relative to a heteroatom in said isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, theinyl, substituted thienyl, pyrazolyl and substituted pyrazolyl.  
     
     
         17 . A pharmaceutical formulation comprising an effective amount of a compound as defined in claim  8 ; and a pharmaceutically acceptable carrier or diluent therefor.  
     
     
         18 . A pharmaceutical formulation according to  claim 17 , wherein said agent is selected from ddl, ddC or AZT.  
     
     
         19 . A compound having the formula IA  
       
         
           
           
               
               
           
         
       
       wherein 
 A is  
                     
  and 
 Z i  is O, Se or C(R a ) 2 , and  
 Z ii  is O or (═O) 2 ; 
 and R a  is H, OR b , CN, NO 2 , N(R b ) 2 , SR b , SO 2 R b , SO 2 N(R b ) 2 , COR b , CO 2 R b , CON(R b ) 2 , PO(R b ) 2 , PO(OR b ) 2 , PO(NR b ) 2 , wherein R b  is hydrogen, C 1 -C 6  alkyl, C 1 -C 6  substituted alkyl, C 2 -C 6  alkenyl, C 2 -C 6  substituted alkenyl, C 2 -C 8  allkynyl, C 2 -C 8  substituted alkynyl, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, C 4-10  aralkyl, C 1-10  alkaryl, C 1-10  alkaryl, C 1-10  alkylthio, C 4-10  aralkylthio, C 1-10  alkylsulfinyl, C 4-10  aralkylsulfinyl, C 1 - 10  alkylsulfonyl, C 4-10  aralkylsulfonyl, carboxy, C 1-10  alkylthiocarbonyl, C 4-10  aralkoxycarbonyl, C 4-10  aralkoxycarbonyl, C 1-4  alkyl, C 4-10  aralkoxy, C 1-12  dialkylamino-C 1-6  aralkyanoylamino C 4-10  aralkylamino or C 1-4  alkanoyloxy;  
 
 
 R 3  and R 4  are independently hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 8  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, substituted alkoxy, amino, cyano, nitro, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, halo-substituted (C 1 -C 6 )alkyl, or carbamoyl;  
 R 1  is isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, imidazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, theinyl, substituted thienyl, pyrazolyl or substituted pyrazolyl; the substituents being singe or multiple substituents selected from 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    
 R 2  is a group of the formula  
                     wherein R 5  is a stable, unsaturated, substituted or unsubstituted 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; R 3  and R 4  are independently hydrogen, hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, substituted alkoxy, amino, cyano, nitro, C 1 -C 6  alkoxy, C 1 -C 6  substituted alkoxy, carboxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, halo-substituted (C 1 -C 6 )alkyl, or carbamoyl; and R 6 , R 7 , R 8  and R 9  are independently C 3 -C 8  cycloalkyl, hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, substituted C 1 -C 6  alkyl, substituted C 2 -C 6  alkenyl, or substituted C 2 -C 6  alkynyl, C 1 -C 6  substituted alkoxy, halo, amino, nitro, cyano, C 1 -C 5  alkoxy, hydroxy, hydroxymethyl, aminomethyl, carboxymethyl, C 1 -C 4  alkylthio, C 1 -C 4  alkanoyloxy, carbamoyl, or a halo substituted C 1 -C 6  alkyl;    or a pharmaceutically acceptable salt thereof;    
 
     
     
         20 . The compound according to  claim 19 , wherein R 1  is thiazclyl, (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, imidazolyl,  
     
     
         21 . The compound of  claim 19 , wherein R 5  is cyclo(C 3 -C 8 )alkenyl, thiazolyl, substituted thiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, pyridyl, substutited pyridyl, imidazolyl, substituted imidazolyl, phenyl, substituted phenyl, thiazolyl, substituted thiazolyl, oxazolyl, substituted oxazolyl, pyrazinyl, substituted pyrazinyl, pyridazinyl, substituted pyridazinyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, usbstituted pyrrolyl, thienyl, substituted thienyl, furyl, substituted furyl, pyrazolyl, and substituted pyrazolyl.  
     
     
         22 . The compound of  claim 21 , 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-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.  
     
     
         23 . The compound of  claim 19 , wherein R 3  and R 4  are hydrogen.  
     
     
         24 . The compound of  claim 19 , wherein Z i  is O.  
     
     
         25 . The compound of  claim 19 , wherein the N′linkage to R 1  is at the 2 position relative to a heteroatom in said isothiazolyl, substituted isothiazolyl, tetrazolyl, substituted tetrazolyl, triazolyl, substituted triazolyl, substituted imidazolyl, thiazolyl, substituted thiazolyl, thiadiazolyl, substituted thiadiazolyl, pyrrolyl, substituted pyrrolyl, theinyl, substituted thienyl, pyrazolyl and substituted pyrazolyl.  
     
     
         26 . A pharmaceutical composition comprising an effective anti-HIV amount of a compound of claim  19 ; and a pharmaceutically acceptable carrier or diluent.  
     
     
         27 . The composition according to  claim 26 , further comprising at least one other therapeutic agent.  
     
     
         28 . A pharmaceutical composition according to  claim 25 , wherein said at least one other therapeutic agent is ddl, ddC or AZT.  
     
     
         29 . A method for treating or inhibiting HIV, comprising administering to a patient suffering from HIV infection an amount of a compound of  claim 19  effective for treating or inhibiting HIV.  
     
     
         30 . A method for treating or inhibiting HIV, comprising administering to a patient suffering from HIV infection an amount of a compound of  claim 8  effective for treating or inhibiting HIV.