HIV protease inhibitors, compositions containing the same, their pharmaceutical uses and materials for their synthesis

Abstract

Compounds of the formula: where the formula variables are as defined herein, are disclosed that advantageously inhibit or block the biological activity of the HIV protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with the HIV virus. Intermediates and synthetic methods for preparing such compounds are also described.

1 - 19 . (canceled)  
     
     
         20 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is saturated, partially unsaturated or fully unsaturated and is unsubstituted or substituted by one or more suitable substituents;  
 R 2  is a substituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted phenyl group, a substituted phenylalkyl group, a substituted or unsubstituted phenylalkenyl group or a substituted or unsubstituted phenylalkynyl group,  
 R 2′  is H or a substituted or unsubstituted C 1 -C 4  alkyl group;  
 X is  
                     
  wherein R x  is H or one or more suitable substituents;  
 Z is CH 2  or CFH;  
 R 3  is H or a substituted or unsubstituted C 1 -C 4  alkyl group;  
 R 4 , R 5 , R 6  and R 7  are independently selected from H or a C 1 -C 6  alkyl group; and  
 R 8  and R 8′  are independently selected from H, halo, a C 1 -C 4  aliphatic group or a C 1 -C 4  halo-substituted aliphatic group;  
 where any of said substituted alkyl, alkenyl or alkynyl groups or said alkyl, alkenyl or are substituted by one or more suitable substituents;  
 provided that said 5- or 6-membered mono-cyclic heterocycloalkyl, heterocycloalkenyl or heteroaryl group contains at least two heteroatoms when R 2  is a substituted phenyl group, a substituted phenylalkyl group, a substituted or unsubstituted phenylalkenyl group or a substituted or unsubstituted phenylalkynyl group; or  
 provided that said alkyl, alkenyl or alkynyl moiety of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by one or more substituents selected from halo or keto; or  
 provided that said substituted phenyl group or phenyl moiety of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by one or more suitable substituents other than halo or methyl;  
 or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.  
 
     
     
         21 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a 5- or 6-membered monocyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, where said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, amino, cyano, halogen, hydroxyl, alkoxy, haloalkoxy, alkylenedioxy, di-haloalkylenedioxy, aryloxy, cycloalkoxy, cycloalkylalkoxy, cycloalkenoxy, cycloalkenylalkoxy, heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy, heteroaryloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylamino, dialkylamino, keto, alkylsulfonyl, arylsulfonyl, alkylcarbonylamino, alkylthio, haloalkylthio and arylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents are further substituted by one or more groups independently selected from alkyl, haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio, haloalkylthio and arylthio groups;  
 R 2  is a substituted alkyl group, a substituted or unsubstituted alkenyl group, or a substituted or unsubstituted alkynyl group, wherein said alkyl, alkenyl or alkynyl group is a straight or branched chained group, and  
 where said substituted alkyl, alkenyl or alkynyl group is substituted by one or more substituents independently selected from amino, cyano, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, cycloalkoxy, cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy, heteroaryloxy, alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylthio, haloalkylthio, arylthio and heteroarylthio groups, wherein any of the alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, or heteroaryl moieties present in the above substituents are further substituted by one or more groups independently selected from alkyl, haloalkyl, halogen, hydroxyl, alkoxy, haloalkoxy, alkylthio and haloalkylthio groups;  
 R 2′  is H, methyl, ethyl or propyl, where said methyl, ethyl or propyl is unsubstituted or substituted by halo or hydroxyl;  
 X is  
                     
  wherein R x  is H or one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, alkylenedioxy, di-haloalkylenedioxy, alkylamino, dialkylamino, alkylthio and haloalkylthio;  
 Z is CH 2  or CFH;  
 R 3  is H;  
 R 4 , R 1 , R 6  and R 7  are independently selected from H or methyl; and  
 R 8  and R 8′  are independently selected from H, halogen, methyl, monohalo-methyl, dihalo-methyl and tri-halomethyl;  
 or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.  
 
     
     
         22 . The compound according to  claim 21 , wherein: 
 R 1  is phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl, where said phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, halogen, and hydroxyl;    R 2  is a substituted alkyl group, a substituted or unsubstituted C 1 -C 6  alkenyl group, or a substituted or unsubstituted C 1 -C 6  alkynyl group, wherein said alkyl, alkenyl or alkynyl group is a straight or branched chained group, and    where said substituted alkyl, alkenyl or alkynyl group is substituted by one or more substituents independently selected from cyano, halogen and alkylamino;    R 2′  is H, methyl or ethyl;    X is                           wherein R x  is H, halogen, or alkoxy;    Z is CH 2  or CFH;    R 3 , R 4 , R 5 , R 8  and R 8′  are each H; and    R 6  and R 7  are independently selected from H or methyl;    or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.    
     
     
         23 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is a 5- or 6-membered mono-cyclic cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group, where said cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl group is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, amino, cyano, halogen, hydroxyl, alkoxy, haloalkoxy, alkylenedioxy, dihaloalkylenedioxy, aryloxy, cycloalkyloxy, cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy, heteroaryloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy, alkylamino, dialkylamino, kato, alkylsulfonyl, arylsulfonyl, alkylcarbonylamino, alkylthio, haloalkylthio and arylthio, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the above substituents are substituted by one or more groups independently selected from alkyl, haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio, haloalkylthio and arylthio groups;  
 R 2  is a substituted phenyl group, a substituted phenylalkyl group, a substituted or unsubstituted phenylalkenyl group or a substituted or unsubstituted phenylalkynyl group;  
 where said alkyl, alkenyl or alkynyl moiety of said phenylalkyl, phenylalkenyl or phenylalkynyl group is a straight or branched chain moiety;  
 R 2′  is H, methyl, ethyl or propyl, where said methyl, ethyl or propyl is unsubstituted or substituted with halo or hydroxyl;  
 X is  
                     
  wherein R x  is H or one or more substituents independently selected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, alkylenedioxy, di-haloalkylenedioxy, alkylamino, dialkylamino, alkylthio and haloalkylthio;  
 Z is CH 2  or CFH;  
 R 3  is H;  
 R 4 , R 5 , R 6  and R 7  are independently selected from H or methyl; and  
 R 8  and R 8′  are independently selected from H, halogen, methyl, monohalo-methyl, dihalo-methyl and tri-halomethyl;  
 provided that said 5- or 6-membered mono-cyclic heterocycloalkyl, heterocycloalkenyl or heteroaryl group contains at least two heteroatoms; or  
 provided that said alkyl, alkenyl or alkynyl moiety of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by one or more substituents selected from halo or keto; or  
 provided that said substituted phenyl group or phenyl moiety of said substituted phenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by one or more substituents other than halo or methyl, where said one or more substituents is independently selected from haloalkyl, hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, alkylcarbonylalkyl, haloalkoxyalkyl, aryloxyalkyl, alkylthioalkyl, haloalkylthioalkyl, arylthioalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitro, amino, cyano, hydroxyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, alkylenedioxy, aryloxy, cycloalkoxy, cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy, heteroaryloxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl, heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, cycloalkylaminothiocarbonyl, arylaminothiocarbonyl, heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino, arylcarbonylamino, heterocycloalkylcarbonylamino, heteroarylcarbonylamino, alkylthiocarbonylamino, cycloalkylthiocarbonylamino, arylthiocarbonylamino, heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino, alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino, arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio and heteroarylthio groups, wherein any of the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in the above substituents are unsubstituted or substituted by one or more groups independently selected from alkyl, haloalkyl, halogen, hydroxyl, alkoxy, haloalkoxy, alkylthio and haloalkylthio groups;  
 or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.  
 
     
     
         24 . The compound according to  claim 23 , wherein: 
 R 1  is phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl, where said phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, halogen, and hydroxyl;    R 2  is a substituted phenylalkyl group, where said alkyl moiety of said substituted phenylalkyl group is a straight or branched chain alkyl moiety;    R 2′  is H, methyl, ethyl or propyl, where said methyl, ethyl or propyl is unsubstituted or substituted with hydroxyl;    X is                           wherein R x  is H, halogen, or alkoxy;    Z is CH 2  or CFH;    R 3 , R 4 , R 5 , R 8  and R 8′  are each H; and    R 6  and R 7  are independently selected from H or methyl;    provided that R 1  is selected from isoxazolyl, pyrazolyl, thiazolyl or tetrahydropyridazinyl, where said is isoxazolyl, pyrazolyl, thiazolyl or tetrahydropyridazinyl is unsubstituted or substituted with one or more substituents independently selected from alkyl, haloalkyl, halogen, and hydroxyl when R 2  is a substituted or unsubstituted phenylalkyl group or    provided that R 1  is selected from phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl when R 2  is a substituted phenylalkyl group and said phenyl moiety of said substituted phenylalkyl group comprises one or more substituents other than halo or methyl, where said one or more substituents is independently selected from haloalkyl, amino, hydroxyl, alkoxy, haloalkoxy, alkylenedioxy, di-haloalkylenedioxy, cycloalkylalkyloxy, dialkylamino, alkylsulfonyl and alkylthio;    or a prodrug, pharmaceutically active metabolite or pharmaceutically active salt or solvate thereof.    
     
     
         25 . The compound, according to any one of claims  20 ,  21  or  23 , having the formula:  
       
         
           
           
               
               
           
         
         or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.  
       
     
     
         26 . The compound, according to any one of claims  20 ,  21  or  23 , having the formula:  
       
         
           
           
               
               
           
         
         or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.  
       
     
     
         27 . The compound, according to any one of claims  20 ,  21  or  23 , having the formula:  
       
         
           
           
               
               
           
         
         or a prodrug, pharmaceutically acceptable salt, pharmaceutically active metabolite, or pharmaceutically acceptable solvate thereof.  
       
     
     
         28 . A pharmaceutical composition comprising: 
 a therapeutically effective amount of at least one HIV agent selected from compounds defined in any one of claims  20 ,  21  or  23 ; and    a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.    
     
     
         29 . The pharmaceutical composition according to  claim 28  wherein the composition further comprises a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.  
     
     
         30 . The pharmaceutical composition according to  claim 29 , wherein the composition further comprises a therapeutically effective amount of at least one antiviral agent selected from the group consisting of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside HIV reverse transcriptase inhibitors.  
     
     
         31 . The pharmaceutical composition according to  claim 30 , further comprising a therapeutically effective amount of at least one HIV protease inhibitor.  
     
     
         32 . A method of treating a mammalian disease condition mediated by HIV protease activity, comprising administering to a mammal in need thereof a therapeutically effective amount of at least one compound defined in any one of claims  20 ,  21  or  23 .  
     
     
         33 . A method of inhibiting the activity of HIV protease in a subject in need thereof, comprising contacting the HIV protease with an effective amount of at least one compound defined in any one of claims  20 ,  21  or  23 .  
     
     
         34 . A method of preventing or treating infection by HIV in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to any one of claims  20 ,  21  or  23 .  
     
     
         35 . The method according to  claim 34 , wherein the compound is administered in combination with a therapeutically effective amount of at least one HIV infection/AIDS treatment agent selected from the group consisting of HIV/AIDS antiviral agents, immunomodulators, and anti-infective agents.  
     
     
         36 . A compound selected from  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and the prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts and solvates thereof.