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 . A compound having the Formula I:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a carbocyclic group;  
         V is C═O, C═S or SO 2 ;  
         R 2  is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, a heterocyclic-aliphatic group or N(R 2a )R 2b , wherein R 2a  is an aliphatic, carbocyclic or heterocyclic group, and R 2b  is H or a C 1 -C 6  aliphatic group;  
         W is N;  
         R 2′  is H or a C 1 -C 6  aliphatic group or R 2  and R 2′  taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;  
         X is  
         
           
             
             
                 
                 
             
           
         
         where R x  is H or one or more substituents independently selected from C 1 -C 6  alkyl, nitro, amino, cyano, halogen, C 1 -C 6  haloalkyl, hydroxyl, C 1 -C 6  alkoxy, alkylenedioxy, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkyloxycarbonyl, C 1 -C 6  alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C 1 -C 6  alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, di-C 1 -C 6 -alkylaminothiocarbonyl, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylsulfenyl, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  alkylthiocarbonylamino, C 1 -C 6  alkylsulfonyloxy, C 1 -C 6  alkylsulfonylamino, mercapto, and C 1 -C 6  alkylthio;  
         R 8  and R 8′  are each independently H, halo or a C 1 -C 4  aliphatic group;  
         A is CH 2 , CH(R A ) or is absent;  
         Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ), CH(S—R Z ), C(═O), or CH(R Z ), where R Z  is a C 1 -C 6  aliphatic group or a carbocyclic or heterocyclic group and R Z′  is H or a C 1 -C 6  aliphatic group;  
         or R A  and R Z  , taken together with A and Z form an unsubstituted or substituted 5 or 6 membered carbocyclic or heterocyclic ring;  
         R 3  is H or a C 1 -C 6  aliphatic group;  
         R 4  and R 5  are independently selected from H, halo, a C 1 -C 6  aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′  is an aliphatic, carbocyclic or heterocyclic group;  
         or R 4  and R 5 , taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic ring;  
         or R 4  and R 6  or R 7 , together with the atoms to which they are bound, form an unsubstituted or substituted carbocyclic ring;  
         R 6  and R 7  are independently selected from H, halo or a C 1 -C 6  aliphatic group;  
         or R 6  and R 7 , taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic or heterocyclic group;  
         wherein any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and  
         wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;  
         provided that R 2  is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when A is absent, Z is CHF or CH 2 , V is C═O; W is N, R 2 , R 3 , R 8  and R 8′  are H or a C 1 -C 4  alkyl group, R 4 , R 5 , R 6  and R 7  are H or a C 1 -C 6  alkyl group,  
         X is  
         
           
             
             
                 
                 
             
           
         
         and R 1  is a substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic group;  
         or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.  
       
     
     
         2 . A compound having the Formula I-A:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a mono-, bi- or tri-cyclic carbocyclic group;  
         R 2  is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;  
         R 2′  is H or a C 1 -C 6  alkyl group;  
         or R 2  and R 2′  taken together with the nitrogen atom to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;  
         X is  
         
           
             
             
                 
                 
             
           
         
         wherein R x  is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;  
         R 8  and R 8′  are each independently H, halo or a C 1 -C 4  aliphatic group;  
         Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ),  
         CH(S—R Z ), C(═O), or CH(R Z ), where R Z  is a C 1 -C 6  aliphatic group or a carbocyclic or heterocyclic group and R Z′  is H or a C 1 -C 6  aliphatic group;  
         R 3  is H or a C 1 -C 6  aliphatic group;  
         R 4  and R 5  are independently selected from H, halo, a C 1 -C 6  aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′  is an aliphatic, carbocyclic or heterocyclic group;  
         R 6  and R 7  are independently selected from H, halo or a C 1 -C 6  aliphatic group;  
         wherein any of said aliphatic groups are unsubstituted or substituted by one or more suitable substituents and saturated, partially unsaturated or fully unsaturated; and  
         wherein any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic saturated, partially unsaturated or fully unsaturated or unsubstituted or substituted by one or more suitable substituents;  
         provided that R 2  is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is CHF or CH 2 , R 2 , R 3 , R 8  and R 8′  are H or a C 1 -C 4  alkyl group, R 4 , R 5 , R 6  and R 7  are H or a C 1 -C 6  alkyl group, X is  
         
           
             
             
                 
                 
             
           
         
         and R 1  is a substituted or unsubstituted 5- or 6-membered mono-cyclic carbocyclic group;  
         or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.  
       
     
     
         3 . The compound, prodrug, salt, or solvate according to  claim 2 , wherein: 
 R 1  is a 5- or 6-membered monocyclic carbocyclic group; and    R 2  is cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, a bi- or tri-cyclic carbocyclic group, a bi- or tri-cyclic carbocyclic-alkyl group, a bi- or tri-cyclic carbocyclic-alkenyl group, a bi- or tri-cyclic carbocyclic-alkynyl group, a heterocyclic group, a heterocyclic-alkyl group, a heterocyclic-alkenyl group or a heterocyclic-alkynyl group.    
     
     
         4 . The compound, prodrug, salt, or solvate according to  claim 2 , wherein: 
 R 1  is a bi- or tri-cyclic carbocyclic group, wherein said carbocyclic group is saturated, partially unsaturated or fully unsaturated; and unsaturated or substituted by one or more suitable substituents.    
     
     
         5 . A compound having the Formula I-A′:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a bi- or tri-cyclic cycloalkyl, cycloalkenyl, or aryl group;  
         R 2  is a cycloalkyl, cycloalkylalkyl, cycloalkenyl, or cycloalkenylalkyl group, a bi- or tri-cyclic aryl group, a bi- or tri-cyclic arylalkyl group, a bi- or tri-cyclic arylalkenyl group, a bi- or tri-cyclic arylalkynyl group, or a heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkenyl, heterocycloalkenylalkyl, heteroaryl or heteroarylalkyl group;  
         R 2′  is H or a C 1 -C 6  alkyl group;  
         or R 2  and R 2′  taken together with the nitrogen atom to which they are attached form a heterocycloalkyl or heterocycloalkenyl ring;  
         X is  
         
           
             
             
                 
                 
             
           
         
         wherein R x  is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;  
         Z is CH 2 , CHF, CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ), CH(S—R Z ), C(═O), or CH(R Z ), where R Z  is a C 1 -C 6  aliphatic group or a carbocyclic or heterocyclic group and R Z′  is H or a C 1 -C 6  aliphatic group;  
         R 3  is H or a C 1 -C 6  aliphatic group;  
         R 4  and R 5  are independently selected from H, halo, and a C 1 -C 6  aliphatic group;  
         R 6  and R 7  are independently selected from H, halo and a C 1 -C 6  aliphatic group;  
         where any of the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl groups or the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl or heteroaryl moieties of the cycloalkylalkyl, cycloalkenylalkyl, arylalkyl, heterocycloalkylalkyl, heterocycloalkenylalkyl, heteroarylalkyl, cycloalkylalkenyl, cycloalkenylalkenyl, arylalkenyl, heterocycloalkylalkenyl, heterocycloalkenylalkenyl, heteroarylalkenyl, cycloalkylalkynyl, cycloalkenylalkynyl, arylalkynyl, heterocycloalkylalkynyl, heterocycloalkenylalkynyl, and heteroarylalkynyl groups are unsubstituted or substituted by one or more suitable substituents; and  
         where any of said carbocyclic or heterocyclic groups are mono-, bi- or tri-cyclic; saturated, partially unsaturated or fully unsaturated, and unsubstituted or substituted by one or more suitable substituents;  
         provided that R 2  is not an aliphatic group, a phenyl group or a phenyl-substituted aliphatic group, when Z is CHF or CH 2 , R 2′  and R 3  are H or a C 1 -C 4  alkyl group, R 4 , R 5 , R 6  and R 7  are H or a C 1 -C 6  alkyl group, X is  
         
           
             
             
                 
                 
             
           
         
         and R 1  is a substituted or unsubstituted 5 or 6-membered mono-cyclic carbocyclic group;  
         or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.  
       
     
     
         6 . The compound, prodrug, salt, or solvate according to  claim 7 , wherein: 
 Z is CF 2 , CH(OH), CH(O—R Z ), CH(N—R Z R Z′ ), CH(S—R Z ), C═O or CH(R Z ), where R Z  is a C 1 -C 6  aliphatic group or a carbocyclic or heterocyclic group and R Z′  is H a C 1 -C 6  aliphatic group.    
     
     
         7 . A compound having the Formula I-C:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a carbocyclic group;  
         R 2  is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;  
         W is N;  
         R 2′  is H or a C 1 -C 6  alkyl group or R 2  and R 2′  taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;  
         X is  
         
           
             
             
                 
                 
             
           
         
         R x  is H or one or more substituents independently selected from alkyl, nitro, amino, cyano, halogen, haloalkyl, hydroxyl, alkoxy, alkylenedioxy, alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, carboxyl, carbamoyl, formyl, alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, and alkylthio;  
         R 8  and R 8′  are each independently H, halo or a C 1 -C 4  aliphatic group;  
         Z is CF 2 , CH(OH), CH(O—R Z ) or CH(R Z ), where R Z  is a C 1 -C 6  aliphatic group or a carbocyclic or heterocyclic group;  
         R 3  is H or a C 1 -C 6  aliphatic group;  
         R 4  and R 5  are independently selected from H, halo, a C 1 -C 6  aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′  is an aliphatic, carbocyclic or heterocyclic group;  
         R 6  and R 7  are independently selected from H, halo or a C 1 -C 6  aliphatic group;  
         where any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and  
         where any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; mono-, bi- or tri-cyclic;  
         or a prodrug, pharmaceutically acceptable salt or solvate thereof.  
       
     
     
         8 . A compound having the Formula I-C:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a carbocyclic group;  
         R 2  is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;  
         W is N;  
         R 2′  is H or a C 1 -C 6  alkyl group;  
         X is  
         
           
             
             
                 
                 
             
           
         
         wherein R x  is H dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, alkylsulfonyl, alkylsulfenyl, alkylcarbonylamino, alkylthiocarbonylamino, alkylsulfonyloxy, alkylsulfonylamino, mercapto, or alkylthio;  
         Z is CF 2 , CH(OH) or C(═O);  
         R 3 , R 4  and R 5  are each H; and  
         R 6  and R 7  are each methyl;  
         or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.  
       
     
     
         9 . The compound, prodrug, salt, or solvate according to  claim 8 , wherein: 
 R 1  is an aryl group;    R 2  is an alkyl, alkenyl, or alkynyl group, an arylalkyl group; a heteroarylalkyl group, an indanyl group, a chromanyl group, a tetrahydronaphthalene group, an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, or a heterocyclic-aliphatic group;    R 2′  is H;    wherein the alkyl, alkenyl, alkynyl, arylalkyl, heteroarylalkyl, indanyl, chromanyl or tetrahydronaphthalene group is unsubstituted or substituted with one or more substituents independently selected from alkyl, hydroxy, halo, haloalkyl, cyano, alkoxy and methylenedioxy.    
     
     
         10 . A compound of formula I-C:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a phenyl group, where the phenyl group is unsubstituted or substituted by at least one substitutent selected from hydroxyl and methyl;  
         R 2  is an C 1 -C 5  alkyl, C 1 -C 6  alkenyl, or C 1 -C 4  alkynyl group, a benzyl group; a furanylmethyl group, a thienylmehtyl group, an indanyl group, a chromanyl group, a tetrahydronaphthalene group, or a cyclohexenyl group, where the alkyl groups is unsubstituted or substituted with one or more halogen; and the phenyl group is unsubstituted or substituted with halogen, hydroxyl, methoxy, methylenedioxy or methyl;  
         R 2′  is H;  
         X is  
         
           
             
             
                 
                 
             
           
         
         wherein R x  is H;  
         Z is CF 2 ;  
         R 3 , R 4  and R 5  are each H; and  
         R 6  and R 7  are each methyl;  
         or a prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate thereof.  
       
     
     
         11 . The compound, prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to  claim 1 , having the formula:  
       
         
           
           
               
               
           
         
         wherein R 1 -R 8 , R 2′ , R 8′ , V, X, A, Z and W are as defined in  claim 1 .  
       
     
     
         12 . The compound, prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to  claim 1 , having the formula:  
       
         
           
           
               
               
           
         
         wherein R 1 -R 8 , R 2′ , R 8′ , V, X, A, Z and W are as defined in  claim 1 .  
       
     
     
         13 . The compound, prodrug, pharmaceutically acceptable salt, or pharmaceutically acceptable solvate according to  claim 1 , having the formula:  
       
         
           
           
               
               
           
         
         wherein R 1 -R 8 , R 2′ , R 8′ , V, X, A, Z and W are as defined in  claim 1 .  
       
     
     
         14 . A pharmaceutical composition comprising: 
 a therapeutically effective amount of at least one HIV agent selected from compounds, prodrugs, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates defined in any one of claims  1 ,  2 ,  7  or  8 ; and    a pharmaceutically acceptable carrier, diluent, vehicle, or excipient.    
     
     
         15 . The pharmaceutical composition according to  claim 14 , 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.  
     
     
         16 . The pharmaceutical composition according to  claim 15 , 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.  
     
     
         17 . The pharmaceutical composition according to  claim 16 , further comprising a therapeutically effective amount of at least one HIV protease inhibitor.  
     
     
         18 . A compound selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or the prodrugs, and pharmaceutically acceptable salts and solvates thereof.  
     
     
         19 . A compound having the formula:  
       
         
           
           
               
               
           
         
         wherein:  
         R 1  is a carbocyclic;  
         R 2  is an aliphatic group, a carbocyclic group, a carbocyclic-aliphatic group, a heterocyclic group, a heterocyclic-aliphatic group or N(R 2a )R 2b , wherein R 2a  is an aliphatic, carbocyclic or heterocyclic group, and R 2b  is H or a C 1 -C 6  aliphatic group;  
         W is N;  
         R 2′  is H or a C 1 -C 6  aliphatic group or R 2  and R 2′  taken together with the atom W to which they are attached form an unsubstituted or substituted carbocyclic or heterocyclic ring;  
         X is  
         
           
             
             
                 
                 
             
           
         
         R x  is H or one or substituents independently selected from C 1 -C 6  alkyl, nitro, amino, cyano, halogen, C 1 -C 6  haloalkyl, hydroxyl, C 1 -C 6  alkoxy, alkylenedioxy, C 1 -C 6  alkylcarbonyl, C 1 -C 6  alkyloxycarbonyl, C 1 -C 6  alkylcarbonyloxy, carboxyl, carbamoyl, formyl, C 1 -C 6  alkylamino, dialkylamino, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, di-C 1 -C 6 -alkylaminothiocarbonyl, C 1 -C 6  alkylsulfonyl, C 1 -C 6  alkylsulfenyl, C 1 -C 6  alkylcarbonylamino, C 1 -C 6  alkylthiocarbonylamino, C 1 -C 6  alkylsulfonyloxy, C 1 -C 6  alkylsulfonylamino, mercapto, and C 1 -C 6  alkylthio;  
         R 3  is H or a C 1 -C 6  aliphatic group;  
         R 4  and R 5  are independently selected from H, halo, a C 1 -C 6  aliphatic group or a group having the formula C(O)R 4′ , wherein R 4′  is an aliphatic, carbocyclic or heterocyclic group;  
         or R 4  and R 5 , taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic ring;  
         R 6  and R 7  are independently selected from H, halo or a C 1 -C 6  aliphatic group;  
         or R 6  and R 7 , taken together with the atom to which they are bound, form an unsubstituted or substituted carbocyclic or heterocyclic group;  
         wherein any of said aliphatic groups are saturated, partially saturated or fully unsaturated and unsubstituted or substituted by one or more suitable substituents; and  
         wherein any of said carbocyclic or heterocyclic groups are unsubstituted or substituted by one or more suitable substituents; saturated, partially unsaturated or fully unsaturated; or mono-, bi- or tri-cyclic;  
         or a prodrug, pharmaceutically aceptable salt, or pharmaceutically acceptable solvate thereof.