Cyclic sulfone containing retroviral protease inhibitors

Abstract

The present invention relates to cyclic sulfone moiety-containing hydroxyethylamine protease inhibitor compounds and pharmaceutical or method of use therefor, particularly as an inhibitor of HIV protease.

1 . A compound having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof wherein W represents  
       
         
           
           
               
               
           
         
       
       Y′ represents ═O, ═S or ═NR 15 , wherein R 15  represents a hydrogen radical, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or mono- or di-substituted aminoalkyl that are mono- or di-substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, or, in the case of di-substituted aminoalkyl, said two substituents along with the nitrogen atom to which they are bonded form heterocycloalkyl or heteroaryl;  
       t represents 0, 1, or 2;  
       t′ represents 1 or 2;  
       u represents 0, 1, or 2;  
       R 40 , R 41 , R 42 , R 43 , R 48 , R 49 , R 50  and R 51  independently represent a hydrogen radical or alkyl; R 44 , R 45 , R 46 , and R 47  independently represent a hydrogen radical, alkyl, or hydroxy; or one of (a) R 40  together with R 48 , (b) R 43  together with R 45 , (c) R 45  together with R 47  and (d) R 47  together with R 48 , represent a bond; or one of (a) R 44  together with R 45  and the carbon atom to which they are bonded, (b) R 46  together with R 47  and the carbon atom to which they are bonded and (c) R 50  together with R 51  and the carbon atom to which they are bonded, represent carbonyl;  
       R 6  represents a hydrogen radical or alkyl;  
       R 2  represents alkyl, aryl, cycloalkyl, cycloalkylalkyl, or aralkyl, each of which may optionally be substituted with a substituent selected from the group consisting of alkyl, —NO 2 , —CN, —CF 3 , —OR 9 , —SR 9 , and halogen, wherein R 9  represents a hydrogen radical or alkyl;  
       Q represents  
       
         
           
           
               
               
           
         
       
       R 3  represents isobutyl, n-propyl, n-butyl, isoamyl, cyclohexylmethyl, or cyclohexyl;  
       Y represents a radical as defined for Y′;  
       X represents N, CH, or O;  
       R 4  and R 5  independently represent a hydrogen radical, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or mono- or di-substituted aminoalkyl that are mono- or di-substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, or, in the case of di-substituted aminoalkyl, said two substituents along with the nitrogen atom to which they are bonded form heterocycloalkyl or heteroaryl, or when X represents N, R 4  and R 5  together with N represent heterocycloalkyl or heteroaryl, or when X represents CH, R 4  and R 5  together with CH represent cycloalkyl, with the proviso that R 5  is absent when X is O;  
       R 4′  and R 5′  together with the nitrogen atom to which they are bonded form an N-heterocyclic moiety;  
       R 4″ , R 9 , and R 9′  independently represent a radical as defined for R 3 ;  
       q represents 1 or 2;  
       n represents 0, 1, 2, 3, 4, 5, or 6;  
       R 7  and R 7′  independently represent a hydrogen radical, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or mono- or di-substituted aminoalkyl that are mono- or di-substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, or, in the case of di-substituted aminoalkyl, said two substituents along with the nitrogen atom to which they are bonded form heterocycloalkyl or heteroaryl, or R 7  and R 7′  independently represent a side chain of an amino acid selected from the group consisting of valine, isoleucine, glycine, alanine, alloisoleucine, asparagine, leucine, glutamine, and t-butylglycine, or R 7  and R 7′  together with the carbon atom to which they are bonded form cycloalkyl;  
       R 8  represents cyano, hydroxyl, alkyl, alkoxy, cycloalkyl, aryl, aralkyl, heterocycloalkyl, heteroaryl, —C(O)R 16 , —CO 2 R 16 , —SO 2 R 16 , —SR 16 , —CONR 16 R 17 , —CF 3 , or —NR 16 R 17 ;  
       wherein R 16  and R 17  independently represent a hydrogen radical, alkyl, haloalkyl, alkenyl, alkynyl, hydroxyalkyl, alkoxyalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heteroaryl, heterocycloalkylalkyl, aryl, aralkyl, heteroaralkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, the sulfone or sulfoxide derivatives of thioalkyl, alkylthioalkyl, or arylthioalkyl, aminoalkyl, or mono- or di-substituted aminoalkyl that are mono- or di-substituted with one or two substituents independently selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroaralkyl, heterocycloalkyl, or heterocycloalkylalkyl, or, in the case of di-substituted aminoalkyl, said two substituents along with the nitrogen atom to which they are bonded form heterocycloalkyl or heteroaryl, or, in the case of —NR 16 R 17 , R 16  and R 17  together with a nitrogen atom to which they are bonded represent hetrocycloalkyl or heteroaryl.  
     
   
   
       2 . A compound of  claim 1  or a pharmaceutically acceptable salt thereof wherein W represents (a).  
   
   
       3 . A compound of  claim 2  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       4 . A compound of  claim 3  or a pharmaceutically acceptable salt thereof wherein t represents 1, R 6  represents a hydrogen radical, and R 2  represents aralkyl, alkyl, or cycloalkylalkyl.  
   
   
       5 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       6 . A compound of  claim 5  or a pharmaceutically acceptable salt thereof wherein Y and Y′ represent ═O, R 6  represents a hydrogen radical, t represents 1, and X represents N.  
   
   
       7 . A compound of  claim 5  wherein R 2  represents benzyl, cyclohexylmethyl, n-butyl, 2-naphthylmethyl, p-fluorobenzyl, or isobutyl.  
   
   
       8 . A compound of  claim 5  or a pharmaceutically acceptable salt thereof wherein R 4  and R 5  independently represent a hydrogen radical, methyl, ethyl, isopropyl, or t-butyl, or R 4  and R 5  together with the nitrogen atom to which they are bonded represent heterocycloalkyl having 5 to 8 ring members.  
   
   
       9 . A compound of  claim 5  wherein R 3  is isobutyl or isoamyl.  
   
   
       10 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof.  
     
   
   
       11 . A compound of  claim 10  or a pharmaceutically acceptable salt thereof wherein Y′ represents ═O, t represents 1, and R 6  represents a hydrogen radical.  
   
   
       12 . A compound of  claim 10  or a pharmaceutically acceptable salt thereof wherein R 2  represents benzyl, p-fluorobenzyl, cyclohexylmethyl, 2-naphthylmethyl, n-butyl, or isobutyl.  
   
   
       13 . A compound of  claim 10  or a pharmaceutically acceptable salt thereof wherein  
     
       
         
         
             
             
         
       
       represents  
       
         
           
           
               
               
           
         
       
     
   
   
       14 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 3  represents isobutyl or isoamyl.  
     
   
   
       15 . A compound of  claim 14  or a pharmaceutically acceptable salt thereof wherein Y′ represents ═O, t represents 1, R 6  represents a hydrogen radical, and q represents 2.  
   
   
       16 . A compound of  claim 14  or a pharmaceutically acceptable salt thereof wherein R 2  represents benzyl, p-fluorobenzyl, cyclohexylmethyl, 2-naphthylmethyl, n-butyl, or isobutyl.  
   
   
       17 . A compound of  claim 14  or a pharmaceutically acceptable salt thereof wherein R 4 ″ represents aryl or heteroaryl.  
   
   
       18 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 3  represents isobutyl or isoamyl.  
     
   
   
       19 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 3  represents isobutyl or isoamyl.  
     
   
   
       20 . A compound of  claim 3  having the formula  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof, wherein R 3 represents isobutyl or isoamyl.