Hiv protease inhibitors, compositions containing the same, their pharmaceutical uses, 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 process for preparing a compound of formula (I-A), or a prodrug, pharmaceutically active metabolite, or pharmaceutically active salt or solvate thereof,  
     
       
         
         
             
             
         
       
     
     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 optionally substituted by at least one substituent chosen from C 1-6  alkyl, hydroxyl, C 1-6  alkylcarbonyloxy, C 6-10  arylcarbonyloxy, and heteroarylcarbonyloxy;  
 R 2  is C 2-6  alkenyl or C 1-6  alkyl optionally substituted with at least one halogen;  
 R 2′  is H or C 1-4  alkyl;  
 Z is S, O, SO, SO 2 , CH 2  or CFH;  
 R 3  is H or C 1 -C 4  alkyl; and  
 R 4 , R 5 , R 6  and R 7  are independently chosen from H and C 1 -C 6  alkyl;  
 prepared by:  
 reacting a compound of formula (II), wherein Y 1  is hydroxyl or a leaving group, with a compound of formula (III), or a salt or solvate thereof,  
                     
 
   
   
       2 . A process according to  claim 1 , wherein in the compound of formula (II), Y 1  is hydroxyl.  
   
   
       3 . A process according to  claim 1 , wherein in the compound of formula (I-A): 
 R 1  is phenyl optionally substituted by at least one substituent independently chosen from C 1-6  alkyl, hydroxyl, C 1-6  alkylcarbonyloxy, C 6-10  arylcarbonyloxy, and heteroarylcarbonyloxy; and    R 4 , R 5 , R 6  and R 7  are independently chosen from H and methyl.    
   
   
       4 . A process according to  claim 3 , wherein in the compound of formula (I-A): 
 R 2′  is H; and    Z is S, O, SO, or SO 2 .    
   
   
       5 . A process according to  claim 4 , wherein in the compound of formula (I-A) R 2  is C 2-6  alkenyl.  
   
   
       6 . A process according to  claim 5 , wherein in the compound of formula (I-A): 
 Z is S or O; and    R 3  is H.    
   
   
       7 . A process according to  claim 6 , wherein in the compound of formula (I-A): 
 Z is S;    R 4  and R 5  are H; and    R 6  and R 7  are methyl.    
   
   
       8 . A process according to  claim 7 , wherein in the compound of formula (I-A), R 1  is phenyl substituted by at least one substituent independently chosen from C 1-6  alkyl, hydroxyl, C 1-6  alkylcarbonyloxy, C 6-10  arylcarbonyloxy, and heteroarylcarbonyloxy.  
   
   
       9 . A process according to  claim 8 , wherein in the compound of formula (I-A): 
 R 1  is phenyl substituted by C 1-6  alkyl and hydroxyl; and    R 2  is allyl.    
   
   
       10 . A process according to  claim 9 , wherein in the compound of formula (I-A), R 1  is phenyl substituted by methyl and hydroxyl.  
   
   
       11 . A process according to  claim 10 , wherein the compound of formula (I-A) is:  
     
       
         
         
             
             
         
       
     
   
   
       12 . A process according to  claim 8 , wherein in the compound of formula (I-A), R 1  is phenyl substituted by at least one substituent independently chosen from C 1-6  alkyl and C 1-6  alkylcarbonyloxy.  
   
   
       13 . A process according to  claim 12 , wherein in the compound of formula (I-A): 
 R 1  is phenyl substituted by methyl and methylcarbonyloxy; and    R 2  is allyl.    
   
   
       14 . A process according to  claim 13 , wherein the compound of formula (I-A) is:  
     
       
         
         
             
             
         
       
     
   
   
       15 . A process for preparing a compound of formula (I-B),  
     
       
         
         
             
             
         
       
     
     comprising: 
 reacting a compound of formula (II-A) with a compound of formula (III-A), or a salt or solvate thereof,  
                     
 
   
   
       16 . A process for preparing a compound of formula (I-C),  
     
       
         
         
             
             
         
       
     
     comprising: 
 (i) reacting a compound of formula (II-A) with a compound of formula (III-A), or a salt or solvate thereof,  
                     
  to afford a compound of formula (I-B); and  
 (ii) deprotecting the compound of formula (I-B).  
 
   
   
       17 . A process for preparing a compound of formula (I-C),  
     
       
         
         
             
             
         
       
     
     comprising: 
 reacting a compound of formula (II-B) with a compound of formula (III-A), or a salt or solvate thereof,