HIV protease inhibitors

Abstract

The present invention relates to novel dihydropyrones with tethered heterocycles having improved pharmacologic properties which potently inhibit the HIV aspartyl protease blocking HIV infectivity. The dihydropyrones are useful in the development of therapies for the treatment of viral infections and diseases, including AIDS. The present invention is also directed to methods of synthesis of the dihydropyrones and intermediates useful in the preparation of the final compounds.

1 . A compound of Formula I  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof wherein: 
 R 1  is H, a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons;  
 R 2  is H, a straight or branched alkyl of 1-5 carbons;  
 R 3  is H, (CR′ 2 ) n OR, (CR′ 2 ) n N(R) 2 , (CR′ 2 ) n NR′COR, (CR′ 2 ) n CO 2 R, (CR′ 2 ) n OCOR, (CR′ 2 ) n CON(R) 2 , (CR′ 2 ) n OCON(R) 2 , (CR′ 2 ) n R, (CR′ 2 ) n NR′CON(R) 2 , (CR′ 2 ) n NR′CO 2 R, (CR′ 2 ) n OSO 2 N(R) 2 , (CR′ 2 ) n NR′SO 20 R, (CR′ 2 ) n NR′SO 2 N(R) 2 , (CR′ 2 ) n OSO 2 R, (CR′ 2 ) n NR′SO 2 R, (CR′ 2 ) n SO p R, (CR′ 2 ) n NR′CSN(R) 2 , (CR′ 2 ) n NR′C(NR′)N(R) 2 , (CR′ 2 ) n SO 2 N(R) 2 , (CR′ 2 ) n C(NR′)N(R) 2 , (CR′ 2 ) n COR, O(CR′ 2 ) m OR, NR(CR′ 2 ) m OR, F, Cl, Br, CF 3 , CN, or ═O;  
 R 4 , R 5 , and R 6  are independently H, a straight or branched alkyl of 1-6 carbons, a cycloalkyl of 3-6 carbons, (CR′ 2 ) n OR, (CR′ 2 ) n N(R) 2 , F, Cl, Br, CN, CF 3 , ═O, (CR′ 2 ) p NR′COR, (CR′ 2 ) p SO p R, (CR′ 2 ) p R, (CR′ 2 ) p OCOR, O(CR′ 2 ) m OR, NR(CR′ 2 ) m OR, (CR′ 2 ) p NR′CON(R) 2 , (CR′ 2 ) p OCON(R) 2 , (CR′ 2 ) p NR′CO 2 R, (CR′ 2 ) p COR, (CR′ 2 ) p CO 2 R, (CR′ 2 ) p CON(R) 2 , (CR 2 ) p NR′SO 2 R, (CR′ 2 ) p SO 2 N(R) 2 , (CR′ 2 ) p NR′SO 2 OR, (CR′ 2 ) p OSO 2 N(R) 2 , (CR 2 ) p NR′SO 2 N(R) 2 , (CR′ 2 ) p C(NR′)N(R) 2 , (CR′ 2 ) p NR′C(NR′)N(R) 2 , (CR′ 2 ) p Het;  
 any two of R 1 -R 3  or R 4 -R 6  may together form a ring of 5-6 total atoms which may contain 0-3 heteroatoms;  
 n is an integer of from 0 to 3;  
 m is an integer of from 2 to 4;  
 p is an integer from 0 to 2;  
 R 7  is a straight or branched alkyl of 1-6 carbons or a carbocycle of 3-6 carbons;  
 R is independently H, a straight or branched alkyl of 1-4 carbons, (CH 2 ) n Ph, or a (CH 2 ) n heterocycle of 5-6 atoms containing 1-2 heteroatoms and wherein the (R) 2  in N(R) 2  may form a heterocycle containing the nitrogen, all optionally substituted by F, Cl, Br, OR′, CN, CO 2 R′, N(R′) 2 , NR′COR′, CF 3 , or ═O;  
 R′ is independently H, a straight or branched alkyl of 1-4 carbons, or phenyl;  
 R″ is independently H, a straight or branched alkyl of 14 carbons, F, Cl, Br, OR′ or N(R′) 2 ;  
 Ar 1  and Ar 2  are independently phenyl or Het with the proviso that at least one Ar is Het;  
 Het is a heterocycle of from 5-6 atoms having from 1-4 heteroatoms or a fused heterocycle of from 9-10 atoms having 1-3 heteroatoms.  
 
     
     
         2 - 18 . (canceled).  
     
     
         19 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with AZT.  
     
     
         20 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with ddC.  
     
     
         21 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with an HIV protease inhibitor.  
     
     
         22 - 45 . (canceled).  
     
     
         46 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with AZT and another antiretroviral agent.  
     
     
         47 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with ddC and another antiretroviral agent.  
     
     
         48 . A method of treatment of infection or disease caused by a retrovirus, which comprises administering to a subject in need of such treatment a compound of  claim 1  in combination with an HIV protease inhibitor and another antiretroviral agent.