Inhibitors of aspartyl protease

Abstract

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

We claim:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof;  
       wherein: 
 A is selected from H; Ht; —R 1 -Ht; —R 1 —C 1 -C 6  alkyl, which is optionally substituted with one or more groups independently selected from hydroxy, —CN, C 1 -C 4  alkoxy, Ht, —O-Ht, —NR 2 -Ht, —NR 2 —CO—N(R 2 ) 2 , —SO 2 —N(R 2 ) 2 , —SO 2 —R 2  or —CO—N(R 2 ) 2 ; —R 1 —C 2 -C 6  alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4  alkoxy, Ht, —O-Ht, —NR 2 —CO—N(R 2 ) 2  or —CO—N(R 2 ) 2 ; or R 7 ;  
 each R 1  is independently selected from —C(O)—, —S(O) 2 —, —C(O)—C (O)—, —O—C(O)—, —O—S (O) 2 , —NR 2 —, —NR 2 —S(O) 2 —, —NR 2 —C(O)— or —NR 2 —C(O)—C(O)—;  
 each Ht is independently selected from C 3 -C 7  cycloalkyl; C 5 -C 7  cycloalkenyl; C 6 -C 14  aryl; or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R 2 ), O, S and S(O) n ; wherein said aryl or said heterocycle is optionally fused to Q; and wherein any member of said Ht is optionally substituted with one or more substituents independently selected from oxo, —OR 2 , SR 2 , —R 2 , —N(R 2 )(R 2 ), —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2 , —S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —N(R 2 )—C(O)O—R 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n -Q, methylenedioxy, —N(R 2 )—S(O) 2  (R 2 ), halo, —CF 3 , —NO 2 , Q, —OQ, —OR 7 , —SR 7 , —R 7 , —N(R 2 )(R 7 ) or —N(R 7 ) 2 ;  
 each R 2  is independently selected from H, or C 1 -C 4  alkyl optionally substituted with a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O) n  or N(R 33 ); wherein any of said ring systems or N(R 33 ) is optionally substituted with 1 to 4 substituents independently selected from —X′—Y′, —O-arylalkyl, —S-arylalkyl, —N(Y′) 2 , —N(H)-arylalkyl, —N(C 1 -C 4  alkyl)-arylalkyl, oxo, —O—(C 1 -C 4  alkyl), OH, C 1 -C 4  alkyl, —SO 2 H, —SO 2 —(C 1 -C 4  alkyl), —SO 2 —NH 2 , —SO 2 —NH(C 1 -C 4  alkyl), —SO 2 —N(C 1 -C 4  alkyl) 2 , —NH 2 , —NH(C 1 -C 4  alkyl), —N(C 1 -C 4  alkyl) 2 , —NH—C(O)H, —N(C 1 -C 4  alkyl)—C(O)H, —NH—C(O)—C 1 -C 4  alkyl, —C 1 -C 4  alkyl-OH, —OH, —CN, —C(O)OH, —C(O)O—C 1 -C 4  alkyl, —C(O)—NH 2 , —C(O)—NH(C 1 -C 4  alkyl), —C(O)—N(C 1 -C 4  alkyl) 2 , halo or —CF 3 ;  
 X′ is —O—, —S—, —NH—, —NHC(O)—, —NHC(O)O—, —NHSO 2 —, or —N(C 1 -C 4 )alkyl-;  
 Y′ is C 1 -C 5  alkyl, C 2 -C 15  alkenyl or alkynyl, wherein one to five carbon atoms in Y are optionally substituted with C 3 -C 7  cycloalkyl or C 5 -C 6  cycloalkenyl, C 6 -C 14  aryl or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, NH, O, S and S(O) n ;  
 each R 3  is independently selected from H, Ht, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 5 -C 6  cycloalkenyl; wherein any member of said R 3 , except H, is optionally substituted with one or more substituents selected from —OR 2 , —C(O)—N(R 2 ) 2 , —S(O) n —N(R 2 ) 2 , —N(R 2 ) 2 , —N(R 2 )—C(O)O(R 2 ), —N(R 2 )—C(O)N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 Ht, —CN, —SR 2 , —C(O)OR 2 , N(R 2 )—C(O)—R 2 ;  
 each R 33  is selected from H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 6  cycloalkyl or C 5 -C 6  cycloalkenyl, C 6 -C 14  aryl or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, NH, O, S and S(O) n ;  
 each n is independently 1 or 2;  
 G, when present, is selected from H, R 7  or C 1 -C 4  alkyl, or, when G is C 1 -C 4  alkyl, G and R 7  are bound to one another either directly or through a C 1 -C 3  linker to form a heterocyclic ring; or  
 when G is not present (i.e., when x in (G) x  is 0), then the nitrogen to which G is attached is bound directly to the R 7  group in —OR 7  with the concomitant displacement of one -ZM group from R 7 ;  
 D is selected from C 1 -C 6  alkyl which is substituted with Q, which is optionally substituted with one or more groups selected from C 3 -C 6  cycloalkyl, —R 3 , —O-Q or Q; C 2 -C 4  alkenyl which is substituted with Q, which is optionally substituted with one or more groups selected from —OR 2 , —S-Ht, —R 3 , —O-Q or Q; C 3 -C 6  cycloalkyl, which is optionally substituted with or fused to Q; or C 5 -C 6  cycloalkenyl, which is optionally substituted with or fused to Q;  
 each Q is independently selected from a 3-7 membered saturated, partially saturated or unsaturated carbocyclic ring system; or a 5-7 membered saturated, partially saturated or unsaturated heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O) n  or N(R 2 ); wherein Q contains one substituent selected from —OR 2 , —OR 8 , —O-arylalkyl, —SR 8 , —S-arylalkyl, —N(R 2 )R 8 , —N(R 2 )-arylalkyl and may be optionally substituted with one or more additional substituents independently selected from oxo, —OR 8 , —O-arylalkyl —SR 8 , —S-arylalkyl, —N(R 2 )R 8 , —N(R 2 )-arylalkyl, —OR 2 , —R 2 , —SO 2 R 2 , —SO 2 —N(R 2 ) 2 , —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —OH, (C 1 -C 4 )—OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2 , halo or —CF 3 ;  
 each R 8  is independently selected from Ht, —C 1 -C 15  branched or straight chain alkyl, alkenyl or alkynyl wherein one to five carbon atoms in said alkyl, alkenyl or alkynyl are independently replaced by W, or wherein one to five carbon atoms in said alkyl, alkenyl or alkynyl are substituted with Ht; and wherein R 8  is additionally and optionally substituted with one or more groups independently selected from —OH, —S(C 1 -C 6  alkyl), —CN, —CF 3 , —N(R 2 ) 2 , halo, —C 1 -C 4 -alkyl, —C 1 -C 4 -alkoxy; -Ht; —O-Ht; —NR 2 —CO—N(R 2 ) 2 ; —CO—N(R 2 ) 2 ; —R 1 —C 2 -C 6  alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4  alkoxy, Ht, —O-Ht, —NR 2 —CO—N(R 2 ) 2  or —CO—N(R 2 ) 2 ; or R 7 ;  
 wherein W is —O—, —NR 2 , —S—, —C(O)—, —C(S)—, —C(═NR 2 )—, —S(O) 2 —, —NR 2 —S(O) 2 —, —S(O) 2 —NR 2 —, —NR 2 —C(O) O—,O—C(O)NR 2 —, —NR 2 —C(O)NR 2 —, —NR 2 —C(S)NR 2 —, —CONR 2 , —NR 2 C (O)—, —C(S)NR 2 , —NR 2 C(S)—, —NR 2 —C(═N—CN)—NR 2 —, —NR 2 C(═N—CN)O— or —C(O)O—;  
 D′ is selected from C 1 -C 15  alkyl, C 1 -C 15  alkoxy, C 2 -C 15  alkenyl, C 2 -C 15  alkenyloxy, C 2 -C 15  alkynyl, or C 2 -C 15  alkynyloxy, wherein D′ optionally comprises one or more substituents independently selected from Ht, oxo, halo, —CF 3 , —OCF 3 , —NO 2 , azido, —SH, —SR 3 , —N(R 3 )—N(R 3 ) 2 , —O—N(R 3 ) 2 , —(R 3 )N—O—(R 3 ), —N(R 3 ) 2 , —CN, —CO 2 R 3 , —C(O)—N(R 3 ) 2 , —S(O) n —N(R 3 ) 2 , —N(R 3 )—C(O)—R 3 , —N(R 3 )—C(O)—N(R 3 ) 2 , —C(O)—R 3 , —S(O) n —R 3 , —N(R 3 )—S(O) n (R 3 ), —N(R 3 )—S(O) n —N(R 3 ) 2 , —S—NR 3 —C(O)R 3 , —C(S)N(R 3 ) 2 , —C (S)R 3 , —NR 3 —C(O)OR 3 , —O—C(O)OR 3 , —O—C(O)N(R 3 ) 2 , —NR 3 —C(S)R 3 , ═N—OH, ═N—OR 3 , ═N—N(R 3 ) 2 , ═NR 3 , ═NNR 3 C(O)N(R 3 ) 2 , ═NNR 3 C(O)OR 3 , ═NNR 3 S(O) n —N(R 3 ) 2 , —NR 3 —C(S)OR 3 , —NR 3 —C(S)N(R 3 ) 2 , —NR 3 —C[═N(R 3 )]—N(R 3 ) 2 , —N(R 3 )—C[═N—NO 2 ]—N(R 3 ) 2 , —N(R 3 )—C[═N—NO 2 ]—OR 3 , —OC(O)R 3 , —OC(S)R 3 , —OC(O)N(R 3 ) 2 , —C(O)N(R 3 )—N(R 3 ) 2 , —N(R 3 )—N(R 3 )C(O)R 3 , —N(R 3 )—OC(O)R 3 —N(R 3 )—OC(O)R 3 , —N(R 3 )—OC(O)R 3 , —OC(S)N(R 3 ) 2 , —OC(S)N(R 3 )(R 3 ), or —PO 3 —R 3 ;  
 E is selected from Ht; O-Ht; Ht-Ht; Ht fused with Ht; —O—R 3 ; —N(R 2 )(R 3 ); —N(R 2 )-Ht; C 1 -C 6  alkyl, which is optionally substituted with one or more groups selected from R 4  or Ht; C 2 -C 6  alkenyl, which is optionally substituted with one or more groups selected from R 4  or Ht; C 3 -C 6  saturated carbocycle, which is optionally substituted with one or more groups selected from R 4  or Ht; or C 5 -C 6  unsaturated carbocycle, which is optionally substituted with one or more groups selected from R 4  or Ht;  
 each R 4  is independently selected from —R 2 , —OR 2  , —OR 3 , —SR 2 , —SOR 2 , —SO 2 R 2 , —CO 2 R 2 , —OC(O)—R 2 , —C(O)—N(R 2 ) 2 , —C(O)—NR 2 (OR 2 ), —S(O) 2 —N(R 2 ) 2 , halo, —NR 2 —C(O)—R , —NR—OR 2 , —N(R 2 ) 2  or —CN;  
 each R 7  is independently selected from hydrogen,  
                     
 wherein each M is independently selected from H, Li, Na, K, Mg, Ca, Ba, —N(R 2 ) 4 , C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, or —R 6 ; wherein 1 to 4 —CH 2  radicals of the alkyl or alkenyl group, other than the —CH 2  that is bound to Z, is optionally replaced by a heteroatom group selected from O, S, S(O), S(O 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6  is optionally replaced with a substituent selected from oxo, —C 1 -C 4  alkyl, —N(R 2 ) 2 , —N(R 2 ) 3 , —OH, —O—(C 1 -C 4  alkyl), —CN, —C(O)OR 2 , —C(O)—N(R 2 ) 2 , S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , C(O)R 2 , —S(O) n —R 2 —OCF 3 , —S(O) n —R 6 , —N(R 2 )—S(O) 2 (R 2 ), halo, —CF 3 , or —NO 2 ;  
 M′ is H, C 1 -C 12 -alkyl, C 2 -C 12 -alkenyl, or —R 6 ; wherein 1 to 4 —CH 2  radicals of the alkyl or alkenyl group is optionally replaced by a heteroatom group selected from O, S, S(O), S(O 2 ), or N(R 2 ); and wherein any hydrogen in said alkyl, alkenyl or R 6  is optionally replaced with a substituent selected from oxo, —OR 2 , —C 1 -C 4  alkyl, —N(R 2 ) 2 , N(R 2 ) 3 , —OH, —O—(C 1 -C 4  alkyl), —CN, —C(O)OR 2 , —C(O)—N(R 2 ) 2 , —S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —C(O)R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n —R 6 , —N(R 2 )—S(O) 2 (R 2 ), halo, —CF 3 , or —NO 2 ;  
 x is 0 or 1;  
 Z is O, S, N(R 2 ) 2 , or, when M is not present, H.  
 Y is P or S;  
 X is O or S; and  
 R 9  is C(R 2 ) 2 , O or N(R 2 ); and wherein when Y is S, Z is not S; and  
 R 6  is a 5-6 membered saturated, partially saturated or unsaturated carbocyclic or heterocyclic ring system, or an 8-10 membered saturated, partially saturated or unsaturated bicyclic ring system; wherein any of said heterocyclic ring systems contains one or more heteroatoms selected from O, N, S, S(O) n  or N(R 2 ); and wherein any of said ring systems optionally contains 1 to 4 substituents independently selected from —OH, —C 1 -C 4  alkyl, —O—(C 1 -C 4  alkyl) or —O—C(O)—(C 1 -C 4  alkyl).  
 
     
     
         2 . The compound according to  claim 1 , wherein R 8  is —C 1 -C 4 -branched or straight chain alkyl, wherein one to two carbon atoms in said alkyl are independently replaced by W, wherein R 8  is additionally and optionally substituted with one or more groups independently selected from —OH; —C 1 -C 4 -alkoxy; -Ht; —O-Ht; —NR 2 —CO—N(R 2 ) 2 ; —CO—N(R 2 ) 2 ; —R 1 —C 2 -C 6  alkenyl, which is optionally substituted with one or more groups independently selected from hydroxy, C 1 -C 4  alkoxy, Ht, —O-Ht, —NR 2 —CO—N(R 2 ) 2  or —CO—N(R 2 ) 2 ; or R 7 ; 
 wherein W is —O—, —NR 2 —, —NR 2 —S(O) 2 —, —NR 2 —C(O)O—, —O—C(O)NR 2 —, —NR 2 —C(O)NR 2 —, —NR 2 —C(S)NR 2 —, —NR 2 C(O)—, —C(═NR 2 )—, —C(O)NR 2 —, —NR 2 —C (═N—CN)—NR 2 —, —NR 2 C(═N—CN)O— or —C(O)O—; and  
 wherein Ht, R 1 , R 2  and R 7  are as defined in  claim 1 .  
 
     
     
         3 . The compound according to  claim 1 , wherein R 8  is a —C 1 -C 4 -branched or straight alkyl chain, wherein one to two carbon atoms are substituted with Ht; 
 wherein Ht is C 6 - 14  aryl or a 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R 2 ), O, S and S(O) n , wherein any member of Ht is optionally substituted with one or more substituents independently selected from oxo, —OR 2 , SR 2 , —R 2 , —N(R 2 )(R 2 ), —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2 , —S(O) 2 —N(R 2 ) 2 , —N(R 2 )—C(O)—R 2 , —N(R 2 )—C(O)OR 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n -Q, methylenedioxy, —N(R 2 )—S(O) 2 (R 2 ), halo, —CF 3 , —NO 2 , Q, —OQ, —OR 7 , —SR 7 , —R 7 , —N(R 2 )(R 7 ) or —N(R 7 ) 2 ;  
 
     
     
         4 . The compound according to  claim 1 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound according to  claim 1 , wherein at least one R 7  is selected from:  
       
         
           
           
               
               
           
         
       
       -(L)-  
       
         
           
           
               
               
           
         
       
       lysine, —P 3 Na 2 , —PO 3 Mg, —PO 3 (NH 4 ) 2 , —CH 2 —OPO 3 Na 2 ,  
       
         
           
           
               
               
           
         
       
       -(L)-serine, —SO 3 Na 2 ,  
       
         
           
           
               
               
           
         
       
       —SO 3 Mg, —SO 3 (NH 4 ) 2 , —CH 2 —OSO 3 Na 2 , —CH 2 —OSO 3 (NH 4 ) 2 ,  
       
         
           
           
               
               
           
         
       
       -(L)-valine, -(L)-glutamic acid, -(L)-aspartic acid, -(L)-γ-t-butyl-aspartic acid,  
       
         
           
           
               
               
           
         
       
       -(L)-(L)-3-pyridylalanine, -(L)-histidine, -CHO,  
       
         
           
           
               
               
           
         
       
       PO 3 K 2 , PO 3 Ca, PO 3 -spermine, PO 3 -(spermidine) 2  or PO 3 -(meglamine) 2   
     
     
         6 . The compound according to  claim 1 , wherein: A is R′—C(O), wherein R′ is selected from —C 1 -C 6  alkyl,  
       
         
           
           
               
               
           
         
       
       or  
     
     
         7 . The compound according to  claim 1 , wherein: 
 D′ is —CH 2 —R″, wherein R″ is selected from: isobutyl,                          wherein m is 0 to 3.    
     
     
         8 . The compound according to  claim 1 , wherein: 
 E is selected from:                          
     
     
         9 . The compound according to  claim 1 , having the formula (II):  
       
         
           
           
               
               
           
         
       
       wherein A, R 7 , D′, R 8  and E are as defined in  claim 1 .  
     
     
         10 . The compound according to  claim 9 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         11 . The compound according to  claim 9 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         12 . The compound according to  claim 9 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         13 . The compound according to  claim 9 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound according to  claim 9 , wherein R 8  is selected from:  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound according to  claim 9 , wherein said compound is selected from compound numbers: 18, 19, 20, 22, 24, 25, 26, 27, 31, 33, 35, 36, 38, 41, 43, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 68, 69, 71, 72, 73, 74, 202-204, 209, 213, 215, 217, 223, 227, 231, 233, 236, 237, 239, 243, 247, 250, 260, 263, 271, 281, 289, 293, 295, 304, 309, 317, 319, 320, 322, 334, 335, 348, 364, 367, 368, 375, 382, 383 and 396.  
     
     
         16 . The compound according to  claim 15 , wherein said compound is selected from compound numbers: 26, 27, 31, 33, 35, 36, 38, 41, 43, 48, 49, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 69, 71, 72, 73, 74, 209, 215, 227, 233, 237, 281, 289, 295, 304, 309, 322, 335, 364, 368, 382 and 383.  
     
     
         17 . The compound according to  claim 16 , wherein said compound is selected from: 54, 209, 237, 281, 295, 309, 367 and 368.  
     
     
         18 . A composition comprising a compound according to any one of  claims 1  to  17 , in an amount sufficient to inhibit an aspartyl protease; and a pharmaceutically acceptable carrier.  
     
     
         19 . The composition according to  claim 18 , wherein said composition is in a pharmaceutically acceptable form for administration to a human being.  
     
     
         20 . The composition according to  claim 18 , wherein said composition additionally comprises an additional anti-viral agent.  
     
     
         21 . The composition according to  claim 18 , wherein said composition comprises at least one additional therapeutic agent'selected from (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]-guanine [(−)BHCG, SQ-34514]; oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine); acyclic nucleosides, such as acyclovir, valaciclovir, famciclovir, ganciclovir or penciclovir; acyclic nucleoside phosphonates, such as (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC); ribonucleotide reductase inhibitors, such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone, 3′ azido-3′-deoxythymidine; other 2′,3′-dideoxynucleosides such as 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, or 2′,3′-didehydrothymidine; other aspartyl protease inhibitors, such as indinavir, ritonavir, nelfinavir, or [3S-[3R*(1R*, 2S*)]]-[3[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]-tetrahydro-3-furanyl ester (amprenavir); oxathiolane nucleoside analogues, such as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC); 3′-deoxy-3′-fluorothymidine; 5-chloro-2′,3′-dideoxy-3′-fluorouridine; (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol; ribavirin; 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G); tat inhibitors, such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335) or 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429); interferons, such as α-interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; pentoxifylline; N-acetylcysteine (NAC); Procysteine; α-trichosanthin; phosphonoformic acid; immunomodulators, such as interleukin II or thymosin; granulocyte macrophage colony stimulating factors; erythropoetin; soluble CD 4  and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (BI-RG-587), loviride (α-APA) or delavuridine (BHAP); phosphonoformic acid; 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs, such as (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266); or quinoxaline NNRTIs, such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarboxylate (HBY1293).  
     
     
         22 . The composition according to any one of claims  18 - 21 , wherein said composition is in an orally available dosage form.  
     
     
         23 . A method of treating a patient infected with a virus that depends upon an aspartyl protease for an obligatory event in its life cycle comprising the step of administering to said patient a composition according to  claim 18 .  
     
     
         24 . A method of treating a patient infected with HIV-I or HIV-II comprising the step of administering to said patient. a composition according to  claim 18 .  
     
     
         25 . The method according to  claim 23  or  24 , comprising the additional step of administering to said patient an additional therapeutic agent selected from (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl) cyclobutyl]guanine [(−)BHCG, SQ-34514]; oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine); acyclic nucleosides, such as acyclovir, valaciclovir, famciclovir, ganciclovir or penciclovir; acyclic nucleoside phosphonates, such as (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine (HPMPC); ribonucleotide reductase inhibitors, such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone, 3′azido-3′-deoxythymidine; other 2′,3′-dideoxynucleosides such as 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, or 2′,3′-didehydrothymidine; other aspartyl protease inhibitors, such as indinavir, ritonavir, nelfinavir, or [3S-[3R*(1R*, 2S*)]]-[3[[(4-aminophenyl)sulfonyl] (2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl) propyl]-tetrahydro-3-furanyl ester (amprenavir); oxathiolane nucleoside analogues, such as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC); 3′-deoxy-3′-fluorothymidine; 5-chloro-2′,3′-dideoxy-3′-fluorouridine; (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol; ribavirin; 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G); tat inhibitors, such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335) or 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1, 4-benzodiazepin-2-amine (Ro24-7429); interferons, such as a-interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; pentoxifylline; N-acetylcysteine (NAC); Procysteine; α-trichosanthin; phosphonoformic acid; immunomodulators, such as interleukin II or thymosin; granulocyte macrophage colony stimulating factors; erythropoetin; soluble CD 4  and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (BI-RG-587), loviride (α-APA) or delavuridine (BHAP); phosphonoformic acid; 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs, such as (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266); or quinoxaline NNRTIs, such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarboxylate (HBY1293), wherein said additional agent is administered to said patient as either a separate dosage form or as a single dosage form together with said compound.  
     
     
         26 . A method of treating a patient diagnosed with AIDS; AIDS related complex (ARC); progressive generalized lymphadenopathy (PGL); Kaposi's sarcoma, thrombocytopenic purpura; AIDS-related neurological conditions such as AIDS dementia complex, multiple sclerosis or tropical paraperesis; anti-HIV antibody-positive conditions; or HIV-positive conditions, comprising the step of administering to said patient a composition according to  claim 18 .  
     
     
         27 . The method according to  claim 26 , comprising the additional step of administering to said patient an additional therapeutic agent selected from (1 alpha, 2 beta, 3 alpha)-9-[2,3-bis(hydroxymethyl) cyclobutyl]guanine [(−)BHCG, SQ-34514]; oxetanocin-G (3,4-bis-(hydroxymethyl)-2-oxetanosyl]guanine); acyclic nucleosides, such as acyclovir, valaciclovir, famciclovir, ganciclovir or penciclovir; acyclic nucleoside phosphonates, such as (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC); ribonucleotide reductase inhibitors, such as 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone, 3′azido-3′-deoxythymidine; other 2′,3′-dideoxynucleosides such as 2′,3′-dideoxycytidine, 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine, or 2′,3′-didehydrothymidine; other aspartyl protease inhibitors, such as indinavir, ritonavir, nelfinavir, or [3S-[3R*(1R*, 2S*)]]-[3[[(4-aminophenyl)sulfonyl](2-methylpropyl)amino]-2-hydroxy-1-(phenylmethyl)propyl]-tetrahydro-3-furanyl ester (amprenavir); oxathiolane nucleoside analogues, such as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine) or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC); 3′-deoxy-3′-fluorothymidine; 5-chloro-2′,3′-dideoxy-3′-fluorouridine; (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol; ribavirin; 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G); tat inhibitors, such as 7-chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2-(H)one (Ro5-3335) or 7-chloro-1,3-dihydro-5-(1H-pyrrol-2yl)-3H-1,4-benzodiazepin-2-amine (Ro24-7429); interferons, such as α-interferon; renal excretion inhibitors such as probenecid; nucleoside transport inhibitors such as dipyridamole; pentoxifylline; N-acetylcysteine (NAC); Procysteine; α-trichosanthin; phosphonoformic acid; immunomodulators, such as interleukin II or thymosin; granulocyte macrophage colony stimulating factors; erythropoetin; soluble CD 4  and genetically engineered derivatives thereof; non-nucleoside reverse transcriptase inhibitors (NNRTIs), such as nevirapine (BI-RG-587), loviride (α-APA) or delavuridine (BHAP); phosphonoformic acid; 1,4-dihydro-2H-3,1-benzoxazin-2-ones NNRTIs, such as (−)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one (L-743,726 or DMP-266); or quinoxaline NNRTIs, such as isopropyl (2S)-7-fluoro-3,4-dihydro-2-ethyl-3-oxo-1(2H)-quinoxalinecarboxylate (HBY1293), wherein said additional agent is administered to said patient as either a separate dosage form or as a single dosage form together with said compound.