Novel sulfonamide 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.

1 . A compound of formula I: 
       
         
           
           
               
               
           
         
       
       wherein:
 A is selected from the group consisting of Het A ; and —R 1 —Het A ; 
 each R 1  is independently selected from the group consisting of —C(O)—, —S(O) 2 —, —C(O)—C(O)—, —O—C(O)—, —O—S(O) 2 , —NR 2 —S(O) 2 —, —NR 2 —C(O)— and —NR 2 —C(O)—C(O)—; 
 each Het A  is independently selected from 5-7 membered saturated or unsaturated heterocycle, containing one or more O, wherein said heterocycle may optionally be benzofused; and wherein said Het A  may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 —R 2 —N(R 2 )(R 2 )— R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 )(R 2 ), —S(O) 2 —N(R 2 )(R 2 ), —N(R 2 )—C(O)—R 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n —Ar, methylenedioxy, —N(R 2 )—S(O) 2 (R 2 ) halo, —CF 3 , —NO 2 , Ar and —O—Ar; 
 each Het is independently selected from the group consisting of C 3 -C 7  cycloalkyl; C 5 -C 7  cycloalkenyl; C 6 -C 10  aryl; and 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 heterocycle may optionally be benzofused; and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 )(R 2 ), —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 )(R 2 ), —S(O) 2 —N(R 2 )(R 2 ), —N(R 2 )—C(O)—R 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n —Ar, methylenedioxy, —N(R 2 )—S(O) 2 (R 2 ), halo, —CF 3 , —NO 2 , Ar and —O—Ar; 
 each R 2  is independently selected from the group consisting of H and C 1 -C 3  alkyl optionally substituted with Ar; 
 B, when present, is —N(R 2 )—C(R 3 )(R 3 )—C(O)—; 
 x is 0 or 1; 
 each R 3  is independently selected from the group consisting of H, Het, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkyl and C 5 -C 6  cycloalkenyl, wherein any member of said R 3 , except H, may be optionally substituted with one or more substituents selected from the group consisting of —OR 2 , —C(O)—NH—R 2 , —S(O) n —N(R 2 )(R 2 ), Het, —CN, —SR 2 , —CO 2 R 2 , NR 2 —C(O)—R 2 ; 
 each n is independently 1 or 2; 
 D and D′ are independently selected from the group consisting of Ar; C 1 -C 4  alkyl, which may be optionally substituted with one or more groups selected from C 3 -C 6  cycloalkyl, —OR 2 , —R 3 , —O—Ar and Ar; C 2 -C 4  alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C 3 -C 6  cycloalkyl, —OR 2 , —R 3 , —O—Ar and Ar; C 3 -C 6  cycloalkyl, which may be optionally substituted with or fused with Ar; and C 5 -C 6  cycloalkenyl, which may be optionally substituted with or fused with Ar; 
 each Ar is independently selected from the group consisting of phenyl; 3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O) n  and N(R 2 ), wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 )(R 2 ), —N(R 2 )—C(O)—R 2 , —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 )(R 2 ), halo and —CF 3 ; 
 E is selected from the group consisting of Het E ; O-Het E ; Het E -Het E ; 
 each Het E  is independently selected from 5-7 membered saturated or unsaturated heterocycle, containing a N or N(R 2 ) and a S and S(O) n , wherein said heterocycle may optionally be benzofused; and wherein any member of said Het E  may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 )(R 2 ), —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 )(R 2 ), —S(O) 2 —N(R 2 )(R 2 ), —N(R 2 )—C(O)—R 2 , —C(O)—R 2 , —S(O) n —R 2 , —OCF 3 , —S(O) n —Ar, methylenedioxy, —N(R 2 )—S(O) 2 (R 2 ), halo, —CF 3 , —NO 2 , Ar and —O—Ar. 
 
     
     
         2 . The compound according to  claim 1 , wherein said compound has the structure of formula XXII: 
       
         
           
           
               
               
           
         
       
       wherein A, D′ and E are defined as in  claim 1 . 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The compound according to  claim 1 , wherein:
 A is selected from the group consisting of R 1 -Het A ;   each R 1  is independently selected from the group consisting of —C(O)—, —S(O) 2 —, —C(O)—C(O)—, —O—CO—, —O—S(O) 2 — and —NR 2 —S(O) 2 —;   each Het A  is independently selected from 5-7 membered saturated or unsaturated heterocycle, containing one or more O, wherein said heterocycle may optionally be benzofused; wherein any member of said Het A  may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2  and —S(O) 2 —N(R 2 ) 2 ;   each Het is independently selected from the group consisting of C 3 -C 7  cycloalkyl; C 5 -C 7  cycloalkenyl; C 6 -C 10  aryl; and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, O and S, which may optionally be benzofused; wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2  and —S(O) 2 —N(R 2 ) 2 ;   each R 2  is independently selected from the group consisting of H and C 1 -C 3  alkyl;   B, when present, is —NH—CH(R 3 )—C(O)—;   x is 0 or 1;   R 3  is selected from the group consisting of Het, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 3 -C 6  cycloalkyl and C 5 -C 6  cycloalkenyl, wherein any member of said R 3  may be optionally substituted with one or more substituents selected from the group consisting of —OR 2 , —C(O)—NH—R 2 , —S(O) n —N(R 2 ) 2 , Het and —CN;   n is 1 or 2;   D and D′ are independently selected from the group consisting of Ar; C 1 -C 4  alkyl, which may be optionally substituted with C 3 -C 6  cycloalkyl or Ar; C 2 -C 4  alkenyl, which may be optionally substituted with C 3 -C 6  cycloalkyl or Ar; C 3 -C 6  cycloalkyl, which may be optionally substituted or fused with Ar; and C 5 -C 6  cycloalkenyl, which may be optionally substituted or fused with Ar; with the proviso that when D is attached to N, D may not be methyl or C 2  alkenyl;   Ar is selected from the group consisting of phenyl; 3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, N and S, wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , —N(R 2 )—C(O)R 2 , —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2 , halo and —CF 3 ;   E is selected from the group consisting of Het E ;   each Het E  is independently selected from 5-7 membered saturated or unsaturated heterocycle, containing N and S, wherein said heterocycle may optionally be benzofused; wherein any member of said Het E  may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR 2 , —R 2 , —N(R 2 ) 2 , —R 2 —OH, —CN, —CO 2 R 2 , —C(O)—N(R 2 ) 2  and —S(O) 2 —N(R 2 ) 2 .   
     
     
         6 . The compound according to  claim 2 , wherein:
 A is R 1 -Het A ; and   D′ is selected from the group consisting of C 1 -C 3  alkyl and C 3  alkenyl, wherein said alkyl or alkenyl may optionally be substituted with one or more groups selected from the group consisting of C 3 -C 6  cycloalkyl, —OR 2 , —O—Ar and Ar.   
     
     
         7 - 10 . (canceled) 
     
     
         11 . The compound according to  claim 1 , wherein said compound has a molecular weight less than or equal to about 700 g/mol. 
     
     
         12 . A compound according to  claim 11 , wherein said compound has a molecular weight less than or equal to about 600 g/mol. 
     
     
         13 - 15 . (canceled) 
     
     
         16 . A pharmaceutical composition effective against viral infection comprising a pharmaceutically effective amount of a compound according to  claim 1  and a pharmaceutically acceptable carrier, adjuvant or vehicle. 
     
     
         17 . The pharmaceutical composition according to  claim 16 , further comprising an additional anti-viral agent. 
     
     
         18 . A method for using of a compound according to claim  14  as a therapeutic agent against viral infection, said virus requiring an aspartyl protease for an obligatory life cycle event. 
     
     
         19 . The method according to  claim 18 , wherein said virus is HIV-1, HIV-2, or HTLV. 
     
     
         20 - 21 . (canceled) 
     
     
         22 . A method for preventing HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to  claim 16  or  17 . 
     
     
         23 . A method for treating HIV infection in a mammal comprising the step of administering to said mammal a pharmaceutically effective amount of a pharmaceutical composition according to  claim 16  or  17 . 
     
     
         24 . The method according to  claim 23 , wherein said step of administering comprises oral administration or administration by injection. 
     
     
         25 - 27 . (canceled)