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 H; Het; —R 1 -Het; —R′—C 1 -C 6  alkyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C 1 -C 4  alkoxy, Het, —O-Het, —NR 2 —CO—N(R 2 )(R 2 ) and —CO—N(R 2 )(R 2 ); and —R 1 —C 2 -C 6  alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C 1 -C 4  alkoxy, Het, —O-Het, —NR 2 —CO—N(R 2 )(R 2 ) and —CO—N(R 2 )(R 2 ); 
 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 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; O-Het; Het-Het; —O—R 3 ; —NR 2 R 3 ; C 1 -C 6  alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R 4  and Het; C 2 -C 6  alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R 4  and Het; C 3 -C 6  saturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R 4  and Het; and C 5 -C 6  unsaturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R 4  and Het; and 
 each R 4  is independently selected from the group consisting of −OR 2 , —C(O)—NHR 2 , —S(O) 2 —NHR 2 , halo, —NR 2 —C(O)—R 2  and —CN. 
 
   
   
       2 . The compound according to  claim 1 , wherein said compound has the structure of formula XXII: 
     
       
         
         
             
             
         
       
     
     and A, D′ and E are defined as in  claim 1 . 
   
   
       3 . The compound according to  claim 1 , wherein said compound has the structure of formula XXIII: 
     
       
         
         
             
             
         
       
     
     and x, Het, R 3 , D′ and E are defined as in  claim 1 . 
   
   
       4 . The compound according to  claim 1 , wherein said compound has the structure of formula XXXI: 
     
       
         
         
             
             
         
       
     
     and A, R 3 , D′ and E are defined as in  claim 1 . 
   
   
       5 . A compound according to  claim 1 , wherein:
 A is selected from the group consisting of H; —R 1 -Het; —R 1 -C 1 -C 6  alkyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C 1 -C 4  alkoxy, Het and —O-Het; and —R 1 —C 2 -C 6  alkenyl, which may be optionally substituted with one or more groups selected from hydroxy, C 1 -C 4  alkoxy, Het and —O-Het;   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 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; —O—R 3 ; —NR 2 R 5 ; C 1 -C 6  alkyl, which may be optionally substituted with one or more R 4  or Het; C 2 -C 6  alkenyl, which may be optionally substituted with one or more R 4  or Het; C 3 -C 6  saturated carbocycle, which may optionally be substituted with one or more R 4  or Het; and C 5 -C 6  unsaturated carbocycle, which may optionally be substituted with one or more R 4  or Het;   each R 4  is independently selected from the group consisting of —OR 2 , —C(O)—NHR 2 , —S(O) 2 —NHR 2 , halo and —CN; and   each R 5  is independently selected from the group consisting of H and R 3 , with the proviso that at least one R 5  is not H.   
   
   
       6 . The compound according to  claim 2 , wherein:
 A is R 1 -Het; 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 . The compound according to  claim 3 , wherein:
 R 3  is selected from the group consisting of C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 5 -C 6  cycloalkyl, C 5 -C 6  cycloalkenyl and a 5-6 membered saturated or unsaturated heterocycle, wherein any member of said R 3  may optionally be 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 ) 2 , Het, —CN, —SR 2 , —C(O) 2 R 2 , NR 2 —C(O)—R 2 ; 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.   
   
   
       8 . The compound according to  claim 4 , wherein:
 A is R′-Het;   each R 3  is independently C 1 -C 6  alkyl, which may be optionally substituted with a substituent selected from the group consisting of —OR 2 , —C(O)—NH—R 2 , —S(O) n N(R 2 ) 2 , Het, —CN, —SR 2 , —CO 2 R 2 , —NR 2 —C(O)—R 2 ; and   D′ is C 1 -C 4  alkyl, which may be optionally substituted with a group selected from the group consisting of C 3 -C 6  cycloalkyl, —OR 2 , —O—Ar and Ar; and   E is selected from the group consisting of Het, Het-Het and —NR 2 R 3 .   
   
   
       9 - 10 . (canceled) 
   
   
       11 . The compound according to  claim 1 , wherein said compound has a molecular weight less than or equal to about 700g/mol. 
   
   
       12 . A compound according to  claim 11 , wherein said compound has a molecular weight less than or equal to about 600g/mol. 
   
   
       13 . A compound having the following structural and physicochemical characteristics:
 (1) a first and a second hydrogen bond acceptor moiety, at least one of which is more highly polarizable than a carbonyl, said moieties being the same or different, and being capable of hydrogen bonding with the hydrogen atoms of the flap water molecule of an HIV aspartyl protease when the compound is bound thereto;   (2) substantially hydrophobic moieties which associate with the P 1i  and P 1 ′ binding pockets of said HIV aspartyl protease when the compound is bound thereto;   (3) a third hydrogen bonding moiety, which may be either a hydrogen bond donor or acceptor, capable of simultaneously hydrogen bonding to Asp25 and Asp25′ of said HIV aspartyl protease when the compound is bound thereto;   (4) an additional occupied volume of space of at least 100 Å 3  when the compound is bound to the active site of said HIV aspartyl protease, said space overlapping with the volume of space that would be filled by a native substrate of said HIV aspartyl protease or a nonhyrolyzable isostere thereof;   (5) a deformation energy of binding of the compound to said HIV aspartyl protease of not greater than 10 kcal/mole; and   (6) a neutral or favorable enthalpic contribution from the sum of all electrostatic interactions between the compound and the protease when the compound is bound to said HIV aspartyl protease.   
   
   
       14 - 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 - 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 . 
   
   
       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 . 
   
   
       24 . The method according to  claim 22 , wherein said step of administering comprises oral administration or administration by injection. 
   
   
       25 . A method for identification, design, or prediction of an HIV protease inhibitor comprising the steps of:
 (a) selecting a candidate compound of defined chemical structure containing a first and a second hydrogen bond acceptor moiety, at least one of which is more highly polarizable than a carbonyl, said moieties being the same or different; a third hydrogen bonding moiety, which may be either a hydrogen bond donor or acceptor; and at least two substantially hydrophobic moieties;   (b) determining a low-energy conformation for binding of said compound to the active site of an HIV aspartyl protease;   (c) evaluating the capability of said first and second hydrogen bond acceptor moieties to form hydrogen bonds to the flap water molecule of said HIV aspartyl protease when said compound is bound thereto in said conformation;   (d) evaluating the capability of said substantially hydrophobic moieties to associate with the P 1  and P 1 ′ binding pockets of said HIV aspartyl protease when said compound is bound thereto in said conformation;   (e) evaluating the capability of said third hydrogen bonding moiety to form hydrogen bonds to Asp25 and Asp25′ of said HIV aspartyl protease when said compound is bound thereto in said conformation;   (f) evaluating the overlap of the occupied volume of said compound when said compound is bound to said HIV aspartyl protease in said conformation and the occupied volume of a native substrate of HIV aspartyl protease or a nonhydrolyzable isostere thereof, when said polypeptide is bound to said HIV aspartyl protease;   (g) evaluating the deformation energy of binding of said compound to said HIV aspartyl protease;   (h) evaluating the enthalpic contribution of the sum of all electrostatic interactions between said compound and said HIV aspartyl protease when said compound is bound thereto in said conformation; and   (i) accepting or rejecting said candidate compound as an HIV protease inhibitor based upon the determinations and evaluations carried out in steps (b) through (h).   
   
   
       26 - 27 . (canceled) 
   
   
       28 . The method according to  claim 23 , wherein said step of administering comprises oral administration or administration by injection.