C-3 and c-17 modified triterpenoids as hiv-1 inhibitors

Abstract

Compounds having drug and bio-affecting properties, their pharmaceutical compositions and methods of use are set forth. In particular, betulinic acid derivatives that possess unique antiviral activity are provided as HIV maturation inhibitors, as represented by compounds of Formula I:These compounds are useful for the treatment of HIV and AIDS.

What is claimed is: 
     
         1 . A compound of Formula I, including pharmaceutically acceptable salts thereof:
                       wherein R 1  is isopropenyl or isopropyl;   A is -C 1-6  alkyl-OR 0 ;   wherein R 0  is heteroaryl-Q 0;     Q 0  is selected from the group of —H, —CN, -C 1-6  alkyl, —COOH, —Ph, -OC 1-6  alkyl, -halo, —CF 3 ,   Y is selected from the group of —COOR 2 , —C(O)NR 2 SO 2 R 3 , —C(O)NHSO 2 NR 2 R 2 , —SO 2 NR 2 C(O)R 2 , -tetrazole, and -CONHOH,   wherein n = 1-6;   R 2  is —H, -C 1-6  alkyl, -alkylsubstituted C 1-6  alkyl or-arylsubstituted C 1-6  alkyl;   W is absent, or is —CH 2 — or —CO—;   R 3  is —H, -C 1-6  alkyl or -alkylsubstituted C 1-6  alkyl;   R 4  is selected from the group of —H, -C 1-6  alkyl, -C 1-6  alkyl-C 3-6  cycloalkyl, -C 1-6  substituted -C 1-6  alkyl, -C 1-6  alky1-Q 1 , -C 1-6  alkyl-C 3-6  cycloalky1-Q 1 , aryl, heteroaryl, substituted heteroaryl, —COR 6 , —SO 2 R 7 , —SO 2 NR 2 R 2 , and
                     
                     
   wherein G is selected from the group of —O—, —SO 2 — and —NR 12 —;   wherein Q 1  is selected from the group of -C 1-6  alkyl, - C 1-6  fluoroalkyl, heteroaryl, substituted heteroaryl, halogen, —CF 3 , —OR 2 , —COOR 2 , —NR 8 R 9 , —CONR 8 R 9  and —SO 2 R 7 ;   R 5  is selected from the group of —H, -C 1-6  alkyl, -C 3-6  cycloalkyl, -C 1-6  alkylsubstituted alkyl, -C 1-6  alkyl-NR 8 R 9 , —COR 3 , —SO 2 R 7  and —SO 2 NR 2 R 2 ;   with the proviso that R 4  or R 5  is not —COR 6  when W is —CO—;   with the further proviso that only one of R 4  or R 5  is selected from the group of —COR 6 , —COCOR 6 ,—SO 2 R 7  and —SO 2 NR 2 R 2 ;   R 6  is selected from the group of —H, -C 1-6  alkyl, -C 1-6  alkyl-substitutedalkyl, -C 3-6  cycloalkyl, -C 3-6  substitutedcycloalkyl-Q 2 , -C 1-6  alkyl-Q 2 , -C 1-6  alkyl-substitutedalkyl-Q 2 ,-C 3-6  cycloalkyl-Q 2 , aryl-Q 2 , -NR 13 R 14 , and —OR 15 ;   wherein Q 2  is selected from the group of aryl, heteroaryl, substituted heteroaryl, —OR 2 , —COOR 2 , —NR 8 R 9 , SO 2 R 7 , —CONHSO 2 R 3 , and —CONHSO 2 NR 2 R 2 ;   R 7  is selected from the group of —H, -C 1-6  alkyl, -C 1-6  substituted alkyl, -C 3-6  cycloalkyl, —CF 3 , aryl, and heteroaryl;   R 8  and R 9  are independently selected from the group of —H, -C 1-6  alkyl, -C 1-6  substituted alkyl, aryl, heteroaryl, substituted aryl, substituted heteroaryl, -C 1-6  alkyl-Q 2 , and —COOR 3 , or R 8  and R 9  are taken together with the adjacent N to form a cycle selected from the group of:
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
   M is selected from the group of -R 15 , —SO 2 R 2 , —SO 2 NR 2 R 2 , —OH and —NR 2 R 12 ;   V is selected from the group of —CR 10 R 11 —, —SO 2 —, —O— and —NR 12 —;   with the proviso that only one of Rs or R 9  can be —COOR 3 ;   R 10  and R 11  are independently selected from the group of —H, -C 1-6  alkyl, -C 1-6  substituted alkyl and -C 3-6  cycloalkyl;   R 12  is selected from the group of —H, -C 1-6  alkyl, -alkylsubstituted C 1-6  alkyl, —CONR 2 R 2 , —SO 2 R 3 , and —SO 2 NR 2 R 2 ;   R 13  and R 14  are independently selected from the group of —H, -C 1-6  alkyl, -C 3-6  cycloalkyl, -C 1-6  substituted alkyl, -C 1-6  alkyl-Q 3 , -C 1-6  alkyl-C 3-6  cycloalkyl-Q 3 , and C 1-6  substituted alkyl-Q 3 ;   Q 3  is selected from the group of heteroaryl, substituted heteroaryl, —NR 2 R 12 , —CONR 2 R 2 , —COOR 2 , —OR 2 , and —SO 2 R 3 ;   R 15  is selected from the group of -C 1-6  alkyl, -C 3-6  cycloalkyl, -C 1-6  substituted alkyl, -C 1-6  alkyl-Q 3 , -C 1-6  alkyl-C 3-6  cycloalkyl-Q 3  and -C 1-6  substituted alkyl-Q 3;     R 16  is selected from the group of —H, -C 1-6  alkyl, —NR 2 R 2 , and —COOR 2 ; with the proviso that when V is —NR 12 —; R 16  is not —NR 2 R 2 ; and   R 17  is selected from the group of —H, -C 1-6  alkyl, —COOR 3 , and aryl.   
     
     
         2 . The compound of  claim 1 , wherein in the R 0  group the heteroaryl moiety is selected from the group of
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
 . 
 
     
     
         3 . The compound of  claim 2 , wherein R 1  is isopropenyl. 
     
     
         4 . The compound of  claim 3 , wherein Y is —COOR 2 . 
     
     
         5 . The compound of  claim 4 , wherein R 2  is —H. 
     
     
         6 . The compound of  claim 1 , wherein R 4  is -C 1-6  alkyl-Q 1 . 
     
     
         7 . The compound of  claim 6 , wherein Q 1  is —NR 8 R 9 . 
     
     
         8 . The compound of  claim 7 , wherein when R 8  and R 9  are taken together with the adjacent
 —N to form a cycle, the cycle is selected from the group of:
                     
                     
 
. 
     
     
         9 . The compound of  claim 8 , wherein R 7  and R 16  are each selected from the group of -H and -C 1-6  alkyl. 
     
     
         10 . The compound of  claim 1 , wherein Q 0  is —CN. 
     
     
         11 . The compound of  claim 1 , wherein R 1  is isopropenyl, in the R 0  group the “heteroaryl” moiety is selected from the group of:
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
                     
 Y is -COOH, R 
 4  is -C 1-6  alkyl-Q 1 , Q 1  is —NR 8 R g , and Rs and R 9  are taken together with the adjacent —N to form a cycle which is selected from the group of:
                     
                     
 . 
 
     
     
         12 . A composition which comprises an HIV ameliorating amount of one or more compounds as claimed in  claim 1 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents. 
     
     
         13 . A method for treating a mammal infected with the HIV virus comprising administering to said mammal an HIV ameliorating amount of a compound as claimed in  claim 1 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents. 
     
     
         14 . The triple mutant protein identified as T332S/V362I/pr R41G.