Triterpenoids with HIV maturation inhibitory activity

1. A compound of Formula I, including pharmaceutically acceptable salts thereof:

wherein R 1 is isopropenyl or isopropyl;

X is selected from the group of C 4-8 cycloalkyl, C 4-8 cycloalkenyl, C 4-9 spirocycloalkyl, C 4-9 spirocycloalkenyl, C 4-8 oxacycloalkyl, C 4-8 dioxacycloalkyl, C 6-8 oxacycloalkenyl, C 6-8 dioxacycloalkenyl, C 6 cyclodialkenyl, C 6 oxacyclodialkenyl, C 6-9 oxaspirocycloalkyl and C 6-9 oxaspirocycloalkenyl ring,

wherein X is substituted with A, and wherein A is —C 1-6 alkyl-halo;

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 , —NR 2 SO 2 R 2 , —SO 2 NR 2 R 2 , —C 3-6 cycloalkyl-COOR 2 , —C 2-6 alkenyl-COOR 2 , —C 2-6 alkynyl-COOR 2 , —C 1-6 alkyl-COOR 2 , -alkylsubstituted C 1-6 alkyl, —CF 2 —COOR 2 , —NHC(O)(CH2) n -COOR 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 alkyl-Q 1 , —C 1-6 alkyl-C 3-6 cycloalkyl-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 cannot be —COR 6 when W is —CO;

with the further proviso that only one of R 4 or R 5 can be selected from the group of —COR 6 , —SO 2 R 7 and —SO 2 NR 2 R 2 ;

or when W is absent or is —CH 2 , then R 4 and R 5 can be taken together with the adjacent N to form

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 R 8 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 , —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 C 1-6 substituted alkyl-Q 3 and

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 , —C1-6 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 cannot be —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 as claimed in claim 1 , wherein R 1 is isopropenyl.

3. The compound as claimed in claim 2 , wherein W is absent.

4. The compound as claimed in claim 1 , wherein X is C 4-8 cycloalkenyl.

5. The compound as claimed in claim 4 , wherein X is C 6 cycloalkenyl.

6. The compound as claimed in claim 5 , wherein A is C 1 -C 3 alkyl-halo.

7. The compound as claimed in claim 6 , wherein A is methyl-fluoro.

8. The compound as claimed in claim 1 , wherein A is methyl-halo.

9. The compound as claimed in claim 8 , wherein A is methyl-fluoro.

10. The compound as claimed in claim 1 , wherein Y is —COOR 2 .

11. The compound as claimed in claim 10 , wherein Y is —COOH.

12. A compound, or a pharmaceutically acceptable salt thereof, which is selected from the group of:

13. A pharmaceutical composition which comprises one or more of the compounds as claimed in claim 1 , together with one or more pharmaceutically acceptable carriers, excipients and/or diluents.

14. A pharmaceutical composition which comprises one or more of the compounds as claimed in claim 12 , together with one or more pharmaceutically acceptable carriers, excipients and/or diluents.

15. A pharmaceutical composition which comprises the compound

together with one or more pharmaceutically acceptable carriers, excipients and/or diluents.

16. A method for treating a mammal infected with the HIV virus comprising administering to said mammal an antiviral effective amount of a compound as claimed in claim 1 , and one or more pharmaceutically acceptable carriers, excipients or diluents.

17. The compound as claimed in claim 9 , wherein Y is —COOH.

18. A compound of Formula I, including pharmaceutically acceptable salts-or a pharmaceutically acceptable salt thereof:

wherein R 1 is isopropenyl or isopropyl;

X is selected from the group of C 4-8 cycloalkyl, C 4-8 cycloalkenyl, C 4-9 spirocycloalkyl, C 4-9 spirocycloalkenyl, C 4-8 oxacycloalkyl, C 4-8 dioxacycloalkyl, C 6-8 oxacycloalkenyl, C 6-8 dioxacycloalkenyl, C 6 cyclodialkenyl, C 6 oxacyclodialkenyl, C 6-9 oxaspirocycloalkyl and C 6-9 oxaspirocycloalkenyl ring,

wherein X is substituted with A, wherein A is —C 1-6 alkyl-halo;

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 , —NR 2 SO 2 R 2 , —SO 2 NR 2 R 2 , —C 3-6 cycloalkyl-COOR 2 , —C 2-6 alkenyl-COOR 2 , —C 2-6 alkynyl-COOR 2 , —C 1-6 alkyl- COOR 2 , -alkylsubstituted C 1-6 alkyl, —COOR 2 , CF 2 —COOR 2 , —NHC(O)(CH 2 ) n —COOR 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, CH 2 or CO;

R 3 is —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(OR 3 ) 2 —C 3-6 cycloalkyl, —C 1-6 substituted alkyl, —C 1-6 alkyl-C 3-6 cycloalkyl, —C 1-6 alkyl-Q 1 , —C 1-6 alkyl-C 3-6 cycloalkyl-Q 1 , aryl, heteroaryl, substituted heteroaryl, —COR 6 , —COCOR 6 , —SO 2 R 7 , —SO 2 NR 2 R 2 ,

with the proviso that R 4 or R 5 cannot be COR 6 or COCOR 6 when W is CO;

wherein Q 1 is selected from the group of heteroaryl, substituted heteroaryl, halogen, —CF3, —OR2, —COOR 2 , —NR 8 R 9 , —CONR 10 R 11 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 10 , —COR 6 , —COCOR 6 , —SO 2 R 7 and —SO 2 NR 2 R 2 ;

with the proviso that only one of R 4 or R 5 can be selected from the group of —COR 6 , —COCOR 6 , —SO 2 R 7 and —SO 2 NR 2 R 2 ;

or when W is absent or is CH 2 , then R 4 and R 5 can be taken together with the adjacent N to form

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 —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 , and R 8 and R 9 can also be independently selected from the group of

or R 8 and R 9 are taken together with the adjacent N to form a cycle selected from the group of:

with the proviso that only one of R 8 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,

or R 10 and R 11 are taken together with the adjacent N to form

R 12 is selected from the group of —C 1-6 alkyl, —C 1-6 alkyl-OR; —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 3-6 cycloalkyl, —COR 3 , —COONR 22 R 23 , —S(O) m R 7 , and —SONR 24 R 25 , wherein m=1 or 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 , C 1-6 substituted alkyl-Q 3 and

Q 3 is selected from the group of heteroaryl, substituted heteroaryl, —NR 20 R 21 , —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 3 ;

R 17 is selected from the group of —H, —C 1-6 alkyl, —COOR 3 , and aryl;

R 20 and R 21 are independently selected from the group of —H, —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 1-6 substituted alkyl-OR 2 , and —COR 3 ,

or R 20 and R 21 are taken together with the adjacent N to form a cycle selected from the group of

with the proviso that only one of R 20 or R 21 can be —COR 3 ;

R 22 and R 23 are independently selected from the group of H, —C 1-6 alkyl, —C 1-6 substituted alkyl, and —C 1-6 cycloalkyl,

or R 22 and R 23 are taken together with the adjacent N to form a cycle selected from the group of

R 24 and R 25 are independently from the group of H, —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 1-6 alkyl- Q 5 , —C 1-6 cycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and

Q 5 is selected from the group of halogen and SO 2 R 3 .