Betulinic acid derivatives with HIV maturation inhibitory activity

1. A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:

a compound of formula I

a compound of formula II

and a compound of formula III

wherein R 1 is isopropenyl or isopropyl;

E 1 is selected from the group of —CHOR 22 , —CO, —CHF and —CF 2 ;

E 2 and E 3 are selected from —CHOR 22 and F; or

E 2 and E 3 can together form a ketal such as:

wherein X is selected from the group of phenyl, heteroaryl ring, 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 and C 6 cyclodialkenyl;

X is substituted with A, wherein A is at least one member selected from the group of —H, -halo, -hydroxyl, —C 1-6 alkyl, —C 1-6 alkoxy, —C 1-6 haloalkyl, —NR 2 R 2 , —COOR 2 , and —C(O)NR 2 R 2 ,

wherein R 2 is selected from the group of —H, —C 1-6 alkyl, -alkylsubstituted C 1-6 alkyl, and -arylsubstituted C 1-6 alkyl;

Y is selected from the group of —COOR 2 , —C(O)NR 2 SO 2 R 3 , —C 3-6 cycloalkyl-COOR 2 , —C 1-6 alkyl-COOR 2 , -alkylsubstituted C 1-6 alkyl-COOR 2 , —SO 2 NR 2 C(O)R 2 , and tetrazole,

R 3 is —C 1-6 alkyl or -alkylsubstituted C 1-6 alkyl;

W is —COOR 2 , —(CH 2 ) 0-1 NR 4 R 5 , or —CONR 20 R 21 ;

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 , and —SO 2 NR 2 R 2 ,

wherein Q 1 is selected from the group of -heteroaryl, substituted heteroaryl, -halogen, —CF 3 , —OR 2 , —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 ;

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, 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:

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 —C 1-6 alkyl, —C 1-6 alkyl-OH; —C 1-6 alkyl, —C 1-6 substituted alkyl, —C 3-6 cycloalkyl, and —COR 7 ;

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 18 R 19 , —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 18 and R 19 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 ;

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

and

R 22 is selected from H and —COR 3 .

2. The compound as claimed in claim 1 , wherein X is phenyl.

3. The compound as claimed in claim 2 , wherein Y is —COOH.

4. The compound as claimed in claim 3 , wherein said compound has the Formula I.

5. The compound as claimed in claim 4 , wherein E 1 is —CHOR 22 .

6. The compound as claimed in claim 5 , wherein E 1 is —CHOH.

7. The compound as claimed in claim 4 , wherein E 1 is —CO.

8. The compound as claimed in claim 4 , wherein E 1 is —CHF.

9. The compound as claimed in claim 3 , wherein said compound has the Formula II.

10. The compound as claimed in claim 9 , wherein E 2 and E 3 are each —CHOR 22 .

11. The compound as claimed in claim 9 , wherein E 2 and E 3 together form said ketal.

12. The compound as claimed in claim 11 , wherein R 3 is methyl.

13. The compound as claimed in claim 3 , wherein said compound has the Formula III.

14. The compound as claimed in claim 1 , wherein W is —(CH 2 ) 0-1 NR 4 R 5 .

15. A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:

16. A compound, including pharmaceutically acceptable salts thereof, which is selected from the group of:

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

18. A composition which comprises one or more compounds as claimed in claim 15 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.

19. A composition which comprises one or more compounds as claimed in claim 16 , together with one or more pharmaceutically acceptable carriers, excipients, and/or diluents.