Propenoate derivatives of betulin

1. A compound of the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from —CH 2 — or —C(═O)—;

X is selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, NH 2 , —CN, —C(O)R 6 , -(Q) n R 3 , —(C 1 -C 6 )alkyl-N(R 3 ) 2 , —(C 1 -C 6 )alkyl-OR 3 —(C 1 -C 6 )alkoxy, and amino-(C 1 -C 6 )alkyl;

Y is selected from —NR 1 R 2 or —OR 5 ;

Z is

R 1 is selected from the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, —(C 1 -C 6 )alkyl-N(R 3 ) 2 , —(C 1 -C 6 )alkyl-OR 3 ;

R 2 is selected from the group consisting of H, (C 1 -C 12 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, and -(Q) n R 3 ;

R 1 and R 2 can optionally join together along with the nitrogen to which they are joined to form a 4 to 12 membered heterocyclyl or heteroaryl ring, each independently containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein said heterocyclyl or heteroaryl ring may be also optionally and independently substituted with one to three R 10 groups;

R 3 is independently selected from the group consisting of H, (C 1 -C 6 )alkyl, —R 4 ,

 wherein:

A is (C 5 -C 14 )aryl,

B is selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O, and

C is (C 3 -C 8 )cycloalkyl;

R 4 is independently selected from the group consisting of halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl; —CF 3 , —OCF 3 , —N(R 5 ) 2 , —(CH 2 ) r -heterocycle, —C(O)OH, —C(O)NH 2 , and —NO 2 ;

R 5 is selected from the group consisting of H, (C 1 -C 6 )alkyl, and (C 3 -C 8 )cycloalkyl;

R 6 is independently H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, haloalkyl, —OCF 3 , —NR 7 R 8 , heterocycle, —(CH 2 ) r NR 7 R 8 , —C(O)OH, —C(O)NH 2 , wherein two R 6 groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, wherein the cycloalkyl ring may be optionally substituted by one to three R 10 groups;

R 7 and R 8 are independently selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, -Q-aryl-(R 4 ) n , —NR 14 R 15 , —C(O)CH 3 , wherein R 7 and R 8 can optionally be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 10 groups;

R 9 , R 10 , and R 11 are independently selected from the group consisting of oxo, halo, (C 1 -C 6 )alkoxy, —R 3 (R 6 ) q , —OR 3 (R 6 ) q , nitro, —NR 14 R 15 , —SO 2 R 3 , (C 1 -C 6 )alkyl, —C(O)R 7 , —YR 1 R 3 and —CO(O)R 2 , wherein any two R 9 , R 10 or R 11 groups can optionally join to form a 3 to 8 membered cycloalkyl, aryl, heterocyclyl or heteroaryl ring, wherein the heterocyclyl or heteroaryl ring may contain one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, and wherein the cycloalkyl, aryl, heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 4 groups;

R 12 and R 13 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, halo, —C(O)R 7 , —NR 1 R 2 , and —CO(O)R 2 , wherein R 12 and R 13 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by one to three R 10 groups;

R 14 and R 15 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —R 3 (R 6 ) q , and —OR 3 (R 6 ) q , wherein R 14 and R 15 may be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring optionally containing one or three heteroatoms from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 10 groups;

Q is —[C(R 6 ) 2 ] r —;

m and n are independently 0, 1, 2, 3, or 4;

p is independently 0, 1, 2, 3, or 4; and

r and q are independently 0, 1, 2, 3, or 4.

2. A compound of the structure of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

W is selected from —CH 2 — or —C(═O)—;

X is selected from H or C 1 -C 6 -alkyl;

Y is selected from —NR 1 R 2 or —OR 5 ;

Z is

R 1 and R 2 are each independently selected from the group consisting of H, —(C 1 -C 6 )alkyl-OR 3 , and -(Q) n R 3 ;

R 3 is selected from the group consisting of

 wherein:

A is (C 5 -C 14 )aryl,

B is selected from (C 2 -C 9 )heterocycle or (C 2 -C 9 )heteroaryl, each having one to three heteroatoms selected from S, N or O, and

C is (C 3 -C 7 )cycloalkyl;

R 5 is H;

R 6 is independently selected from H or (C 1 -C 6 )alkyl, wherein two R 6 alkyl groups can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring, wherein the cycloalkyl ring may be optionally substituted by one to three R 10 groups;

R 9 , R 10 , and R 11 are independently selected from the group consisting of oxo, halo, (C 1 -C 6 )alkoxy, —R 3 (R 6 ) q , —OR 3 (R 6 ) q , nitro, —NR 14 R 15 , —SO 2 R 3 , (C 1 -C 6 )alkyl, —C(O)R 7 , —R 1 YR 3 and —CO(O)R 2 ;

R 12 and R 13 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —[C(R 6 ) 2 ] r —, —O[C(R 6 ) 2 ] r —, oxo, halo, —C(O)R 7 , —NR 1 R 2 , and —CO(O)R 2 , wherein R 12 and R 13 can optionally be taken together with the carbon to which they are joined to form a 3 to 8 membered cycloalkyl ring or 4 to 8 membered heterocyclyl ring containing one to three heteroatoms selected from —NR 5 —, —O—, —S—, —S(O)—, —SO 2 —, wherein the cycloalkyl ring or heterocyclyl ring may be optionally substituted by one to three R 10 groups;

R 14 and R 15 are independently selected from the group consisting of H, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkoxy, —R 3 (R 6 ) q , and —OR 3 (R 6 ) q , wherein R 14 and R 15 may be taken together with the nitrogen to which they are joined to form a 4 to 8 membered heterocyclyl or heteroaryl ring optionally containing one or three heteroatoms from —NR 5 —, —O—, —S—, —S(O)—, or —SO 2 —, wherein the heterocyclyl or heteroaryl ring may be optionally substituted by one to three R 10 groups;

Q is —[C(R 6 ) 2 ] r —;

m and n are independently 0, 1, 2, 3, or 4;

p is independently 0, 1, 2, 3, or 4; and

r and q are independently 0, 1, 2, 3, or 4.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z is

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is —CH 2 .

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein W is carbonyl.

9. A compound or a pharmaceutically acceptable salt thereof of the structure:

10. A compound or a pharmaceutically acceptable salt thereof of the structure:

11. A compound or a pharmaceutically acceptable salt thereof of the structure:

12. A compound or a pharmaceutically acceptable salt thereof of the structure:

13. A compound or a pharmaceutically acceptable salt thereof of the structure:

14. A compound or a pharmaceutically acceptable salt thereof of the structure:

15. A compound or a pharmaceutically acceptable salt thereof of the structure:

16. A compound or a pharmaceutically acceptable salt thereof of the structure:

17. A compound or a pharmaceutically acceptable salt thereof of the structure:

18. A compound or a pharmaceutically acceptable salt thereof of the structure:

19. A compound or a pharmaceutically acceptable salt thereof of the structure:

20. A compound or a pharmaceutically acceptable salt thereof of the structure:

21. A compound or a pharmaceutically acceptable salt thereof of the structure:

22. A compound or a pharmaceutically acceptable salt thereof of the structure:

23. A compound or a pharmaceutically acceptable salt thereof of the structure:

24. A compound or a pharmaceutically acceptable salt thereof of the structure:

25. A compound or a pharmaceutically acceptable salt thereof of the structure:

26. A compound or a pharmaceutically acceptable salt thereof of the structure:

27. A pharmaceutical composition comprising 1) a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and 2) a pharmaceutically acceptable excipient.