Salinomycin derivatives and therapeutic uses thereof

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

or a pharmaceutically acceptable salt thereof, wherein:

X is

R is selected from the group consisting of H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl, 5-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl;

n is an integer from 0 to 6;

Y is selected from the group consisting of —NR 1 C(O), —C(O)NR 1 —, —OC(O)—, C(O)O—, —CR 1 (COOR 2 )—CR 3 ═CR 4 —, and —CR 1 ═CR 2 —;

m is an integer from 0 to 6;

Z is —CR 1 ═CR 2 —, —CR 1 (COOR 2 )—CR 3 ═CR 4 , or absent;

G is selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 3 -C 7 carbocyclyl, 5-10 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl, each optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenC 1-4 alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 ; and

each of R 1 , R 2 , R 3 , R 4 , and R 5 are independently selected from —H, —CN, —NO 2 , —NH 2 , —OH, C 1-4 alkyl, halogenC 1-4 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-7 cycloalkyl, 3-8 membered heterocyclyl, C 6-10 aryl, and 5-10 membered heteroaryl.

2. The compound of claim 1 , wherein R is H or CH 3 .

3. The compound of claim 1 , wherein n is 0, 2, or 4.

4. The compound of claim 1 , wherein Y is —NR 1 C(O), —C(O)NR 1 —, —OC(O)—, or C(O)O—.

5. The compound of claim 4 , wherein R 1 is H.

6. The compound of claim 1 , wherein Y is —CR 1 ═CR 2 —.

7. The compound of claim 6 , wherein R 1 is CN and R 2 is H.

8. The compound of claim 1 , wherein Y is —CR 1 (COOR 2 )—CR 3 ═CR 4 —.

9. The compound of claim 8 , wherein R 1 , R 3 , and R 4 are H, and R 2 is CH 3 .

10. The compound of claim 1 , wherein m is 0, 1, or 3.

11. The compound of claim 1 , wherein Z is —CR 1 ═CR 2 —.

12. The compound of claim 11 , wherein each of R 1 and R 2 are independently H or CN.

13. The compound of claim 12 , wherein Z is C(CN)═CH.

14. The compound of claim 1 , wherein Z is —CR 1 (COOR 2 )—CR 3 ═CR 4 .

15. The compound of claim 14 , wherein each of R 1 , R 2 , R 3 , and R 4 are H or C 1-4 alkyl.

16. The compound of claim 15 , wherein R 1 , R 3 , and R 4 are H, and R 2 is CH 3 .

17. The compound of claim 1 , wherein Z is absent.

18. The compound of claim 1 , wherein G is C 6-10 aryl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenC 1-4 alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 .

19. The compound of claim 18 , wherein G is a phenyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenC 1-4 alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 .

20. The compound of claim 19 , wherein G is selected from the group consisting of

21. The compound of claim 1 , wherein G is 5-10 membered heteroaryl optionally substituted with 0-3 substituents selected from the group consisting of halogen, C 1-4 alkyl, halogenC 1-4 alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 .

22. The compound of claim 21 , wherein G is selected from imidazole, pyrazole, triazole, tetrazole, thiazole, thiadiazole, oxazole, oxadiazole, isoxazole, isothiazole, pyridine, pyrazine, pyrimidine, pyridazine, azetidine, and pyrazine, each optionally substituted with halogen, C 1-4 alkyl, halogenC 1-4 alkyl, —OR 1 , —CN, —NO 2 , —NR 1 R 2 , —C(O)NR 1 R 2 , and —NR 1 C(O)R 5 .

23. The compound of claim 21 , wherein G is pyridine.

24. The compound of claim 1 , having a structure selected from the group consisting of:

or pharmaceutically acceptable salts thereof.

25. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable excipient.