Benzothiophene-based selective mixed estrogen receptor downregulators
This invention is benzothiophene-based selective mixed estrogen receptor downregulators and their compositions and uses to treat estrogen-related disorders.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
X is —C(O)—;
Ring B is phenyl, or naphthyl;
Ring C is phenyl, or C 3 -C 6 cycloalkyl;
R 1 is selected from hydroxyl, hydrogen, halogen, —O(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), —OC(O)C 6 H 5 , —OC(O)O(C 1 -C 6 alkyl), —OC(O)OC 6 H 5 , and —OSO 2 (C 2 -C 6 alkyl);
R 2 is selected from —OCH═CHCOOH, —NHC(O)COOH, —COOH, —C 2 -C 6 alkylene-COOH, and —C 2 -C 6 alkynylene-COOH; and
R 3 and R 4 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —O(C 1 -C 6 alkyl), and —O(C 1 -C 6 fluoroalkyl).
2. The compound of claim 1 , wherein Ring B is phenyl.
3. The compound of claim 1 , wherein R2 is selected from —OCH═CHCOOH and —C 2 -C 6 alkylene-COOH.
4. The compound of claim 1 , wherein R 4 is selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and —O(C 1 -C 6 fluoroalkyl).
5. The compound of claim 1 , wherein R4 is hydroxyl.
6. The compound of claim 1 , wherein m is 0.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (II):
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (III):
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, of Formula (IV):
wherein t is 1, 2, 3, or 4.
10. A compound of Formula (V), or a pharmaceutically acceptable salt thereof:
wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
X is —C(O)—;
Ring B is phenyl, or naphthyl;
Ring C is phenyl, or C 3 -C 6 cycloalkyl;
Ring D is C 3 -C 6 cycloalkyl;
R 1 is selected from hydroxyl, hydrogen, halogen, —O(C 1 -C 6 alkyl), —OC(O)(C 1 -C 6 alkyl), —OC(O)C 6 H 5 , —OC(O)O(C 1 -C 6 alkyl), —OC(O)OC 6 H 5 , and —OSO 2 (C 2 -C 6 alkyl);
R 2a is selected from —OH, —NH(CO)NHOH, —CH═CHCOOH, —NH(CO)COOH, —COOH, —NH 2 , —C 2 -C 6 alkylene-COOH, and —C 2 -C 6 alkynylene-COOH; and
R 3 and R 4 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —O(C 1 -C 6 alkyl), and —O(C 1 -C 6 fluoroalkyl).
11. The compound of claim 10 , wherein Ring B is phenyl.
12. The compound of claim 10 , wherein R 2a is selected from —OH, —COOH, and —NH 2 .
13. The compound of claim 10 , wherein m is 0.
14. A compound of Formula (VII), or a pharmaceutically acceptable salt thereof:
wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
Ring D 1 is selected from
R 2b is selected from —OH, —NH 2 , and —COOH; and
R 3 and R 4 are independently selected at each occurrence from hydrogen, halogen, hydroxyl, —NO 2 , C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, —CN, —O(C 1 -C 6 alkyl), and —O(C 1 -C 6 fluoroalkyl).
15. The compound of claim 14 , wherein R4 is selected from halogen, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, and —O(C 1 -C 6 fluoroalkyl).
16. The compound of claim 14 , wherein m is 0.
17. The compound of claim 14 , wherein R4 is independently selected from halogen, C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl.
18. A pharmaceutically composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
19. A pharmaceutically composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier or excipient.
20. A pharmaceutically composition comprising a compound of claim 14 and a pharmaceutically acceptable carrier or excipient.
21. A method of treating a hormone-related cancer that is an estrogen-mediated disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.
22. A method of treating a hormone-related cancer that is an estrogen-mediated disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 10 or a pharmaceutically acceptable salt thereof.
23. A method of treating a hormone-related cancer that is an estrogen-mediated disorder in a subject in need thereof comprising administering a therapeutically effective amount of a compound according to claim 14 or a pharmaceutically acceptable salt thereof.
24. The method of claim 21 , wherein the hormone-related cancer is breast cancer, uterine cancer, ovarian cancer, lung cancer, prostate cancer or endometrial cancer.
25. The method of claim 22 , wherein the hormone-related cancer is breast cancer, uterine cancer, ovarian cancer, lung cancer, prostate cancer or endometrial cancer.
26. The method of claim 23 , wherein the hormone-related cancer is breast cancer, uterine cancer, ovarian cancer, lung cancer, prostate cancer or endometrial cancer.
27. The compound of claim 1 , wherein Ring B is naphthyl.
28. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
29. The compound of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
30. The compound of claim 14 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.