Benzothiophene-based selective estrogen receptor downregulators
View Patent ↗This invention is benzothiophene-based estrogen receptor downregulators and their compositions and uses to treat estrogen-related medical disorders.
1. A method of treating an estrogen-related disorder in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound of Formula:
or a pharmaceutically acceptable salt thereof;
wherein:
m is 0, 1, 2, 3, or 4;
n is 0, 1, 2, 3, or 4;
X A is —O—;
Ring B is phenyl, naphthyl, quinolinyl, 5- or 6-membered monocyclic heteroaryl, or 7-, 8-, 9- or 10 membered bicyclic heterocyclyl;
Ring C is phenyl, thiophenyl, 5- or 6-membered monocyclic heteroaryl, or 7-, 8-, 9-, or 10-membered bicyclic heterocyclyl;
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 —CH═CHCOOH, —NH(CO)COOH, —COOH, C 2 -C 6 alkenylene-COOH, and C 2 -C 6 alkynylene-COOH;
R 3 is independently selected at each occurrence from hydrogen, halogen, —CN, —NO 2 , C 1 -C 6 alkyl, and C 1 -C 6 fluoroalkyl; and
R 4 is independently selected at each occurrence from hydrogen, halogen, hydroxyl, 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 method of claim 1 , wherein the subject is a human.
3. The method of claim 2 , wherein the estrogen-related disorder is a cancer.
4. The method of claim 3 , wherein the cancer is selected from the group consisting of kidney cancer, prostate cancer, and lung cancer.
5. The method of claim 3 , wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.
6. The method of claim 3 , wherein the cancer is breast cancer.
7. The method of claim 6 , wherein the breast cancer is hormone receptor positive metastatic breast cancer.
8. The method of claim 6 , wherein the breast cancer is a tamoxifen resistant breast cancer.
9. The method of claim 6 , wherein the breast cancer is a triple negative breast cancer.
10. The method of claim 2 , wherein the estrogen-related disorder is bone loss.
11. The method of claim 10 , wherein the bone loss is caused by osteoporosis.
12. The method of claim 2 , wherein R 1 is hydroxyl.
13. The method of claim 12 , wherein Ring B and Ring C are phenyl.
14. The method of claim 13 , wherein m is 0.
15. The method of claim 14 , wherein R 2 is —CH═CHCOOH.
16. The method of claim 15 , wherein the estrogen related disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.
17. The method of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
18. The method of claim 17 , wherein the estrogen related disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.
19. The method of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
20. The method of claim 19 , wherein the estrogen related disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.
21. The method of claim 2 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein the estrogen related disorder is a cancer selected from the group consisting of breast cancer, ovarian cancer, and endometrial cancer.
23. The method of claim 2 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
24. The method of claim 2 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
25. The method of claim 2 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
26. The method of claim 2 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
27. The method of claim 2 , wherein the compound is selected from
or a pharmaceutically acceptable salt thereof.
28. The method of claim 19 , wherein the estrogen-related disorder is a cancer.
29. The method of claim 28 , wherein the cancer is selected from the group consisting of kidney cancer, prostate cancer, and lung cancer.
30. The method of claim 28 , wherein the cancer is breast cancer.
31. The method of claim 30 , wherein the breast cancer is hormone receptor positive metastatic breast cancer.
32. The method of claim 30 , wherein the breast cancer is a tamoxifen resistant breast cancer.
33. The method of claim 30 , wherein the breast cancer is a triple negative breast cancer.
34. The method of claim 19 , wherein the estrogen-related disorder is bone loss.
35. The method of claim 34 , wherein the bone loss is caused by osteoporosis.
36. The method of claim 21 , wherein the estrogen-related disorder is a cancer.
37. The method of claim 36 , wherein the cancer is selected from the group consisting of kidney cancer, prostate cancer, and lung cancer.
38. The method of claim 36 , wherein the cancer is breast cancer.
39. The method of claim 38 , wherein the breast cancer is hormone receptor positive metastatic breast cancer.
40. The method of claim 38 , wherein the breast cancer is a tamoxifen resistant breast cancer.
41. The method of claim 38 , wherein the breast cancer is a triple negative breast cancer.
42. The method of claim 21 , wherein the estrogen-related disorder is bone loss.
43. The method of claim 42 , wherein the bone loss is caused by osteoporosis.