Benzothiophene-based selective estrogen receptor downregulators
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 receptor positive breast cancer in a human comprising administering to the human a selective estrogen receptor downregulator (SERD) compound having the structure:
wherein:
n is 0, 1, 2, 3, or 4;
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);
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the SERD compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
3. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
5. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the SERD compound is
or a pharmaceutically acceptable salt thereof.
10. The method of claim 1 , wherein the estrogen receptor positive breast cancer is metastatic.
11. The method of claim 1 , wherein the human is post-menopausal.
12. The method of claim 1 , wherein the SERD compound is administered in combination with a PI3 kinase inhibitor.
13. The method of claim 1 , wherein the SERD compound is administered in combination with a mTOR inhibitor.
14. The method of claim 13 , wherein the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, zotarolimus, and sirolimus.
15. The method of claim 1 , wherein the estrogen receptor positive breast cancer is resistant to anti-hormonal treatment.
16. The method of claim 15 , wherein the anti-hormonal treatment is selected from the group consisting of tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.
17. The method of claim 15 , wherein the anti-hormonal treatment is selected from the group consisting of anastrozole, letrozole, exemestane, formestane, aminoglutethimide, testolactone, and fadrozole.
18. The method of claim 12 , wherein the PI3 kinase inhibitor is selected from the group consisting of idelalisib, pictilisib, duvelisib, buparlisib, BYL719, perifosine, BAY80-6946, GDC-0941, GDC-0032, PF-04691502, GDC-0941, PF-05212384, SAR245409, and BEZ235.
19. The method of claim 2 , wherein the estrogen receptor positive breast cancer is metastatic.
20. The method of claim 2 , wherein the human is post-menopausal.
21. The method of claim 2 , wherein the SERD compound is administered in combination with a PI3 kinase inhibitor.
22. The method of claim 2 , wherein the SERD compound is administered in combination with a mTOR inhibitor.
23. The method of claim 22 , wherein the mTOR inhibitor is selected from the group consisting of everolimus, temsirolimus, ridaforolimus, zotarolimus, and sirolimus.
24. The method of claim 2 , wherein the estrogen receptor positive breast cancer is resistant to anti-hormonal treatment.
25. The method of claim 24 , wherein the anti-hormonal treatment is selected from the group consisting of tamoxifen, fulvestrant, steroidal aromatase inhibitors, and non-steroidal aromatase inhibitors.
26. The method of claim 24 wherein the anti-hormonal treatment is selected from the group consisting of anastrozole, letrozole, exemestane, formestane, aminoglutethimide, testolactone, and fadrozole.
27. The method of claim 21 , wherein the PI3 kinase inhibitor is selected from the group consisting of idelalisib, pictilisib, duvelisib, buparlisib, BYL719, perifosine, BAY80-6946, GDC-0941, GDC-0032, PF-04691502, GDC-0941, PF-05212384, SAR245409, and BEZ235.