Tetrahydro-1H-pyrido [3,4-b]indole anti-estrogenic drugs
The present disclosure provides tetrahydro-1H-pyrido[3,4-b]indole compounds or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, stereoisomer, tautomer, rotamer, N-oxide and/or substituted derivative or, optionally in a pharmaceutical composition, for the modulation of disorders mediated by estrogen, or other disorders as more fully described herein.
1. A method of treating a subject suffering from a cancer comprising administering a compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
X is —CH 2 - or —O—;
Y is
R 1 and R 2 are each hydrogen;
R 3 and R 4 are each independently selected from hydrogen and halo, and when one of R 3 or R 4 is halo, the other of R 3 or R 4 is hydrogen;
R 5 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 0 -C 4 (C 3 -C 6 cycloalkyl), or C 1 -C 6 heteroalkyl;
R 6 is hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 0 -C 4 (C 3 -C 6 cycloalkyl); and
R 7 and R 8 are each independently selected from hydrogen and C 1 -C 6 alkyl;
in combination with an anti-cancer agent.
2. The method of claim 1 , wherein the anti-cancer agent is selected from an mTOR inhibitor, a CDK4/6 inhibitor, a PI3 kinase inhibitor, an aromatase inhibitor, an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4, or an antibody to or inhibitor of EGFR, PGFR, or IGFR.
3. The method of claim 2 , wherein the anti-cancer agent is an mTOR inhibitor.
4. The method of claim 3 , wherein the mTOR inhibitor is selected from everolimus and rapamycin.
5. The method of claim 2 , wherein the anti-cancer agent is a CDK4/6 inhibitor.
6. The method of claim 5 , wherein the CDK4/6 inhibitor is selected from palbociclib, abemaciclib and ribociclib.
7. The method of claim 2 , wherein the anti-cancer agent is an antibody to or inhibitor of PD-1, PD-L1 or CTLA-4.
8. The method of claim 2 , wherein the anti-cancer agent is an antibody to or inhibitor of EGFR, PGFR, or IGFR.
9. The method of claim 1 , wherein the anti-cancer agent is selected from trastuzumab, pertuzumab, ado-trastuzumab, trastuzumab emtansine, erlotinib, gefitinib, and neratinib.
10. The method of claim 2 , wherein the anti-cancer agent is a PI3 kinase inhibitor.
11. The method of claim 10 , wherein the PI3 kinase inhibitor is selected from perifosine, CAL101, BEZ235, XL147, XL765, GDC-0941, and IPI-145.
12. The method of claim 2 , wherein the anti-cancer agent is an aromatase inhibitor.
13. The method of claim 12 , wherein the aromatase inhibitor is selected from aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatrien-3, 17-dione, and 4-androstene-3,6, 17-trione.
14. The method of claim 12 , wherein the aromatase inhibitor is selected from anastrozole, letrozole, and exemestane.
15. The method of claim 1 , wherein X is —O—.
16. The method of claim 1 , wherein Y is
17. The method of claim 1 , wherein Y is
18. The method of claim 16 , wherein R 5 is C 1 -C 6 alkyl.
19. The method of claim 17 , wherein R 5 is C 1 -C 6 haloalkyl.
20. The method of claim 1 , wherein R 6 is C 1 -C 6 haloalkyl.
21. The method of claim 1 , wherein the compound is selected from:
or a pharmaceutically acceptable salt thereof.
22. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23. The method of claim 21 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24. The method of claim 21 , wherein the compound is
or a pharmaceutically acceptable salt thereof.