Dihydrochromene derivatives
The present invention relates to the compound of formula (I) wherein R 1A , R 1B , R 1C , and R 1D are hydrogen atom, etc., R 2A and R 2B are hydrogen atom, etc., R 3A , R 3B , R 3C , and R 3D are hydrogen atom, etc., L is bond, etc., V is C 1-6 alkylene, Q is optionally-substituted imidazole, or a pharmaceutically acceptable salt thereof, as a novel anti-tumor agent that targets CSCs which are thought to be closely involved in the persistent proliferation of malignant tumor, metastasis or recurrence of cancer, and resistance to anti-tumor agents.
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of:
(4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran],
(4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran], and
(4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,11′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran].
8. The compound of claim 1 wherein the salt is a phosphate.
9. The compound of claim 8 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-y)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
10. The compound of claim 8 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
11. The compound of claim 8 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
12. The compound of claim 8 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
13. The compound of claim 8 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
14. The compound of claim 8 , which is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-y)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] diphosphate.
15. The compound of claim 1 wherein the salt is a fumurate.
16. The compound of claim 15 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
17. The compound of claim 15 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazo-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
18. The compound of claim 15 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
19. The compound of claim 15 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
20. The compound of claim 15 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
21. The compound of claim 15 , which is (4′aR,10′bR)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] difumarate.
22. The compound of claim 1 wherein the salt is a p-toluenesulfonate.
23. The compound of claim 22 , which is (4′aS,10′bS)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.
24. The compound of claim 22 , which is (4′aR,10′bR)-8′-chloro-5′,5′-dimethyl-1-[(4-methyl-1H-imidazol-5-yl)methyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.
25. The compound of claim 22 , which is (4′aR,10′bR)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.
26. The compound of claim 22 , which is (4′aS,10′bS)-8′-chloro-1-[2-(1H-imidazol-1-yl)ethyl]-5′,5′-dimethyl-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.
27. The compound of claim 22 , which is (4′aS,10′bS)-9′-fluoro-5′,5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4′a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.
28. The compound of claim 22 , which is (4′aR,10′bR)-9′-fluoro-5′5′-dimethyl-1-[2-(2-methyl-1H-imidazol-1-yl)ethyl]-4a,10′b-dihydro-2′H,4′H,5′H-spiro[piperidine-4,3′-pyrano[3,2-c][1]benzopyran] di-p-toluenesulfonate.