Aryl ethers and uses thereof
The present disclosure relates to HIF-2α inhibitors and methods of making and using them for treating cancer. Certain compounds were potent in HIF-2α scintillation proximity assay, luciferase assay, and VEGF ELISA assay, and led to tumor size reduction and regression in 786-O xenograft bearing mice in vivo.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is monocyclic aryl or monocyclic heteroaryl;
R 2 is carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
R 3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, ester, amido or acyl, or R 2 /R 3 and atoms they are attached to form a 5- or 6-membered carbocycle with at least one sp 3 hybridized carbon; and
R 4 is cyano, fluoroalkyl, alkylsulfonamide or sulfoximinyl;
with the proviso that when R 3 is H,
R 4 is —S(═O)(═NR b )R a , wherein R a is fluoroalkyl and R b is hydrogen or alkyl; and
R 1 is selected from the group consisting of
wherein X is N or CR 7 , R 6 is cyano, halo, alkyl or alkoxy, and R 7 is hydrogen, cyano, halo, alkyl or alkoxy; and
may optionally be substituted with one or more substituents selected from the group consisting of cyano, halo, alkyl and alkoxy.
2. The compound of claim 1 , wherein R 1 is phenyl or pyridyl.
3. The compound of claim 2 , wherein said phenyl or pyridyl is substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano.
4. The compound of claim 1 , wherein R 4 is —S(═O) 2 —NHR, wherein R is alkyl or cycloalkyl.
5. A compound of Formula III:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is monocyclic aryl or monocyclic heteroaryl;
R 4 is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl or sulfoximinyl;
n is 1, 2, 3 or 4;
R 8 is hydrogen, hydroxy, alkoxy or amino;
R 9 is hydrogen, alkyl, alkenyl or alkynyl, or R 8 and R 9 in combination form oxo; and
each of R 10 is independently selected from the group consisting of fluoro, hydroxy, alkyl, and heteroalkyl, with the proviso that when R 10 is hydroxy, n is 1 or 2.
6. The compound of claim 5 , wherein R 8 is hydroxy or amino.
7. The compound of claim 5 , wherein R 9 is hydrogen.
8. The compound of claim 5 , wherein n is 1 or 2 and R 10 is fluoro.
9. The compound of claim 5 , having the structure of Formula IV:
or a pharmaceutically acceptable salt thereof, wherein R 8 is hydroxy or amino.
10. The compound of claim 9 , having the structure of Formula V:
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 5 , wherein R 4 is fluoroalkyl, sulfonyl or sulfoximinyl.
12. The compound of claim 10 , wherein the enantiomeric excess of said compound is at least about 85%.
13. The compound of claim 5 , wherein R 1 is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with one or more substituents selected from the group consisting of halo, alkyl, alkoxy and cyano.
14. A compound that is (S)-3-((2,2-difluoro-1-hydroxy-7-(methylsulfonyl)-2,3-dihydro-1H-inden-4-yl)oxy)-5-fluorobenzonitrile, represented by the formula:
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt according to claim 1 and a pharmaceutically acceptable carrier.
16. A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt according to claim 5 and a pharmaceutically acceptable carrier.
17. A pharmaceutical composition comprising a therapeutically effective amount of the compound or pharmaceutically acceptable salt according to claim 14 and a pharmaceutically acceptable carrier.
18. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 15 .
19. The method of claim 18 , wherein said subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor or a renal cell carcinoma.
20. The method of claim 19 , wherein said subject suffers from renal cell carcinoma.
21. The method of claim 20 , wherein said renal cell carcinoma is clear cell renal cell carcinoma.
22. A method of treating renal cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical composition according to claim 15 .
23. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt according to claim 5 .
24. The method of claim 23 , wherein said subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor or a renal cell carcinoma.
25. A method of treating renal cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt according to claim 5 .
26. A method of treating von Hippel-Lindau (VHL) disease, comprising administering to a subject in need thereof an effective amount of the compound or pharmaceutically acceptable salt according to claim 14 .
27. The method of claim 26 , wherein said subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor or a renal cell carcinoma.
28. A method of treating renal cell carcinoma, comprising administering to a subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt according to claim 14 .