Claims for Patent: 9,908,845

Summary for Patent: 9,908,845

Title:	Aryl ethers and uses thereof
Abstract:	The present disclosure relates to HIF-2.alpha. inhibitors and methods of making and using them for treating cancer. Certain compounds were potent in HIF-2.alpha. 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.
Inventor(s):	Dixon; Darryl David (Dallas, TX), Grina; Jonas (Coppell, TX), Josey; John A. (Dallas, TX), Rizzi; James P. (Irving, TX), Schlachter; Stephen T. (Dallas, TX), Wallace; Eli M. (Richardson, TX), Wang; Bin (Dallas, TX), Wehn; Paul (Dallas, TX), Xu; Rui (Dallas, TX), Yang; Hanbiao (Coppell, TX)
Assignee:	PELOTON THERAPEUTICS, INC. (Dallas, TX)
Application Number:	14/905,776
Patent Claims:	1. A compound of Formula I: ##STR00575## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is monocyclic aryl or monocyclic heteroaryl; R.sub.2 is carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl; R.sub.3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, ester, amido or acyl, or R.sub.2/R.sub.3 and atoms they are attached to form a 5- or 6-membered carbocycle with at least one sp.sup.3 hybridized carbon; and R.sub.4 is cyano, fluoroalkyl, alkylsulfonamide or sulfoximinyl; with the proviso that when R.sub.3 is H, R.sub.4 is --S(.dbd.O)(.dbd.NR.sub.b)R.sub.a, wherein R.sub.a is fluoroalkyl and R.sub.b is hydrogen or alkyl; and R.sub.1 is selected from the group consisting of ##STR00576## wherein X is N or CR.sub.7, R.sub.6 is cyano, halo, alkyl or alkoxy, and R.sub.7 is hydrogen, cyano, halo, alkyl or alkoxy; and ##STR00577## 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.sub.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.sub.4 is --S(.dbd.O).sub.2--NHR, wherein R is alkyl or cycloalkyl. 5. A compound of Formula III: ##STR00578## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is monocyclic aryl or monocyclic heteroaryl; R.sub.4 is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl or sulfoximinyl; n is 1, 2, 3 or 4; R.sub.8 is hydrogen, hydroxy, alkoxy or amino; R.sub.9 is hydrogen, alkyl, alkenyl or alkynyl, or R.sub.8 and R.sub.9 in combination form oxo; and each of R.sub.10 is independently selected from the group consisting of fluoro, hydroxy, alkyl, and heteroalkyl, with the proviso that when R.sub.10 is hydroxy, n is 1 or 2. 6. The compound of claim 5, wherein R.sub.8 is hydroxy or amino. 7. The compound of claim 5, wherein R.sub.9 is hydrogen. 8. The compound of claim 5, wherein n is 1 or 2 and R.sub.10 is fluoro. 9. The compound of claim 5, having the structure of Formula IV: ##STR00579## or a pharmaceutically acceptable salt thereof, wherein R.sub.8 is hydroxy or amino. 10. The compound of claim 9, having the structure of Formula V: ##STR00580## or a pharmaceutically acceptable salt thereof. 11. The compound of claim 5, wherein R.sub.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.sub.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: ##STR00581## 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.