Claims for Patent: 9,969,689

Summary for Patent: 9,969,689

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 (Somerset, NJ), 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:	15/439,308
Patent Claims:	1. A compound of Formula Vd: ##STR00557## or a pharmaceutically acceptable salt thereof, wherein: R.sub.1 is aryl or heteroaryl; R.sub.4 is halo, cyano, alkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl; R.sub.5 is hydrogen, halo or alkyl; and R.sub.8 is hydroxy, alkylamino, alkoxy or amino. 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 at least one substituent selected from the group consisting of halo, C1-C4 alkyl, C1-C4 alkoxy, and cyano. 4. The compound of claim 1, wherein R.sub.4 is cyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl. 5. The compound of claim 4, wherein R.sub.4 is selected from the group consisting of --CN, --CF.sub.3, --S(.dbd.O)CH.sub.3, --S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2F, --S(.dbd.O).sub.2CHF.sub.2, --S(.dbd.O).sub.2CF.sub.3, --S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NHCH.sub.3, --S(.dbd.O)(.dbd.NH)CH.sub.3, --S(.dbd.O)(.dbd.NH)CH.sub.2F, --S(.dbd.O)(.dbd.NH)CHF.sub.2, --S(.dbd.O)(.dbd.NH)CF.sub.3, --S(.dbd.O)(.dbd.N--CN)CH.sub.3, --S(.dbd.O)(.dbd.N--CN)CH.sub.2F, --S(.dbd.O)(.dbd.N--CN)CHF.sub.2, and --S(.dbd.O)(.dbd.N--CN)CF.sub.3. 6. The compound of claim 1, wherein R.sub.5 is hydrogen. 7. The compound of claim 6, wherein R.sub.1 is phenyl, monocyclic heteroaryl or bicyclic heteroaryl. 8. The compound of claim 7, wherein R.sub.4 is cyano, fluoroalkyl, sulfonamide, sulfinyl, sulfonyl or sulfoximinyl. 9. The compound of claim 8, wherein R.sub.4 is selected from the group consisting of --S(.dbd.O).sub.2CH.sub.3, --S(.dbd.O).sub.2CH.sub.2F, --S(.dbd.O).sub.2CHF.sub.2, --S(.dbd.O).sub.2CF.sub.3, --S(.dbd.O).sub.2NH.sub.2, --S(.dbd.O).sub.2NHCH.sub.3, --S(.dbd.O)(.dbd.N--CN)CH.sub.3, --S(.dbd.O)(.dbd.N--CN)CH.sub.2F, --S(.dbd.O)(.dbd.N--CN)CHF.sub.2, and --S(.dbd.O)(.dbd.N--CN)CF.sub.3. 10. The compound of claim 8, wherein R.sub.8 is hydroxy or amino. 11. The compound of claim 1, wherein R.sub.8 is hydroxy or amino. 12. The compound of claim 11, wherein R.sub.8 is hydroxy. 13. The compound of claim 1, wherein the enantiomeric excess of said compound is at least 80%. 14. A compound selected from the group consisting of: ##STR00558## 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 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 1. 17. The method of claim 16, wherein said subject also suffers from a hemangioblastoma, a pheochromocytoma, a pancreatic neuroendocrine tumor or a renal cell carcinoma. 18. The method of claim 17, wherein said subject suffers from renal cell carcinoma. 19. The method of claim 18, wherein said renal cell carcinoma is clear cell renal cell carcinoma. 20. A method of treating renal cell carcinoma in a subject, comprising administering to said subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt according to claim 1.