Aryl ethers and uses thereof
AssigneePeloton Therapeutics, Inc.
InventorsDarryl David Dixon, Jonas Grina, John A. Josey, James P. Rizzi, Stephen T. Schlachter, Eli M. Wallace, Bin Wang, Paul Wehn, Rui Xu, Hanbiao Yang
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Abstract
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.
Claims28
A compound of Formula I:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is monocyclic aryl or monocyclic heteroaryl;
- R2 is carboxaldehyde, carboxylic acid, ester, amido, cyano, halo, sulfonyl or alkyl;
- R3 is hydrogen, halo, cyano, alkyl, heteroalkyl, alkenyl, alkynyl, alkylamino, carboxaldehyde, carboxylic acid, ester, amido or acyl, or R2/R3 and atoms they are attached to form a 5- or 6-membered carbocycle with at least one sp3 hybridized carbon;
- and
- R4 is cyano, fluoroalkyl, alkylsulfonamide or sulfoximinyl;
- with the proviso that when R3 is H,
- R4 is —S(═O)(═NRb)Ra, wherein Ra is fluoroalkyl and Rb is hydrogen or alkyl;
- and
- R1 is selected from the group consisting of
- wherein X is N or CR7, R6 is cyano, halo, alkyl or alkoxy, and R7 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.
A compound of Formula III:
- or a pharmaceutically acceptable salt thereof, wherein:
- R1 is monocyclic aryl or monocyclic heteroaryl;
- R4 is halo, cyano, fluoroalkyl, sulfinyl, alkylsulfonamide, sulfonyl or sulfoximinyl;
- n is 1, 2, 3 or 4;
- R8 is hydrogen, hydroxy, alkoxy or amino;
- R9 is hydrogen, alkyl, alkenyl or alkynyl, or R8 and R9 in combination form oxo;
- and
- each of R10 is independently selected from the group consisting of fluoro, hydroxy, alkyl, and heteroalkyl, with the proviso that when R10 is hydroxy, n is 1 or 2.
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.
Dependencies are inferred from the claim text.