Tetralin and tetrahydroquinoline compounds as inhibitors of HIF-2alpha
Inventors
BEATTY, Joel Worley • DREW, Samuel Lawrie • EPPLIN, Matthew • FOURNIER, Jeremy Thomas Andre • GAL, Balint • Guney, Tezcan • HAELSIG, Karl T. • Hardman, Clayton • JACOB, Steven Donald • JEFFREY, Jenna Leigh • Kalisiak, Jaroslaw • LAWSON, Kenneth Victor • Leleti, Manmohan Reddy • LINDSEY, Erick Allen • MAILYAN, Artur Karenovich • MANDAL, Debashis • MATA, Guillaume • MOON, Hyunyoung • Powers, Jay Patrick • Rosen, Brandon Reid • Su, Yongli • TRAN, Anh Thu • Wang, Zhang • Yan, Xuelei • Yu, Kai
Assignees
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Publication Number
US-12103907-B2
Publication Date
2024-10-01
Expiration Date
Abstract
Compounds that inhibit HIF-2α, and compositions containing the compound(s) and methods for synthesizing the compounds, are described herein. Also described are the use of such compounds and compositions for the treatment of a diverse array of diseases, disorders, and conditions, including cancer- and immune-related disorders that are mediated, at least in part, by HIF-2α.
Core Innovation
The invention relates to HIF-2α inhibitor compounds defined by chemical formulas, including Formula (I) and related Formula (II) through Formula (V-f) embodiments. The structures include tetralin/tetrahydroquinoline-like fused ring systems, chiral fluorinated tetrahydronaphthalene/dihydroinden carbonitrile derivatives, and other fluorinated fused bicyclic or heteroaryl compounds, with extensive substituent definitions and defined stereochemistry in some embodiments.
The disclosure specifies variable combinations, ring formation, and substituent options for the compound framework, including aryl/heteroaryl substituent groups, heteroaromatic motifs, fluorine, cyano, hydroxyl, sulfonyl/sulfonate, halogen, and nitrogen-containing ring features. It also includes pharmaceutically acceptable salt, hydrate, and solvate forms, pharmaceutical compositions, and routes of administration.
The document presents example compounds and characterization data, and it includes assay-based characterization in HIF-2α Luciferase assay and HIF-2α Scintillation/Proximity Assay formats. The compounds are stated to be useful for treating diseases and disorders mediated by HIF-2α and are described in administration alone or in combination with combination agents, including immune checkpoint inhibitors.
Claims Coverage
The provided independent claim coverage is limited to compounds having a chemical formula, including HIF-2α inhibitor compounds. Across the supplied claim excerpts, the identifiable inventive features remain formula-based and no further independent claim limitations are fully present in the partial text.
HIF-2α inhibitor compound defined by formula
A compound having the formula as stated in the claim and described as a HIF-2α inhibitor.
Compound defined by a chemical formula
A compound defined by a chemical formula without additional limitations in the supplied claim text.
Claim coverage is centered on formula-defined compounds, including HIF-2α inhibitor compounds, with no further claim refinements or additional inventive features explicitly available in the provided claim content.
Stated Advantages
Selective inhibition over other HIF isoforms.
Pharmacokinetic/selectivity considerations are discussed, including CYP inhibition, hepatocyte stability, and clearance.
Documented Applications
Treating diseases and disorders mediated by HIF-2α, including cancer.
Treating inflammatory/immune disorders, including autoimmune disorders and anti-immune/inflammatory disorders.
Treating metabolic disorders.
Use of the HIF-2α inhibitors alone or with combination agents for the stated indications.
Potency categorization of example compounds against HIF-2α using HIF-2α Luciferase assay and HIF-2α Scintillation/Proximity Assay.
Combination therapy together with immune checkpoint inhibitors.
Pharmaceutical compositions including pharmaceutically acceptable salt, hydrate, and solvate forms, with routes of administration.
Identification of HIF-2α inhibitors.
Example embodiments of specific compounds are documented with characterization data such as ESI MS and 1H NMR.
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