Indane derivatives as hypoxia inducible factor-2(α) inhibitors
Inventors
Fu, Jiping • Lou, Yan • HE, Yigang
Assignees
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Publication Number
US-12077506-B2
Publication Date
2024-09-03
Expiration Date
Abstract
The present disclosure provides certain indane compounds that are Hypoxia Inducible Factor 2α (HIF-2α) inhibitors and are therefore useful for the treatment of diseases treatable by inhibition of HIF-2α. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Core Innovation
The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof as selective HIF-2α inhibitors. The compounds are defined by variable substituent patterns across X, R1 through R9, together with a linkage group L selected from bond, S, SO, SO2, O, CO, or NR16, and representative embodiments include formula (IIa) or (IIb) and constrained substitution patterns such as fluoro at R3 and/or R4 and haloalkyl at R9.
The disclosure further describes fluorinated tetrahydro-indene, indane, and dihydroindene scaffolds, including nitrile and aryl-oxy compounds, as well as deuterated and stereochemically resolved variants. Representative structures include difluoromethyl and tetrafluoro motifs, hydroxyl and nitrile substituents, aryl/heteroaryl ether substituents, and substituted analogs bearing methyl, vinyl, ethyl, bromo, and chloro substituents.
The compounds are described for treatment of HIF-2α mediated diseases and diseases treatable by HIF-2α inhibition, including cancers, von Hippel-Lindau disease, and non-cancer hypoxia-associated diseases. The disclosure also states pharmaceutical compositions comprising the compound and pharmaceutically acceptable excipients, and combination therapy with various other therapeutic agents.
Claims Coverage
The provided claim coverage centers on broad independent compound claims for Formula (I) with variable substituent patterns across X, R1 through R9, and linkage group L, together with narrower embodiments limiting L or specific substituents. It also includes pharmaceutical composition and treatment method coverage. In total, the independent coverage highlights the Formula (I) scaffold, specific fluoro and haloalkyl selections, and therapeutic use claims.
Formula (I) compound with variable substituent pattern
A compound of Formula (I) wherein X is CH or N; R1 is selected from hydroxy, amino, phosphate/ester and carboxylate/amide/ester-related groups as defined; R2 is hydrogen, deuterium, alkyl, haloalkyl, alkynyl, or alkenyl; R3 and R4 are independently selected from the stated options with halo or ring-forming limitations; R5 and R6 are selected from the stated options with optional ring formation; R7 is hydrogen, deuterium, alkyl, alkoxy, cyano, halo, haloalkyl, or haloalkoxy; L is a bond, S, SO, SO2, O, CO, or NR16; R8 is selected from the listed ring systems and substituent-substituted variants; R9 is haloalkyl; and the compound includes pharmaceutically acceptable salts.
Specific Formula (IIa) or (IIb) embodiments
A compound according to formula (IIa) or (IIb), or a pharmaceutically acceptable salt of the compound.
Fluoro substitution at R3 and R4
A compound wherein R3 is fluoro, or wherein R3 and R4 are fluoro, or a pharmaceutically acceptable salt of the compound.
R9 as trifluoromethyl or difluoromethyl
A compound wherein R9 is trifluoromethyl or difluoromethyl, or a pharmaceutically acceptable salt thereof.
Linkage group L restricted to O, S, SO, SO2, or NH
The compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L is O, S, SO, SO2, or NH.
Pharmaceutical composition containing the Formula (I) compound
A pharmaceutical composition comprising a therapeutically relevant amount of the Formula (I) compound or a pharmaceutically acceptable salt together with a pharmaceutically acceptable excipient.
Method of treating selected listed diseases by administering the pharmaceutical composition
A method for treating a selected cancer or non-cancer disease in a patient by administering a therapeutically effective amount of a pharmaceutical composition containing the claimed compound or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
The claims coverage centers on a broad Formula (I) scaffold with variable substituents across X, R1 through R9 and linkage group L, refined by specific embodiments including formula (IIa) or (IIb), fluoro substitution at R3 and R4, and haloalkyl at R9. The set also includes pharmaceutical composition and treatment method coverage for selected listed diseases and cancers.
Stated Advantages
Selectivity as HIF-2α inhibitors.
Documented Applications
Treatment of diseases treatable by HIF-2α inhibition, including multiple cancers and non-cancer hypoxia-associated diseases.
Treatment of HIF-2α mediated diseases, including von Hippel-Lindau disease, using a therapeutically effective amount of a pharmaceutical composition containing the claimed Formula (I) compound and a pharmaceutically acceptable excipient.
Treatment of selected cancer or non-cancer disease in a patient by administering a pharmaceutical composition containing the claimed compound and a pharmaceutically acceptable excipient.
Pharmaceutical compositions comprising the compound and pharmaceutically acceptable excipients.
Combination therapy with various other therapeutic agents.
Compounds are evaluated in a VEGF (HIF-2α) ELISA using 786-O cells, reporting EC50 values for compound I-1.
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