Tetrahydro-1H-cyclopenta[cd]indene derivatives as hypoxia inducible factor-2(alpha) inhibitors
Inventors
Fu, Jiping • Lou, Yan • HE, Yigang
Assignees
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Publication Number
US-11753366-B2
Publication Date
2023-09-12
Expiration Date
Abstract
The present disclosure provides certain tetrahydro-1H-cyclopenta[cd]indene 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 relates to a compound of Formula, wherein R2 and R9 together with the carbon atom to which they are attached form a carbonyl or oxo group, or alternatively R2 is hydrogen and R9 is hydroxy. The compound scope includes tetrahydro-1H-cyclopenta[cd]indene scaffold HIF-2α inhibitors and fluorinated benzonitrile compounds featuring a tetrafluoro-cyclopenta[cd]inden scaffold.
The disclosure further includes pharmaceutically acceptable salts, pharmaceutical compositions, medicament use, protecting groups, polymorphs, prodrugs, isotopic labeling, stereochemistry, and tautomers. Representative embodiments are described within the scaffold family using specific substituent selections and fluorinated variants, including hydroxy and oxo variants.
The described subject matter also includes methods and uses that involve HIF2α inhibition by administering the disclosed compounds or by contacting with the compounds. The document indicates treatment of HIF2α-mediated or HIF-2α-associated diseases, including cancer, renal cancer, glioblastoma, NASH, pulmonary artery hypertension, inflammatory bowel disease, ccRCC, VHL disease, and iron disorders.
Claims Coverage
The claim coverage centers on Formula-defined compounds with an R2/R9 relationship that yields either an oxo or carbonyl-type feature, or an alternative hydrogen/hydroxy specification. Dependent claims narrow the scope to specific structure-defined embodiments highlighted by NC, F, O/OH, and in one embodiment a C−N+ motif, along with multiple fluorine atom variants.
Compound defined by formula with oxo or hydroxy alternative
A compound of Formula wherein R2 and R9 together with the carbon atom to which they are attached form a carbonyl or oxo group, or alternatively R2 is hydrogen and R9 is hydroxy.
Structure-defined embodiment with NC, F, and O/OH
A compound of the Formula defined by a specific chemical structure shown in the provided images and files, highlighting NC, F, and O/OH functional entities.
Structure-defined embodiment with C−N+ motif
A compound of the Formula defined by a specific chemical structure shown in the provided images, explicitly including a C−N+ motif together with NC, F, and O/OH elements.
Structurally distinct embodiment with multiple fluorine atoms and OH
A compound of the Formula defined by a specific structure shown in the images, including multiple F atoms and an OH, together with NC and O/OH related elements.
Overall, the claim set defines compounds with an R2/R9 relationship that yields either an oxo-forming carbonyl-type feature or a hydrogen/hydroxy alternative. Dependent claims narrow the scope to specific structure-defined embodiments emphasized by NC, F, O/OH, including one embodiment containing a C−N+ motif and another structurally distinct embodiment with multiple fluorine atoms and an OH.
Stated Advantages
Inhibition of HIF2α is stated as a mechanism for treatment of HIF2α-mediated diseases.
Treatment of HIF2α-mediated diseases including cancer, renal cancer, glioblastoma, NASH, pulmonary artery hypertension, inflammatory bowel disease, ccRCC, VHL disease, and iron disorders is stated.
Documented Applications
Use of the disclosed compounds and pharmaceutical compositions for HIF2α inhibition in treating cancer.
Use of the disclosed compounds and pharmaceutical compositions for treating renal cancer via HIF2α inhibition.
Use of the disclosed compounds and pharmaceutical compositions for treating glioblastoma via HIF2α inhibition.
Use of the disclosed compounds and pharmaceutical compositions for treating NASH via HIF2α inhibition.
Use of the disclosed compounds and pharmaceutical compositions for treating pulmonary artery hypertension via HIF2α inhibition.
Use of the disclosed compounds and pharmaceutical compositions for treating inflammatory bowel disease via HIF2α inhibition.
Methods of treating HIF-2α-associated diseases, including ccRCC, VHL disease, and iron disorders.
Pharmaceutical compositions and medicament use of the disclosed compounds for HIF-2α inhibition by contacting with the compounds.
Combination therapy for HIF-2α-associated disease with additional agents including immunotherapeutics, CAR-T, and agents associated with HER2/neu, EGFR, PI3K-mTOR, and VEGF.
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