Inhibitors of HIF-2α and methods of use thereof
Inventors
BEATTY, Joel Worley • DREW, Samuel Lawrie • EPPLIN, Matthew • FOURNIER, JEREMY • GAL, Balint • Hardman, Clayton • MAILYAN, Artur Karenovich • LAWSON, Kenneth Victor • Leleti, Manmohan Reddy • Liu, Dongdong • MATA, Guillaume • Podunavac, Ma{hacek over (s)}a • Powers, Jay Patrick • Rosen, Brandon Reid • Yu, Kai
Assignees
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Publication Number
US-12071411-B2
Publication Date
2024-08-27
Expiration Date
Abstract
The present disclosure is directed to compounds that are inhibitors of HIF-2α having a structure according to Formula I, and compositions containing those compounds. Methods of using the compounds for the treatment of diseases, disorders, or conditions are also described.
Core Innovation
The invention relates to a compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula I. The structural scope is defined by the values of n and m, and by the independently selected substituent groups R1, R2, R3, R4, X, and Y. R1 is selected from halo, —OH, and —O—(C1-C3 alkyl), while R2 is selected from —C1-C6 alkyl, —CN, and —S(O)2—(C1-C3 alkyl) with optional halo substitution. R3 and R4 are defined using alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, and substituted variants with constraints on the number of substituents and allowed heteroatoms.
The compounds of Formula I include substitution patterns where X is —C2-C3 alkylene- and Y is —C1-C3 alkylene-. The allowed substituents include halo, —C1-C6 alkyl, —C1-C6 haloalkyl, —OH, —O—(C1-C6 alkyl), and sulfur-containing groups such as —S—(C1-C6 alkyl), —S(O)—(C1-C6 alkyl), and —S(O)2—(C1-C6 alkyl), with optional halo substitution. The invention therefore provides a defined chemical space of fluorinated cyclopenta[c]pyrazol-4-ol title compounds, including diastereomeric separation into DIAST-1 and DIAST-2.
The invention further encompasses refinement to particular sub-structures through formula variants and constrained parameter settings, including Formula III-related variants and quantitative constraints for specific sub-formulas. The patent specifies particular substitutions such as R2 being a specified fluorinated group and requires at least one R1 to be a fluorinated substituent in certain embodiments. These refinements narrow the overall structural space to particular formula-defined compound classes.
Claims Coverage
The provided independent claim coverage consists of one independent compound claim defining a Formula I structure with multiple substituent-variable ranges. Dependent claims in the provided set further refine that structure by specifying particular substituent choices or formula variants, and one dependent claim specifies a therapeutic treatment method for HIF-2α-associated conditions.
Formula I compound structure with constrained substituent variables
A compound, or a pharmaceutically acceptable salt thereof, having a structure according to Formula I, wherein n is 1 or 2 and m is 2–8 with the stated constraint when n is 1; each R1 is independently selected from halo, —OH, and —O—(C1-C3 alkyl); R2 is selected from —C1-C6 alkyl, —CN, and —S(O)2—(C1-C3 alkyl) with 0–3 halo substitution on the specified groups; R3 is selected from the listed alkyl/cycloalkyl/heterocycloalkyl/heteroaryl options (each optionally substituted with 0–3 R4) and X and Y are defined as —C2-C3 alkylene- and —C1-C3 alkylene-, respectively.
Formula III-related compound variants
A compound, or a pharmaceutically acceptable salt thereof, whose structure corresponds to Formula III, Formula IIIa, Formula IIIc, or Formula IIId, with specified substituent definitions for R1, R2, and R3 including detailed definitions for R4, and with p defined for certain sub-formulas, where p is constrained to 0-3 halo for the applicable sub-formulas.
R2 fixed to CF3
The compound according to claim 1 wherein R2 is —CF3.
At least one fluorinated R1 substituent
The compound according to claim 1 wherein at least one substituent R1 is —F.
Therapeutic treatment of HIF-2α-associated conditions
A method for treating a disease, disorder, or condition associated with HIF-2α by administering to a human subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt of the compound as specified in the Formula I claim.
Overall, claim coverage is anchored in a Formula I compound definition with extensive substituent-variable constraints across R1/R2/R3/R4 and linkage variables X and Y. The dependent claims further narrow the scope by fixing R2 to —CF3, requiring at least one R1 equal to —F, constraining the structure to specified Formula variants, and adding a method of treating HIF-2α-associated diseases or conditions by administration to a human subject.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating a disease, disorder, or condition associated with HIF-2α in a human subject by administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt as specified by the Formula I structure.
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