EP2 antagonist compounds
Inventors
Duncton, Matthew Alexander James • SENATOROV, Jr., Vladimir V. • FRIEDMAN, Aaron R. • Olson, Steven Howard
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Assignees
Member
Glycos Biomedical LtdWe are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
We are UK/US entity with a team based in Maryland and North Carolina comprising an expert team that has linked triggers to disease states including TBI and acute injuries associated with radiation, acute lung injury and infection.
Publication Number
US-12624024-B2
Publication Date
2026-05-12
Expiration Date
Abstract
Described herein are compounds of Formula (II): that are EP2 antagonists, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of diseases or conditions associated with EP2 activity.
Core Innovation
The invention relates to compounds having the structure of Formula (II), or pharmaceutically acceptable salts thereof, with multiple variable substituent positions and ring definitions. The structure includes R1 through R10, RA1 and RA2, RB, RC, and Ring C or Ring C′, with allowed groups including hydrogen, deuterium, halogen, C1-4 alkyl, and various functional groups. Certain substituent pairs are taken together with the carbon atom to which they are attached to form an oxetane, cyclopropane, or an oxetane.
Ring C is a bicyclic heterocycle having one or more nitrogen atoms, or Ring C′, and Ring C′ is selected from a defined group of ring options. The disclosure further enumerates RB and RC as independently selected from halogen, cyano, alkyl, haloalkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, alkoxy, carbonyl-related, sulfur-containing, cycloalkyl, and heterocyclyl options, with two RC taken together optionally forming a carbonyl. The definition also includes index constraints such as m being 0 to 3 and n being 1, 2 or 3.
Dependent claims refine the scaffold by specifying Ring C as indole in some embodiments, including substituted or unsubstituted indole, and by allowing tautomeric and pharmaceutically acceptable salt forms. The provided material also depicts related structural embodiments within the same scaffold, including halogen-substituted bicyclic or heteroaromatic ring systems, oxygen-containing ring motifs, and nitrogen-containing heterocycles. Across the consolidated content, the core innovation is the definition of a large Formula (II) structural genus with constrained substituent options, ring-closure variants, and selected ring identities.
Claims Coverage
The independent claim centers on a Formula (II) compound and pharmaceutically acceptable salts with multiple independently defined substituent groups and ring-closure options, yielding a broad structural genus with three inventive feature groups.
Formula (II) compound with defined substituent options
A compound having the structure of Formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 and R2, R3 and R4, and R5 and R6 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl, with R5 and R6 optionally taken together with the carbon atom to form an oxetane; R7 and R8 are each independently selected from enumerated groups or are taken together with the carbon atom to form a cyclopropane or an oxetane; R9 and R10 are each independently hydrogen, deuterium, halogen, or C1-4 alkyl, or are taken together with the carbon atom to form an oxetane; RA1 is halogen, C1-4 alkyl, or cyclopropyl; and RA2 is hydrogen, deuterium, halogen, or optionally deuterated or halogenated methyl.
Variable RB and RC functional-group enumerations
RB is independently selected from halogen, CN, C1-4 alkyl, C1-4 haloalkyl, C1-4 aminoalkyl, C1-4 hydroxyalkyl, C1-4 methoxyalkyl, (C1-4 alkyl)O(C1-4 alkyl), C(O)(C1-4 alkyl), C(O)OH, C(O)O(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NH2, NH(C1-4 alkyl), NH(C3-6 cycloalkyl), NH(C3-6 heterocycloalkyl), N(C1-4 alkyl)2, NHC(O)C1-4 alkyl, NHC(O)O(C1-4 alkyl), NHS(O)2C1-4 alkyl, OH, O(C1-4 alkyl), O(C1-4 haloalkyl), SH, S(C1-4 alkyl), S(O)(C1-4 alkyl), S(O)(NH)(C1-4 alkyl), S(O)2(C1-4 alkyl), S(O)2NH2, S(O2)NHCH3, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; and RC is independently selected from halogen, CN, C1-4 alkyl, C1-4 haloalkyl, (C1-4 alkyl)O(C1-4 alkyl), C(O)OH, C(O)O(C1-4 alkyl), C(O)NH2, C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, OH, O(C1-4 alkyl), O(C1-4 haloalkyl), S(C1-4 alkyl), SO2C1-4 alkyl, SO2NHC1-4 alkyl, substituted or unsubstituted C3-6 cycloalkyl, or substituted or unsubstituted 3- to 6-membered heterocyclyl; or two RC taken together form a carbonyl.
Ring C definition and index constraints
m is 0 to 3; n is 1, 2 or 3; and Ring C is bicyclic heterocycle having one or more nitrogen atoms; or Ring C is Ring C′, with Ring C′ selected from the defined group of options.
Indole ring C refinement
Ring C is an indole that may be substituted or unsubstituted.
EP2 modulation use
Administering a compound, or its pharmaceutically acceptable salt or solvate, to modulate the activity of the prostaglandin E2 receptor 2 (EP2) in a mammal.
The claims center on a Formula (II) compound with broad but enumerated substituent coverage, optional oxetane and cyclopropane formation from paired substituents, Ring C as a bicyclic nitrogen-containing heterocycle or Ring C′, and index constraints for m and n. Dependent claims further refine Ring C in some embodiments and extend coverage to salts, tautomers, and an EP2 modulation use in mammals.
Stated Advantages
Provides EP2 antagonist potency via cAMP TR-FRET (IC50 categories in Table B1).
Includes microsome and hepatocyte stability assessments (Tables B2/B3).
Documented Applications
Pharmaceutical compositions are described in example formats including parenteral, oral, topical gel, and ophthalmic solution.
Administering a compound, or its pharmaceutically acceptable salt or solvate, to modulate the activity of prostaglandin E2 receptor 2 (EP2) in a mammal.
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