EP2 antagonist compounds
Inventors
Duncton, Matthew Alexander James • SENATOROV, Jr., Vladimir V. • FRIEDMAN, Aaron R. • Olson, Steven Howard
Assignees
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Publication Number
US-12297171-B2
Publication Date
2025-05-13
Expiration Date
Abstract
Described herein are compounds 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 (I), including pharmaceutically acceptable salts or solvates thereof. The Formula (I) scaffold is defined by extensive variable substituent sets at positions including R1, Rd, Re, R2, R3, Z, L, ring A, ring B, ring E, R4, R5, R6, R7, R8, R9 to R14, R16, R18, and R19, with allowed options expressed through functional group and substitution patterns.
A central aspect of the disclosure is the constrained structural relationships within Formula (I), including R2 and R3 taken together with the carbon atom to form a carbonyl (C=O), thiocarbonyl (C=S), or ring B, and R18 and R19 taken together with the carbon atom to form ring E. The invention further defines Z as N or CR8, L as absent or —NH—, and ring A as a substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.
The substituent framework includes R1 defined as —C(O)NRd, with Rd and Re or R1d/R1d-linked options spanning alkyl, deuteroalkyl, fluoroalkyl, alkoxy, cycloalkyl, heterocycloalkyl, phenyl, and heteroaryl variants. Additional variable positions include broad permitted groups for R4, R5, R7, R8, and R6, as well as R9 to R14 and R16, with optional substitution by R12, R13, or R14 as stated in the claim sets.
The disclosure further characterizes the Formula (I) compounds through example scaffold variants and, in the EP2-related items, identifies the compounds as EP2 inhibitors or EP2 receptor antagonists. The described chemical scope includes stereoisomers, isotopically labeled compounds, active metabolites, deuterium, N-oxides, and polymorphs in the EP2-related disclosure.
Claims Coverage
One independent claim is present, directed to a Formula (I) compound, including pharmaceutically acceptable salts and solvates, with extensive substituent definitions. The coverage centers on the defined scaffold and the variable relationships for R1, Rd, Re, R2/R3, Z, L, ring A, ring B, ring E, R4/R5/R6/R7/R8, and R9-R19, with m and n constraints where stated.
Formula (I) compound scaffold with salts and solvates
A compound having the structure of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof.
R1 defined as carbonyl-linked N substituent
R1 is —C(O)NRd, with Rd or related R-group options spanning alkyl, deuteroalkyl, fluoroalkyl, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyl, and substituted aryl or heteroaryl definitions as stated.
R2 and R3 relationship with carbonyl, thiocarbonyl, or ring B formation
R2 and R3 are independently defined or may be taken together with the carbon atom to form C=O, C=S, or ring B, where ring B is a substituted or unsubstituted C3-C6 cycloalkyl or C2-C6 heterocycloalkyl, optionally substituted by R12.
Z, L, and ring A definition
Z is N or CR8; L is absent or —NH—; and ring A is a substituted or unsubstituted phenyl or substituted or unsubstituted heteroaryl.
Broad substituent sets for R4, R5, R6, R7, R8, and R9-R14
R4, R5, R7, R8, and R6 each have enumerated hydrogen, halogen, cyano, alkyl, deuteroalkyl, fluoroalkyl, alkoxy, carbonyl, ester, amide, and amino-type options, with R6 optionally being substituted with one or more R13; each of R9, R10, R11, R12, R13, and R14 is independently defined by the listed hydrogen, deuterium, halogen, alkyl, cycloalkyl, heterocycloalkyl, cyano, and functional substituent options.
R16 and ring E formation with m and n constraints
R16 is independently defined by hydrogen, alkyl, deuteroalkyl, fluoroalkyl, cycloalkyl, heterocycloalkyl, phenyl, heteroaryl, and alkyl-linked aryl or heterocycle groups, with optional formation of a substituted or unsubstituted C2-C6 heterocycloalkyl with N; R18 and R19 may form ring E, and m and n are constrained as stated.
The claim coverage is directed to a Formula (I) compound with pharmaceutically acceptable salts and solvates, defined by a highly structured substitution framework. The main inventive features are the R1 carbonyl-linked substituent, the R2/R3 options for carbonyl/thiocarbonyl or ring B formation, the Z and L linkage definitions, the ring A selection, and the broad but enumerated substituent sets extending through R4-R19 and the ring E/m/n parameters.
Stated Advantages
Improved pharmacokinetic/pharmacodynamic profiles versus other EP2 antagonists.
Documented Applications
EP2 antagonists, described as EP2-antagonist-like compounds.
Treating EP2-related inflammatory diseases and allergies.
Treating cancers, including colon cancer, in the context of EP2 activity modulation.
EP2 antagonism potency evaluation using a cAMP TR-FRET assay with IC50 potency categories.
In vitro stability assessment using human liver microsome stability and human hepatocyte stability with half-life and intrinsic clearance categories.
Pharmaceutical composition examples for parenteral, oral, topical gel, and ophthalmic solution compositions using compound salts.
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