MASP-2 inhibitors and methods of use
Inventors
Cutshall, Neil S. • Gage, Jennifer Lynn • Goldstein, Sara Rebecca • Keshipeddy, Santosh Kumar • Kwon, Do Yeon • Lemus, Robert Huerta • Little, Thomas L. • Metz, Markus • Nguyen, Jeremiah H. • Nollert von Specht, Peter Kurt • Price, Loren Michael • Tsoung, Jennifer • Vaddela, Sudheer Babu
Assignees
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Publication Number
US-12486278-B2
Publication Date
2025-12-02
Expiration Date
Abstract
The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.
Core Innovation
The independent claim describes a compound having Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, which acts as a MASP-2 inhibitor. The chemical scaffold comprises an aryl or heteroaryl R1 group, a substituted or unsubstituted 4-membered heterocyclyl formed by R2 and R3 together with attached carbon and nitrogen atoms, and defined alternatives for R4, R5, and linker L1. The technical problem being solved is not explicitly described in patent.
Synthesized embodiments include substituted pyrrolidine- and piperidine-carboxamide compounds bearing varied aryl, heteroaryl, cyclic, and linker moieties with amino, halogen, alkyl, alkoxy, cyano, or carboxyalkyl substituents, along with trifluoroacetate and hydrochloride salt forms. Reported screening results demonstrate MASP-2 inhibition, with compounds exhibiting Ki values below 0.5 ̂ΔM and selectivity over thrombin. The disclosure documents these compounds for pharmaceutical compositions and the treatment of MASP-2-associated disorders.
Claims Coverage
The claims identify one independent claim, claim 1, directed to compounds of Structure (I) and specified forms thereof, characterized by two inventive features.
Structure (I) compound and specified forms
A compound having Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
Defined substituent and linker alternatives
R1 is a substituted or unsubstituted aryl or heteroaryl; R2 and R3, together with the attached carbon and nitrogen, form an unsubstituted or substituted 4-membered heterocyclyl; R4 is a substituted or unsubstituted aryl, heteroaryl, cycloalkyl, or heterocyclyl; R5 is selected from hydrogen, alkyl, haloalkyl, cycloalkyl, and specified carbonyl-containing or sulfonamide-containing groups; and L1 is —CR8aR8b—, —S(O)t—, NR8c, or —O—, with defined alternatives for R6, R7, R8a, R8b, R8c, m, and t.
Claim 1 covers the Structure (I) compound genus, its specified substituent and linker alternatives, and the stated stereoisomeric, tautomeric, and pharmaceutically acceptable salt forms, defining alternatives for all elements of the claim.
Stated Advantages
The described compounds include embodiments exhibiting selectivity over thrombin.
Documented Applications
A method of inhibiting MASP-2 in a subject by administering an effective amount of the compound or a specified form thereof.
A method of treating a MASP-2-associated disease or disorder in a subject in need by administering an effective amount of the compound or a specified form thereof, including complement and coagulation disorders, thrombotic microangiopathy, renal disease, and transplant-associated complications.
A pharmaceutical composition comprising the compound or a specified form thereof and a pharmaceutically acceptable carrier or excipient.
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