MASP-2 inhibitors and methods of use
Inventors
Cutshall, Neil S. • Gage, Jennifer Lynn • Kwon, Do Yeon • Little, Thomas L • Metz, Markus • Nollert von Specht, Peter Kurt • Tsoung, Jennifer • Nguyen, Jeremiah H. • Davis, Melinda • Lemus, Robert Huerta • Keshipeddy, Santosh Kumar • Goldstein, Sara Rebecca
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12110288-B2
Publication Date
2024-10-08
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 invention relates to compounds having a Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The compounds are defined by substituent variables including R1, R2, R3, R4, R5a, R5b, and a linker L1 with a parameter t of 0, 1, or 2. R1 is a substituted or unsubstituted heteroaryl, and R2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl.
R2 is optionally substituted with one or more substituents selected from defined groups including alkyl, deuterated alkyl, halo, aminylalkyl, hydroxyalkyl, cyano, nitro, ORa, SRa, and carbonyl- and sulfonyl-containing groups. The definitions also establish ring-size ranges and allowed ring systems for the aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties, and permit fused or bridged ring systems.
Additional constraints define R3, R4, R5a, R5b, and L1, together with provisos that exclude certain R2 structures and, when R2 is unsubstituted phenyl, exclude certain R1 structures. The core structural concept is a parameterized Structure (I) scaffold with a defined heteroaryl-containing substitution (R1) and an aryl/heteroaryl-containing substitution (R2), where the compound can be provided as stereoisomers, tautomers, or pharmaceutically acceptable salts.
Claims Coverage
The provided material identifies one independent claim covering a compound having Structure (I) and a separate independent aspect covering a pharmaceutical composition. The compound claim defines 5 inventive features around substituted R1 and R2 groups, parameterized R3, R4, R5a, R5b, and L1/t, ring-size and composition ranges, and structural exclusions.
Structure (I) compound with stereoisomer, tautomer, or pharmaceutically acceptable salt
A compound having Structure (I) or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
R1 heteroaryl and R2 aryl or heteroaryl with optional substituents
R1 is a substituted or unsubstituted heteroaryl, and R2 is a substituted or unsubstituted aryl or a substituted or unsubstituted heteroaryl, wherein R2 is optionally substituted with one or more substituents selected from the defined groups.
Parameterized substituent definitions for R3, R4, R5a, R5b, and linker L1 with t
R3 is hydrogen or alkyl; R4 is alkyl, an arylalkyl, or a heterocyclyl substituted with phenyl or pyridinyl, or R3 and R4 together with the nitrogen form a 4-10 membered heterocyclyl; R5a is hydrogen or halo; R5b is selected from the enumerated classes; L1 is a direct bond, —CH2—, —S(O)t—, NR5b, —O—, —C≡C—, or related connectivity options, with t being 0, 1, or 2.
Ring-size ranges and exclusion provisos for R2 and, optionally, R1
The aryl, heteroaryl, cycloalkyl, and heterocyclyl moieties have specified ring-size ranges and composition limits, including fused or bridged features; and the provisos exclude certain R2 structures, and when R2 is unsubstituted phenyl they exclude certain R1 structures.
Pharmaceutical composition including the compound and a pharmaceutically acceptable carrier or excipient
A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier or excipient.
Overall, the claim coverage centers on Structure (I) compounds defined by parameterized aromatic and heteroaromatic substitution, optional substituent sets, ring-size ranges, and specified linker/connectivity constraints, subject to structural exclusions. A separate independent aspect covers a pharmaceutical composition containing the claimed compounds with a pharmaceutically acceptable carrier or excipient.
Stated Advantages
Not explicitly described in patent.
Documented Applications
A pharmaceutical composition including a compound of Structure (I) with a pharmaceutically acceptable carrier or excipient.
Enzymatic MASP-2 inhibition assay for measuring inhibition of enzyme MASP-2 (CCP1-CCP2-SP) using a fluorogenic substrate cleaved at the native substrate C2 cleavage site, including reporting MASP-2 Ki values categorized into ranges.
Interested in licensing this patent?