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 • Nollert von Specht, Peter Kurt • Price, Loren Michael • Tsoung, Jennifer
Assignees
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Publication Number
US-11661418-B2
Publication Date
2023-05-30
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 disclosure describes MASP-2 inhibitor compounds having Structure (I) to (III), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof. The chemical genus is defined through substituent alternatives for R1, R2, R3, R4, R5a, R5b, R6, R7, R8, and n, encompassing aryl, cycloalkyl, heterocyclyl, heteroaryl, alkyl, haloalkyl, phosphonalkyl, and phosphorus-containing groups. In addition, R2 and R3 optionally form an optionally substituted 4–7 membered heterocyclyl ring with their attached carbon and nitrogen atoms.
The compounds target the lectin complement pathway without interfering with antibody-dependent classical pathway activation and target MASP-2-associated diseases. Disclosed embodiments include chemical variants based on a stereodefined 4-phenylpiperidine-2-carboxamide scaffold, including substituted piperidine- and azetidine-containing carboxamides, as well as pyrazole, tetrazole, aminopyridine, amidine, hydroxyamidine, ester, and phosphonic acid derivatives. Structural definitions impose specified conditions linking R5a alternatives and R1 substituents, while excluding designated structures under stated circumstances unless the heterocyclyl ring is formed.
Claims Coverage
The provided claims identify two independent compound claims comprising two inventive features.
Structure (I) compound and substituent alternatives
A compound having Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, with defined substituent alternatives for R1, R2, R3, R4, R5a, R5b, R6, R7, R8, and n, ring-closure options between R2 and R3 to form an optionally substituted 4–7 membered heterocyclyl, and specified conditional exclusions.
Individually depicted compound structures
A compound having one of the specific chemical structures depicted in the claim, or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof.
The independent claims cover the broad Structure (I) chemical genus and specific depicted compound structures, supported by dependent claims covering substituent refinements, pharmaceutical compositions comprising carriers or excipients, and methods of treating MASP-2-associated disorders.
Stated Advantages
The compounds exhibit selectivity over thrombin.
Documented Applications
A pharmaceutical composition comprising the claimed compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient.
A method of treating a MASP-2-associated disease or disorder, including thrombotic microangiopathies, renal disorders, transplant-related complications, and other complement-associated conditions, by administering an effective amount of the claimed compound to a subject.
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