MASP-2 inhibitors and methods of use
Inventors
Cutshall, Neil S. • Gage, Jennifer Lynn • Goldstein, Sara Rebecca • Kwon, Do Yeon • Little, Thomas L. • Metz, Markus • Nollert von Specht, Peter Kurt • Tsoung, Jennifer
Assignees
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Publication Number
US-12030853-B2
Publication Date
2024-07-09
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 provides compounds having Structure (I), including stereoisomers, tautomers, and pharmaceutically acceptable salts, and defines the compound structures through substituent groups and ring system constraints. In Structure (I), R1 is selected from substituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl, with further defined options for additional substituents on the R1 ring system. The disclosure further specifies detailed definitions for multiple variable groups, including R2a-R2d, R3, R3a-R3b, R4, R5-R8, n, and t, and describes that the substituted and unsubstituted ring systems can be monocyclic, bicyclic, tricyclic, or tetracyclic and can include fused or bridged ring systems, with heteroatoms selected from nitrogen, oxygen, and sulfur.
The disclosure states that compounds of Structures (I), (II), and (III) and embodiments thereof can be provided as pharmaceutically acceptable salts. The disclosure characterizes these compounds as MASP-2 inhibitors. The therapeutic use is described in terms of treating MASP-2-associated diseases, including MASP-2-dependent lectin/complement-associated diseases, and providing a therapeutically effective amount optionally in salt form.
The disclosure identifies thrombotic microangiopathies and other inflammatory and organ-related disease categories as targets for MASP-2 inhibition. Listed disease categories include TTP/aHUS/HUS, including thrombotic microangiopathies, transplant- and complement-mediated inflammatory disorders, renal conditions, and coagulation and inflammatory conditions. The disclosure further includes additional specific named conditions such as Upshaw-Schulman syndrome and complement-associated pulmonary and vascular disorders.
Claims Coverage
The provided material centers on a Structure (I) compound family with extensive interdependent substituent and ring-system constraints, while also covering stereoisomers, tautomers, and pharmaceutically acceptable salts. Independent and dependent claim content combines these structural definitions with pharmaceutical composition coverage and MASP-2 inhibitor characterization.
Structure (I) compound with variable R-group and ring-system constraints
A compound having Structure (I), or a stereoisomer, tautomer, or pharmaceutically acceptable salt thereof, wherein R1 is selected from substituted phenyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted heterocyclyl, and wherein the remaining variables R2a-R2d, R3, R3a-R3b, R4, R5-R8, n, and t are defined with specific constraints on ring sizes, heteroatoms, and fused, bridged, or spiro ring-system possibilities.
Pharmaceutical composition with pharmaceutically acceptable carrier or excipient
A pharmaceutical composition containing a compound having Structure (I), or one of its stereoisomers, tautomers, or pharmaceutically acceptable salts, together with a pharmaceutically acceptable carrier or excipient.
Overall, the claim coverage is centered on a Structure (I) compound defined by extensive substituent and ring-system constraints, with optional stereoisomers, tautomers, and pharmaceutically acceptable salts, and includes a pharmaceutical composition embodiment.
Stated Advantages
MASP-2 enzymatic inhibition outcomes are reported via Ki categories for exemplary compounds, with Ki corresponding to IC50.
Provides MASP-2 inhibitors for therapeutic use against MASP-2-associated diseases.
Selects therapeutic treatment for MASP-2-dependent lectin/complement-associated diseases by administering a therapeutically effective amount.
Selectively inhibit MASP-2 (lectin pathway) without interfering with the classical complement pathway.
Documented Applications
MASP-2 enzymatic inhibition assay context is documented, with outcomes summarized as MASP-2 Ki categories in Table 2 for exemplary compounds.
Therapeutic treatment of MASP-2-associated diseases, including MASP-2-dependent lectin/complement-associated diseases.
Treatment of thrombotic microangiopathies, including TTP/aHUS/HUS and Upshaw-Schulman syndrome.
Treatment of transplant- and complement-mediated inflammatory disorders.
Treatment of renal conditions.
Treatment of coagulation and inflammatory conditions.
Use of pharmaceutical compositions and manufacture of medicament.
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