Immunoproteasome inhibitors
Inventors
Lou, Yan • Owens, Timothy Duncan • Brameld, Kenneth Albert • Goldstein, David Michael
Assignees
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Publication Number
US-12024531-B2
Publication Date
2024-07-02
Expiration Date
Abstract
Provided herein are compounds, such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof that are immunoproteasome (such as LMP2 and LMP7) inhibitors. The compounds described herein can be useful for the treatment of diseases treatable by inhibition of immunoproteasomes. Also provided herein are pharmaceutical compositions containing such compounds and processes for preparing such compounds.
Core Innovation
The invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, and to compounds of Formula (I′) and pharmaceutically acceptable salts thereof, defined by variable substituent frameworks including Y, R1, R2, ring A, X, X1, Het, R6, R7, Rb1, Rb2, and Rb3. Ring A is an optionally substituted five- to six-membered heterocyclyl that is benzofused as shown and includes a ring nitrogen atom, while X1 is —C(=O)— or —S(=O)2—. The disclosed compounds include chiral boronic acid title compounds, including (R)-configured boronic acid compounds and E or Z isomer specification for listed structures.
Within Formula (I), Y is —OR2, —N(R′)R2, or a group of formula A1, and R2 is a group of Formula (a) or (b). Within Formula (I′), the scaffold is defined by analogous substituent variables, with X limited to linked alkyl-aryl or alkyl-O-aryl patterns in the provided claim coverage and with explicit optional substitution rules for alkyl, aryl, heteroaryl, and heterocyclyl groups. The disclosure also includes optional cyclic boronic ester formation via Rb2 and Rb3, and parameters m and n are independently 0 or 1.
The invention frames the compounds as immunoproteasome-selective inhibitors and uses LMP2 and LMP7 as therapeutic targets. The disclosure also presents multiple specific examples of chiral boronic acid analogs with variations in aryl, vinyl, heteroaryl, and amino substituents, including fluoro and heteroaryl rings such as pyridinyl, pyrimidinyl, pyrazinyl, and benzofuranyl.
Claims Coverage
The consolidated claim coverage centers on two independent compound claims, Formula (I) and Formula (I′), and a method of inhibiting LMP2 or LMP7 by administering a therapeutically effective amount of a claimed compound. In total, the consolidated set reflects three inventive features: the Formula (I) scaffold, the Formula (I′) scaffold, and the therapeutic inhibition method, all built around a benzofused heterocyclyl ring A system and defined substituent constraints.
Substituted boronic acid scaffold of Formula (I)
A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein Y is —OR2, —N(R′)R2, or a group of formula A1; R′ is H or optionally substituted alkyl; R1 is H or optionally substituted alkyl; R2 is a group of Formula (a) or (b); ring A is an optionally substituted five- to six-membered heterocyclyl benzofused as shown; X1 is —C(=O)— or —S(=O)2—; and the definition includes further substituent variables such as X, Het, R6, R7, Rb1, Rb2, Rb3, m, and n.
Substituted boronic acid scaffold of Formula (I′)
A compound of Formula (I′) or a pharmaceutically acceptable salt thereof, wherein Y is —OR2, —N(R′)R2, or a group of formula A1; R′ is H or alkyl; R1 is H or alkyl; R2 is a group of Formula (a) or (b); ring A is a five- to six-membered heterocyclyl that is benzofused as shown; X1 is —C(=O)— or —S(=O)2—; and the provided claim coverage includes linked alkyl-aryl and alkyl-O-aryl X options, optional substitution rules for heteroaryl and related groups, and m and n independently 0 or 1.
LMP2 or LMP7 inhibition by administration of Formula (I) compound
A method that inhibits Large Multifunctional Protease 2 (LMP2) or Large Multifunctional Protease 7 (LMP7) in a subject by administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
Overall, the claim coverage is directed to structurally defined chiral boronic acid compounds of Formula (I) and Formula (I′), with a benzofused heterocyclyl ring A, defined X1 as —C(=O)— or —S(=O)2—, and nested substituent definitions for Y, R1, R2, and related groups. The consolidated claim set also includes a therapeutic method for inhibiting LMP2 or LMP7 through administration of a claimed compound.
Stated Advantages
Selective immunoproteasome inhibitors targeting LMP2 (β2i) and LMP7 (β5i).
Inhibits Large Multifunctional Protease 2 (LMP2) or Large Multifunctional Protease 7 (LMP7) in a subject.
Documented Applications
A method of inhibiting Large Multifunctional Protease 2 (LMP2) or Large Multifunctional Protease 7 (LMP7) in a subject by administering a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
Methods of treating disease by administering the Formula (I) compounds, or pharmaceutically acceptable salts, to patients with diseases treatable by LMP2/LMP7 inhibition.
Proteasome/protease inhibition assays focused on LMP2 and LMP7, with reported IC50 values for representative compounds.
Cell-based Proteasome-Glo assays for proteasome activity in connection with representative compounds.
PBMC-related IL-2 production measurements in connection with reference inhibitors and representative compounds.
Assay descriptions addressing dialysis reversibility and durability/active-site occupancy for representative compounds.
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