Quinoline cGAS antagonist compounds
Inventors
Wei, Qi • Shi, Heping • TSCHANTZ, MATT • Qiu, Jian • WU, Youtong • TAN, Huiling • Sun, Lijun • Chen, Chuo • Chen, Zhijian
Assignees
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Publication Number
US-12091387-B2
Publication Date
2024-09-17
Expiration Date
Abstract
The present disclosure provides compounds that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.
Core Innovation
The invention relates to compounds of Formula I, or pharmaceutically acceptable salts thereof, in which Ring A is an optionally substituted triazole. The structural scope includes constrained substitution on substitutable carbon atoms and substitutable nitrogen atoms, with allowed groups including halogen, alkyl, alkoxy, aryl, heteroaryl, carbonyl-containing, sulfonyl-containing, phosphonate-containing, silicon-containing, and other heteroatom-containing substituents. The triazole ring is the central scaffold, with substitution patterns defined by the recited variable meanings.
The Formula I framework further defines Ring B1 as a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms, or one of the named heteroaryl ring systems, and Ring B2 as phenyl or a specified alternative ring class. The variables R2, R3, R5, R6, RB, R, m, n, and q are constrained by explicit allowed sets and ranges. R2 is defined as —NRaR5, and each R3 is independently selected from halogen, —OR, —NR2, or —SR.
The disclosure also presents multiple specific embodiments for R2, R5, and R6 through embedded chemical structures and depicted compound selections. These examples include carboxylic acid, ester, amide, ether, sulfonyl, sulfonamide, phosphonate, phosphonate/phosphoryl-like, boronic acid, and boron-containing motifs, as well as fused, bicyclic, and bridged ring-containing substituents. The overall disclosure centers on a broadly defined Formula I scaffold with tightly enumerated ring and substituent definitions.
Claims Coverage
The consolidated claim coverage includes a broad independent compound claim to Formula I, selected compound claims directed to depicted chemical structures, and a method claim directed to cGAS antagonism. The inventive features center on the optionally substituted triazole Ring A, defined Ring B1 and Ring B2 ring systems, and constrained substituent variables including R2, R3, R5, R6, RB, R, m, n, and q.
Formula I compound with optionally substituted triazole Ring A
A compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Ring A is an optionally substituted triazole with substitution on substitutable carbon atoms and substitutable nitrogen atoms selected from the enumerated group sets.
Defined ring systems Ring B1 and Ring B2
Ring B1 is a 4- to 10-membered saturated or partially unsaturated monocyclic or bicyclic carbocyclic or heterocyclic ring having 1 to 3 heteroatoms, or a named heteroaryl ring system, and Ring B2 is phenyl or a specified additional ring set.
R2, R3, R5, R6, RB, and parameter constraints
R2 is —NRaR5; each R3 is independently halogen, —OR, —NR2, or —SR; R5 and R6 are defined by enumerated functional-group classes including carboxylic acid, ester, amide, sulfonyl, phosphonate, boronic acid, and related groups; RB is an optionally substituted aliphatic, phenyl, carbocyclic, heterocyclic, or heteroaryl group; and m, n, and q are limited to the stated integer ranges.
Selected depicted compound from a chemical structure
A compound selected from a depicted chemical structure, or a pharmaceutically acceptable salt thereof, as expressly claimed in the provided material.
Antagonizing cGAS by administering the Formula I compound
A method of antagonizing cyclic GMP-AMP synthase (cGAS) in a patient by administering an effective amount of the compound described in claim 1.
The claim coverage centers on a Formula I scaffold built around an optionally substituted triazole Ring A, constrained Ring B1 and Ring B2 ring systems, and detailed substituent definitions for R2, R3, R5, R6, RB, R, m, n, and q. The provided claims also include a selected depicted compound and a method of antagonizing cGAS by administering the claimed compound.
Stated Advantages
Antagonizing cyclic GMP-AMP synthase (cGAS) in a patient.
Documented Applications
Antagonizing cyclic GMP-AMP synthase (cGAS) in a patient by administering an effective amount of the compound described in claim 1.
Treating diseases associated with aberrant cGAS activation, including autoimmune/inflammatory conditions, allergic disease, autoimmune disease, and cancer/tumor-related immune responses.
Studying cGAS signaling in vitro and in vivo as tools.
cGAS inhibition is evaluated in an in vitro ATP consumption inhibition assay and a cellular ISRE-luciferase reporter assay in THP1 cells.
Pharmaceutical compositions and methods of cGAS antagonism are described.
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