cGAS antagonist compounds
Inventors
Zhong, Boyu • Sun, Lijun • Shi, Heping • Li, Jing • Chen, Chuo • Chen, Zhijian
Assignees
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Publication Number
US-12065416-B2
Publication Date
2024-08-20
Expiration Date
Abstract
Disclosed are novel compounds of Formula I that are cGAS antagonists, methods of preparation of the compounds, pharmaceutical compositions comprising the compounds, and their use in medical therapy.
Core Innovation
The disclosure provides compounds defined as one of Formula Ib, with X being S, Y being O or S, Z being O or NR1a, and G being N or C. The scaffold includes conditional rules for R1 and R1a depending on whether G is N or C and whether Z is O or NR1a, together with linked carbon, nitrogen, and methylene patterns as recited. The compounds further include extensive substitution rules through R2, R3, R5, R6, and R3a/R3b/R4a, with optional substitution patterns and pharmaceutically acceptable salts.
R2 is defined as hydrogen, halogen, C1-6 alkyl, or C1-6 alkyl substituted with one or more halogen, thiol, hydroxyl, carbonyl, carboxyl, carbonyloxyl, C1-6 alkoxy, C1-6 hydroxyalkoxy, amino, C1-6 alkylamino, di(C1-6 alkyl)amino, or azido groups. R3 is halogen or a CH2CH2 or CH2CH2CH2 connectivity, and R5 and R6 are defined by multiple sulfur-, oxygen-, nitrogen-, azido-, cyano-, carbonyl-, alkyl-, alkenyl-, and alkynyl-containing options, including ether-like forms for R6. R3a, R3b, and R4a are independently selected from phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl, C1-6 alkyl, and cyclic or unsaturated groups, with optional substitution of the aromatic and heteroaromatic groups.
The invention relates to cGAS antagonist small molecules of Formula I, including Formula Ia-Id and related sub-formulas, for use in medical therapy. The immunological rationale described is that cytosolic DNA leads to cGAS activation, which produces cGAMP, which then activates STING to drive type-I interferon and autoinflammatory signaling. Representative structures are embedded within the disclosure, and the scope includes compounds and pharmaceutically acceptable salts.
Claims Coverage
The consolidated claim coverage centers on one independent claim defining a compound within Formula Ib. The claim coverage centers on the Formula Ib scaffold, the G- and Z-dependent R1/R1a connectivity rules, broad substituent definitions for R2, R3, R5, and R6, optional substitution of aromatic and heteroaromatic groups through R3a/R3b/R4a, and pharmaceutically acceptable salts.
Formula Ib scaffold with heteroatom selections
A compound defined as one of Formula Ib, wherein X is S, Y is O or S, Z is O or NR1a, and G is N or C.
G-dependent R1 and R1a connectivity
When G is N and Z is O, R1 is methyl; when G is N and Z is NR1a, R1 and R1a are connected as listed methylene or carbon-containing linkages; when G is C, Z is NR1a and R1 and R1a are connected as listed CH, N-CH, or CH-N linkage patterns.
Extensive substituent definitions for R2 and R3
R2 is hydrogen, halogen, C1-6 alkyl, or C1-6 alkyl substituted with one or more listed functional groups; R3 is halogen or connected as CH2CH2 or CH2CH2CH2.
Functional-group options for R5 and R6
R5 and R6 include hydrogen, halogen, sulfur-, oxygen-, nitrogen-, azido-, aldehyde-, carboxylate-, cyano-, alkyl-, alkenyl-, and alkynyl-containing forms, including ether-like forms for R6.
Optional substitution of aromatic and heteroaromatic groups
R3a, R3b, and R4a are independently selected from phenyl, naphthyl, pyridyl, pyrimidinyl, imidazolyl, 1,2,3-triazolyl, quinolinyl, isoquinolinyl, thiazolyl, tetrazolyl, C1-6 alkyl, and cyclic or unsaturated groups, and the aromatic/heteroaromatic groups are optionally substituted with 1-3 substituents.
Pharmaceutically acceptable salts
The compound is provided as a pharmaceutically acceptable salt thereof.
The independent claim defines a broad Formula Ib compound class with fixed heteroatom choices, conditional R1/R1a connectivity, extensive but enumerated substituent scope, optional aromatic and heteroaromatic substitution, and pharmaceutically acceptable salts.
Stated Advantages
The disclosed subject matter is directed to cGAS antagonism and is described as addressing a need for potent and specific inhibitors.
The disclosure states that cytosolic DNA leads to cGAS activation, which produces cGAMP and activates STING to drive type-I interferon and autoinflammatory signaling.
Modulating cGAS activity.
Treatment of inflammatory disease.
Treatment of allergic disease.
Treatment of autoimmune disease.
Treatment of infectious disease.
Treatment of senescence- or age-related disease.
Documented Applications
Use in medical therapy.
Use of Formula I compounds for modulating cGAS activity.
Treatment of inflammatory, allergic, autoimmune, infectious, and senescence- or age-related diseases.
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