NLRP3 inflammasome inhibitors
Inventors
Farady, Christopher • GOMMERMANN, Nina • Janser, Philipp • Mackay, Angela • Mattes, Henri • Stiefl, Nikolaus Johannes • Velcicky, Juraj
Assignees
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Publication Number
US-12168012-B2
Publication Date
2024-12-17
Expiration Date
Abstract
The present invention relates to novel thienopyrrolotriazinacetamide compounds of Formula (I): wherein R1, R2 and R3 are defined herein, which inhibit NOD-like receptor protein 3 (NLRP3) inflammasome activity. The invention further relates to the processes for their preparation, pharmaceutical compositions and medicaments containing them, and their use in the treatment of diseases and disorders mediated by NLRP3.
Core Innovation
The invention relates to compounds of Formula (I) or pharmaceutically acceptable salts thereof, defined by substituent ranges for R1, R2, R3 and X, where X is N or CH. The scaffold includes thienopyrrolotriazinacetamide, thienopyrrolotriazin-7(8H)-one, and thieno[2′,3′:4,5]pyrrolo[1,2-d][1,2,4]triazin-7(8H)-one type core descriptions, with multiple chemical embodiments through different selections for R1, R2 and R3.
The substituent definitions include R1 as H, halo, or methyl; R2 as an ethyl-substituted group bearing OH, C1-C4 alkoxy, or one or more halo groups, or as C3-C6 alkyl optionally substituted with OH, halo, or C1-C4 alkoxy, or as C3-C6 cycloalkyl. R3 is defined broadly as C2-C8 alkyl, C3-C10 cycloalkyl, C3-C5 cycloalkyl-CH2, mono or bicyclic aryl, mono or bicyclic heteroaryl, or mono or bicyclic heterocyclyl, with optional substitution patterns including hydroxyl, alkoxy, halo, amino, carboxylic-acid derivative, cycloalkyl, NH2, NH(C1-C4 alkyl), NHC(O)O(C1-C4 alkyl), NHC(O)(C1-C4 alkyl), and haloC1-C4 alkoxy as specified.
The compounds inhibit NLRP3 inflammasome activity, including inhibition of NLRP3 signaling. The disclosure ties this activity to IL-1β and IL-18 release and frames the compounds as medicaments and pharmaceutical compositions intended for modulating NLRP3 activity or signaling. The examples include preparation and characterization of multiple compounds and salt forms, with stereochemical variants, hydrochloride salts, and NMR, LC-MS, or retention time data reported for specific analogs.
Claims Coverage
The provided claim coverage centers on one independent Formula (I) compound claim and dependent claims that refine substituent choices and extend to pharmaceutical compositions, combination therapy, and methods for treating disease involving NLRP3 signaling. Across the combined items, the inventive features are dominated by the Formula (I) scaffold with detailed R1, R2, R3, and X definitions.
Formula (I) compound family with variable substituents
A compound of Formula (I) or a pharmaceutically acceptable salt thereof wherein X is N or CH; R1 is H, halo, or methyl; R2 is ethyl substituted with OH, C1-C4 alkoxy, or one or more halo groups, or C3-C6 alkyl optionally substituted with OH, halo or C1-C4 alkoxy, or C3-C6 cycloalkyl; and R3 is defined by alkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl classes with optional substituents as specified in the claim text.
Specific substituent selection for R1
In a refined embodiment, R1 is chloro, or a pharmaceutically acceptable salt of the compound.
Pharmaceutical composition with a Formula (I) compound
A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers.
Combination therapy with additional therapeutic agents
A combination comprising a therapeutically effective amount of a compound according to the claim set and one or more independently selected therapeutic agents, including FXR agonists, anti-steatotic and anti-fibrotic agents, JAK/checkpoint inhibitors, chemotherapy/radiation/surgery therapies, IL-17 blockade, complement inhibitors, BTK inhibitors, TLR7/8 inhibitors, CAR-T therapy, and other enumerated therapeutic categories.
Method for treating disease involving NLRP3 signaling
A method for treating a disease or disorder whose pathology, symptoms, and/or progression involves NLRP3 signaling by administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
The claim coverage is centered on the Formula (I) compound family defined by the R1, R2, R3, and X substituent framework, with pharmaceutically acceptable salts included. Dependent claim coverage further includes a specific R1 selection, pharmaceutical compositions with carriers, combination therapy with listed therapeutic agent categories, and methods of treating NLRP3-signaling-related disease by administration.
Stated Advantages
Inhibits NLRP3 inflammasome activity and NLRP3 signaling.
Provides pharmaceutical compositions and combination therapy for diseases where NLRP3 signaling contributes to pathology, symptoms, or progression.
Inhibition is reflected in IL-1β secretion assay results, and a counterscreen is reported using TNF-α secretion assay.
Documented Applications
Treatment of diseases or disorders whose pathology, symptoms, and/or progression involve NLRP3 signaling.
Use as medicaments and pharmaceutical compositions for modulating NLRP3 activity or signaling.
Treatment of broad inflammasome-related, immune, and inflammatory diseases.
Use in therapeutic settings across inflammatory/auto-inflammatory and immune diseases, broad inflammation conditions, cancers, infections, CNS diseases, and metabolic/cardiovascular diseases, as well as ocular, skin, renal disorders, and pain/allodynia.
Combination therapy where NLRP3 inhibitors are administered with other therapeutic agents in fixed/non-fixed and sequential/simultaneous arrangements.
Use for research/tool compounds.
In vitro biological assay use for NLRP3 inflammasome inhibition and counterscreen measurement, including IL-1β secretion assay and TNF-α secretion assay.
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