Discovery of Novel NLRP3 Inflammasome Inhibitors Composed of an Oxazole Scaffold Bearing an Acylsulfamide.

The NLRP3 inflammasome plays an important role in the defense mechanism of the innate immune system and has recently attracted much attention as a drug target for various inflammatory disorders. Among the strategies for generating the novel chemotype in current drug discovery, scaffold hopping and bioisosteric replacement are known to be attractive approaches. As the results of our medicinal chemistry campaign, which involved exploration of core motifs using a ring closing approach, a five-membered oxazole-based scaffold was identified, and subsequent implementation of bioisosteric replacement led to discovery of a novel chemical class of NLRP3 inflammasome inhibitor bearing the acylsulfamide group. Further optimization of aniline and sulfamide moieties to improve potency in human whole blood assay led to the identification of the orally bioactive compound 32 in the LPS challenge model. Furthermore, compound 32 attenuated kidney injury in adriamycin-induced glomerulonephritis in mice. These investigations indicated that the NLRP3 inhibitor could be a potential therapeutic agent for glomerulonephritis.

Nickel-Catalyzed [5+2] Cycloaddition of 10π-Electron Aromatic Benzothiophenes with Alkynes To Form Thermally Metastable 12π-Electron Nonaromatic Benzothiepines.

The nickel-catalyzed formal [5+2] cycloaddition of five-membered benzothiophenes and alkynes giving seven-membered benzothiepines via unprecedented dearomatization is reported. The reaction involves the carbothiolation of alkynes with sulfur-containing aromatic heterocycles affording sulfur-containing heterocyclic compounds via ring expansion. As a result, this method facilitates divergent access to thermally metastable benzothiepines. The structure of the thianickelacycle intermediate, which is formed via oxidative addition of the C-S bond in benzothiophenes to nickel(0), was confirmed by in situ X-ray absorption fine structure spectroscopy and density functional theory calculation.

Nickel-catalysed synthesis of tetrasubstituted vinyl sulfides from thiocarbamates and internal alkynes.

The thiocarbamoylation of internal alkynes to produce tetrasubstituted ß-aminocarbonyl vinyl sulfides was demonstrated using a nickel catalyst. This reaction was successful with a wide variety of substituents, and gave the syn-adducts exclusively.

Nickel-catalyzed reaction of thioisatins and alkynes: a facile synthesis of thiochromones.

A new synthetic method for thiochromones was developed by using nickel-catalyzed decarbonylative cycloaddition of readily available thioisatins with alkynes. This reaction proceeded under very mild conditions and has quite high functional group compatibility.

Methylenecyclopropanes in [4+1] cycloaddition with enones.

A nickel-catalyzed [4+1] cycloaddition of enones with methylenecyclopropanes leading to dihydrofurans was developed. The reaction outcome is attributed to the transformation of methlenecyclopropane, which is incorporated into a five-membered ring as a one-carbon fragment.

Methylenecyclopropane as C1 synthetic units: [1+4] cycloaddition via a nickel catalyst.

Nickel-catalyzed reactions of methylenecyclopropanes and thioanhydrides afford sulfur-containing heterocyclic compounds via [1+4] cycloaddition. The reactions represent a new use for methylenecyclopropane as a possible one-carbon building block to replace carbon monoxide, isocyanides, and Fischer carbene complexes.

Nickel-catalyzed cycloadditions of thiophthalic anhydrides with alkynes.

Nickel-catalyzed cycloadditions have been developed where thiophthalic anhydrides react with alkynes to afford substituted sulfur-containing heterocyclic compounds. Selective formations of thioisocoumarins, benzothiophenes, and thiochromones were accomplished with three different reaction conditions.

Nickel-catalyzed cycloaddition of anthranilic acid derivatives to alkynes.

A nickel-catalyzed cycloaddition has been developed where readily available anthranilic acid derivatives react with alkynes to afford substituted indoles. The reaction involves oxidative addition of Ni(0) to an ester moiety, which allows intermolecular addition to alkynes via decarbonylation and 1,3-acyl migration.