Novel Macrocyclic NLRP3 Inhibitors.

Aberrant activation of NLRP3 due to persistent tissue damage, misfolded proteins or crystal deposits has been linked to multiple chronic inflammatory disorders such as cryopyrin-associated periodic syndrome (CAPS), neurodegenerative diseases, gouty arthritis, and numerous others. Hence, there has been an increasing interest in NLRP3 inhibitors as therapeutics. A first generation of NLRP3 inhibitors bearing a sulfonylurea core such as MCC950 (developed by Pfizer) were discovered by phenotypic screening, however their mode of action was only elucidated later.

Pd-Catalyzed C-H aziridination of 3,3,5,5-tetrasubstituted piperazin-2-ones.

A palladium mediated C-H aziridination reaction of 3,3,5,5-substituted-piperazin-2-ones has been developed using phenyliodonium diacetate (PIDA) and succinic acid to give synthetically useful bicyclic aziridines, in moderate to good yields. Succinic acid was found to be key for selectively promoting C-N bond formation (aziridination) and suppressing competitive acetoxylation. Analysis of the reaction kinetics revealed the role of succinic acid in promoting an equilibrium between monomeric and dimeric palladium species in the rate determining step of the reaction.

Studies towards the synthesis of indolizin-5(3H)-one derivatives and related 6,5-azabicyclic scaffolds by ring-closing metathesis.

Herein, we report on work towards the development of a new strategy for the synthesis of rare and biologically interesting indolizin-5(3H)-ones, which is based around the use of ring-closing metathesis to construct the carbocyclic ring system. This study has provided insights into the general stability of indolizin-5(3H)-ones and their tendency to exist as the tautomeric indolizin-5-ols. Furthermore, this approach has allowed access to other novel structurally related compounds based around unusual 6,5-azabicyclic scaffolds, which are also difficult to generate using typical methods.