Discovery of a Series of Substituted 1H-((1,2,3-Triazol-4-yl)methoxy)pyrimidines as Brain Penetrants and Potent GluN2B-Selective Negative Allosteric Modulators.

Herein, we describe a series of substituted 1H-((1,2,3-triazol-4-yl)methoxy)pyrimidines as potent GluN2B negative allosteric modulators. Exploration of several five- and six-membered heterocycles led to the identification of O-linked pyrimidine analogues that possessed a balance of potency and desirable ADME profiles. Due to initial observations of metabolic saturation, early metabolite identification studies were conducted on compound 18, and the results drove further iterative optimization efforts to avoid the formation of undesired saturating metabolites. The comprehensive investigation of substitution on the pyrimidine moiety of the 1H-1,2,3-triazol-4-yl)methoxy)pyrimidines allowed for the identification of compound 31, which demonstrated high GluN2B receptor affinity, improved solubility, and a clean cardiovascular profile. Compound 31 was profiled in an ex vivo target engagement study in rats at a 10 mg/kg oral dose and achieved an ED50 of 1.7 mg/kg.

Lanthanide(III)-Catalyzed Synthesis of trans-Diaminocyclopentenones from Substituted Furfurals and Secondary Amines via a Domino Ring-Opening/4π-Electrocyclization Pathway.

A strategy toward the synthesis of trans-4,5-diaminocyclopent-2-enones is described. This core motif is embedded in the marine sponge derived alkaloids agelamadin B and nagelamide J. A variety of 2-substituted trans-4,5-diaminocyclopent-2-enones were synthesized in good to quantitative yields using lanthanide(III) catalysis. The products were formed exclusively as the trans-diastereomers via a mechanism in which the C4-C5 bond formation occurs through a 4π-conrotatory electrocyclization. The precursor 3-substituted furfurals can be readily accessed using palladium(0)-catalyzed cross-coupling between 3-bromofurfural and boronic acids, trifluoroborate salts, or alkynes.