Two classes of trisubstituted pyrimidines related to PI-103 1 have been prepared and their inhibitory activities against phosphatidylinositol 3-kinase (PI3K) p110α were determined. From those with direct 6-aryl substitution compound 11a was the most potent inhibitor with an IC₅₀ value of 62 nM, and showed similar activity against other class 1a PI3K isoforms tested, p110β and p110γ. When a linking chain was introduced, as in the second exemplified class, compound 15f inhibited p110α with IC₅₀ 142 nM, and showed greater selectivity towards p110α. Compounds of both classes showed promising inhibition of cellular proliferation in IGROV-1 ovarian cancer cells. Among compounds designed to replace the 3-phenolic motif with structural isosteres, analogues incorporating a 4-indazolyl group possessed enzyme and cellular activities comparable to the parent phenols.

An effective parallel solid phase route to methylenesulfonamides and amides bearing a wide variety of substituents is described. The three key reaction steps were reductive amination of a haloheteroaromatic aldehyde onto a benzhydrylamine type polystyrene resin, sulfonamide or amide formation and palladium catalysed transformation of the remaining heteroaromatic halogen. A process of virtual library design and filtering, together with solution and solid phase optimizations, aided the preparation of several novel drug-like product classes in high purities and should allow access to a variety of further useful analogues.

Reagents and conditions: (i) 4equiv nBuLi, toluene 60°C, 3h; (ii) 10equiv ArCN, toluene, rt, 20min; and (iii) add 20% v/v MeOH, then 20equiv NaBH4, rt, 30min.

An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.

The reaction of dichloropyrazines with a dithiane anion gave isomers of the expected formylated chloropyrazines after deprotection with methyl iodide. A tele-substitution mechanism accounts for these observations and is supported by deuterium labelling studies.