A potent seven-membered cyclic BTK (Bruton's tyrosine Kinase) chiral inhibitor conceived by structure-based drug design to lock its bioactive conformation.

Abstract A seven-membered cyclic chiral analog of potent lead BTK inhibitor 1 was envisioned by structure-based design to lock the molecule into its bioactive conformation. For the elaboration of the seven-membered ring, compound 1 pyridone 6-position was substituted with the purpose to prevent formation of reactive metabolites. Eventually, the cyclic chiral compound 3 maintained the high potency of 1 , and most importantly showed no activity at either GSH or TDI assays suggesting no formation of reactive metabolites. The anticipated bound conformation of 3 to BTK was confirmed by X-ray crystallography. Synthetically, the crucial seven-membered ring formation was obtained by using TosMIC as a connective reagent.