By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.

A general procedure for the preparation of C 3 -symmetric TREN derivatives with backbone chirality has been developed. Stereo-and regioselective ring opening by ammonia of (S)-N-tosyl-2-isopropylaziridine, obtained starting from either the corresponding amino alcohol or amino acid, followed by deprotection of the amino groups afforded the par-

A modular approach was developed for the preparation of chiral, enantiopure sulfonamide ligands with C 1 , C 2 , and C 3 symmetry by ring opening of chiral N-sulfonylaziridines with ammonia, primary amines, and diamines. The new ligands were assessed in the titanium-mediated addition of di- [a]

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