Recent advances in drug discovery are based on privileged structures. In this fashion, we propose a new potential privileged structure containing a triazole moiety mimicking a cis-amide bond. This [1,2,3]-triazolo[1,5-d]-benzo-1,4-diazepin-2-one scaffold was synthesized and decorated via a solid-phase strategy using a-amino acids 2  , 2-ethynylaniline 3a  or 2-amino-3-ethynylpyridine building blocks 3b  and N-alkylating agents 4 .Building blocks 3  , which are synthesized in solution in a combinatorial way, are submitted to a Ru(II)-catalyzed 1,3-dipolar cycloaddition onto a resin-bound a-amino acid derivative, introducing three diversity elements in a single step. The desired products can be cleaved from the resin in high crude purities (> 95%) using cyclisation-release. In this fashion, several libraries of this [1,2,3]-triazolo[1,5-d]benzo-1,4-diazepin-2-one scaffold have been synthesized in moderate yields by successfully varying all diversity points.Taking into account future screening results of the synthesized libraries, a well-thought decoration of this scaffold leading to discovery of new lead molecules is within reach.Interestingly, fully diversified compounds 1  exhibit atropoisomeric effects. This fast-slow exchange between two or more conformers can be studied via 1H NMR spectroscopy and therefore more information about the thermodynamics of this scaffold can be revealed.

Synthesis of privileged scaffolds: Mimicking the 1,5-benzodiazepin-2,4-diones via a modular approach on solid-phase

246th National Meeting (2013)

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