A newly established pyrimidine synthetic methodology enabled access to an array of complex mTOR kinase inhibitors possessing excellent cell potency, selectivity, and in vivo oral exposure in preclinical species. The developed synthetic method stands as a flexible, expeditious, and synthetically practical approach for the synthesis of tetrasubstituted pyrimidines from readily accessible N-vinyl tertiary enamide starting materials. Application of this methodology provided the opportunity to test critical medicinal chemistry hypotheses during a lead optimization phase. These efforts culminated in the discovery of a pyrimidoaminotropane mTOR inhibitor that displayed similar efficacy in a tumor growth inhibition study at lower doses than our clinical candidate GDC-0349.

Access to potent, selective, efficacious, and highly functionalized pyrimidoaminotropane mTOR inhibitors through the development of a flexible pyrimidine methodology

248th National Meeting (2014)

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