H. Hobbs, G. Bravi, I. Campbell
Jul 8, 2019
Citations
0
Influential Citations
13
Citations
Journal
Journal of medicinal chemistry
Abstract
4-(Pyrimidin-4-yl)morpholines are privileged pharmacophores for PI3K and PIKKs inhibition by virtue of the morpholine oxygen both forming the key hydrogen bonding interaction and conveying selectivity over the broader kinome. Key to the morpholine utility as a kinase hinge binder is its ability to adopt a co-planar conformation with an adjacent aromatic core favoured by the morpholine nitrogen non-bonding pair of electrons interacting with the electron deficient pyrimidine π-system. Few selective morpholine replacements have been identified to date. Herein we describe the discovery of a potent non-nitrogen containing morpholine isostere, with the ability to mimic this conformation and its application in a potent selective dual inhibitor of mTORC1 and mTORC2 [26b].