2,4,6-Triaminopyrimidine as a Novel Hinge Binder in a Series of PI3Kδ Selective Inhibitors

Inhibition of phosphoinositide 3-kinase
δ (PI3Kδ) is
an appealing target for several hematological malignancies and inflammatory
diseases. Herein, we describe the discovery and optimization of a
series of propeller shaped PI3Kδ inhibitors comprising a novel
triaminopyrimidine hinge binder. Combinations of electronic and structural
strategies were employed to mitigate aldehyde oxidase mediated metabolism.
This medicinal chemistry effort culminated in the identification of 52, a potent and highly selective inhibitor of PI3Kδ
that demonstrates efficacy in a rat model of arthritis.