Discovery and Structure Enabled Synthesis of 2,6-Diaminopyrimidin-4-one IRAK4 Inhibitors

We report the identification and synthesis of a series of aminopyrimidin-4-one IRAK4 inhibitors. Through high throughput screening, an aminopyrimidine hit was identified and modified via structure enabled design to generate a new, potent, and kinase selective pyrimidin-4-one chemotype. This chemotype is exemplified by compound <b>16</b>, which has potent IRAK4 inhibition activity (IC₅₀ = 27 nM) and excellent kinase selectivity (>100-fold against 99% of 111 tested kinases), and compound <b>31</b>, which displays potent IRAK4 activity (IC₅₀ = 93 nM) and good rat bioavailability (<i>F</i> = 42%)