Design, synthesis, evaluation and optimization of potent IRAK4 inhibitors alleviating production of inflammatory cytokines in LPS-induced SIRS model

•Potent IRAK4 inhibitors were synthesized based on CA-4948.•Structural optimization mitigated hERG activity while improved IRAK4 inhibition.•Compound 42 had favorable in vitro ADME and in vivo pharmacokinetic properties.•Compound 42 significantly reduced LPS-induced cytokine release in mouse model.