Targeting dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) has been verified to regulate the progression of tau pathology as a promising treatment for Alzheimer's disease (AD), while the research progress on DYRK1A inhibitors seemed to be in a bottleneck period. In this work, we identified () as the most potential DYRK1A inhibitor (IC = 0.68 nM) through rational design, systematic structural optimization, and comprehensive evaluation. Compound exhibited acceptable absorption, distribution, metabolism, and excretion (ADME) properties and significantly reduced the expression of p-Tau Thr212 in Tau (P301L) 293T cells and SH-SY5Y cells. Moreover, compound showed favorable bioavailability, blood-brain barrier (BBB) permeability, and the potential of ameliorating cognitive dysfunction by obviously reducing the expression of phosphorylated tau and neuronal loss , which was deserved as a valuable molecular tool to reveal the role of DYRK1A in the pathogenesis of AD and to further promote the development of anti-AD drugs.