Dual-specificity tyrosine-regulated kinase 1A (DYRK1A) regulates the proliferation and differentiation of neuronal progenitor cells during brain development. Consequently, DYRK1A has attracted interest as a target for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD) and Down's syndrome. Recently, the inhibition of DYRK1A has been investigated as a potential treatment for diabetes, while DYRK1A's role as a mediator in the cell cycle has garnered interest in oncologic indications. Structure-activity relationship (SAR) analysis in combination with high-resolution X-ray crystallography leads to a series of pyrazolo[1,5-<i>b</i>]pyridazine inhibitors with excellent ligand efficiencies, good physicochemical properties, and a high degree of selectivity over the kinome. Compound <b>11</b> exhibited good permeability and cellular activity without P-glycoprotein liability, extending the utility of <b>11</b> in an <i>in vivo</i> setting. These pyrazolo[1,5-<i>b</i>]pyridazines are a viable lead series in the discovery of new therapies for the treatment of diseases linked to DYRK1A function.