Alzheimer's disease (AD) is the most common neurodegenerative disorder, whose most evident symptom is a progressive, age-related decline in cognitive functions. There is currently no available disease-modifying therapy. With 24.3 million people affected world-wide in 2005 and an estimated rise to nearly 45 million in 2020, AD is a leading unmet medical need. It has recently become apparent that targeting Alzheimer's disease (AD) pathology at single components is not likely to be feasible, and a successful therapeutic strategy will require pleiotropic interventions. During recent years, several kinases have been identified and are being explored as attractive pleiotropic targets due to their multiple biological functions in AD pathology. Among those, the dual-specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) is an emerging target for the treatment of neurodegenerative diseases. This drug discovery program builds upon existing potent, well-tolerated, selective and brain penetrant small molecule leads which have been demonstrated to mitigate the Alzheimer-type pathology via two critical mechanistic pathways - neurofibrilliary tangles and soluble Abeta oligomers. In addition, cognitive decline was also significantly addressed. The overarching goals of this project are to design orally bioavailable potent, selective and brain penetrant DYRK1A inhibitors to provide a novel approach to the treatment of AD, through the unique simultaneous modulation of both major AD pathologies.