Tricyclic Inhibitors of β-Secretase and Their Methods of Use for the Treatment of Alzheimer's Disease

Abstract

Alzheimer's disease, a progressive neurodegenerative disorder, remains a major unmet medical need. As of 2018, the Alzheimer's Association (https://www.alz.org/facts/) estimated that there were over 5 million patients in the U.S. and predicted that this number would increase to 16 million by 2050. Treatment costs for this condition and related disorders exceeded $259 billion. To date, there are no approved disease modifying therapies and the root cause of Alzheimer's disease remains unclear. Prevention or elimination of β-amyloid plaques and neurofibrillary tangles in the cortical and subcortical regions of the brain has been the focus of numerous efforts to develop novel therapeutics. The β-amyloid plaques are formed from Aβ42 protein, a cleavage product of the amyloid precursor protein (APP). Two enzymes, β-secretase 1 (BACE1) and γ-secretase, cleave APP in two locations to form Aβ42. Initial cleavage of APP by BACE1 produces the soluble protein β-APP and a membrane bound fragment designated C-99. The C-99 protein is further processed by γ-secretase to liberate Aβ42, which then forms aggregates that become the main component of β-amyloid plaques. It has been hypothesized that inhibition of BACE1 would prevent the formation of β-amyloid plaques and arrest progression of Alzheimer's disease. The present application discloses a series of compounds that inhibit BACE1 and are potentially useful for the treatment of Alzheimer's disease.