Antagonism of the A_2A receptor has long been pursued as a potential treatment for Parkinson’s disease, with istradefylline having gained US regulatory approval for this indication in 2019. More recently, antagonism of A_2A along with the related A_2B receptor has been explored as a potential immunotherapy treatment for cancer. Herein we present the discovery and optimization of a novel series of potent dual inhibitors of the A_2A and A_2Breceptors. The triazolopyrimidine and triazolopyrazine cores of this series represent a hybrid of series from previous efforts, with tractable properties and three vectors for independent SAR exploration. Vectors 1 and 2 were robustly explored in library fashion, leading to rapid identification of preferred substituents. Vector 3 SAR was explored through both knowledge-based and library methods, including employing a continuous flow metallophotoredox reductive coupling reaction. This chemistry enabled completion of a 20-membered library in a single day, and resulted in a pivot from benzylic substituents at Vector 3. Upon mining of our historical collection of adenosine receptor antagonists to identify compounds with dual potency at the A_2A and A_2B receptors, an N-ethylene imidazopiperazine substituent had been identified. Installation of this piece at Vector 3 provided an attractive potency profile, alongside improved physicochemical properties and oral bioavailability relative to the initial hit. Further optimization culminated in a lead compound with favorable pharmacological profile in a human whole blood TNF-α release assay and low projected human dose. This presentation will describe the effort that led to the identification of this advanced lead molecule.

Zachary Brill

Associate Principal Scientist, Discovery Chemistry, Merck

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