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.

Yeon-Hee Lim

Merck Research Laboratories, South San Francisco, CA

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