Discovery of Potent 1,3-Cyclobutane-Containing Dual A2A/A2B Receptor Antagonists with Low Projected Human Dose for the Treatment of Cancer.

The tumor microenvironment is characterized by conditions that frequently lead to immunosuppression, allowing tumors to escape immune surveillance and potentially contributing to resistance to immuno-oncology therapeutics. A potential strategy for combination therapy with checkpoint inhibitors is to target the A2A and A2B receptors with a dual antagonist that could rescue T cells from adenosine-mediated suppression. Herein, we describe efforts toward highly potent and selective A2A/A2B dual receptor antagonists with improved pharmacokinetic and solubility profiles compared to initial lead compounds. We discovered that a 1,3-cyclobutane linker between our triazoloquinazoline core and a pendant aryl substituent decorated with a tertiary carbinamine provided a desirable balance of potency and physicochemical properties. Our lead molecule 34 demonstrated an exceptional effective half-life across multiple species. Chemistry advances guided by high-throughput experimentation (HTE) facilitated efficient, late-stage access to complex derivatives in this series.