Diversifying the triquinazine scaffold of a Janus kinase inhibitor

The exploration of novel three-dimensional scaffolds remains essential for expanding chemical space and discovering new bioactive molecules. Here, we describe a robust synthetic strategy that enables modulation of Janus Kinase activity through systematic diversification of the triquinazine skeleton, a highly sp³-rich scaffold derived from generated databases (GDBs). By employing ring enlargement and deconstruction approaches, four unprecedented chiral scaffolds were accessed, leading to the synthesis of 26 analogues. Biological evaluation against the Janus kinase family demonstrated how subtle modifications to the triquinazine skeleton influence the activity against JAK1, JAK2, JAK3, and TYK2. Notably, compound (<i>S</i>,<i>R</i>,<i>R</i>)-40a emerged as a potent JAK1 inhibitor (IC₅₀ = 18 nM), with similar potency as the FDA-approved inhibitors abrocitinib and upadacitinib. These findings highlight the potential of GDB-inspired molecules as a source for drug discovery.