PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 >9) and by careful manipulation of the pKa and lipophilicity we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in-vivo studies where significant target engagement could be demonstrated
