Discovery of a series of 5-AzaQuinazolines as orally efficacious IRAK4 inhibitors targeting MyD88L265P mutant Diffuse Large B Cell Lymphoma

In this article, we report the discovery of a series of 5-azaquinazolines as selective IRAK4 inhibitors. From modestly potent quinazoline 4, we introduced a 5-aza substitution to mask the 4-NH hydrogen bond donor (HBD). This allowed us to substitute the core with a 2-aminopyrazole, which showed large gains in cellular potency despite the additional formal HBD. Further optimization led to 6-cyanomethyl-5-azaquinazoline 13, a selective IRAK4 inhibitor which proved efficacious in combination with ibrutinib, whilst showing very little activity as a single agent up to 100 mg/kg. This contrasted to previously reported IRAK4 inhibitors that exhibited efficacy in the same model as single agents, and was attributed to the enhanced specificity of 13 towards IRAK4.