Discovery of 3-morpholino-imidazole[1,5-a]pyrazine BTK inhibitors for rheumatoid arthritis ☆

Abstract 8-Amino-imidazo[1,5- a ]pyrazine-based Bruton’s tyrosine kinase (BTK) inhibitors, such as 6 , exhibited potent inhibition of BTK but required improvements in both kinase and hERG selectivity (Liu et al., 2016; Gao et al., 2017). In an effort to maintain the inhibitory activity of these analogs and improve their selectivity profiles, we carried out SAR exploration of groups at the 3-position of pyrazine compound 6 . This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds 13 , 23 and 38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.