Discovery of 3-morpholino-imidazole[1, 5-a]pyrazine BTK inhibitors for rheumatoid arthritis. Issue 16 (15th August 2017) - Boga, Sobhana Babu
Graphical abstract: Abstract: 8-Amino-imidazo[1, 5- a ]pyrazine-based Bruton's tyrosine kinase (BTK) inhibitors, such as6, 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 compound6 . This effort led to the discovery of the morpholine group as an optimized pharmacophore. Compounds13, 23 and38 displayed excellent BTK potencies, kinase and hERG selectivities, and pharmacokinetic profiles.