Approaching the active conformation of 1,3-diaminopyrimidine based covalent inhibitors of Bruton’s tyrosine kinase for treatment of Rheumatoid arthritis

Abstract By applying conformational restrictions, we were able to discover highly potent 1,3-diaminopyrimidine based covalent inhibitors of BTK, such as 8a (IC 50  = 3.76 nM), and providing useful information of its active conformation. We are developing these novel small molecule covalent inhibitors of BTK toward oral agents for Rheumatoid arthritis.