Design and Synthesis of Novel Amino-triazine Analogues as Selective Bruton’s Tyrosine Kinase Inhibitors for Treatment of Rheumatoid Arthritis

Bruton’s
tyrosine kinase (BTK) is a promising drug target
for the treatment of multiple diseases, such as B-cell malignances,
asthma, and rheumatoid arthritis. A series of novel aminotriazines
were identified as highly selective inhibitors of BTK by a scaffold-hopping
approach. Subsequent SAR studies of this series using two conformationally
different BTK proteins, an activated form of BTK and an unactivated
form of BTK, led to the discovery of a highly selective BTK inhibitor, 4b. With significant efficacy in models in vivo and good ADME
and safety profiles, 4b was advanced into preclinical
studies.