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• A series of novel pyrazolo[3,4- d ]pyrimidine-based JAK3 inhibitors was developed. • 13t displayed excellent JAK3 inhibitory activity (IC 50 = 0.1 nM) and selectivity. • 13t blocks phosphorylation of JAK3 kinase and downstream signalling. • 13t inhibited proliferation of IL-2-induced rat T -cell (IC 50 = 0.66 μM). • Compound 13t dose-dependently improved pawswelling in rats with AIA. Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k , 13n and 13 t) , displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor 13t (IC 50 = 0.1 nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound 13 t , could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that 13t is a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis. [ABSTRACT FROM AUTHOR]