Receptor-interacting protein (RIP) kinase 1 is involved in immune-mediated inflammatory diseases including ulcerative colitis (UC) by regulating necroptosis and inflammation.Our group previ-ously identified TAK-632 (5) as an effective necroptosis inhibitor by dual-targeting RIP1 and RIP3.In this study,using ligand-based substituent-anchoring design strategy,we focused on the benzothiazole ring to obtain a series of TAK-632 analogues showing significantly improving on the anti-necroptosis activity and RIP1 selectivity over RIP3.Among them,a conformational constrained fluorine-substituted deriva-tive (25) exhibited 333-fold selectivity for RIP1 (Kd =15 nmol/L) than RIP3 (Kd ＞ 5000 nmol/L).This compound showed highly potent activity against cell necroptosis (EC50 =8 nmol/L) and systemic in-flammatory response syndrome (SIRS) induced by TNF-α in vivo.Especially,it was able to exhibit remarkable anti-inflammatory treatment efficacy in a DSS-induced mouse model of UC.Taken together,the highly potent,selective,orally active anti-necroptosis inhibitor represents promising candidate for clinical treatment of UC.