Organ fibrosis, such as lung fibrosis and liver fibrosis, is a progressive and fatal disease. Fibroblast growth factor receptors (FGFRs) play an important role in the development and progression of fibrosis. Through scaffold hopping, bioisosteric replacement design, and structure-activity relationship optimization, we developed a series of highly potent FGFRs inhibitors, and the indazole-containing candidate compound A16 showed potent kinase activity comparable to that of AZD4547. In addition, A16 effectively suppressed the activation of lung fibroblasts and hepatic stellate cells (HSCs) induced by TGF-β1, leading to a reduction in collagen deposition. Notably, A16 exhibited potent anti-fibrotic effects through the inhibition of the FGFR pathway in vitro. Compound A16 also showed reasonable pharmacokinetic properties (F = 21.84 %) and favorable cardiac safety (hERG IC50 > 20 μM). Moreover, in models of pulmonary fibrosis, A16 ameliorated (in the prevention model) and reversed (in the treatment model) bleomycin-induced lung fibrosis, as well as mitigated inflammatory immune response in the lung. Furthermore, in the CCl4-induced liver fibrosis model, when A16 was administrated orally at a dose of 30 mg/kg/day for 3 weeks, it effectively improved liver function, restored damaged liver structures, and reduced collagen deposition. Taken together, these results suggest that A16 could be a potential drug candidate for the treatment of organ fibrosis.Copyright © 2025 Elsevier Masson SAS. All rights reserved.