Inflammatory and autoimmune diseases, such as rheumatoid arthritis, asthma, and coronary heart disease, are closely associated with dysregulation of IL-6 signaling. IL-6 and its signaling pathway are promising targets for the treatment of inflammatory and autoimmune diseases. However, FDA-approved monoclonal antibodies and small-molecule drugs currently in clinical use pose significant challenges, such as high cost, administration-related toxicity, limited oral dosing options, and adverse effects. IL-6 forms a complex with IL-6R, which couples with GP130 and induces its homodimerization, thereby activating downstream JAK/STAT signaling, which regulates immune responses, cell growth, differentiation, and hematopoiesis. Thus, development and optimization of small-molecule inhibitors that effectively target IL-6 signaling is essential. In this study, we report small-molecule GP130 inhibitors targeting the IL-6/IL-6R/GP130 complex.