AP-2-associated protein kinase 1 (AAK1) plays a crucial role in the clathrin-mediated endocytosis (CME) pathway, which is involved in various cellular processes including viral entry to the host cells. Therefore, AAK1 is considered as a promising therapeutic target for the treatment of viral infections. Herein, we reported design and synthesis of 1H-indazole based novel AAK1 inhibitors from known AAK1 inhibitors SGC-AAK1-1 and compound 6. Among 42 compounds synthesized with the assistance of microwave, compounds 9i, 11f and 11l exhibited comparable antiviral activity against SARS-CoV-2 entering host cells compared to the reference compound 6 at the concentration of 3 μM. Particularly, 11f exhibited lower cytotoxicity on hACE2-293T than compounds 9i, 11l and reference compound 6. 11f also exhibited good pharmacokinetic prediction properties. In conclusion, the novel AAK1 inhibitor 11f demonstrates remarkable efficacy in suppressing SARS-CoV-2 infection, while exhibiting almost no obvious cytotoxicity, thus making it as a promising candidate for the development of novel antiviral drugs against severe SARS-CoV-2 and possible other viruses.