Abstract：Glycogen synthase kinase 3β (GSK-3β) is an important drug target of neurodegenerative diseases including Alzheimer's, diabetes type Ⅱ, cancer. α-Carboline derivatives have many biological activities such as anti-anxiolytic effect, anti-inflammatory, and central nervous system stimulating activities. In this work, a series of 4-N substituted α-carbolines derivatives were discussed as GSK-3β inhibitors. The modified Graebe-Ullmann reaction was optimized to synthesize α-carboline, and polyphosphoric acid was used as cyclizing agent and solvent. After oxidation and chlorination, an important intermediate 4-chloro-α-carboline was obtained. Buchwald-Hartwig coupling reaction was choosed to be the appropriate route for 4-N substituted α-carboline, tris(dibenzylideneacetone) dipalladium(0) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl were used as catalyst and ligand respectively. All the compounds were confirmed by 1H NMR, 13C NMR and ESI-MS techniques. 9 compounds were screened by Caliper Mobility Shift Assay on kinase GSK-3β in vitro and staurosporine was used as the reference compound. Four new inhibitors with moderate inhibitory activities were found and the smallest IC50 value of compound 3c was 5.1 μmol·L-1. Moreover, the molecular docking method was used to study the interaction modes of the inhibitors and GSK-3β. Our results will be helpful in the future designing of GSK-3β inhibitors.