Lenalidomide　is　a　type　of　immunomodulatory　agent　with　anti-tumor　activity　by　mainly　expressed　in　the　anti-angiogenesis.　In　order　to　enhance　the　pharmacological　activity　of　Lenalidomide,　a　series　of　Lenalidomide　derivatives　were　designed　as　tumor　angiogenesis　inhibitors.　The　potential　anti-angiogenesis　targets　of　Lenalidomide　derivatives　were　virtual　screened　on　Auto-Dock　4.0　by　using　reverse　docking　method.　The　six　target　proteins,　such　as　vascular　endothelial　growth　factor　receptor,　epidermal　growth　factor　receptor,　fibroblast　growth　factor　receptor,　BCR-ABL　tyrosine　kinase,　p38　mitogen　activated　protein　kinase　and　metal　protein　kinase,　were　chosen　as　the　targets.　The　Lenalidomide　derivatives　were　synthesized　by　alkylated,　acylated　or　sulfonylated　Lenalidomide　and　verified　by　the　H-1　NMR,　C-13　NMR　and　LC-MS.　Their　anti-cancer　activities　were　detected　by　using　CCK-8　in　the　esophageal　carcinoma　cell　line　EC9706.　The　results　indicate　that　the　inhibitory　activities　of　Lenalidomide　derivatives　were　higher　than　that　of　Lenalidomide.　(C)　2017　Published　by　Elsevier　Ltd.