In　a　continuing　effort　to　develop　orally　bioavailable　small-molecule　STAT3　inhibitors　as　potential　therapeutic　agents　for　human　cancer,　a　series　of　novel　diversified　analogues　based　on　our　identified　lead　compound　HJC0149　(1)　(5-chloro-N-(1,1-dioxo-1H-1λ6-benzo[b]thiophen-6-yl)　-2-hydroxybenzamide,　Eur.　J.　Med.　Chem.　2013,　62,　498-507)　have　been　rationally　designed,　synthesized,　and　pharmacologically　evaluated.　Molecular　docking　studies　and　biological　characterization　supported　our　earlier　findings　that　the　O-alkylamino-tethered　side　chain　on　the　hydroxyl　group　is　an　effective　and　essential　structural　determinant　for　improving　biological　activities　and　druglike　properties　of　these　molecules.　Compounds　with　such　modifications　exhibited　potent　antiproliferative　effects　against　breast　and　pancreatic　cancer　cell　lines　with　IC50　values　from　low　micromolar　to　nanomolar　range.　Among　them,　the　newly　discovered　STAT3　inhibitor　12　(HJC0416)　displayed　an　intriguing　anticancer　profile　both　in　vitro　and　in　vivo　(i.p.　&　p.o.).　More　importantly,　HJC0416　is　an　orally　bioavailable　anticancer　agent　as　a　promising　candidate　for　further　development.　©　2014　Elsevier　Masson　SAS.　All　rights　reserved.