Ethyl 4-(1-benzyl-1H-indazol-3-yl)benzoate (YD-3) was first synthesized in our laboratory as a novel inhibitor of protease-activated receptor 4 (PAR4) in platelet. In this study, a series of N2-regioisomer analogs (5—10) of YD-3 was synthesized and examined for their cytotoxicity. The starting material, 1-(N-morpholino)cyclohexene, was treated with terephthalic acid monomethyl ester chloride via a Stork enamine reaction to yield methyl 4-[(2-oxocyclohexyl)carbonyl]benzoate (1). Compound 1 was treated with hydrazine hydrate to yield methyl 4-(4,5,6,7-tetrahydro-1H-indazol-3-yl)benzoate (2). Subsequently, compound 2 was treated with palladium and the mixture was heated to form the expected 3 with high yield. Starting from 3, various N2-regioisomer analogs (5—10) of YD-3 were synthesized. These N2-regioisomer analogs (5—10) of YD-3 were assayed for their cytotoxicity against HL-60, A549 and HA22T cell lines. Among them, compounds 2 and 10 showed significant cytotoxicity.
