Preparation of novel 2-amino-4-(imidazo[1,2-a]pyridin-3-yl)pyrimidine derivative as polo-like kinase 1 (PLK1) inhibitors.

Abstract

The title compds. [I; R1, R2 = H, substituent α, each (un)substituted lower alkyl or C3-6 cycloalkyl; R3, R4 = H, (un)substituted NH2, substituent β, each (un)substituted lower alkyl, lower alkenyl, phenyl-lower alkyl, 4- to 7-membered aliph. heterocyclyl, or 4- to 7-membered aliph. heterocyclyl-lower alkyl; or R3 and R4 together form (un)substituted 4- to 7-membered aliph. heterocyclic ring; R5 = H, cyano, halo, lower alkyl; substituent α = halo, HO, NO2, cyano, NH2, CONH2, SO2NH2, imino, lower alkylamino, di(lower alkyl)amino, lower alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio, CO2H; substituent β = halo, HO, NO2, cyano, NH2, CONH2, SO2NH2, imino, alkylsulfonyl, lower alkylsulfonylamino, lower alkoxy, lower alkoxycarbonyl, lower alkoxycarbonylamino, lower alkanoyl, lower alkanoyloxy, lower alkylthio, CO2H, benzyl] or pharmaceutically acceptable salts or esters thereof were prepd. These compds. show cell-proliferation inhibitory activity based on polo-like kinase 1 (PLK1) inhibition and are useful as anticancer agents. Thus, oxidn. of 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile by m-chloroperbenzoic acid in CHCl3 at 0° for 30 min followed by condensation with [(1S)-1-[4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl]ethyl]amine in the presence of Et3N in THF at room temp. for 1 h gave 2-[((1S)-1-[4-[(1S)-2-(tert-butylamino)-1-hydroxyethyl]phenyl]ethyl)amino]-4-(8-ethylimidazo[1,2-a]pyridin-3-yl)pyrimidine-5-carbonitrile (II). II and 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-[[(1S)-1-[4-[(1S)-hydroxy(1-methylpiperidin-4-yl)methyl]phenyl]ethyl]amino]pyrimidine-5-carbonitrile (III) showed IC50 of 2.3 and 1.4 nM, resp., against wild-type PLK1 and EC50 of 2.6 and 4.6 nM, resp., for inhibiting the proliferation of HeLaS3 cells. [on SciFinder(R)]