Preparation of novel aminopyridine derivatives having selective Aurora-A protein kinase inhibitory effect.

Abstract

The title compds. (I) or pharmaceutically acceptable salts or ester thereof [wherein m1, m2 = 1, 2, 3; n1, n2 = 0, 1; i = an integer of from 1 to m1; j = an integer of from 1 to m2; R = (un)substituted aryl, heteroaryl or cycloalkyl; Rai, Rai', Rbj, Rbj', Rc, Rd, Re = H, lower alkyl; X1 = CH, CX1a, N; wherein X1a = (un)substituted lower alkyl; X2 = CH, N; X3 = CH, N, CX3a; wherein X3a = (un)substituted lower alkyl; X4 = CH, N; 1 or 2 of X1-X4 is N ; Y1, Y2, Y3 = CH, N; Z1, Z2 = CH, N; W = a 5-membered arom. heterocycle of formula Q including pyrazole or thiazole; wherein W1 = CH, N, NH, O, S; W2 = CH, CW2a, N, NW2b, O, S; wherein W2a, W2b = H, halo, cyano, C1-2 alkyl, C3-5 cycloalkyl, 1 or 2 halo-substituted C1-2 alkyl] are prepd. These compds. are selective inhibitors of Aurora-A protein kinase over Aurora-B protein kinase and exhibit synergistic anticancer activity in combination with other anticancer agents. An anticancer agent contg. the compd. I, and the combined use of the above anticancer agent with another anticancer agent are also disclosed. Thus, a mixt. of 2.70 g 6-chloromethyl-N-(thiazol-2-yl)pyridin-2-amine, 4.00 g 1-(3-chloro-2-fluorobenzoyl)piperazine, and 6.25 mL N,N-diisopropylethylamine, and 30 mL DMF was stirred at 90° for 2 h to give, after workup and silica gel chromatog., 6-[(4-(3-chloro-2-fluorobenzoyl)piperazin-1-yl)methyl]-N-thiazol-2-ylpyridin-2-amine (II; R = H). II (R = H) and II (R = 2-methyl-2H-tetrazol-5-yl) showed IC50 of 0.67 and 0.32 nM against Aurora-A protein kinase, resp., and 440 and 190 nM against Aurora-B protein kinase, resp. They showed IC50 of 11.00 and 0.21 μM against human cervical cancer cell (HeLa S3), resp., and also showed synergistic antiproliferative activity against HeLa S3 cells in combination with paclitaxel. [on SciFinder(R)]