Preparation of imidazothiazole derivatives as protein kinase inhibitors.

Abstract

Title copounds I [X = CH, N; A1 = R1, OR1, NHCOR1, NHR1, etc.; R1 = Ph, heteroaryl, cycloalk(en)yl, heterocycloalk(en)yl, each of them optionally fused wit benzene; or R1 = (un)substituted alk(en/yn)yl; B1, D1, E1, G1, H1, J1 = independently H, R1, CN, NO2, Cl, NHCOOR1, etc.; F1 = H, R10, COR10, R11, R110; R10 = Ph unfused or fused with R10A; R10A = benzene, heteroarene, (hetero)cycloalkane, (hetero)cycloalkene; R11 = heteroaryl unfused or fused with any of R10A; R110 = (un)substituted alkyl; wherein each forgoing variable cyclic moiety can be optionally substituted; and their therapeutically acceptable salts] were preared as protein kinase inhibitors for treating neoplasm. Thus, imidazothiazole II was prepd. by (a) cyclization of 2-bromo-1-(3-nitrophenyl)ethanone with thiazol-2-amine, (b) iodination of imidazothiazole III, (c) conversion of 5-iodoimidazothiazole intermediate to 5-acetyl deriv. by treatment with tributyl(1-ethoxyvinyl)stannane in the presence of bis(triphenylphosphine)palladium(II) dichloride, followed by treatment with HCl, (d) treatment of the acetylimidazothiazole with 1,1-di-tert-butoxy-N,N-dimethylmethanamine, (e) cyclization of IV with phenylguanidine to V, (f) redn. of the nitro intermediate V, and (g) amidation of 2-chlorobenzoyl chloride with the resulting amine. Some data was given for the ability of imidazothiazoles I to inhibit the EGFR(L858R) kinase activity in an HTRF in vitro kinase assay. [on SciFinder(R)]