Eighteen new 4-[2-amino-3-cyano-5-oxo-4-substitutedaryl-4H-indeno[1,2-b]pyridin-1-(5H)-yl]benzenesulfonamide derivatives 6a-q were synthesized via a reaction of aromatic aldehydes, enaminone 3 and malononitrile in one-pot reaction. Also, compounds 6a-q were obtained, via another route by reaction of enaminone 3 with arylidenemalononitriles 4a-q. The structure of the synthesized compounds was characterized by microanalysis, IR, $^1H$-NMR, $^{13}C$-NMR and mass spectral data. All the target compounds were subjected to in vitro anticancer activity against breast cancer cell line (MCF7). Compound 6d showed a higher potency with $IC_{50}$ value (4.34 ${mu}M$) than that of the Doxorubicin (5.40 ${mu}M$), as the reference drug, while compound 6n with $IC_{50}$ value (6.84 ${mu}M$) is nearly as active as Doxorubicin. Also, compounds 6a-c, 6e, 6f, 6h and 6p exhibited a moderate activity, while compounds 3, 6g, 6i-m, 6o and 6q showed weak activity.