A novel series of nicotinonitrile and pyrazolyl nicotinonitrile were synthesized, and their PIM-1 kinase inhibitors and caspase activators were investigated. New Manich bases 6–8 were synthesized via reaction of pyridine 4 with piperidine, dimethyl amine, and morpholine in the presence of formalin. On the other hand, the pyrazolyl analogues 10–12 were synthesized via heterocyclization of acetohydrazide derivative 9 with acetylacetone, malononitrile, and ethyl cyanoacetate, respectively, in ethanol. The cytotoxic activity of compound 9 against MCF-7 and HepG2 cells was particularly noteworthy, with IC50 values of 0.34 mM and 0.18 mM, respectively, among these derivatives. Compared to staurosporine with potent PIM-1 kinase inhibition, which had an IC50 value of 16.7 nM and an inhibition of 95.6%, compound 9 had a strong inhibitory effect, with IC50 values of 20.4 nM and 93.8%. It induced apoptosis activity in HepG2 cancer cells. Accordingly, compound 9 was proven to be an effective chemotherapeutic drug that targets PIM-1 in treating liver cancer.