The transcription factor hypoxia-inducible factor-1α (HIF-1α) plays an important role in apoptosis, metastasis, and proliferation and is recognized as an important potential therapeutic target for cancer. Six series of 3(5)-(6-methylpyridin-2-yl)-4-(quinolin-4-yl)pyrazoles (11a-d, 12a-d, and 18a-d) and 3(5)-(6-methylpyridin-2-yl)-4-(2-phenyl-pyridin-4-yl)pyrazoles (19a-d, 20a-d, and 21a-d) were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) and HIF-1α inhibitory activity at the enzyme and cell levels. The effect of the lead compound 20d (J-1012) on HIF-1α activation in HCT116 cells was investigated. J-1012 markedly decreased the hypoxia-induced or TNF-induced accumulation of HIF-1α protein dose-dependently. Analysis revealed that J-1012 inhibited HIF-1α protein synthesis, without affecting the degradation of HIF-1α protein. Furthermore, by inhibiting the activation of HIF-1α, J-1012 suppressed the metastasis and proliferation and promoted apoptosis of HCT116 cells. These results suggest that J-1012 may be a potential therapeutic agent against human colon cancer.