Inhibition of methionine adenosyltransferase 2A (MAT2A) in cancers with a deletion of methylthioadenosine phosphorylase (MTAP) gene leads to synthetic lethality, thus receiving significant interest in the field of precise cancer treatment. Herein, we report the discovery of a tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine fragment which occupies the MAT2A allosteric pocket. The lead compound 8 exhibited extremely high potency to inhibit MAT2A enzymatic activity (IC50 = 18 nM) and proliferation of MTAP-null cancer cells (IC50 = 52 nM). 8 had a favorable pharmacokinetic profile with a bioavailability of 116% in mice. More importantly, introducing an amide motif (28) to the core structure raised the plasma drug exposure from 11 718 to 41 192 ng·h·mL-1. 28 displayed a significantly better in vivo potency than AG-270, which is being evaluated in clinical trails, and induced -52% tumor regression in a xenograft MTAP-depleted colon tumor model.