METTL1 is the human RNA methyltransferase that catalyzes the methylation of N7-guanosine in RNA. Overexpression of METTL1 has been linked to cancer, and increasing evidence supports the therapeutic potential of METTL1 inhibition in oncology. In this study, we have optimized a series of adenosine 5′-carboxamide derivatives as METTL1 inhibitors through structure-guided modifications of a previously discovered hit compound. The advanced inhibitor B22 shows an IC50 of 1 μM in an enzymatic assay, which is a 178-fold improvement with respect to the initial hit. The crystal structure of the des-methyl analogue of B22 (compound B19, IC50 = 0.4 μM) provides evidence that the benzylpiperazine moiety is accommodated within the Guanosine-binding subsite of METTL1. The inhibitor B22 shows high solubility and metabolic stability and is selective against a panel of seven histone methyltransferases and the RNA-methyltransferase METTL3/METTL14.