Non-covalent inhibitors of the main protease (M<sup>pro</sup>) of SARS-CoV-2 having a pyridinone core were previously reported with IC<sub>50</sub> values as low as 0.018 μM for inhibition of enzymatic activity and EC<sub>50</sub> values as low as 0.8 μM for inhibition of viral replication in Vero E6 cells. The series has now been further advanced by consideration of placement of substituted five-membered-ring heterocycles in the S4 pocket of M<sup>pro</sup> and N-methylation of a uracil ring. Free energy perturbation calculations provided guidance on the choice of the heterocycles, and protein crystallography confirmed the desired S4 placement. Here we report inhibitors with EC<sub>50</sub> values as low as 0.080 μM, while remdesivir yields values of 0.5-2 μM in side-by-side testing with infectious SARS-CoV-2. A key factor in the improvement is enhanced cell permeability, as reflected in PAMPA measurements. Compounds <b>19</b> and <b>21</b> are particularly promising as potential therapies for COVID-19, featuring IC<sub>50</sub> values of 0.044-0.061 μM, EC<sub>50</sub> values of ca. 0.1 μM, good aqueous solubility, and no cytotoxicity.