The use of highly active antiretroviral therapy (HAART) has made the human immunodeficiency virus (HIV) a chronic disease rather than a terminal disease. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are an important component of HAART, although we are seeing clinically relevant drug-resistant mutants such that there is a need to develop new molecules. We recently identified a new class of -phenyl-1-(phenylsulfonyl)-1-1,2,4-triazol-3-amine HIV-1 NNRTI, with one known as compound 12126065, with sub nanomolar (nM) potency in TZM-bl cells (HeLa cells expressing CD4, CCR5, and CXCR4) with no in vivo acute or subacute toxicity. We now describe the cryo-EM structure of this molecule (resolution of 3.53 Å) and compare it to analogues and other known NNRTIs. We also describe the synthesis and activity of five additional analogues of this class of compounds, some of which have promising activity against a K103N/Y181C (A17) double mutant, which will enable the design of future molecules.