Abstract: In 2024, drug discovery continues to develop on the basis of the achievement before. The number of approved first-in-class (FIC) drugs reach a higher level. The Center for Drug Evaluation and Research of U.S. Food and Drug Administration has totally approved 50 novel drugs, including 30 small molecule drugs and 20 macromolecule drugs. Comparing to the number of approved drugs in 2023, the total in 2024 falls slightly. But the proportion of FIC drugs increase obviously. There are 24 FIC drugs (48%) approved in 2024, which include 13 FIC small molecule drugs and 11 FIC macromolecule drugs and whose indications mainly focus on tumor, and endocrine and metabolic disease. Among 24 FIC drugs, many drugs have breakthrough clinical value, such as the first combination of muscarinic acetylcholine receptor M1/M4 agonist and peripheral muscarinic acetylcholine receptor antagonist, xanomeline and trospium chloride, the first thyroid hormone receptor beta agonist, resmetirom, the first dual antagonist of endothelin receptor type A and B to treat hypertension, aprocitentan. The huge value of FIC drugs in clinical therapy, academic research and commerce, is attracting wide attention from the patients, researchers and enterprises. This review will analyze the research background, development process and therapeutic application of three first-in-class small molecule drugs in this year from a medicinal chemistry perspective, expecting to provide more research directions and methods for the development and research of FIC drugs.