Thyroid Stimulating Hormone (TSH) is a heterodimeric glycoprotein hormone that regulates thyroid homeostasis upon interaction with the TSH receptor (TSHR). TSH binds to the TSH receptor, which couples preferentially to the G-alpha (s) (Gs) protein, resulting in activation of adenylate cyclase and increase in cyclic adenosine 3′, 5′ monophosphate (cAMP). In this report, we describe the discovery and SAR studies of a series of dihydroquinazolin-4-ones as TSHR agonists. ML109 (CID-25246343) is the first selective and orally available small-molecule TSHR agonist, and the probe will be a useful pharmacological tool to study TSHR biology in thyroidal and extrathyroidal tissues.