In this work, we report the discovery of 2,4-diaminopyrimidine derivatives bearing a urea moiety as FAK inhibitors capable of activating the Hippo pathway in Esophageal Squamous Cell Carcinoma (ESCC). Extensive structure-activity relationship studies were conducted based on the lead FAK inhibitor TAE-226 to enhance the inhibitory potency, and the most potent compound 8b (MY-1576) as a FAK inhibitor ultimately was identified. Compound MY-1576 exhibited potent FAK inhibitory activity, in vitro anticancer activities, and acceptable PK properties. Notably, MY-1576 could activate the Hippo pathway, resulting in impeding YAP/TAZ regulation. MY-1576 also effectively suppressed the tumor growth in the KYSE30 xenograft mouse models with good safety profiles, and potently down-regulated the autophosphorylation of FAK and the levels of YAP/TAZ in vivo. Taken together, these results indicate that MY-1576, functioning as a FAK inhibitor capable of activating the Hippo pathway, is a promising candidate against ESCC.