Anoctamin 6 (ANO6), also known as TMEM16F, is a calcium-activated phospholipid scramblase that plays a critical role in platelet activation and phosphatidylserine (PS) exposure. The externalization of PS provides a procoagulant surface required for thrombin generation, making ANO6 a promising therapeutic target for the development of novel antithrombotic agents. Previously identified first-in-class ANO6 inhibitors showed promising inhibitory activity; however, their limited aqueous solubility remained a major challenge for further drug development. In this study, we aimed to improve the physicochemical properties, particularly aqueous solubility, of ANO6 inhibitors through structural modification. The aromatic ring located in Part C of lead scaffold was considered an important structural feature contributing to molecular interactions but was also expected to contribute to compound\'s hydrophobicity. Therefore, systematic structural modifications were performed by replacing the aromatic ring with various sp³-rich structural motifs in order to increase the solubility of the compounds. The synthesized analogues were evaluated to investigate the relationship between structural modification, solubility, and biological activity. This study provides insights into the structural determinants governing the balance between physicochemical properties and ANO6 inhibitory activity and may contribute to the development of improved ANO6 inhibitors as potential novel antithrombotic agents.