Bruton tyrosine kinase (BTK), a non-receptor tyrosine kinase falling within the Tec kinase family, forms an essential part of the B cell receptor (BCR) signaling cascade. It has come to be regarded as a potential drug target for addressing a wide range of diseases, with a particular focus on hematopoietic malignancies and autoimmune disorders related to B lymphocytes. In the present study, by uncovering the binding mechanisms of the inhibitor Orelabrutinib with BTK, we identified four crucial structural elements requisite for the inhibition. Using scaffold hopping strategies, 28 novel derivatives belonging to the tricyclic and pyridine amide series were designed and synthesized from the lead compound Orelabrutinib. The outcomes revealed that 11a and 11k were able to effectively restrain the growth and migration of the tumor cell TMD8 upon comparing their in vitro activities, meriting further examination.