4,pyrimidine derivatives were explored as irreversible Bruton's tyrosine kinase (BTK) inhibitors. The structure-activity relationship was established with over 20 derivatives synthesized to determine initial hit compounds, based on activities against BTK enzyme and TMD8 cells. It turned out that introducing 1-acrylamido-4-aminopiperdine (1b) at the C4 position of pyrazolopyrimidine as in 5e, and 3-acrylamido-aniline (1j) as 4-position substituent, such as in 9d, 10d, and 10e, delivered potent in vitro enzyme activities as well as TMD8 cell-based cytotoxicities. Considering kinase selectivity profiles, 5e was selected for in vivo efficacy studies with a murine xenograft model using TMD8 cells, where 5e exhibited moderate tumor growth inhibition activities. Further optimization of 5e and 9d may lead to clinically useful compounds to overcome B-cell-mediated hematologic cancers.

Harmala alkaloid (HA) derivatives having 4,9-dihydro-3H-pyrido [3,4-b]indolium core structure were prepared and their anti-ovarian cancer activities were explored. In the first screening of 14 compounds, dibenzylated 4e and 4f were found to be active against A2780 ovarian cancer cell line. Further preparation of active analogs led to discover 4f 1 as active as 4f in three ovarian cancer cell lines including cisplatin-resistant A2780 and SKOV3. Three compounds in 4f series showed single-digit micromolar GI 50 values against A2780 and cisplatinresistant A2780 cells. While the mechanism of action for the active compounds turned out to be involved in caspase-dependent apoptotic cell death, antiovarian cancer activities could be induced by inhibition of AKT Serine/Threonine Kinase 1 (AKT) signaling. This unprecedented scaffold 4 may be optimized further to find out clinically useful compounds for the treatment of ovarian cancers.