Synthesis of 6-CF3-1,2,4-triazine-based Tyrosine Kinase Inhibitors and The Evaluation of Biological Activities★

Trifluoromethyl group has strong electron-withdrawing ability and stable C-F bond, and its introduction into organic molecules could often significantly modify the acidity, dipole moment, lipophilicity and metabolic stability of parent compounds.Therefore, the incorporation of trifluoromethyl group into bioactive molecules has become a common strategy for drug development.Trifluoromethylated arene moiety is the important unit of many drugs and related candidates, such as Nilotinib, Radotinib, Ponatinib, Regorafenib, Pexidartinib, Bimiralisi, and Defactinib.Therefore, it is of great interest to design new compounds containing trifluoromethyl group and explore their potential applications in the development of protein kinase inhibitors.Imatinib is the first-generation tyrosine kinase inhibitor and the first small molecule targeting anti-tumor drug that inspires the synthesis of a large number of excellent anti-tumor drugs.Therefore, in this study, we aimed to design new trifluoromethyl-containing tyrosine kinase inhibitors via combining the aniline-pyrimidine structure of Imatinib with 1,2,4-triazines.In particular, we developed a one-pot [3＋3] cycloaddition sequence to construct a series of 3-ester-5-aryl-6-CF3-1,2,4-triazines in good yields.Subsequently, a series of new compounds containing the trifluoromethyl 1,2,4-triazine skeleton were obtained via a sequence of hydrolysis, chlorination, and amidation reactions.Finally, a preliminary evaluation of biological activity was conducted and a hit compound 4a was found with good activity in promoting apoptosis protein Caspase 9. A representative procedure for the synthesis of model product 4a is described as following: Starting from trifluoroethylamine (9.91 g, 100 mmol), tert-butyl nitrite (11.34 g, 110 mmol) and AcOH (1.2 g, 20 mmol) were used to generate trifluorodiazoethane in situ in tetrahydrofuran (THF, 20 mL) at 55 ℃ for 30 min.Then the CF3CHN2 solution was added to the mixture of glycine imine 1 (50 mmol), silver fluoride catalyst (0.64 g, 5 mmol) and cesium carbonate (20.36 g, 62.5 mmol) in THF (80 mL), and the reaction mixture reacted at 0 ℃ for 24 h to give the corresponding 6-CF3-tetrahydrotriazine 2. Afterwards, 2,3-dichloro-5,6-dicyanophenoquinone (DDQ) (2.72 g, 12 mmol) was used as oxidant for compound 2 (3 mmol) to produce the corresponding 3-ester-5-aryl-6-trifluoromethyl-1,2,4-triazine 3. The obtained trifluoromethyl-1,2,4-triazine 3 (3 mmol) was hydrolyzed under the promotion of lithium hydroxide (0.15 g, 3.6 mmol) in THF/H2O (5 mL THF, 10 mL H2O) at r.t. for 1 h to give the corresponding carboxylic acid.The carboxylic acid intermediate reacted with oxalyl chloride (0.31 mL, 3.6 mmol) under the catalysis of N,N-dimethylformamide (DMF, 1～2 drop) in CH2Cl2 at r.t. for 2 h to give the corresponding acyl chlorides.Finally, in a mixture of CH2Cl2 (5 mL) and DMF (2 mL), acyl chloride intermediates reacted with the corresponding aniline-pyrimidine intermediate (0.92 g, 3.3 mmol) to give the desired product 4.