Synthesis And Biological Evaluation Of Novel Pvrazolo[4,3-d]pyrimidine Derivatives

Autoimmune diseases occur due to lymphocytes' over activity when the antibody attacks and damages specific organ or numbers of organs.They can result in substantial morbidity and mortality.The treatment of autoimmune diseases had been limited to non-selective immunosuppressant or cytotoxic drugs until in the nineties,the appearance of monoclonal antibodies and small molecular targeted drugs which exerted significant influence on the disease process and quality of life of patients.Whereas,the limitations of cytotoxic drugs and biologicals are low selectivity and high prices.The study on small molecule drugs with potential bioactivity is of great significance in order to control and treat immune disorders.Bruton tyrosine kinase(BTK)inhibitor Ibrutinib was approved by the U.S.Food and Drug Administration in 2013.BTK,which is a member of Tec kinase family is mainly expressed in hematopoietic cells.It regulates the development of B lymphocytes.Ibrutinib is employed clinically for the treatment of B lymphocyte malignancies and has good prospects in therapy of immune diseases.In this work,a series of pyrazolo[3,4-d]pyrimidine derivatives were synthesized based on the Ibrutinib and HM-71224.pyrazolo[3,4-d]pyrimidine nucleus was modified into pyrazolo[4,3-d]pyrimidine nucleus according to bioisosterism.Then the key groups were introduced at 5,7-positions and the acrylamide bond which plays the role of inhibition was reserved.We also optimized the synthetic route.In all synthesized compounds,13b-3 and 13b-6 exhibited intense inhibition of T?B lymphocytes in mice.They showed equal IC50 values to HM-71224 with lower cytotoxicity but exhibited no kinase inhibitory activity.The results showed that 13b-3 had a lower bioavailability which slightly lower than13b-6.It will be very helpful for subsequent research about designing compounds for the treatment of autoimmune diseases.