Design And Synthesis Of Quinazolines Containing Pyrazole Substituent As Inhibitors Of JAK2

Janus kinases(JAK)are intracellular,non-receptor tyrosine kinases that transduce cytokine-mediated signal by the JAK-STAT signaling pathway.JAK family includes JAK1?JAK2?JAK3 and TYK2.There is a high degree of sequence homology across the JAK family.A common ATP binding site in the kinase domain of JAKs,makes it possible to develop ATP competitive JAK inhibitors.Due to the recently discovery of the JAK2V617F allosteric sites.JAK2 has become a hot target for drug development.Myeloproliferative Neoplasms(MPN)are clonal malignancies that arise from hematopoietic stem and manifest clinically by uncontrolled myeloid proliferation.The WHO classification of MPNs mainly includes four different entities:chronic myeloid leukemia(CML)?primary myelofibrosis(PMF)?polycythemia vera(PV)and essential thrombocythemia(ET).The mutation of JAK2(JAK2V617F)exists in high proportion of MPN patients.The JAK2V617F mutation in the pseudokinase domain disrupts its autoinhibitory activity,thereby resulting in constitutive activation of the kinase domain.The constitutive activation of JAK2V617F triggers the activation of signal transducer and activator of transcription-3(STAT3)?STAT5?ERK and PI3K/AKT pathways,that result in unchecked cell proliferation.Accordingly,the inhibition of JAK2 presents an opportunity for targeted therapy for MPNs.Recently,a variety of JAK2 inhibitors have been reported in the literature and some have entered clinical trials.Our research team has discovered a class of quinazoline derivatives as JAK inhibitors.This thesis chooses compound 2-10 as a lead for optimization.We take the bioisosteric approach with pyrazole ring to replace the benzene ring.Thus,we designed and synthesized 29 compounds as potential selective inhibitors.The target compounds were prepared,using 3-chloro-2-fluorobenzaldehyde as the starting material,through a four-step sequence of ring closing reaction?Buchwald-Hartwig coupling?Suzuki-Miyaura coupling and substitution reaction.Seven compounds show JAK2 inhibition with IC50 under InM.Through further optimization,we obtained the compound 5-7 and 5-9 which the selectivity of JAK1/2 over 100 times,JAK3/2 10 times.