Design And Synthesis Of Sulfanilamides And Amides Of Quinazoline Derived Amines As JAK Inhibitors

JAKs are intracellular and a non-receptor tyrosine kinases which link cytokine signalling from membrane receptors to signal transducers and activators of transcription(STAT)transcription factors.JAK family members includes JAK1,JAK2,JAK3 and TYK2.they play a key role in the cytokine receptor signal.Overactivation of JAK-STAT signaling leads to various inflammatory diseases and cancers.Thus far,two JAK inhibitors have been approved by the FDA.Tofacitinib a JAK3 inhibitor for the treatment of rheumatoid arthritis was developed by Pfizer,JAX2 inhibitor Ruxolitinib developed by Incyte,for the treatment of myelofibrosis.In previous studies,our group discovered novel quinazoline derivatives as JAK inhibitors.In this thesis,we will use fragments based approach to introduce well-known JAK fragments in the literatures to our quinazoline scaffold.We synthesized 14 compounds of substituted piperazines.and found that ethylpiperazine(2-6c)and acetyl piperazine(2-6j)with IC50 below 1 nM.In this sebsequent study,we synthesized 7 8-arylquinazolines,and found four of them inhibiting JAK1 at IC50 below 1 nM.Based on above work,we combined the active fragments and synthesized 27 compounds.The inhibition of 3 compounds are bellow 1 nM.In the TF-1 cellular assay,the activity of 2-llm and 2-lln against IL-4-mediated JAK1/3 are 92.8 nM and 77.7 nM which are simil to that of Tofacitinib(IC50=91 nM).In another study,the benzene rine of the quinazoline nucleus was replaced with diazepine,pteridine ketone and pyridone to result in 5 compounds.The kinase activity of these compounds are very weak.Ths results shows that benzene moiety of quinazoline nucleus plays a very important role.In summary,by studing the SAR,we found better quinazoline kinase inhibitors which contain sulfonamides and amides groups.Among them,two compounds showed cell activity close to that of marketed drug.