The mitogen-activated protein kinase (MAPK) pathway,including the Ras/Raf/MEK/ERK signaling cascade,is one of the most important pathways involved in a wide range of cell events such as proliferation,growth and differentiation,etc.Constitute activation of ERK pathway has been observed in many kinds of tumors.In recent years,a variety of inhibitors of ERK pathway have been uncovered as potential antitumor agents.To our knowledge,MEK is the only target of ERK,and ERK is only substrate of MEK,this one to one interaction is very important that can avoid many side effects.Targeting MEK1,a number of compounds have progressed into clinical trials,but none of them have yet reached FDA approval.Most of them share a scaffold of biarylamine and bind to the allosteric site of MEK1.Here we developed a series of nonbiarylamine structtaes as allosteric MEK1 inhibitors which have excellent selectivity compared to ATP-competitive inhibitors and introduced the design,synthesis and biological evaluation of them.