CN105837572B - N- substituted-phenyl amide derivatives and its preparation method and application - Google Patents

N- substituted-phenyl amide derivatives and its preparation method and application Download PDF

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CN105837572B
CN105837572B CN201610051840.XA CN201610051840A CN105837572B CN 105837572 B CN105837572 B CN 105837572B CN 201610051840 A CN201610051840 A CN 201610051840A CN 105837572 B CN105837572 B CN 105837572B
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alkyl
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CN105837572A (en
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陈俐娟
魏于全
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Chengdu zeiling Biomedical Technology Co.,Ltd.
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Abstract

The invention belongs to chemical medicines, and in particular to N- substituted-phenyl amide derivatives and its preparation method and application.The present invention provides a kind of N- substituted-phenyl amide derivatives, and structure is as shown in formula I.The present invention also provides the preparation methods and purposes of above-mentioned N- substituted-phenyl amide derivatives.N- substituted-phenyl amide derivatives provided by the invention, inhibit JAK3 to the property of can choose, and to treat associated disease, such as rheumatoid arthritis, asthma, Chronic Obstructive Pulmonary Disease and tumour provide new selection.

Description

N- substituted-phenyl amide derivatives and its preparation method and application
Technical field
The invention belongs to chemical medicines, and in particular to N- substituted-phenyl amide derivatives and preparation method thereof and use On the way.
Background technique
Protein kinase is made of a series of relevant enzyme in structures, is mainly responsible for the control of intracellular signal transduction process. In general, phosphinylidyne group-transfer of the protein kinase by influence from ribonucleoside triphosphote to the protein receptor for participating in signal transduction path, and Mediate intracellular signal.These phosphorylation events play the role of modulation or adjust the molecular switch of target protein biological function.Very much Disease is all related with the abnormal cell reaction caused by above-mentioned protein kinase mediated event.
Janus Kinase (JAK), including JAK1, JAK2, JAK3 and TYK2, belong to cytoplasm protein kinases, with I type and II cytokines receptor acting adjusts cytokine signaling.JAK1, JAK2 and TYK2 can inhibit several genes table It reaches, however JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor are existed as heterodimer form, Therefore not usually a kind of IAK kinases and cytokine receptor act on.
The stream substrates of JAK family include signal transduction agent and the activator (STAT) of transcription factor.JAK/STAT signal Transduction is related to many abnormal immune reactions, such as allergy, asthma, autoimmunity disease such as graft rejection, rheumatoid arthritis, flesh Meat contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukaemia, lymthoma.
JAK3 specificity acts on gamma cells factor acceptor chain, it is in IL-2, IL-4, IL-7, IL-9, IL-15, IL- Exist in 21 equal cytokine receptors.JAK3 is in lymphocyte growth, hyperplasia, plays an important role in mutation process, occurs different Serious immune deficiency can often be caused.The effect of lymphocyte is adjusted based on it, the access that JAK3 and JAK3 are mediated is used for Adjust immunosuppressive indication.JAK3 implication in the mediation of many abnormal immune responses, such as allergy, asthma, from Body immunological diseases such as inhibit graft rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and Hematologic malignancies such as leukaemia, lymthoma.
In conclusion there is an urgent need to develop go out to can be used for the compound of kinases inhibitor specifically to need to develop The compound of highly selective JAK3 inhibitor.
Summary of the invention
The present invention provides a kind of N- substituted-phenyl amide derivatives, and structure is as shown in formula I:
Wherein, X1~X3、Y1~Y4Stand alone as C, N or S；
R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；
R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynes Base,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；
R4~R6Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynes Base, C3~C8Naphthenic base or halogen.
As preferred embodiments of the present invention, X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C8Alkyl, halogen ,- CN、-OH、C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkane Oxygroup, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,- O(C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~ C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alcoxyl Base,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Alkyl halide Base, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3 Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,X1 ~X3、Y1~Y4Stand alone as C or N；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4 Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4 ~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6 Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl ,-CN, C1~C4Alkoxy,X1~X3、Y1~Y4Stand alone as C or N；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1 ~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8 Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1 ~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；X1~X3、Y1~Y4Solely It stands as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；X1~X3、Y1~ Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6It is independent For-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or Halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl or C3~C6Cycloalkanes Base；X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl or halogen Element.
It is further preferred that R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；X1~ X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy, R2、R3 Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
Still more preferably, R4~R6Stand alone as-H or C1~C4Alkyl；X1~X3、Y1~Y4Stand alone as C or N；R1For- H、C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~ C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
Preferably, X1~X3、Y1~Y4Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R4~R6Stand alone as-H or C1~C4 Alkyl.
Optimal, X1~X3、Y1~Y4Stand alone as C or N；R1For-H, methyl ,-F ,-Cl ,-CN, methoxyl group, two
Methylamino orR2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1And X3For N, X2For C, Y3And Y4When for C, structure such as II institute of formula Show:
Wherein, Y1、Y2Stand alone as C or N；R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen Element；R4~R6Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3 ~C8Naphthenic base or halogen.
Preferably, Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen Element；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3 ~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy, Y1、Y2Stand alone as C or N；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base Or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl ,-CN, C1~C4Alkoxy,Y1、Y2Stand alone as C or N；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4It is halogenated Alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3 Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base, C3~C6Naphthenic base or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkane Oxygroup,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4 Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6 Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4 Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；Y1、Y2Stand alone as C Or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4 Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl or C3~C6Cycloalkanes Base；Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy, R2、R3 Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；Y1、 Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3It is independent For-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
Still more preferably, R4~R6Stand alone as-H or C1~C4Alkyl；Y1、Y2Stand alone as C or N；R1For-H, C1~C4 Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
Preferably, Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R4~R6Stand alone as-H or C1~C4Alkyl.
Optimal, Y1、Y2Stand alone as C or N；R1For-H, methyl ,-F ,-Cl ,-CN, methoxyl group, dimethylamino orR2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1And X2For C, X3For N, Y1~Y4When for C, structure such as III institute of formula Show:
Wherein, R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or- CON(CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen, C1~C4Alkoxy,R2、R3Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、 C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1 ~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R1For-H, C1~C4Alkane Base, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；R1For-H, C1~ C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；R1For-H, C1 ~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkane Oxygroup, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H or C1~C4Alkyl；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~ C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4 Alkynyl or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~C4Alkyl, C2 ~C4Alkenyl or halogen.
Optimal, R1For-H, methyl ,-F ,-Cl or methoxyl group；R2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1~X3For C, Y1~Y4When for C, structure is as shown in formula IV:
Wherein, R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or- CON(CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen, C1~C4Alkoxy,R2、R3Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、 C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1 ~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R1For-H, C1~C4Alkane Base, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；R1For-H, C1~ C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；R1For-H, C1 ~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkane Oxygroup, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H or C1~C4Alkyl；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~ C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4 Alkynyl or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~C4Alkyl, C2 ~C4Alkenyl or halogen.
Optimal, R1For-H, methyl ,-F ,-Cl or methoxyl group；R2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1For C, X2And X3For N, Y1~Y4When for C, structure such as V institute of formula Show:
Wherein, R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or- CON(CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen, C1~C4Alkoxy,R2、R3Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、 C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1 ~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R1For-H, C1~C4Alkane Base, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；R1For-H, C1~ C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；R1For-H, C1 ~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkane Oxygroup, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H or C1~C4Alkyl；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~ C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4 Alkynyl or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~C4Alkyl, C2 ~C4Alkenyl or halogen.
Optimal, R1For-H, methyl ,-F ,-Cl or methoxyl group；R2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1For N, X2And X3For C, Y1~Y4When for C, structure such as VI institute of formula Show:
Wherein, R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or- CON(CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen, C1~C4Alkoxy,R2、R3Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、 C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1 ~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R1For-H, C1~C4Alkane Base, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；R1For-H, C1~ C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；R1For-H, C1 ~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkane Oxygroup, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H or C1~C4Alkyl；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~ C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4 Alkynyl or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~C4Alkyl, C2 ~C4Alkenyl or halogen.
Optimal, R1For-H, methyl ,-F ,-Cl or methoxyl group；R2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, work as X1And X3For C, X2For N, Y1~Y4When for C, structure such as VII institute of formula Show:
Wherein, R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alkoxy,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynyl, C3~C8Naphthenic base or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen ,-CN ,-OH, C1~C4Alkoxy,Or- CON(CH3)2；R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynes Base,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R1For-H, C1~C4Alkyl, halogen, C1~C4Alkoxy,R2、R3Solely It stands as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen；R4~R6Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R1For-H, C1~C4Alkyl ,-F ,-Cl or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~ C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl,-CN、-OH、 C3~C6Naphthenic base ,-O (C1~C8Alkyl) CF3Or halogen.
Preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2 ~C4Alkynyl, C3~C6Naphthenic base or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
It is further preferred that R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4Alkynyl Or halogen；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1 ~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still more preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl or halogen；R1For-H, C1~C4Alkane Base, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Still further preferably, R2、R3Stand alone as-H, C1~C4Alkyl, C2~C4Alkenyl ,-Cl or-Br；R1For-H, C1~ C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alcoxyl Base, C1~C4Halogenated alkyl, C2~C4Alkenyl, C2~C4Alkynyl, C3~C6Naphthenic base or halogen.
Preferably, R4~R6Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy or C1~C4Halogenated alkyl；R1For-H, C1 ~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkane Oxygroup, C2~C4Alkenyl, C2~C4Alkynyl or halogen.
It is further preferred that R4~R6Stand alone as-H or C1~C4Alkyl；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~ C4Alkoxy,R2、R3Stand alone as-H, C1~C4Alkyl, C1~C4Alkoxy, C2~C4Alkenyl, C2~C4 Alkynyl or halogen.
Preferably, R1For-H, C1~C4Alkyl, halogen or C1~C4Alkoxy；R2、R3Stand alone as-H, C1~C4Alkyl, C2 ~C4Alkenyl or halogen.
Optimal, R1For-H, methyl ,-F ,-Cl or methoxyl group；R2、R3Stand alone as-H, methyl, vinyl ,-Cl or-Br.
Above-mentioned N- substituted-phenyl amide derivatives, structural formula are as follows:
The present invention also provides the preparation method of above-mentioned N- substituted-phenyl amide derivatives, synthetic routes are as follows:
Wherein, X1~X3、Y1~Y4Stand alone as C, N or S；R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alcoxyl Base,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Alkyl halide Base, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3 Or halogen；R4~R6Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynes Base, C3~C8Naphthenic base or halogen.
The raw materials used in the present invention or the Chinese meaning of reagent english abbreviation are shown in Table 1.
The Chinese meaning of 1 raw material of table or reagent english abbreviation
The preparation method of above-mentioned N- substituted-phenyl amide derivatives, operating procedure are as follows:
A, raw material 1 and p-methyl benzenesulfonic acid are stirred at room temperature in EtOAc, 3,4- dihydro -2H- pyrans is added dropwise, will react Liquid is heated to reflux about 2h；To reaction solution close to clear state, it is filtered to remove part material 1 while hot, by filtrate water, saturated common salt Water washs respectively, collects oil reservoir, anhydrous Na2SO4Dry oil reservoir removes solvent and obtains intermediate 2；The raw material 1, to methylbenzene Sulfonic acid, 3,4- dihydro -2H- pyrans molar ratio be 1 ︰, 0.02 ︰ 2；
B, by intermediate 2, compound 3, Pd (PPh3)4Or PdCl2(dppf) and K2CO3, in N2Under protection, in PhMe/ EtOH (7/3, v/v) and H2O is (by K2CO3Be made into the amount of 2M) in be heated to reflux and overnight；It is filtered to remove insoluble matter with diatomite, Filtrate is collected, filtrate is spin-dried for, filtrate is extracted with EtOAc and water, collects oil reservoir, then with saturated common salt water washing oil reservoir 3 times, Anhydrous Na2SO4Dry oil reservoir, oil reservoir use column chromatographic purifying after removing solvent, obtain intermediate 4；The intermediate 2, compound 3, Pd(PPh3)4Or PdCl2(dppf)、K2CO3Molar ratio be 1 ︰, 1.1 ︰, 0.05 ︰ 3；
C, by intermediate 4,10%Pd/C (the 0.5% of 2 mass of intermediate) and HOOCNH4, it was heated to reflux in MeOH Night；It is filtered to remove reducing agent Pd/C with diatomite, filtrate is spin-dried for and obtains solid, solid is washed with water and filters, collecting solid is Intermediate 5；The intermediate 4, HOOCNH4Molar ratio be 1 ︰ 3；
D, compound 6 and water removal DCM are stirred at room temperature, sequentially add PyBOP and DIEA, after reacting 30min, then Intermediate 5 is added, room temperature reaction is overnight.It is spin-dried for reaction solution, filtrate is extracted with EtOAc and water, collects oil reservoir, then use saturated common salt Water washing oil reservoir 3 times, anhydrous Na2SO4Dry oil reservoir, oil reservoir use column chromatographic purifying after removing solvent, obtain intermediate 7；Describedization Close object 6, PyBOP, DIEA, intermediate 5 molar ratio be 1 ︰, 1 ︰, 3 ︰ 1；
E, a little HCl solution is added dropwise into the MeOH solution of intermediate 7 at room temperature, is then heated to reflux about 1h, TLC prison It surveys the de- THP of raw material to finish, is spin-dried for reaction solution, washs solid with PE and filter, obtain type I compound.
The present invention also provides above-mentioned N- substituted-phenyl amide derivatives pharmaceutically acceptable salts.It is at salt with acid wherein Refer to, is obtained by the free alkali of parent compound with inorganic acid or reacting for organic acid.Inorganic acid includes hydrochloric acid, hydrobromic acid, nitre Acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid and perchloric acid etc..Organic acid includes acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) Malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, gamma-hydroxybutyric acid, methoxy benzoic acid, phthalic acid, methanesulfonic acid, second Sulfonic acid, naphthalene -1- sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or Malonic acid etc..
The present invention also provides the above-mentioned pharmaceutically acceptable hydrates of N- substituted-phenyl amide derivatives.
A kind of pharmaceutical composition is that N- substituted-phenyl amide derivatives and its salt or hydrate as shown in formula I~VII add The pharmaceutically complementary ingredient of acceptable is added to be prepared.
The present invention also provides above-mentioned N- substituted-phenyl amide derivatives and its salt or hydrate in preparation JAK3 inhibitor In purposes.
The present invention also provides above-mentioned N- substituted-phenyl amide derivatives and its salt or hydrate to treat rheumatoid in preparation Purposes in arthritis, asthma, Chronic Obstructive Pulmonary Disease or tumour medicine.
N- substituted-phenyl amide derivatives provided by the invention, inhibit JAK3 to the property of can choose, associated to treat Disease, such as rheumatoid arthritis, asthma, Chronic Obstructive Pulmonary Disease and tumour provide new selection.
Specific embodiment
The preparation method of N- substituted-phenyl amide derivatives, synthetic route are as follows:
Wherein, X1~X3、Y1~Y4Stand alone as C, N or S；R1For-H, C1~C8Alkyl, halogen ,-CN ,-OH, C1~C8Alcoxyl Base,Or-CON (CH3)2；R2、R3Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Alkyl halide Base, C2~C8Alkenyl, C2~C8Alkynyl,-CN、-OH、C3~C8Naphthenic base ,-O (C1~C8Alkyl) CF3 Or halogen；R4~R6Stand alone as-H, C1~C8Alkyl, C1~C8Alkoxy, C1~C8Halogenated alkyl, C2~C8Alkenyl, C2~C8Alkynes Base, C3~C8Naphthenic base or halogen.
The preparation method of above-mentioned N- substituted-phenyl amide derivatives, operating procedure are as follows:
A, raw material 1 and p-methyl benzenesulfonic acid are stirred at room temperature in EtOAc, 3,4- dihydro -2H- pyrans is added dropwise, will react Liquid is heated to reflux about 2h；To reaction solution close to clear state, it is filtered to remove part material 1 while hot, by filtrate water, saturated common salt Water washs respectively, collects oil reservoir, anhydrous Na2SO4Dry oil reservoir removes solvent and obtains intermediate 2；The raw material 1, to methylbenzene Sulfonic acid, 3,4- dihydro -2H- pyrans molar ratio be 1 ︰, 0.02 ︰ 2；
B, by intermediate 2, compound 3, Pd (PPh3)4Or PdCl2(dppf) and K2CO3, in N2Under protection, in PhMe/ EtOH (7/3, v/v) and H2O is (by K2CO3Be made into the amount of 2M) in be heated to reflux and overnight；It is filtered to remove insoluble matter with diatomite, Filtrate is collected, filtrate is spin-dried for, filtrate is extracted with EtOAc and water, collects oil reservoir, then with saturated common salt water washing oil reservoir 3 times, Anhydrous Na2SO4Dry oil reservoir, oil reservoir use column chromatographic purifying after removing solvent, obtain intermediate 4；The intermediate 2, compound 3, Pd(PPh3)4Or PdCl2(dppf)、K2CO3Molar ratio be 1 ︰, 1.1 ︰, 0.05 ︰ 3；
C, by intermediate 4,10%Pd/C (the 0.5% of 2 mass of intermediate) and HOOCNH4, it was heated to reflux in MeOH Night；It is filtered to remove reducing agent Pd/C with diatomite, filtrate is spin-dried for and obtains solid, solid is washed with water and filters, collecting solid is Intermediate 5；The intermediate 4, HOOCNH4Molar ratio be 1 ︰ 3；
D, compound 6 and water removal DCM are stirred at room temperature, sequentially add PyBOP and DIEA, after reacting 30min, then Intermediate 5 is added, room temperature reaction is overnight.It is spin-dried for reaction solution, filtrate is extracted with EtOAc and water, collects oil reservoir, then use saturated common salt Water washing oil reservoir 3 times, anhydrous Na2SO4Dry oil reservoir, oil reservoir use column chromatographic purifying after removing solvent, obtain intermediate 7；Describedization Close object 6, PyBOP, DIEA, intermediate 5 molar ratio be 1 ︰, 1 ︰, 3 ︰ 1；
E, a little HCl solution is added dropwise into the MeOH solution of intermediate 7 at room temperature, is then heated to reflux about 1h, TLC prison It surveys the de- THP of raw material to finish, is spin-dried for reaction solution, washs solid with PE and filter, obtain type I compound.
The preparation of 1 N- of embodiment (3- (9H- purine -6- base) phenyl) acrylamide (compound II-1)
Raw material 1 is 6-chloropurine, and compound 3 is m-nitro boric acid, and compound 6 is acyl chlorides propylene.
A, 6-chloropurine (1,7.7g, 50mmol) and p-methyl benzenesulfonic acid (172mg, 1mmol) room temperature in EtOAc are stirred It mixes, is added dropwise 3,4- dihydro -2H- pyrans (8.4g, 100mmol), reaction solution is heated to reflux about 2h；To the close clarification shape of reaction solution State is filtered to remove part material 1 while hot, and filtrate water, saturated salt solution are washed respectively, collects oil reservoir, anhydrous Na2SO4It is dry Oil reservoir removes solvent and obtains the chloro- 9- of 6- (tetrahydro -2H-2- pyrans -2- base) -9H- purine (intermediate 2,11.3g)；
B, by the chloro- 9- of 6- (tetrahydro -2H-2- pyrans -2- base) -9H- purine (intermediate 2,2.38g, 10mmol), to nitre Base phenyl boric acid (3,1.84g, 11mmol), Pd (PPh3)4(578mg, 0.5mmol) or PdCl2(dppf) (366mg, 0.5mmol) And K2CO3(4.14g, 30mmol), in N2Under protection, in PhMe/EtOH (7/3, v/v, 35ml/15ml) and H2Add in O (15ml) Heat flows back and stays overnight；It is filtered to remove insoluble matter with diatomite, filtrate is collected, is spin-dried for filtrate, with EtOAc and water extraction filter Liquid collects oil reservoir, then with saturated common salt water washing oil reservoir 3 times, anhydrous Na2SO4Dry oil reservoir, oil reservoir use column layer after removing solvent Analysis purifying, obtains 6- (3- nitrobenzophenone) -9- (tetrahydro -2H- pyrans -2- base) -9H- purine (intermediate 4,1.78g)；
C, by 6- (3- nitrobenzophenone) -9- (tetrahydro -2H- pyrans -2- base) -9H- purine (intermediate 4,1.78g), 10%Pd/C (89mg) and HOOCNH4(1.0g, 16.4mmol), the heated overnight at reflux in MeOH；It is filtered to remove with diatomite Reducing agent Pd/C is spin-dried for filtrate and obtains solid, and solid is washed with water and filters, and collecting solid is 3- (9- (tetrahydro -2H- pyrrole Mutter -2- base) -9H- purine -6- base) aniline (intermediate 5,1.2g)；
D, by 3- (9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base) aniline (intermediate 5,118mg, It 0.4mmol) is stirred at room temperature with water removal DMF, is added DIEA (155mg, 1.2mmol), after reacting 30min, adds propylene Acyl chlorides (6,36.2mg, 0.4mmol), room temperature reaction is overnight.Filtrate is extracted with EtOAc and water, collects oil reservoir, then use saturated common salt Water washing oil reservoir 3 times, anhydrous Na2SO4Dry oil reservoir, oil reservoir use column chromatographic purifying after removing solvent, obtain N- (3- (9- (tetrahydro Change -2H- pyrans -2- base) -9H- purine -6- base) phenyl) acrylamide (intermediate 7,85mg)；
E, at room temperature to N- (3- (9- (tetrahydro -2H- pyrans -2- base) -9H- purine -6- base) phenyl) acrylamide (in Mesosome 7,85mg) MeOH solution in, a little HCl solution is added dropwise, is then heated to reflux about 1h, TLC monitors raw material, and to take off THP complete Finish, is spin-dried for reaction solution, washs solid with PE and filter, obtain compound II-1 (43mg).
1H NMR(400MHz,DMSO-d6) δ: 13.66 (s, 1H), 10.49 (s, 1H), 8.99 (s, 2H), 8.71 (s, 1H), 8.58 (d, J=6.7Hz, 1H), 8.00 (d, J=7.3Hz, 1H), 7.56 (t, J=7.7Hz, 1H), 6.53 (dd, J=16.4, 9.8Hz, 1H), 6.31 (d, J=16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H).MS(ESI),m/z:266.20[M+H]+。
The preparation of 2 N- of embodiment (2- methyl 5- (9H- purine -6- base) phenyl) acrylamide (compound II-2)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- methyl-3-nitro benzene boron Acid, compound 6 are acyl chlorides propylene.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.49(s,1H),8.99(s,2H),8.71(s,1H), 8.53 (d, J=6.7Hz, 1H), 7.92 (d, J=7.3Hz, 1H), 6.53 (dd, J=16.4,9.8Hz, 1H), 6.31 (d, J= 16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H), 2.21 (s, 3H).MS (ESI), m/z:280.20 [M+H]+。
The preparation of 3 N- of embodiment (2- methyl -3- (9H- purine -6- base) phenyl) acrylamide (compound II-3)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2- methyl-3-nitro benzene boron Acid, compound 6 are acyl chlorides propylene.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.49(s,1H),8.99(s,1H),8.71(s,1H), 8.58 (d, J=6.7Hz, 1H), 8.00 (d, J=7.3Hz, 1H), 7.56 (t, J=7.7Hz, 1H), 6.53 (dd, J=16.4, 9.8Hz, 1H), 6.31 (d, J=16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H), 2.47 (s, 3H).MS(ESI),m/z: 280.20[M+H]+。
The preparation of 4 N- of embodiment (the chloro- 5- of 2- (9H- purine -6- base) phenyl) acrylamide (compound II-4)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the chloro- 3- nitrobenzene boronic acid of 4-, Compound 6 is acyl chlorides propylene.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.49(s,1H),8.99(s,2H),8.71(s,1H), 8.63 (d, J=6.7Hz, 1H), 8.10 (d, J=7.3Hz, 1H), 6.53 (dd, J=16.4,9.8Hz, 1H), 6.31 (d, J= 16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H).MS(ESI),m/z:300.20[M+H]+。
The preparation of 5 N- of embodiment (the fluoro- 5- of 2- (9H- purine -6- base) phenyl) acrylamide (compound II-5)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 3- nitrobenzene boronic acid of 4-, Compound 6 is acyl chlorides propylene.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.49(s,1H),8.99(s,2H),8.71(s,1H), 8.61 (d, J=6.7Hz, 1H), 8.04 (d, J=7.3Hz, 1H), 6.53 (dd, J=16.4,9.8Hz, 1H), 6.31 (d, J= 16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H), 2.47 (s, 3H).MS(ESI),m/z:284.20[M+H]+。
The preparation of 6 N- of embodiment (2- methoxyl group -5- (9H- purine -6- base) phenyl) acrylamide (compound II-6)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2- methoxyl group -3- nitrobenzene boron Acid, compound 6 are acyl chlorides propylene.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.49(s,1H),8.99(s,2H),8.71(s,1H), 8.52 (d, J=6.7Hz, 1H), 7.92 (d, J=7.3Hz, 1H), 6.53 (dd, J=16.4,9.8Hz, 1H), 6.31 (d, J= 16.7Hz, 1H), 5.79 (d, J=9.9Hz, 1H), 3.97 (s, 3H).MS(ESI),m/z:296.20[M+H]+。
The preparation of 7 N- of embodiment (the fluoro- 3- of 4- (9H- purine -6- base) phenyl) acrylamide (compound II-7)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 5- nitrobenzene boronic acid of 2-, Compound 6 is acyl chlorides propylene.
MS(ESI),m/z:284.20[M+H]+。
The preparation of 8 N- of embodiment (the fluoro- 3- of 2- (9H- purine -6- base) phenyl) acrylamide (compound II-8)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 3- nitrobenzene boronic acid of 2-, 6 acyl chlorides propylene of compound.
MS(ESI),m/z:284.20[M+H]+。
The preparation of 9 N- of embodiment (the fluoro- 5- of 3- (9H- purine -6- base) phenyl) acrylamide (compound II-9)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 5- nitrobenzene boronic acid of 3-, Compound 6 is acyl chlorides propylene.
MS(ESI),m/z:284.20[M+H]+。
The preparation of 10 N- of embodiment (3- cyano -5- (9H- purine -6- base) phenyl) acrylamide (compound II-10)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3- cyano -5- nitrobenzene boron Acid, compound 6 are acyl chlorides propylene.
MS(ESI),m/z:291.20[M+H]+。
The preparation of 11 N- of embodiment (3- methyl -5- (9H- purine -6- base) phenyl) acrylamide (compound II-11)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3- methyl-5-nitro benzene boron Acid, compound 6 are acyl chlorides propylene.
MS(ESI),m/z:280.20[M+H]+。
The preparation of 12 N- of embodiment (2- cyano -5- (9H- purine -6- base) phenyl) acrylamide (compound II-12)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- cyano -3- nitrobenzene boron Acid, compound 6 are acyl chlorides propylene.
MS(ESI),m/z:291.20[M+H]+。
The system of 13 N- of embodiment (2- mesyl -5- (9H- purine -6- base) phenyl) acrylamide (compound II-13) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- methylsulphur base -3- nitrobenzene boron Acid, compound 6 are acyl chlorides propylene.
MS(ESI),m/z:344.20[M+H]+。
14 N- of embodiment (2- dimethylamino methyl -5- (9H- purine -6- base) phenyl) acrylamide (compound II-14) Preparation
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- dimethylamino methyl -3- nitre Base phenyl boric acid, compound 6 are acyl chlorides propylene.
MS(ESI),m/z:323.20[M+H]+。
The preparation of 15 N- of embodiment (3- (9H- purine -6- base) phenyl -2- base) fluoropropene amide (compound II-15)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is p-nitrophenyl boric acid, compound 6 be 2- fluorine acyl chlorides propylene.
MS(ESI),m/z:284.20[M+H]+。
The system of the fluoro- N- of 16 2- of embodiment (2 fluoro- 5- (9H- purine -6- base) phenyl) fluoropropene amide (compound II-16) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 3- nitrobenzene boronic acid of 4-, Compound 6 is 2- fluorine acyl chlorides propylene.
The preparation of 17 N- of embodiment (3- (9H- purine -6- base) phenyl -2- base) chloroacrylamide (compound II-17)
Preparation method is identical as compound II-1.
MS(ESI),m/z:302.20[M+H]+。
The preparation of 18 N- of embodiment (3- (9H- purine -6- base) phenyl -2- base) bromopropene amide (compound II-18)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3- nitrobenzene boronic acid, compound 6 be 2- bromopropene acyl chlorides.
MS(ESI),m/z:344.20[M+H]+。
The preparation of 19 N- of embodiment (5- (9H- purine -6- base) pyridin-3-yl) acrylamide (compound II-19)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 5- nitro -3- pyridine boronic acid, Compound 6 is acryloyl chloride.
MS(ESI),m/z:267.20[M+H]+。
The preparation of 20 N- of embodiment (4- (9H- purine -6- base) pyridine -2- base) acrylamide (compound II-20)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2- nitro -4- pyridine boronic acid, Compound 6 is acryloyl chloride.
MS(ESI),m/z:267.20[M+H]+。
The preparation of 21 N- of embodiment (3- (9H- purine -6- base) phenyl) Methacrylamide (compound II-21)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is m-nitro boric acid, and raw material 6 is Methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),9.01(s,1H),8.99(s,1H), 8.72 (s, 1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s,1H),5.56(s,1H),1.99(s,3H)。MS(ESI),m/z:280.20[M+H]+。
The system of 22 N- of embodiment (2- methyl 5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-22) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4- methyl-3-nitro phenyl boric acid, Raw material 6 is methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),9.01(s,1H),8.99(s,1H), 8.72 (s, 1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s,1H),5.56(s,1H),2.21(s,3H),1.99(s,3H)。MS(ESI),m/z:280.20[M+H]+。
23 N- of embodiment (2- methyl -3- (9H- purine -6- base) phenyl) Methacrylamide
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 2- methyl-3-nitro phenyl boric acid, Raw material 6 is methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),8.99(s,1H),8.72(s,1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s, 1H), 5.56 (s,1H),2.47(s,3H),1.99(s,3H)。MS(ESI),m/z:294.20[M+H]+。
The preparation of 24 N- of embodiment (the chloro- 5- of 2- (9H- purine -6- base) phenyl) Methacrylamide (compound II-24)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is the chloro- 3- nitrobenzene boronic acid of 4-, former Material 6 is methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),9.01(s,1H),8.99(s,1H), 8.72 (s, 1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s,1H),5.56(s,1H),2.21(s,3H),1.99(s,3H)。MS(ESI),m/z:314.20[M+H]+。
The preparation of 25 N- of embodiment (the fluoro- 5- of 2- (9H- purine -6- base) phenyl) Methacrylamide (compound II-25)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is the fluoro- 3- nitrobenzene boronic acid of 4-, former Material 6 is methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),9.01(s,1H),8.99(s,1H), 8.72 (s, 1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s,1H),5.56(s,1H),2.21(s,3H),1.99(s,3H)。MS(ESI),m/z:298.20[M+H]+。
26 N- of embodiment (2- methoxyl group -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-26) Preparation
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4- methoxyl group -3- nitrobenzene boron Acid, raw material 6 are methacrylic chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.07(s,1H),9.01(s,1H),8.99(s,1H), 8.72 (s, 1H), 8.59 (d, J=7.6Hz, 1H), 7.92 (d, J=8.0Hz, 1H), 7.55 (t, J=7.9Hz, 1H), 5.90 (s,1H),5.56(s,1H),3.97(s,3H),1.99(s,3H)。MS(ESI),m/z:310.20[M+H]+。
The preparation of 27 N- of embodiment (the fluoro- 3- of 4- (9H- purine -6- base) phenyl) Methacrylamide (compound II-27)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 5- nitrobenzene boronic acid of 2-, Compound 6 is methacrylic chloride.
MS(ESI),m/z:298.20[M+H]+。
The preparation of 28 N- of embodiment (the fluoro- 3- of 2- (9H- purine -6- base) phenyl) Methacrylamide (compound II-28)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 3- nitrobenzene boronic acid of 2-, Compound 6 is methacrylic chloride.
MS(ESI),m/z:298.20[M+H]+。
The preparation of 29 N- of embodiment (the fluoro- 5- of 3- (9H- purine -6- base) phenyl) Methacrylamide (compound II-29)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is the fluoro- 5- nitrobenzene boronic acid of 3-, Compound 6 is methacrylic chloride.
MS(ESI),m/z:305.20[M+H]+。
The system of 30 N- of embodiment (3- cyano -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-30) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3- cyano -5- nitrobenzene boron Acid, compound 6 are methacrylic chloride.
MS(ESI),m/z:298.20[M+H]+。
The system of 31 N- of embodiment (2- cyano -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-31) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- cyano -3- nitrobenzene boron Acid, compound 6 are methacrylic chloride.
MS(ESI),m/z:305.20[M+H]+。
The system of 32 N- of embodiment (3- methyl -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-32) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3- methyl-5-nitro benzene boron Acid, compound 6 are methacrylic chloride.
MS(ESI),m/z:294.20[M+H]+。
33 N- of embodiment (2- mesyl -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-33) Preparation
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- methylsulphur base -3- nitrobenzene boron Acid, compound 6 are methacrylic chloride.
MS(ESI),m/z:358.20[M+H]+。
34 N- of embodiment (2- dimethylamino methyl -5- (9H- purine -6- base) phenyl) Methacrylamide (compound II-34 preparation)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4- dimethylamino methyl -3- nitre Base phenyl boric acid, compound 6 are methacrylic chloride.
MS(ESI),m/z:337.20[M+H]+。
The preparation of 35 N- of embodiment (5- (9H- purine -6- base) pyridin-3-yl) Methacrylamide (compound II-35)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 5- nitro -3- pyridine boronic acid, Compound 6 is methacrylic chloride.
MS(ESI),m/z:281.20[M+H]+。
The preparation of 36 N- of embodiment (4- (9H- purine -6- base) pyridine -2- base) Methacrylamide (compound II-36)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2- nitro -4- pyridine boronic acid, Compound 6 is methacrylic chloride.
MS(ESI),m/z:281.20[M+H]+。
The preparation of 37 N- of embodiment (3- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-37)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is m-nitro boric acid, and raw material 6 is Chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,2H),8.67(s,1H), 8.63 (d, J=7.6Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 4.31 (s, 2H).MS (ESI),m/z:288.20[M+H]+。
The preparation of 38 N- of embodiment (2- methyl 5- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-38)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4- methyl-3-nitro phenyl boric acid, Raw material 6 is chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,2H),8.67(s,1H), 8.63 (d, J=7.6Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 4.31 (s, 2H), 2.21 (s, 3H).MS(ESI),m/z: 288.20[M+H]+。
The system of 39 N- of embodiment (2- methyl -3- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-39) It is standby
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 2- methyl-3-nitro phenyl boric acid, Raw material 6 is chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,1H),8.67(s,1H), 8.63 (d, J=7.6Hz, 1H), 7.89 (d, J=8.1Hz, 1H), 7.56 (t, J=8.0Hz, 1H), 4.31 (s, 2H), 2.47 (s,3H)。MS(ESI),m/z:288.20[M+H]+。
The preparation of 40 N- of embodiment (the chloro- 5- of 2- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-40)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is the chloro- 3- nitrobenzene boronic acid of 4-, former Material 6 is chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,2H),8.67(s,1H), 8.61 (d, J=7.6Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 4.31 (s, 2H), 2.21 (s, 3H).MS(ESI),m/z: 322.20[M+H]+。
The preparation of 41 N- of embodiment (the fluoro- 5- of 2- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-41)
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is the chloro- 3- nitrobenzene boronic acid of 4-, former Material 6 is chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,2H),8.67(s,1H), 8.62 (d, J=7.6Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 4.31 (s, 2H), 2.21 (s, 3H).MS(ESI),m/z: 306.20[M+H]+。
42 N- of embodiment (2- methoxyl group -5- (9H- purine -6- base) phenyl) -2- chloroacetamide (compound II-42) Preparation
Preparation method is identical as compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is the chloro- 3- nitrobenzene boronic acid of 4-, former Material 6 is chloracetyl chloride.
1H NMR(400MHz,DMSO-d6)δ:13.66(s,1H),10.57(s,1H),8.97(s,2H),8.67(s,1H), 8.61 (d, J=7.6Hz, 1H), 7.86 (d, J=8.1Hz, 1H), 4.31 (s, 2H), 3.97 (s, 3H).MS(ESI),m/z: 318.20[M+H]+。
The preparation of 43 compound II-43~II-52 of embodiment
Preparation method is identical as compound II-1, using corresponding raw material, compound II-43~II-52 is prepared, sees Shown in table 2.
2 compound II-43~II-52 of table
The preparation of 44 compound III-1~III-15 of embodiment
Preparation method is identical as compound II-1, and using corresponding raw material, compound III-1~III-15 is prepared, It is shown in Table 3.
3 compound III-1~III-15 of table
The preparation of 44 compound IV-1~IV-15 of embodiment
Preparation method is identical as compound II-1, using corresponding raw material, compound IV-1~IV-15 is prepared, sees Shown in table 4.
4 compound IV-1~IV-15 of table
The preparation of 45 compound V-1~V-15 of embodiment
Preparation method is identical as compound II-1, and compound V-1~V-15 is prepared using corresponding raw material, is shown in Table 4 It is shown.
5 compound V-1~V-15 of table
The preparation of 46 compound VI-1~VI-15 of embodiment
Preparation method is identical as compound II-1, using corresponding raw material, compound VI-1~VI-15 is prepared, sees Shown in table 4.
6 compound VI-1~VI-15 of table
The preparation of 47 compound VII-1~VII-15 of embodiment
Preparation method is identical as compound II-1, and using corresponding raw material, compound VII-1~VII-15 is prepared, It is shown in Table 4.
7 compound VII-1~VII-15 of table
The experiment of 48 Pharmacological Activity Screening of embodiment
Material: JAK1, JAK2, JAK3 and TYK2 kinases (are purchased from Carna company)；Polypeptide FAM-P22 and polypeptide FAM-P30 (being purchased from GL Biochem company)；ATP (atriphos), DMSO (dimethyl sulfoxide) and EDTA (ethylenediamine tetra-acetic acid) (purchase From Sigma company)；96 orifice plates (are purchased from Corning company), and positive control Staurosporine (is purchased from Sigma company).
Wherein, the structural formula of Staurosporine (staurosporin) are as follows:
Method:
1, the alkali buffer and stop buffer of 1x kinases are equipped with.
1) the 1x kinases alkali buffer of JAK1 and JAK3 includes 50mM HEPES (4- hydroxyethyl piperazineethanesulfonic acid), Ph 7.5；0.0015%Brij-35 (Bu Lijie 35)；10mM MgCl2；2mM DTT (dithiothreitol dithio).
2) the 1x kinases alkali buffer of JAK2 and TYK2 includes 25mM HEPES, Ph 7.5；0.001%Brij-35； 0.01%Triton (2,4,6- trinitrotoluene)；0.5mM EGTA (bis- (the 2- amino-ethyl ether) tetraacethyls of ethylene glycol)；10mM MgCl2；2mM DTT.
3) stop buffer includes 100mM HEPES, Ph 7.5；0.015%Brij-35；0.2%Coating Reagent (applying membrane reagent) #3；50mM EDTA.
2, the preparation of compound.
1) test-compound is configured to 50 times of highest test concentrations with 100% DMSO.It is dilute to shift 100 μ L compounds It releases in liquid to orifice plate.
2) in 100%DMSO to 2 holes for increasing by 100 μ L, and the plate is denoted as original plate.10 μ L are shifted from original plate Compound is to one piece of 96 new orifice plate and is denoted as intermediate plate, and the 1x kinases alkali buffering of 90 μ L is added into each hole of intermediate plate Liquid, and plank, which is placed on shaking table, is uniformly mixed compound solution with 1x kinases alkali buffer.5 μ L are respectively taken from intermediate plate again Multiple holes are formed on mixture to 384 orifice plates, and the plate is denoted as detection plate.
3, enzyme reaction.
1) 2.5x enzyme solutions are equipped with, kinases is added in the kinases alkali buffer of 1x.
2) it is equipped with 2.5x polypeptide buffer, FAM- tag polypeptide and ATP are added in the kinases alkali buffer of 1x.
3) transfer 2.5x enzyme solutions are into detection plate.Compound of each hole of detection plate equipped with 5 μ L comprising 10%DMSO Solution adds the 2.5x enzyme solutions of 10 μ L, in 25 DEG C of incubation 10min.
4) 2.5x polypeptide solution is added into each hole of detection plate, the end of 25 μ L is added after being incubated for suitable duration in 28 DEG C Only buffer is to terminate enzyme reaction.
4, the initial data in every hole is read and recorded, and initial data is converted accordingly.
1) inhibiting rate=(maximum value-compound conversion value)/(maximum value-minimum value) * 100, wherein maximum value DMSO Control group data, minimum value are the blank value that enzyme is not added.
2) calculation of half inhibitory concentration IC50Value, with log [administration concentration] for abscissa, inhibiting rate is ordinate, A dose-effect curve is fitted in Graphpad Prism 5, obtains drug concentration when its 50% inhibiting rate, i.e., thus IC of the compound on Kinase levels50Value.
Table 8 provides average IC of the compounds of this invention about JAK1, JAK2, JAK3 and TYK250Range, wherein " A " table Show IC50Value is less than 10nM, and " B " indicates IC50For value between 10nM and 100nM, " C " indicates IC50Value 100nM and 1000nM it Between, " D " indicates IC50Value is greater than 1000nM.
Average IC of 8 the compounds of this invention of table about JAK1, JAK2, JAK3 and TYK250Range
N- substituted-phenyl amide derivatives provided by the invention, inhibit JAK3 to the property of can choose, associated to treat Disease, such as rheumatoid arthritis, asthma, Chronic Obstructive Pulmonary Disease and tumour provide new selection.

Claims (17)

1.N- substituted-phenyl amide derivatives, structure is as shown in formula I:
Wherein, X1~X3、Y1~Y4Stand alone as C or N, X1、X2It is not simultaneously C；R1For-H, C1~C8Alkyl, halogen ,-CN, C1~C8 Alkoxy,R2For-H or C1~C8Alkyl；R3For C2~C8Alkenyl or halogen；R4~R6Stand alone as-H or C1 ~C8Alkyl.
2. N- substituted-phenyl amide derivatives according to claim 1, it is characterised in that:
X1~X3、Y1~Y4Stand alone as C or N, X1、X2It is not simultaneously C；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alcoxyl Base,R2For-H or C1~C4Alkyl；R3For C2~C4Alkenyl or halogen；R4~R6Stand alone as-H or C1~C4 Alkyl.
3. N- substituted-phenyl amide derivatives according to claim 2, it is characterised in that:
X1~X3、Y1~Y4Stand alone as C or N, X1、X2It is not simultaneously C；R1For-H, methyl ,-F ,-Cl ,-CN, methoxyl group, dimethyl Amino orR2For-H or methyl；R3For vinyl ,-Cl or-Br.
4. N- substituted-phenyl amide derivatives according to claim 1, it is characterised in that: work as X1And X3For N, X2For C, Y3With Y4When for C, structure is as shown in formula II:
Wherein, Y1、Y2Stand alone as C or N；
R1For-H, C1~C8Alkyl, halogen ,-CN, C1~C8Alkoxy,
R2For-H or C1~C8Alkyl；R3For C2~C8Alkenyl or halogen；
R4~R6Stand alone as-H or C1~C8Alkyl.
5. N- substituted-phenyl amide derivatives according to claim 4, it is characterised in that:
Y1、Y2Stand alone as C or N；R1For-H, C1~C4Alkyl, halogen ,-CN, C1~C4Alkoxy,R2For- H or C1~C4Alkyl；R3For C2~C4Alkenyl or halogen；R4~R6Stand alone as-H or C1~C4Alkyl.
6. N- substituted-phenyl amide derivatives according to claim 5, it is characterised in that: Y1、Y2Stand alone as C or N；R1For- H, methyl ,-F ,-Cl ,-CN, methoxyl group, dimethylamino orR2For-H or methyl；R3For vinyl ,-Cl or-Br.
7. N- substituted-phenyl amide derivatives according to claim 1, it is characterised in that: work as X1For C, X2And X3For N, Y1~ Y4When for C, structure is as shown in formula V:
Wherein, R1For halogen；R2For-H；R3For C2~C8Alkenyl or halogen.
8. N- substituted-phenyl amide derivatives according to claim 7, it is characterised in that: R1For halogen；R2For-H；R3For C2 ~C4Alkenyl or halogen.
9. N- substituted-phenyl amide derivatives according to claim 8, it is characterised in that: R1For-F or-Cl；R2For-H；R3 For vinyl ,-Cl or-Br.
10. N- substituted-phenyl amide derivatives according to claim 1, it is characterised in that: work as X1For N, X2And X3For C, Y1 ~Y4When for C, structure is as shown in formula VI:
Wherein, R1For-H or halogen；R2For-H or C1~C8Alkyl；R3For C2~C8Alkenyl or halogen.
11. N- substituted-phenyl amide derivatives according to claim 10, it is characterised in that: R1For-H or halogen；R2For-H Or C1~C4Alkyl；R3For C2~C4Alkenyl or halogen.
12. N- substituted-phenyl amide derivatives according to claim 11, it is characterised in that: R1For-H ,-F or-Cl；R2 For-H or methyl；R3For vinyl ,-Cl or-Br.
13.N- substituted-phenyl amide derivatives, structural formula are as follows:
14. the described in any item N- substituted-phenyl amide derivatives pharmaceutically acceptable salts of claim 1~13.
15. a kind of pharmaceutical composition is by the described in any item N- substituted-phenyl amide derivatives of claim 1~13 or right It is required that salt described in 14 adds what the pharmaceutically complementary ingredient of acceptable was prepared.
16. salt described in the described in any item N- substituted-phenyl amide derivatives of claim 1~13 or claim 14 is being made Purposes in standby JAK3 inhibitor.
17. salt described in the described in any item N- substituted-phenyl amide derivatives of claim 1~13 or claim 14 is being made Purposes in standby treatment rheumatoid arthritis, asthma, Chronic Obstructive Pulmonary Disease or tumour medicine.
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