CN105837572A

CN105837572A - N-substituted phenylacrylamide derivative and its preparation method and purpose

Info

Publication number: CN105837572A
Application number: CN201610051840.XA
Authority: CN
Inventors: 陈俐娟; 魏于全
Original assignee: Sichuan University
Current assignee: Chengdu zeiling Biomedical Technology Co.,Ltd.
Priority date: 2015-02-02
Filing date: 2016-01-26
Publication date: 2016-08-10
Anticipated expiration: 2036-01-26
Also published as: CN105837572B

Abstract

The invention relates to the field of chemical medicines and concretely relates to an N-substituted phenylacrylamide derivative and its preparation method and use. The invention provides the N-substituted phenylacrylamide derivative. The N-substituted phenylacrylamide derivative has a structure shown in the formula I. The invention also provides a preparation method and a use of the N-substituted phenylacrylamide derivative. The N-substituted phenylacrylamide derivative can selectively inhibit JAK3 and provide a novel choice for treating JAK3-related diseases such as rheumatoid arthritis, asthma, chronic obstructive pulmonary diseases and tumors.

Description

N-substituted-phenyl acrylamide derivative and its production and use

Technical field

The invention belongs to chemical medicine, be specifically related to N-substituted-phenyl acrylamide derivative and preparation method thereof and Purposes.

Background technology

Protein kinase is made up of enzyme relevant in a series of structures, the main control being responsible for intracellular signal transduction process. Generally, protein kinase is shifted from ribonucleoside triphosphote to the phosphoryl of the protein receptor participating in signal transduction path by impact, and Mediate intracellular signal.These phosphorylation events play modulation or the molecular switch effect of regulation target protein biological function.A lot Disease is all relevant with the abnormal cell reaction caused by above-mentioned protein kinase mediated event.

Janus Kinase (JAK), including JAK1, JAK2, JAK3 and TYK2, belongs to cytoplasm protein kinases, with I type and II cytokines receptor acting, regulates cytokine signaling.JAK1, JAK2 and TYK2 can suppress several genes table Reach, but JAK3 only plays a role in granulocyte.The exemplary functions of cytokine receptor is to exist as heterodimer form, Therefore a kind of IAK kinases and cytokine receptor effect it are frequently not.

The stream substrates of JAK family includes signal transduction agent and the activator (STAT) of transcription factor.JAK/STAT signal Transduction relates to the reaction of a lot of abnormal immune, such as allergy, asthma, autoimmune disease such as transplant rejection, rheumatoid arthritis, flesh Meat contracting lateral sclerosis and multiple sclerosis and entity and hematologic malignancies such as leukemia, lymphoma.

JAK3 is specific acts on gamma cells factor acceptor chain, and it is at IL-2, IL-4, IL-7, IL-9, IL-15, IL- 21 cytokine receptor such as grade exist.JAK3, in lymphocyte growth, hypertrophy, plays an important role in mutation process, occurs different Often can cause serious immune deficiency.Effect based on its regulation lymphocyte, the path of JAK3 and JAK3 mediation is used for Regulation immunosuppressant indication.JAK3 implication in the mediation of a lot of abnormal immune responses, such as allergy, asthma, from Body immunological diseases such as suppress transplant rejection, rheumatoid arthritis, muscle contracting lateral sclerosis and multiple sclerosis and entity and Hematologic malignancies such as leukemia, lymphoma.

In sum, in the urgent need to developing the compound that can be used for kinases inhibitor, specifically, exploitation is needed The compound of high selective JAK 3 restrainer.

Summary of the invention

The invention provides a kind of N-substituted-phenyl acrylamide derivative, its 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～C₈Alkoxyl,Or-CON (CH₃)₂；

R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynes Base,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；

R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynes Base, C₃～C₈Cycloalkyl 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～C₈Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkane Epoxide, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,- O(C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂~ C₈Thiazolinyl, C₂～C₈Alkynyl, C₃～C₈Cycloalkyl 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～C₄Alkoxyl, C₁～C₄Halo Alkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl, C₃～C₆Cycloalkyl or halogen.

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,X₁ ～X₃、Y₁～Y₄Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄ Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄ ～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆ Cycloalkyl or halogen.

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl ,-CN, C₁～C₄Alkoxyl,X₁～X₃、Y₁～Y₄Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁ ～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁~ C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂ ～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁ ～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Alkyl halide Base, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl Or halogen；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；X₁～X₃、Y₁～Y₄Solely Stand as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as- H、C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen Element.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；X₁～X₃、Y₁~ Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Independent For-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or Halogen.

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl or C₃～C₆Cycloalkanes Base；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen Element.

It is further preferred that R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；X₁~ X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、 R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

Further preferred, R₄～R₆Stand alone as-H or C₁～C₄Alkyl；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For- H、C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁~ C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

Preferably, X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₄～R₆Stand alone as-H or C₁～C₄ Alkyl.

Optimum, X₁～X₃、Y₁～Y₄Stand 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 acrylamide derivative, works as X₁And X₃For N, X₂For C, Y₃And Y₄During for C, its structure such as formula II Shown in:

Wherein, Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₈Alkyl, halogen ,-CN ,-OH, C₁～C₈Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Alkyl halide Base, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or Halogen；R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl, C₃～C₈Cycloalkyl or halogen.

Preferably, Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN ,-OH, C₁～C₄Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen Element；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃ ～C₆Cycloalkyl or halogen.

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, Y₁、Y₂Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Solely Stand as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl Or halogen.

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl ,-CN, C₁～C₄Alkoxyl,Y₁、Y₂Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Halo Alkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl, C₃～C₆Cycloalkyl or halogen.

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂ ～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkane Epoxide,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂~ C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl Or halogen；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆ Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄ Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；Y₁、Y₂Stand alone as C Or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl or C₃～C₆Cycloalkanes Base；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃ Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

It is further preferred that R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；Y₁、 Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Independent For-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

Further preferred, R₄～R₆Stand alone as-H or C₁～C₄Alkyl；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄ Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alcoxyl Base, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

Preferably, Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₄～R₆Stand alone as-H or C₁～C₄Alkyl.

Optimum, 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 acrylamide derivative, works as X₁And X₂For C, X₃For N, Y₁～Y₄During for C, its structure such as formula III Shown in:

Wherein, R₁For-H, C₁～C₈Alkyl, halogen ,-CN ,-OH, C₁～C₈Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁~ C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl, C₃～C₈Cycloalkyl or halogen.

Preferably, R₁For-H, C₁～C₄Alkyl, halogen ,-CN ,-OH, C₁～C₄Alkoxyl,Or- CON(CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynes Base,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen, C₁～C₄Alkoxyl,R₂、R₃ Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl or C₁～C₄Alkoxyl；R₂、R₃Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、 C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen.

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂ ～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl Or halogen；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁ ～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₁For-H, C₁～C₄Alkane Base, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；R₁For-H, C₁~ C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkane Epoxide, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；R₁For-H, C₁ ～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkane Epoxide, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen.

It is further preferred that R₄～R₆Stand alone as-H or C₁～C₄Alkyl；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁~ C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl or halogen.

Preferably, R₁For-H, C₁～C₄Alkyl, halogen or C₁～C₄Alkoxyl；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂ ～C₄Thiazolinyl or halogen.

Optimum, R₁For-H, methyl ,-F ,-Cl or methoxyl group；R₂、R₃Stand alone as-H, methyl, vinyl ,-Cl or-Br.

Above-mentioned N-substituted-phenyl acrylamide derivative, works as X₁～X₃For C, Y₁～Y₄During for C, its structure is as shown in formula IV:

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂ ～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Above-mentioned N-substituted-phenyl acrylamide derivative, works as X₁For C, X₂And X₃For N, Y₁～Y₄During for C, its structure such as formula V Shown in:

Above-mentioned N-substituted-phenyl acrylamide derivative, works as X₁For N, X₂And X₃For C, Y₁～Y₄During for C, its structure such as formula VI Shown in:

Above-mentioned N-substituted-phenyl acrylamide derivative, works as X₁And X₃For C, X₂For N, Y₁～Y₄During for C, its structure such as formula VII Shown in:

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen, C₁～C₄Alkoxyl,R₂、R₃Solely Stand as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；R₁For-H, C₁~ C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alcoxyl Base, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen.

Above-mentioned N-substituted-phenyl acrylamide derivative, its structural formula is:

Present invention also offers the preparation method of above-mentioned N-substituted-phenyl acrylamide derivative, synthetic route is:

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～C₈Alkoxyl, C₁～C₈Alkyl halide Base, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃ Or halogen；R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynes Base, C₃～C₈Cycloalkyl or halogen.

Raw materials used or reagent english abbreviation the Chinese implication of the present invention is shown in Table 1.

Table 1 raw material or the Chinese implication of reagent english abbreviation

The preparation method of above-mentioned N-substituted-phenyl acrylamide derivative, operating procedure is:

A, raw material 1 and p-methyl benzenesulfonic acid are stirred at room temperature in EtOAc, drip 3,4-dihydro-2H-pyrans, will reaction Liquid is heated to reflux about 2h；Question response liquid is close to clear state, and filtered while hot removes part material 1, by filtrate water, saturated common salt Water washs respectively, collects oil reservoir, anhydrous Na₂SO₄It is dried oil reservoir, removes solvent and obtain intermediate 2；Described raw material 1, to methylbenzene Sulfonic acid, the mol ratio of 3,4-dihydro-2H-pyrans are 1 0.02 2；

B, by intermediate 2, compound 3, Pd (PPh₃)₄Or PdCl₂And K (dppf)₂CO₃, at 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 kieselguhr, Collecting filtrate, rotation steaming is spin-dried for filtrate, extracts filtrate with EtOAc and water, collects oil reservoir, then washs oil reservoir 3 times with saturated aqueous common salt, Anhydrous Na₂SO₄Being dried oil reservoir, oil reservoir is purified with column chromatography after removing solvent, obtains intermediate 4；Described intermediate 2, compound 3, Pd(PPh₃)₄Or PdCl₂(dppf)、K₂CO₃Mol ratio be 1 1.1 0.05 3；

C, by intermediate 4,10%Pd/C (the 0.5% of intermediate 2 mass) and HOOCNH₄, it was heated to reflux in MeOH Night；It is filtered to remove reducing agent Pd/C with kieselguhr, is spin-dried for filtrate and obtains solid, wash solid with water and filter, collect solid and be Intermediate 5；Described intermediate 4, HOOCNH₄Mol ratio be 13；

D, it is stirred at room temperature by compound 6 with except water DCM, sequentially adds PyBOP and DIEA, after reaction 30min, then Adding intermediate 5, room temperature reaction is overnight.It is spin-dried for reactant liquor, extracts filtrate with EtOAc and water, collect oil reservoir, then use saturated common salt Water washing oil reservoir 3 times, anhydrous Na₂SO₄Being dried oil reservoir, oil reservoir is purified with column chromatography after removing solvent, obtains intermediate 7；Describedization Compound 6, PyBOP, DIEA, the mol ratio of intermediate 5 are 1131；

Under e, room temperature in the MeOH solution of intermediate 7, drip a little HCl solution, be then heated to reflux about 1h, TLC prison It is complete that survey raw material takes off THP, is spin-dried for reactant liquor, washs solid with PE and filters, obtaining type I compound.

Present invention also offers above-mentioned N-substituted-phenyl acrylamide derivative pharmaceutically acceptable salt.Wherein become with acid Salt refers to, is obtained by the free alkali of parent compound and mineral acid or the reaction of organic acid.Mineral acid includes hydrochloric acid, hydrogen bromine Acid, nitric acid, phosphoric acid, Metaphosphoric acid, sulphuric acid, sulfurous acid and perchloric acid etc..Organic acid includes acetic acid, propanoic acid, acrylic acid, oxalic acid, (D) Or (L) malic acid, fumaric acid, maleic acid, hydroxy benzoic acid, gamma-hydroxybutyric acid, methoxybenzoic acid, phthalic acid, first sulphur Acid, ethyl sulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-methyl benzenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, amber Amber acid or malonic acid etc..

Present invention also offers the above-mentioned N-pharmaceutically acceptable hydrate of substituted-phenyl acrylamide derivative.

A kind of pharmaceutical composition, is by the N-substituted-phenyl acrylamide derivative shown in formula I～VII and salt thereof or hydration Thing adds what the complementary composition of pharmaceutically acceptable was prepared from.

Present invention also offers above-mentioned N-substituted-phenyl acrylamide derivative and salt thereof or hydrate to press down at preparation JAK3 Purposes in preparation.

Present invention also offers above-mentioned N-substituted-phenyl acrylamide derivative and salt thereof or hydrate in preparation treatment class Purposes in rheumatic arthritis, asthma, chronic obstructive pulmonary disease or tumour medicine.

The N-substituted-phenyl acrylamide derivative that the present invention provides, can optionally suppress JAK3, for treatment therewith Relevant disease, provides new selection such as rheumatoid arthritis, asthma, chronic obstructive pulmonary disease and tumor etc..

Detailed description of the invention

The preparation method of N-substituted-phenyl acrylamide derivative, synthetic route is:

The preparation of embodiment 1 N-(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 Mix, drip 3,4-dihydro-2H-pyrans (8.4g, 100mmol), reactant liquor is heated to reflux about 2h；Question response liquid is close to clarification shape State, filtered while hot removes part material 1, filtrate water, saturated aqueous common salt is washed respectively, collects oil reservoir, anhydrous Na₂SO₄It is dried 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 chloro-for 6-9-(tetrahydro-2H-2-pyrans-2-base)-9H-purine (intermediate 2,2.38g, 10mmol), to nitre Base phenylboric acid (3,1.84g, 11mmol), Pd (PPh₃)₄(578mg, 0.5mmol) or PdCl₂(dppf) (366mg, 0.5mmol) And K₂CO₃(4.14g, 30mmol), at N₂Under protection, in PhMe/EtOH (7/3, v/v, 35ml/15ml) and H₂O (15ml) adds Hot reflux overnight；Being filtered to remove insoluble matter with kieselguhr, collect filtrate, rotation steaming is spin-dried for filtrate, extracts filter with EtOAc and water Liquid, collects oil reservoir, then washs oil reservoir 3 times with saturated aqueous common salt, anhydrous Na₂SO₄Being dried oil reservoir, oil reservoir uses post layer after removing solvent Analysis purification, 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), heated overnight at reflux in MeOH；It is filtered to remove with kieselguhr Reducing agent Pd/C, is spin-dried for filtrate and obtains solid, washes solid with water and filters, and collects solid and 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, 0.4mmol) and except water DMF it is stirred at room temperature, adds DIEA (155mg, 1.2mmol), after reaction 30min, add propylene Acyl chlorides (6,36.2mg, 0.4mmol), room temperature reaction is overnight.Extract filtrate with EtOAc and water, collect oil reservoir, then use saturated common salt Water washing oil reservoir 3 times, anhydrous Na₂SO₄Being dried oil reservoir, oil reservoir is purified with column chromatography after removing solvent, obtains N-(3-(9-(tetrahydrochysene Change-2H-pyrans-2-base)-9H-purine-6-base) phenyl) acrylamide (intermediate 7,85mg)；

Under e, room temperature to N-(3-(9-(tetrahydro-2H-pyrans-2-base)-9H-purine-6-base) phenyl) acrylamide (in Mesosome 7,85mg) MeOH solution in, drip a little HCl solution, being then heated to reflux about 1h, TLC monitoring raw material, to take off THP complete Finish, be spin-dried for reactant liquor, wash solid with PE and filter, obtaining 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 embodiment 2 N-(2-methyl 5-(9H-purine-6-base) phenyl) acrylamide (compound II-2)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-methyl-3-nitro benzene boron Acid, 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), 8.53 (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 embodiment 3 N-(2-methyl-3-(9H-purine-6-base) phenyl) acrylamide (compound II-3)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-methyl-3-nitro benzene boron Acid, compound 6 is 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 embodiment 4N-(the chloro-5-of 2-(9H-purine-6-base) phenyl) acrylamide (compound II-4)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-chloro-3-nitrobenzene boronic acid, 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 embodiment 5 N-(the fluoro-5-of 2-(9H-purine-6-base) phenyl) acrylamide (compound II-5)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-fluoro-3-nitrobenzene boronic acid, 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 embodiment 6 N-(2-methoxyl group-5-(9H-purine-6-base) phenyl) acrylamide (compound II-6)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-methoxyl group-3-Nitrobenzol boron Acid, 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), 8.52 (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 embodiment 7 N-(the fluoro-3-of 4-(9H-purine-6-base) phenyl) acrylamide (compound II-7)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-fluoro-5-nitrobenzene boronic acid, Compound 6 is acyl chlorides propylene.

MS(ESI),m/z:284.20[M+H]⁺。

The preparation of embodiment 8 N-(the fluoro-3-of 2-(9H-purine-6-base) phenyl) acrylamide (compound II-8)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-fluoro-3-nitrobenzene boronic acid, Compound 6 acyl chlorides propylene.

MS(ESI),m/z:284.20[M+H]⁺。

The preparation of embodiment 9 N-(the fluoro-5-of 3-(9H-purine-6-base) phenyl) acrylamide (compound II-9)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-fluoro-5-nitrobenzene boronic acid, Compound 6 is acyl chlorides propylene.

MS(ESI),m/z:284.20[M+H]⁺。

The preparation of embodiment 10 N-(3-cyano group-5-(9H-purine-6-base) phenyl) acrylamide (compound II-10)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-cyano group-5-Nitrobenzol boron Acid, compound 6 is acyl chlorides propylene.

MS(ESI),m/z:291.20[M+H]⁺。

The preparation of embodiment 11 N-(3-methyl-5-(9H-purine-6-base) phenyl) acrylamide (compound II-11)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-methyl-5-nitro benzene boron Acid, compound 6 is acyl chlorides propylene.

MS(ESI),m/z:280.20[M+H]⁺。

The preparation of embodiment 12 N-(2-cyano group-5-(9H-purine-6-base) phenyl) acrylamide (compound II-12)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-cyano group-3-Nitrobenzol boron Acid, compound 6 is acyl chlorides propylene.

MS(ESI),m/z:291.20[M+H]⁺。

The system of embodiment 13 N-(2-mesyl-5-(9H-purine-6-base) phenyl) acrylamide (compound II-13) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-first sulfo group-3-Nitrobenzol boron Acid, compound 6 is acyl chlorides propylene.

MS(ESI),m/z:344.20[M+H]⁺。

Embodiment 14 N-(2-dimethylamino methyl-5-(9H-purine-6-base) phenyl) acrylamide (compound II-14) Preparation

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-dimethylamino methyl-3-nitre Base phenylboric acid, compound 6 is acyl chlorides propylene.

MS(ESI),m/z:323.20[M+H]⁺。

The preparation of embodiment 15 N-(3-(9H-purine-6-base) phenyl-2-base) fluoropropene amide (compound II-15)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is p-nitrophenyl boric acid, compound 6 is 2-fluorine acyl chlorides propylene.

MS(ESI),m/z:284.20[M+H]⁺。

The system of the fluoro-N-of embodiment 16 2-(2 fluoro-5-(9H-purine-6-base) phenyl) fluoropropene amide (compound II-16) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-fluoro-3-nitrobenzene boronic acid, Compound 6 is 2-fluorine acyl chlorides propylene.

The preparation of embodiment 17 N-(3-(9H-purine-6-base) phenyl-2-base) chloroacrylamide (compound II-17)

Preparation method is identical with compound II-1.

MS(ESI),m/z:302.20[M+H]⁺。

The preparation of embodiment 18 N-(3-(9H-purine-6-base) phenyl-2-base) bromopropene amide (compound II-18)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-nitrobenzene boronic acid, compound 6 is 2-bromopropene acyl chlorides.

MS(ESI),m/z:344.20[M+H]⁺。

The preparation of embodiment 19 N-(5-(9H-purine-6-base) pyridin-3-yl) acrylamide (compound II-19)

Preparation method is identical with 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 embodiment 20 N-(4-(9H-purine-6-base) pyridine-2-base) acrylamide (compound II-20)

Preparation method is identical with 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 embodiment 21 N-(3-(9H-purine-6-base) phenyl) Methacrylamide (compound II-21)

Preparation method is identical with 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 embodiment 22 N-(2-methyl 5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-22) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-methyl-3-nitro phenylboric 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]⁺。

Embodiment 23 N-(2-methyl-3-(9H-purine-6-base) phenyl) Methacrylamide

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 2-methyl-3-nitro phenylboric 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 embodiment 24 N-(the chloro-5-of 2-(9H-purine-6-base) phenyl) Methacrylamide (compound II-24)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-chloro-3-nitrobenzene boronic acid, 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 embodiment 25 N-(the fluoro-5-of 2-(9H-purine-6-base) phenyl) Methacrylamide (compound II-25)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-fluoro-3-nitrobenzene boronic acid, 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]⁺。

Embodiment 26 N-(2-methoxyl group-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-26) Preparation

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-methoxyl group-3-Nitrobenzol boron 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),3.97(s,3H),1.99(s,3H)。MS(ESI),m/z:310.20[M+H]⁺。

The preparation of embodiment 27 N-(the fluoro-3-of 4-(9H-purine-6-base) phenyl) Methacrylamide (compound II-27)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-fluoro-5-nitrobenzene boronic acid, Compound 6 is methacrylic chloride.

MS(ESI),m/z:298.20[M+H]⁺。

The preparation of embodiment 28 N-(the fluoro-3-of 2-(9H-purine-6-base) phenyl) Methacrylamide (compound II-28)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 2-fluoro-3-nitrobenzene boronic acid, Compound 6 is methacrylic chloride.

MS(ESI),m/z:298.20[M+H]⁺。

The preparation of embodiment 29 N-(the fluoro-5-of 3-(9H-purine-6-base) phenyl) Methacrylamide (compound II-29)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-fluoro-5-nitrobenzene boronic acid, Compound 6 is methacrylic chloride.

MS(ESI),m/z:305.20[M+H]⁺。

The system of embodiment 30 N-(3-cyano group-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-30) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-cyano group-5-Nitrobenzol boron Acid, compound 6 is methacrylic chloride.

MS(ESI),m/z:298.20[M+H]⁺。

The system of embodiment 31 N-(2-cyano group-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-31) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-cyano group-3-Nitrobenzol boron Acid, compound 6 is methacrylic chloride.

MS(ESI),m/z:305.20[M+H]⁺。

The system of embodiment 32 N-(3-methyl-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-32) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 3-methyl-5-nitro benzene boron Acid, compound 6 is methacrylic chloride.

MS(ESI),m/z:294.20[M+H]⁺。

Embodiment 33 N-(2-mesyl-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-33) Preparation

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-first sulfo group-3-Nitrobenzol boron Acid, compound 6 is methacrylic chloride.

MS(ESI),m/z:358.20[M+H]⁺。

Embodiment 34 N-(2-dimethylamino methyl-5-(9H-purine-6-base) phenyl) Methacrylamide (compound II-34) preparation

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and compound 3 is 4-dimethylamino methyl-3-nitre Base phenylboric acid, compound 6 is methacrylic chloride.

MS(ESI),m/z:337.20[M+H]⁺。

The preparation of embodiment 35 N-(5-(9H-purine-6-base) pyridin-3-yl) Methacrylamide (compound II-35)

Preparation method is identical with 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 embodiment 36 N-(4-(9H-purine-6-base) pyridine-2-base) Methacrylamide (compound II-36)

Preparation method is identical with 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 embodiment 37 N-(3-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-37)

Preparation method is identical with 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 embodiment 38 N-(2-methyl 5-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-38)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-methyl-3-nitro phenylboric 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 embodiment 39 N-(2-methyl-3-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-39) Standby

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 2-methyl-3-nitro phenylboric 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 embodiment 40 N-(the chloro-5-of 2-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-40)

Preparation method is identical with compound II-1, and raw material 1 is 6-chloropurine, and raw material 3 is 4-chloro-3-nitrobenzene boronic acid, 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 embodiment 41 N-(the fluoro-5-of 2-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-41)

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]⁺。

Embodiment 42 N-(2-methoxyl group-5-(9H-purine-6-base) phenyl)-2-chloroacetamide (compound II-42) Preparation

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 embodiment 43 compound II-43～II-52

Preparation method is identical with compound II-1, uses corresponding raw material, prepares compound II-43～II-52, sees Shown in table 2.

Table 2 compound II-43～II-52

The preparation of embodiment 44 compound III-1～III-15

Preparation method is identical with compound II-1, uses corresponding raw material, prepares compound III-1～III-15, It is shown in Table 3.

Table 3 compound III-1～III-15

The preparation of embodiment 44 compound IV-1～IV-15

Preparation method is identical with compound II-1, uses corresponding raw material, prepares compound IV-1～IV-15, sees Shown in table 4.

Table 4 compound IV-1～IV-15

The preparation of embodiment 45 compound V-1～V-15

Preparation method is identical with compound II-1, uses corresponding raw material to prepare compound V-1～V-15, is shown in Table 4 Shown in.

Table 5 compound V-1～V-15

The preparation of embodiment 46 compound VI-1～VI-15

Preparation method is identical with compound II-1, uses corresponding raw material, prepares compound VI-1～VI-15, sees Shown in table 4.

Table 6 compound VI-1～VI-15

The preparation of embodiment 47 compound VII-1～VII-15

Preparation method is identical with compound II-1, uses corresponding raw material, prepares compound VII-1～VII-15, It is shown in Table 4.

Table 7 compound VII-1～VII-15

Embodiment 48 Pharmacological Activity Screening is tested

Material: JAK1, JAK2, JAK3 and TYK2 kinases (purchased from Carna company)；Polypeptide FAM-P22 and polypeptide FAM-P30 (purchased from GL Biochem company)；ATP (adenosine triphosphate), DMSO (dimethyl sulfoxide) and EDTA (ethylenediaminetetraacetic acid) (purchase From Sigma company)；96 orifice plates (purchased from Corning company), positive control Staurosporine (purchased from Sigma company).

Wherein, the structural formula of Staurosporine (D-82041 DEISENHOFEN) is:

Method:

1, it is equipped with 1x kinase whose alkali buffer and stop buffer.

1) the 1x kinases alkali buffer of JAK1 and JAK3 comprises 50mM HEPES (4-hydroxyethyl piperazine ethanesulfonic acid), Ph 7.5；0.0015%Brij-35 (background of cloth outstanding person 35)；10mM MgCl₂；2mM DTT (dithiothreitol dithio).

2) the 1x kinases alkali buffer of JAK2 and TYK2 comprises 25mM HEPES, Ph 7.5；0.001%Brij-35； 0.01%Triton (2,4,6-trinitrotoluene)；0.5mM EGTA (ethylene glycol bis (2-amino-ethyl ether) tetraacethyl)；10mM MgCl₂；2mM DTT.

3) stop buffer comprises 100mM HEPES, Ph 7.5；0.015%Brij-35；0.2%Coating Reagent (painting membrane reagent) #3；50mM EDTA.

2, the preparation of compound.

1) with the DMSO of 100% test-compound is configured to 50 times of the highest test concentrations.Shift 100 μ L compounds dilute Release liquid in orifice plate.

2) increase in 100%DMSO to 2 hole of 100 μ L, and this plate is designated as original plate.10 μ L are shifted from original plate 96 orifice plates that compound to one piece is new are also designated as intermediate plate, add the 1x kinases alkali buffering of 90 μ L in each hole of intermediate plate Liquid, and plank is placed on shaking table makes compound solution mix homogeneously with 1x kinases alkali buffer.5 μ L are respectively taken again from intermediate plate Mixture forms multiple hole on 384 orifice plates, and is designated as this plate detecting plate.

3, enzyme reaction.

1) it is equipped with 2.5x enzymatic solution, kinases is joined in the kinases alkali buffer of 1x.

2) it is equipped with 2.5x polypeptide buffer, FAM-tag polypeptide and ATP is joined in the kinases alkali buffer of 1x.

3) transferase 12 .5x enzymatic solution is to detecting in plate.Each hole of detection plate comprises the compound of 10%DMSO equipped with 5 μ L Solution, adds the 2.5x enzymatic solution of 10 μ L, hatches 10min in 25 DEG C.

4) in each hole of detection plate, add 2.5x polypeptide solution, after hatching suitable duration in 28 DEG C, add the end of 25 μ L Only buffer is to terminate enzyme reaction.

4, read and record the initial data in every hole, and initial data is changed accordingly.

1) suppression ratio=(maximum-compound conversion value)/(maximum-minima) * 100, wherein, maximum is DMSO Control group data, minima is not add the blank value of enzyme.

2) calculation of half inhibitory concentration IC₅₀Value, with log [administration concentration] as abscissa, suppression ratio is vertical coordinate, Graphpad Prism 5 simulates a dose-effect curve, draws drug level during its 50% suppression ratio, be this Compound IC on Kinase levels₅₀Value.

Table 8 provides the compounds of this invention average IC about JAK1, JAK2, JAK3 and TYK2₅₀Scope, wherein, " A " table Show IC₅₀Value is less than 10nM, and " B " represents IC₅₀Value is between 10nM and 100nM, and " C " represents IC₅₀Be worth 100nM Yu 1000nM it Between, " D " represents IC₅₀Value is more than 1000nM.

Table 8 the compounds of this invention is about the average IC of JAK1, JAK2, JAK3 and TYK2₅₀Scope

Claims

1.N-substituted-phenyl acrylamide derivative, its structure is as shown in formula I:

Wherein, X₁～X₃、Y₁～Y₄Stand alone as C, N or S；

R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；

R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl, C₃ ～C₈Cycloalkyl or halogen.

2. the N-substituted-phenyl acrylamide derivative described in claim 1, it is characterised in that:

X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₈Alkyl, halogen ,-CN ,-OH, C₁～C₈Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl,-CN、-OH、C₃～C₈Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen Element；R₄～R₆Stand alone as-H, C₁～C₈Alkyl, C₁～C₈Alkoxyl, C₁～C₈Haloalkyl, C₂～C₈Thiazolinyl, C₂～C₈Alkynyl, C₃ ～C₈Cycloalkyl or halogen；

Preferably, X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN ,-OH, C₁～C₄Alkoxyl,Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Alkyl halide Base, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃ Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynes Base, C₃～C₆Cycloalkyl or halogen；

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,X₁～X₃、 Y₁～Y₄Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Solely Stand as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl Or halogen；

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl ,-CN, C₁～C₄Alkoxyl,X₁ ～X₃、Y₁～Y₄Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄ Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄ ～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆ Cycloalkyl or halogen；

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl, C₃～C₆Cycloalkyl or halogen；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄ Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂ ～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen Element；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；X₁～X₃、Y₁～Y₄Stand alone as C Or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；X₁～X₃、Y₁～Y₄Independent For C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁ ～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl or C₃～C₆Cycloalkyl；X₁ ～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

It is further preferred that R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；X₁～X₃、Y₁ ～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃Solely Stand as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

Further preferred, R₄～R₆Stand alone as-H or C₁～C₄Alkyl；X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁~ C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alcoxyl Base, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

Preferably, X₁～X₃、Y₁～Y₄Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₄～R₆Stand alone as-H or C₁～C₄ Alkyl；

N-substituted-phenyl acrylamide derivative the most according to claim 1 and 2, it is characterised in that: work as X₁And X₃For N, X₂ For C, Y₃And Y₄During for C, its structure is as shown in formula II:

Wherein, Y₁、Y₂Stand alone as C or N；

4. the N-substituted-phenyl acrylamide derivative described in claim 3, it is characterised in that:

Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN ,-OH, C₁～C₄Alkoxyl, Or-CON (CH₃)₂；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂~ C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Independent For-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or Halogen；

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,Y₁、Y₂Solely Stand as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynes Base,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl ,-CN, C₁～C₄Alkoxyl,Y₁、 Y₂Stand alone as C or N；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂~ C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Independent For-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or Halogen；

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl, C₃～C₆Cycloalkyl or halogen；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen Element；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₄~ R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Ring Alkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；Y₁、Y₂Stand alone as C or N；R₁ For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；Y₁、Y₂Stand alone as C or N； R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkane Base, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl or C₃～C₆Cycloalkyl； Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃Solely Stand as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

It is further preferred that R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；Y₁、Y₂Independent For C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁ ～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

Further preferred, R₄～R₆Stand alone as-H or C₁～C₄Alkyl；Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, Halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂~ C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

Preferably, Y₁、Y₂Stand alone as C or N；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₄～R₆Stand alone as-H or C₁～C₄Alkyl；

Optimum, Y₁、Y₂Stand alone as C or N；R₁For-H, methyl ,-F ,-Cl ,-CN, methoxyl group, dimethylaminoR₂、 R₃Stand alone as-H, methyl, vinyl ,-Cl or-Br.

N-substituted-phenyl acrylamide derivative the most according to claim 1 and 2, it is characterised in that: work as X₁And X₂For C, X₃ For N, Y₁～Y₄During for C, its structure is as shown in formula III:

Wherein, R₁For-H, C₁～C₈Alkyl, halogen ,-CN ,-OH, C₁～C₈Alkoxyl,-CON (CH₃)₂；

N-substituted-phenyl acrylamide derivative the most according to claim 5, it is characterised in that:

R₁For-H, C₁～C₄Alkyl, halogen ,-CN ,-OH, C₁～C₄Alkoxyl,Or-CON (CH₃)₂；R₂、R₃ Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

It is further preferred that R₁For-H, C₁～C₄Alkyl, halogen, C₁～C₄Alkoxyl,R₂、R₃Independent For-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；R₄～R₆Stand alone as-H, C₁~ C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₁For-H, C₁～C₄Alkyl ,-F ,-Cl or C₁～C₄Alkoxyl；R₂、R₃Stand alone as-H, C₁～C₄Alkane Base, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl,-CN、-OH、C₃ ～C₆Cycloalkyl ,-O (C₁～C₈Alkyl) CF₃Or halogen；

Preferably, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄ Alkynyl, C₃～C₆Cycloalkyl or halogen；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Alkene Base, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

It is further preferred that R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen Element；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄ Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl or halogen；R₁For-H, C₁～C₄Alkyl, Halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁ ～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Further preferred, R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Thiazolinyl ,-Cl or-Br；R₁For-H, C₁～C₄Alkane Base, halogen ,-CN, C₁～C₄Alkoxyl,R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₁～C₄Haloalkyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl, C₃～C₆Cycloalkyl or halogen；

Preferably, R₄～R₆Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl or C₁～C₄Haloalkyl；R₁For-H, C₁～C₄Alkane Base, halogen ,-CN, C₁～C₄Alkoxyl,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl or halogen；

It is further preferred that R₄～R₆Stand alone as-H or C₁～C₄Alkyl；R₁For-H, C₁～C₄Alkyl, halogen ,-CN, C₁～C₄Alkane Epoxide,R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₁～C₄Alkoxyl, C₂～C₄Thiazolinyl, C₂～C₄Alkynyl Or halogen；

Preferably, R₁For-H, C₁～C₄Alkyl, halogen or C₁～C₄Alkoxyl；R₂、R₃Stand alone as-H, C₁～C₄Alkyl, C₂～C₄Alkene Base or halogen；

N-substituted-phenyl acrylamide derivative the most according to claim 1 and 2, it is characterised in that: work as X₁～X₃For C, Y₁ ～Y₄During for C, its structure is as shown in formula IV:

N-substituted-phenyl acrylamide derivative the most according to claim 7, it is characterised in that:

N-substituted-phenyl acrylamide derivative the most according to claim 1 and 2, it is characterised in that: work as X₁For C, X₂And X₃ For N, Y₁～Y₄During for C, its structure is as shown in formula V:

N-substituted-phenyl acrylamide derivative the most according to claim 9, it is characterised in that:

11. N-substituted-phenyl acrylamide derivatives according to claim 1 and 2, it is characterised in that: work as X₁For N, X₂With X₃For C, Y₁～Y₄During for C, its structure is as shown in formula VI:

Wherein, R₁For-H, C₁～C₈Alkyl, halogen ,-CN ,-OH, C₁～C₈Alkoxyl,Or-CON (CH₃)₂；

12. N-substituted-phenyl acrylamide derivatives according to claim 11, it is characterised in that:

13. N-substituted-phenyl acrylamide derivatives according to claim 1 and 2, it is characterised in that: work as X₁And X₃For C, X₂For N, Y₁～Y₄During for C, its structure is as shown in formula VII:

14. N-substituted-phenyl acrylamide derivatives according to claim 13, it is characterised in that:

15.N-substituted-phenyl acrylamide derivative, its structural formula is:

N-substituted-phenyl acrylamide derivative pharmaceutically acceptable salt described in 16. any one of claim 1～15.

The N-pharmaceutically acceptable hydrate of substituted-phenyl acrylamide derivative described in 17. any one of claim 1～15.

18. 1 kinds of pharmaceutical compositions, be by the N-substituted-phenyl acrylamide derivative described in any one of claim 1～15, Salt described in claim 16 or the hydrate described in claim 17 add the pharmaceutically complementary composition of acceptable to be prepared ?.

N-substituted-phenyl acrylamide derivative described in 19. any one of claim 1～15, the salt described in claim 16 or The hydrate described in claim 17 purposes in preparing JAK3 inhibitor.

N-substituted-phenyl acrylamide derivative described in 20. any one of claim 1～15, the salt described in claim 16 or Hydrate described in claim 17 is at preparation treatment rheumatoid arthritis, asthma, chronic obstructive pulmonary disease or tumour medicine In purposes.