CN105017159A - 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and preparation method and application thereof - Google Patents

5-fluorine-2,4-bis-substituted aminopyrimidine derivative and preparation method and application thereof Download PDF

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CN105017159A
CN105017159A CN201410174964.8A CN201410174964A CN105017159A CN 105017159 A CN105017159 A CN 105017159A CN 201410174964 A CN201410174964 A CN 201410174964A CN 105017159 A CN105017159 A CN 105017159A
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CN105017159B (en
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杨胜勇
魏于全
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Sichuan University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to the field of chemical medicine and particularly relates to a 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and a preparation method and application thereof. The structure of the 5-fluorine-2,4-bis-substituted aminopyrimidine derivative is shown in the formula I. The preparation method of the 5-fluorine-2,4-bis-substituted aminopyrimidine derivative and the application of the 5-fluorine-2,4-bis-substituted aminopyrimidine derivative in preparation of medicine for treating tumors are further provided. The synthetic route is short, reaction conditions are simple, the yield is high, and derivatization is easy. A series of compounds have good anti-tumor activity and low toxicity. A new choice is provided for preparation of the anti-tumor medicine. See the formula in the specification.

Description

Fluoro-2,4-disubstituted amido pyrimidine derivatives of 5-and its production and use
Technical field
The invention belongs to organic synthesis technical field of pharmaceuticals, particularly fluoro-2,4-disubstituted amido pyrimidine derivatives of 5-and its production and use.
Background technology
Kinases is the primary clustering of intracellular signal transduction pathway, and abnormal kinase also can cause cell signal abnormal usually, thus causes the generation of the various diseases comprising cancer, autoimmune disorder, diabetes, inflammation etc.Given this, kinases, as the most important disease treatment target spot of a class, has become the focus of current research.
As important a member of kinase families, spleen tyrosine kinase (spleen tyrosine kinase, Syk) be a kind of non-receptor type protein tyrosine kinase, 2 series connection Src homeodomain 2 (SH2) that Syk albumen is held by N and C hold 1 kinase domain to form.Syk is expressed in all hematopoietic cells, wherein B cell high level expression, and T cell, thrombocyte and medullary cell expression level are lower.Syk function is observed in B-cell receptor signal transduction process, and Syk grows for pre B cell is extremely important ancestral's B cell, and immature B cells can be impelled to enter splenic white pulp, and Syk defect can cause the disappearance completely of mature B cell.Research shows, Syk is active abnormal closely related with tumour, autoimmune type disease, inflammation etc., has been listed in the critical treatment target of these diseases.
Another kind of kinase families member, focal adhesion kinase (focal adhesion kinase, FAK) is also a kind of non-receptor protein tyrosine kinase.FAK take part in many cell-signaling pathways, and it is the maincenter of born of the same parents' internal/external signal transduction.It can integrate the signal from aspects such as the nutrition outside born of the same parents, pressure, cell adhesions, regulates the activity of downstream molecules, controls the metabolism of cell, propagation, or even the destiny of cell.Research show FAK can regulating cell growth, grappling, move, cancerate and the process such as apoptosis.The protein level of FAK in the kinds of tumors such as ovarian cancer, thyroid carcinoma, mammary cancer, colorectal cancer is all in high expression level or overactivity state, its high expression level between cell and cell and extracellular matrix stick in invasion and attack and play an important role, survive with tumour cell simultaneously, cycle regulating, propagation, apoptosis, migration and metastases etc. have substantial connection.FAK is also listed in important oncotherapy target.
Conventional needle mainly pays close attention to the kinase inhibitor for single kinase whose highly selective to kinase whose medicament research and development.But for this kind of complex disease such as tumour, autoimmune disorder, simultaneously the multiple kinases of target (such as SYK and FAK) Mutiple Targets medicine may in curative effect, avoid, in recurrence etc., there is larger advantage.
Summary of the invention
First technical problem to be solved by this invention there is provided fluoro-2, the 4-disubstituted amido pyrimidine derivatives of a kind of 5-, and its structural formula is such as formula shown in I:
Wherein, R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted 6 yuan of heteroaryls; The substituting group of the phenyl of described replacement or 6 yuan of heteroaryls is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is the substituting group of 6 yuan of Heterocyclylalkyls of described replacement is-H ,-F ,-Cl ,-Br ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 alkoxyl group, or the alkyl of the C1 ~ C4 of halogen substiuted, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group, or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of 6 yuan of Heterocyclylalkyls of described replacement be C1 ~ C4 alkyl or described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group,
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
R2 is
It is most preferred,
R1 is
R2 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in II:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
It is most preferred,
R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in III:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
It is most preferred,
R1 is
As preferred version of the present invention, in the merit of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in IV:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in V:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in VI:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, fluoro-2, the 4-disubstituted amido pyrimidine derivates material evidences of above-mentioned 5-, work as R 2for time, structure is such as formula shown in VII:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in VIII:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in IX:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
As preferred version of the present invention, in fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, work as R 2for time, structure is such as formula shown in X:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
Most preferred, R1 is
In fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, comprise following compound:
The fluoro-N4-of 5-(2-methyl cyclohexylamine)-N2-(3, 4, 5-trimethoxy-aniline) pyrimidine-2, 4-diamines, N6-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-yl)-2-toluquinoline-4, 6-diamines, the fluoro-N2-(3 of N4-(the chloro-3-of 4-(trifluoromethyl) phenyl)-5-, 4, 5-trimethoxy-aniline) pyrimidine-2, 4-diamines, 5-amino-6-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino)-3, 4-dihydro-quinolinone, N4-(3, 4-difluorophenyl) the fluoro-N2-(3 of-5-, 4, 5-trimethoxyphenyl) pyrimidine-2, 4-diamines, the chloro-2-of 4-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino) benzamide, 5-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino)-1H-benzimidazolone, 3-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino) benzamide, the chloro-2-of 4-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide, N6-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl)-2-toluquinoline-4, 6-diamines, 3-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide.
Second technical problem solved by the invention is to provide the preparation method of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, and synthetic route is as follows:
The aliphatic amide of a, 2,4-bis-chloro-5-FUs (1) and different replacement or aromatic amine compound (2) is obtained by reacting under the catalysis of weakly alkaline catalyzer;
Wherein, solvent is any one in tetrahydrofuran (THF), methylene dichloride, ethyl acetate, dimethylbenzene, toluene, acetonitrile, and catalyzer is DIPEA, triethylamine, salt of wormwood, pyridine, N, any one in accelerine, N, N-Diethyl Aniline; Temperature of reaction is 0 DEG C ~ 120 DEG C; Reaction times is 0.5 ~ 12h;
B, by the aromatic amine (H of compound (2) from different replacement 2n-R 2) under acid or base catalysis, be obtained by reacting compound (3);
Wherein, acid is any one in concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid, tosic acid; Alkali is any one in DIPEA, triethylamine, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide; Solvent is any one in tetrahydrofuran (THF), acetone, butanone, Virahol, propyl carbinol, DMF, dioxane; Temperature of reaction is 45 DEG C ~ 125 DEG C; Reaction times is 6h ~ 16h;
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
3rd technical problem solved by the invention is to provide the purposes in fluoro-2,4-disubstituted amido pyrimidine derivatives preparation treatment tumour, autoimmune disorder or the anti-inflammatory drugs of above-mentioned 5-.
4th technical problem solved by the invention is to provide prodrug or the hydrate of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-.Described prodrug is the derivative of above-claimed cpd, they self may have more weak activity or even not have activity, but (such as by metabolism, solvolysis or other mode) is converted to corresponding biologically active form upon administration, in physiological conditions.
5th technical problem solved by the invention is to provide fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-and adds that the complementary composition of pharmaceutically acceptable is prepared from.
The intermediate used when present invention also offers preparation fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, structure is as shown in XI:
R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
Preferably,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4.
It is preferred further,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl.
It is further preferred,
R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl.
Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl.
It is most preferred,
R1 is
The intermediate used when present invention also offers preparation fluoro-2, the 4-disubstituted amido pyrimidine derivatives of above-mentioned 5-, structure is as shown in XII:
R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
Preferably, R2 is substituted or unsubstituted phenyl or substituted or unsubstituted 6 yuan of heteroaryls; The substituting group of the phenyl of described replacement or 6 yuan of heteroaryls is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is the substituting group of 6 yuan of Heterocyclylalkyls of described replacement is-H ,-F ,-Cl ,-Br ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 alkoxyl group, or the alkyl of the C1 ~ C4 of halogen substiuted, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
Preferred further, R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group, or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of 6 yuan of Heterocyclylalkyls of described replacement be C1 ~ C4 alkyl or described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
It is further preferred,
R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group,
Most preferred, R2 is
Compound prepared by the present invention is can the Mutiple Targets medicine of the simultaneously multiple kinases of target (such as SYK and FAK), therefore in curative effect, avoid, in recurrence etc., there is larger advantage.
Accompanying drawing explanation
The tumor growth curve of different group in Fig. 1 RAMOS model;
The tumor growth curve of different group in Fig. 2 HBL-1 model.
Embodiment
Below in conjunction with embodiment, the present invention is further set forth, but be not limitation of the present invention; All technology realized based on foregoing of the present invention all belong to scope of the present invention.
The synthesis of embodiment 1, the fluoro-N-of the chloro-5-of intermediate 2-(2-methyl cyclohexylamine) pyrimidine-4-amine (2a-1)
By 2, fluoro-pyrimidine (the 1.67g of the chloro-5-of 4-bis-, 10mmol) and the N of catalytic amount, N-diisopropylethylamine (DIEA) is dissolved in the methylene dichloride of 150ml, by 2-methyl cyclohexylamine (1.13g under ice-water bath condition, dichloromethane solution 10mmol) slowly instills in above solution, react stopped reaction after 0.5 hour, use water extracting twice, after organic over anhydrous dried over mgso, underpressure distillation, residue obtains product after column chromatography (eluent is Shi You Mi ︰ ethyl acetate=10 ︰ 1) purifying, productive rate: 68%.1H NMR(400MHz,DMSO-d6)：δ8.064(s,1H),7.74(d,J＝6.8Hz,1H),4.09(s,1H),2.05(s,1H),1.69-1.47(m,6H),1.33(s,2H),0.84(d,J＝4.8Hz,3H)ppm。
The synthesis of embodiment 2, the fluoro-N-of the chloro-5-of intermediate 2-(the chloro-3-of 4-(trifluoromethyl) aniline) pyrimidine-4-amine (2a-2)
By 2, fluoro-pyrimidine (the 1.67g of the chloro-5-of 4-bis-, 10mmol), the DIPEA (DIEA) of the chloro-3-of 4-(trifluoromethyl) aniline (1.96g, 10mmol) and catalytic amount is dissolved in the ethanolic soln of 100ml, reaction backflow is spent the night, after stopped reaction, underpressure distillation is except desolventizing, and residue obtains product, productive rate: 78% after column chromatography (eluent is stone oil ether ︰ ethyl acetate=7 ︰ 1) purifying.
1H NMR(400MHz,DMSO-d6):δ10.37(s,1H),8.43(d，J＝3.6Hz,1H),8.33(d,J＝2.4Hz,1H),8.06(dd,J＝8.0Hz，J＝2.4Hz，1H),7.75(d,J＝9.2Hz,1H)ppm。
The synthesis of the fluoro-N4-of embodiment 3,5-(2-methyl cyclohexylamine)-N2-(3,4,5-trimethoxy-aniline) pyrimidine-2,4-diamines (3a-1)
By the fluoro-N-of chloro-for 2-5-(2-methyl cyclohexylamine) pyrimidine-4-amine (2a-1,280mg, 1.2mmol) He 3,4,5-trimethoxy-aniline (221mg, 1.25mmol) and the N of catalytic amount, N-diisopropylethylamine (DIEA) is dissolved in the propyl carbinol of 50mL, react at above reaction system is placed in 100 DEG C and spend the night, stopped reaction, after underpressure distillation removes desolventizing, residue obtains product, productive rate: 94% after column chromatography (eluent is stone oil ether ︰ ethyl acetate=4 ︰ 1) purifying; Purity: 99%.1H NMR(400MHz,DMSO-d6):δ8.86(s,1H),7.86(s,1H),7.12(s,2H),6.83(d,J＝6.4Hz,2H),4.30(s,1H),3.74(s,6H),3.60(s,3H),2.00(s,1H),1.73-1.65(m,2H),1.51-1.47(m,4H),1.33(s,2H),0.86(d,J＝4.8Hz,3H)ppm；LCMS m/z:391.2[M+H].
The synthesis of embodiment 4, N6-(the fluoro-2-of 5-(3,4,5-trimethoxy-aniline) pyrimidine-4-yl)-2-toluquinoline-4,6-diamines (3a-2)
By 4-nitro-2-cyano-aniline (1.6g, 10mmol) molten with dry toluene with a certain amount of acetone, under ice-water bath condition, tin tetrachloride (1.2ml, 10mmol) is slowly added dropwise in above-mentioned reaction solution, then by this reaction solution back flow reaction 4.5h.After stopped reaction, be cooled in room temperature process and have a large amount of solid to separate out, suction filtration solid, obtain 2-methyl-6-nitro-4-quinolylamine with after a small amount of washed with diethylether.Then, be amino by nitroreduction under ammonium chloride catalysis with reduced iron powder, then with 2 under DIPEA (DIEA) catalysis, react in the chloro-5-FU of 4-bis-ethanol under reflux conditions and spend the night, the solid of separating out in suction filtration reaction obtains 2a-3.Intermediate 2a-3 and 3,4,5-trimethoxy-aniline is finally used to obtain final product by the synthetic method of 3a-1, overall yield: 46%; Purity: 99%.
1H NMR(400MHz,DMSO-d6):δ9.42(s,1H),9.08(s,1H),8.31(s,1H),8.10(d,J＝4.0Hz,1H),7.78(d,J＝8.8Hz,1H),7.76(d,J＝8.8Hz,1H),7.03(s,2H),6.44(s,3H),3.56(s,3H),3.48(s,6H),2.41(s,3H)ppm；LCMS m/z:451.2[M+H].
The synthesis of embodiment 5, N4-(the chloro-3-of 4-(trifluoromethyl) phenyl) the fluoro-N2-of-5-(3,4,5-trimethoxy-aniline) pyrimidine-2,4-diamines (3a-3)
The synthetic method of pressing compound (3a-1) with intermediate (2a-2) and 3,4,5-trimethoxy-anilines synthesizes final product (3a-3), productive rate 82%, purity 98%.
1H NMR(400MHz,DMSO-d6):δ9.76(s,1H),9.18(s,1H),8.32(d,J＝7.2Hz,2H),8.18(d,J＝8.0Hz,2H),7.59(d,J＝7.6Hz,1H),6.98(s,1H),3.63(s,6H),3.61(s,3H)ppm。
The synthesis of embodiment 6,5-amino-6-(the fluoro-2-of 5-(3,4,5-trimethoxy-aniline) pyrimidine-4-is amino)-3,4-dihydro-quinolinones (3a-4)
By the intermediate 5-amino-6-(the chloro-5-FU of 2--4-is amino)-3 of synthesis, 4-dihydro-quinolinone (850mg, 2.7moml) with 3,4,5-trimethoxy-aniline (586mg, 3.1mol) react 8 hours at n-butanol solvent 110 DEG C under the hydrochloric acid catalysis of catalytic amount, TLC detection reaction progress, stopped reaction after question response, underpressure distillation except after desolventizing with water and extraction into ethyl acetate 3 times, after after organic over anhydrous dried over mgso, underpressure distillation removes desolventizing, ethanol and sherwood oil recrystallization obtain product, two step overall yields 64%, purity 99%.
1H NMR(400MHz,DMSO-d6):δ9.28(s,1H),9.02(s,1H),8.93(s,1H),8.01(d, J＝4.0Hz,1H),7.02(s,2H),6.91(s,1H),6.83(s,1H),5.05(br s,2H),3.59(d,J＝3.2Hz,9H),2.71(t,J＝6.8Hz,2H),2.38(t,J＝6.8Hz,2H)ppm；LCMS m/z:455.2[M+H].
The synthesis of embodiment 7, the fluoro-N2-of N4-(3,4-difluorophenyl)-5-(3,4,5-trimethoxyphenyl) pyrimidine-2,4-diamines (3a-5)
3a-5 is synthesized, two step overall yields 61%, purity 99% according to the synthetic method of end product (3a-1) with the chloro-N-of intermediate 2-(3, the 4-difluorophenyl)-5-FU-4-amine synthesized and 3,4,5-trimethoxy-aniline.
1H NMR(400MHz,DMSO-d6):δ10.43(s,1H),9.60(s,1H),8.20(d,J＝5.2Hz,1H),7.40-7.35(m,2H),7.17(s,1H),6.83(s,2H),4.65(d,J＝5.2Hz,2H),3.65(s,6H),3.63(s,3H)ppm；LCMS m/z:421.1[M+H].
The synthesis of the chloro-2-of embodiment 8,4-(the fluoro-2-of 5-(3,4,5-trimethoxy-aniline) pyrimidine-4-is amino) benzamide (3a-6)
Utilize the chloro-2-of intermediate 4-(the chloro-5-FU of 2--4-the is amino) aniline (300mg of synthesis, 1.0mmol) He 3, 4, 5-trimethoxy-aniline (450mg, 1.75mmol), react 6 hours under the hydrochloric acid of catalytic amount is left 95 DEG C of DMF, TLC detection reaction liquid, stopped reaction after question response, after a large amount of water and extraction into ethyl acetate 3 times, organic layer is after anhydrous magnesium sulfate drying, pressure distillation is except desolventizing, residue obtains product again after column chromatography (eluent is Er Lv Jia Wan ︰ methyl alcohol=70 ︰ 1) purifying after ethanol and sherwood oil recrystallization, two step overall yields 66%, purity 98%.
1H NMR(400MHz,DMSO-d6):δ11.96(s,1H),9.24(s,1H),8.92(d,J＝9.2Hz,1H),8.44(s,1H),8.19(d,J＝2.8Hz,1H),7.95-7.91(m,2H),7.47(d,J＝8.8Hz,1H),7.06(s,2H),3.71(s,6H),3.63(s,3H)ppm；LCMS m/z:448.1[M+H].
The synthesis of embodiment 9,5-(the fluoro-2-of 5-(3,4,5-trimethoxy-aniline) pyrimidine-4-is amino)-1H-benzimidazolone (3a-7)
The intermediate 5-of synthesis (the chloro-5-FU of 2--4-is amino)-1H-benzimidazolone and 3,4,5-trimethoxy-aniline is utilized to press the synthetic method synthesis 4a-7 of end product (3a-1), two step overall yields 64%, purity 99%.
1H NMR(400MHz,DMSO-d6):δ10.54(s,1H),10.51(s,1H),9.17(s,1H),8.94(s,1H),8.04(s,1H),7.28(d,J＝7.6Hz,1H),7.14(s,1H),7.03(s,2H),6.85(d,J＝8.4Hz,1H),3.57(s,3H),3.52(s,6H)ppm；LCMS m/z:427.1[M+H].
The synthesis of embodiment 10,3-(the fluoro-2-of 5-(3,4,5-trimethoxy-aniline) pyrimidine-4-is amino) benzamide (3a-8)
By intermediate 3-(the chloro-5-FU of 2--4-the is amino) benzamide (600mg of synthesis, 2.26mmol), 3,4,5-trimethoxy-aniline (600mg, 3.2mmol) be dissolved in the DMF of 45ml with the concentrated hydrochloric acid of Cui Hualiang, at above reaction solution is placed in 100 DEG C reaction spend the night after with after water and extraction into ethyl acetate 3 times, organic layer residue after underpressure distillation obtains end product, two step overall yields 68%, purity 98% after column chromatography (eluent is Er Lv Jia Wan ︰ methyl alcohol=70 ︰ 1) purifying.1H NMR(400MHz,DMSO-d6):δ9.45(s,1H),9.06(s,1H),8.12(d,J＝3.6Hz,1H),8.05(d,J＝8.0Hz,1H),8.01(s,1H),7.88(s,1H),7.56(d,J＝8.0Hz,1H),7.39-7.33(m,2H),7.03(s,2H),3.39(s,9H)ppm；LCMS m/z:413.1[M+H].
The synthesis of the chloro-2-of embodiment 11,4-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide (3a-9)
Utilize the chloro-2-of intermediate 4-(the chloro-5-FU of 2--4-the is amino) aniline (300mg of synthesis, 1.0mmol) with 4-(4-methylpiperazine-1-yl) aniline (384mg, 2.0mmol) under concentrated hydrochloric acid catalysis, by the synthetic method synthesis 3a-9 of 3a-6, two step overall yields 32%, purity 98%.
1H NMR(400MHz,DMSO-d6):δ11.91(s,1H),9.09(s,1H),8.89(d,J＝8.8Hz,1H),8.43(s,1H),8.13(d,J＝2.8Hz,1H),7.91(d,J＝8.8Hz,2H),7.51-7.45(m,3H),6.90(d,J＝8.8Hz,2H),3.08(s,4H),2.46(s,4H),1.99(s,3H)ppm；LCMS m/z:456.1[M+H].
The synthesis of embodiment 12, N6-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl)-2-toluquinoline-4,6-diamines (3a-10)
Utilize the 2a-3 (300mg of synthesis, 1.0mmol) with 4-(4-methylpiperazine-1-yl) aniline (384mg, 2.0mmol) under concentrated hydrochloric acid catalysis, by the synthetic method synthesis 3a-10 of 3a-6, two step overall yields 64%, purity 98%.
1H NMR(400MHz,DMSO-d6):δ9.34(s,1H),8.93(s,1H),8.35(s,1H),8.04(d,J＝3.6Hz,1H),7.73(d,J＝8.8Hz,1H),7.64(d,J＝8.8Hz,1H),7.43(d,J＝8.8Hz,2H),6.70(d,J＝8.4Hz,2H)6.47(d,J＝8.8Hz,3H)ppm；LCMS m/z:458.2[M+H].
The synthesis of embodiment 13,3-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide (3a-11)
Utilize intermediate 3-(the chloro-5-FU of 2--4-the is amino) benzamide and 4-(4-methylpiperazine-1-yl) aniline of synthesizing under concentrated hydrochloric acid catalysis, by the synthetic method synthesis 3a-11 of 3a-6, two step overall yields 45%, purity 98%.
1H NMR(400MHz,DMSO-d6):δ9.40(s,1H),8.93(s,1H),8.08-8.06(m,2H),7.91(s,2H),7.56(d,J＝7.2Hz,1H),7.45(d,J＝8.4Hz,2H),7.41-7.37(m,2H),6.79(d,J＝8.8Hz,2H),3.02(s,4H),2.44(s,4H),1.99(s,3H)ppm；LCMS m/z:422.2[M+H].
Pharmaceutical test part
1, the kinase inhibiting activity test of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-of the present invention
The object of this experiment detects the compounds of this invention to the inhibit activities of vitro kinase, and the method for employing is isotope-labelling method (the γ phosphate group on mark ATP).This experiment is respectively to focal adhesion kinase (FAK), spleen tyrosine kinase (SYK), human protein kinase B α (PKB α), SRC, Axl, cell cycle dependent kinase 2 (CDK2)/cyclin E (cyclinE), EphA3, IGF-1R (IGF-1R), Janus kinases 2 (JAK2), vascular endothelial growth factor (KDR), Lyn, Met, pyruvate kinase 2 (Pyk2), the kinases such as phosphatidylinositol3 3 kinase p110 α/p85 α (PI3K (p110 α/p85 α)) carry out external activity and suppress test.The kinase inhibiting activity of test-compound represents the inhibiting rate of kinase activity under 10 μMs of concentration with IC50 (half-inhibition concentration) or test-compound.IC50 value calculates the inhibiting rate of kinase activity by test-compound and obtains under a series of different concns.
1) experiment material:
20mM3-(N-morpholinyl) propanesulfonic acid (MOPS); 1mM ethylenediamine tetraacetic acid (EDTA) (EDTA); Outstanding 35 (Brij-35) in 0.01% cloth; 5% glycerine (Glycerol); 0.1% mercaptoethanol (mercaptoethanol); The bovine serum albumin (BSA) of 1mg/mL; The manganous chloride solution (MnCl2) of 10mM;
100 μMs of EEEEYEEEEEEYYIIEEEEEEYEEEEEEYYEEEEEEKKKK (substrate of FAK)
0.1mg/mL poly (Glu, Tyr) 4:1 (substrate of SYK)
30 μMs of GRPRTSSFAEGKK (substrate of PKB α)
500mM GGEEEEYFELVKKKK (substrate of SRC)
250 μMs of KKSRGDYMTMQIG (substrate of Axl)
0.1mg/mL histone H1 (substrate of CDK2/cyclinE)
0.1mg/mL poly (Glu, Tyr) 4:1 (substrate of EphA3)
250 μMs of KKKSPGEYVNIEFG (substrate of IGF-1R)
100 μMs of KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (substrate of JAK2)
250 μMs of KKKSPGEYVNIEFG (substrate of KDR)
0.1mg/mL poly (Glu, Tyr) 4:1 (substrate of Lyn)
250 μMs of GGMEDIYFEFMGGKKK (substrate of MET)
0.1mg/mL poly (Glu, Tyr) 4:1 (substrate of Pyk2)
10 μMs of phosphatidylinositol4,5-bisphosphate (substrate of PI3Kinase (p110 α/p85 α))
The magnesium acetate of 10mM and γ-33P-ATP solution; Stop buffer (3% phosphate buffered saline buffer); Lavation buffer solution (phosphate solution of 75mM); Methyl alcohol (methanol); Filtermat A film; The kinases such as focal adhesion kinase (FAK), spleen tyrosine kinase (SYK), human protein kinase B α (PKB α), SRC, Axl, cell cycle dependent kinase 2 (CDK2)/cyclin E (cyclinE), EphA3, IGF-1R (IGF-1R), Janus kinases 2 (JAK2), vascular endothelial growth factor (KDR), Lyn, Met, pyruvate kinase 2 (Pyk2), phosphatidylinositol3 3 kinase p110 α/p85 α (PI3K (p110 α/p85 α)), test-compound.
2) experimental technique:
In a reaction tubes, add damping fluid (8mM MOPS, pH7.0,0.2mM EDTA, 10mM MnCl successively 2), kinases to be measured (5-10mU) (FAK, SYK, PKB α, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110 α/p85 α)) kinase whose substrate to be measured (reference experiment material), and the magnesium acetate of 10mM and γ 33P-ATP solution, the test-compound of different concns.Reaction is initial to add MgATP, at room temperature hatches 40 minutes.The 3% phosphate buffered saline buffer termination reaction of final use 5 μ L, and the reaction solution of 10 μ L is titrated on Filtermat A film, washes three times with the phosphate solution of 75mM, each 5 minutes, then with methanol wash column once.Final drying Filtermat A film also carries out scintillation counting to it, and the size of scintillometer numerical value reflects the degree that substrate is phosphorylated, thus can characterize the suppressed situation of kinase activity.
3) experimental result:
By above experimental technique, test compound in the present invention respectively for FAK, SYK, PKB α, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110 α/p85 α) kinase whose inhibit activities.
Table 1 gives the IC50 value of test-compound to the kinase whose inhibit activities of part.
Table 2 gives part test-compound 3a-9 under the concentration of 10 μMs respectively to the inhibiting rate (%) of the kinase activities such as PKB α, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110 α/p85 α).
Table 1. test-compound is to the kinase whose inhibit activities of part
Table 2. test-compound 3a-9 under the concentration of 10 μMs to the inhibiting rate of multiple kinase activity
Test kinase Test-compound under the concentration of 10 μMs to the inhibiting rate (%) of kinase activity
Axl 100
CDK2/cyclinE 83
EphA3 81
IGF-1R,activated 100
JAK2 100
KDR 100
Lyn 100
Met 100
PKBα 69
Pyk2 99
Src(1-530) 100
PI3Kinase 41
Experimental result shows, test-compound not only has stronger inhibit activities to SYK, FAK, and test-compound also has good inhibit activities to PKB α, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2 kinases.
2, the vitro human Cytostatic to tumor cell experiment of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-of the present invention
The object of this experiment detects the compounds of this invention to vitro human tumor cell proliferation inhibition activity, and the method for employing is MTT (tetramethyl-azo azoles salt) colorimetry.
1) experiment material:
Main agents: RPMI-1640, foetal calf serum, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), and IMDM substratum is purchased from ATCC (American Type Culture Collection).Tetramethyl-azo azoles salt (MTT), dimethyl sulfoxide (DMSO) (DMSO) are Sigma company (USA) product.XXX series derivates is synthesized by contriver, is mixed with 10mM storage liquid during experiment in vitro with 100%DMSO, puts-20 DEG C of refrigerators and keeps in Dark Place for subsequent use, faces the used time to be diluted to desired concn with complete culture solution.
Clone and cultivation: this tests human B cell lymphoma cell strain Ramos used, Raji, large B cell lymphoid tumor cell strain LY-10, HBL-1, LY-1, SuDHL-6, t cell lymphoma cell strain Jurkat, human pancreas cancer cell strain panc-1, HPAC, Miapaca-2, CFPAC-1, Breast cancer lines MDA-MB-231, MCF-7/ADR, human lung carcinoma cell line A549, H358, human leukemia cell line MV4-11, human hepatoma cell strain Huh7, PLC/PRF/5, human melanoma cell strain A2058, UACC62 etc. are all purchased from U.S. ATCC (American type culture collection), preserved by this laboratory.Everyone B cell lymphoma cell strain, large B cell lymphoid tumor cell strain, the RPMI-1640 perfect medium of t cell lymphoma cell strain containing 10% foetal calf serum, 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates are cultivated under 5%CO2,37 DEG C of conditions above.All the other cell strains use the DMEM perfect medium containing 10% foetal calf serum (MV4-11 cell is 20%), 100U/mL penicillin, 100 μ g/mL Streptomycin sulphates to cultivate under 5%CO2,37 DEG C of conditions.
2) experimental technique:
With the cell suspension that complete cell culture fluid adjustment cell concn is 1 ~ 2 × 104/mL, be inoculated in 96 orifice plates, every hole 200 μ l cell suspension, overnight incubation.Next day, inhale and abandon supernatant (the centrifugal rear absorption supernatant of suspension cell), then use the test-compound process cell of gradient concentration respectively.Establish the negative control group of not drug containing and isopyknic solvent control group, DMSO concentration is 0.1% simultaneously, and each dosage group establishes 3 multiple holes, at 37 DEG C, cultivates under 5%CO2 condition.After 72 hours, every hole adds the MTT reagent 20 μ l that concentration is 5mg/mL, after cultivating 2-4h again, abandon supernatant, every hole adds DMSO150 μ L again, vibration mixing 15min, measures absorbancy (A) value (A value is directly proportional to viable count) by microplate reader (λ=570nm), gets its mean value.Relative cell proliferation inhibiting rate=(control group A 570-experimental group A570)/control group A 570 × 100%.Experiment at least repeats 3 times.Experimental data mean represents, data statistics data adopts t inspection, and P<0.05 is that difference has statistical significance.Following compound on intracellular inhibited proliferation all represents with IC50 or inhibiting rate.
3) experimental result:
Adopt above method, to human B cell lymphoma cell strain Ramos, Raji, large B cell lymphoid tumor cell strain LY-10, HBL-1, LY-1, SuDHL-6, t cell lymphoma cell strain Jurkat, human pancreas cancer cell strain panc-1, HPAC, Miapaca-2, CFPAC-1, Breast cancer lines MDA-MB-231, MCF-7/ADR, human lung carcinoma cell line A549, H358, human leukemia cell line MV4-11, human hepatoma cell strain Huh7, PLC/PRF/5, human melanoma cell strain A2058, UACC62 etc. have carried out proliferation inhibition activity test.
Table 3. test-compound is to the proliferation inhibition activity (IC50: μ g/ml) of various cell strain
Test-compound 3a-6 3a-11 3a-9 3a-10
A549 - ≈0.35 <0.04 1.423
H358 - 0.65 ≈0.1 1.564
MV4-11 - 0.01531 0.002641 0.002134
Huh7 - 0.17 <0.04 0.23
PLC/PRF/5 - 1.25-2.5 0.24 2
A2058 - 1.1 0.04 0.9803
UACC62 - 0.37 0.04 1.282
Miapaca-2 - 1.53 0.034 3.12
PANC-1 - 3.61 0.23 >10
HBL-1 1.407 4.619 0.4644 0.8576
OCI-LY10 3.3-10 2.447 0.1 1.577
MDA-MB-231 >10 1.1 0.1072 1.011
MCF-7/ADR 3.3-10 >10 1.1-3.3 >10
RAJI 1.1-3.3 3.3-10 0.8908 2.547
CFPAC-1 >10 >10 3.3 10
SW1990 3.3 10 0.3-1 3.3
HPAC >10 >10 >10 3.3
SMMC7721 >10 10 1 3.3-10
SuDHL-6 1.1-3.3 3.254 0.4098 0.9155
RAMOS 0.1562 0.1379 0.03 0.5693
LY-1 >10 3.3-10 0.7311 1.529
Result shows, test-compound 3a-9 has very strong inhibit activities to RAMOS cell, and test-compound comprises A549, Huh7 to other tumor cell line, and MV4-11 etc. also have inhibit activities.
3, anti-B cell lymphoma Ramos tumor model experiment in compound 3a-9 body
The object of this experiment detects the anti-tumor in vivo effect of the compounds of this invention.This experiment uses the subcutaneous human lymphoma tumor model of Balb/C mouse, and the anti-tumor in vivo of test invention compound 3a-9 is active.Cell strain used is B cell lymphoma cell strain Ramos.Medicine R788 is being ground for positive control to carry out anti-B cell lymphoma.
1) experiment material:
IMDM, foetal calf serum, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), IMDM substratum is purchased from ATCC (American Type Culture Collection), human B cell lymphoma cell strain RAMOS is purchased from ATCC company of the U.S., and Balb/C mouse is purchased from biotech inc of dimension tonneau China of BeiJing, China.R788 is purchased from Chinese Shanghai Han Xiang Bioisystech Co., Ltd.
2) experimental technique:
Use BALB/C mice in 6 ~ 8 week age, the subcutaneous rear flank of mouse is inoculated according to about 8 × 106/0.1mL/ RAMOS cell concn, grow to (about 15 days) after 200 ~ 300mm3 until tumour, mice group (n=8) also starts gavage oral administration.
Experiment grouping: drug solvent control group (5%DMSO+25%PEG-400+75% water);
Compound 3a-9:40mg/kg q.d.;
Compound 3a-9:20mg/kg q.d.;
Positive control R788:80mg/kg q.d.;
Each group of medicine dissolution is in 5%DMSO+25%PEG-400+70% water.
Observation index: measure a Mouse Weight and tumour major diameter, minor axis calculate gross tumor volume (length × width2 × 0.5) every day, observe with or without diarrhoea, twitch, fash, body weight such as obviously to reduce at the reaction.
3) experimental result:
Experimental result shows, test-compound 3a-9 has obvious tumor growth restraining effect to B cell lymphoma cell strain Ramos, every day 20mg/kg and above dosage under, obviously can grow or complete regressing tumors by Tumor suppression, and show the inhibition being better than positive control (R788).Do not find in administration process that the untoward reactions such as body weight reduction, fash, diarrhoea appear in mouse, show under proof load, test-compound 3a-9 is endotoxic very low in dosage scope.
4, anti-B cell lymphoma HBL-1 tumor model experiment in compound 3a-9 body
The object of this experiment detects the anti-tumor in vivo effect of the compounds of this invention.This experiment uses the subcutaneous human lymphoma tumor model of Balb/C mouse, and the anti-tumor in vivo of test invention compound 3a-9 is active.Cell strain used is large B cell lymphoid tumor cell strain HBL-1.Medicine R788 is being ground for positive control to carry out Chinese People's Anti-Japanese Military and Political College's B cell lymphoma.
1) experiment material:
IMDM, foetal calf serum, pancreatin etc. are purchased from Gibco BRL company (Invitrogen Corporation, USA), IMDM substratum is purchased from ATCC (American Type Culture Collection), human B cell lymphoma cell strain RAMOS is purchased from ATCC company of the U.S., and Balb/C mouse is purchased from biotech inc of dimension tonneau China of BeiJing, China.R788 is purchased from Chinese Shanghai Han Xiang Bioisystech Co., Ltd.
2) experimental technique:
Use BALB/C mice in 6 ~ 8 week age, the subcutaneous rear flank of mouse is inoculated according to about 8 × 106/0.1mL/ HBL-1 cell concn, grow to (about 15 days) after 200 ~ 300mm3 until tumour, mice group (n=8) also starts gavage oral administration.
Experiment grouping: drug solvent control group (5%DMSO+25%PEG-400+75% water);
Compound 3a-9:40mg/kg q.d.;
Compound 3a-9:20mg/kg q.d.;
Positive control R788:80mg/kg q.d.;
Each group of medicine dissolution is in 5%DMSO+25%PEG-400+70% water.
Observation index: measure a Mouse Weight and tumour major diameter, minor axis calculate gross tumor volume (length × width2 × 0.5) every day, observe with or without diarrhoea, twitch, fash, body weight such as obviously to reduce at the reaction.
3) experimental result:
Experimental result shows, test-compound 3a-9 has obvious tumor growth restraining effect to B cell lymphoma cell strain HBL-1, every day 40mg/kg and above dosage under, obviously can grow or complete regressing tumors by Tumor suppression, and show the inhibition being better than positive control (R788).Do not find in administration process that the untoward reactions such as body weight reduction, fash, diarrhoea appear in mouse, show under proof load, test-compound 3a-9 is endotoxic very low in dosage scope.
Compound prepared by the present invention all have detected it to focal adhesion kinase (FAK), spleen tyrosine kinase (SYK), human protein kinase B α (PKB α), SRC, Axl, cell cycle dependent kinase 2 (CDK2)/cyclin E (cyclinE), EphA3, IGF-1R (IGF-1R), Janus kinases 2 (JAK2), vascular endothelial growth factor (KDR), Lyn, Met, pyruvate kinase 2 (Pyk2), the kinase whose inhibitions such as phosphatidylinositol3 3 kinase p110 α/p85 α (PI3K (p110 α/p85 α)), also have detected prepared compound to human B cell lymphoma cell strain Ramos simultaneously, Raji, large B cell lymphoid tumor cell strain LY-10, HBL-1, LY-1, SuDHL-6, t cell lymphoma cell strain Jurkat, human pancreas cancer cell strain panc-1, HPAC, Miapaca-2, CFPAC-1, Breast cancer lines MDA-MB-231, MCF-7/ADR, human lung carcinoma cell line A549, H358, human leukemia cell line MV4-11, human hepatoma cell strain Huh7, PLC/PRF/5, human melanoma cell strain A2058, the proliferation inhibition activity tests such as UACC62, partial data is shown in above-mentioned table 1, 2 and 3.Result shows, compound prepared by the present invention has the well kinase whose effect of suppression, show as the cultivation effect of inhibition tumor cell further, what is more important, compound of the present invention has the effect of the multiple kinases of target (such as SYK and FAK) simultaneously, and particularly compound 3a-9 and 3a-10 shows unforeseeable effect.

Claims (17)

  1. Fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 1.5-, is characterized in that: structural formula is such as formula shown in I:
    Wherein, R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
  2. 2. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that:
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    R2 is substituted or unsubstituted phenyl or substituted or unsubstituted 6 yuan of heteroaryls; The substituting group of the phenyl of described replacement or 6 yuan of heteroaryls is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is the substituting group of 6 yuan of Heterocyclylalkyls of described replacement is-H ,-F ,-Cl ,-Br ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 alkoxyl group, or the alkyl of the C1 ~ C4 of halogen substiuted, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group, or substituted or unsubstituted 6 yuan of Heterocyclylalkyls; The substituting group of 6 yuan of Heterocyclylalkyls of described replacement be C1 ~ C4 alkyl or described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; The phenyl of described replacement or the substituting group of pyridyl be-H ,-F ,-Cl ,-Br, methyl, methoxyl group,
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    R2 is
    It is most preferred,
    R1 is
    R2 is
  3. 3. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in II:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  4. 4. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in III:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  5. 5. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in IV:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  6. 6. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in V:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  7. 7. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in VI:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  8. 8. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in VII:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    R1 is
  9. 9. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in VIII:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  10. 10. fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in IX:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  11. Fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 11. 5-according to claim 1, is characterized in that: work as R 2for time, structure is such as formula shown in X:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    Preferably,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of the phenyl of described replacement is the alkoxyl group of-H ,-F ,-Cl ,-Br, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; R3 is the alkyl of-H ,-F ,-Cl ,-Br or C1 ~ C4;
    It is preferred further,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is the alkyl of-H or C1 ~ C4; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 ,-CF3, the alkyl of C1 ~ C4 or-OCF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl ,-Br, the alkyl of C1 ~ C4 or-OCF3; R3 is-H ,-F ,-Cl ,-Br or methyl;
    It is further preferred,
    R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H, methyl, ethyl or propyl group; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H ,-F ,-Cl ,-Br or methyl;
    Further preferred, R1 be substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted Bian Ji, the substituting group of the cyclohexyl of described replacement is-H or methyl; The substituting group of the phenyl of described replacement is-H ,-F ,-Cl ,-Br ,-CONH2 or-CF3; The substituting group of the Bian Ji of described replacement is-H ,-F ,-Cl or-Br; R3 is-H or methyl;
    It is most preferred,
    R1 is
  12. 12. 5-fluoro-2 according to any one of claim 1 ~ 11, 4-disubstituted amido pyrimidine derivatives, it is characterized in that: comprise following compound: the fluoro-N4-of 5-(2-methyl cyclohexylamine)-N2-(3, 4, 5-trimethoxy-aniline) pyrimidine-2, 4-diamines, N6-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-yl)-2-toluquinoline-4, 6-diamines, the fluoro-N2-(3 of N4-(the chloro-3-of 4-(trifluoromethyl) phenyl)-5-, 4, 5-trimethoxy-aniline) pyrimidine-2, 4-diamines, 5-amino-6-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino)-3, 4-dihydro-quinolinone, N4-(3, 4-difluorophenyl) the fluoro-N2-(3 of-5-, 4, 5-trimethoxyphenyl) pyrimidine-2, 4-diamines, the chloro-2-of 4-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino) benzamide, 5-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino)-1H-benzimidazolone, 3-(the fluoro-2-(3 of 5-, 4, 5-trimethoxy-aniline) pyrimidine-4-amino) benzamide, the chloro-2-of 4-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide, N6-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-yl)-2-toluquinoline-4, 6-diamines, 3-(the fluoro-2-of 5-(4-(4-methylpiperazine-1-yl) anilino) pyrimidine-4-is amino) benzamide.
  13. The preparation method of fluoro-2, the 4-disubstituted amido pyrimidine derivatives of the 5-described in 13. any one of claim 1 ~ 12, is characterized in that: synthetic route is as follows:
    The aliphatic amide of a, 2,4-bis-chloro-5-FUs (1) and different replacement or aromatic amine compound (2) is obtained by reacting under the catalysis of weakly alkaline catalyzer;
    Wherein, solvent is any one in tetrahydrofuran (THF), methylene dichloride, ethyl acetate, dimethylbenzene, toluene, acetonitrile, and catalyzer is DIPEA, triethylamine, salt of wormwood, pyridine, N, any one in accelerine, N, N-Diethyl Aniline; Temperature of reaction is 0 DEG C ~ 120 DEG C; Reaction times is 0.5 ~ 12h;
    B, by the aromatic amine (H of compound (2) from different replacement 2n-R 2) under acid or base catalysis, be obtained by reacting compound (3);
    Wherein, acid is any one in concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid, tosic acid; Alkali is any one in DIPEA, triethylamine, salt of wormwood, sodium carbonate, sodium hydroxide, potassium hydroxide; Solvent is any one in tetrahydrofuran (THF), acetone, butanone, Virahol, propyl carbinol, DMF, dioxane; Temperature of reaction is 45 DEG C ~ 125 DEG C; Reaction times is 6h ~ 16h;
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen;
    R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
  14. Intermediate used during fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-described in 14. preparation any one of claim 1 ~ 12, structural formula is as shown in XI:
    R1 be the cycloalkyl of substituted or unsubstituted C4 ~ C8, the alkyl of C1 ~ C8, substituted or unsubstituted C6 ~ C14 aryl, substituted or unsubstituted aralkyl, the substituting group of C4 ~ C8 cycloalkyl of described replacement is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4 or the alkoxyl group of C1 ~ C4; The substituting group of C6 ~ C14 aryl of described replacement is-H, halogen ,-NH 2,-NO 2, the aminoacyl of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted, the alkyl of C1 ~ C4 or C1 ~ C4 alkoxyl group; The substituting group of described substituted aralkyl is-H, halogen ,-NH 2,-NO 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, the alkyl of the C1 ~ C4 of halogen substiuted or the aminoacyl of C1 ~ C4; R3 is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, C1 ~ C4 the alkyl of C1 ~ C4 that replaces of alkoxy or halogen.
  15. Intermediate used during fluoro-2, the 4-disubstituted amido pyrimidine derivatives of 5-described in 15. preparation any one of claim 1 or 2, structure is as shown in XII:
    R2 is substituted or unsubstituted C6 ~ C14 aryl or substituted or unsubstituted 5 ~ 14 yuan of heteroaryls; The substituting group of C6 ~ C14 aryl of described replacement or 5 ~ 14 yuan of heteroaryls is-H, halogen, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5 ~ 10 yuan of Heterocyclylalkyls; The substituting group of the aminoacyl of described replacement is 5 ~ 10 yuan of Heterocyclylalkyls of the alkyl replacement of C1 ~ C4, and described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3; The substituting group of 5 ~ 10 yuan of Heterocyclylalkyls of described replacement is-H, halogen ,-NH 2, the alkyl of C1 ~ C4, the alkoxyl group of C1 ~ C4, carbonyl that the alkyl of C1 ~ C4 replaces or halogen substiuted the alkyl of C1 ~ C4, described heteroatoms is N, S or O, and heteroatoms number is 1 ~ 3.
  16. Purposes in fluoro-2,4-disubstituted amido pyrimidine derivatives preparation treatment tumour, autoimmune disorder or the anti-inflammatory drugs of 5-described in 16. any one of claim 1 ~ 12.
  17. 17. pharmaceutical compositions, are added by fluoro-2, the 4-disubstituted amido pyrimidine derivatives of the 5-described in any one of claim 1 ~ 12 that the complementary composition of pharmaceutically acceptable is prepared from.
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