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

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

5-fluoro-2,4-disubstituted aminopyrimidine derivatives and their preparation methods and uses

technical field

The invention belongs to the technical field of organic synthetic medicines, in particular to 5-fluoro-2,4-disubstituted aminopyrimidine derivatives and their preparation methods and uses. the

Background technique

Kinases are the main components of cell signal transduction pathways, and abnormal kinase activity usually leads to abnormal cell signaling, which leads to the occurrence of various diseases including cancer, autoimmune diseases, diabetes, inflammation, etc. In view of this, kinases, as one of the most important targets for disease treatment, have become the hotspots of current research. the

As an important member of the kinase family, spleen tyrosine kinase (Syk) is a non-receptor protein tyrosine kinase. The Syk protein consists of two tandem Src homology domains 2 (SH2) at the N-terminal and a C-terminal kinase domain. Syk is expressed in all cells of the hematopoietic system, with high expression in B cells and low expression in T cells, platelets and bone marrow cells. The function of Syk was first observed in the process of B cell receptor signal transduction. Syk is very important for the development of progenitor B cells into pre-B cells, which can promote the entry of immature B cells into the white pulp of the spleen. Syk deficiency can lead to the complete loss of mature B cells. missing. Studies have shown that abnormal Syk activity is closely related to tumors, autoimmune diseases, inflammation, etc., and has been listed as an important therapeutic target for these diseases. the

Another kinase family member, focal adhesion kinase (FAK) is also a non-receptor protein tyrosine kinase. FAK is involved in many cell signaling pathways, and it is the center of intracellular and extracellular signal transduction. It can integrate signals from extracellular nutrition, pressure, cell adhesion, etc., regulate the activity of downstream molecules, control cell metabolism, proliferation, and even cell fate. Studies have shown that FAK can regulate cell growth, anchorage, migration, malignant transformation and apoptosis. The protein level of FAK is highly expressed or overactivated in ovarian cancer, thyroid cancer, breast cancer, colorectal cancer and other tumors, and its high expression plays an important role in the adhesion and invasion between cells and between cells and extracellular matrix At the same time, it is closely related to tumor cell survival, cycle regulation, proliferation, apoptosis, migration and tumor metastasis. FAK is also listed as an important target for tumor therapy. the

Traditional kinase-specific drug development focuses on highly selective kinase inhibitors targeting a single kinase. However, for complex diseases such as tumors and autoimmune diseases, multi-targeted drugs that simultaneously target multiple kinases (such as SYK and FAK) may have greater advantages in terms of curative effect and avoidance of recurrence. the

Contents of the invention

The first technical problem to be solved by the present invention is to provide a 5-fluoro-2,4-disubstituted aminopyrimidine derivative, the structural formula of which is shown in Formula I:

Wherein, R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl;

R2 is a substituted or unsubstituted C6~C14 aryl group or a substituted or unsubstituted 5~14 membered heteroaryl group; the substituents of the substituted C6~C14 aryl group or 5~14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted with an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl;

R2 is a substituted or unsubstituted phenyl or a substituted or unsubstituted 6-membered heteroaryl; the substituents of the substituted phenyl or 6-membered heteroaryl are -H, -F, -Cl, -Br, C1 ~C4 alkyl, C1~C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted aminoacyl is The substituents of the substituted 6-membered heterocycloalkyl are -H, -F, -Cl, -Br, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy, Or a C1-C4 alkyl group substituted by halogen, the heteroatom is N, S or O, and the number of heteroatoms is 1-3.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl;

R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; the substituents of the substituted phenyl or pyridyl are -H, -F, -Cl, -Br, methyl, methoxy, Or a substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted 6-membered heterocycloalkyl is C1～C4 alkyl or The heteroatoms are N, S or O, and the number of heteroatoms is 1-3.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl 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 substituents of the substituted phenyl or pyridyl are -H, -F, -Cl, -Br, methyl, methoxy,

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl;

R2 is

most preferred,

R1 is

R2 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is , the structure is shown in Formula II:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

most preferred,

R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is , the structure is shown in Formula III:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

most preferred,

R1 is

As a preferred version of the present invention, among the above-mentioned 5-fluoro-2,4 _- disubstituted aminopyrimidine derivatives, when R2 is When, the structure is as shown in formula IV:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is , the structure is shown in Formula V:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is , the structure is shown in formula VI:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives prove that when R ₂ is , the structure is as shown in formula VII:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is When, the structure is as shown in formula VIII:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is When, the structure is as shown in formula IX:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

As a preferred version of the present invention, in the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, when R ₂ is , the structure is as shown in Formula X:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

Most preferably, R1 is

The above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives include the following compounds:

5-fluoro-N4-(2-methylcyclohexylamine)-N2-(3,4,5-trimethoxyaniline)pyrimidine-2,4-diamine, N6-(5-fluoro-2-(3 ,4,5-trimethoxyaniline)pyrimidin-4-yl)-2-methylquinoline-4,6-diamine, N4-(4-chloro-3-(trifluoromethyl)phenyl)- 5-fluoro-N2-(3,4,5-trimethoxyaniline)pyrimidine-2,4-diamine, 5-amino-6-(5-fluoro-2-(3,4,5-trimethoxy Aniline) pyrimidine-4-amino)-3,4-dihydroquinolinone, N4-(3,4-difluorophenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl ) pyrimidine-2,4-diamine, 4-chloro-2-(5-fluoro-2-(3,4,5-trimethoxyaniline) pyrimidine-4-amino)benzamide, 5-(5- Fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4-amino)-1H-benzimidazolone, 3-(5-fluoro-2-(3,4,5-trimethoxyaniline) )pyrimidine-4-amino)benzamide, 4-chloro-2-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzidine Amide, N6-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidin-4-yl)-2-methylquinoline-4,6-diamine, 3-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzamide. the

The second technical problem solved by the present invention is to provide the preparation method of the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, the synthetic route is as follows:

a, 2,4-dichloro-5-fluoropyrimidine (1) and different substituted aliphatic or aromatic amines Under the catalysis of weakly basic catalyst, react to obtain compound (2);

Wherein, the solvent is any one of tetrahydrofuran, methylene chloride, ethyl acetate, xylene, toluene, and acetonitrile, and the catalyst is N,N-diisopropylethylamine, triethylamine, potassium carbonate, pyridine, N, Any one of N-dimethylaniline and N,N-diethylaniline; the reaction temperature is 0℃～120℃; the reaction time is 0.5～12h;

b. Reaction of compound (2) with different substituted aromatic amines (H ₂ NR ₂ ) under acid or base catalysis to obtain compound (3);

Wherein, the acid is any one of concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid; the base is N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, Any one of potassium hydroxide; the solvent is any one of tetrahydrofuran, acetone, butanone, isopropanol, n-butanol, N,N-dimethylformamide, and dioxane; the reaction temperature is 45 ℃～125℃; the reaction time is 6h～16h;

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl;

R2 is a substituted or unsubstituted C6~C14 aryl group or a substituted or unsubstituted 5~14 membered heteroaryl group; the substituents of the substituted C6~C14 aryl group or 5~14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted with an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3.

The third technical problem solved by the present invention is to provide the use of the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives in the preparation of drugs for treating tumors, autoimmune diseases or inflammations. the

The fourth technical problem solved by the present invention is to provide prodrugs or hydrates of the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives. Said prodrugs are derivatives of the aforementioned compounds, which themselves may have weak or even no activity, but after administration, are converted under physiological conditions (e.g. by metabolism, solvolysis or otherwise) to corresponding biologically active form. the

The fifth technical problem solved by the present invention is to provide the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivative prepared by adding pharmaceutically acceptable auxiliary components. the

The present invention also provides intermediates used in the preparation of the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, the structure of which is shown in XI:

R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl.

preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1-C4 alkyl or C1-C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1-C4 alkyl.

Further preferred,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl.

More preferably,

R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benzyl group is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl.

More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituents are -H, -F, -Cl or -Br; R3 is -H or methyl.

most preferred,

R1 is

The present invention also provides intermediates used in the preparation of the above-mentioned 5-fluoro-2,4-disubstituted aminopyrimidine derivatives, the structure of which is shown in XII:

R2 is a substituted or unsubstituted C6~C14 aryl group or a substituted or unsubstituted 5~14 membered heteroaryl group; the substituents of the substituted C6~C14 aryl group or 5~14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted with an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3.

Preferably, R2 is a substituted or unsubstituted phenyl or a substituted or unsubstituted 6-membered heteroaryl; the substituents of the substituted phenyl or 6-membered heteroaryl are -H, -F, -Cl, - Br, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted aminoacyl is The substituents of the substituted 6-membered heterocycloalkyl are -H, -F, -Cl, -Br, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy, Or a C1-C4 alkyl group substituted by halogen, the heteroatom is N, S or O, and the number of heteroatoms is 1-3.

Further preferably, R2 is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl; the substituents of the substituted phenyl or pyridyl are -H, -F, -Cl, -Br, methyl, Methoxy, Or a substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted 6-membered heterocycloalkyl is C1～C4 alkyl or The heteroatoms are N, S or O, and the number of heteroatoms is 1-3.

More preferably,

R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; the substituents of the substituted phenyl or pyridyl are -H, -F, -Cl, -Br, methyl, methoxy,

Most preferably, R2 is

The compound prepared by the present invention is a multi-target drug capable of simultaneously targeting multiple kinases (such as SYK and FAK), so it has greater advantages in curative effect, recurrence avoidance and the like. the

Description of drawings

Figure 1 The tumor growth curves of different groups in the RAMOS model;

Figure 2 Tumor growth curves of different groups in the HBL-1 model. the

Detailed ways

The present invention will be further elaborated below in conjunction with the examples, but the present invention is not limited; all technologies realized based on the above contents of the present invention belong to the scope of the present invention. the

Embodiment 1, the synthesis of intermediate 2-chloro-5-fluoro-N-(2-methylcyclohexylamine) pyrimidin-4-amine (2a-1)

2,4-dichloro-5-fluoro-pyrimidine (1.67g, 10mmol) and a catalytic amount of N,N-diisopropylethylamine (DIEA) were dissolved in 150ml of dichloromethane, and the The dichloromethane solution of 2-methylcyclohexylamine (1.13g, 10mmol) was slowly dropped into the above solution, and the reaction was stopped after 0.5 hours of reaction, extracted twice with water, and the organic layer was dried with anhydrous magnesium sulfate, and then distilled under reduced pressure , the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 10:1) to obtain the product, yield: 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

Embodiment 2, the synthesis of intermediate 2-chloro-5-fluoro-N-(4-chloro-3-(trifluoromethyl)aniline)pyrimidin-4-amine (2a-2)

2,4-Dichloro-5-fluoro-pyrimidine (1.67g, 10mmol), 4-chloro-3-(trifluoromethyl)aniline (1.96g, 10mmol) and a catalytic amount of N,N-diisopropyl Diethylamine (DIEA) was dissolved in 100ml of ethanol solution, and the reaction was refluxed overnight. After the reaction was stopped, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 7: 1) The product was obtained in a yield of 78%. the

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＝8.0 Hz, J = 2.4Hz, 1H), 7.75 (d, J = 9.2Hz, 1H) ppm. the

Embodiment 3, the synthesis of 5-fluoro-N4-(2-methylcyclohexylamine)-N2-(3,4,5-trimethoxyaniline) pyrimidine-2,4-diamine (3a-1)

2-Chloro-5-fluoro-N-(2-methylcyclohexylamine)pyrimidin-4-amine (2a-1, 280mg, 1.2mmol) and 3,4,5-trimethoxyaniline (221mg, 1.25 mmol) and a catalytic amount of N,N-diisopropylethylamine (DIEA) were dissolved in 50mL of n-butanol, and the above reaction system was placed at 100°C for overnight reaction, the reaction was stopped, and the residue was distilled off under reduced pressure to remove the solvent The product was purified by column chromatography (eluent: petroleum ether: ethyl acetate = 4: 1), yield: 94%; 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]. 

Example 4, N6-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidin-4-yl)-2-methylquinoline-4,6-diamine (3a-2) Synthesis

4-Nitro-2-cyanoaniline (1.6g, 10mmol) and a certain amount of acetone were dissolved in anhydrous toluene, and tin tetrachloride (1.2ml, 10mmol) was slowly added dropwise to the above reaction solution under ice-water bath conditions In, then this reaction solution was refluxed for 4.5h. After stopping the reaction, a large amount of solids precipitated during cooling to room temperature. The solids were suction filtered and washed with a small amount of ether to obtain 2-methyl-6-nitro-4-aminoquinoline. Next, use reduced iron powder to reduce the nitro group to an amino group under the catalysis of ammonium chloride, and then reflux with 2,4-dichloro-5-fluoropyrimidine under the catalysis of N,N-diisopropylethylamine (DIEA). The reaction was carried out in ethanol under the condition overnight, and the solid precipitated in the reaction was filtered with suction to obtain 2a-3. Finally, the final product was obtained by using the intermediate 2a-3 and 3,4,5-trimethoxyaniline according to the synthesis method of 3a-1, with a total yield of 46% and a purity of 99%. the

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]. 

Example 5, N4-(4-chloro-3-(trifluoromethyl)phenyl)-5-fluoro-N2-(3,4,5-trimethoxyaniline)pyrimidine-2,4-diamine ( 3a-3) Synthesis

The final product (3a-3) was synthesized according to the synthetic method of compound (3a-1) by intermediate (2a-2) and 3,4,5-trimethoxyaniline, with a yield of 82% and a purity of 98%. the

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

Example 6, 5-amino-6-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4-amino)-3,4-dihydroquinolinone (3a-4) Synthesis

The synthetic intermediate 5-amino-6-(2-chloro-5-fluoropyrimidine-4-amino)-3,4-dihydroquinolinone (850mg, 2.7moml) and 3,4,5-trimethoxy Aniline (586 mg, 3.1 mol) was reacted at 110 °C in n-butanol solvent for 8 hours under the catalysis of a catalytic amount of hydrochloric acid, and the progress of the reaction was detected by TLC. Extracted 3 times, dried the organic layer with anhydrous magnesium sulfate, distilled off the solvent under reduced pressure, and then recrystallized with ethanol and petroleum ether to obtain the product with a total yield of 64% and a purity of 99%. the

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]. 

Example 7, N4-(3,4-difluorophenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine (3a-5) synthesis

Using the synthetic intermediate 2-chloro-N-(3,4-difluorophenyl)-5-fluoropyrimidin-4-amine and 3,4,5-trimethoxyaniline according to the final product (3a-1) Synthetic methods 3a-5 was synthesized with a two-step total yield of 61% and a purity of 99%. the

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].

Synthesis of Example 8, 4-chloro-2-(5-fluoro-2-(3,4,5-trimethoxyaniline) pyrimidine-4-amino)benzamide (3a-6)

Using the synthesized intermediates 4-chloro-2-(2-chloro-5-fluoropyrimidine-4-amino)aniline (300mg, 1.0mmol) and 3,4,5-trimethoxyaniline (450mg, 1.75mmol), React in DMF at 95°C under a catalytic amount of hydrochloric acid for 6 hours, detect the reaction solution by TLC, stop the reaction after the reaction is complete, extract 3 times with a large amount of water and ethyl acetate, and dry the organic layer over anhydrous magnesium sulfate. The solvent was distilled off under pressure, and the residue was purified by column chromatography (dichloromethane:methanol=70:1) and then recrystallized by ethanol and petroleum ether to obtain the product. The total yield of the two steps was 66%, and the purity was 98%. the

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]. 

Synthesis of Example 9, 5-(5-fluoro-2-(3,4,5-trimethoxyaniline) pyrimidine-4-amino)-1H-benzimidazolone (3a-7)

Using the synthetic intermediate 5-(2-chloro-5-fluoropyrimidine-4-amino)-1H-benzimidazolone and 3,4,5-trimethoxyaniline according to the synthetic method of the final product (3a-1) 4a-7 was synthesized with a two-step total yield of 64% and a purity of 99%. the

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]. 

Synthesis of Example 10, 3-(5-fluoro-2-(3,4,5-trimethoxyaniline) pyrimidine-4-amino) benzamide (3a-8)

The synthetic intermediate 3-(2-chloro-5-fluoropyrimidine-4-amino)benzamide (600mg, 2.26mmol), 3,4,5-trimethoxyaniline (600mg, 3.2mmol) and Cui amount of Concentrated hydrochloric acid was dissolved in 45ml of DMF, and the above reaction solution was placed at 100°C to react overnight, then extracted three times with water and ethyl acetate, the organic layer was distilled under reduced pressure, and the residue was subjected to column chromatography (the eluent was di Chloromethane: methanol = 70: 1) to obtain the final product after purification, the total yield of the two steps is 68%, and the purity is 98%. 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]. 

Example 11, 4-chloro-2-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzamide (3a-9) synthesis

Using the synthetic intermediate 4-chloro-2-(2-chloro-5-fluoropyrimidine-4-amino)aniline (300mg, 1.0mmol) and 4-(4-methylpiperazin-1-yl)aniline (384mg , 2.0 mmol) under the catalysis of concentrated hydrochloric acid, 3a-9 was synthesized according to the synthesis method of 3a-6, the total yield of two steps was 32%, and the purity was 98%. the

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]. 

Example 12, N6-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidin-4-yl)-2-methylquinoline-4,6-di Synthesis of Amines (3a-10)

Using the synthesized 2a-3 (300mg, 1.0mmol) and 4-(4-methylpiperazin-1-yl) aniline (384mg, 2.0mmol) under the catalysis of concentrated hydrochloric acid, synthesize 3a-3 according to the synthesis method of 3a-6 10. The two-step total yield is 64%, and the purity is 98%. the

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]. 

Synthesis of Example 13, 3-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzamide (3a-11)

Using the synthetic intermediate 3-(2-chloro-5-fluoropyrimidine-4-amino)benzamide and 4-(4-methylpiperazin-1-yl)aniline under the catalysis of concentrated hydrochloric acid, according to 3a-6 The synthesis method of 3a-11 was synthesized, the two-step total yield was 45%, and the purity was 98%. the

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 experiment part

1. Kinase inhibitory activity test of 5-fluoro-2,4-disubstituted aminopyrimidine derivatives of the present invention

The purpose of this experiment is to detect the inhibitory activity of the compounds of the present invention on in vitro kinases, and the method used is isotope labeling (labeling the γ-phosphate group on ATP). In this experiment, focal adhesion kinase (FAK), spleen tyrosine kinase (SYK), human protein kinase Bα (PKBα), SRC, Axl, cell cycle-dependent kinase 2 (CDK2)/cyclin E (cyclinE) , EphA3, Insulin-like Growth Factor-1 Receptor (IGF-1R), Janus Kinase 2 (JAK2), Vascular Endothelial Growth Factor (KDR), Lyn, Met, Pyruvate Kinase 2 (Pyk2), Phosphatidylinositol 3 Kinases such as kinase p110α/p85α (PI3K(p110α/p85α)) were tested for in vitro activity inhibition. The kinase inhibitory activity of the test compound is expressed by IC50 (half inhibitory concentration) or the inhibitory rate of the test compound on the kinase activity at a concentration of 10 μM. The IC50 value can be obtained by calculating the inhibition rate of the kinase activity of the test compound at a series of different concentrations. the

1) Experimental materials:

20mM 3-(N-morpholino)propanesulfonic acid (MOPS); 1mM ethylenediaminetetraacetic acid (EDTA); 0.01% Brij-35 (Brij-35); 5% glycerol (Glycerol); 0.1% mercaptoethanol ( mercaptoethanol); 1mg/mL bovine serum albumin (BSA); 10mM manganese dichloride solution (MnCl2);

100μM EEEEYEEEEEEYYIIEEEEEEYEEEEEEYYEEEEEEKKKK (substrate of FAK)

0.1mg/mL poly(Glu,Tyr)4:1 (substrate of SYK) 

30 μM GRPRTSSFAEGKK (substrate of PKBα)

500mM GGEEEEYFELVKKKK (substrate of SRC)

250 μM 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 μM KKKSPGEYVNIEFG (substrate of IGF-1R)

100 μM KTFCGTPEYLAPEVRREPRILSEEEQEMFRDFDYIADWC (substrate of JAK2)

250 μM KKKSPGEYVNIEFG (substrate of KDR)

0.1mg/mL poly(Glu,Tyr)4:1 (Substrate of Lyn) 

250 μM GGMEDIYFEFMGGKKK (substrate of MET)

0.1mg/mL poly(Glu,Tyr)4:1 (substrate of Pyk2)

10μM phosphatidylinositol4,5-bisphosphate (substrate of PI3Kinase(p110α/p85α))

10mM magnesium acetate and γ-33P-ATP solution; stop buffer (3% phosphate buffer); wash buffer (75mM phosphate solution); methanol (methanol); Filtermat A membrane; ), spleen tyrosine kinase (SYK), human protein kinase Bα (PKBα), SRC, Axl, cell cycle-dependent kinase 2 (CDK2)/cyclin E (cyclinE), EphA3, insulin-like growth factor-1 receptor Janus kinase 2 (JAK2), vascular endothelial growth factor (KDR), Lyn, Met, pyruvate kinase 2 (Pyk2), phosphatidylinositol 3-kinase p110α/p85α (PI3K (p110α/p85α )) and other kinases, test compounds. the

2) Experimental method:

In a reaction tube, sequentially add buffer solution (8mM MOPS, pH7.0, 0.2mM EDTA, 10mM MnCl ₂ ), kinases to be tested (5-10mU) (FAK, SYK, PKBα, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110α/p85α)) the substrates of the kinases to be tested (reference experimental materials), and 10mM magnesium acetate and γ33P-ATP solutions, different concentrations of the subject test compound. Reactions were initiated with the addition of MgATP and incubated for 40 minutes at room temperature. Finally, the reaction was terminated with 5 μL of 3% phosphate buffer, and 10 μL of the reaction solution was titrated onto the Filtermat A membrane, washed three times with 75 mM phosphate solution for 5 minutes each time, and washed once with methanol. Finally, the Filtermat A membrane was dried and scintillation counted. The scintillation count value reflected the degree of phosphorylation of the substrate, which could characterize the inhibition of the kinase activity.

3) Experimental results:

Through the above experimental methods, the compounds of the present invention were tested against FAK, SYK, PKBα, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110α/p85α) Kinase inhibitory activity. the

Table 1 shows the IC50 values of the inhibitory activities of the test compounds on some kinases. the

Table 2 shows the effects of some test compounds 3a-9 on PKBα, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2, PI3Kinase (p110α/p85α) at a concentration of 10 μM, respectively. ) and other kinase activity inhibition rate (%). the

Table 1. Inhibitory activity of test compounds on some kinases

Table 2. The inhibitory rate of test compound 3a-9 to various kinase activities at a concentration of 10 μM

test kinase Inhibition rate (%) of the test compound on kinase activity at a concentration of 10 μM Axl 100 CDK2/cyclinE 83 EphA3 81 IGF-1R,activated 100 JAK2 100 KDR 100 Lynn 100 met 100 PKBα 69 Pyk2 99 Src(1-530) 100 PI3Kinase 41

The experimental results show that the tested compounds not only have strong inhibitory activity on SYK and FAK, but also have strong inhibitory activity on PKBα, SRC, Axl, CDK2/cyclinE, EphA3, IGF-1R, JAK2, KDR, Lyn, Met, Pyk2 kinases Has good inhibitory activity. the

2. In vitro human tumor cell proliferation inhibition experiment of 5-fluoro-2,4-disubstituted aminopyrimidine derivatives of the present invention

The purpose of this experiment is to detect the inhibitory activity of the compound of the present invention on the proliferation of human tumor cells in vitro, and the method adopted is the MTT (tetramethyl azolium salt) colorimetric method. the

1) Experimental materials:

Main reagents: RPMI-1640, fetal bovine serum, trypsin, etc. were purchased from Gibco BRL (Invitrogen Corporation, USA), and IMDM medium was purchased from ATCC (American Type Culture Collection). Tetramethylazolium salt (MTT) and dimethyl sulfoxide (DMSO) are products of Sigma Company (USA). The XXX series derivatives were synthesized by the inventors, prepared in vitro experiments with 100% DMSO to make 10mM storage solutions, stored in a refrigerator at -20°C in the dark for future use, and diluted with complete culture solution to the required concentration before use. the

Cell lines and culture: the human B-cell lymphoma cell lines Ramos and Raji used in this experiment, the large B-cell lymphoma cell lines LY-10, HBL-1, LY-1, SuDHL-6, and the T-cell lymphoma cell line Jurkat , human pancreatic cancer cell lines panc-1, HPAC, Miapaca-2, CFPAC-1, human breast cancer cell lines MDA-MB-231, MCF-7/ADR, human lung cancer cell lines A549, H358, human leukemia cell line MV4 -11, human liver cancer cell lines Huh7, PLC/PRF/5, human melanoma cell lines A2058, UACC62, etc. were purchased from ATCC (American type culture collection) in the United States and kept in our laboratory. Use RPMI-1640 complete medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 μg/mL streptomycin for all human B-cell lymphoma cell lines, large B-cell lymphoma cell lines, and T-cell lymphoma cell lines. Cultivate at 5% CO2, 37°C. The remaining cell lines were cultured in DMEM complete medium containing 10% fetal bovine serum (20% for MV4-11 cells), 100 U/mL penicillin, and 100 μg/mL streptomycin at 5% CO2 and 37°C. the

2) Experimental method:

Use complete cell culture medium to adjust the cell suspension to a cell concentration of 1-2×104/mL, inoculate in a 96-well plate with 200 μl of cell suspension per well, and culture overnight. On the next day, the supernatant was discarded (the supernatant was aspirated after the suspended cells were centrifuged), and then the cells were treated with test compounds at gradient concentrations. At the same time, a negative control group without drugs and a solvent control group of equal volume were set up. The concentration of DMSO was 0.1%. Three replicate wells were set up for each dose group, and they were cultured at 37°C and 5% CO2. After 72 hours, add 20 μl of MTT reagent with a concentration of 5 mg/mL to each well, and after culturing for 2-4 hours, discard the supernatant, add 150 μL of DMSO to each well, shake and mix for 15 minutes, and measure the absorbance with a microplate reader (λ=570nm) (A) value (A value is directly proportional to the number of living cells), which is the average value. Relative cell proliferation inhibition rate=(control group A570−experimental group A570)/control group A570×100%. Experiments were repeated at least 3 times. The experimental data are represented by the mean, and the statistical data are t-tested, and P<0.05 means that the difference is statistically significant. The inhibitory effects of the following compounds on cell proliferation are expressed by IC50 or inhibition rate. the

3) Experimental results:

Using the above method, human B-cell lymphoma cell line Ramos, Raji, large B-cell lymphoma cell line LY-10, HBL-1, LY-1, SuDHL-6, T-cell lymphoma cell line Jurkat, human pancreatic cancer Cell lines panc-1, HPAC, Miapaca-2, CFPAC-1, human breast cancer cell lines MDA-MB-231, MCF-7/ADR, human lung cancer cell lines A549, H358, human leukemia cell lines MV4-11, human Liver cancer cell lines Huh7, PLC/PRF/5, human melanoma cell lines A2058, UACC62, etc. were tested for their proliferation inhibitory activity. the

Table 3. Proliferation inhibitory activity (IC50: μg/ml) of test compounds on various cell lines

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 HPACs >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

The results show that the test compound 3a-9 has strong inhibitory activity on RAMOS cells, and the test compound also has inhibitory activity on other tumor cell lines including A549, Huh7, MV4-11 and so on. the

3. Anti-B cell lymphoma Ramos tumor model experiment of compound 3a-9 in vivo

The purpose of this experiment is to detect the anti-tumor effect of the compound of the present invention in vivo. In this experiment, the subcutaneous human lymphoma tumor model of Balb/C mice was used to test the anti-tumor activity of the inventive compound 3a-9 in vivo. The cell line used was B-cell lymphoma cell line Ramos. R788, an anti-B-cell lymphoma drug under investigation, was used as a positive control. the

1) Experimental materials:

IMDM, fetal bovine serum, and trypsin were purchased from Gibco BRL (Invitrogen Corporation, USA), IMDM medium was purchased from ATCC (American Type Culture Collection), and human B-cell lymphoma cell line RAMOS was purchased from ATCC, Balb/ C mice were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd., China. R788 was purchased from Shanghai Hanxiang Biotechnology Co., Ltd., China. the

2) Experimental method:

BALB/C mice aged 6-8 weeks were used to inoculate the subcutaneous rear ribs of the mice at a concentration of about 8×106/0.1mL RAMOS cells. After the tumor grew to 200-300mm3 (about 15 days), the small Rats were divided into groups (n=8) and oral administration was started by gavage. the

Experimental 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.;

The drugs of each group were dissolved in 5% DMSO+25% PEG-400+70% water. the

Observation indicators: The body weight of the mice and the long and short diameters of the tumors were measured once a day, and the tumor volume (length×width2×0.5) was calculated to observe whether there were reactions such as diarrhea, convulsions, rashes, and significant weight loss. the

3) Experimental results:

The experimental results show that the test compound 3a-9 has obvious in vivo growth inhibitory effect on the B-cell lymphoma cell line Ramos, and can obviously inhibit the growth of the tumor or completely regress the tumor at a dose of 20 mg/kg or more per day, and show excellent Inhibitory effect on positive control (R788). During the administration process, no adverse reactions such as weight loss, rash, and diarrhea were found in the mice, indicating that under the test dose, the test compound 3a-9 has very low toxicity within the dose range. the

4. Anti-B cell lymphoma HBL-1 tumor model experiment of compound 3a-9 in vivo

The purpose of this experiment is to detect the anti-tumor effect of the compound of the present invention in vivo. In this experiment, the subcutaneous human lymphoma tumor model of Balb/C mice was used to test the anti-tumor activity of the inventive compound 3a-9 in vivo. The cell line used was large B-cell lymphoma cell line HBL-1. R788, an anti-large B-cell lymphoma drug under investigation, was used as a positive control. the

1) Experimental materials:

IMDM, fetal bovine serum, and trypsin were purchased from Gibco BRL (Invitrogen Corporation, USA), IMDM medium was purchased from ATCC (American Type Culture Collection), and human B-cell lymphoma cell line RAMOS was purchased from ATCC, Balb/ C mice were purchased from Beijing Weitong Lihua Biotechnology Co., Ltd., China. R788 was purchased from Shanghai Hanxiang Biotechnology Co., Ltd., China. the

2) Experimental method:

Use 6-8 week-old BALB/C mice, inoculate the HBL-1 cells subcutaneously at the rear flank of the mice at a concentration of about 8×106/0.1mL/mouse, and wait until the tumor grows to 200-300mm3 (about 15 days) , the mice were divided into groups (n=8) and oral administration was started by gavage. the

Experimental 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.;

The drugs of each group were dissolved in 5% DMSO+25% PEG-400+70% water. the

Observation indicators: The body weight of the mice and the long and short diameters of the tumors were measured once a day, and the tumor volume (length×width2×0.5) was calculated to observe whether there were reactions such as diarrhea, convulsions, rashes, and significant weight loss. the

3) Experimental results:

The experimental results show that the test compound 3a-9 has obvious in vivo growth inhibitory effect on the B-cell lymphoma cell line HBL-1, and can obviously inhibit the growth of the tumor or completely regress the tumor at a dose of 40 mg/kg or more per day, and show The inhibitory effect was better than that of the positive control (R788). During the administration process, no adverse reactions such as weight loss, rash, and diarrhea were found in the mice, indicating that under the test dose, the test compound 3a-9 has very low toxicity within the dose range. the

The compounds prepared by the present invention have all detected their effects on focal adhesion kinase (FAK), spleen tyrosine kinase (SYK), human protein kinase Bα (PKBα), SRC, Axl, cell cycle-dependent kinase 2 (CDK2)/ Cyclin E (cyclinE), EphA3, insulin-like growth factor-1 receptor (IGF-1R), Janus kinase 2 (JAK2), vascular endothelial growth factor (KDR), Lyn, Met, pyruvate kinase 2 (Pyk2 ), phosphatidylinositol 3-kinase p110α/p85α (PI3K (p110α/p85α)) and other kinase inhibitory effects, but also detected the prepared compound on human B-cell lymphoma cell line Ramos, Raji, large B-cell lymphoma Cell lines LY-10, HBL-1, LY-1, SuDHL-6, T cell lymphoma cell line Jurkat, human pancreatic cancer cell lines panc-1, HPAC, Miapaca-2, CFPAC-1, human breast cancer cell lines Strains MDA-MB-231, MCF-7/ADR, human lung cancer cell lines A549, H358, human leukemia cell lines MV4-11, human liver cancer cell lines Huh7, PLC/PRF/5, human melanoma cell lines A2058, UACC62, etc. Proliferation inhibitory activity test, see the above Tables 1, 2 and 3 for some data. The results show that the compound prepared by the present invention has a good inhibitory effect on kinases, and further shows the effect of inhibiting the proliferation of tumor cells. More importantly, the compound of the present invention has the ability to simultaneously target multiple kinases (such as SYK and FAK) , especially compounds 3a-9 and 3a-10 showed unexpected effects. the

Claims (17)

1.5-fluoro-2,4-disubstituted aminopyrimidine derivatives, characterized in that: the structural formula is as shown in formula I: Wherein, R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; R2 is a substituted or unsubstituted C6~C14 aryl group or a substituted or unsubstituted 5~14 membered heteroaryl group; the substituents of the substituted C6~C14 aryl group or 5~14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted with an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3. 2. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; R2 is a substituted or unsubstituted phenyl or a substituted or unsubstituted 6-membered heteroaryl; the substituents of the substituted phenyl or 6-membered heteroaryl are -H, -F, -Cl, -Br, C1 ~C4 alkyl, C1~C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted aminoacyl is The substituents of the substituted 6-membered heterocycloalkyl are -H, -F, -Cl, -Br, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy, Or a halogen-substituted C1-C4 alkyl group, the heteroatom is N, S or O, and the number of heteroatoms is 1-3; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; R2 is substituted or unsubstituted phenyl or substituted or unsubstituted pyridyl; the substituents of the substituted phenyl or pyridyl are -H, -F, -Cl, -Br, methyl, methoxy, Or a substituted or unsubstituted 6-membered heterocycloalkyl; the substituent of the substituted 6-membered heterocycloalkyl is C1～C4 alkyl or The heteroatoms are N, S or O, and the number of heteroatoms is 1 to 3; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; R2 is a substituted or unsubstituted phenyl or a substituted or unsubstituted pyridyl; the substituent of the substituted phenyl or pyridyl is -H, -F, -Cl, -Br, methyl, methoxy, More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; R2 is most preferred, R1 is R2 is 3. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is shown in Formula II: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 4. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is shown in Formula III: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 5. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is When, the structure is as shown in formula IV: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 6. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is shown in Formula V: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 7. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is shown in formula VI: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 8. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is as shown in formula VII: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; R1 is 9. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is When, the structure is as shown in formula VIII: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 10. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is When, the structure is as shown in formula IX: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 11. 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to claim 1, characterized in that: when R ₂ is , the structure is as shown in Formula X: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, C1～C4 alkyl or C1～C4 alkoxy; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, C1～C4 aminoacyl, halogen substituted C1～C4 alkyl, C1～C4 alkyl or C1～C4 alkoxy; the substituents of the substituted benzyl are -H, -F, -Cl , -Br, C1~C4 alkyl or C1~C4 alkoxy; R3 is -H, -F, -Cl, -Br or C1~C4 alkyl; Further preferred, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H or C1～C4 alkyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2, -CF3, C1～ C4 alkyl or -OCF3; the substituent of the substituted benyl is -H, -F, -Cl, -Br, C1～C4 alkyl or -OCF3; R3 is -H, -F, -Cl , -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is -H, methyl, ethyl or propyl; the substituent of the substituted phenyl is -H, -F, -Cl, -Br, -CONH2 or -CF3; The substituent of the substituted benyl is -H, -F, -Cl or -Br; R3 is -H, -F, -Cl, -Br or methyl; More preferably, R1 is substituted or unsubstituted cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, The substituent of the substituted cyclohexyl is-H or methyl; the substituent of the substituted phenyl is-H,-F,-Cl,-Br,-CONH2 or-CF3; the substituted benzyl The substituent is -H, -F, -Cl or -Br; R3 is -H or methyl; most preferred, R1 is 12. The 5-fluoro-2,4-disubstituted aminopyrimidine derivative according to any one of claims 1 to 11, characterized in that it comprises the following compound: 5-fluoro-N4-(2-methylcyclohexyl Amine)-N2-(3,4,5-trimethoxyaniline)pyrimidine-2,4-diamine, N6-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4 -yl)-2-methylquinoline-4,6-diamine, N4-(4-chloro-3-(trifluoromethyl)phenyl)-5-fluoro-N2-(3,4,5- Trimethoxyaniline)pyrimidine-2,4-diamine, 5-amino-6-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4-amino)-3,4- Dihydroquinolinone, N4-(3,4-difluorophenyl)-5-fluoro-N2-(3,4,5-trimethoxyphenyl)pyrimidine-2,4-diamine, 4-chloro -2-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4-amino)benzamide, 5-(5-fluoro-2-(3,4,5-trimethoxy phenylaniline)pyrimidine-4-amino)-1H-benzimidazolone, 3-(5-fluoro-2-(3,4,5-trimethoxyaniline)pyrimidine-4-amino)benzamide, 4- Chloro-2-(5-fluoro-2-(4-(4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzamide, N6-(5-fluoro-2-(4 -(4-methylpiperazin-1-yl)anilino)pyrimidin-4-yl)-2-methylquinoline-4,6-diamine, 3-(5-fluoro-2-(4-( 4-methylpiperazin-1-yl)anilino)pyrimidine-4-amino)benzamide. the 13. The preparation method of 5-fluoro-2,4-disubstituted aminopyrimidine derivatives according to any one of claims 1 to 12, characterized in that the synthesis route is as follows: a, 2,4-dichloro-5-fluoropyrimidine (1) and different substituted aliphatic or aromatic amines Under the catalysis of weakly basic catalyst, react to obtain compound (2); Wherein, the solvent is any one of tetrahydrofuran, methylene chloride, ethyl acetate, xylene, toluene, and acetonitrile, and the catalyst is N,N-diisopropylethylamine, triethylamine, potassium carbonate, pyridine, N, Any one of N-dimethylaniline and N,N-diethylaniline; the reaction temperature is 0℃～120℃; the reaction time is 0.5～12h; b. Reaction of compound (2) with different substituted aromatic amines (H ₂ NR ₂ ) under acid or base catalysis to obtain compound (3); Wherein, the acid is any one of concentrated hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid; the base is N,N-diisopropylethylamine, triethylamine, potassium carbonate, sodium carbonate, sodium hydroxide, Any one in potassium hydroxide; the solvent is any one in tetrahydrofuran, acetone, butanone, isopropanol, n-butanol, N,N-dimethylformamide, dioxane; the reaction temperature is 45 ℃～125℃; the reaction time is 6h～16h; R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl; R2 is a substituted or unsubstituted C6~C14 aryl group or a substituted or unsubstituted 5~14 membered heteroaryl group; the substituents of the substituted C6~C14 aryl group or 5~14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted with an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3. 14. The intermediate used when preparing the 5-fluoro-2,4-disubstituted aminopyrimidine derivative described in any one of claims 1 to 12, the structural formula is as shown in XI: R1 is a substituted or unsubstituted C4-C8 cycloalkyl group, a C1-C8 alkyl group, a substituted or unsubstituted C6-C14 aryl group, a substituted or unsubstituted aralkyl group, The substituent of the substituted C4～C8 cycloalkyl is -H, halogen, -NH ₂ , -NO ₂ , C1～C4 alkyl or C1～C4 alkoxy; the substituted C6～C14 aromatic The substituent of the radical is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 aminoacyl, halogen-substituted C1-C4 alkyl, C1-C4 alkyl or C1-C4 alkoxy; The substituent of the substituted aralkyl group is -H, halogen, -NH ₂ , -NO ₂ , C1-C4 alkyl, C1-C4 alkoxy, halogen-substituted C1-C4 alkyl or C1-C4 C4 aminoacyl; R3 is -H, halogen, -NH ₂ , C1-C4 alkyl, C1-C4 alkoxy or halogen-substituted C1-C4 alkyl. 15. The intermediate used when preparing the 5-fluoro-2,4-disubstituted aminopyrimidine derivative described in any one of claims 1 or 2, the structure is as shown in XII: R2 is a substituted or unsubstituted C6-C14 aryl group or a substituted or unsubstituted 5-14 membered heteroaryl group; the substituents of the substituted C6-C14 aryl group or 5-14 membered heteroaryl group are -H, Halogen, C1-C4 alkyl, C1-C4 alkoxy, substituted or unsubstituted aminoacyl or substituted or unsubstituted 5-10 membered heterocycloalkyl; the substituent of the substituted aminoacyl is C1 A 5- to 10-membered heterocycloalkyl group substituted by an alkyl group of ~C4, the heteroatom is N, S or O, and the number of heteroatoms is 1 to 3; the substituted 5-10-membered heterocycloalkyl group The substituents are -H, halogen, -NH ₂ , C1~C4 alkyl, C1~C4 alkoxy, C1~C4 alkyl substituted carbonyl or halogen substituted C1~C4 alkyl, said The heteroatoms are N, S or O, and the number of heteroatoms is 1-3. 16. Use of the 5-fluoro-2,4-disubstituted aminopyrimidine derivative according to any one of claims 1 to 12 in the preparation of drugs for treating tumors, autoimmune diseases or inflammation. the 17. A pharmaceutical composition prepared by adding pharmaceutically acceptable auxiliary ingredients to the 5-fluoro-2,4-disubstituted aminopyrimidine derivative as claimed in any one of claims 1-12. the