CN105936635B - Compound and its application as phosphatidyl-inositol 3-kinase delta inhibitor - Google Patents

Abstract

The invention belongs to medicinal chemistry arts, it is related to a kind of compound as phosphatidyl-inositol 3-kinase (PI3K) δ inhibitor and its application, specifically, the present invention provides Formulas I compound represented or its isomers, pharmaceutically acceptable salt, solvate or prodrug, their preparation method and the purposes of pharmaceutical composition and these compound or compositions for treating cancer, hyperblastosis class disease or inflammatory disease containing these compounds.The compound of the present invention has good inhibitory activity to PI3K δ, and selectivity is high, promises to be very much the therapeutic agent of cancer, hyperblastosis class disease and inflammatory disease.

Description

Compound and its application as phosphatidyl-inositol 3-kinase delta inhibitor

Technical field

The invention belongs to medicinal chemistry arts, and in particular to one kind is used as phosphatidyl-inositol 3-kinase (PI3K) δ inhibitor Compound or its isomers, pharmaceutically acceptable salt, solvate or prodrug, their preparation method and contain these The pharmaceutical composition of compound and these compound or compositions are used for treating cancer, hyperblastosis class disease or inflammatory disease Purposes.

Background technique

PI3K (phosphatidyl-inositol 3-kinase) is the member of unique and conservative lipid within endothelial cells kinase families, phosphorylation 3 '-OH groups on phosphatidylinositols.According to the difference of structure and phosphorylated substrate, PI3K can be divided into tri- type of I, II, III Type, wherein I type PI3K is the hot spot studied at present, has PI3K is active, facilitates inflammatory cell to promote tumour generation adjusting Play an important role (Coussens and Werb, Nature, 2002,420,860-867) in the immunocyte of effect, has treatment each The therapeutic value of the Cancerous disease of kind form, including solid tumor (such as cancer and sarcoma), leukaemia and lymphoid malignancy.I type PI3K is made of p110 unit and p85 unit, and there are four types of the p110 subunits being currently known, i.e. p110 α, p110 β, p110 γ and P110 δ, wherein p110 δ includes mainly leucocyte such as T cell, dendritic cells, neutrophil cell, hypertrophy in spleen and hematopoietic cell It is expressed in cell, B cell and macrophage.PI3K δ fully participated in immune system function such as T cell function, Dendritic Cell Function, neutrophil activity, Mast cell activation, B cell activation.Therefore, PI3K δ also assist in it is a variety of with it is different The normal relevant disease of immune response, for example, allergy, inflammatory disease, inflammation mediated angiogenesis, rheumatoid arthritis, Itself property immunity disease such as erythematosus lupus, asthma, pulmonary emphysema and other respiratory diseases.

Drug research for targeting PI3K approach has been carried out for many years, clinically achieves some successes, especially closely PI3K δ inhibitor to find selective has apparent curative effect in the treatment of the diseases such as cancer.But, it is still desirable to which exploitation is more Excellent PI3K inhibitor, especially selectivity PI3K δ inhibitor, specifically to regulate and control and/or reconcile PI3K and correlation The transduction of protein kinase, for treating disease relevant to the kinase mediated event of PI3K.

Summary of the invention

It is an object of the present invention to provide compounds or its isomery that one kind shown in general formula I has PI3K inhibitory activity Body, pharmaceutically acceptable salt, solvate or prodrug,

Wherein,

Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, alkyl, halogenated alkyl and naphthenic base；

X¹、X²、X³、X⁴Separately it is selected from N and C (R²), wherein R²Selected from hydrogen, hydroxyl, halogen, alkyl, halogenated alkyl, Hydroxy alkyl, alkoxy, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino and double alkyl aminos；

R^cSelected from alkylidene, alkenylene, alkynylene and cycloalkylidene, the alkylidene, alkenylene, alkynylene and sub- cycloalkanes Base can be by one or more alkyl, halogenated alkyl, hydroxyl, hydroxy alkyl, halogen, oxo group, alkoxy, carboxyl, cyano, ammonia Base, alkyl monosubstituted amino or double alkyl aminos replace；

Cy¹Selected from aryl and heteroaryl, the aryl and heteroaryl can be by one or more halogens, hydroxyl, amino, carboxylics Base, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, alkoxy, halogenated alkyl, hydroxy alkyl, aminoalkyl, carboxyalkyl, Cyanoalkyl, nitro alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, alkoxyalkyl, alkyl monosubstituted amino, alkyl monosubstituted amino alkane Base, double alkyl aminos, double alkylaminoalkyl groups, alkyl acyl, alkyl acyl alkyl, alkoxyacyl, alkoxyacyl alkyl, Alkyl acyl oxygroup, alkyl acyl oxygroup alkyl, aminoacyl, aminoacyl alkyl, alkyl monosubstituted amino acyl group, alkyl monosubstituted amino Acyl, double alkylaminoacyls, double alkylaminoacyl alkyl, alkyl acylamino or alkyl acylamino alkyl take Generation；

R^aSelected from H and alkyl, and R^bSelected from hexa-atomic hexa-atomic to ten binary nitrogen-containing heteros to the nitrogenous heteroaryl of ten binary and-C (O)- Aryl or R^a、R^bN atom connected to them constitute together it is hexa-atomic to the nitrogenous heteroaryl of ten binary, wherein described is hexa-atomic To the nitrogenous heteroaryl of ten binary and-C (O)-it is hexa-atomic to the nitrogenous heteroaryl of ten binary can be by one or more halogens, hydroxyl, oxygen For group, amino, carboxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, alkoxy, halogenated alkyl, hydroxy alkyl, amino Alkyl, carboxyalkyl, cyanoalkyl, nitro alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, alkoxyalkyl, monoalkyl ammonia Base, Mono-alkylaminoalkyl, double alkyl aminos, double alkylaminoalkyl groups, alkyl acyl, alkyl acyl alkyl, alkoxyacyl, Alkoxyacyl alkyl, alkyl acyl oxygroup, alkyl acyl oxygroup alkyl, aminoacyl, aminoacyl alkyl, alkyl monosubstituted amino Acyl group, alkyl monosubstituted amino acyl, double alkylaminoacyls, double alkylaminoacyl alkyl, alkyl acylamino or alkyl Acylaminoalkyl replaces.

It is a further object to provide prepare compounds of formula I or its isomers of the invention, pharmaceutically may be used The method of the salt of receiving, solvate or prodrug.

It is also another object of the present invention to provide comprising compounds of formula I of the invention or its isomers, pharmaceutically may be used Salt, solvate or the prodrug of receiving and the composition of pharmaceutically acceptable carrier, and the chemical combination comprising general formula I of the invention The composition of object or its isomers, pharmaceutically acceptable salt, solvate or prodrug and one or more PI3K inhibitor.

Of the invention a further object is provides compounds of formula I or its isomers of the invention, pharmaceutically acceptable Salt, solvate or prodrug treatment and/or pre- preventing tumor, hyperblastosis class disease or inflammatory disease method and this hair Bright compounds of formula I or its isomers, pharmaceutically acceptable salt, solvate or prodrug preparation for treat and/ Or the application in the drug of pre- preventing tumor, hyperblastosis class disease or inflammatory disease.

For above-mentioned purpose, the present invention the following technical schemes are provided:

In a first aspect, the present invention provides general formula I compound represented or its isomers, pharmaceutically acceptable salt, solvent Compound or prodrug,

Wherein,

Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, alkyl, halogenated alkyl and naphthenic base；

X¹、X²、X³、X⁴Separately it is selected from N and C (R²), wherein R²Selected from hydrogen, hydroxyl, halogen, alkyl, halogenated alkyl, Hydroxy alkyl, alkoxy, nitro, carboxyl, cyano, amino, alkyl monosubstituted amino and double alkyl aminos；

R^cSelected from alkylidene, alkenylene, alkynylene and cycloalkylidene, the alkylidene, alkenylene, alkynylene and sub- cycloalkanes Base can be by one or more alkyl, halogenated alkyl, hydroxyl, hydroxy alkyl, halogen, oxo group, alkoxy, carboxyl, cyano, ammonia Base, alkyl monosubstituted amino or double alkyl aminos replace；

Cy¹Selected from aryl and heteroaryl, the aryl and heteroaryl can be by one or more halogens, hydroxyl, amino, carboxylics Base, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, alkoxy, halogenated alkyl, hydroxy alkyl, aminoalkyl, carboxyalkyl, Cyanoalkyl, nitro alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, alkoxyalkyl, alkyl monosubstituted amino, alkyl monosubstituted amino alkane Base, double alkyl aminos, double alkylaminoalkyl groups, alkyl acyl, alkyl acyl alkyl, alkoxyacyl, alkoxyacyl alkyl, Alkyl acyl oxygroup, alkyl acyl oxygroup alkyl, aminoacyl, aminoacyl alkyl, alkyl monosubstituted amino acyl group, alkyl monosubstituted amino Acyl, double alkylaminoacyls, double alkylaminoacyl alkyl, alkyl acylamino or alkyl acylamino alkyl take Generation；With

R^aSelected from H and alkyl, and R^bSelected from hexa-atomic hexa-atomic to ten binary nitrogen-containing heteros to the nitrogenous heteroaryl of ten binary and-C (O)- Aryl or R^a、R^bN atom connected to them constitute together it is hexa-atomic to the nitrogenous heteroaryl of ten binary, wherein described is hexa-atomic To the nitrogenous heteroaryl of ten binary and-C (O)-it is hexa-atomic to the nitrogenous heteroaryl of ten binary can be by one or more halogens, hydroxyl, oxygen For group, amino, carboxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, alkoxy, halogenated alkyl, hydroxy alkyl, amino Alkyl, carboxyalkyl, cyanoalkyl, nitro alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, alkoxyalkyl, monoalkyl ammonia Base, Mono-alkylaminoalkyl, double alkyl aminos, double alkylaminoalkyl groups, alkyl acyl, alkyl acyl alkyl, alkoxyacyl, Alkoxyacyl alkyl, alkyl acyl oxygroup, alkyl acyl oxygroup alkyl, aminoacyl, aminoacyl alkyl, alkyl monosubstituted amino Acyl group, alkyl monosubstituted amino acyl, double alkylaminoacyls, double alkylaminoacyl alkyl, alkyl acylamino or alkyl Acylaminoalkyl replaces.

In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

X¹、X²、X³、X⁴It is C (R²)。

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

X¹、X²、X³、X⁴In have one for N, excess-three is C (R²)。

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

X¹、X²、X³、X⁴In there are two be N, other two be C (R²)。

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

X¹、X²、X³、X⁴In there are three be N, remaining one be C (R²)。

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, C_1-6Alkyl, halogenated C_1-6Alkyl and C_3-6Naphthenic base；

It is further preferred that Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, C_1-3Alkyl, halogenated C_1-3Alkyl and C_3-6Cycloalkanes Base；

It is further preferred that Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl Base, cyclobutyl, cyclopenta and cyclohexyl.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

R²Selected from hydrogen, hydroxyl, halogen, C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, C_1-6Alkoxy, nitro, carboxylic Base, cyano, amino, list C_1-6Alkyl amino and double C_1-6Alkyl amino；

It is further preferred that R²Selected from hydrogen, hydroxyl, halogen, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, C_1-3Alkane Oxygroup, nitro, carboxyl, cyano, amino, list C_1-3Alkyl amino and double C_1-3Alkyl amino；

It is further preferred that R²Selected from hydrogen, hydroxyl, halogen, methyl, ethyl, propyl, isopropyl, trifluoromethyl, trifluoro Ethyl, methylol, ethoxy, hydroxypropyl, 2- hydroxypropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, nitro, carboxyl, Cyano, amino, methylamino, ethylamino, propylcarbamic, isopropylamino, dimethylamino, lignocaine, methylethylamine, Dipropyl amino, methylpropylamino and ethylpropylamino.

In some preferred embodiments, the compound of the present invention is compounds of formula I or or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

R^cSelected from C_1-10Alkylidene, Asia C_3-10Naphthenic base, Asia C_2-10Alkenyl and Asia C_2-10Alkynyl, the sub- C_1-10Alkyl, Sub- C_3-10Naphthenic base, Asia C_2-10Alkenyl and Asia C_2-10Alkynyl can be by one or more C_1-6Alkyl, halogenated C_1-6Alkyl, hydroxyl, hydroxyl C_1-6Alkyl, halogen, oxo group, C_1-6Alkoxy, carboxyl, cyano, amino, list C_1-6Alkyl amino or double C_1-6Alkyl amino takes Generation；

It is further preferred that R^cSelected from C_1-6Alkylidene, Asia C_3-6Naphthenic base, Asia C_2-6Alkenyl and Asia C_2-6Alkynyl, it is described Sub- C_1-6Alkyl, Asia C_3-6Naphthenic base, Asia C_2-6Alkenyl and Asia C_2-6Alkynyl can be by one or more C_1-3Alkyl, halogenated C_1-3Alkyl, Hydroxyl, hydroxyl C_1-3Alkyl, halogen, oxo group, C_1-3Alkoxy, carboxyl, cyano, amino, list C_1-3Alkyl amino or double C_1-3 Alkyl amino replaces；

It is further preferred that R^cFor C_1-3Alkylidene, the C_1-3Alkylidene can be by one or more C_1-3It is alkyl, halogenated C_1-3Alkyl, hydroxyl, hydroxyl C_1-3Alkyl, halogen, oxo group, C_1-3Alkoxy, carboxyl, cyano, amino, list C_1-3Alkyl amino Or double C_1-3Alkyl amino replaces.

It is further preferred that R^cSelected from methylene, ethylidene and propylidene, the methylene, ethylidene and Asia third Base can be replaced by one or more methyl, ethyl, propyl, isopropyl, oxo group.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

Cy¹Selected from aryl and heteroaryl, the aryl and heteroaryl can be by one or more halogens, hydroxyl, amino, carboxylics Base, cyano, nitro, C_1-6Alkyl, C_3-8Naphthenic base, C_3-8Heterocyclylalkyl, C_1-6Alkoxy, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, Amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, naphthenic base C_1-6Alkyl, C_3-8Heterocyclylalkyl C_1-6 Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6Alkyl, double C_1-6Alkyl amino, double C_1-6 Alkyl amino C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alkoxyacyl, C_1-6Alkoxyacyl C_1-6 Alkyl, C_1-6Alkyl acyl oxygroup, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, aminoacyl, aminoacyl C_1-6Alkyl, list C_1-6Alkane Base aminoacyl, list C_1-6Alkylaminoacyl C_1-6Alkyl, double C_1-6Alkylaminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkane Base, C_1-6Alkyl acylamino or C_1-6Alkyl acylamino C_1-6Alkyl replaces；

It is further preferred that Cy¹Selected from phenyl, pyridyl group, pyrimidine radicals, pyrrole radicals, thienyl, furyl, indyl, different Indyl and quinolyl, the phenyl, pyridyl group, pyrimidine radicals, pyrrole radicals, thienyl, furyl, indyl, isoindolyl and Quinolyl can be by one or more halogens, hydroxyl, amino, carboxyl, cyano, nitro, C_1-6Alkyl, C_3-8Naphthenic base, C_3-8Heterocycle alkane Base, C_1-6Alkoxy, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-8Naphthenic base C_1-6Alkyl, C_3-8Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6Alkyl, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alkoxyacyl, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl acyl oxygroup, C_1-6Alkyl acyl oxygroup C_1-6 Alkyl, aminoacyl, aminoacyl C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkylaminoacyl C_1-6It is alkyl, double C_1-6Alkylaminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acylamino or C_1-6Alkyl acylamino C_1-6 Alkyl replaces；

It is further preferred that Cy¹Selected from phenyl, pyridyl group and pyrimidine radicals, the phenyl, pyridyl group and pyrimidine radicals can quilts One or more halogens, hydroxyl, amino, carboxyl, cyano, nitro, C_1-3Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-3Alcoxyl Base, halogenated C_1-3Alkyl, hydroxyl C_1-3Alkyl, amino C_1-3Alkyl, carboxyl C_1-3Alkyl, cyano C_1-3Alkyl, nitro C_1-3Alkyl, C_3-6Naphthenic base C_1-3Alkyl, C_3-6Heterocyclylalkyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, list C_1-3Alkyl amino, list C_1-3Alkyl Amino C_1-3Alkyl, double C_1-3Alkyl amino, double C_1-3Alkyl amino C_1-3Alkyl, C_1-3Alkyl acyl, C_1-3Alkyl acyl C_1-3Alkane Base, C_1-3Alkoxyacyl, C_1-3Alkoxyacyl C_1-3Alkyl, C_1-3Alkyl acyl oxygroup, C_1-3Alkyl acyl oxygroup C_1-3Alkyl, Aminoacyl, aminoacyl C_1-3Alkyl, list C_1-3Alkylaminoacyl, list C_1-3Alkylaminoacyl C_1-3Alkyl, double C_1-3Alkyl Aminoacyl, double C_1-3Alkylaminoacyl C_1-3Alkyl, C_1-3Alkyl acylamino or C_1-3Alkyl acylamino C_1-3Alkyl takes Generation.

In some preferred embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

R^aSelected from H and C_1-6Alkyl, and R^bContain to the nitrogenous heteroaryl of ten binary and-C (O)-are hexa-atomic to ten binary selected from hexa-atomic Azepine aryl or R^a、R^bN atom connected to them constitute together it is hexa-atomic to the nitrogenous heteroaryl of ten binary, wherein described It is hexa-atomic to the nitrogenous heteroaryl of ten binary and-C (O)-it is hexa-atomic to the nitrogenous heteroaryl of ten binary can be by one or more halogens, hydroxyl Base, oxo group, amino, carboxyl, cyano, nitro, alkyl, naphthenic base, Heterocyclylalkyl, alkoxy, halogenated alkyl, hydroxyl alkane Base, aminoalkyl, carboxyalkyl, cyanoalkyl, nitro alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, alkoxyalkyl, list Alkyl amino, Mono-alkylaminoalkyl, double alkyl aminos, double alkylaminoalkyl groups, alkyl acyl, alkyl acyl alkyl, alcoxyl Base acyl group, alkoxyacyl alkyl, alkyl acyl oxygroup, alkyl acyl oxygroup alkyl, aminoacyl, aminoacyl alkyl, list Alkylaminoacyl, alkyl monosubstituted amino acyl, double alkylaminoacyls, double alkylaminoacyl alkyl, alkyl acyl ammonia Base or alkyl acylamino alkyl replace；

It is further preferred that R^aSelected from H and C_1-3Alkyl, and R^bSelected from hexa-atomic to the nitrogenous heteroaryl of ten binary and-C (O)-six Member is to the nitrogenous heteroaryl of ten binary or R^a、R^bN atom connected to them constitutes hexa-atomic to 12 membered nitrogen-containing heteroaryls together Base, wherein it is described it is hexa-atomic to the nitrogenous heteroaryl of ten binary and-C (O)-nitrogenous heteroaryl can be by one or more halogens, hydroxyl Base, oxo group, amino, carboxyl, cyano, nitro, C_1-6Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6It is alkoxy, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-6Naphthenic base C_1-6Alkyl, C_3-6Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6Alkane Base, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alcoxyl Base acyl group, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl acyl oxygroup, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, aminoacyl, Aminoacyl C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkylaminoacyl C_1-6Alkyl, double C_1-6Alkylaminoacyl, Double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acylamino or C_1-6Alkyl acylamino C_1-6Alkyl replaces.

In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmaceutically Acceptable salt, solvate or prodrug, in which:

R^aSelected from H and C_1-3Alkyl, and R^bSelected from pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, three nitrogen piperazine bases, pyrido pyrrole Cough up base, pyrido pyrazolyl, pyridine-imidazole base, pyrido triazol radical, pyrimido pyrrole radicals, pyrimido imidazole radicals, pyrimidine And pyrazolyl, pyrimido triazol radical, pyrazine and pyrrole radicals, pyrazine and imidazole radicals, pyrazine and pyrazolyl, pyrazine and triazole Base, pyridazine and pyrrole radicals, pyridazine and imidazole radicals, pyridazine and pyrazolyl and pyridazine and triazol radical, the pyridyl group, pyrimidine Base, pyrazinyl, pyridazinyl, three nitrogen piperazine bases, pyrido pyrrole radicals, pyrido pyrazolyl, pyridine-imidazole base, pyrido triazole Base, pyrimido pyrrole radicals, pyrimido imidazole radicals, pyrimido pyrazolyl, pyrimido triazol radical, pyrazine and pyrrole radicals, pyrazine are simultaneously It imidazole radicals, pyrazine and pyrazolyl, pyrazine and triazol radical, pyridazine and pyrrole radicals, pyridazine and imidazole radicals, pyridazine and pyrazolyl and rattles away Simultaneously triazol radical can be by one or more halogens, hydroxyl, oxo group, amino, carboxyl, cyano, nitro, C for piperazine_1-6Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6Alkoxy, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkane Base, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-6Naphthenic base C_1-6Alkyl, C_3-6Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkane Base, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6Alkyl, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkyl, C_1-6 Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alkoxyacyl, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl acyl oxygen Base, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, aminoacyl, aminoacyl C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkane Base aminoacyl C_1-6Alkyl, double C_1-6Alkylaminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acylamino Or C_1-6Alkyl acylamino C_1-6Alkyl replaces.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

R^aFor H, and R^bSelected from pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrido pyrazolyl and pyrimido imidazole radicals, Pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, pyrido pyrazolyl and the pyrimido imidazole radicals can be one or more Halogen, hydroxyl, oxo group, amino, carboxyl, cyano, nitro, C_1-6Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6Alcoxyl Base, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-6Naphthenic base C_1-6Alkyl, C_3-6Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl Amino C_1-6Alkyl, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkane Base, C_1-6Alkoxyacyl, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl acyl oxygroup, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, Aminoacyl, aminoacyl C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkylaminoacyl C_1-6Alkyl, double C_1-6Alkyl Aminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acylamino or C_1-6Alkyl acylamino C_1-6Alkyl takes Generation.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

R^a、R^bN atom connected to them constitute together pyridyl group, pyrimidine radicals, pyrazinyl, pyridazinyl, three nitrogen piperazine bases, Pyrido pyrrole radicals, pyrido pyrazolyl, pyridine-imidazole base, pyrido triazol radical, pyrimido pyrrole radicals, pyrimido imidazoles Base, pyrimido pyrazolyl, pyrimido triazol radical, pyrazine and pyrrole radicals, pyrazine and imidazole radicals, pyrazine and pyrazolyl, pyrazine are simultaneously Triazol radical, pyridazine and pyrrole radicals, pyridazine and imidazole radicals, pyridazine and pyrazolyl or pyridazine and triazol radical, the pyridyl group, Pyrimidine radicals, pyrazinyl, pyridazinyl, three nitrogen piperazine bases, pyrido pyrrole radicals, pyrido pyrazolyl, pyridine-imidazole base, pyrido three Nitrogen oxazolyl, pyrimido pyrrole radicals, pyrimido imidazole radicals, pyrimido pyrazolyl, pyrimido triazol radical, pyrazine and pyrrole radicals, pyrrole Piperazine and imidazole radicals, pyrazine and pyrazolyl, pyrazine and triazol radical, pyridazine and pyrrole radicals, pyridazine and imidazole radicals or pyridazine and pyrazoles Simultaneously triazol radical can be by one or more halogens, hydroxyl, oxo group, amino, carboxyl, cyano, nitro, C for base, pyridazine_1-6Alkane Base, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6Alkoxy, halogenated C_1-6Alkyl, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-6Naphthenic base C_1-6Alkyl, C_3-6Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6Alkyl, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkane Base, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alkoxyacyl, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl Acyloxy, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, aminoacyl, aminoacyl C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkylaminoacyl C_1-6Alkyl, double C_1-6Alkylaminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acyl Amino or C_1-6Alkyl acylamino C_1-6Alkyl replaces.

In other specific embodiments, the compound of the present invention is compounds of formula I or its isomers, pharmacy Upper acceptable salt, solvate or prodrug, in which:

R^aFor H；With

R^bGroup selected from the following:

Described in wherein It can be by one or more halogens, hydroxyl, oxygen For group, amino, carboxyl, cyano, nitro, C_1-6Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-6Alkoxy, halogenated C_1-6Alkane Base, hydroxyl C_1-6Alkyl, amino C_1-6Alkyl, carboxyl C_1-6Alkyl, cyano C_1-6Alkyl, nitro C_1-6Alkyl, C_3-6Naphthenic base C_1-6Alkane Base, C_3-6Heterocyclylalkyl C_1-6Alkyl, C_1-6Alkoxy C_1-6Alkyl, list C_1-6Alkyl amino, list C_1-6Alkyl amino C_1-6It is alkyl, double C_1-6Alkyl amino, double C_1-6Alkyl amino C_1-6Alkyl, C_1-6Alkyl acyl, C_1-6Alkyl acyl C_1-6Alkyl, C_1-6Alkoxy acyl Base, C_1-6Alkoxyacyl C_1-6Alkyl, C_1-6Alkyl acyl oxygroup, C_1-6Alkyl acyl oxygroup C_1-6Alkyl, aminoacyl, amino Acyl group C_1-6Alkyl, list C_1-6Alkylaminoacyl, list C_1-6Alkylaminoacyl C_1-6Alkyl, double C_1-6It is alkylaminoacyl, double C_1-6Alkylaminoacyl C_1-6Alkyl, C_1-6Alkyl acylamino or C_1-6Alkyl acylamino C_1-6Alkyl replaces.

In some specific embodiments, the compound of the present invention is compounds of formula I or its isomers, N- oxidation Object, pharmaceutically acceptable salt, solvate, prodrug or the form of chemoproection, in which:

Y is selected from O and N (R¹), wherein R¹Selected from hydrogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta And cyclohexyl；

X¹、X²、X³、X⁴It is C (R²), wherein R²Selected from hydrogen, hydroxyl, halogen, C_1-3Alkyl, halogenated C_1-3Alkyl, hydroxyl C_1-3 Alkyl, C_1-3Alkoxy, nitro, carboxyl, cyano, amino, list C_1-3Alkyl amino and double C_1-3Alkyl amino；

R^cSelected from methylene, ethylidene and propylidene, the methylene, ethylidene and propylidene can be by one or more A methyl, ethyl, propyl, isopropyl, oxo group replace；

Cy¹Selected from phenyl, pyridyl group and pyrimidine radicals, the phenyl, pyridyl group and pyrimidine radicals can by one or more halogens, Hydroxyl, amino, carboxyl, cyano, nitro, C_1-3Alkyl, C_3-6Naphthenic base, C_3-6Heterocyclylalkyl, C_1-3Alkoxy, halogenated C_1-3Alkyl, Hydroxyl C_1-3Alkyl, amino C_1-3Alkyl, carboxyl C_1-3Alkyl, cyano C_1-3Alkyl, nitro C_1-3Alkyl, C_3-6Naphthenic base C_1-3Alkyl, C_3-6Heterocyclylalkyl C_1-3Alkyl, C_1-3Alkoxy C_1-3Alkyl, list C_1-3Alkyl amino, list C_1-3Alkyl amino C_1-3Alkyl, double C_1-3 Alkyl amino, double C_1-3Alkyl amino C_1-3Alkyl, C_1-3Alkyl acyl, C_1-3Alkyl acyl C_1-3Alkyl, C_1-3Alkoxyacyl, C_1-3Alkoxyacyl C_1-3Alkyl, C_1-3Alkyl acyl oxygroup, C_1-3Alkyl acyl oxygroup C_1-3Alkyl, aminoacyl, aminoacyl C_1-3Alkyl, list C_1-3Alkylaminoacyl, list C_1-3Alkylaminoacyl C_1-3Alkyl, double C_1-3Alkylaminoacyl, double C_1-3Alkane Base aminoacyl C_1-3Alkyl, C_1-3Alkyl acylamino or C_1-3Alkyl acylamino C_1-3Alkyl replaces；

R^aSelected from H and C_1-3Alkyl；With

R^bGroup selected from the following:

The present invention provides compounds in detail below:

Or its pharmaceutically acceptable salt.

On the other hand, the present invention provides the preparation method of general formula compound of the invention, comprising:

1, Y is the preparation of the compound of Formula I of O:

A) the compound esterification of the compound of formula (1) and formula (2) obtains the intermediate of formula (3)；

B) intermediate with highly basic (such as sodium hydrogen) of formula (3) react to obtain the intermediate of formula (4)；

C) cyclization obtains the intermediate of formula (5) to the intermediate of formula (4) in acid condition；

D) intermediate of formula (5) obtains the intermediate of formula (6) through halogenating reaction；

E) intermediate of formula (6) obtains the compound of logical formula (I) through popular response.

Wherein, the popular response of step e) includes but is not limited to following reaction, such as by after the intermediate ammonification of formula (6) with Y-R^bIt carries out necleophilic reaction and obtains the compound of logical formula (I)；Or by the intermediate of formula (6) after at ester, hydrolysis, oxidation with uncle Butyl sulfenamide reacts to obtain intermediateAgain by after this intermediate and alkyl reagent, further with Y-R^b It carries out necleophilic reaction and obtains the compound of logical formula (I)；Or by the intermediate of formula (6) through it is cyanalation, hydrolyze again after with NH₂-R^bCondensation Obtain the compound etc. of logical formula (I).

Wherein, X¹、X²、X³、X⁴、Cy¹、R^bAnd R^cWith the meaning in general formula I；R^aIndicate hydrogen；M indicates alkyl, preferably C_1-6Alkyl, further preferably C_1-3Alkyl；M ' indicate M a H replaced by X after alkylidene；M " indicates that M removes a carbon Remaining group after atom, when M is methyl, M " indicates H；X, Y indicates halogen, preferably chlorine, bromine, iodine.

2, Y is N (R¹) compound of Formula I preparation:

A ') compound of formula (11) reacts to obtain the intermediate of formula (12) with triphosgene；

B ') intermediate of formula (12) reacts to obtain the intermediate of formula (14) with the compound of formula (13)；

C ') intermediate of formula (14) obtains the intermediate of formula (15) through reduction reaction；

D ') intermediate of formula (15) obtains the intermediate of formula (16) through oxidation reaction；

E ') formula (16) intermediate and alkylating reagent addition reaction obtain the intermediate of formula (17)；

F ') intermediate of formula (17) obtains the intermediate of formula (18) through oxidation reaction；

G ') formula (18) intermediate and azanol reaction obtain the intermediate of formula (19)；

H ') intermediate of formula (19) obtains the intermediate of formula (20) through reduction reaction；

I ') intermediate of formula (20) reacts to obtain the intermediate of formula (21) with amino protecting group；

J ') formula (21) intermediate and R¹- X necleophilic reaction obtains the intermediate of formula (22)；

K ') formula (22) intermediate deamination protecting group, with X-R^bCompounds of formula I is obtained through necleophilic reaction.

Wherein, X¹、X²、X³、X⁴、Cy¹、R^bAnd R¹With the meaning in general formula I；R^aIndicate H；R^cIndicate alkylidene, it can be into one Step is replaced by alkyl, works as R^cWhen indicating methylene, the intermediate of formula (16) directly and azanol reaction, then through step h '), i '), J ') and k ') method obtain compounds of formula I；T indicates alkyl, preferably C_1-6Alkyl, further preferably C_1-3Alkyl；X Indicate halogen, preferably chlorine, bromine, iodine.

The third aspect, the present invention provide pharmaceutical composition, it includes the compound of the present invention or its isomers, pharmaceutically may be used Salt, solvate or the prodrug of receiving.

In some embodiments, the present invention provides pharmaceutical composition, it includes the compound of the present invention or its isomers, Pharmaceutically acceptable salt, solvate or prodrug, also comprising one or more selected from following composition: the suppression of tyrosine protein enzyme Preparation, EGFR inhibitor, VEGFR inhibitor, Bcr-Abl inhibitor, c-kit inhibitor, c-Met inhibitor, Raf inhibitor, Mek inhibitor, inhibitors of histone deacetylase, VEGF antibody, EGF antibody, HIV kinases inhibitor, HMG-CoA reduction Enzyme inhibitor etc..

In some embodiments, the present invention provides the compound of the present invention or itself or its isomers, pharmaceutically acceptable Salt, solvate or prodrug and comprising the compound of the present invention or its isomers, pharmaceutically acceptable salt, solvate or The pharmaceutical composition of prodrug, the compound or pharmaceutical composition for treat and/or pre- anti-cancer, hyperblastosis class disease or Person's inflammatory disease.

It can be by the compound of the present invention or its isomers, pharmaceutically acceptable salt, solvate or prodrug and pharmacy Upper acceptable carrier, diluent or excipient are prepared by mixing into pharmaceutical preparation, to be suitable for oral or parenteral.Administration Method includes, but are not limited in intradermal, intramuscular, peritonaeum, intravenous, subcutaneous, intranasal and peroral route.The preparation can pass through Any approach application, such as by being transfused or injecting, inhaled by transepithelial or mucocutaneous (such as oral mucosa or rectum etc.) The approach of receipts is applied.Administration can be whole body or local.The example of oral administration preparation includes solid or liquid dosage form, tool For body, including tablet, pill, granula, pulvis, capsule, syrup, emulsion, suspension etc..The preparation can pass through this field Known method preparation, and include the conventional use of carrier of field of pharmaceutical preparations, diluent or excipient.Fourth aspect, this hair It is bright that general formula I compound represented of the present invention or its isomers, pharmaceutically acceptable salt, solvate or prodrug, or packet are provided Pharmaceutical composition containing it is in the drug of preparation treatment and/or pre- anti-cancer, hyperblastosis class disease or inflammatory disease Purposes, wherein the cancer is selected from melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, lung cancer, pernicious Lympha tumour, liver, kidney, bladder, prostate, the cancer and sarcoma and skin of mammary gland and pancreas, colon, thyroid gland, lung and ovary Primary and recurrent solid tumor or leukaemia, the inflammatory disease be selected from allergy, asthma, rheumatoid arthritis, bone Arthritis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease (COPD), lupus erythematosus, psoriasis, Multiple sclerosis and end-stage renal disease etc..In some embodiments, the present invention relates to a kind for the treatment of cancers, hyperblastosis class disease Or the method for inflammatory disease comprising give the general formula I compound represented or its isomers, medicine of required bacterium Acceptable salt, solvate or prodrug on, or comprising its pharmaceutical composition, wherein the cancer be selected from melanoma, Papillary thyroid carcinoma, cholangiocarcinoma, colon cancer, oophoroma, lung cancer, malignant lymphatic tumor, liver, kidney, bladder, prostate, cream The cancer and sarcoma and skin of gland and pancreas, colon, thyroid gland, lung and ovary primary and recurrent solid tumor or white blood Disease, the inflammatory disease are selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, allergic conjunctivitis, anaphylaxis angle Film inflammation, xerophthalmia, chronic obstructive pulmonary disease (COPD), lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease etc..

Term explanation

Unless stated to the contrary, the term used in the specification and in the claims has following meanings.

" halogen " of the invention refers to fluorine, chlorine, bromine, iodine.

" alkyl " of the invention refers to the saturated fat hydrocarbyl group of linear chain or branched chain, preferably contains the straight chain or branch of 1 to 6 carbon atom Chain group, the linear chain or branched chain group of further preferably 1 to 3 carbon atom, non-limiting example include methyl, ethyl, N-propyl, isopropyl, normal-butyl, isobutyl group, tert-butyl, sec-butyl, n-pentyl, 1,1- dimethyl propyl, 1,2- dimethyl propylene Base, 2,2- dimethyl propyl, 1- ethyl propyl, 2- methyl butyl, 3- methyl butyl, n-hexyl etc..Alkyl can be substituted Or it is unsubstituted, when substituted, substituent group can be on any workable tie point." halogenated alkyl " of the invention refers to The alkyl at least replaced by a halogen.

" alkylidene " of the invention refers to that alkyl formally removes group remained by a hydrogen atom, as methylene (- CH₂), ethylidene (- CH₂-CH₂), propylidene (- CH₂-CH₂-CH₂) etc., herein, " the sub- C_1-10Alkyl " refers to C_1-10Alkyl formally removes group remained by a hydrogen atom, " the sub- C_1-6Alkyl " refers to C_1-6Alkyl is from form On remove group remained by a hydrogen atom.

" alkenylene " of the invention refers to that alkenyl formally removes group, such as ethenylidene remained by a hydrogen atom (- CH=CH-), allylidene (- CH=CH-CH₂Or-CH₂- CH=CH-) etc., herein, " the sub- C_2-10Alkenyl " Refer to C_2-10Alkenyl formally removes group remained by a hydrogen atom, " the sub- C_2-6Alkenyl " refers to C_2-6Alkenyl from Remove group remained by a hydrogen atom in form.

" alkynylene " of the invention refers to that alkynyl formally removes group, such as ethynylene remained by a hydrogen atom (- C ≡ C-), sub- propinyl (- C ≡ C-CH₂Or-CH₂- C ≡ C-) etc., herein, " the sub- C_2-10Alkynyl " refers to C_2-10Alkynyl formally removes group remained by a hydrogen atom, " the sub- C_2-6Alkynyl " refers to C_2-6Alkynyl is from form On remove group remained by a hydrogen atom.

" cycloalkylidene " of the invention refers to that naphthenic base formally removes group remained by a hydrogen atom, such as sub- ring PropylSub- cyclobutylDeng, herein, " the sub- C_3-10Naphthenic base " refers to C_3-10Naphthenic base formally removes group remained by a hydrogen atom, " the sub- C_3-6Naphthenic base " refers to C_3-6Naphthenic base Formally remove group remained by a hydrogen atom.

" naphthenic base " of the invention refers to cricoid saturated hydrocarbyl.Suitable naphthenic base can be substituted or unsubstituted tool There are the monocyclic, bicyclic or tricyclic saturated hydrocarbyl of 3-10 carbon atom, such as cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl.

" Heterocyclylalkyl " of the invention refers to containing heteroatomic cricoid saturated hydrocarbyl.

" alkoxy " of the invention refers to-O- alkyl.The non-limiting example of alkoxy includes: methoxyl group, ethyoxyl, the third oxygen Base, positive propoxy, isopropoxy, isobutoxy, sec-butoxy etc..Alkoxy can be optionally it is substituted or unsubstituted, when When being substituted, substituent group can be on any workable tie point." aryl " of the invention, which refers to, may include monocycle or thick Polycyclic aroma system is closed, the aroma system of monocycle or condensed-bicyclic is preferably comprised, contains 6 to 18 carbon atoms, preferably Contain about 6 to about 14 carbon atoms.Suitable aryl includes but is not limited to phenyl, naphthalene, anthryl, tetralyl, fluorenyl, indane Base." heteroaryl " of the invention refers to the aryl that at least one carbon atom is substituted by hetero atom, the hetero atom be O, S, N.Suitable heteroaryl includes but is not limited to imidazole radicals, benzimidazolyl, imidazopyridyl, quinazoline ketone group, pyrrole radicals, miaow Oxazolone base, furyl, thienyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, oxadiazoles base, triazolyl Deng.Wherein, " hexa-atomic to 12 unit's heteroaryls " of the invention refers to by 6-12 atomic building, and at least one atom is miscellaneous The heteroaryl of atom.It is suitable it is hexa-atomic to 12 unit's heteroaryls include but is not limited to pyrimidine radicals, pyridyl group, pyrazinyl, pyridazinyl, Pyrimido pyrazolyl, pyrimido imidazole radicals etc..

Of the invention " solvate " refers to solute (such as salt of reactive compound, reactive compound) and molten in a conventional sense The compound that agent (such as water) combination is formed.Solvent refers to the solvent of known to those of skill in the art or easy determination.If It is water, then solvate is commonly referred to as hydrate, such as monohydrate, dihydrate, trihydrate etc..

" prodrug " of the invention refer under the physiological condition in organism, is converted to due to reacting with enzyme, gastric acid etc. The compound of the compound of formula (I) passes through the compound of the compound of the conversion such as the oxidation of an enzyme, reduction, hydrolysis accepted way of doing sth (I) And/or the compound etc. of the compound by the conversion such as hydrolysis of gastric acid an etc. accepted way of doing sth (I).

Of the invention " pharmaceutical composition " refers to comprising any compound as described herein, including corresponding isomers, Prodrug, solvate, pharmaceutically acceptable salt or its chemical protection form and one or more pharmaceutically acceptable carriers Mixture.The purpose of Pharmaceutical composition is to promote the administration of compound on organism body.The composition, which is commonly used for preparing, to be controlled Treat and/or prevent the drug by one or more kinase mediated diseases.

" pharmaceutically acceptable carrier " of the invention, which refers to, not to be caused obvious irritation to organism and does not interfere to be given The bioactivity of compound and the carrier of property, it is living comprising all solvents, diluent or other excipient, dispersing agent, surface Property agent isotonic agent, thickener or emulsifier, preservative, solid binder, lubricant etc..Unless any conventional carrier medium and sheet Invention compound is incompatible.The some examples that can be used as pharmaceutically acceptable carrier include, but are not limited to carbohydrate, such as cream Sugar, dextrose and saccharose；Starch, such as cornstarch and potato starch；Cellulose and its derivates, such as carboxymethyl cellulose Sodium and cellulose and cellulose acetate；Malt, gelatin etc..

" excipient " of the invention, which refers to, to be added in Pharmaceutical composition with the further inert substance for promoting to give compound.It assigns Shape agent may include calcium carbonate, calcium phosphate, various saccharides and a plurality of types of starch, cellulose derivative, gelatin, vegetable oil, Polyethylene glycol.

The present invention " purposes in the drug for the treatment of and/or pre- anti-cancer, hyperblastosis class disease or inflammatory disease " refers to Cancer, hyperblastosis class disease or inflammatory disease can be made to be improved, inhibit the growth, development and/or transfer of cancer, or drop The risk of low cancer stricken, hyperblastosis class disease or inflammatory disease mainly gives treatment and/or pre- to required human or animal A effective amount of the compound of the present invention is prevented to inhibit, slow down or reverse the growth, development or diffusion of cancer in subject, makes cancer Disease, hyperblastosis class disease or inflammatory disease are improved, or reduce risk, and the tumour includes cancer, for example including Bladder cancer, breast cancer, kidney, liver cancer, lung cancer (including Small Cell Lung Cancer), cancer of the esophagus, gallbladder cancer, oophoroma, cancer of pancreas, stomach Cancer, cervical carcinoma, thyroid cancer, prostate cancer and cutaneum carcinoma (including squamous cell carcinoma)；The hematopoetic tumor of Lymphatic System, for example including Leukaemia, acute lymphoblastic leukemia, acute lymphoblastic leukemia, B cell lymphoma, T- cell lymphoma, Huo Qi Golden lymthoma, non-Hodgkin lymphoma, hairy cell lymphoma and Burkitt lymphoma；The tumour in mesenchymal cell source, such as Including fibrosarcoma, rhabdomyosarcoma；The hematopoetic tumor of medullary system, it is different for example including acute and chronic myelomatosis, myelosis Normal syndrome and promyelocitic leukemia；Maincenter and peripheral nervous system neoplasms, for example including astrocytoma, neuroblast Tumor, glioma and neurinoma；With other tumours, for example including melanoma, seminoma, teratocarcinoma, osteosarcoma, color Property xeroderma, keratoacanthoma, thyroid follcular carcinoma and Kaposi's sarcoma.The inflammatory disease is selected from allergy, asthma, class Rheumatic arthritis, osteoarthritis, allergic conjunctivitis, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease (COPD), Lupus erythematosus, psoriasis, multiple sclerosis and end-stage renal disease etc..

" pharmaceutically acceptable salt " of the invention refers to the salt of the compounds of this invention, when this kind of salt is used in the mammalian body With safety and validity, and there is due bioactivity.

Specific embodiment

Representative embodiment is protection model and is not intended to limit the present invention in order to better illustrate the present invention below It encloses.

1 3- of embodiment (9H- purine -6- base aminomethyl) -2- phenyl -4H- chromene -4- ketone

The preparation of step 1 2- benzoyloxy propiophenone

By 2- hydroxypropiophenonepreparation (5g, 33.33mmol), chlorobenzoyl chloride (11.7g, 83.33mmol) and potassium carbonate (23g, It 166.6mmol) is added in 120ml acetone, oil bath heating to back flow reaction is stayed overnight, and TLC, which is detected to reaction, to be terminated.Reaction terminates Afterwards, solvent is spin-dried for；Water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease 6.5g, yield 76.7%.

The preparation of step 2 3- methyl -2- phenyl -4H- chromene -4- ketone

2- benzoyloxy propiophenone (6.5g, 25.6mmol) is dissolved in 80ml DMSO, sets in ice-water bath and cools down, point Sodium hydrogen (3.1g, 76.7mmol) is added in batch.About 2h, TLC tracking and monitoring is stirred at room temperature, reaction terminates, is added into reaction solution Water, dilute hydrochloric acid tune pH value to faintly acid, ethyl acetate extraction, anhydrous sodium sulfate is dry, is concentrated to give grease, obtains intermediate 1- (2- cyano-phenyl) -2- methyl -3- phenyl -1,3- diacetone.80ml acetic acid and a few drop concentrated hydrochloric acids, reflux are added into grease About 3h is reacted, TLC tracking reaction terminates.Reaction solution is spin-dried for, water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, concentration Sand processed, column chromatographic purifying obtain white solid 5g, yield: 82.7%.

The preparation of step 3 3- bromomethyl -2- phenyl -4H- chromene -4- ketone

By 3- methyl -2- phenyl -4H- chromene -4- ketone (300mg, 1.27mmol), N-bromosuccinimide (NBS, 225mg, 1.27mmol) and benzoyl peroxide (BPO, 30mg, 0.12mmol) be dissolved in 15ml carbon tetrachloride, set in oil bath plus Heat is refluxed overnight, and TLC tracking and monitoring, reaction terminates.Water is added in reaction solution, and ethyl acetate extraction, anhydrous sodium sulfate is dry, concentration Sand processed, column chromatographic purifying obtain white solid 157mg, yield: 39.4%.

The preparation of step 4 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride

3- bromomethyl -2- phenyl -4H- chromene -4- ketone (157mg, 0.5mmol) is dissolved in 5ml DMF, 2ml ammonia is added Water is stirred overnight at room temperature.TLC monitoring, reaction terminate.Water is added in reaction solution, and ethyl acetate extraction, anhydrous sodium sulfate is dry, will Organic layer is concentrated into about 5ml, and the ethyl acetate hydrogen chloride solution of saturation is added, and gradually has pale solid precipitation, filters, and does It is dry, 82mg product is obtained, yield: 57.1%.

The preparation of step 5 3- (9H- purine -6- base aminomethyl) -2- phenyl -4H- chromene -4- ketone

By 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride (100mg, 0.34mmol), 6- bromine purine (76mg, It 0.38mmol) is dissolved in the 3ml tert-butyl alcohol with DIEA (135mg, 1.04mmol), oil bath heating to back flow reaction is stayed overnight, TLC tracking Monitoring reaction terminates.Water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white Solid 15mg, yield: 11.7%.

¹H NMR(300MHz,DMSO-d₆): δ 12.91-12.90 (d, 1H, J=3.1Hz), 8.14-8.08 (m, 3H), 7.87-7.78(m,3H),7.70-7.67(m,1H),7.57-7.51(m,5H),4.53(s,2H).ES:m/z 370.1[M+H]⁺。

2 4- amino-5-cyano -6- of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) methylaminopyrimidin

By 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 1 step 4 of embodiment (80mg, 0.28mmol), 4- amino-5-cyano -6- chlorine pyrimidine (47mg, 0.30mmol) and potassium carbonate (116mg, 0.84mmol) are dissolved in In 3ml DMF, overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Water, ethyl acetate extraction is added, anhydrous sodium sulfate is done It is dry, sand processed is concentrated, preparation HPLC purifying obtains white solid 12mg, yield: 11.6%.

¹H NMR(300MHz,DMSO-d₆): δ 8.13-8.12 (d, 1H, J=4.23Hz), 7.94 (s, 1H), 7.85-7.82 (t, 1H, J=4.27Hz), 7.74-7.72 (d, 2H, J=3.54Hz), 7.69-7.67 (d, 1H, J=4.95Hz), 7.57- 7.52(m,4H),7.23(s,1H),7.18(s,2H),4.40(s,2H).ES:m/z 370.1[M+H]⁺。

3 2,4- diamino -5- cyano -6- of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) methylaminopyrimidin

By 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 1 step 4 of embodiment (100mg, 0.34mmol), 2,4- diamino -5- cyano -6- chlorine pyrimidine (70mg, 0.38mmol) and potassium carbonate (140mg, 1mmol) are dissolved in In 3ml DMF, overnight, the reaction of TLC tracking and monitoring terminates oil bath heating to 100 DEG C of reactions.Water, ethyl acetate extraction, nothing is added Aqueous sodium persulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white solid 15mg, yield: 11.5%.

¹H NMR(300MHz,DMSO-d₆): δ 8.14-8.11 (d, 1H, J=7.86Hz), 7.86-7.82 (t, 1H, J= 7.03Hz), 7.76-7.73 (t, 2H, J=3.66Hz), 7.69-7.67 (d, 1H, J=8.46Hz), 7.59-7.51 (m, 4H), 6.65 (s, 1H), 6.49 (s, 2H), 6.22 (s, 2H), 4.32-4.30 (d, 2H, J=3.69Hz) .ES:m/z 385.0 [M+H]⁺。

4 3- of embodiment (1- (9H- purine -6- base aminoethyl)) -2- phenyl -4H- chromene -4- ketone

The preparation of step 1 3- acetyl-o-methyl -2- phenyl -4H- chromene -4- ketone

By 3- bromomethyl -2- phenyl -4H- chromene -4- ketone (33.1g, 0.105mol) obtained in 1 step 3 of embodiment and Sodium acetate (43g, 0.527mol) is dissolved in 700ml DMF, is set and is heated to 75 DEG C in oil bath, reacts 4h, TLC tracking and monitoring, instead It should terminate.Reaction solution is slowly poured into water, solid is precipitated, is filtered, wet product is directly thrown in next step.

The preparation of step 2 3- methylol -2- phenyl -4H- chromene -4- ketone

The wet product that upper step is obtained is added in 530ml THF and 200ml water, addition sodium hydroxide (12.65g, 0.315mol), overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Most of THF is rotated and is removed, it is solid that yellow is gradually precipitated Body filters, dry 22.1g solid, two step yields 83.5%.

The preparation of step 3 3- formoxyl -2- phenyl -4H- chromene -4- ketone

By 3- methylol -2- phenyl -4H- chromene -4- ketone (22.1g, 87.7mmol) and adjacent iodoxybenzoic acid (IBX, 27g, It 96.4mmol) is dissolved in 500ml DMSO, overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Reaction solution is poured into a large amount of water In, white solid is precipitated.Solid is added to the water, and is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, is spin-dried for obtaining white-yellowish solid 15.2g, yield 68.7%.

Step 4 2- methyl-N- ((4- oxo -2- phenyl -4H- chromene -3- base) methylene) propane -2- sulfenamide Preparation

By 3- formoxyl -2- phenyl -4H- chromene -4- ketone (1g, 4mmol), t-butyl sulfonamide (0.53g, It 4.4mmol) is dissolved in 25ml DCM with cesium carbonate (1.95g, 6mmol), overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction. Reaction solution is spin-dried for, is extracted with ethyl acetate, anhydrous sodium sulfate is dry, is spin-dried for obtaining white-yellowish solid 0.8g, yield 56.6%.

The preparation of step 5 3- (1- aminoethyl) -2- phenyl -4H- chromene -4- keto hydrochloride

By 2- methyl-N- ((4- oxo -2- phenyl -4H- chromene -3- base) methylene) propane -2- sulfenamide (5.3g, It 15mmol) is dissolved in 60ml THF, argon gas is replaced three times, and cooling in -20 DEG C of cold-traps, the THF for being slowly added to methyl-magnesium-chloride is molten Liquid (10ml, 30mmol), 2h is reacted in cold-trap, and the reaction of TLC tracking and monitoring terminates.Saturated aqueous ammonium chloride quenching reaction liquid, It is extracted with ethyl acetate, anhydrous sodium sulfate is dry, and the grease being spin-dried for is dissolved with a small amount of ethyl acetate, and the acetic acid of hydrogen chloride is added dropwise Ethyl ester solution, gradually there is a gray solid precipitation, and stirring in a moment, filters, dry solid 3.8g, two step yields 84.2%.

The preparation of step 6 3- (1- (9H- purine -6- base aminoethyl)) -2- phenyl -4H- chromene -4- ketone

By 3- (1- aminoethyl) -2- phenyl -4H- chromene -4- keto hydrochloride (700mg, 3.32mmol), 6- bromine purine (925mg, 4.65mmol) and potassium carbonate (1.6g, 11.62mmol) are dissolved in 20ml DMF, 100 DEG C of oil bath reaction for 24 hours, TLC with Track monitoring reaction terminates.Water is added in reaction solution, is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, is spin-dried for sand processed, column chromatography for separation Obtain white solid 32mg, yield 2.5%.

¹H NMR(300MHz,DMSO-d₆):δ9.25(s,1H),8.55(s,1H),8.45(s,1H),8.14-8.11(d, 1H, J=8.1Hz), 7.86-7.81 (t, 1H, J=8.1Hz), 7.75 (s, 2H), 7.66-7.63 (m, 5H), 7.55-7.50 (t, 1H, J=7.5Hz), 5.34-5.30 (t, 1H, J=6.3Hz), 384.2 [M of 1.75-1.73 (d, 3H, J=6.3Hz) .ES:m/z +H]⁺。

5 4- amino-5-cyano -6- of embodiment (1- (4- oxo -2- phenyl -4H- chromene -3- base) ethylamino-) pyrimidine

By 3- (1- aminoethyl) -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 4 step 5 of embodiment (700mg, 3.32mmol), 4- amino-5-cyano -6- chlorine pyrimidine (716mg, 4.65mmol) and potassium carbonate (1.6g, 11.62mmol) are dissolved in In 20ml DMF, for 24 hours, the reaction of TLC tracking and monitoring terminates for 100 DEG C of oil bath reactions.Water is added in reaction solution, is extracted with ethyl acetate, Anhydrous sodium sulfate is dry, is spin-dried for sand processed, column chromatography for separation obtains white solid 200mg, yield 52.2%.

¹H NMR(300MHz,DMSO-d₆): δ 8.18-8.15 (d, 1H, J=7.5Hz), 7.91 (s, 1H), 7.87-7.82 (t, 1H, J=7.6Hz), 7.71-7.67 (m, 2H), 7.63 (s, 4H), 7.57-7.52 (t, 1H, J=7.9Hz), 7.30 (s, 3H), 5.39-5.35 (t, 1H, J=6.9Hz), 1.50-1.48 (d, 3H, J=6.6Hz) .ES:m/z 383.9 [M+H]⁺。

6 2,4- diamino -5- cyano -6- of embodiment (1- (4- oxo -2- phenyl -4H- chromene -3- base) ethylamino-) is phonetic Pyridine

By 3- (1- aminoethyl) -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 4 step 5 of embodiment (700mg, 3.32mmol), 2,4- diamino -5- cyano -6- chlorine pyrimidine (716mg, 4.65mmol) and potassium carbonate (1.6g, 11.62mmol) It is dissolved in 20ml DMF, for 24 hours, the reaction of TLC tracking and monitoring terminates for 100 DEG C of oil bath reactions.Water is added in reaction solution, is extracted with ethyl acetate It takes, anhydrous sodium sulfate is dry, is spin-dried for sand processed, column chromatography for separation obtains white solid 20mg, yield 5.2%.

¹H NMR(300MHz,DMSO-d₆): δ 8.16-8.15 (d, 1H, J=4.2Hz), 7.86-7.83 (t, 1H, J= 4.6Hz), 7.73-7.72 (m, 2H), 7.66-7.63 (m, 4H), 7.56-7.53 (t, 1H, J=4.5Hz), 6.92-6.90 (d, 1H, J=5.5Hz), 6.57 (s, 2H), 6.00 (br, 2H), 5.40-5.34 (m, 1H), 1.44-1.43 (d, 3H, J=4.1Hz) .ES:m/z 399.0[M+H]⁺。

7 4- amino-5-cyano -6- of embodiment (1- (the chloro- 4- oxo -2- phenyl -4H- chromene -3- base of 8-) ethylamino-) is phonetic Pyridine

The preparation of the chloro- 2- phenyl -4H- chromene -4- ketone of step 1 3- bromomethyl -8-

The preparation side of 3- bromomethyl -2- phenyl -4H- chromene -4- ketone obtained in the preparation method is the same as that of Example 1 step 1-3 Method, the difference is that raw material 2- hydroxypropiophenonepreparation is replaced with 2- hydroxyl -3- chlorophenyl acetone.

The preparation of the chloro- 2- phenyl -4H- chromene -4- keto hydrochloride of step 2 3- (1- aminoethyl) -8-

Preparation method is the same as 3- (1- aminoethyl) -2- phenyl -4H- chromene -4- keto hydrochloride made from 4 step 1-5 of embodiment Preparation method, it is different that raw material 3- bromomethyl -2- phenyl -4H- chromene -4- ketone is replaced with into the chloro- 2- benzene of 3- bromomethyl -8- Base -4H- chromene -4- ketone.

Step 3 4- amino-5-cyano -6- (1- (the chloro- 4- oxo -2- phenyl -4H- chromene -3- base of 8-) ethylamino-) pyrimidine Preparation

By the chloro- 2- phenyl -4H- chromene -4- keto hydrochloride (200mg, 0.59mmol) of 3- (1- aminoethyl) -8-, 4- amino - 5- cyano -6- chlorine pyrimidine (101mg, 0.65mmol) and potassium carbonate (244mg, 1.77mmol) are dissolved in 20ml DMF, oil bath 100 DEG C reaction for 24 hours, TLC tracking and monitoring reaction terminate.Water is added in reaction solution, is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, is spin-dried for Sand processed, column chromatography for separation obtain white solid 35mg, yield 14.2%.

¹H NMR(300MHz,DMSO-d₆): δ 8.12-8.10 (d, 1H, J=7.8Hz), 8.03-8.00 (d, 1H, J= 7.8Hz), 7.92 (s, 1H), 7.76-7.74 (m, 2H), 7.65 (s, 3H), 7.56-7.51 (t, 1H, J=7.9Hz), 7.30 (s, 2H), 7.20-7.17 (d, 1H, J=8.6Hz), 5.44-5.36 (m, 1H), 1.52-1.50 (d, 3H, J=6.8Hz) .ES:m/z 418.1[M+H]⁺。

8 2,4- diamino -5- cyano -6- of embodiment (1- (the chloro- 4- oxo -2- phenyl -4H- chromene -3- base of 8-) ethamine Base) pyrimidine

By the chloro- 2- phenyl -4H- chromene -4- keto hydrochloride of 3- (1- aminoethyl) -8- obtained in 7 step 2 of embodiment (200mg, 0.59mmol), 2,4- diamino -5- cyano -6- chlorine pyrimidine (101mg, 0.65mmol) and potassium carbonate (244mg, It 1.77mmol) is dissolved in 20ml DMF, for 24 hours, the reaction of TLC tracking and monitoring terminates for 100 DEG C of oil bath reactions.Water is added in reaction solution, uses Ethyl acetate extraction, anhydrous sodium sulfate is dry, is spin-dried for sand processed, column chromatography for separation obtains white solid 23mg, yield 9.0%.

¹H NMR(300MHz,DMSO-d₆): δ 8.12-8.09 (d, 1H, J=7.2Hz), 8.03-8.01 (d, 1H, J= 7.6Hz), 7.76-7.75 (d, 2H, J=2.8Hz), 7.67-7.66 (d, 3H, J=2.3Hz), 7.56-7.50 (t, 1H, J= 7.9Hz), 6.84-6.81 (d, 1H, J=9.0Hz), 6.60 (s, 2H), 6.12 (br, 2H), 5.47-5.39 (m, 1H), 1.45- 1.43 (d, 3H, J=6.8Hz) .ES:m/z 433.2 [M+H]⁺。

9 4- amino-5-cyano -6- of embodiment (1- (8- fluorin-4-oxygen generation -2- phenyl -4H- chromene -3- base) ethylamino-) is phonetic Pyridine

The preparation of the fluoro- 2- phenyl -4H- chromene -4- keto hydrochloride of step 1 3- (1- aminoethyl) -8-

Preparation method is the same as the chloro- 2- phenyl -4H- chromene -4- ketone salt of 3- (1- aminoethyl) -8- made from 7 step 1-2 of embodiment The preparation method of hydrochlorate is different that raw material 2- hydroxyl -3- chlorophenyl acetone is replaced with 2- hydroxyl -3- fluorobenzene acetone.

Step 2 4- amino-5-cyano -6- (1- (8- fluorin-4-oxygen generation -2- phenyl -4H- chromene -3- base) ethylamino-) pyrimidine Preparation

By the fluoro- 2- phenyl -4H- chromene -4- keto hydrochloride (200mg, 0.59mmol) of 3- (1- aminoethyl) -8-, 4- amino - 5- cyano -6- chlorine pyrimidine (101mg, 0.65mmol) and potassium carbonate (244mg, 1.77mmol) are dissolved in 20ml DMF, oil bath 100 DEG C reaction for 24 hours, TLC tracking and monitoring reaction terminate.Water is added in reaction solution, is extracted with ethyl acetate, and anhydrous sodium sulfate is dry, is spin-dried for Sand processed, column chromatography for separation obtain white solid 51mg, yield 21.5%.

¹H NMR(300MHz,DMSO-d₆): δ 7.97-7.92 (m, 2H), 7.85-7.78 (t, 1H, J=9.5Hz), 7.74- 7.72 (m, 2H), 7.64-7.63 (m, 3H), 7.55-7.51 (m, 1H), 7.32 (s, 2H), 7.20-7.17 (d, 1H, J= 8.3Hz), 5.43-5.35 (m, 1H), 1.52-1.49 (d, 3H, J=6.8Hz) .ES:m/z 402.1 [M+H]⁺。

10 2,4- diamino -5- cyano -6- of embodiment (1- (8- fluorin-4-oxygen generation -2- phenyl -4H- chromene -3- base) ethamine Base) pyrimidine

By the fluoro- 2- phenyl -4H- chromene -4- keto hydrochloride of 3- (1- aminoethyl) -8- obtained in 9 step 1 of embodiment (190mg, 0.59mmol), 2,4- diamino -5- cyano -6- chlorine pyrimidine (101mg, 0.65mmol) and potassium carbonate (244mg, It 1.77mmol) is dissolved in 20ml DMF, for 24 hours, the reaction of TLC tracking and monitoring terminates for 100 DEG C of oil bath reactions.Water is added in reaction solution, uses Ethyl acetate extraction, anhydrous sodium sulfate is dry, is spin-dried for sand processed, column chromatography for separation obtains white solid 32mg, yield 13.0%.

¹H NMR(300MHz,DMSO-d₆):δ7.92-7.88(m,2H),7.85-7.75(m,2H),7.70-7.65(m, 2H), 7.61-7.56 (m, 3H), 7.50-7.46 (m, 1H), 7.27 (s, 2H), 7.17-7.13 (d, 1H, J=8.0Hz), 5.40- 5.32 (m, 1H), 1.55-1.50 (d, 3H, J=6.6Hz) .ES:m/z 417.1 [M+H]⁺。

11 3- of embodiment ((4- amino -1H- pyrazolo [3,4-d] pyrimidine -1- base) methyl) -2- phenyl -4H- chromene -4- Ketone

By 4- amino-pyrazol, simultaneously [3,4-d] pyrimidine (71mg, 0.47mmol) is dissolved in 3ml DMF, addition NaH (23mg, 0.57mmol), 3- bromomethyl -2- phenyl -4H- chromene -4- ketone obtained in 1 step 3 of embodiment is added in room temperature reaction a moment (150mg, 0.47mmol), room temperature reaction, the reaction of TLC tracking and monitoring terminate.Water, ethyl acetate extraction, anhydrous sodium sulfate is added It is dry, sand processed is concentrated, preparation HPLC purifying obtains white solid 18mg, yield: 10.4%.

¹H NMR(300MHz,DMSO-d₆): δ 8.50 (s, 1H), 8.13-8.06 (m, 2H), 8.00-7.98 (d, 2H, J= 3.9Hz), 7.89-7.86 (t, 1H, J=4.5Hz), 7.75-7.73 (d, 1H, J=5.0Hz), 7.64-7.62 (m, 4H), 7.56-7.53 (t, 2H, J=4.5Hz), 5.35 (s, 2H) .ES:m/z 370.1 [M+H]⁺。

12 3- amino-N- of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) methyl -2- formamide-pyrazine

By 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 1 step 4 of embodiment (400mg, 1.59mmol), 3- Aminopyrazine -2- carboxylic acid (243mg, 1.75mmol), EDC hydrochloride (396mg, 2.07mmol), DMAP (38mg, 0.32mmol) and DIEA (410mg, 3.18mmol) are dissolved in 10ml DMF, and room temperature reaction is stayed overnight, TLC tracking and monitoring Reaction terminates.Water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white solid 55mg, yield: 9.2%.

¹H NMR(400MHz,DMSO-d₆): δ 8.78-8.76 (t, 1H, J=5.4Hz), 8.43 (s, 1H), 8.20-8.19 (d, 1H, J=2.4Hz), 8.15-8.12 (dd, 1H, J₁=1.6Hz, J₂=8.0Hz), 7.87-7.83 (m, 1H), 7.80-7.78 (m, 3H), 7.70-7.68 (d, 1H, J=8.0Hz), 7.64-7.62 (m, 3H), 7.56-7.52 (m, 2H), 4.39 (s, 2H) .ES:m/z 373.1[M+H]⁺。

13 2- amino-N- of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) methyl -3- formamide-pyrazolo [1, 5-a] pyrimidine

By 3- aminomethyl -2- phenyl -4H- chromene -4- keto hydrochloride obtained in 1 step 4 of embodiment (130mg, 0.45mmol), 2- amino-pyrazol simultaneously [1,5-a] pyrimidine -3- carboxylic acid (81mg, 0.45mmol), PyBOP (345mg, 0.68mmol) It is dissolved in 5ml DMF with DIEA (172mg, 1.35mmol), overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Water is added, Ethyl acetate extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white solid 25mg, yield: 13.51%.

¹H NMR(300MHz,DMSO-d₆): δ 8.87-8.85 (d, 1H, J=6.6Hz), 8.47-8.45 (d, 1H, J= 4.4Hz), 8.22-8.18 (t, 1H, J=5.4Hz), 8.15-8.12 (d, 1H, J=7.5Hz), 7.85-7.82 (m, 3H), 7.69-7.66 (d, 1H, J=8.5Hz), 7.61-7.60 (m, 3H), 7.55-7.50 (t, 1H, J=7.5Hz), 6.96-6.92 (m, 1H), 6.44 (s, 2H), 4.49-4.48 (d, 2H, J=5.4Hz) .ES:m/z 411.9 [M+H]⁺。

14 N- of embodiment (2-aminopyridine -4- base) -2- (4- oxo -2- phenyl -4H- chromene -3- base) acetamide

The preparation of step 1 2- (4- oxo -2- phenyl -4H- chromene -3- base) acetonitrile

By 3- bromomethyl -2- phenyl -4H- chromene -4- ketone (1g, 3.18mmol) obtained in 1 step 3 of embodiment and cyaniding Tetraethyl ammonium (1g, 6.37mmol) is dissolved in the dry DMF of 25ml, reacts at room temperature about 2h, TLC tracking and monitoring, and reaction terminates.Instead Answer liquid that water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and column chromatographic purifying obtains white solid 488mg, receives Rate: 58.77%.

The preparation of step 2 2- (4- oxo -2- phenyl -4H- chromene -3- base) acetic acid

By 2- (4- oxo -2- phenyl -4H- chromene -3- base) acetonitrile (200mg, 0.76mmol) be dissolved in 2ml dioxane and In 1ml water, the 1ml concentrated sulfuric acid is added, oil bath heating to back flow reaction about 5h, TLC tracking and monitoring, reaction terminates.Reaction solution is added Water, ethyl acetate extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and column chromatographic purifying obtains white solid 121mg, yield: 56.8%.

The preparation of step 3 N- (2-aminopyridine -4- base) -2- (4- oxo -2- phenyl -4H- chromene -3- base) acetamide

By 2- (4- oxo -2- phenyl -4H- chromene -3- base) acetic acid (80mg, 0.214mmol), 2,4- diamino-pyridine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, 0.642mmol) are dissolved in 2ml DMF, Overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Water is added, ethyl acetate extraction, anhydrous sodium sulfate is dry, sand processed is concentrated, HPLC purifying is prepared, obtains white solid 17mg, yield: 21.4%.

¹H NMR(300MHz,DMSO-d₆): δ 10.12 (s, 1H), 8.28 (s, 1H), 8.09-8.08 (d, 1H, J= 4.7Hz), 7.86-7.83 (t, 1H, J=4.6Hz), 7.77-7.72 (m, 3H), 7.70-7.68 (m, 2H), 7.60-7.59 (m, 3H), 7.55-7.52 (d, 1H, J=4.5Hz), 7.26 (s, 1H), 6.23-6.22 (d, 1H, J=3.1Hz), 3.52 (s, 2H) .ES:m/z 372.1[M+H]⁺。

15 N- of embodiment (2-aminopyridine -3- base) -2- (4- oxo -2- phenyl -4H- chromene -3- base) acetamide

By 2- obtained in 14 step 2 of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) acetic acid (80mg, 0.214mmol), 2,3- diamino-pyridine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, It 0.642mmol) is dissolved in 2ml DMF, overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Water is added, ethyl acetate extracts, Anhydrous sodium sulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white solid 13mg, yield: 16.4%.

¹H NMR(500MHz,DMSO-d₆): δ 9.39 (s, 1H), 8.11-8.09 (d, 1H, J=7.9Hz), 7.86-7.83 (m, 1H), 7.81-7.78 (m, 3H), 7.71-7.69 (d, 1H, J=8.4Hz), 7.61-7.60 (m, 3H), 7.54-7.51 (t, 1H, J=7.5Hz), 7.49-7.47 (d, 1H, J=7.5Hz), 6.55-6.52 (m, 1H), 5.74 (s, 2H), 3.54 (s, 2H) .ES:m/z 372.1[M+H]⁺。

16 N- of embodiment (2- oxo -1,2- dihydropyridine -3- base) -2- (4- oxo -2- phenyl -4H- chromene -3- base) Acetamide

By 2- obtained in 14 step 2 of embodiment (4- oxo -2- phenyl -4H- chromene -3- base) acetic acid (80mg, 0.214mmol), 3- amino -2 hydroxy pyrimidine (35mg, 0.235mmol), PyBOP (222mg, 0.321mmol) and DIEA (110mg, 0.642mmol) is dissolved in 2ml DMF, and overnight, the reaction of TLC tracking and monitoring terminates for room temperature reaction.Water, acetic acid second is added Ester extraction, anhydrous sodium sulfate is dry, and sand processed is concentrated, and preparation HPLC purifying obtains white solid 15mg, yield: 18.9%.

¹H NMR(500MHz,DMSO-d₆): δ 11.92 (s, 1H), 9.46 (s, 1H), 8.20-8.18 (d, 1H, J= 7.1Hz), 8.09-8.07 (d, 1H, J=7.9Hz), 7.86-7.83 (t, 1H, J=7.7Hz), 7.78-7.76 (m, 2H), 7.70-7.69 (d, 1H, J=8.4Hz), 7.60-7.59 (m, 3H), 7.54-7.51 (t, 1H, J=7.5Hz), 7.09-7.07 (d, 1H, J=5.9Hz), 6.20-6.17 (t, 1H, J=6.8Hz), 3.62 (s, 2H) .ES:m/z 373.1 [M+H]⁺。

17 4- amino-5-cyano -6- of embodiment ((1- (the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) second Base) amino) pyrimidine

The preparation of step 1 3- chloroisatoic anhydride

2- amino -3- chlorobenzoic acid (34.2g, 0.2mol) and 175ml acetonitrile are added in 500ml three-necked bottle, is heated to 55 DEG C, the dichloromethane solution (triphosgene (29.6g, 0.1mol) is dissolved in 150ml methylene chloride) of triphosgene is then added dropwise, together When pyridine (50ml, 0.6mol) is added dropwise, 30min or so is added dropwise, and reacts 5h, TLC tracking reaction is to fully reacting.It will reaction Liquid filters while hot, and filter cake is washed with 100ml ethyl acetate, filtrate precipitation, obtains dark oil object, and mixture of ice and water is added, and has big Solid precipitation is measured, is filtered, drying, ethyl acetate petroleum ether system recrystallization filters, gray solid 30.8g, yield are obtained after drying 78.2%.

The preparation of the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- Ethyl formate of step 2 8-

Ethyl benzoylacetate (19.2g, 0.1mol) and 50ml DMF are added in 250ml three-necked bottle, is cooled to -20 DEG C, 60%NaH (4.0g, 0.1mol) is then added portionwise, there are a large amount of bubbles to emerge, keeps temperature to be no more than 0 DEG C, 30min is left The right side finishes, and continues to stir 15min, is warming up to room temperature, and stirring is stand-by.3- chloroisatoic anhydride (19.7g, 0.1mol) is dissolved in It in 100ml DMF, is added drop-wise in above-mentioned reaction solution by constant pressure funnel, holding reaction system anhydrous and oxygen-free, after 30min, It is added dropwise, reaction solution is warming up to 150 DEG C, stirring, TLC tracking is reacted to fully reacting.Reaction solution is depressurized into precipitation, black Mixture of ice and water is added in grease, is extracted with the ethyl acetate of 150ml × 3, merges organic layer, dry precipitation sand, column chromatography point Faint yellow solid 18.3g, yield 55.9% are obtained from after.

The preparation of chloro- 3- methylol -2- phenylchinoline -4- (1H) -one of step 3 8-

By the chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- Ethyl formate (16.4g, 0.05mol) of 8- and 100ml THF is added in 250ml three-necked bottle, and stirring and dissolving is cooled to -20 DEG C, and tetrahydrochysene lithium aluminium (3.8g, 0.1mol) is added portionwise, there is gas Bubble is emerged, and speed is added in control, and temperature is maintained to be no more than 0 DEG C, and 15min or so is finished, and then heats to room temperature, stirs 2h, TLC Track to fully reacting.Stop reaction, 3.8g sal glauberi is added portionwise, there is bubble releasing, control is added speed, prevents from rushing Material.After adding, reaction 0.5h is stirred at room temperature, filters, solid is washed 3 times with tetrahydrofuran, filtrate precipitation, and solid is obtained after being spin-dried for 12.7g, yield 88.6%.

The preparation of the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- formaldehyde of step 4 8-

Chloro- 3- methylol -2- phenylchinoline -4- (1H) -one (11.4g, 0.04mol) of 8- and 100ml DMSO are added In 250ml three-necked bottle, then IBX (14g, 0.05mol) is added in stirring and dissolving, be warming up to 35 DEG C, stirs 5h, TLC tracking reaction To fully reacting.Stop reaction, 300ml ethyl acetate is added, is warming up to reflux 15min, filters while hot, the hot acetic acid second of solid Ester washs 3 times, merging filtrate, and 200ml water, layering is added, and water layer is extracted with the ethyl acetate of 100ml × 2, merges organic layer, satisfies And brine It, anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains faint yellow solid 9.9g, yield 87.5%.

The preparation of the chloro- 3- of step 5 8- (1- ethoxy) -2- phenylchinoline -4 (1H) -one

By the chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- formaldehyde (8.5g, 0.03mol) of 8- and the anhydrous tetrahydro of 50ml Furans is added in two neck bottle of 100ml, stirring and dissolving, is cooled to -35 DEG C, then methyl chloride is added with syringe in argon gas protection Magnesium tetrahydrofuran solution (concentration 3M) (3ml, 0.09mol) adds and is warming up to 0 DEG C, stirs 2h, TLC tracking reaction to reaction Completely.Stopping reaction, 5ml ethyl alcohol quenching reaction is added, 200ml water and 100ml ethyl acetate is added in evaporating solvent under reduced pressure, point Layer, water layer are extracted with the ethyl acetate of 100ml × 2, merge organic layer, and saturated common salt water washing, anhydrous sodium sulfate is dry, depressurizes dense Contracting, obtains faint yellow solid 8.2g, yield 91.2%.

The preparation of chloro- 2- phenylchinoline -4 (1H) -one of step 6 3- acetyl group -8-

The chloro- 3- of 8- (1- ethoxy) -2- phenylchinoline -4 (1H) -one (6g, 0.02mol) and 60ml DMSO are added In 100ml three-necked bottle, then IBX (8.4g, 0.03mol) is added in stirring and dissolving, be warming up to 35 DEG C, stirs 5h, and TLC tracking is anti- It should be to fully reacting.Stop reaction, 300ml ethyl acetate is added, be warming up to reflux 15min, heat filters, the hot acetic acid second of solid Ester washs 3 times, merging filtrate, and 200ml water, layering is added, and water layer is extracted with the ethyl acetate of 100ml × 2, merges organic layer, satisfies And brine It, anhydrous sodium sulfate is dry, and evaporating solvent under reduced pressure obtains faint yellow solid 5.4g, yield 90.2%.

The preparation of the chloro- 3- of step 7 8- (1- (oxyimino) ethyl) -2- phenylchinoline -4 (1H) -one

Chloro- 2- phenylchinoline -4 (1H) -one (4.5g, 0.015mol) of 3- acetyl group -8- and 50ml anhydrous methanol are added In 100ml three-necked bottle, then hydroxylamine hydrochloride (6.3g, 0.09mol) and sodium acetate (9.8g, 0.12mol) is added in stirring and dissolving, 45 DEG C are warming up to, 5h, TLC tracking reaction to fully reacting are stirred.Stop reaction, removed under reduced pressure solvent, 100ml is added in residue Water has a large amount of faint yellow solids to be precipitated, and filters, washing, obtains beige solid 4.8g, yield 87.1% after filter cake drying.

The preparation of chloro- 2- phenylchinoline -4 (1H) -one of step 8 3- (1- amino-ethyl) -8-

By the chloro- 3- of 8- (1- (oxyimino) ethyl) -2- phenylchinoline -4 (1H) -one (3.1g, 0.01mol) and 50ml Acetic acid is added in 100ml three-necked bottle, stirring and dissolving, and activated zinc powder (3.3g, 0.05mol) and 10ml methanol, heating is then added To 45 DEG C, 5h, TLC tracking reaction to fully reacting are stirred.Stop reaction, filter, filter cake is washed with a large amount of ethyl acetate, is depressurized Solvent is removed, 50ml water and 100ml ethyl acetate is added in residue, removes organic layer, and water layer adjusts pH value with 5M sodium hydroxide It is 12, there are a large amount of faint yellow solids to be precipitated, filter, washing obtains faint yellow solid 1.7g, yield 58.1% after filter cake drying.

Step 9 4- amino-5-cyano -6- ((1- (the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) ethyl) Amino) pyrimidine preparation

By chloro- 2- phenylchinoline -4 (1H) -one (1.5g, 0.005mol) of 3- (1- amino-ethyl) -8- and 50ml isopropanol It is added in 100ml three-necked bottle, stirring and dissolving, 4- amino-5-cyano -6- chlorine pyrimidine (0.93g, 0.006mol) and carbon is then added Sour potassium (2.1g, 0.015mol), is warming up to 80 DEG C, is stirred at reflux 5h, TLC tracking reaction to 9 fully reacting of compound.Stop anti- It answers, filters, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, and methanol and silica gel sand, column chromatography point is added in residue From obtaining white solid 1.3g, yield 62.2%.

¹H NMR(500MHz,DMSO-d₆): δ 11.06 (s, 1H), 8.23-8.21 (d, 1H, J=10.0Hz), 8.01- 7.99 (d, 1H, J=10.0Hz), 7.90 (s, 1H), 7.88 (s, 1H), 7.59-7.52 (m, 5H), 7.40-7.43 (t, 1H, J= 7.5Hz), 7.24 (s, 2H), 5.14-5.17 (m, 1H), 1.39-1.37 (d, 3H, J=10.0Hz) .ES:m/z 416.9 [M+H]⁺。

18 4- amino-5-cyano -6- of embodiment ((1- (4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) ethyl) ammonia Base) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike raw material 2- amino -3- chlorobenzoic acid replaced with into 2- Target compound, yield 66.6% is made in aminobenzoic acid.

¹H NMR(500MHz,DMSO-d₆): δ 11.06 (s, 1H), 8.36-8.35 (d, 1H, J=5.0Hz), 8.21-8.20 (d, 1H, J=5.0Hz), 7.87 (s, 1H), 7.81-7.82 (m, 2H), 7.62-7.63 (m, 3H), 7.44-7.51 (m, 3H), 7.17 (s, 2H), 4.90-4.87 (m, 1H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 383.1 [M+H]⁺。

19 4- amino-5-cyano -6- of embodiment ((1- (the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 5-) second Base) amino) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike raw material 2- amino -3- chlorobenzoic acid replaced with into 2- Target compound, yield 58.6% is made in amino -6- chlorobenzoic acid.

¹H NMR(500MHz,DMSO-d₆): δ 11.05 (s, 1H), 8.24-8.22 (d, 1H, J=10.0Hz), 8.02- 8.00 (d, 1H, J=10.0Hz), 7.91 (s, 1H), 7.86 (s, 1H), 7.55-7.51 (m, 5H), 7.41-7.44 (t, 1H, J= 7.5Hz), 7.24 (s, 2H), 5.14-5.17 (m, 1H), 1.38-1.36 (d, 3H, J=10.0Hz) .ES:m/z 416.9 [M+H]⁺。

20 4- amino-5-cyano -6- of embodiment ((1- (8- fluorin-4-oxygen generation -2- phenyl -1,4- dihydroquinoline -3- base) second Base) amino) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike raw material 2- amino -3- chlorobenzoic acid replaced with into 2- Target compound, yield 62.1% is made in amino -3- fluobenzoic acid.

¹H NMR(500MHz,DMSO-d₆): δ 11.06 (s, 1H), 8.22-8.20 (d, 1H, J=10.0Hz), 8.02- 8.00 (d, 1H, J=10.0Hz), 7.91 (s, 1H), 7.88 (s, 1H), 7.59-7.53 (m, 5H), 7.40-7.43 (t, 1H, J= 7.5Hz), 7.24 (s, 2H), 5.14-5.16 (m, 1H), 1.39-1.37 (d, 3H, J=10.0Hz) .ES:m/z 400.9 [M+H]⁺。

21 4- amino-5-cyano -6- of embodiment ((1- (4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) propyl) ammonia Base) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike raw material 2- amino -3- chlorobenzoic acid replaced with into 2- Aminobenzoic acid, and methyl-magnesium-chloride is replaced with into ethylmagnesium chloride, target compound, yield 52.6% is made.

¹H NMR(500MHz,DMSO-d₆): δ 11.06 (s, 1H), 8.34-8.35 (d, 1H, J=5.0Hz), 8.21-8.22 (d, 1H, J=5.0Hz), 7.88 (s, 1H), 7.80-7.81 (m, 2H), 7.62-7.63 (m, 3H), 7.44-7.51 (m, 3H), 7.17(s,2H),5.09-5.12(m,1H),1.80-1.84(m,2H),0.59-0.62(m,3H).ES:m/z 397.2[M+H]⁺。

22 4- amino-5-cyano -6- of embodiment (((the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) first Base) amino) pyrimidine

The preparation of the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- formaldoxime of step 1 8-

By the chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- formaldehyde of 8- made from 17 step 1-4 of embodiment (4.3g, 0.015mol) and 50ml anhydrous methanol be added 100ml three-necked bottle in, stirring and dissolving, then be added hydroxylamine hydrochloride (6.3g, 0.09mol) with sodium acetate (9.8g, 0.12mol), 45 DEG C are warming up to, stirs 5h, TLC tracking reaction to fully reacting.Stop anti- It answers, removed under reduced pressure solvent, 100ml water is added in residue, has a large amount of faint yellow solids to be precipitated, it filters, washing, after filter cake drying Beige solid 4.0g, yield 88.9%.

The preparation of chloro- 2- phenylchinoline -4 (1H) -one of step 2 3- aminomethyl -8-

The chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- formaldoxime (3.0g, 0.01mol) of 8- and 50ml acetic acid are added Enter in 100ml three-necked bottle, stirring and dissolving, activated zinc powder (3.3g, 0.05mol) and 10ml methanol be then added, is warming up to 45 DEG C, Stir 5h, TLC tracking reaction to fully reacting.Stop reaction, filter, filter cake is washed with a large amount of ethyl acetate, and removed under reduced pressure is molten 50ml water and 100ml ethyl acetate is added in agent, residue, removes organic layer, and it is 12 that water layer 5M sodium hydroxide, which adjusts pH value, is had Largely faint yellow solids are precipitated, and filter, washing, obtain faint yellow solid 1.56g, yield 55.2%. after filter cake drying

Step 3 4- amino-5-cyano -6- (((the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) methyl) ammonia Base) pyrimidine preparation

Chloro- 2- phenylchinoline -4 (1H) -one (1.42g, 0.005mol) of 3- aminomethyl -8- and 50ml isopropanol are added In 100ml three-necked bottle, then 4- amino-5-cyano -6- chlorine pyrimidine (0.93g, 0.006mol) and potassium carbonate is added in stirring and dissolving (2.1g, 0.015mol) is warming up to 80 DEG C, is stirred at reflux 5h, TLC tracking reaction to 9 fully reacting of compound.Stop reaction, It filtering, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, residue addition methanol and silica gel sand, column chromatography for separation, Obtain white solid 1.37g, yield 68.1%.

¹H NMR(500MHz,DMSO-d₆): δ 10.78 (s, 1H), 8.18-8.17 (d, 1H, J=5.0Hz), 7.86-7.85 (d, 1H, J=5.0Hz), 7.57-7.53 (m, 4H), 7.33-7.38 (t, 1H, J=7.5Hz), 6.36-6.43 (m, 3H), 6.14 (s,2H),4.21(s,2H).ES:m/z 403.1[M+H]⁺。

23 4- amino-5-cyano -6- of embodiment (((the chloro- 2- phenyl -1,4- dihydroquinoline -3- base of 8-) methyl) amino) Pyrimidine

The preparation of step 1 4- oxo -2- phenyl -1,4- dihydroquinoline -3- formaldehyde

The system of the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- formaldehyde of 8- of the preparation method is the same as that of Example 17 step 1-4 Target compound is made the difference is that raw material 2- amino -3- chlorobenzoic acid is replaced with 2- aminobenzoic acid in Preparation Method.

The preparation of -4 (1H) -one of step 2 3- aminomethyl -2- phenylchinoline

System of the preparation method with chloro- 2- phenylchinoline -4 (1H) -one of 3- aminomethyl -8- made from 22 step 1-2 of embodiment Preparation Method is made the difference is that the chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- formaldehyde of raw material 8- is replaced in above step Target compound is made in the 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- formaldehyde obtained.

Step 3 4- amino-5-cyano -6- (((the chloro- 2- phenyl -1,4- dihydroquinoline -3- base of 8-) methyl) amino) pyrimidine Preparation

100ml tri- is added in -4 (1H) -one (1.25g, 0.005mol) of 3- aminomethyl -2- phenylchinoline and 50ml isopropanol In neck bottle, stirring and dissolving, be then added 4- amino-5-cyano -6- chlorine pyrimidine (0.93g, 0.006mol) and potassium carbonate (2.1g, 0.015mol), 80 DEG C are warming up to, 5h, TLC tracking reaction to fully reacting are stirred at reflux.Stop reaction, filter, filter cake is with greatly Ethyl acetate washing is measured, removed under reduced pressure solvent, methanol is added in residue and silica gel sand, column chromatography for separation obtain white solid 1.37g, yield 68.1%.

¹H NMR(500MHz,DMSO-d₆): δ 10.80 (s, 1H), 8.18-8.17 (d, 1H, J=5.0Hz), 7.88-7.87 (d, 1H, J=5.0Hz), 7.56-7.54 (m, 5H), 7.36-7.39 (t, 1H, J=7.5Hz), 6.43 (s, 3H), 6.10 (s, 2H),4.23(s,2H).ES:m/z 368.9[M+H]⁺。

24 4- amino-5-cyano -6- of embodiment (((8- fluorin-4-oxygen generation -2- phenyl -1,4- dihydroquinoline -3- base) first Base) amino) pyrimidine

The preparation of fluoro- 2- phenylchinoline -4 (1H) -one of step 1 3- aminomethyl -8-

Preparation side of the preparation method with -4 (1H) -one of 3- aminomethyl -2- phenylchinoline made from 23 step 1-2 of embodiment Target compound is made the difference is that raw material 2- aminobenzoic acid is replaced with 2- amino -3- fluobenzoic acid in method.

Step 2 4- amino-5-cyano -6- (((8- fluorin-4-oxygen generation -2- phenyl -1,4- dihydroquinoline -3- base) methyl) ammonia Base) pyrimidine preparation

Fluoro- 2- phenylchinoline -4 (1H) -one (1.34g, 0.005mol) of 3- aminomethyl -8- and 50ml isopropanol are added In 100ml three-necked bottle, then 4- amino-5-cyano -6- chlorine pyrimidine (0.93g, 0.006mol) and potassium carbonate is added in stirring and dissolving (2.1g, 0.015mol) is warming up to 80 DEG C, is stirred at reflux 5h, TLC tracking reaction to fully reacting.Stop reaction, filters, filter Cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, and methanol and silica gel sand, column chromatography for separation is added in residue, is obtained white Solid 1.23g, yield 63.8%.

¹H NMR(500MHz,DMSO-d₆): δ 10.78 (s, 1H), 8.18-8.17 (d, 1H, J=5.0Hz), 7.86-7.85 (d, 1H, J=5.0Hz), 7.57-7.53 (m, 4H), 7.33-7.38 (t, 1H, J=7.5Hz), 6.36-6.43 (m, 3H), 6.14 (s,2H),4.21(s,2H).ES:m/z 387.1[M+H]⁺。

25 2,4- diamino -5- cyano -6- of embodiment (((2- phenyl -1,4- dihydroquinoline -3- base) methyl) amino) is phonetic Pyridine

By -4 (1H) -one (1.25g, 0.005mol) of 3- aminomethyl -2- phenylchinoline obtained in 23 step 2 of embodiment and 50ml isopropanol is added in 100ml three-necked bottle, then 2,4- diamino -5- cyano -6- chlorine pyrimidine is added in stirring and dissolving (1.01g, 0.006mol) and DBU (2.1g, 0.015mol), is warming up to 80 DEG C, is stirred at reflux 5h, TLC tracking reaction to reaction Completely.Stop reaction, removed under reduced pressure solvent, methanol is added in residue and silica gel sand, column chromatography for separation obtain white solid 0.70g, yield 36.3%.

¹H NMR(500MHz,DMSO-d₆): δ 10.81 (s, 1H), 8.18-8.17 (d, 1H, J=5.0Hz), 7.89-7.88 (d, 1H, J=5.0Hz), 7.56-7.54 (m, 4H), 7.36-7.39 (t, 1H, J=7.5Hz), 6.43 (s, 3H), 6.10 (s, 2H),6.02(s,2H),4.23(s,2H).ES:m/z 384.1[M+H]⁺。

26 2,4- diamino -5- cyano -6- ((the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) of embodiment Methyl) amino) pyrimidine

By chloro- 2- phenylchinoline -4 (1H) -one of 3- aminomethyl -8- obtained in 22 step 2 of embodiment (1.42g, It 0.005mol) is added in 100ml three-necked bottle with 50ml isopropanol, then 2,4- diamino -5- cyano -6- is added in stirring and dissolving Chlorine pyrimidine (1.01g, 0.006mol) and potassium carbonate (2.1g, 0.015mol), are warming up to 80 DEG C, are stirred at reflux 5h, TLC is tracked to Fully reacting.Stop reaction, filter, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, and methanol and silicon is added in residue Glue sand, column chromatography for separation obtain white solid 0.62g, yield 29.6%.

¹H NMR(500MHz,DMSO-d₆): δ 10.78 (s, 1H), 8.17-8.18 (d, 1H, J=5.0Hz), 7.85-7.86 (d, 1H, J=5.0Hz), 7.51-7.54 (m, 3H), 7.33-7.38 (t, 1H, J=7.5Hz), 6.36-6.43 (m, 3H), 6.16 (s,2H),6.08(s,2H),4.21(s,2H).ES:m/z 418.1[M+H]⁺。

27 4- amino-5-cyano -6- of embodiment ((1- (the chloro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline-of 8- 3- yl) ethyl) amino) pyrimidine

The preparation of step 1 1- (the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) ethylamino t-butyl formate

By chloro- 2- phenylchinoline -4 (1H) -one of 3- (1- amino-ethyl) -8- obtained in 17 step 8 of embodiment (1.5g, 0.005mol) it is added in 100ml three-necked bottle with 20ml THF, then the sodium hydroxide solution of 10ml 1M is added in stirring and dissolving, It is cooled to 0 DEG C, the 5ml tetrahydrofuran solution of di-tert-butyl dicarbonate (1.38g, 0.006mol) is then added dropwise, 1h is stirred at room temperature, TLC tracking is reacted to fully reacting.Stop reaction, revolving removes tetrahydrofuran, and 50ml water and 50ml acetic acid second is added in residue Ester, water layer use the ethyl acetate of 25ml × 2 to extract again, merge organic layer, and saturated common salt water washing, anhydrous sodium sulfate is dry, decompression Solvent is evaporated off, column chromatographs to obtain white solid 1.65g, yield 82.8%.

Step 2 1- (the chloro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) ethylamino t-butyl formate Preparation

By 1- (the chloro- 4- oxo -2- phenyl-Isosorbide-5-Nitrae-dihydroquinoline -3- base of 8-) ethylamino t-butyl formate (1.59g, 0.004mol), 100ml tri- is added in potassium carbonate (1.69g, 0.012mol), iodomethane (2.84g, 0.020mol) and 25ml DMF In neck bottle, 45 DEG C are warming up to, stirs 2h, TLC tracks to fully reacting, stops reaction, filters, and filter cake is washed with ethyl acetate, Filtrate decompression removes solvent, and 50ml ethyl acetate and the extraction of 50ml water is added, and water layer is washed with the ethyl acetate of 25ml × 2, merges Organic layer, saturated sodium-chloride water solution washing is dry, the white solid 1.53g after precipitation, yield 92.6%.

The preparation of chloro- 1- methyl -2- phenylchinoline -4 (1H) the -one hydrochloride of step 3 3- (1- amino-ethyl) -8-

By 1- (the chloro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 8-) ethylamino t-butyl formate The ethanol solution (HCl concentration is 6.2M) of (1.24g, 0.003mol) and 20ml hydrogen chloride is added in 100ml three-necked bottle, and room temperature is stirred Mix 1h, TLC tracking reaction to fully reacting.Stop reaction, revolving removes solvent, and 50ml dehydrated alcohol is added in residue, again Revolving removing solvent, obtains crude product 1.21g, direct plunges into and react in next step..

Step 4 4- amino-5-cyano -6- ((1- (the chloro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- of 8- Base) ethyl) amino) and pyrimidine preparation

By chloro- -4 (1H) the -one hydrochloride, crude (1.21g) of 1- methyl -2- phenylchinoline of 3- (1- amino-ethyl) -8- and 50ml isopropanol be added 100ml three-necked bottle in, stirring and dissolving, then be added 4- amino-5-cyano -6- chlorine pyrimidine (0.36g, 0.036mol) with potassium carbonate (1.25g, 0.09mol), 80 DEG C are warming up to, is stirred at reflux 5h, TLC tracking reaction is anti-to compound 9 It should be complete.Stop reaction, filter, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, and methanol and silica gel is added in residue Sand processed, column chromatography for separation obtain white solid 0.93g, yield 72.1%.

¹H NMR(500MHz,DMSO-d₆): δ 8.36-8.35 (d, 1H, J=5.0Hz), 8.21-8.20 (d, 1H, J= 5.0Hz),7.87(s,1H),7.81-7.82(m,2H),7.62-7.63(m,2H),7.44-7.51(m,3H),7.17(s,2H), 4.90-4.87 (m, 1H), 3.42 (s, 3H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 430.9 [M+H]⁺。

28 4- amino-5-cyano -6- of embodiment ((1- (the fluoro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline-of 8- 3- yl) ethyl) amino) pyrimidine

The preparation of fluoro- 2- phenylchinoline -4 (1H) -one of step 1 3- (1- amino-ethyl) -8-

The chloro- 2- phenylchinoline -4 of 3- (1- amino-ethyl) -8- obtained in the preparation method is the same as that of Example 17 step 1-8 The preparation method of (1H) -one is made the difference is that raw material 2- amino -3- chlorobenzoic acid is replaced with 2- amino -3- fluobenzoic acid Target compound.

The preparation of fluoro- 1- methyl -2- phenylchinoline -4 (1H) the -one hydrochloride of step 2 3- (1- amino-ethyl) -8-

Preparation method is the same as the chloro- 1- methyl -2- phenylchinoline-of 3- (1- amino-ethyl) -8- made from 27 step 1-3 of embodiment The preparation method of 4 (1H) -one hydrochlorides, the difference is that by the chloro- 2- phenylchinoline -4 (1H)-of raw material 3- (1- amino-ethyl) -8- Ketone replaces with fluoro- 2- phenylchinoline -4 (1H) -one of 3- (1- amino-ethyl) -8- obtained in above step, and target chemical combination is made Object.

Step 3 4- amino-5-cyano -6- ((1- (the fluoro- 1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- of 8- Base) ethyl) amino) and pyrimidine preparation

By fluoro- -4 (1H) the -one hydrochloride, crude (1.18g) of 1- methyl -2- phenylchinoline of 3- (1- amino-ethyl) -8- and 50ml isopropanol be added 100ml three-necked bottle in, stirring and dissolving, then be added 4- amino-5-cyano -6- chlorine pyrimidine (0.36g, 0.036mol) with potassium carbonate (1.25g, 0.09mol), 80 DEG C are warming up to, is stirred at reflux 5h, TLC tracking reaction is anti-to compound 9 It should be complete.Stop reaction, filter, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, and methanol and silica gel is added in residue Sand processed, column chromatography for separation obtain white solid 0.93g, yield 72.1%.

¹H NMR(500MHz,DMSO-d₆): δ 8.38-8.37 (d, 1H, J=5.0Hz), 8.20-8.19 (d, 1H, J= 5.0Hz),7.87(s,1H),7.81-7.83(m,2H),7.61-7.63(m,2H),7.44-7.50(m,3H),7.16(s,2H), 4.90-4.86 (m, 1H), 3.41 (s, 3H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 415.2 [M+H]⁺。

29 4- amino-5-cyano -6- of embodiment ((1- (1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) Methyl) amino) pyrimidine

The preparation of -4 (1H) -one hydrochloride of step 1 3- (1- amino methyl) -1- methyl -2- phenylchinoline

Preparation method is the same as the chloro- 1- methyl -2- phenylchinoline-of 3- (1- amino-ethyl) -8- made from 27 step 1-3 of embodiment The preparation method of 4 (1H) -one hydrochlorides, the difference is that by the chloro- 2- phenylchinoline -4 (1H)-of raw material 3- (1- amino-ethyl) -8- Ketone replaces with 3- aminomethyl -2- phenylchinoline -4 (1H) -one obtained in 23 step 2 of embodiment, and target compound is made.

Step 2 4- amino-5-cyano -6- ((1- (1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) first Base) amino) pyrimidine preparation

- 4 (1H) -one hydrochloride, crude (1.12g) of 3- (1- amino methyl) -1- methyl -2- phenylchinoline and 50ml is different Propyl alcohol is added in 100ml three-necked bottle, stirring and dissolving, and 4- amino-5-cyano -6- chlorine pyrimidine (0.36g, 0.036mol) then is added With potassium carbonate (1.25g, 0.09mol), 80 DEG C are warming up to, is stirred at reflux 5h, TLC tracking reaction to fully reacting.Stop reaction, It filtering, filter cake is washed with a large amount of ethyl acetate, removed under reduced pressure solvent, residue addition methanol and silica gel sand, column chromatography for separation, Obtain white solid 0.79g, yield 68.5%.

¹H NMR(500MHz,DMSO-d₆): δ 8.17-8.18 (d, 1H, J=5.0Hz), 7.86-7.87 (d, 1H, J= 5.0Hz), 7.48-7.53 (m, 5H), 7.36-7.39 (t, 1H, J=7.5Hz), 6.43 (s, 3H), 6.10 (s, 2H), 4.23 (s, 2H),3.41(s,3H).ES:m/z 383.2[M+H]⁺。

30 2,4- diamino -5- cyano -6- of embodiment ((1- (4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) second Base) amino) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike raw material 2- amino -3- chlorobenzoic acid replaced with into 2- Aminobenzoic acid, and raw material 4- amino-5-cyano -6- chlorine pyrimidine is replaced with into 2,4- diamino -5- cyano -6- chlorine pyrimidine, it makes Obtain target compound, yield 45.1%.

¹H NMR(500MHz,DMSO-d₆) δ: 11.05 (s, 1H), 8.35-8.34 (d, 1H, J=5.0Hz), 8.22-8.21 (d, 1H, J=5.0Hz), 7.81-7.82 (m, 2H), 7.61-7.62 (m, 3H), 7.45-7.52 (m, 3H), 6.11 (s, 2H), 6.03 (s, 2H), 4.90-4.87 (m, 1H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 398.2 [M+H]⁺。

31 2,4- diamino -5- cyano -6- ((1- (the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- of 8- of embodiment Base) ethyl) amino) pyrimidine

The preparation method is the same as that of Example 17 preparation method, unlike by raw material 4- amino-5-cyano -6- chlorine pyrimidine replace For 2,4- diamino -5- cyano -6- chlorine pyrimidine, target compound, yield 32.1% is made.

¹H NMR(500MHz,DMSO-d₆) δ: 11.05 (s, 1H), 8.20-8.22 (d, 1H, J=10.0Hz), 8.00- 8.02 (d, 1H, J=10.0Hz), 7.91 (s, 1H), 7.53-7.58 (m, 5H), 7.40-7.43 (t, 1H, J=7.5Hz), 6.12 (s, 2H), 6.04 (s, 2H), 5.14-5.17 (m, 1H), 1.35-1.37 (d, 3H, J=10.0Hz) .ES:m/z 432.1 [M+H]⁺。

32 4- amino-5-cyano -6- of embodiment ((1- (1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline -3- base) Ethyl) amino) pyrimidine

Preparation method with embodiment 28 preparation method, unlike raw material 2- amino -3- fluobenzoic acid replaced with into 2- Target compound, yield 81.1% is made in aminobenzoic acid.

¹H NMR(500MHz,DMSO-d₆) δ: 8.36-8.35 (d, 1H, J=5.0Hz), 8.21-8.20 (d, 1H, J= 5.0Hz),7.87(s,1H),7.81-7.82(m,2H),7.62-7.63(m,2H),7.44-7.51(m,4H),7.17(s,2H), 4.90-4.87 (m, 1H), 3.42 (s, 3H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 397.2 [M+H]⁺。

33 2,4- diamino -5- cyano -6- of embodiment ((1- (1- methyl -4- oxo -2- phenyl -1,4- dihydroquinoline - 3- yl) ethyl) amino) pyrimidine

Preparation method with embodiment 28 preparation method, unlike raw material 2- amino -3- fluobenzoic acid replaced with into 2- Aminobenzoic acid, and raw material 4- amino-5-cyano -6- chlorine pyrimidine is replaced with into 2,4- diamino -5- cyano -6- chlorine pyrimidine, it makes Obtain target compound, yield 81.1%.

¹H NMR(500MHz,DMSO-d₆) δ: 8.36-8.35 (d, 1H, J=5.0Hz), 8.22-8.21 (d, 1H, J= 5.0Hz),7.81-7.83(m,2H),7.62-7.64(m,2H),7.44-7.50(m,4H),6.12(s,2H),6.04(s,2H), 4.87-4.90 (m, 1H), 3.42 (s, 3H), 1.29-1.31 (d, 3H, J=10.0Hz) .ES:m/z 412.2 [M+H]⁺。

34 4- amino-5-cyano -6- of embodiment ((1- (1- methyl -4- oxo -2- (3- fluorophenyl) -1,4- dihydro quinoline Quinoline -3- base) ethyl) amino) pyrimidine

Preparation method with embodiment 28 preparation method, unlike raw material 2- amino -3- fluobenzoic acid replaced with into 2- Aminobenzoic acid, and benzene feedstock carbamoyl ethyl is replaced with into 3- fluorobenzoyl ethyl ester, target compound, yield 32.8% is made.

¹H NMR(500MHz,DMSO-d₆) δ: 8.33-8.32 (d, 1H, J=5.0Hz), 8.18-8.19 (d, 1H, J= 5.0Hz),7.87(s,1H),7.83-7.84(m,3H),7.55-7.58(m,1H),7.49-7.53(m,3H),7.19(s,2H), 4.88-4.91 (m, 1H), 3.43 (s, 3H), 1.31-1.33 (d, 3H, J=10.0Hz) .ES:m/z 415.2 [M+H]⁺。

Embodiment 35 2,4- diamino -5- cyano -6- ((1- (the chloro- 1- methyl -4- oxo -2- phenyl -1,4- dihydro of 8- Quinoline -3- base) ethyl) amino) pyrimidine

Preparation method with embodiment 28 preparation method, unlike raw material 2- amino -3- fluobenzoic acid replaced with into 2- Amino -3- chlorobenzoic acid, and it is phonetic that raw material 4- amino-5-cyano -6- chlorine pyrimidine replaced with 2,4- diamino -5- cyano -6- chlorine Target compound, yield 33.5% is made in pyridine.

¹H NMR(500MHz,DMSO-d₆) δ: 8.21-8.23 (d, 1H, J=10.0Hz), 8.00-8.03 (d, 1H, J= 10.0Hz), 7.92 (s, 1H), 7.53-7.55 (m, 5H), 7.40-7.43 (t, 1H, J=7.5Hz), 6.15 (s, 2H), 6.01 (s, 2H), 5.14-5.17 (m, 1H), 3.43 (s, 3H), 1.35-1.37 (d, 3H, J=10.0Hz) .ES:m/z 446.1 [M+H]⁺。

36 2,4- diamino -5- cyano -6- of embodiment ((8- fluorin-4-oxygen generation -2- phenyl -1,4- dihydroquinoline -3- base) Methyl) amino) pyrimidine

Preparation method with embodiment 23 preparation method, unlike raw material 2- aminobenzoic acid replaced with into 2- amino- Target compound, yield 22.8% is made in 3- fluobenzoic acid.

¹H NMR(500MHz,DMSO-d₆) δ: 10.78 (s, 1H), 8.17-8.18 (d, 1H, J=5.0Hz), 7.86-7.87 (d, 1H, J=5.0Hz), 7.52-7.55 (m, 3H), 7.35-7.39 (t, 1H, J=7.5Hz), 6.36-6.43 (m, 2H), 6.16 (s,2H),6.08(s,2H),4.21(s,2H).ES:m/z 387.1[M+H]⁺。

37 4- amino-5-cyano -6- of embodiment (((the chloro- 4- oxo -2- phenyl -1,4- dihydroquinoline -3- base of 5-) first Base) amino) pyrimidine preparation

Preparation method with embodiment 23 preparation method, unlike raw material 2- aminobenzoic acid replaced with into 2- amino- Target compound, yield 88.1% is made in 6- chlorobenzoic acid.

¹H NMR(500MHz,DMSO-d₆) δ: 10.78 (s, 1H), 8.18-8.17 (d, 1H, J=5.0Hz), 7.82-7.85 (d, 1H, J=5.0Hz), 7.52-7.56 (m, 4H), 7.33-7.38 (t, 1H, J=7.5Hz), 6.36-6.41 (m, 3H), 6.11 (s,2H),4.20(s,2H).ES:m/z 403.1[M+H]⁺。

38 2,4- diamino -5- cyano -6- of embodiment (1- (2- (3- fluorophenyl) -4- oxo -4H- chromene -3- base) second Amido) pyrimidine

The preparation of step 1 3- bromomethyl -2- (3- fluorophenyl) -4H- chromene -4- ketone

The preparation side of 3- bromomethyl -2- phenyl -4H- chromene -4- ketone obtained in the preparation method is the same as that of Example 1 step 1-3 Method, it is different that raw material chlorobenzoyl chloride is replaced with into 3- fluorobenzoyl chloride, target compound is made.

Step 2 2,4- diamino -5- cyano -6- (1- (2- (3- fluorophenyl) -4- oxo -4H- chromene -3- base) ethamine Base) pyrimidine preparation

Preparation method with 7 step 2-3 of embodiment preparation method, unlike by the chloro- 2- phenyl -4H- of 3- bromomethyl -8- Chromene -4- ketone replaces with 3- bromomethyl -2- (3- fluorophenyl) -4H- chromene -4- ketone obtained in above step, and by 4- amino - 5- cyano -6- chlorine pyrimidine replaces with 2,4- diamino -5- cyano -6- chlorine pyrimidine, and target compound, yield 3.1% is made.

¹H NMR(300MHz,DMSO-d₆) δ: 8.17-8.14 (d, 1H, J=7.8Hz), 7.88-7.83 (t, 1H, J= 7.5Hz), 7.72-7.46 (m, 6H), 6.87-6.84 (d, 1H, J=9.0Hz), 6.50 (s, 2H), 6.07 (br, 2H), 5.37- 5.30 (t, 1H, J=6.9Hz), 1.44-1.42 (d, 3H, J=6.6Hz) .ES:m/z 417.1 [M+H]⁺。

39 2,4- diamino -5- cyano -6- of embodiment (1- (2- (3,5- difluorophenyl) -4- oxo -4H- chromene -3- Base) ethylamino-) pyrimidine

Preparation method with embodiment 38 preparation method, it is different that raw material 3- fluorobenzoyl chloride is replaced with into 3,5- difluorobenzene Target compound, yield 7.9% is made in formyl chloride.

¹H NMR(300MHz,DMSO-d₆) δ: 8.17-8.14 (d, 1H, J=7.9Hz), 7.89-7.83 (t, 1H, J= 7.7Hz), 7.68-7.65 (d, 1H, J=8.5Hz), 7.58-7.52 (m, 4H), 6.81-6.78 (d, 1H, J=8.8Hz), 6.60 (s, 2H), 6.08 (br, 2H), 5.37-5.27 (m, 1H), 1.45-1.43 (d, 3H, J=6.7Hz) .ES:m/z 435.1 [M+H]⁺。

40 2,4- diamino -5- cyano -6- of embodiment (1- (4- oxo -2- phenyl -4H- chromene -3- base) Propylamino) is phonetic Pyridine

Preparation method with embodiment 38 preparation method, it is different that raw material 3- fluorobenzoyl chloride is replaced with into chlorobenzoyl chloride, And raw material methyl-magnesium-chloride is replaced with into ethylmagnesium chloride, target compound, yield 5.7% is made.

¹H NMR(300MHz,DMSO-d₆) δ: 8.17-8.14 (d, 1H, J=7.8Hz), 7.89-7.86 (t, 1H, J= 7.7Hz), 7.77-7.53 (m, 7H), 7.09-7.04 (s, 1H), 6.77 (s, 2H), 6.21 (br, 2H), 5.31-5.23 (m, 1H), 1.85-1.83 (m, 2H), 0.67-0.62 (t, 3H, J=7.0Hz) .ES:m/z 413.1 [M+H]⁺。

1 4- amino -5- itrile group -6- of comparative example (1- (the fluoro- 1- methyl -4- oxo -1,4 two of 3- (3,5- difluorophenyl) -6- Hydrogen quinoline -2- base) ethylamino-) pyrimidine

Titled reference compound is prepared according to method disclosed in WO2010/151735 embodiment 17, and passes through hydrogen spectrum and mass spectrum Identification.The vitro kinase activity of the compound is measured using the method for following experimental example 1, the compound is to PI3K δ as the result is shown IC₅₀Being worth is 20nM, and poor selectivity.

The evaluation of 1 Compound ira vitro kinase activity of experimental example

1. experimental material

Compound: the compound of the present invention of above embodiments preparation, after each compound is configured to 10mM with DMSO, according to It is secondary to be diluted to 1 μM, 100nM, 10nM, 1nM, 0.1nM, 0.01nM.

Reagent: PI3K α (p110 α/p85a) is purchased from Invitrogen company, Cat.No.PV4788；PIK3Cδ(p110 δ/p85a) it is purchased from Millipore company, Cat.No.14-604-K；PIK3C β (p110 β) is purchased from Millipore company, Cat.No.14-603-K；PIK3C γ (pp110 γ) is purchased from Invitrogen company, Cat.No.PR8641C；Dimethyl is sub- Sulfone (DMSO) is purchased from Sigma Co., USA；EDTA is purchased from Sigma Co., USA；1 × kinase buffer liquid (50mM HEPES, pH 7.5,0.0015%Brij-35,10mM MgCl₂, 2mM DTT), prepared before use；Terminate liquid (100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mM EDTA), prepared before use.

Instrument: LabChip EZ Reader is purchased from U.S. Caliper company.

2. experimental method

2.1. it takes the 10 μ l of compound solution of each concentration into 96 orifice plates, 90 μ 1 × kinase buffer liquids of l is added；Simultaneously It sets up DMSO control group and without enzyme activity control group, contains only 10 μ l DMSO and 90 μ 1 × kinase buffer liquids of l.Each group solution is existed 10min is mixed at room temperature, then shifts 5 μ l respectively into 384 orifice plates；

2.2. kinases is dissolved in 1 × kinase buffer liquid, is configured to 2.5 × kinase solution, then shift 10 μ l 2.5 × swash Enzyme solutions are into above-mentioned 384 orifice plates containing each concentration compound；10 μ 2.5 × kinase solutions of l are added in DMSO control group；Without enzyme activity 1 × kinase buffer liquid that 10 μ l are free of kinases is added in control group.It is incubated for 10min at room temperature；

2.3. the polypeptide of FAM label and ATP are dissolved in 1 × kinase buffer liquid, are configured to 2.5 × substrate solution, then turn 10 2.5 × substrate solutions of μ l are moved into above-mentioned 384 orifice plate, 28 DEG C of incubation 1hr；

2.4. 25 μ l terminate liquids are added in each hole and terminate reaction；

2.5. reading and converting rate data on LabChip EZ Reader are placed in, and calculate inhibiting rate (I%), calculation formula For I%=(Max-Com)/(Max-Min) × 100, wherein Max is the conversion ratio of DMSO control group, and Min is no enzyme activity control group Conversion ratio, Com be compound processing group conversion ratio.Data are handled through XLfit, are fitted to obtain IC₅₀。IC₅₀Value indicates and does not add Compound processing group is compared, corresponding compound concentration when compound inhibits 50% enzyme activity.The IC of part of compounds₅₀As a result see Table 1.IC of the compounds of this invention to PI3K δ enzyme₅₀Value shows PI3K δ enzyme significantly to select inhibitory activity in nM level.

Table 1

"-" expression is not surveyed.

It can be seen that the inhibitory activity that the compound of the present invention has had PI3K δ from the above experimental result, while right PI3K α, PI3K β and PI3K γ have low inhibiting effect, and selectivity is high, promise to be very much curative effect is higher, side effect more Small cancer therapeutic agent, hyperblastosis class Remedies for diseases or the treatment of inflammatory diseases agent.

The evaluation of 2 Compound ira vitro cell activity of experimental example

1. experimental material

Test-compound: the compound of the present invention of above embodiments preparation, each compound are configured to 10mM with DMSO, Then successively 3 times be diluted to 20000.00nM, 6666.67nM, 2222.22nM, 740.74nM, 246.91nM, 27.43nM, 9.14nM、3.05nM。

Lymphoma cell strain SU-DHL-5 and SU-DHL-6 are purchased from American type culture collection (ATCC).

Reagent: RPMI-1640 is purchased from U.S. Invitrogen company；FBS is purchased from U.S. Invitrogen company； EDTA is purchased from Sigma Co., USA；Luminescent Cell Viability Assay Kit, purchase From in Progema company, the U.S.；Backseal film is purchased from U.S. Perkin Elmer company.

2. experimental method

2.1 cell culture:

Cell recovery: cell being placed in 37 degree of water-baths and is dissolved, and is then transferred into the warmed-up culture medium of 15ml, 1000rpm is centrifuged 5 minutes, discards culture medium, and cell is resuspended with 15ml fresh culture, is transferred in T75 culture bottle, is placed in 37 DEG C, 5%CO₂Incubator in cultivate, after 24 hours cell replace fresh culture.

Cell passage: the cell of above-mentioned recovery is transferred in 50ml sterile centrifugation tube, and 1000rpm is centrifuged 5 minutes, is discarded Culture medium takes finely dispersed cell count, adjusts suitable cell concentration to 15ml fresh culture, is added to T75 culture In bottle, 37 degree are placed in, 5%CO₂Incubator in cultivate.

2.2 experimental procedures:

T75 cell cell in culture bottle is long to 1 × 10⁵-1×10⁶After a cell/ml, fresh culture (RPMI is used It 1640+20%FBS) is resuspended, and counts.The cell of resuspension is adjusted into cell concentration to following 8 concentration gradients: 1 × 10⁴It is a thin Born of the same parents/ml, 2 × 10⁴A cell/ml, 3 × 10⁴A cell/ml, 5 × 10⁴A cell/ml, 8 × 10⁴A cell/ml, 1 × 10⁵It is a Cell/ml, 1.5 × 10⁵A cell/ml and 2 × 10⁵A cell/ml.The training of 96 hole cells is added in the cell suspension of above-mentioned concentration It supports in plate, 100 μ l (respectively 1 × 10 are added in every hole³A cell/well, 2 × 10³A cell/well, 3 × 10³A cell/ well,5×10³A cell/well, 8 × 10³A cell/well, 1 × 10⁴A cell/well, 1.5 × 10⁴A cell/well With 2 × 10⁴A cell/well).Every kind of two multiple holes of concentration, spread three blocks of plates.100 μ l are added to gaging hole backward in 72hLuminescent Cell Viability Assay buffer.Gently shake up.After ten minutes, exist Backseal film is sticked in Assay board bottom portion, is placed on Envison and reads fluorescence reading, and calculates cell survival rate (cell Survive (%)), calculation formula is cell survive (%)=(Com-Min)/(Max-Min), and wherein Max is solvent pair According to the reading of group, Min is the reading of cell-free control group, and Com is the reading of compound processing group, and data are handled through XLfit, is intended Close to obtain IC₅₀, experimental result is shown in Table 2.

Table 2

"-" expression does not detect.

From the above experiment as can be seen that the compound of the present invention shows SU-DHL-5 and SU-DHL-6 lymphoma cell Go out good inhibitory activity, promises to be very much lymphoma treating agent.

It was found by the inventors of the present invention that the compound of the present invention has very high subtype-selective to PI3K kinases.This Outside, the compound of the present invention has extraordinary bioavilability and long half-life period, and druggability is good.

Although being described in detail above to the present invention, however it is understood by skilled practitioners that without departing from this hair The present invention can be carry out various modifications and be changed under the premise of bright spirit and scope.Interest field of the invention is not limited to Detailed description made by above, and claims should be belonged to.

Claims (5)

1. a kind of compound or its pharmaceutically acceptable salt, wherein the compound is selected from following compound:

2. a kind of pharmaceutical composition, it includes compound described in claim 1 or its pharmaceutically acceptable salts and pharmaceutically acceptable Carrier.

3. compound described in claim 1 or its pharmaceutically acceptable salt or pharmaceutical composition as claimed in claim 2 exist Preparation for treat and/or the drug of pre- anti-cancer, hyperblastosis class disease or inflammatory disease in application.

4. application according to claim 3, wherein the cancer is selected from cholangiocarcinoma, malignant lymphatic tumor, liver, kidney, wing Cancer and sarcoma and skin, the primary and recurrent reality of colon, thyroid gland, lung and ovary of Guang, prostate, mammary gland and pancreas Body tumor and leukaemia, the inflammatory disease are selected from allergy, asthma, rheumatoid arthritis, osteoarthritis, anaphylaxis conjunctiva Inflammation, anaphylactic keratitis, xerophthalmia, chronic obstructive pulmonary disease, lupus erythematosus, psoriasis.

5. application according to claim 3, wherein the cancer is selected from melanoma, Papillary thyroid carcinoma, colon Cancer, oophoroma and lung cancer.