CN104803925B - A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use - Google Patents

A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use Download PDF

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CN104803925B
CN104803925B CN201510180883.3A CN201510180883A CN104803925B CN 104803925 B CN104803925 B CN 104803925B CN 201510180883 A CN201510180883 A CN 201510180883A CN 104803925 B CN104803925 B CN 104803925B
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amine
fgfr
class compounds
pyrimidine class
benzene
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CN104803925A (en
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梁广
刘志国
王怡
陈凌锋
蔡跃飘
冯建鹏
张亚丽
李校堃
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Wenzhou Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Abstract

The invention belongs to medicinal chemistry art, more particularly to 2 of one kind using FGFR as target spot, 4,5 trisubstituted pyrimidine class compounds and its production and use, the compound can optionally suppress the phosphorylation of FGFR kinases so as to the malignant tumour maintained close ties with for treatment with this kinases, while can reduce adverse reaction；It can be used in treating the disease of the related tumour of FGFR kinases or correlation.The formula of 2,4,5 trisubstituted pyrimidine class compounds is：Wherein：Above R1、R2、R3It can be selected with a variety of substituents, R1、R2、R3Substituent can be in any combination.It is of the present invention using FGFR as 2,4,5 trisubstituted pyrimidine class compounds of target spot to FGFR1 kinases with good inhibitory action and to FGFR1 dependent tumors cell line KG1 cells with antiproliferative effect；Available for preparing antineoplastic, and antitumous effect is preferable.

Description

A kind of 2,4,5- trisubstituted pyrimidine class compounds and its preparation side using FGFR as target spot Method and purposes
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of 2,4,5- trisubstituted pyrimidine classes using FGFR as target spot Compound and its production and use.
Background technology
In this field of protein kinase, fibroblast growth factor acceptor FGFR families are one and had a great attraction Target spot is in oncotherapy.The FGFR families of receptor tyrosine kinase include four members, are FGFR1, FGFR2, FGFR3 respectively And FGFR4.They have highly similar sequence homology.The imbalance of FGFR kinases and Several Kinds of Malignancy are closely related, such as The kinds cancers such as breast cancer, carcinoma of urinary bladder, stomach cancer, prostate cancer, the carcinoma of the rectum, therefore medical oncology is constantly studied it and to cancer Diagnosis and treatment.
Suppress the protein kinase related to disease, blocking and tumoricidal signal transmission, a variety of methods can be passed through To realize, but because the ASON of synthesis is easily degraded by the attack of ribozyme, there is security, steady in RNA perturbation techniques It is qualitative and miss the target effect the problems such as, therefore new drug development personnel attempt to screen chemical small point of FGFR from organic synthesis small molecule Sub- inhibitor.So far, existing multiple micromolecular inhibitors enter clinical experimental stage, such as NVP-BGJ398,
BIBF-1120, TKI-258, BMS-582664, AZD-2171, AB-1010, TSU-68, AP-24534 and E- 7080。
The most fast medicine of research is NVP-BGJ398 at present, and its FGFR inhibitor as high selectivity is solid for treating Body malignant tumour, it is in during the clinical I phases study.In the market is urgently ground there has been no the FGFR inhibitor using pyrimidine as parent nucleus Make the FGFR inhibitor using pyrimidine as parent nucleus.
The content of the invention
An object of the present invention is in order to solve the above technical problems, providing a kind of 2,4,5- tri- taking using FGFR as target spot For pyrimidines and its production and use, the compound can optionally suppress the phosphorylation of FGFR kinases so as to For treating adverse reaction can be reduced with the malignant tumour of this kinases close ties simultaneously；It can be used in treating FGFR kinases correlation Tumour or correlation disease.
To realize above-mentioned technique effect, the technical scheme is that：
A kind of 2,4,5- trisubstituted pyrimidine class compounds using FGFR as target spot, there is general formula：
Wherein：R1Following any substituted radical can be selected from：
R2Following any substituted radical can be selected from：
R3Cl or NO can be selected from2In any one；
Above R1、R2、R3In substituent can be in any combination.
A kind of method for preparing above-mentioned a kind of 2,4,5- trisubstituted pyrimidine class compounds using FGFR as target spot, including such as Lower step：
Step 1：Weigh the chloro- 5- nitro-pyrimidines of 2,4- bis-, DIPEA and R1-NH2In flask, under stirring Adding methylene chloride makes its dissolving, reacts at room temperature 5h, after completion of the reaction, adds saturated aqueous common salt, and mixture is extracted with dichloromethane, Concentration, obtains the powdered 2-R of red solid1The chloro- 5- nitro-pyrimidines of-ammonia -4-.
Step 2：Weigh the 2-R1The chloro- 5- nitro-pyrimidines of-ammonia -4- and the R2-NH2In flask, lower add is stirred Sec-butyl alcohol makes its dissolving, and flow back 2h, after reaction terminates, is cooled to room temperature, adds sodium acid carbonate and neutralizes, is extracted with ethyl acetate 3 Secondary, concentration, silica gel column chromatography, eluant, eluent is acetate-methanol, and the volume ratio of ethyl acetate and methanol is 20: 1, obtains 2-R1- Ammonia -4-R2- ammonia -5-R3Pyrimidine.
Wherein, R3For nitro, R1And R2Define identical with above-mentioned definition, can have the selections of a variety of substituents.
Further, per 1g 2, the chloro- 5- nitro-pyrimidines dichloromethane 20ml of 4- bis- in the step 1；The amount of material The ratio between：2,4- bis- chloro- 5- nitro-pyrimidines: DIPEA: R1-NH2=1: 1: 1.
Further, 2-R described in every 500mg1The chloro- 5- nitro-pyrimidines sec-butyl alcohol 15-20ml of-ammonia -4-, then by trifluoro second Acid is instilled in flask, the ratio between amount of material：2-R1The chloro- 5-R of-ammonia -4-3Pyrimidine: R2-NH2: trifluoroacetic acid 1: 1: 1.
A kind of method for preparing above-mentioned a kind of 2,4,5- trisubstituted pyrimidine class compounds using FGFR as target spot, including such as Lower step：
Step 1：Weigh 2,4,5- trichloropyrimidines, Anhydrous potassium carbonate and the R1-NH2In flask, stirring, which adds DMF, to be made It dissolves, per the ratio between the trichloropyrimidine DMF 5-10ml of 1g 2,4,5-, amount of material：2,4,5- trichloropyrimidines: Anhydrous potassium carbonate ∶R1-NH2=1: 2: 1,60 DEG C of reaction 2-3h, after completion of the reaction, are cooled to room temperature, add a large amount of frozen water, have solid precipitation, take out Filter, dry, obtain 2-R1- ammonia -4,5- dichloro pyrimidine；
Step 2：Weigh the 2-R1The chloro- 5- dichloro pyrimidines of-ammonia -4- and the R2-NH2In flask, lower add is stirred The sec-butyl alcohol makes its dissolving, 2-R described in per 500mg1The chloro- 5- dichloro pyrimidines sec-butyl alcohol 20-30ml of-ammonia -4-, then by trifluoro Acetic acid is instilled in flask, the ratio between amount of material：2-R1The chloro- 5- dichloro pyrimidines of-ammonia -4-: R2-NH2: trifluoroacetic acid=1: 1: 1, return Flow 2h.After reaction terminates, room temperature is cooled to, sodium acid carbonate is added and neutralizes, be extracted with ethyl acetate 3 times, concentrate, silica gel column layer Analysis, eluant, eluent are acetate-methanol, and the volume ratio of ethyl acetate and methanol is 20: 1, obtains 2-R1- ammonia -4-R2- ammonia -5-R3It is phonetic Pyridine.
R3For chlorine, R1And R2Define identical with above-mentioned definition, can have the selections of a variety of substituents.
The purposes of a kind of 2,4,5- trisubstituted pyrimidine class compounds using FGFR as target spot, the purposes are antitumor to prepare Application in medicine.
A kind of pharmaceutical composition, including pharmaceutic adjuvant and a kind of 2,4,5- trisubstituted pyrimidine class chemical combination using FGFR as target spot Thing.
Contain 2 of one kind using FGFR as target spot, the pharmaceutical composition of 4,5- trisubstituted pyrimidine class compounds, described medicine The dosage form of composition is injection, tablet, capsule, aerosol, suppository, film, pill, ointment, controlled release agent, slow Release any of agent or nanometer formulation.
Beneficial effects of the present invention include：2,4, the 5- trisubstituted pyrimidine class chemical combination of the present invention using FGFR as target spot Thing is to FGFR1 kinases with good inhibitory action and FGFR1 dependent tumors cell line KG1 cells with antiproliferative effect. Available for preparing antineoplastic, and antitumous effect is preferable.
Embodiment
The present invention is described in detail below in conjunction with specific embodiment.It should be noted that the skill described in following embodiments The combination of art feature or technical characteristic is not construed as isolated, and they can be mutually combined so as to reach more preferable Technique effect.
The N- of embodiment 1 { 4- { { 2- { [4- methylpiperazine-1-yls] benzene } amine } -5- nitro-pyrimidine -4- bases } benzene } acetamide The preparation of (compound 1)
(1) preparation of N- { 4- [(the chloro- 5- nitro-pyrimidines -4- bases of 2-) amine] phenyl } acetamide
Under conditions of ice bath, the chloro- 5- nitro-pyrimidines (5g, 25.7mmol) of 2,4- bis- are dissolved in dichloromethane In (100ml), add DIPEA (4.3ml, 25.7mmol) and acetparaminosalol aniline (3.87g, 25.7mmol). Ice bath is removed, reactant mixture reacts 5h at room temperature, then adds saturated aqueous common salt (200ml).Mixture dichloromethane (300ml) is extracted.Organic layer is dried with anhydrous magnesium sulfate, is concentrated to give solid, and product is not further purified, and obtains 6.34g red solids, yield 90.0%.
(2) N- { 4- { { 2- { [4- methylpiperazine-1-yls] benzene } amine } -5- nitro-pyrimidine -4- bases } benzene } acetamide (compound 1) preparation
Weigh N- { 4- [(the chloro- 5- nitro-pyrimidines -4- bases of 2-) amine] phenyl } acetamide (1g, 3.25mmol), 4- methyl piperazines Piperazine aniline (746.0mg, 3.90mmol) and trifluoroacetic acid (0.25ml, 3.25mmol) are dissolved in sec-butyl alcohol (20ml), finish 100 DEG C React 6h.Cooling, be concentrated under reduced pressure system, and obtained grease is poured into frozen water, is added sodium acid carbonate and is neutralized to neutrality, acetic acid second Ester extracts, and dries, and concentration organic phase obtains crude product, and column chromatography (ethyl acetate: methanol=20: 1) obtains red solid product 2.78g, yield 61.7%.
The N- of embodiment 2 { 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amido } pyrimidine-4-yl } amine } phenyl } The preparation of acetamide (compound 2)
(1) preparation of N- { 4- [(2,5- dichloro pyrimidine -4- bases) amine] phenyl } acetamide
Weigh acetparaminosalol aniline (1.31g, 8.72mmol) and be dissolved in DMF (20ml), add Anhydrous potassium carbonate (2.42g, 17.5mmol) and 2,4,5- trichloropyrimidines (1.0ml, 8.72mmol).Reactant mixture is heated to 60 DEG C of reaction 2h. After completion of the reaction, room temperature is cooled to, adds a large amount of frozen water, separates out solid, is filtered, is dried, product is not further purified, obtained 2.3g, yield 90%.
(2) N- { 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amido } pyrimidine-4-yl } amine } phenyl } acetyl The preparation of amine
Weigh N- { 4- [(2,5- dichloro pyrimidine -4- bases) amine] phenyl } acetamide (1.6g, 5.45mmol), 4- methyl piperazines Aniline (1.24g, 6.46mmol) and trifluoroacetic acid (0.42ml, 5.45mmol) are dissolved in sec-butyl alcohol (30ml), are heated to 100 DEG C instead Answer 6h.Cooling, be concentrated under reduced pressure system, and obtained grease is poured into frozen water, is added sodium acid carbonate and is neutralized to neutrality, ethyl acetate Extraction, dry, concentration organic phase obtains crude product, and column chromatography (ethyl acetate: methanol=20: 1) obtains white solid product 1.47g, yield 60.3%.
By any one method of embodiment 1 or 2, with the chloro- 5- nitro-pyrimidines of 2,4- bis- or 2,4,5- trichloropyrimidines and difference The aniline of substitution form be raw material, synthesized 2 using FGFR as target spot listed by table 1,4,5- trisubstituted pyrimidine class compounds 1 ~26.
Each R group in 2,4,5- trisubstituted pyrimidine class compounds in the formula I of table 1 using FGFR as target spot
Note：Initial feed is purchased from aladdin companies.
Measure of the compound of embodiment 3 to FGFR kinase activities
Compound is determined to FGFR1 inhibitory activity by LANCE ULTRA Assay methods, and with positive control drug ratio Compared with filtering out the good compound of activity.FGFR1 buys for CARNA companies.
Specific method：Compound, ATP, specific substrate and the dilution of FGFR1 kinases kinase dilutions liquid tested. Containing FGFR1, ATP, substrate, HEPES (PH=7.5), MgCl in kinase reaction mixture2、EGTA、Tween-20.It is not added with any Compound group makees the control of 100% phosphorylation, adds after FGFR1 kinases and adds EDTA terminating reactions group at once as 0% phosphorylation pair According to.After kinase reaction mixture is incubated 1h altogether at room temperature, add EDTA terminating reactions 5 minutes.Specific antibody is added, at room temperature Continue common incubation 1h, exciting light is detected with PerkinElmer Envision kinases instrument.Gained signal value is detected according to kinases instrument, Inhibiting rate or GraphPad calculating test-compounds IC are calculated to obtain with formula50Value.
Measure of the compound of embodiment 4 to KG1 cell inhibitory rates
Compound is detected to the inhibited proliferation of KG1 cells with CCK-8 Cell counting Kits (Dojindo).Specifically Step is as follows：KG1 cells in exponential phase are seeded in 96 well culture plates by proper density, per the μ L of hole 90, are cultivated After night, the compound effects 72h of various concentrations, and setting solvent control group (negative control) are added.Treat compound effects cell After 72h, the influence of compound on intracellular propagation is detected using CCK-8 Cell counting Kits (Dojindo), and 10 μ L are added per hole CCK-8 reagents, it is placed in 37 DEG C of incubators after placing 2-4h, is read with the all-wave length orifice plate ELIASA SpectraMax 190 that declines Number, measure wavelength is 450nm.
Use the inhibiting rate (%) that compound on tumor cell growth is calculated with following equation：
Inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100%
The test result of the external FGFR1 kinase activities of the part of compounds of table 2
The external FGFR1 kinase activities of the part of compounds of table 3 are to KG1 cytoactive test results
(compound numbers correspond to compound numbers above in table)
Pharmacology test result shows that the compounds of this invention 15,16,17,18 has good FGFR1 inhibitory activity, and With good Anti-tumor angiogenesis, available for prevention or treatment and the inhibitor of fibroblast growth factor acceptor kinases 1 Relevant clinical disease, these diseases can be：The kinds cancers such as breast cancer, carcinoma of urinary bladder, stomach cancer, prostate cancer, the carcinoma of the rectum.
Determine character, yield, fusing point, hydrogen modal data and the mass spectrum that compound numbers are 1~26：
The N- of embodiment 5 { 4- { { 2- { [4- methylpiperazine-1-yls] benzene } amine } -5- nitro-pyrimidine -4- bases } benzene } acetamide (1) measurement result is：
Red powder；Yield 61.7%；m.p：269.5-270.4℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.251 (1H, s ,-NH), 10.206 (1H, s ,-NH), 10.119 (1H, s ,-NH), 8.998 (1H, s, H-6), 7.594 (2H, D, J=8.4Hz, H-3 ", H-5 "), 7.4 00 (2H, d, J=8.4Hz, H-3 ', H-5 '), 7.326 (2H, d, J=9.0Hz, H- 2 ", H-6 "), 6.712 (2H, d, J=9.0Hz, H-2 ', H-6 '), 3.093 (4H, s ,-CH2N(aryl)CH2-), 2.591 (4H, S ,-CH2N(CH3)CH2-), 2.317 (3H, s ,-NCH3), 2.063 (3H, s ,-NHCOCH3).13C NMR (600MHz, DMSO- d6)：δ (ppm) 168.77,159.18,157.73,155.08,147.33,137.25,132.37,130.52,126.12 × 2, 121.94 × 2,119.50 × 2,115.48 × 2,54.43 × 2,48.01 × 2,45.26,24.12.ESI-MS m/z：463.1 (M+H)+.
The N of embodiment 62- [4- (4- methylpiperazine-1-yls) benzene]-N4- (4- morpholines benzene) -5- nitro-pyrimidine -2,4- diamines (2) measurement result is：
Red powder；Yield 65.4%；m.p：253.4-255.6℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.184 (1H, s ,-NH), 10.168 (1H, s ,-NH), 8.991 (1H, s, H-6), 7.335 (2H, d, J=8.4Hz, H-2 ', H- 6 '), 7.312 (2H, d, J=8.4Hz, H-2 ", H-6 "), 6.974 (2H, d, J=8.4Hz, H-2 ', H-6 '), 6.702 (2H, d, J=8.4Hz, H-3 ", H-5 "), 3.128 (8H, s, morpholine), 3.098 (3H, s ,-NCH3), 2.610 (4H, s ,-CH2N (aryl)CH2-), 2.335 (4H, s ,-CH2N(CH3)CH2-).ESI-MS m/z：491.1(M+H)+.
The N of embodiment 72- [4- (4- methylpiperazine-1-yls) benzene] -5- nitros-N4- [3- (trifluoromethyl) benzene] pyrimidine -2, The measurement result of 4- diamines (3) is：
Red powder；Yield 71.2%；m.p：219.3-220.7℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.463 (1H, s ,-NH), 10.303 (1H, s ,-NH), 9.047 (1H, s, H-6), 7.914 (1H, s, H-2 "), 7.823 (1H, D, J=6.6Hz, H-6 "), 7.619 (1H, t, J=7.2Hz, H-5 "), 7.613 (1H, t, J=7.2Hz, H-4 "), 7.299 (2H, d, J=9.0Hz, H-3 ', H-5 '), 6.699 (2H, d, J=9.0Hz, H-2 ', H-6 '), 3.029 (4H, s ,-CH2N (aryl)CH2-), 2.425 (4H, s ,-CH2N(CH3)CH2-), 2.195 (3H, s ,-NCH3).ESI-MS m/z：474.2(M+H )+.
The N of embodiment 84- (9H- fluorenes -2- bases)-N2- [4- (4- methylpiperazine-1-yls) benzene] -5- nitro-pyrimidines -2,4- bis- The measurement result of amine (4) is：
Brown ceramic powder；Yield 66.7%；m.p：248.9-250.4℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.487 (1H, s ,-NH), 10.322 (1H, s ,-NH), 9.066 (1H, s, H-6), 7.955 (2H, d, J=7.8Hz, H-7 ", H- 8 "), 7.850 (1H, s, H-2 "), 7.646 (1H, d, J=7.2Hz, H-4 "), 7.476 (1H, d, J=8.4Hz, H-9 "), 7.434 (1H, t, J=7.8Hz, H-6 "), 7.354 (1H, t, J=7.8Hz, H-5 "), 7.341 (2H, d, J=8.4Hz, H-3 ', H-5 '), 6.590 (2H, d, J=8.4Hz, H-2 ', H-6 '), 3.886 (2H, s ,-CH2-), 3.443 (4H, s ,-CH2N(aryl) CH2-), 2.793 (4H, s ,-CH2N(CH3)CH2-), 2.515 (3H, s ,-NCH3).ESI-MS m/z：494.1(M+H)+.
The N of embodiment 94- (3- bromophenyls)-N2- [4- (4- methylpiperazine-1-yls) phenyl] -5- nitro-pyrimidine -2,4- diamines (5) measurement result is：
Red powder；Yield 69.8%；m.p：222.1-224.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.377 (1H, s ,-NH), 10.319 (1H, s ,-NH), 9.036 (1H, s, H-6), 7.877 (1H, s, H-2 '), 7.482 (1H, D, J=7.2Hz, H-6 "), 7.430 (1H, d, J=7.8Hz, H-4 "), 7.369 (2H, d, J=7.8Hz, H-3 ', H-5 '), 7.335 (1H, t, J=7.8Hz, H-5 "), 6.816 (2H, d, J=9.0Hz, H-2 ', H-6 '), 3.098 (4H, s ,-CH2N (aryl)CH2-), 2.547 (4H, s ,-CH2N(CH3)CH2-), 2.281 (3H, s ,-NCH3).ESI-MS m/z：474.9(M+H )+.
The N of embodiment 104- (1H- indoles -5- bases)-N2- [4- (4- methylpiperazine-1-yls) benzene] -5- nitro-pyrimidines -2,4- The measurement result of diamines (6) is：
Yellow powder；Yield 65.9%；m.p 269.8-271.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 11.288 (1H, s, H-1 "), 10.362 (1H, s ,-NH), 10.248 (1H, s ,-NH), 9.041 (1H, s, H-6), 7.740 (1H, S, H-4 "), 7.439 (1H, d, J=9.0Hz, H-7 "), 7.370 (1H, d, J=8.4Hz, H-2 "), 7.286 (1H, d, J= 9.0Hz, H-6 "), 7.142 (1H, d, J=8.4Hz, H-3 "), 6.555 (2H, d, J=8.4Hz, H-3 ', H-5 '), 6.431 (2H, d, J=8.4Hz, H-2 ', H-6 '), 3.121 (4H, t, J=7.8Hz ,-CH2N(aryl)CH2-), 3.019 (4H, t, J= 12Hz ,-CH2N(CH3)CH2-), 2.791 (3H, s ,-NCH3).ESI-MS m/z：445.1(M+H)+.
The N of embodiment 112- [4- (4- methylpiperazine-1-yls) phenyl] -5- nitros-N4- (tolyl) pyrimidine -2,4- bis- The measurement result of amine (7) is：
Red powder；Yield 70.1%；m.p：218.3-219.8℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.318 (1H, s ,-NH), 10.258 (1H, s ,-NH), 9.021 (1H, s, H-6), 7.443 (1H, d, J=9.6Hz, H-6 "), 7.384 (2H, d, J=8.4Hz, H-3 ', H-5 '), 7.297 (1H, d, J=7.2Hz, H-4 "), 7.254 (1H, t, J=7.8Hz, H-5 "), 7.053 (1H, s, H-2 "), 6.760 (2H, d, J=8.4Hz, H-2 ', H-6 '), 3.058 (4H, s ,-CH2N(aryl) CH2-), 2.444 (4H, s ,-CH2N(CH3)CH2-), 2.250 (3H, s ,-NCH3), 2.206 (3H, s ,-CH3).13C NMR (600MHz, DMSO-d6)：δ (ppm) 159.50,157.90,154.48,147.91,138.34,137.11,130.14, 128.77,126.32,124.66,122.38 × 2,121.32,120.29,115.54 × 2,54.68 × 2,48.44 × 2, 45.84.ESI-MS m/z：420.0(M-H)-.
The N of embodiment 124- (3,5- dimethoxy benzene)-N2- [4- (4- methylpiperazine-1-yls) benzene] -5- nitro-pyrimidine -2, The measurement result of 4- diamines (8) is：
Brown ceramic powder；Yield 75.8%；m.p 188.1-190.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.304 (1H, s ,-NH), 10.270 (1H, s ,-NH), 9.029 (1H, s, H-6), 7.445 (2H, d, J=9.0Hz, H-3 ', H- 5 '), 6.783 (2H, d, J=8.4Hz, H-2 ", H-6 "), 6.762 (2H, d, J=8.4Hz, H-2 ', H-6 '), 5.73 (1H, s, H-4 "), 3.668 (6H, s, 3 "-OCH3, 5 "-OCH3), 3.070 (4H, s ,-CH2N(aryl)CH2-), 2.487 (4H, s ,-CH2N (CH3)CH2-), 2.250 (3H, s ,-NCH3).ESI-MS m/z：466.2(M+H)+.
The N of embodiment 132- [4- (4- methylpiperazine-1-yls) phenyl] -5- nitros-N4- (3,4,5- trifluorophenyl) pyrimidine- The measurement result of 2,4- diamines (9) is：
Brown ceramic powder；Yield 80.7%；m.p 256.3-257.2℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.396 (1H, s ,-NH), 10.375 (1H, s ,-NH), 9.073 (1H, s, H-6), 7.680 (2H, d, J=9.0Hz, H-2 ', H- 6 '), 7.340 (2H, d, J=9.0Hz, H-3 ', H-5 '), 6.847 (2H, d, J=9.0Hz, H-2 ", H-6 "), 3.109 (4H, S ,-CH2N (aryl) CH2-), 2.497 (4H, s ,-CH2N(CH3)CH2-), 2.269 (3H, s ,-NCH3).ESI-MS m/z： 460.1(M+H)+.
The N of embodiment 144- (4- luorobenzyls)-N2- [4- (4- methylpiperazine-1-yls) benzene] -5- nitro-pyrimidine -2,4- diamines (10) measurement result is：
Red powder；Yield 78.3%；m.p：221.7-223.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.285 (1H, s ,-NH), 9.428 (1H, s ,-NH), 8.967 (1H, s, H-6), 7.557 (2H, d, J=7.8Hz, H-2 ", H- 6 "), 7.141 (2H, d, J=9.0Hz, H-3 ", H-5 "), 7.029 (2H, d, J=9.0Hz, H-3 ', H-5 '), 6.912 (2H, d, J=7.8Hz, H-2 ', H-6 '), 4.717 (2H, s ,-CH2-), 3.477 (4H, s ,-CH2N(aryl)CH2-), 3.126 (4H, s ,- CH2N(CH3)CH2-), 2.785 (3H, s ,-NCH3).ESI-MS m/z：427.1(M+H)+.
The N- of embodiment 15 { 4- { { 2- { [4- (4- methylpiperazine-1-yls) benzene] amine } -5- nitro-pyrimidine -4- bases } amine } benzene } The measurement result of acrylamide (11) is：
Red powder；Yield 82.6%；320 DEG C of of m.p ＞1H NMR (600MHz, DMSO-d6)：δ(ppm)10.571 (1H, s ,-NH), 10.286 (1H, s ,-NH), 10.254 (1H, s ,-NH), 9.016 (1H, s, H-6), 7.770 (2H, d, J= 8.4Hz, H-3 ", H-5 "), 7.430 (2H, d, J=8.4Hz, H-3 ', H-5 '), 7.331 (2H, d, J=8.4Hz, H-2 ", H- 6 "), 6.698 (2H, d, J=8.4Hz, H-2 ', H-6 '), 6.586-6.541 (1H, m ,-CH=CH2), 6.281 (1H, d, J= 16.8Hz ,-CH=CH2), 6.149 (1H, d, J=16.8Hz ,-CH=CH2), 3.034 (4H, s ,-CH2N(aryl)CH2-), 2.408 (4H, s ,-CH2N(CH3)CH2-), 2.206 (3H, s ,-CH3).ESI-MS m/z：475.1(M+H)+.
Embodiment 16 (Z)-N- { 4- { { 2- { [4- (4- methylpiperazine-1-yls) benzene] amine } -5- nitro-pyrimidine -4- bases } amine } Benzene } measurement results of -3- Phenyl Acrylamides (12) is：
Red powder；Yield 84.2%；320 DEG C of of m.p ＞1H NMR (600MHz, DMSO-d6)：δ(ppm)10.375 (1H, s ,-NH), 10.292 (1H, s ,-NH), 10.229 (1H, s ,-NH), 9.017 (1H, s, H-6), 7.781 (1H, d, J= 8.4Hz ,-CH=CH-), 7.684-7.618 (5H, m, C-Ar-H), 7.487-7.406 (8H, m, A, B-H), 7.295 (1H, d, J =8.4Hz ,-CH=CH-), 2.998 (4H, s ,-CH2N(aryl)CH2-), 2.325 (4H, s ,-CH2N(CH3)CH2-), 2.027 (3H, s ,-CH3).ESI-MS m/z：551.3(M+H)+.
The chloro- N- of the 4- of embodiment 17 { 4- { { 2- { [4- (4- methylpiperazine-1-yls) benzene] amine } -5- nitro-pyrimidine -4- bases } Amine } benzene } measurement result of benzamide (13) is：
Red powder；Yield 66.3%；320 DEG C of of m.p ＞1H NMR (600MHz, DMSO-d6)：δ(ppm)10.444 (1H, s ,-NH), 10.312 (1H, s ,-NH), 10.249 (1H, s ,-NH), 9.027 (1H, s, H-6), 8.038 (2H, d, J= 8.4Hz, H-2 " ', H-6 " '), 7.830 (2H, d, J=8.4Hz, H-3 " ', H-5 " '), 7.658 (2H, d, J=8.4Hz, H-3 ", H-5 "), 7.468 (2H, d, J=9.0Hz, H-3 ', H-5 '), 7.337 (2H, d, J=9.0Hz, H-2 ", H-6 "), 6.715 (2H, D, J=9.0Hz, H-2 ', H-6 '), 2.992 (4H, s ,-CH2N(aryl)CH2-), 2.285 (4H, s ,-CH2N(CH3)CH2-), 2.150 (3H, s ,-NCH3).ESI-MSm/z：559.1(M)+.
The chloro- N- of the 3- of embodiment 18 { 4- { { 2- { [4- (methylpiperazine-1-yl) benzene] amine } -5- nitro-pyrimidine -4- bases } amine } Benzene } measurement result of propionamide (14) is：
Red powder；Yield 74.2%；m.p 272.8-273.9℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 10.497 (1H, s ,-NH), 10.298 (1H, s ,-NH), 10.289 (1H, s ,-NH), 9.032 (1H, s, H-6), 7.734 (2H, D, J=8.4Hz, H-3 ", H-5 "), 7.450 (2H, d, J=8.4Hz, H-3 ', H-5 '), 7.387 (2H, d, J=9.0Hz, H- 2 ", H-6 "), 6.788 (2H, d, J=9.0Hz, H-2 ', H-6 '), 2.887 (4H, s ,-CH2N(aryl)CH2-), 2.728 (4H, S ,-CH2N(CH3)CH2-), 2.653 (3H, s ,-NCH3), 2.499 (4H, t, J=1.8Hz ,-COCH2CH2Cl).ESI-MS m/ z：511.0(M+H)+.
The N- of embodiment 19 { 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amido } pyrimidine-4-yl } amine } benzene Base } measurement result of acetamide (16) is：
White powder；Yield 60.3%；m.p 250.9-252.7℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.028 (1H, s ,-NH), 9.009 (1H, s ,-NH), 8.683 (1H, s ,-NH), 8.035 (1H, s, H-6), 7.545 (4H, s, H- 2 ", H-6 ", H-3 ', H-5 '), 7.403 (2H, d, J=7.8Hz, H-2 ', H-6 '), 6.757 (2H, d, J=7.8Hz, H-3 ", H- 5 "), 3.025 (4H, s, CH2N (aryl) CH2-), 2.454 (4H, s ,-CH2N(CH3)CH2-), 2.222 (3H, s ,-NCH3), 2.026 (3H, s ,-CH3).ESI-MS m/z：452.4(M+H)+.
The N- of embodiment 20 { the chloro- 4- of 2- { { the chloro- 2- of 5- [(4- (4- methylpiperazine-1-yls) benzene)] amine } pyrimidine-4-yl } amine } Benzene } measurement result of acetamide (17) is：
White powder；Yield 83.5%；m.p：110.5-111.9℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.532 (1H, s ,-NH), 9.135 (1H, s ,-NH), 8.849 (1H, s ,-NH), 8.095 (1H, s, H-6), 7.821 (1H, s, H- 2 "), 7.583 (2H, t, J=8.4Hz, H-5 ", H-6 "), 7.404 (2H, d, J=9Hz, H-3 ', H-5 '), 6.821 (2H, d, J =9Hz, H-2 ', H-6 '), 3.033 (4H, t, J=4.8Hz ,-CH2N(aryl)CH2-), 2.434 (4H, t, J=4.8Hz ,- CH2N(CH3)CH2-), 2.209 (3H, s ,-NCH3), 2.088 (3H, s ,-COCH3).ESI-MS m/z：486.0(M)+.
The N- of embodiment 21 { 2,6- bis- chloro- 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amine } pyrimidine-4-yl } Amine } benzene } measurement result of acetamide (18) is：
White powder；Yield 64.2%；m.p：112.5-114.3℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.679 (1H, s ,-NH), 9.155 (1H, s ,-NH), 8.970 (1H, s ,-NH), 8.106 (1H, s, H-6), 7.950 (1H, s, H- 2 "), 7.827 (1H, s, H-6 "), 7.402 (2H, d, J=8.4Hz, H-2 ', H-6 '), 6.839 (2H, d, J=9.0Hz, H-3 ', H-5 '), 3.029 (4H, t, J=4.8Hz ,-CH2N(aryl)CH2-), 2.435 (4H, t, J=4.8Hz ,-CH2N(CH3)CH2-), 2.209 (3H, s ,-NCH3), 2.052 (3H, s ,-CH3).ESI-MS m/z：521.2(M)+.
The N- of embodiment 22 { 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amine } pyrimidine-4-yl } amine } -2- first Phenyl } measurement result of acetamide (19) is：
White powder；Yield 66.3%；m.p 113.5-115.9℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.116 (1H, s ,-NH), 9.048 (1H, s ,-NH), 8.701 (1H, s ,-NH), 8.055 (1H, s, H-6), 7.805 (2H, d, J =8.4Hz, H-3 ', H-5 '), 7.414 (2H, d, J=9.0Hz, H-5 ", H-6 "), 7.283 (1H, s, H-2 "), 6.767 (2H, D, J=9.0Hz, H-3 ', H-5 '), 3.718 (3H, s ,-OCH3), 3.021 (4H, t, J=4.8Hz ,-CH2N(aryl)CH2-), 2.438 (4H, t, J=4.8Hz ,-CH2N(CH3)CH2-), 2.212 (3H, s ,-NCH3), 2.072 (3H, s ,-CH3).ESI-MS m/z：482.0(M+H)+.
The N- of embodiment 23 { 4- { { the chloro- 2- of 5- { [4- (4- methylpiperazine-1-yls) benzene] amine } pyrimidine-4-yl } amine } -2,5- Dimethoxy benzene } measurement result of acetamide (20) is：
White powder；Yield 55.2%；m.p 245.2-247.3℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.200 (1H, s ,-NH), 9.021 (1H, s ,-NH), 8.142 (1H, s, H-6), 8.051 (1H, s, H-3 "), 7.848 (1H, s, H-6 "), 7.498 (1H, s ,-NH), 7.318 (2H, d, J=7.2Hz, H-3 ', H-5 '), 6.739 (2H, d, J=8.4Hz, H- 2 ', H-6 '), 3.720 (3H, s, 2 "-OCH3), 3.632 (3H, s, 5 "-OCH3), 3.011 (4H, s ,-CH2N(aryl)CH2-), 2.435 (4H, s ,-CH2N(CH3)CH2-), 2.214 (3H, s ,-NCH3), 2.103 (3H, s ,-CH3).ESI-MS m/z：512.2 (M)+.
The N- of embodiment 24 { the chloro- 4- of 2- { { the chloro- 2- of 5- [(2- methoxyl group -4- morpholines phenyl) amine] pyrimidine-4-yl } amine } Benzene } measurement result of acetamide (21) is：
White powder, yield 77.5%；m.p：227.2-229.3℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.417 (1H, s ,-NH), 8.770 (1H, s ,-NH), 8.055 (1H, s ,-NH), 7.942 (1H, s, H-6), 7.802 (1H, s, H- 2 "), 7.734 (1H, d, J=9.0Hz, H-5 "), 7.666 (1H, d, J=9.0Hz, H-6 "), 7.576 (1H, s, H-3 '), 7.515 (1H, d, J=8.4Hz, H-5 '), 7.444 (1H, d, J=8.4Hz, H-6 '), 3.760 (3H, s ,-OCH3), 3.741 (4H, t, J=4.8Hz ,-CH2OCH2-), 3.087 (4H, t, J=4.8Hz ,-CH2NCH2-), 2.075 (3H, s ,-COCH3) .ESI-MS m/z：503.1(M+H)+.
The N- of embodiment 25 2- chloro- 4- the chloro- 2- of 5- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) benzene] amine } pyrimidine - 4- yls } amine } benzene } measurement result of acetamide (22) is：
Brown ceramic powder；Yield 71.5%；mp：177.3-179.2℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.467 (1H, s ,-NH), 8.777 (1H, s ,-NH), 8.052 (1H, s, H-6), 7.935 (1H, s ,-NH), 7.808 (1H, s, H-2 "), 7.587 (1H, d, J=8.4Hz, H-5 "), 7.500 (1H, d, J=9Hz, H-2 '), 7.424 (1H, d, J=9Hz, H- 3 '), 6.604 (1H, s, H-5 '), 6.442 (1H, d, J=8.4Hz, H-6 "), 3.756 (3H, s ,-OCH3), 3.144 (4H, s ,- CH2N(aryl)CH2-), 2.535 (4H, s ,-CH2N(CH3)CH2-), 2.282 (3H, s ,-NCH3), 2.076 (3H, s ,- COCH3).ESI-MS m/z：516.1(M)+.
The N- of embodiment 26 { 2,6- bis- chloro- 4- { { the chloro- 2- of 5- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) benzene] amine } Pyrimidine-4-yl } amine } benzene } measurement result of acetamide (23) is：
White powder；Yield 43.1%；m.p 115.4-116.7℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.668 (1H, s ,-NH), 8.871 (1H, s ,-NH), 8.098 (1H, s, H-2 "), 8.088 (1H, s, H-6 "), 7.950 (1H, S ,-NH), 7.871 (1H, s, H-6), 7.361 (1H, d, J=8.4Hz, H-2 '), 6.609 (1H, s, H-5 '), 6.458 (1H, d, J=9.0Hz, H-3 '), 3.756 (3H, s ,-OCH3), 3.117 (4H, s ,-CH2N(aryl)CH2-), 2.477 (4H, s ,-CH2N (CH3)CH2-), 2.242 (3H, s ,-NCH3), 2.044 (3H, s ,-CH3).ESI-MS m/z：551.2(M)+.
The N- of embodiment 27 { 4- { { the chloro- 2- of 5- [(2- methoxyl group -4- morpholines benzene) amine] pyrimidine-4-yl } amine } -2- methoxies Base benzene } measurement result of acetamide (24) is：
White powder；Yield 74.7%；m.p 202.3-203.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.052 (1H, s ,-NH), 8.642 (1H, s ,-NH), 8.026 (1H, s ,-NH), 7.950 (1H, s, H-6), 7.804 (1H, s, H- 2 "), 7.762 (1H, d, J=9.0Hz, H-5 "), 7.524 (1H, d, J=9.0Hz, H-2 '), 7.804 (1H, s, H-5 '), 7.247 (1H, d, J=8.4Hz, H-3 '), 6.386 (1H, d, J=8.4Hz, H-6 "), 3.755 (3H, s ,-OCH3), 3.741 (4H, t, J=4.8Hz ,-CH2N(aryl)CH2-), 3.705 (3H, s ,-OCH3), 3.077 (4H, t, J=4.8Hz ,-CH2N (CH3)CH2-), 2.068 (3H, s ,-CH3).ESI-MS m/z：499.3(M+H)+.
The N- of embodiment 28 { 4- { { the chloro- 2- of 5- { [2- methoxyl groups -4- (4- methylpiperazine-1-yls) benzene] amine } pyrimidine-4-yl } Amine } -2- methoxybenzenes } measurement result of acetamide (25) is：
White powder；Yield 72.5%；mp：122.3-123.5℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.068 (1H, s ,-NH), 8.644 (1H, s ,-NH), 8.019 (1H, s, H-6), 7.780 (1H, s ,-NH), 7.753 (1H, d, J =9Hz, H-5 "), 7.500 (1H, d, J=9Hz, H-6 "), 7.314 (1H, s, H-2 "), 7.244 (1H, d, J=8.4Hz, H- 2 '), 6.577 (1H, s, H-5 '), 6.366 (1H, d, J=7.2Hz, H-3 '), 3.748 (3H, s ,-OCH3), 3.696 (3H, s ,- OCH3), 3.095 (4H, t, J=4.8Hz ,-CH2N(aryl)CH2-), 2.449 (4H, t, J=4.8Hz ,-CH2N(CH3)CH2-), 2.221 (3H, s ,-CH3), 2.064 (3H, s ,-COCH3).ESI-MS m/z：512.1(M)+.
The N- of embodiment 29 { 4- { { the chloro- 2- of 5- [(2- methoxyl group -4- morpholines benzene) amine] pyrimidine-4-yl } amine } -2.5- two Methoxybenzene } measurement result of acetamide (26) is：
Brown ceramic powder；Yield 78.6%；m.p：243.7-245.3℃.1H NMR (600MHz, DMSO-d6)：δ(ppm) 9.155 (1H, s ,-NH), 8.082 (1H, s ,-NH), 8.03.7 (1H, s, H-6), 7.950 (1H, s ,-NH), 7.831 (1H, s, H-5 "), 7.819 (1H, s, H-5 '), 7.430 (1H, d, J=8.4Hz, H-2 '), 6.587 (1H, d, J=2.4Hz, H-2 "), 6.357 (1H, dd, J=9Hz, J=1.8Hz, H-3 '), 3.749 (3H, s ,-OCH3), 3.738 (3H, s ,-OCH3), 3.731 (3H, s ,-OCH3), 2.888 (4H, s ,-CH2N(aryl)CH2-), 2.729 (4H, s ,-CH2NOCH2-), 2.089 (3H, s ,- COCH3).ESI-MS m/z： 429.0(M)+.
Above-mentioned detailed description is illustrated for the possible embodiments of invention, and the embodiment simultaneously is not used to limit this hair Bright the scope of the claims, all equivalence enforcements or change without departing from the present invention, it should be contained in the scope of the claims of the present invention.
In addition, those skilled in the art can also the claims in the present invention scope of disclosure and spirit in do other forms and Various modifications, addition and replacement in details.Certainly, these various modifications, addition and replacements for being made according to present invention spirit Deng change, should all be included within scope of the present invention.

Claims (7)

1. one kind 2,4,5- trisubstituted pyrimidine class compounds, it is characterised in that be one kind in compound 15~18：
A kind of 2. method of the trisubstituted pyrimidine class compound of one kind 2,4,5- prepared described in claim 1, it is characterised in that bag Include following steps：
Step 1：Weigh 2,4,5- trichloropyrimidines, Anhydrous potassium carbonate and the R1-NH2In flask, stirring, which adds DMF, makes its molten Solution, 60 DEG C of reaction 2-3h, after completion of the reaction, is cooled to room temperature, adds a large amount of frozen water, there is solid precipitation, filter, dry, obtain 4-R1- amine -2,5- dichloro pyrimidines；
Wherein, R1For 4- acetylamino phenyls, the chloro- 4- acetylamino phenyls of 3-, 3,5 2 chloro- 4- acetylamino phenyls or 3- methoxies Base -4- acetylamino phenyls；
Step 2：Weigh the 4-R1- amine -2,5- dichloro pyrimidine and 4- (4- methylpiperazine-1-yls) aniline are in flask, stirring Lower addition sec-butyl alcohol makes its dissolving, flows back, and after reaction terminates, is cooled to room temperature, adds sodium acid carbonate and neutralizes, is extracted with ethyl acetate Take, concentrate, silica gel column chromatography, eluant, eluent is acetate-methanol, obtains 2- [4- (4- methylpiperazine-1-yls)]-aniline -4-R1- Amine -5- chlorine pyrimidines.
3. the method that one kind as claimed in claim 2 prepares a kind of 2,4,5- trisubstituted pyrimidine class compounds, it is characterised in that In the step 1：Per the trichloropyrimidines of 1g 2,4,5- with DMF 5-10ml dissolve, 2,4,5- trichloropyrimidines, Anhydrous potassium carbonate and R1-NH2The ratio between the amount of material be 1:2:1；In the step 2：4-R described in per 500mg1- amine -2,5- dichloro pyrimidines Zhong Ding Alcohol 15-20ml, then trifluoroacetic acid is instilled in flask, 4-R1- amine -2,5- dichloro pyrimidines, 4- (4- methylpiperazine-1-yls) benzene The ratio between amount of material of amine and trifluoroacetic acid is 1:1:1, the return time is 2h, and the extraction times are 3 times, the elution The volume ratio of agent ethyl acetate and methanol is 20:1.
4. the purposes of 2 described in a kind of claim 1,4,5- trisubstituted pyrimidine class compounds, it is characterised in that the purposes is Prepare the application in antineoplastic.
5. the purposes of according to claim 42,4,5- trisubstituted pyrimidine class compounds, it is characterised in that described is anti-swollen Tumor medicine is using FGFR as target spot.
6. a kind of pharmaceutical composition, it is characterised in that including pharmaceutic adjuvant and one kind as claimed in claim 1 using FGFR as target The 2,4,5- trisubstituted pyrimidine class compounds of point.
7. pharmaceutical composition according to claim 6, it is characterised in that the dosage form of described pharmaceutical composition is note Penetrate any of agent, tablet, capsule, aerosol, suppository, film, pill, ointment, controlled release agent, sustained release agent or nanometer formulation Kind.
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