CN104803925A - 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds - Google Patents

2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and application of 2,4,5-trisubstituted pyrimidine compounds Download PDF

Info

Publication number
CN104803925A
CN104803925A CN201510180883.3A CN201510180883A CN104803925A CN 104803925 A CN104803925 A CN 104803925A CN 201510180883 A CN201510180883 A CN 201510180883A CN 104803925 A CN104803925 A CN 104803925A
Authority
CN
China
Prior art keywords
pyrimidine
chloro
take
ammonia
fgfr
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN201510180883.3A
Other languages
Chinese (zh)
Other versions
CN104803925B (en
Inventor
梁广
刘志国
王怡
陈凌锋
蔡跃飘
冯建鹏
张亚丽
李校堃
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wenzhou Medical University
Original Assignee
Wenzhou Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Wenzhou Medical University filed Critical Wenzhou Medical University
Priority to CN201510180883.3A priority Critical patent/CN104803925B/en
Publication of CN104803925A publication Critical patent/CN104803925A/en
Application granted granted Critical
Publication of CN104803925B publication Critical patent/CN104803925B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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 the field of medicinal chemistry and particularly relates to 2,4,5-trisubstituted pyrimidine compounds taking FGFRs (fibroblast growth factor receptors) as targets as well as preparation methods and an application of the 2,4,5-trisubstituted pyrimidine compounds. The compounds can selectively inhibit phosphorylation of FGFR kinase so as to be used for treating malignant tumors closely related with the kinase, and can reduce adverse reactions; the compounds can be used for treating tumors related with the FGFR kinase or relevant diseases. The general formula of the 2,4,5-trisubstituted pyrimidine compounds is shown in the specification, wherein R<1>, R<2> and R<3> can be selected from multiple substituents and can be combined randomly. The 2,4,5-trisubstituted pyrimidine compounds taking the FGFRs as the targets have a good inhibition function on the FGFR1 kinase, have an anti-proliferation function on FGFR1-dependent tumor cell line KG1 cells, can be used for preparing antitumor drugs and have better antitumor effects.

Description

One class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot and its production and use
Technical field
The invention belongs to medicinal chemistry art, being specifically related to a class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot and its production and use.
Background technology
In this field of protein kinase, fibroblast growth factor acceptor FGFR family is that a target spot had a great attraction is in oncotherapy.The FGFR family of receptor tyrosine kinase comprises four members, is FGFR1, FGFR2, FGFR3 and FGFR4 respectively.They have highly similar sequence homology.The kinase whose imbalance of FGFR and Several Kinds of Malignancy closely related, as kinds cancers such as mammary cancer, bladder cancer, cancer of the stomach, prostate cancer, the rectum cancer, therefore medical oncology is constantly to its research and Diagnosis and Treat to cancer.
Suppress the protein kinase with disease-related, block and tumoricidal signal transmission, realize by multiple method, but the antisense oligonucleotide due to synthesis is subject to the attack of ribozyme and degrades, there is security, stability and the problems such as effect of missing the target in RNA perturbation technique, therefore new drug development personnel attempt the chemical small molecule inhibitor screening FGFR from organic synthesis small molecules.Up to now, existing multiple micromolecular inhibitor enters clinical experimental stage, as NVP-BGJ398,
BIBF-1120, TKI-258, BMS-582664, AZD-2171, AB-1010, TSU-68, AP-24534 and E-7080.
The medicine that current research is the fastest is NVP-BGJ398, and it, as the FGFR inhibitor of highly selective, is used for the treatment of solid malignant tumor, is in during the clinical I phase studies.It is the FGFR inhibitor of parent nucleus that market not yet has with pyrimidine, therefore urgently to develop with pyrimidine be the FGFR inhibitor of parent nucleus.
Summary of the invention
An object of the present invention is for solving the problems of the technologies described above, a class is provided to take FGFR as 2 of target spot, 4,5-trisubstituted pyrimidine compounds and its production and use, can reduce untoward reaction while that this compound optionally can suppressing the kinase whose phosphorylation of FGFR thus be used for the treatment of the malignant tumour of kinases close ties therewith; Can be used in treating tumour or relevant disease that FGFR kinases is correlated with.
For realizing above-mentioned technique effect, technical scheme of the present invention is:
One class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, has following general formula:
Wherein: R 1following arbitrary substituted radical can be selected from:
R 2following arbitrary substituted radical can be selected from:
R 3cl or NO can be selected from 2in any one;
Above R 1, R 2, R 3in substituting group can arbitrary combination.
A kind ofly prepare the method that an above-mentioned class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, comprise the steps:
Step one: take the chloro-5-nitro-pyrimidine of 2,4-bis-, DIPEA and R 1-NH 2in flask, add methylene chloride under stirring and make it dissolve, room temperature reaction 5h, after completion of the reaction, add saturated aqueous common salt, mixture dichloromethane extraction, concentrated, obtain the pulverous 2-R of red solid 1the chloro-5-nitro-pyrimidine of-ammonia-4-.
Step 2: take described 2-R 1-ammonia-4-chloro-5-nitro-pyrimidine and described R 2-NH 2in flask, add sec-butyl alcohol and make it dissolve under stirring, backflow 2h, after reaction terminates, be cooled to room temperature, add sodium bicarbonate neutralization, be extracted with ethyl acetate 3 times, concentrated, silica gel column chromatography, eluent is acetate-methanol, and the volume ratio of ethyl acetate and methyl alcohol is 20: 1, obtains 2-R 1-ammonia-4-R 2-ammonia-5-R 3pyrimidine.
Wherein, R 3for nitro, R 1and R 2definition identical with above-mentioned definition, multiple substituting group can be had to select.
Further, every 1g 2,4-bis-chloro-5-nitro-pyrimidine methylene dichloride 20ml in described step one; The chloro-5-nitro-pyrimidine of the ratio of amount of substance: 2,4-bis-: DIPEA: R 1-NH 2=1: 1: 1.
Further, 2-R described in every 500mg 1-ammonia-4-chloro-5-nitro-pyrimidine sec-butyl alcohol 15-20ml, then trifluoroacetic acid is instilled in flask, the ratio of amount of substance: 2-R 1the chloro-5-R of-ammonia-4- 3pyrimidine: R 2-NH 2: trifluoroacetic acid is 1: 1: 1.
A kind ofly prepare the method that an above-mentioned class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, comprise the steps:
Step one: take 2,4,5-trichloropyrimidine, Anhydrous potassium carbonate and described R 1-NH 2in flask, stirring adds DMF makes it dissolve, every 1g 2,4,5-trichloropyrimidine DMF 5-10ml, the ratio of amount of substance: 2,4,5-trichloropyrimidine: Anhydrous potassium carbonate: R 1-NH 2=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 to separate out, suction filtration, dry, obtain 2-R 1-ammonia-4,5-dichloro pyrimidine;
Step 2: take described 2-R 1-ammonia-4-chloro-5-dichloro pyrimidine and described R 2-NH 2in flask, add described sec-butyl alcohol under stirring and make it dissolve, 2-R described in every 500mg 1-ammonia-4-chloro-5-dichloro pyrimidine sec-butyl alcohol 20-30ml, then trifluoroacetic acid is instilled in flask, the ratio of amount of substance: 2-R 1the chloro-5-dichloro pyrimidine of-ammonia-4-: R 2-NH 2: trifluoroacetic acid=1: 1: 1, backflow 2h.After reaction terminates, be cooled to room temperature, add sodium bicarbonate neutralization, be extracted with ethyl acetate 3 times, concentrated, silica gel column chromatography, eluent is acetate-methanol, and the volume ratio of ethyl acetate and methyl alcohol is 20: 1, obtains 2-R 1-ammonia-4-R 2-ammonia-5-R 3pyrimidine.
R 3for chlorine, R 1and R 2definition identical with above-mentioned definition, multiple substituting group can be had to select.
One class take FGFR as the purposes of 2,4,5-trisubstituted pyrimidine compounds of target spot, and described purposes is the application prepared in antitumor drug.
A kind of pharmaceutical composition, comprises 2,4, the 5-trisubstituted pyrimidine compounds that pharmaceutical excipient and a class take FGFR as target spot.
Be 2 of target spot with FGFR containing a class, 4, the pharmaceutical composition of 5-trisubstituted pyrimidine compounds, the dosage form of described pharmaceutical composition is any one of injection, tablet, capsule, aerosol, suppository, film, pill, ointment, control-released agent, sustained release dosage or nanometer formulation.
Beneficial effect of the present invention comprises: of the present invention is that 2,4,5-trisubstituted pyrimidine compounds of target spot have good restraining effect to FGFR1 kinases and FGFR1 dependent tumors cell strain KG1 cell has antiproliferative effect with FGFR.Can be used for preparing antitumor drug, and antitumous effect is better.
Embodiment
Hereafter will describe the present invention in detail in conjunction with specific embodiments.It should be noted that the combination of technical characteristic or the technical characteristic described in following embodiment should not be considered to isolated, they can mutually be combined thus be reached better technique effect.
Embodiment 1 N-{4-{{2-{ [4-methylpiperazine-1-yl] benzene } amine }-5-nitro-pyrimidine-4-base } benzene } preparation of ethanamide (compound 1)
(1) N-{4-[(the chloro-5-nitro-pyrimidine of 2--4-base) amine] phenyl } preparation of ethanamide
Under the condition of ice bath, by chloro-for 2,4-bis-5-nitro-pyrimidine (5g, 25.7mmol) be dissolved in methylene dichloride (100ml), add DIPEA (4.3ml, 25.7mmol) with acetparaminosalol aniline (3.87g, 25.7mmol).Remove ice bath, reaction mixture at room temperature reacts 5h, then adds saturated aqueous common salt (200ml).Mixture methylene dichloride (300ml) extracts.Organic over anhydrous magnesium sulfate carries out drying, and concentrate to obtain solid, product is not further purified, and obtains 6.34g red solid, yield 90.0%.
(2) N-{4-{{2-{ [4-methylpiperazine-1-yl] benzene } amine }-5-nitro-pyrimidine-4-base } benzene } preparation of ethanamide (compound 1)
Take N-{4-[(the chloro-5-nitro-pyrimidine of 2--4-base) amine] phenyl } ethanamide (1g, 3.25mmol), 4-methylpiperazine aniline (746.0mg, 3.90mmol) with trifluoroacetic acid (0.25ml, 3.25mmol) be dissolved in sec-butyl alcohol (20ml), finish 100 DEG C of reaction 6h.Cooling, concentrating under reduced pressure system, the oily matter obtained is poured in frozen water, add sodium bicarbonate and be neutralized to neutrality, extraction into ethyl acetate, dry, concentrated organic phase obtains crude product, column chromatography (ethyl acetate: methyl alcohol=20: 1) obtain red solid product 2.78g, yield 61.7%.
The chloro-2-{ of embodiment 2 N-{4-{{5-[4-(4-methylpiperazine-1-yl) benzene] amido } pyrimidine-4-yl } amine } phenyl } preparation of ethanamide (compound 2)
(1) N-{4-[(2,5-dichloro pyrimidine-4-base) amine] phenyl } preparation of ethanamide
Take acetparaminosalol aniline (1.31g, 8.72mmol) and be dissolved in DMF (20ml), then add Anhydrous potassium carbonate (2.42g, 17.5mmol) and 2,4,5-trichloropyrimidine (1.0ml, 8.72mmol).Reaction mixture is heated to 60 DEG C of reaction 2h.After completion of the reaction, cool to room temperature, adds a large amount of frozen water, separates out solid, suction filtration, and dry, product is not further purified, and obtains 2.3g, yield 90%.
(2) the chloro-2-{ of N-{4-{{5-[4-(4-methylpiperazine-1-yl) benzene] amido } pyrimidine-4-yl } amine } phenyl } preparation of ethanamide
Take N-{4-[(2,5-dichloro pyrimidine-4-base) amine] phenyl } ethanamide (1.6g, 5.45mmol), 4-methylpiperazine aniline (1.24g, 6.46mmol) with trifluoroacetic acid (0.42ml, 5.45mmol) be dissolved in sec-butyl alcohol (30ml), be heated to 100 DEG C of reaction 6h.Cooling, concentrating under reduced pressure system, the oily matter obtained is poured in frozen water, add sodium bicarbonate and be neutralized to neutrality, extraction into ethyl acetate, dry, concentrated organic phase obtains crude product, column chromatography (ethyl acetate: methyl alcohol=20: 1) obtain white solid product 1.47g, yield 60.3%.
By any one method of embodiment 1 or 2, be raw material with the aniline of 2,4-bis-chloro-5-nitro-pyrimidine or 2,4,5-trichloropyrimidine and different replacement forms, having synthesized listed by table 1 take FGFR as 2,4,5-trisubstituted pyrimidine compounds 1 ~ 26 of target spot.
Be each R group in 2,4,5-trisubstituted pyrimidine compounds of target spot with FGFR in table 1 general formula I
Note: initial feed is all purchased from aladdin company.
Embodiment 3 compound is to the mensuration of FGFR kinase activity
Measure compound to the inhibit activities of FGFR1 by LANCE ULTRA Assay method, and compare with positive control drug, filter out active good compound.FGFR1 is that CARNA company buys.
Concrete grammar: the compound tested, ATP, specific substrate and FGFR1 kinases kinase dilution liquid dilute.Containing FGFR1, ATP, substrate, HEPES (PH=7.5), MgCl in kinase reaction mixture 2, EGTA, Tween-20.Do not add any compound group and do 100% phosphorylation contrast, add EDTA termination reaction group after adding FGFR1 kinases at once and contrast as 0% phosphorylation.After hatching 1h altogether under kinase reaction mixture room temperature, add EDTA termination reaction 5 minutes.Add specific antibody again, continue under room temperature to hatch 1h altogether, detect exciting light with PerkinElmer Envision kinases instrument.Detect gained signal value according to kinases instrument, obtain inhibiting rate or GraphPad calculating test-compound IC with formulae discovery 50value.
Embodiment 4 compound is to the mensuration of KG1 cell inhibitory rate
Compound detects with CCK-8 Cell counting Kit (Dojindo) the inhibited proliferation of KG1 cell.Concrete steps are as follows: the KG1 cell being in logarithmic phase is seeded in 96 well culture plates by proper density, and every hole 90 μ L, after overnight incubation, adds the compound effects 72h of different concns, and setting solvent control group (negative control).After compound effects cell 72h, the impact of compound on intracellular propagation adopts CCK-8 Cell counting Kit (Dojindo) to detect, every hole adds 10 μ L CCK-8 reagent, be placed in after 37 DEG C of incubators place 2-4h, with long orifice plate microplate reader SpectraMax 190 reading that declines of all-wave, mensuration wavelength is 450nm.
Adopt with the inhibiting rate (%) of following formulae discovery compound on tumor Growth of Cells:
Inhibiting rate (%)=(OD control wells-OD dosing holes)/OD control wells × 100%
The test result of the external FGFR1 kinase activity of table 2 part of compounds
The external FGFR1 kinase activity of table 3 part of compounds is to KG1 cytoactive test result
(in table, compound numbers corresponds to compound numbers above)
Pharmacology test result shows, the compounds of this invention 15,16,17,18 has good FGFR1 inhibit activities, and there is good Anti-tumor angiogenesis, can be used for the clinical disease prevented or treatment is relevant with fibroblast growth factor acceptor kinases 1 inhibitor, these diseases can be: the kinds cancers such as mammary cancer, bladder cancer, cancer of the stomach, prostate cancer, the rectum cancer.
Measure compound numbers be 1 ~ 26 proterties, productive rate, fusing point, hydrogen modal data and mass spectrum:
Embodiment 5 N-{4-{{2-{ [4-methylpiperazine-1-yl] benzene } amine }-5-nitro-pyrimidine-4-base } benzene } measurement result of ethanamide (1) is:
Red powder; Productive rate 61.7%; M.p:269.5-270.4 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.591 (4H, s ,-CH 2n (CH 3) CH 2-), 2.317 (3H, s ,-NCH 3), 2.063 (3H, s ,-NHCOCH 3). 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) +.
Embodiment 6 N 2-[4-(4-methylpiperazine-1-yl) benzene]-N 4-(4-morpholine benzene)-5-nitro-pyrimidine-2,4-diamines (2) measurement result is:
Red powder; Productive rate 65.4%; M.p:253.4-255.6 DEG C. 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 ,-NCH 3), 2.610 (4H, s ,-CH 2n (aryl) CH 2-), 2.335 (4H, s ,-CH 2n (CH 3) CH 2-) .ESI-MS m/z:491.1 (M+H) +.
Embodiment 7 N 2the measurement result of-[4-(4-methylpiperazine-1-yl) benzene]-5-nitro-N4-[3-(trifluoromethyl) benzene] pyrimidine-2,4-diamines (3) is:
Red powder; Productive rate 71.2%; M.p:219.3-220.7 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.425 (4H, s ,-CH 2n (CH 3) CH 2-), 2.195 (3H, s ,-NCH 3) .ESI-MS m/z:474.2 (M+H) +.
Embodiment 8 N 4the measurement result of-(9H-fluorenes-2-base)-N2-[4-(4-methylpiperazine-1-yl) benzene]-5-nitro-pyrimidine-2,4-diamines (4) is:
Brown ceramic powder, productive rate 66.7%, m.p:248.9-250.4 DEG C. 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,-CH 2-), 3.443 (4H, s ,-CH 2n (aryl) CH 2-), 2.793 (4H, s ,-CH 2n (CH 3) CH 2-), 2.515 (3H, s ,-NCH 3) .ESI-MS m/z:494.1 (M+H) +.
Embodiment 9 N 4-(3-bromophenyl)-N 2the measurement result of-[4-(4-methylpiperazine-1-yl) phenyl]-5-nitro-pyrimidine-2,4-diamines (5) is:
Red powder; Productive rate 69.8%; M.p:222.1-224.5 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.547 (4H, s ,-CH 2n (CH 3) CH 2-), 2.281 (3H, s ,-NCH 3) .ESI-MS m/z:474.9 (M+H) +.
Embodiment 10 N 4the measurement result of-(1H-indoles-5-base)-N2-[4-(4-methylpiperazine-1-yl) benzene]-5-nitro-pyrimidine-2,4-diamines (6) is:
Yellow powder, productive rate 65.9%, m.p 269.8-271.5 DEG C. 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,-CH 2n (aryl) CH 2-), 3.019 (4H, t, J=12Hz ,-CH 2n (CH 3) CH 2-), 2.791 (3H, s ,-NCH 3) .ESI-MS m/z:445.1 (M+H) +.
Embodiment 11 N 2the measurement result of-[4-(4-methylpiperazine-1-yl) phenyl]-5-nitro-N4-(tolyl) pyrimidine-2,4-diamines (7) is:
Red powder; Productive rate 70.1%; M.p:218.3-219.8 DEG C. 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 ') and, 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 ,-CH 2n (aryl) CH 2-), 2.444 (4H, s ,-CH 2n (CH 3) CH 2-), 2.250 (3H, s ,-NCH 3), 2.206 (3H, s ,-CH 3) .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) -.
Embodiment 12 N 4-(3,5-dimethoxy benzene)-N 2the measurement result of-[4-(4-methylpiperazine-1-yl) benzene]-5-nitro-pyrimidine-2,4-diamines (8) is:
Brown ceramic powder; Productive rate 75.8%; M.p 188.1-190.5 DEG C. 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 "-OCH 3, 5 "-OCH 3), 3.070 (4H, s ,-CH 2n (aryl) CH 2-), 2.487 (4H, s ,-CH 2n (CH 3) CH 2-), 2.250 (3H, s ,-NCH 3) .ESI-MS m/z:466.2 (M+H) +.
Embodiment 13 N 2-[4-(4-methylpiperazine-1-yl) phenyl]-5-nitro-N 4the measurement result of-(3,4,5-trifluorophenyl) pyrimidine-2,4-diamines (9) is:
Brown ceramic powder; Productive rate 80.7%; M.p 256.3-257.2 DEG C. 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 ,-CH 2n (aryl) CH2-), 2.497 (4H, s ,-CH 2n (CH 3) CH 2-), 2.269 (3H, s ,-NCH 3) .ESI-MS m/z:460.1 (M+H) +.
Embodiment 14 N 4the measurement result of-(4-luorobenzyl)-N2-[4-(4-methylpiperazine-1-yl) benzene]-5-nitro-pyrimidine-2,4-diamines (10) is:
Red powder; Productive rate 78.3%; M.p:221.7-223.5 DEG C. 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 ,-CH 2-), 3.477 (4H, s ,-CH 2n (aryl) CH 2-), 3.126 (4H, s ,-CH 2n (CH 3) CH 2-), 2.785 (3H, s ,-NCH 3) .ESI-MS m/z:427.1 (M+H) +.
Embodiment 15 N-{4-{{2-{ [4-(4-methylpiperazine-1-yl) benzene] amine }-5-nitro-pyrimidine-4-base } amine } benzene } measurement result of acrylamide (11) is:
Red powder; Productive rate 82.6%; M.p > 320 DEG C. 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=CH 2), 6.281 (1H, d, J=16.8Hz ,-CH=CH 2), 6.149 (1H, d, J=16.8Hz ,-CH=CH 2), 3.034 (4H, s ,-CH 2n (aryl) CH 2-), 2.408 (4H, s ,-CH 2n (CH 3) CH 2-), 2.206 (3H, s ,-CH 3) .ESI-MS m/z:475.1 (M+H) +.
Embodiment 16 (Z)-N-{4-{{2-{ [4-(4-methylpiperazine-1-yl) benzene] amine }-5-nitro-pyrimidine-4-base } amine } benzene } measurement result of-3-Phenyl Acrylamide (12) is:
Red powder; Productive rate 84.2%; M.p > 320 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.325 (4H, s ,-CH 2n (CH 3) CH 2-), 2.027 (3H, s ,-CH 3) .ESI-MS m/z:551.3 (M+H) +.
The chloro-N-{4-{{2-{ of embodiment 17 4-[4-(4-methylpiperazine-1-yl) benzene] amine }-5-nitro-pyrimidine-4-base } amine } benzene } measurement result of benzamide (13) is:
Red powder, productive rate 66.3%, m.p > 320 DEG C. 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,-CH 2n (aryl) CH 2-), 2.285 (4H, s ,-CH 2n (CH 3) CH 2-), 2.150 (3H, s ,-NCH 3) .ESI-MSm/z:559.1 (M) +.
The chloro-N-{4-{{2-{ of embodiment 18 3-[4-(methylpiperazine-1-yl) benzene] amine }-5-nitro-pyrimidine-4-base } amine } benzene } measurement result of propionic acid amide (14) is:
Red powder; Productive rate 74.2%; M.p 272.8-273.9 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.728 (4H, s ,-CH 2n (CH 3) CH 2-), 2.653 (3H, s ,-NCH 3), 2.499 (4H, t, J=1.8Hz ,-COCH 2cH 2cl) .ESI-MS m/z:511.0 (M+H) +.
The chloro-2-{ of embodiment 19 N-{4-{{5-[4-(4-methylpiperazine-1-yl) benzene] amido } pyrimidine-4-yl } amine } phenyl } measurement result of ethanamide (16) is:
White powder; Productive rate 60.3%; M.p 250.9-252.7 DEG C. 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, CH 2n (aryl) CH2-), 2.454 (4H, s ,-CH 2n (CH 3) CH 2-), 2.222 (3H, s ,-NCH 3), 2.026 (3H, s ,-CH 3) .ESI-MS m/z:452.4 (M+H) +.
The chloro-2-of the chloro-4-{{5-of embodiment 20 N-{2-[(4-(4-methylpiperazine-1-yl) benzene)] amine } pyrimidine-4-yl } amine } benzene } measurement result of ethanamide (17) is:
White powder; Productive rate 83.5%; M.p:110.5-111.9 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.434 (4H, t, J=4.8Hz ,-CH 2n (CH 3) CH 2-), 2.209 (3H, s ,-NCH 3), 2.088 (3H, s ,-COCH 3) .ESI-MS m/z:486.0 (M) +.
The chloro-2-{ of embodiment 21 N-{2, the chloro-4-{{5-of 6-bis-[4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine } benzene } measurement result of ethanamide (18) is:
White powder; Productive rate 64.2%; M.p:112.5-114.3 DEG C. 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 ,-CH 2n (aryl) CH 2-), 2.435 (4H, t, J=4.8Hz ,-CH 2n (CH 3) CH 2-), 2.209 (3H, s ,-NCH 3), 2.052 (3H, s ,-CH 3) .ESI-MS m/z:521.2 (M) +.
The chloro-2-{ of embodiment 22 N-{4-{{5-[4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine }-2-p-methoxy-phenyl } measurement result of ethanamide (19) is:
White powder; Productive rate 66.3%; M.p 113.5-115.9 DEG C. 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 ,-OCH 3), 3.021 (4H, t, J=4.8Hz ,-CH 2n (aryl) CH 2-), 2.438 (4H, t, J=4.8Hz ,-CH 2n (CH 3) CH 2-), 2.212 (3H, s ,-NCH 3), 2.072 (3H, s ,-CH 3) .ESI-MS m/z:482.0 (M+H) +.
The chloro-2-{ of embodiment 23 N-{4-{{5-[4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine }-2,5-dimethoxy benzenes } measurement result of ethanamide (20) is:
White powder; Productive rate 55.2%; M.p 245.2-247.3 DEG C. 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 "-OCH 3), 3.632 (3H, s, 5 "-OCH 3), 3.011 (4H, s ,-CH 2n (aryl) CH 2-), 2.435 (4H, s ,-CH 2n (CH 3) CH 2-), 2.214 (3H, s ,-NCH 3), 2.103 (3H, s ,-CH 3) .ESI-MS m/z:512.2 (M) +.
The chloro-2-of the chloro-4-{{5-of embodiment 24 N-{2-[(2-methoxyl group-4-morpholine phenyl) amine] pyrimidine-4-yl } amine } benzene } measurement result of ethanamide (21) is:
White powder, productive rate 77.5%; M.p:227.2-229.3 DEG C. 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 ,-OCH 3), 3.741 (4H, t, J=4.8Hz ,-CH 2oCH 2-), 3.087 (4H, t, J=4.8Hz ,-CH 2nCH 2-), 2.075 (3H, s ,-COCH 3) .ESI-MS m/z:503.1 (M+H) +.
The chloro-2-{ of the chloro-4-{{5-of embodiment 25 N-{2-[2-methoxyl group-4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine } benzene } measurement result of ethanamide (22) is:
Brown ceramic powder; Productive rate 71.5%; Mp:177.3-179.2 DEG C. 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 ,-OCH 3), 3.144 (4H, s ,-CH 2n (aryl) CH 2-), 2.535 (4H, s ,-CH 2n (CH 3) CH 2-), 2.282 (3H, s ,-NCH 3), 2.076 (3H, s ,-COCH 3) .ESI-MS m/z:516.1 (M) +.
The chloro-2-{ of embodiment 26 N-{2, the chloro-4-{{5-of 6-bis-[2-methoxyl group-4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine } benzene } measurement result of ethanamide (23) is:
White powder; Productive rate 43.1%; M.p 115.4-116.7 DEG C. 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 ,-OCH 3), 3.117 (4H, s ,-CH 2n (aryl) CH 2-), 2.477 (4H, s ,-CH 2n (CH 3) CH 2-), 2.242 (3H, s ,-NCH 3), 2.044 (3H, s ,-CH 3) .ESI-MS m/z:551.2 (M) +.
The chloro-2-of embodiment 27 N-{4-{{5-[(2-methoxyl group-4-morpholine benzene) amine] pyrimidine-4-yl } amine }-2-anisole } measurement result of ethanamide (24) is:
White powder; Productive rate 74.7%; M.p 202.3-203.5 DEG C. 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 ,-OCH 3), 3.741 (4H, t, J=4.8Hz ,-CH 2n (aryl) CH 2-), 3.705 (3H, s ,-OCH 3), 3.077 (4H, t, J=4.8Hz ,-CH 2n (CH 3) CH 2-), 2.068 (3H, s ,-CH 3) .ESI-MS m/z:499.3 (M+H) +.
The chloro-2-{ of embodiment 28 N-{4-{{5-[2-methoxyl group-4-(4-methylpiperazine-1-yl) benzene] amine } pyrimidine-4-yl } amine }-2-anisole } measurement result of ethanamide (25) is:
White powder; Productive rate 72.5%; Mp:122.3-123.5 DEG C. 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 ,-OCH 3), 3.696 (3H, s ,-OCH 3), 3.095 (4H, t, J=4.8Hz ,-CH 2n (aryl) CH 2-), 2.449 (4H, t, J=4.8Hz ,-CH 2n (CH 3) CH 2-), 2.221 (3H, s ,-CH 3), 2.064 (3H, s ,-COCH 3) .ESI-MS m/z:512.1 (M) +.
The chloro-2-of embodiment 29 N-{4-{{5-[(2-methoxyl group-4-morpholine benzene) amine] pyrimidine-4-yl } amine }-2.5-dimethoxy benzene } measurement result of ethanamide (26) is:
Brown ceramic powder; Productive rate 78.6%; M.p:243.7-245.3 DEG C. 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 ,-OCH 3), 3.738 (3H, s ,-OCH 3), 3.731 (3H, s ,-OCH 3), 2.888 (4H, s ,-CH 2n (aryl) CH 2-), 2.729 (4H, s ,-CH 2nOCH 2-), 2.089 (3H, s ,-COCH 3) .ESI-MS m/z:429.0 (M) +.
Above-mentioned detailed description is the illustrating of possible embodiments for invention, and this embodiment is also not used to limit the scope of the claims of the present invention, does not allly depart from equivalence of the present invention and implements or change, and all should be contained in the scope of the claims of the present invention.
In addition, those skilled in the art also can make various amendments in other form and details, interpolation and replacement in the claims in the present invention scope of disclosure and spirit.Certainly, the changes such as these various amendments made according to the present invention's spirit, interpolation and replacement, all should be included within the present invention's scope required for protection.

Claims (9)

1. a class take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, it is characterized in that having following general formula:
Wherein: R 1following arbitrary substituted radical can be selected from:
R 2following arbitrary substituted radical can be selected from:
R 3cl or NO can be selected from 2in any one;
Above R 1, R 2and R 3substituting group can arbitrary combination.
2. prepare the method that a class according to claim 1 take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot for one kind, it is characterized in that, comprise the steps:
Step one: take the chloro-5-nitro-pyrimidine of 2,4-bis-, DIPEA and R 1-NH 2in flask, add methylene chloride under stirring and make it dissolve, room temperature reaction, after completion of the reaction, add saturated aqueous common salt, mixture dichloromethane extraction, concentrated, obtain the pulverous 2-R of red solid 1the chloro-5-nitro-pyrimidine of-ammonia-4-;
Step 2: take described 2-R 1-ammonia-4-chloro-5-nitro-pyrimidine and described R 2-NH 2in flask, add sec-butyl alcohol and make it dissolve under stirring, backflow, after reaction terminates, be cooled to room temperature, add sodium bicarbonate neutralization, be extracted with ethyl acetate, concentrated, silica gel column chromatography, eluent is acetate-methanol, obtains 2-R 1-ammonia-4-R 2-ammonia-5-R 3pyrimidine.
3. a kind ofly as claimed in claim 2 prepare the method that a class according to claim 1 take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, it is characterized in that, in described step one, the room temperature reaction time is 5h; 2,4-bis-chloro-5-nitro-pyrimidine methylene dichloride 20ml described in every 1g; The chloro-5-nitro-pyrimidine of the ratio of amount of substance: 2,4-bis-: DIPEA: R 1-NH 2=1:1:1.
4. a kind ofly as claimed in claim 2 prepare the method that a class according to claim 1 take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot, it is characterized in that, in described step 2,2-R described in every 500mg 1-ammonia-4-chloro-5-nitro-pyrimidine sec-butyl alcohol 15-20ml dissolves, then instills in flask by trifluoroacetic acid, the ratio of amount of substance: 2-R 1the chloro-5-R of-ammonia-4- 3pyrimidine: R 2-NH 2: trifluoroacetic acid=1:1:1; Described return time is 2h, and described extraction times is 3 times, and described eluent is acetate-methanol, and the volume ratio of ethyl acetate and methyl alcohol is 20:1.
5. prepare the method that a class according to claim 1 take FGFR as 2,4,5-trisubstituted pyrimidine compounds of target spot for one kind, it is characterized in that, comprise the steps:
Step one: take 2,4,5-trichloropyrimidine, Anhydrous potassium carbonate and described R 1-NH 2in flask, stirring adds DMF makes it dissolve, and 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 to separate out, suction filtration, dry, obtain 2-R 1-ammonia-4,5-dichloro pyrimidine;
Step 2: take described 2-R 1-ammonia-4-chloro-5-dichloro pyrimidine and described R 2-NH 2in flask, add described sec-butyl alcohol and make it dissolve under stirring, backflow, after reaction terminates, be cooled to room temperature, add sodium bicarbonate neutralization, be extracted with ethyl acetate, concentrated, silica gel column chromatography, eluent is acetate-methanol, obtains 2-R 1-ammonia-4-R 2-ammonia-5-R 3pyrimidine.
6. an a kind of class of preparing take FGFR as 2 of target spot as claimed in claim 5,4, the method of 5-trisubstituted pyrimidine compounds, it is characterized in that, in described step one: every 1g 2,4,5-trichloropyrimidine DMF 5-10ml dissolves, the ratio of amount of substance: 2,4,5-trichloropyrimidine: Anhydrous potassium carbonate: R 1-NH 2=1:2:1; In described step 2: 2-R described in every 500mg 1-ammonia-4-chloro-5-dichloro pyrimidine sec-butyl alcohol 15-20ml, then trifluoroacetic acid is instilled in flask, the ratio of amount of substance: 2-R 1the chloro-5-dichloro pyrimidine of-ammonia-4-: R 2-NH 2: trifluoroacetic acid=1:1:1, described return time is 2h, and described extraction times is 3 times, and the volume ratio of described eluant ethyl acetate and methyl alcohol is 20:1.
7. a class take FGFR as the purposes of 2,4,5-trisubstituted pyrimidine compounds of target spot, it is characterized in that, described purposes is the application prepared in antitumor drug.
8. a pharmaceutical composition, is characterized in that, comprises 2,4, the 5-trisubstituted pyrimidine compounds that pharmaceutical excipient and a class as claimed in claim 1 take FGFR as target spot.
9. the class that contains according to claim 8 take FGFR as 2 of target spot, 4, the pharmaceutical composition of 5-trisubstituted pyrimidine compounds, it is characterized in that, the dosage form of described pharmaceutical composition is any one of injection, tablet, capsule, aerosol, suppository, film, pill, ointment, control-released agent, sustained release dosage or nanometer formulation.
CN201510180883.3A 2015-04-16 2015-04-16 A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use Active CN104803925B (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201510180883.3A CN104803925B (en) 2015-04-16 2015-04-16 A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201510180883.3A CN104803925B (en) 2015-04-16 2015-04-16 A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use

Publications (2)

Publication Number Publication Date
CN104803925A true CN104803925A (en) 2015-07-29
CN104803925B CN104803925B (en) 2018-01-12

Family

ID=53689164

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201510180883.3A Active CN104803925B (en) 2015-04-16 2015-04-16 A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use

Country Status (1)

Country Link
CN (1) CN104803925B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105017160A (en) * 2015-06-24 2015-11-04 温州医科大学 Pyrimidine EGFRT790M inhibitors and their synthesis method and use
CN106831730A (en) * 2017-01-11 2017-06-13 温州医科大学 A kind of substituted diaminopyrimidines and its purposes in anti-malignant tumor medicine is prepared
WO2018019204A1 (en) * 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
CN110746402A (en) * 2019-09-21 2020-02-04 温州医科大学 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound and preparation method and application thereof
CN111777592A (en) * 2020-06-22 2020-10-16 温州医科大学 N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN111793035A (en) * 2020-06-22 2020-10-20 温州医科大学 N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN113956234A (en) * 2021-10-27 2022-01-21 温州医科大学 N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application thereof in antitumor activity
CN115141181A (en) * 2022-06-14 2022-10-04 温州医科大学 Novel small molecule compound and preparation method and application thereof
CN115477639A (en) * 2022-08-26 2022-12-16 温州医科大学 Multi-substituted pyrimidine compound with FGFR1 as target spot, and preparation method and application thereof
CN115894381A (en) * 2022-11-11 2023-04-04 温州医科大学 2,4,5-trisubstituted pyrimidine compound and preparation method and application thereof

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101006079A (en) * 2004-08-27 2007-07-25 诺瓦提斯公司 Pyrimidine derivatives
CN101336237A (en) * 2005-12-21 2008-12-31 诺瓦提斯公司 Pyrimidinyl aryl urea derivatives being fgf inhibitors
WO2009101199A2 (en) * 2008-02-15 2009-08-20 Bodo Melnik Treatment of acne vulgaris; rosacea and rhinophym
CN102459236A (en) * 2009-05-27 2012-05-16 雅培制药有限公司 Pyrimidine inhibitors of kinase activity
CN102639510A (en) * 2009-12-07 2012-08-15 诺瓦提斯公司 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
WO2014079709A1 (en) * 2012-11-23 2014-05-30 Ab Science Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections
WO2015003658A1 (en) * 2013-07-11 2015-01-15 Betta Pharmaceuticals Co., Ltd Protein tyrosine kinase modulators and methods of use

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101006079A (en) * 2004-08-27 2007-07-25 诺瓦提斯公司 Pyrimidine derivatives
CN101336237A (en) * 2005-12-21 2008-12-31 诺瓦提斯公司 Pyrimidinyl aryl urea derivatives being fgf inhibitors
WO2009101199A2 (en) * 2008-02-15 2009-08-20 Bodo Melnik Treatment of acne vulgaris; rosacea and rhinophym
CN102459236A (en) * 2009-05-27 2012-05-16 雅培制药有限公司 Pyrimidine inhibitors of kinase activity
CN102639510A (en) * 2009-12-07 2012-08-15 诺瓦提斯公司 Crystalline forms of 3-(2,6-dichloro-3,5-dimethoxy-phenyl)-1-{6-[4-(4-ethyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-1-methyl-urea and salts thereof
WO2014079709A1 (en) * 2012-11-23 2014-05-30 Ab Science Use of small molecule inhibitors/activators in combination with (deoxy)nucleoside or (deoxy)nucleotide analogs for treatment of cancer and hematological malignancies or viral infections
WO2015003658A1 (en) * 2013-07-11 2015-01-15 Betta Pharmaceuticals Co., Ltd Protein tyrosine kinase modulators and methods of use

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
CHI HOON PARK,等: "Novel bis-ortho-alkoxy-para-piperazinesubstituted-2,4-dianilinopyrimidines (KRCA-0008) as potent and selective ALK inhibitors for anticancer treatment", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *
LUXI ZHANG,等: "Characterization of the Novel Broad-Spectrum Kinase Inhibitor CTx-0294885 As an Affinity Reagent for Mass Spectrometry-Based Kinome Profiling", 《JOURNAL OF PROTEOME RESEARCH》 *
QI-ZHENG SUN,等: "Structural modification of an EGFR inhibitor that showed weak off-target activity against RET leading to the discovery of a potent RET inhibitor", 《MOLECULAR DIVERSITY》 *
WEI ZHOU,等: "Discovery of Pteridin-7(8H)-one-Based Irreversible Inhibitors Targeting the Epidermal Growth Factor Receptor (EGFR) Kinase T790M/L858R Mutant", 《JOURNAL OF MEDICINAL CHEMISTRY》 *
张颖,等: "FGFR抗体类肿瘤药物的研发现状及发展趋势", 《生物产业技术》 *

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105017160A (en) * 2015-06-24 2015-11-04 温州医科大学 Pyrimidine EGFRT790M inhibitors and their synthesis method and use
WO2018019204A1 (en) * 2016-07-26 2018-02-01 深圳市塔吉瑞生物医药有限公司 Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
CN108602802A (en) * 2016-07-26 2018-09-28 深圳市塔吉瑞生物医药有限公司 Amino-metadiazine compound for inhibiting protein tyrosine kinase activity
CN108602802B (en) * 2016-07-26 2020-01-21 深圳市塔吉瑞生物医药有限公司 Aminopyrimidines useful for inhibiting protein tyrosine kinase activity
US11111233B2 (en) 2016-07-26 2021-09-07 Shenzhen Targetrx, Inc. Amino pyrimidine compound for inhibiting protein tyrosine kinase activity
CN106831730A (en) * 2017-01-11 2017-06-13 温州医科大学 A kind of substituted diaminopyrimidines and its purposes in anti-malignant tumor medicine is prepared
CN110746402A (en) * 2019-09-21 2020-02-04 温州医科大学 2-N-aryl-4-N-aryl-5-fluoropyrimidine compound and preparation method and application thereof
CN111777592B (en) * 2020-06-22 2021-06-18 温州医科大学 N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN111793035A (en) * 2020-06-22 2020-10-20 温州医科大学 N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN111793035B (en) * 2020-06-22 2021-06-18 温州医科大学 N4- (3-methoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN111777592A (en) * 2020-06-22 2020-10-16 温州医科大学 N4- (2, 5-dimethoxyphenyl) -pyrimidinediamine targeted DDR1 inhibitor and preparation and application thereof
CN113956234A (en) * 2021-10-27 2022-01-21 温州医科大学 N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application thereof in antitumor activity
CN115141181A (en) * 2022-06-14 2022-10-04 温州医科大学 Novel small molecule compound and preparation method and application thereof
CN115477639A (en) * 2022-08-26 2022-12-16 温州医科大学 Multi-substituted pyrimidine compound with FGFR1 as target spot, and preparation method and application thereof
CN115477639B (en) * 2022-08-26 2023-11-03 温州医科大学 Polysubstituted pyrimidine compound with FGFR1 as target point, and preparation method and application thereof
CN115894381A (en) * 2022-11-11 2023-04-04 温州医科大学 2,4,5-trisubstituted pyrimidine compound and preparation method and application thereof

Also Published As

Publication number Publication date
CN104803925B (en) 2018-01-12

Similar Documents

Publication Publication Date Title
CN104803925B (en) A kind of 2,4,5 trisubstituted pyrimidine class compounds using FGFR as target spot and its production and use
AU2018271284B2 (en) Pyrimidine FGFR4 inhibitors
Liu et al. Design, synthesis and biological evaluation of novel thieno [3, 2-d] pyrimidine derivatives possessing diaryl semicarbazone scaffolds as potent antitumor agents
CA2542076C (en) Substituted tricyclic compounds as protein kinase inhibitors
CN101166732B (en) Cyanopyridine derivative and use thereof as medicine
CN1807413B (en) Carbazole sulfonamide derivative and its preparation method
CN103965120A (en) Quinoline and quinazoline derivative, preparation method, intermediate, composition and application
CA2679489A1 (en) Pyrimidine-2,4-diamine derivatives and their use as jak2 kinase inhibitors
CN112204010B (en) Heterocyclic derivatives and uses thereof
Tu et al. Design, synthesis, and docking studies of afatinib analogs bearing cinnamamide moiety as potent EGFR inhibitors
KR102214225B1 (en) 5-membered heterocyclic amide type WNT pathway inhibitor
Zhang et al. Discovery of novel anti-angiogenesis agents. Part 6: Multi-targeted RTK inhibitors
CN103739550B (en) 2,3-dimethyl-6-urea-2H-indazole compounds and its preparation method and application
Shan et al. Expanding the structural diversity of diarylureas as multi-target tyrosine kinase inhibitors
BR112019027292A2 (en) coumarin-like cyclic compound as a mek inhibitor and use of it
CN103450176A (en) Naphthalimide compound containing 2-(4-aminophenyl) benzothiazole and application thereof
CN107383014B (en) A kind of 1H- pyrazolo [3,4-d] pyrimidines and its preparation method and application
CN103382182B (en) Phenylurea coupling quinazoline compounds and preparation method thereof, pharmaceutical composition and medicinal usage
CN108329274A (en) Bruton&#39;s tyrosine kinase inhibitor
CN106349224A (en) JAK kinase inhibitor with 4-amino-(1H)-pyrazole structure and preparation method and application thereof
CN113956234B (en) N-phenyl substituted 1H-indazole-3-amine compound, preparation thereof and application of antitumor activity
CN106866642B (en) Quinazoline compound containing aryl acylhydrazone structure and application thereof
CN115477639A (en) Multi-substituted pyrimidine compound with FGFR1 as target spot, and preparation method and application thereof
CN102234270A (en) Diarylurea derivatives and treatment application thereof
CN106496232B (en) A kind of 1- with anti-tumor activity (2- oxinanes) -1H- pyrazolos [3,4-d] pyrimidines and preparation method thereof

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
EXSB Decision made by sipo to initiate substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant