CN116239603A - 2-aminopyrimidine heterocyclic compound and application thereof - Google Patents
2-aminopyrimidine heterocyclic compound and application thereof Download PDFInfo
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- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
- C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
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- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
Abstract
The invention belongs to the field of chemical synthesis, and particularly relates to a 2-aminopyrimidine heterocyclic compound and application thereof. The invention provides a series of 2-aminopyrimidine heterocyclic compounds containing 4-amide phenoxy with novel structures; it has remarkable inhibiting effect on lung cancer, cervical cancer and breast cancer and has good market prospect.
Description
The application is a divisional application, the original application name is 'preparation and application of a 2-aminopyrimidine heterocyclic compound containing 4-amide phenoxy', the application number is 202010568748.7, and the application date is 2020.06.20.
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to a 2-aminopyrimidine heterocyclic compound and application thereof.
Background
Cancer, i.e., malignant tumor, can lose control of proliferation and differentiation of normal cells, undergo abnormal division, and has various biological pathological features such as wettability and metastasis, which is a disease seriously harming human health.
EGFR has been found to be closely related to inhibition of a range of vital activities of tumor cells such as proliferation, invasion, angiogenesis, tumor metastasis and apoptosis. EGFR family members have a central role and have become the primary targets for the treatment of cancer, particularly NSCLC. By inhibiting the kinase activity of EGFR tyrosine, the signal path conduction is blocked, and the growth of tumors can be effectively inhibited.
Disclosure of Invention
In order to develop a novel and efficient antitumor drug, the inventor conducts extensive research on amino heterocyclic pyrimidine compounds, maintains a U-shaped structural support of a third-generation EGFR inhibitor compound on the basis of retaining active groups such as amino pyrimidine, michael acceptors and the like, introduces active groups such as micromolecular alkyl side chains and halogen and the like on pyrimidine rings and acrylamide side chains to regulate the reactivity of the compound, changes a parent nucleus structure through molecular docking results, and designs and synthesizes a series of 2-amino pyrimidine heterocyclic compounds containing 4-amide phenoxy, wherein the structure of the 2-amino pyrimidine heterocyclic compounds is shown as the following general formula I or II:
wherein the fused ring on which the X ring is located is selected from:
R 1 selected from five-membered or six-membered heterocyclic, aromatic or heteroaromatic rings containing 1-3 groups selected from hydrogen, halogen, trifluoromethyl, cyano, methoxy or C 1 ～C 4 Substituents of alkyl;
R 2 selected from hydrogen, C 1 ～C 4 Alkyl or halogen;
R 3 selected from hydrogen, C 1 ～C 10 Alkyl, C 3 ～C 10 Cycloalkyl, C 1 ～C 4 An alcoholic hydroxyl group,
R 4 、R 5 Identical or different, each independently selected from C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, hydroxyethyl, mercaptoethyl; alternatively, R 4 And R is 5 Together with the nitrogen atom to which they are attached, form a 5-to 10-membered saturated heterocyclic group which, apart from R 4 And R is 5 Optionally containing 1 to 3 heteroatoms selected from O, N and S in addition to the attached nitrogen atom; n is 0 to 3.
The compound can be used for preparing medicines for treating and/or preventing prostate cancer, lung cancer and cervical cancer.
Preferably, R 1 Selected from:
wherein R is 6 Selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, mercapto, carboxyl, trifluoromethoxy, methyl, ethyl, propyl, butyl, cyclopropane, ethylene, propylene, acetylene, propyne, methoxy, ethoxy, propoxy, isopropoxy, butoxy or azido;
R 7 selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, azido, cyano, mercapto, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkenyl, C 1 ～C 4 Alkynyl, C 1 ～C 4 An alkoxy group.
More preferably, R 1 Selected from benzene rings or pyridines containing 1 methoxy substituent.
Preferably, -R 2 (CH) 2 R 3 Selected from:
more preferably, R 2 Selected from H or F. R is R 3 Selected from methyl, ethyl, isopropyl, hydrogen or propyl.
Preferably, the compounds of formula i and ii are one selected from the group consisting of:
n- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) but-2-enamide;
n- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -3-methyl-2-enamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4-methylpent-2-enamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) hex-2-amide;
n- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
2-fluoro-N- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -4- (dimethylamino) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide;
(E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide;
n- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) -pent-2-enamide;
n- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
2-fluoro-N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -4- (dimethylamino) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide;
(E) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide.
The following schemes describe the preparation of the general formulae I and II of the present invention, all of which are prepared by the means described in the schemes, by methods well known to those of ordinary skill in the art of organic chemistry, or are commercially available. All of the final 4-aminophenoxy-containing 2-aminopyrimidine heterocycles of the present invention are prepared by the methods described in the synthetic routes or by methods analogous thereto, which are well known to those of ordinary skill in the art of organic chemistry. All variable factors applied in the synthetic route are as defined below or as defined in the claims.
Taking N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide as an example, the synthesis procedure is as follows, all starting materials being commercially available in analytical purity.
Taking N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide as an example, the synthetic method is as follows, all starting materials being commercially available in analytical purity.
The invention firstly synthesizes an intermediate VII, and then obtains the target compound through butt joint or other modes with different side chain amines and different substituted small molecule acyl chlorides.
The quinazoline compounds of the general formulae I and II described above may form pharmaceutically acceptable salts with acids according to some of the usual methods in the art to which the invention pertains. Pharmaceutically acceptable addition salts include inorganic and organic acid addition salts, with the following acid addition salts being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, and the like.
In addition, prodrugs of the derivatives of the invention are also encompassed by the invention. Prodrugs of the derivatives of the invention are derivatives of formula I above, which may themselves have relatively weak or even no activity, but are converted to the corresponding biologically active form under physiological conditions (e.g., by metabolism, solvolysis or otherwise) after administration.
The invention can contain the 2-aminopyrimidine heterocyclic compounds containing 4-amide phenoxy in the general formulas I and II, and pharmaceutically acceptable salts, hydrates or solvates thereof as active ingredients, and are mixed with pharmaceutically acceptable carriers or excipients to prepare a composition and a clinically acceptable dosage form, wherein the pharmaceutically acceptable excipients refer to any diluent, auxiliary agent and/or carrier which can be used in the pharmaceutical field. The derivatives of the present invention may be used in combination with other active ingredients as long as they do not produce other adverse effects such as allergic reactions.
The clinical dosage of the 4-amidophenoxy-containing 2-aminopyrimidine heterocyclic compounds of the general formulas I and II described above for patients according to the present invention may be as follows: the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolism and excretion rates and the age, sex, disease period of the patient are suitably adjusted, but the daily dose for adults should generally be 10 to 500mg, preferably 50 to 300mg. These formulations may be administered in several doses (preferably one to six) at intervals, according to the direction of the doctor or pharmacist.
The pharmaceutical compositions of the present invention may be formulated in several dosage forms, containing some excipients commonly used in the pharmaceutical arts. The above-mentioned several dosage forms can be made into injection, tablet, capsule, aerosol, suppository, film, dripping pill, external liniment and ointment.
The carriers used in the pharmaceutical compositions of the present invention are of the usual types available in the pharmaceutical arts, including: binders, lubricants, disintegrants, co-solvents, diluents, stabilizers, suspending agents, non-pigmenting agents, flavoring agents, preservatives, solubilizing agents, matrices and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if some drugs are unstable in gastric conditions, they may be formulated as enteric coated tablets.
The beneficial effects of the invention are as follows: the invention provides a series of 2-aminopyrimidine heterocyclic compounds containing 4-amide phenoxy with novel structures; it has remarkable inhibiting effect on lung cancer, cervical cancer and breast cancer and has good market prospect.
Detailed Description
The conception and technical effects of the present invention will be clearly and completely described in conjunction with examples below to fully understand the objects, aspects and effects of the present invention. In the examples, nuclear magnetic resonance hydrogen spectra were measured using Bruker ARX-400 and mass spectra were measured using Agilent 1100LC/TOF MSD; the reagents used are analytically pure or chemically pure.
2-aminopyrimidine heterocycles containing 4-aminophenoxy groups of the general formulae I and II:
the structural formulas of examples 1 to 28 of the present invention are shown in the following table 1.
TABLE 1 structural formulas of examples 1-28
Example 1 preparation of 5n- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide:
step A: preparation of methyl 4-oxo-tetrahydro-2H-thiopyran-3-carboxylate (III 1)
Dimethyl 3,3' -thiodipropionate (II) (1130.0 g,630.3 mmol) and NaH (60%, 22.7g,945.5 mmol) were added to a flask containing 500mL of tetrahydrofuran. The mixture was stirred at room temperature for 4h. After the reaction, the mixture was added to 1000mL of water, and the mixture was extracted with methylene chloride several times. The obtained organic phase was dried over anhydrous sodium sulfate, and methylene chloride was recovered under reduced pressure to obtain 104.3g of a yellow liquid, and the yield was 95.0%.
And (B) step (B): preparation of 7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine-2, 4-diol (IV 1)
Compound III 1 (50.0 g,287.0 mmol) and urea (103.5 g,1723.3 mmol) are dissolved in 500mL sodium methoxide solution. After stirring the reaction at 80℃for about 5 hours, the reaction was completed. 500mL of water is slowly added into the reaction solution, and in the mixing process, macroscopic fine particles are separated out, and the compound IV 1 is obtained after decompression, suction filtration and drying, wherein 40.29g of pale yellow solid is obtained, and the yield is 76.2%.
Step C: preparation of 2, 4-dichloro-7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine (V1)
Compound IV 1 (20.0 g,108.5 mmol) was dissolved in 80mL of phosphorus oxychloride solution and stirred at 120℃for 3h, after the reaction was completed the reaction mixture was cooled to room temperature, then 500mL of ice water was slowly added and stirred vigorously, and the solid precipitated. After vacuum filtration, the filter cake was washed with distilled water. After drying the filter cake, 19.8g of a pale grey solid are obtained in 82.6% yield.
Step D: preparation of (22-chloro-4- (3-nitrophenoxy) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidine (VI 1)
Compound V1 (19.0 g,85.9 mmol) and m-nitrophenol (12.0 g,86.3 mmol) cesium carbonate (31.0 g,95.1 mmol) were stirred in a flask containing 120mL of 4-dioxane at room temperature for 6h, and a large amount of solid precipitated during the reaction. After the completion of the reaction, the reaction mixture was poured into 250mL of water and stirred for 30 minutes, and 27.0g of a white solid was obtained after filtration and drying, with a yield of 97.1%.
Step E: preparation of N- (3-methoxyphenyl) -4- (3-nitrophenoxy) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-2-amine (VII 1 a)
Compound VI 1 (5 g,15.4 mmol) was dissolved in 60mL of acetonitrile, and p-toluenesulfonic acid (5.6 g,32.5 mmol) and amino side chain a (16.5 mmol) were then added sequentially thereto. After stirring at 100℃for 3h, the reaction was complete. After cooling to room temperature, the mixture was concentrated under reduced pressure, and acetonitrile was concentrated by about 50%. After adding twice the amount of water, a large amount of solids precipitated. The solid was suction filtered under reduced pressure and dried to obtain the key intermediate vii 1a.
Step F: preparation of 4- (3-aminophenoxy) -N- (3-methoxyphenyl) -7, 8-dihydro-5H-thiopyrazolo [4,3-d ] pyrimidin-2-amine (VIII 1 a)
Compound VII 1a (13.0 mmol) was dissolved in 60mL ethanol. Ferric trichloride hexahydrate (15.6 mmol) and activated carbon (91.0 mmol) were added sequentially. After heating to 80 ℃, hydrazine hydrate (130.0 mmol) was mixed with 10mL ethanol and added to the solution. The mixture was stirred under reflux for 4 hours, and after the reaction was completed, solids in the reaction system were removed by filtration. The filter cake was then washed with 10mL of absolute ethanol, the filtrate was collected and the solvent recovered by vacuum distillation. The residue was added to 60mL of saturated aqueous sodium bicarbonate and the solid was precipitated with vigorous stirring. The solid was suction filtered under reduced pressure and dried to obtain the key intermediate VIII 1a.
Step G: preparation of N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide (IX 1 a)
Compound VIII 1a (1.5 mmol) was dissolved in 30mL of dichloromethane and DIPEA (3.0 mmol) was added. The solution was stirred in an ice bath for 5 minutes, then amide (3.0 mmol) diluted with an equal amount of dichloromethane was slowly added dropwise to the solution. The reaction was completed within 2 hours, and after completion of the reaction, the reaction mixture was filtered, and the solvent was recovered by distillation under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol=70:1-30:1 as eluent to give the higher purity target compound ix 1a.
Example 1N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
m.p.:225.9–227.3℃；TOF MS ES+(m/z):(M+H)+:435.14； 1 H NMR(400MHz,DMSO-d 6 )δ10.43(s,1H),9.40(s,1H),7.67(s,1H),7.54(d,J＝6.8Hz,1H),7.39(t,J＝7.5Hz,1H),7.19(s,1H),7.04(d,J＝6.0Hz,1H),6.93(s,2H),6.51–6.41(m,1H),6.38(d,J＝6.8Hz,1H),6.25(d,J＝16.9Hz,1H),5.76(d,J＝9.7Hz,1H),3.77(s,2H),3.54(s,3H),2.97(s,4H)。
Synthesis of intermediate VIII 1a with different substituents R according to the procedure of example 1 2 The compounds of examples 2 to 7 were obtained by the reaction.
Example 2 (E) -N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide
m.p.:198.2–202.7℃；TOF MS ES+(m/z):(M+H)+:449.16； 1 H NMR(400MHz,DMSO-d 6 )δ10.53(s,1H),9.37(s,1H),7.70(s,1H),7.57(d,J＝6.5Hz,1H),7.40–7.31(m,1H),7.19(s,1H),7.03(s,1H),6.96–6.85(m,2H),6.76(s,1H),6.38(d,J＝5.0Hz,1H),6.25(d,J＝14.4Hz,1H),3.76(s,2H),3.53(s,3H),2.96(s,4H),1.85(d,J＝5.8Hz,3H)。
Example 3N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) -3-methyl-2-enamide
m.p.:199.7–201.6℃；TOF MS ES+(m/z):(M+H)+:463.18； 1 H NMR(400MHz,DMSO-d 6 )δ9.35(s,1H),7.27(s,1H),7.13(d,J＝8.0Hz,1H),7.05(t,J＝8.0Hz,1H),6.96(t,J＝8.1Hz,1H),6.45(d,J＝8.1Hz,1H),6.40(d,J＝8.0Hz,1H),6.35(s,1H),6.30(s,1H),5.25(s,2H),3.72(s,2H),3.55(s,3H),2.95(s,4H),2.18(s,3H),1,84(s,3H)。
Example 4 (E) -N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) pent-2-enamide
m.p.:200.7–202.4℃；TOF MS ES+(m/z):(M+H)+:463.18； 1 H NMR(400MHz,DMSO-d 6 )δ10.31(s,1H),9.37(s,1H),7.63(s,1H),7.48(d,J＝8.6Hz,1H),7.35(t,J＝8.1Hz,1H),7.18(d,J＝9.2Hz,1H),7.02(d,J＝7.3Hz,1H),6.89(t,J＝8.1Hz,2H),6.36(d,J＝7.2Hz,1H),6.10(d,J＝15.3Hz,1H),5.95(d,J＝15.5Hz,1H),3.75(s,2H),3.51(s,3H),2.95(s,4H),2.06–1.89(m,2H),1.22(d,J＝10.0Hz,3H)。
Example 5 (E) -N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) -4-methylpent-2-enamide
m.p.:230.5–234.5℃；TOF MS ES+(m/z):(M+H)+:477.19； 1 H NMR(400MHz,DMSO-d 6 )δ10.41(s,1H),9.34(s,1H),7.27(s,1H),7.12(d,J＝8.1Hz,1H),7.04(t,J＝7.9Hz,1H),6.96(t,J＝8.1Hz,1H),6.45(d,J＝7.8Hz,1H),6.42–6.34(m,2H),6.30(d,J＝7.6Hz,1H),5.27(s,2H),3.72(s,2H),3.55(s,3H),2.95(s,4H),1.98(s,1H),1.23(s,6H)。
Example 6 (E) -N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) hex-2-enamide
m.p.:226.7–229.4℃；TOF MS ES+(m/z):(M+H)+:477.19； 1 H NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),9.20(s,1H),7.64(s,1H),7.51(s,1H),7.39(t,J＝8.0Hz,1H),7.31(d,J＝8.4Hz,2H),6.89(d,J＝7.7Hz,1H),6.78(dd,J＝14.8,7.4Hz,1H),6.59(d,J＝7.6Hz,2H),6.11(d,J＝15.2Hz,1H),3.76(s,2H),3.63(s,3H),2.99–2.89(m,4H),2.17(q,J＝6.7Hz,2H),1.44(dt,J＝14.4,7.3Hz,2H),0.94–0.89(m,3H)。
Example 7 2-fluoro-N- (3- ((2- ((3-methoxyphenyl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
m.p.:215.2–217.4℃；TOF MS ES+(m/z):(M+H)+:453.14； 1 H NMR(400MHz,DMSO-d 6 )δ10.18(s,1H),9.36(s,1H),7.27(s,1H),7.12(d,J＝8.0Hz,1H),7.05(t,J＝7.9Hz,1H),6.96(t,J＝8.1Hz,1H),6.45(d,J＝7.9Hz,1H),6.40(d,J＝7.9Hz,1H),6.35(s,1H),6.31(d,J＝7.9Hz,1H),5.26(s,2H),3.72(s,2H),3.55(s,3H),2.95(s,4H)。
VI 1 is synthesized by the method of example 1 and reacted with an amino side chain b to give VII 1b, which is reduced to give VIII 1b, the intermediate VIII 1b being reacted with different substituents R 2 The compounds of examples 8 to 13 were obtained by the reaction.
Example 8N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
m.p.:189.2–190.7℃；TOF MS ES+(m/z):(M+H)+:436.14； 1 H NMR(400MHz,DMSO-d 6 )δ10.24(s,1H),9.32(s,1H),8.21(s,1H),7.78(d,J＝8.7Hz,1H),7.65(s,1H),7.48(d,J＝9.1Hz,1H),7.37(t,J＝8.1Hz,1H),6.89(dd,J＝8.0,2.2Hz,1H),6.78(dt,J＝14.3,7.0Hz,1H),6.48(d,J＝8.2Hz,1H),6.12(d,J＝15.3Hz,1H),5.53(d,J＝14.3Hz,1H),3.76(s,2H),3.74(s,3H),2.95(s,4H)。
Example 9 (E) -N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) but-2-enamide
m.p.:187.6–190.1℃；TOF MS ES+(m/z):(M+H)+:450.16； 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.27(s,1H),8.17(s,1H),7.75(d,J＝8.6Hz,1H),7.45(d,J＝7.4Hz,1H),7.38(d,J＝9.1Hz,1H),6.89(d,J＝7.3Hz,1H),6.83–6.73(m,2H),6.45(s,1H),6.11(d,J＝14.8Hz,1H),3.74(s,2H),3.72(s,3H),2.95–2.91(m,4H),1.85(d,J＝6.7Hz,3H)。
Example 10N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) -3-methyl-2-enamide
m.p.:221.1–224.1℃；TOF MS ES+(m/z):(M+H)+:450.16； 1 H NMR(400MHz,DMSO-d 6 )δ10.08(s,1H),9.83(s,1H),8.28(d,J＝5.4Hz,1H),8.05(s,1H),7.92(d,J＝8.4Hz,1H),7.39(s,1H),7.37–7.32(m,2H),7.29(d,J＝6.5Hz,1H),6.53(d,J＝8.1Hz,1H),3.75–3.70(m,5H),2.96(d,J＝21.6Hz,4H),2.10(s,3H),1.84(s,3H)。
Example 11 (E) -N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) pent-2-enamide
m.p.:214.3–216.4℃；TOF MS ES+(m/z):(M+H)+:464.17； 1 H NMR(400MHz,DMSO-d 6 )δ10.14(s,1H),9.31(s,1H),8.21(s,1H),7.79(s,1H),7.65(s,1H),7.47(d,J＝7.6Hz,1H),7.39(d,J＝7.6Hz,1H),6.93–6.81(m,2H),6.49(s,1H),6.09(d,J＝15.4Hz,1H),3.76(s,3H),3.74(s,2H),2.95(s,4H),2.27–2.16(m,2H),1.03(t,J＝7.1Hz,3H)。
Example 12 (E) -N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) -4-methylpent-2-enamide
m.p.:226.8–229.2℃；TOF MS ES+(m/z):(M+H)+:478.19； 1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),9.30(s,1H),8.19(s,1H),7.76(d,J＝8.4Hz,1H),7.63(s,1H),7.45(d,J＝8.0Hz,1H),7.37(d,J＝8.2Hz,1H),6.88(d,J＝7.8Hz,1H),6.81–6.73(m,1H),6.46(d,J＝6.5Hz,1H),6.04(d,J＝15.4Hz,1H),3.74(s,2H),3.72(s,3H),2.94(d,J＝10.9Hz,4H),2.44(dd,J＝13.0,6.5Hz,1H),1.02(d,J＝6.7Hz,6H)。
Example 13 (E) -N- (3- ((2- ((6-methoxypyridin-3-yl) amino) -7, 8-dihydro-5H-thiopyran [4,3-d ] pyrimidin-4-yl) oxy) phenyl) hex-2-enamide
m.p.:230.1–231.7℃；TOF MS ES+(m/z):(M+H)+:478.19； 1 H NMR(400MHz,DMSO-d 6 )δ10.24(s,1H),9.33(s,1H),8.21(s,1H),7.77(d,J＝6.9Hz,1H),7.65(s,1H),7.48(d,J＝8.2Hz,1H),7.37(t,J＝7.5Hz,1H),6.89(d,J＝7.9Hz,1H),6.78(dt,J＝14.6,6.9Hz,1H),6.48(d,J＝8.3Hz,1H),6.12(d,J＝15.3Hz,1H),3.75(s,2H),3.73(s,3H),2.95(s,4H),2.24–2.12(m,2H),1.49–1.42(m,2H),0.90(t,J＝7.0Hz,3H)。
Example 14 preparation of N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide:
step A: preparation of 2, 4-dichloro-6- (thiophen-2-yl) pyrimidine (V2)
2,4, 6-trichloropyrimidine (70.0 g,381.6 mmol), bis (triphenylphosphine) palladium dichloride and thiophen-2-yl boric acid (25.2 g,196.8 mmol) were charged into a 500mL flask using a mixed liquid of 1, 2-dimethoxyethane and water at a temperature of 90℃for about 1.5 hours as a solvent, and the reaction was completed after stirring the compound at a temperature of 90℃using a one-pot method, and the system was black and turbid. The solvent in the system was evaporated to dryness and the residue was purified by silica gel column chromatography using ethyl acetate/diethyl ether=70:1-50:1 as eluent to give 21.0g of the target compound v 2 with higher purity in 23.6% yield.
And (B) step (B): preparation of 2-chloro-4- (3-nitrophenoxy) -6- (thiophen-2-yl) pyrimidine (VI 2)
Compound V2 (19.0 g,82.3 mmol) was dissolved in 120mL of 1, 4-dioxane, m-nitrophenol (12.0 g,86.3 mmol) and cesium carbonate (32.0 g,99.5 mmol) were added sequentially to the solvent, and stirred at room temperature for 4 hours, and a large amount of solids precipitated during the reaction. After the completion of the reaction, the reaction mixture was poured into 250mL of water and stirred for 10 minutes, and the solid was filtered off under reduced pressure and dried to obtain 24.0g of a yellow solid, the yield of which was 87.4%.
Step D: preparation of 3- ((4- (3-nitrophenoxy) -6- (thiophen-2-yl) pyrimidin-2-yl) amino) benzonitrile (VII 2 c)
Compound VI 2 (5.3 g,16.0 mmol) was dissolved in 60mL of acetonitrile, and p-toluenesulfonic acid (5.6 g,32.5 mmol) and amino side chain c (16.0 mmol) were then added to the solution in sequence. Stirring at 100deg.C, reacting for 4-5 hr, cooling to room temperature, and concentrating the reaction system with rotary evaporator. After acetonitrile was concentrated to about 50%, twice the amount of water was added to precipitate a large amount of solids. The solid is filtered off under reduced pressure and dried to obtain the key intermediate VII 2c.
Step E: preparation of 3- ((4- (3-aminophenoxy) -6- (thiophen-2-yl) pyrimidin-2-yl) amino) benzonitrile (VIII 2 c)
Compound VII 2c (13.0 mmol) was dissolved in 60mL ethanol. Ferric trichloride hexahydrate (15.6 mmol) and activated carbon (91.0 mmol) were added sequentially. After heating to 80 ℃, hydrazine hydrate (130.0 mmol) was mixed with 10mL ethanol and added to the solution. The mixture was stirred under reflux for 4 hours, and after the reaction was completed, solids in the reaction system were removed by filtration. The filter cake was then washed with 10mL of absolute ethanol and the filtrate was collected. Most of the solvent was removed by vacuum distillation. 60mL of saturated aqueous sodium bicarbonate was added and the mixture was vigorously stirred to precipitate a solid. The compound VIII 2c is obtained by filtration and cake drying.
Step F: preparation of N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide (IX 2 c)
Compound VIII 2c (1.5 mmol) was dissolved in 30mL of dichloromethane and 3.0mmol of N, N Diisopropylethylamine (DIPEA) was added. The solution was stirred in an ice bath for 5min, then amide (3.0 mmol) diluted with an equal amount of dichloromethane was slowly added dropwise to the solution. The reaction was completed within 2 hours, after the completion of the reaction, the solid in the reaction system was removed by suction filtration under reduced pressure, and the filtrate was recovered by distillation under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane/methanol=70:1-30:1 as eluent to give the higher purity target compound ix 2c.
Example 14N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide
m.p.:207.2–208.4℃；TOF MS ES+(m/z):(M+H) + :440.11； 1 H NMR(400MHz,DMSO-d 6 )δ10.34(s,1H),9.95(s,1H),8.08–8.05(m,1H),7.84(d,J＝5.2Hz,2H),7.71(d,J＝6.3Hz,1H),7.52(d,J＝8.3Hz,1H),7.44(t,J＝8.1Hz,2H),7.33(s,2H),7.28–7.24(m,1H),7.16(s,1H),7.03–6.99(m,1H),6.43(dd,J＝16.9,10.1Hz,1H),6.25(dd,J＝16.9,2.0Hz,1H),5.79–5.74(m,1H)。
According to the method of example 14, intermediate VIII 2c is used with different substituents R 2 The compounds of examples 15 to 18 were obtained by the reaction.
Example 15 (E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) but-2-enamide
m.p.:209.9–211.1℃；TOF MS ES+(m/z):(M+H) + :454.13； 1 H NMR(400MHz,DMSO-d 6 )δ10.13(s,1H),9.95(s,1H),8.07(d,J＝5.8Hz,2H),7.84(d,J＝5.1Hz,2H),7.69(d,J＝10.9Hz,1H),7.49(d,J＝8.2Hz,1H),7.43(d,J＝7.9Hz,1H),7.34(s,2H),7.27–7.24(m,1H),7.16(s,1H),6.98(d,J＝8.1Hz,1H),6.79(dd,J＝15.3,7.6Hz,1H),6.11(d,J＝15.3Hz,1H),1.85(d,J＝7.0Hz,3H)。
Example 16N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -3-methyl-2-enamide
m.p.:197.2–199.2℃；TOF MS ES+(m/z):(M+H) + :468.15； 1 H NMR(400MHz,DMSO-d 6 )δ10.01(s,1H),9.95(s,1H),8.06(d,J＝3.8Hz,1H),7.84(d,J＝4.9Hz,2H),7.67(s,1H),7.42(dt,J＝16.2,8.2Hz,3H),7.34(s,2H),7.27–7.24(m,1H),7.15(s,1H),6.95(d,J＝8.1Hz,1H),5.86(s,1H),2.12(s,3H),1.85(s,3H)。
Example 17 (E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4-methylpent-2-enamide
m.p.:210.5.2–211.9℃；TOF MS ES+(m/z):(M+H) + :482.16； 1 H NMR(400MHz,DMSO-d 6 )δ10.19(s,1H),9.94(s,1H),8.06(d,J＝3.8Hz,1H),7.84(d,J＝5.2Hz,2H),7.69(d,J＝4.5Hz,1H),7.49(d,J＝8.3Hz,1H),7.42(t,J＝8.1Hz,1H),7.33(s,2H),7.25(t,J＝4.4Hz,1H),7.15(s,1H),6.98(d,J＝8.0Hz,1H),6.81(d,J＝6.3Hz,1H),6.79–6.74(m,1H),6.06(d,J＝15.4Hz,1H),2.43(dd,J＝13.1,6.6Hz,1H),1.03(d,J＝6.5Hz,6H)。
Example 18 (E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) hex-2-amide
m.p.:222.3–223.5℃；TOF MS ES+(m/z):(M+H) + :482.16； 1 H NMR(400MHz,DMSO-d 6 )δ10.15(s,1H),9.95(s,1H),8.07(d,J＝3.7Hz,1H),7.85(d,J＝5.0Hz,2H),7.68(s,1H),7.49(d,J＝8.4Hz,1H),7.42(t,J＝8.0Hz,2H),7.33(s,2H),7.26(dd,J＝5.0,3.8Hz,1H),7.16(s,1H),6.98(d,J＝7.9Hz,1H),6.82–6.76(m,1H),6.10(d,J＝15.4Hz,1H),2.18(d,J＝7.0Hz,2H),1.45(d,J＝7.3Hz,2H),0.90(d,J＝3.5Hz,3H)。
Example 19N- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide
TOF MS ES+(m/z):(M+H) + :445.13。
Example 20 2-fluoro-N- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide
TOF MS ES+(m/z):(M+H) + :463.12。
Example 21 (E) -4- (dimethylamino) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide
TOF MS ES+(m/z):(M+H) + :476.18。
Example 22 (E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide
TOF MS ES+(m/z):(M+H) + :516.21。
Example 23N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide
TOF MS ES+(m/z):(M+H) + :395.12。
Example 24 (E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) -pent-2-enamide
TOF MS ES+(m/z):(M+H) + :423.16。
Example 25N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide
TOF MS ES+(m/z):(M+H) + :448.09。
Example 26 2-fluoro-N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide
TOF MS ES+(m/z):(M+H) + :466.08。
Example 27 (E) -4- (dimethylamino) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide
TOF MS ES+(m/z):(M+H) + :505.14。
Example 28 (E) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide
TOF MS ES+(m/z):(M+H) + :545.17。
Pharmacological investigation of the products of the invention
In vitro cytotoxic Activity
Pyrimidine and pyridine quinoline derivatives containing the general formulas I and II are subjected to in vitro activity screening for inhibiting lung cancer cells A549, breast cancer cells MCF-7, cervical cancer cells Hela and human normal cells LO2, and the reference substance is the omarotib.
(1) After resuscitating and passaging 2-3 times for stabilization, the cells were digested from the bottom of the flask with trypsin solution (0.25%). After pouring the cell digests into a centrifuge tube, the culture broth is then added to terminate digestion. Centrifuging the centrifuge tube at 800r/min for 10min, removing supernatant, adding 5mL of culture solution, blowing and mixing uniformly, sucking 10 μL of cell suspension, adding into a cell counting plate, counting, and adjusting cell concentration to 10 4 And/or holes. Except that the A1 well was blank, no cells were added, and 100. Mu.L of the cell suspension was added to the 96-well plate. The 96-well plate was placed in an incubator for cultivation for 24 hours.
(2) The test sample was dissolved with 50. Mu.L of dimethyl sulfoxide, then an appropriate amount of culture solution was added to dissolve the sample into 2mg/mL of a liquid medicine, and then the sample was diluted to 20,4,0.8,0.16,0.032. Mu.g/mL in a 24-well plate.
3 wells were added at each concentration, with two rows and two columns surrounding the well, which had greater environmental impact, and were used only with blank wells. The 96-well plate was placed in an incubator for culturing for 72 hours.
(3) The medicated culture solution in the 96-well plate was discarded, the cells were washed twice with Phosphate Buffered Saline (PBS), 100. Mu.L of MTT (tetrazolium) (0.5 mg/mL) was added to each well, and after 4 hours in the incubator, the MTT solution was discarded, and 100. Mu.L of dimethyl sulfoxide was added. And (3) oscillating on a magnetic oscillator to enable the living cells and MTT reaction product formazan to be fully dissolved, and putting the dissolved cells and MTT reaction product formazan into an enzyme-labeled instrument to measure the result. Drug IC can be determined by the Bliss method 50 Values.
Results of the compounds in inhibiting the activity of lung cancer cell A549, breast cancer cell MCF-7, cervical cancer cell Hela and human normal cell LO2 (see Table 2).
EGFR kinase Activity assay
IC of new synthesized compound for inhibiting various cancer cells is tested by using HMF technology with HMTIB as positive control 50 Values, and test the inhibition of EGFR by a portion of the compounds.
The specific method comprises the following steps: preparing working solutions of ATP, TK Substrate biotin and Kinase buffer with required concentrations, and taking and mixing the ATP, TK Substrate biotin and Kinase buffer uniformly according to a volume ratio of 2:2:2; diluting the medicine with Kinase buffer to prepare the medicine with the required concentration; preparing EGFR enzyme working solution. In a white 384-well plate, 6. Mu.L of the mixture, 2. Mu.L of the drug, 2. Mu.L of the kinase were added to each well, and the mixture was allowed to react at 37℃for 30 minutes. Then 5. Mu.L of streptokinin-labeled XL-665 and 5. Mu.L of Eu3+ conjugated cryptate antibody were added and mixed. After being placed for 30min at room temperature, the enzyme label instrument is excited at 314nm, fluorescence at 665 nm and 620nm wavelength is detected, the kinase inhibition rate is calculated, and the IC of each medicine is calculated by using the Bliss method according to the absorbance 50 Values.
Inhibition (%) = (Ratio 665/620 control well-Ratio 665/620 dosing well)/Ratio 665/620 control well x 100%.
The experimental data are expressed as mean value +/-standard deviation, the significance test between the groups of the metering data adopts single-factor analysis of variance, the comparison between every two groups adopts t test, p <0.05 is significant difference, and p <0.01 is very significant difference.
TABLE 2 in vitro antitumor Activity of partial target Compounds
TABLE 3 partial target compound enzyme Activity
As is clear from the test results, the compounds of the general formulas I and II to be protected by the invention have good in vitro anti-cell proliferation activity and anti-EGFR kinase activity, the toxicity of all target compounds to human normal cells LO2 is lower than that of the omatinib, and the inhibition activity of part of the compounds to L858R/T790M double mutant cell lung cancer cells H1975 is better than that of the omatinib. From the data in the above table, it can be seen that the example compounds have a certain selectivity for EGFR double mutant kinase over anti-EGFR wild type kinase activity, which also demonstrates that the example compounds are targeted well and have high selectivity as in examples 1 and 6. It follows that the compounds of formulae I and II of the present invention may be potential EGFR inhibitors.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Application example 1: capsule preparation
10g of the compound of example 9 is mixed with 20g of auxiliary materials according to the requirement of pharmaceutical capsules, and the mixture is filled into hollow capsules, wherein each capsule weighs 300mg.
Application example 2: tablet formulation
10g of the compound of example 3 is added with 20g of auxiliary materials according to a common pharmaceutical tabletting method, and the mixture is uniformly mixed, and then 100 tablets are pressed, wherein each tablet weighs 300mg.
Application example 3 ointment
The compound of example 4 was prepared by grinding 10g of the compound and mixing with 500g of an oily base such as vaseline.
While the invention has been described in terms of specific embodiments, modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Application example 4: aerosol formulation
10g of the compound of example 9 was dissolved in an appropriate amount of propylene glycol, and distilled water and other radiation materials were added thereto to prepare 500mL of a clear solution.
Application example 5 dripping pill
10g of the compound of example 12 and 50g of matrix such as gelatin are heated, melted and mixed uniformly, and then dripped into low-temperature liquid paraffin to prepare 1000 pills.
Application example 6 external linimentum
10g of the compound of example 16 is mixed and ground with 2.5g of auxiliary materials such as an emulsifier and the like according to a conventional pharmaceutical method, and distilled water is added to 200mL to prepare the compound.
Application example 7 film agent
With 10g of the compound of example 19, polyvinyl alcohol, medicinal glycerol, water and the like are stirred and expanded, then heated and dissolved, a 80-mesh screen is used for filtering, and then the compound of example 14 is added into the filtrate and stirred and dissolved, and a film is coated on 100 films.
Application example 8 suppository
10g of the compound of example 24 was ground, added with an appropriate amount of glycerin, uniformly ground, added with melted glycerogelatin, uniformly ground, and poured into a lubricant-coated mold to prepare 10 suppository particles.
Claims (10)
1. The 2-aminopyrimidine heterocyclic compound is characterized by having a structure shown in the following general formula I or II:
wherein the fused ring on which the X ring is located is selected from:
R 1 selected from five-membered or six-membered heterocyclic, aromatic or heteroaromatic rings containing 1-3 groups selected from hydrogen, halogen, trifluoromethyl, cyano, methoxy or C 1 ～C 4 Substituents of alkyl;
R 2 selected from hydrogen, C 1 ～C 4 Alkyl or halogen;
R 3 selected from hydrogen, C 1 ～C 10 Alkyl, C 3 ～C 10 Cycloalkyl, C 1 ～C 4 An alcoholic hydroxyl group,
R 4 、R 5 Identical or different, each independently selected from C 1 ～C 6 Alkyl, C 3 ～C 6 Cycloalkyl, hydroxyethyl, mercaptoethyl; alternatively, R 4 And R is 5 Together with the nitrogen atom to which they are attached, form a 5-to 10-membered saturated heterocyclic group which, apart from R 4 And R is 5 Optionally containing 1 to 3 heteroatoms selected from O, N and S in addition to the attached nitrogen atom; n is 0 to 3.
2. The 2-aminopyrimidine heterocyclic compound as described in claim 1, wherein,
R 1 selected from:
wherein R is 6 Selected from hydrogen, halogen, trifluoromethyl, cyano, nitro, hydroxy, amino, mercaptoA group, carboxyl, trifluoromethoxy, methyl, ethyl, propyl, butyl, cyclopropane, ethylene, propylene, acetylene, propyne, methoxy, ethoxy, propoxy, isopropoxy, butoxy or azido group;
R 7 selected from halogen, hydroxy, trifluoromethyl, trifluoromethoxy, amino, azido, cyano, mercapto, C 1 ～C 4 Alkyl, C 3 ～C 6 Cycloalkyl, C 1 ～C 4 Alkenyl, C 1 ～C 4 Alkynyl, C 1 ～C 4 An alkoxy group.
3. 2-aminopyrimidine heterocycles according to claim 2, characterized in that R 1 Selected from benzene rings or pyridines containing 1 methoxy substituent.
4. The 2-aminopyrimidine heterocyclic compound according to claim 1, wherein:
-R 2 (CH) 2 R 3 selected from:
5. the 2-aminopyrimidine heterocyclic compound according to claim 4, wherein R 2 Selected from H or F.
6. The 2-aminopyrimidine heterocyclic compound according to claim 4, wherein R 3 Selected from methyl, ethyl, isopropyl, hydrogen or propyl.
7. The 2-aminopyrimidine heterocyclic compound according to claim 1, wherein: the compounds of the general formulas I and II are one selected from the following compounds:
n- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) but-2-enamide;
n- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -3-methyl-2-enamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4-methylpent-2-enamide;
(E) -N- (3- ((2- ((3-cyanophenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) hex-2-amide;
n- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
2-fluoro-N- (3- ((2- ((3-methoxyphenyl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -4- (dimethylamino) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide;
(E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide;
n- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -N- (3- ((2- ((1-methyl-1H-pyrazol-3-yl) amino) -6, 7-dihydrothiophen [3,2-d ] pyrimidin-4-yl) oxy) phenyl) -pent-2-enamide;
n- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
2-fluoro-N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) acrylamide;
(E) -4- (dimethylamino) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -but-2-enamide;
(E) -N- (3- ((2- ((2-mercaptopyridin-4-yl) amino) -6- (thiophen-2-yl) pyrimidin-4-yl) oxy) phenyl) -4- (piperidin-1-yl) -but-2-enamide.
8. Use of a 2-aminopyrimidine heterocyclic compound as described in any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of prostate cancer.
9. Use of a 2-aminopyrimidine heterocyclic compound as described in any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of lung cancer.
10. Use of a 2-aminopyrimidine heterocyclic compound according to any one of claims 1 to 7 for the preparation of a medicament for the treatment and/or prophylaxis of cervical cancer.
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