5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives, processes for their preparation and use

Abstract

The present application relates to 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives and pharmaceutically acceptable salts thereof shown in chemical structural formula I, pharmaceutical compositions and their applications in preparing antitumor drugs: wherein, R is selected from: 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-methoxy, 2-hydroxy-6-methoxy, 3-hydroxy-2-methoxy, 3-hydroxy-4-methoxy, 3-hydroxy-5-methoxy, 3-hydroxy-6-methoxy, 4-hydroxy-2-methoxy, 4-hydroxy-3-methoxy, 4-hydroxy-3,5-dimethoxy, 2,3,4-trimethoxy or 3,4,5-trimethoxy.

Description

TECHNICAL FIELD

[0001] The present application relates to a kind of new compounds, its preparation method and application, specifically 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative and its preparation method and application, its preparation method and its application as antitumor drug. BACKGROUND

[0002] The application of ester compounds is very wide, and is related to the fields of drugs, agriculture, spices, materials, food, etc., such as the main component of traditional Chinese medicine toad venom is bufadienolides compound, studies have shown that bufadienolides compound has certain inhibitory activity on liver cancer, non-small cell lung cancer, breast cancer and other malignant tumors [Oncology Letters, 2012, 4(4):792-798].

[0003] In 2010, Qian et al. [Bioorganic & Medicinal Chemistry, 2010, 18(14): 4991-4996] designed and synthesized a series of cinnamic acid metronidazole ester derivatives, and evaluated their biological activity as potential EGFR and HER-2 kinase inhibitors, wherein compound A1 has certain anti-proliferative activity on MCF-7, and the IC 50 value is 3.76 μM.

[0004]

[0005] In 2019, Cheremnykh et al. [Medicinal Chemistry Research, 2019, 28: 545-558] designed and synthesized a series of 2,4,6-trisubstituted pyrimidine compounds with carbamate groups by using one-pot multi-component method, and evaluated their cytotoxic activity on cancer cell lines using MTT method, wherein the trisubstituted pyrimidine compound A2 shows certain growth inhibitory activity on breast cancer cell line MDA-MB-231 and human prostate cell line DU-145, and the GI 50 value is 10.08 and 12.14 μM, respectively.

[0006] SUMMARY

[0007] The technical problem solved by the present application is to provide 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives, their preparation method, pharmaceutical composition and use.

[0008] To solve the technical problem of the present application, the present application provides the following technical solutions:

[0009] The first aspect of the technical scheme of the present application provides a kind of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives and its pharmaceutically acceptable salt as shown in structural formula I:

[0010]

[0011] Wherein, R is selected from: 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-methoxy, 2-hydroxy-6-methoxy, 3-hydroxy-2-methoxy, 3-hydroxy-4-methoxy, 3-hydroxy-5-methoxy, 3-hydroxy-6-methoxy, 4-hydroxy-2-methoxy, 4-hydroxy-3-methoxy, 4-hydroxy-3,5-dimethoxy, 2,3,4-trimethoxy or 3,4,5-trimethoxy.

[0012] Further, preferred compounds are selected from the group consisting of 2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2,3-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2,4-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3,4-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2-hydroxy-3-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2-hydroxy-4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2-hydroxy-5-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2-hydroxy-6-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3-hydroxy-2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3-hydroxy-4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3-hydroxy-5-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3-hydroxy-6-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 4-hydroxy-2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 4-hydroxy-3-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 4-hydroxy-3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 2,3,4-trimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate or 3,4,5-trimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate.

[0013] The second aspect of the present application is to provide a method for preparing 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives, characterized in that the preparation reaction is as follows:

[0014]

[0015] wherein R is selected from 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-methoxy, 2-hydroxy-6-methoxy, 3-hydroxy-2-methoxy, 3-hydroxy-4-methoxy, 3-hydroxy-5-methoxy, 3-hydroxy-6-methoxy, 4-hydroxy-2-methoxy, 4-hydroxy-3-methoxy, 4-hydroxy-3,5-dimethoxy, 2,3,4-trimethoxy or 3,4,5-trimethoxy.

[0016] The third aspect of the present application is to provide a pharmaceutical composition containing the compound of the first aspect and its pharmaceutically acceptable salt, which contains a therapeutically effective amount of the 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative of the present application and its pharmaceutically acceptable salt, and optionally contains a pharmaceutical carrier. The pharmaceutical carrier mentioned herein refers to the pharmaceutical carrier commonly used in the pharmaceutical field; the pharmaceutical composition can be prepared according to the methods known in the art. The compound of the present application and its pharmaceutically acceptable salt can be combined with one or more pharmaceutically acceptable solid or liquid excipients and / or adjuvants to form any dosage form suitable for human or animal use. The content of the compound of the present application and its pharmaceutically acceptable salt in its pharmaceutical composition is usually 0.1% to 95% by weight.

[0017] The compound of the present application and its pharmaceutically acceptable salt or the pharmaceutical composition containing it can be administered in unit dosage form, and the administration route can be enteral or parenteral, such as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum, etc.

[0018] The administration form can be a liquid form, a solid form or a semi-solid form. The liquid form can be a solution (including true solution and colloidal solution), an emulsion (including o / w type, w / o type and multiple emulsion), a suspension, an injection (including water injection, powder injection and infusion), eye drops, nose drops, lotion and liniment, etc.; the solid form can be a tablet (including ordinary tablet, enteric-coated tablet, chewable tablet, dispersible tablet, effervescent tablet, mouth disintegrating tablet), a capsule (including hard capsule, soft capsule, enteric-coated capsule), a granule, a powder, a pellet, a drop, a suppository, a film, a patch, an aerosol (powder) mist, a spray, etc.; the semi-solid form can be an ointment, a gel, a paste, etc.

[0019] The compound of the present application and the pharmaceutically acceptable salt thereof can be prepared into a common preparation, a sustained-release preparation, a controlled-release preparation, a targeted preparation and various micro-particle administration systems.

[0020] In order to prepare the compound of the present application and the pharmaceutically acceptable salt thereof into a tablet, various excipients known in the art can be widely used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluents can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the wetting agents can be water, ethanol, isopropyl alcohol, etc.; the binders can be starch paste, dextrin, sugar syrup, honey, glucose solution, microcrystalline cellulose, acacia paste, gelatin paste, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, acrylic resin, carbomer, polyvinyl pyrrolidone, polyethylene glycol, etc.; the disintegrants can be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfonate, etc.; the lubricants and glidants can be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, etc.

[0021] The tablet can be further prepared into a coated tablet, such as a sugar-coated tablet, a film-coated tablet, an enteric-coated tablet, or a double-layer tablet and a multi-layer tablet.

[0022] In order to prepare the administration unit into a capsule, the effective ingredient, the compound of the present application and the pharmaceutically acceptable salt thereof, can be mixed with diluents and glidants, and the mixture can be directly placed into a hard capsule or a soft capsule. The effective ingredient, the compound of the present application and the pharmaceutically acceptable salt thereof, can also be first mixed with diluents, binders and disintegrants to prepare granules or pellets, and then placed into a hard capsule or a soft capsule. The various diluents, binders, wetting agents, disintegrants and glidants used for preparing the tablet of the compound of the present application and the pharmaceutically acceptable salt thereof can also be used for preparing the capsule of the compound of the present application and the pharmaceutically acceptable salt thereof.

[0023] For preparing injection of the compound of the present application and its pharmaceutically acceptable salt, water, ethanol, isopropyl alcohol, propylene glycol or their mixture can be used as solvent and proper amount of solubilizer, co-solubilizer, pH regulator, osmotic pressure regulator commonly used in the art can be added. The solubilizer or co-solubilizer can be poloxamer, lecithin, hydroxypropyl-β-cyclodextrin and the like; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like. If lyophilized powder injection is prepared, mannitol, glucose and the like can also be added as supporting agent.

[0024] In addition, if necessary, coloring agent, preservative, flavoring agent, odorant or other additive can also be added to the pharmaceutical preparation.

[0025] For achieving the purpose of administration and enhancing the therapeutic effect, the pharmaceutical or pharmaceutical composition of the present application can be administered by any known administration method.

[0026] The fourth aspect of the technical solution of the present application is to provide the use of the 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative and its pharmaceutically acceptable salt and the pharmaceutical composition of the third aspect in preparing antitumor drugs.

[0027] Beneficial technical effects:

[0028] The 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative of the present application is a novel compound with antitumor activity. DETAILED DESCRIPTION

[0029] The following examples are intended to illustrate the present application rather than further limit it.

[0030] Example 1

[0031] A 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative, whose molecular formula is as follows:

[0032]

[0033] wherein R is selected from 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-methoxy, 2-hydroxy-6-methoxy, 3-hydroxy-2-methoxy, 3-hydroxy-4-methoxy, 3-hydroxy-5-methoxy, 3-hydroxy-6-methoxy, 4-hydroxy-2-methoxy, 4-hydroxy-3-methoxy, 4-hydroxy-3,5-dimethoxy, 2,3,4-trimethoxy or 3,4,5-trimethoxy.

[0034] Example 2

[0035] Preparation of 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid

[0036]

[0037] Dissolve 20.0 mmol of potassium hydroxide in 10 mL of water solution under stirring at room temperature, then add 5.0 mmol of 5-fluorouracil, continue to stir until it dissolves, then raise the temperature to 80°C, slowly add 7.5 mmol of bromoacetic acid, and continue to stir for 10 h. Monitor the reaction progress by TLC. Cool the reaction solution to room temperature, adjust the pH to 2-3 with concentrated hydrochloric acid, remove water from the reaction solution by rotary evaporation under reduced pressure, recrystallize the crude product with an appropriate amount of ethanol, filter and dry to obtain 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid, white solid, melting point > 250°C, yield 92%.

[0038] Example 3

[0039] Preparation of 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)- yl)acetate (M1)

[0040]

[0041] Dissolve 2.0 mmol of 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetic acid, 4.0 mmol of 2,6-dimethoxyphenol and 4.0 mmol of N,N-dicyclohexylcarbodiimide (DCC) in 30 mL of anhydrous dichloromethane solution, and stir at room temperature for 24 h. Monitor the reaction progress by TLC. Filter the reaction mixture, wash the filter cake with an appropriate amount of dichloromethane 3 times, extract the filtrate with water 3 times, concentrate the organic phase by rotary evaporation, and purify the crude product by silica gel column chromatography to obtain 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetate (M1), white solid, melting point 173-175°C, yield 92%. 1H NMR (500 MHz, DMSO-d6) δ: 11.86 (s, 1H, NH), 7.92 (d, J = 6.6 Hz, 1H, C4HN2), 7.19 (d, J = 8.4 Hz, 1H, C6H3), 6.75 (d, J = 8.4 Hz, 2H, C6H3), 4.78 (s, 2H, COCH2), 3.75 (s, 6H, di-OCH3).

[0042] Example 4

[0043] Preparation of 4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate (M2)

[0044]

[0045] 2.0 mmol 2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate, 3.0 mmol 4-methoxyphenol and 3.0 mmol N,N-dicyclohexylcarbodiimide (DCC) were dissolved in 30 mL of anhydrous dichloromethane solution, and the reaction was stirred at room temperature for 24 h, and the reaction progress was monitored by TLC. The reaction mixture was suction filtered, the filter cake was washed with an appropriate amount of dichloromethane for 3 times, the filtrate was extracted with water for 3 times, the organic phase was concentrated by rotary evaporation, and the crude product was purified by silica gel column chromatography and dried to obtain 4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl) acetate (M2), white solid, melting point 177-179 °C, yield 83%. 1 H NMR (500 MHz, DMSO-d6) δ: 12.01 (s, 1H, NH), 8.16 (d, J = 6.7 Hz, 1H, C4HN2), 7.08 (d, J = 6.9 Hz, 2H, C6H4), 6.98 (d, J = 6.9 Hz, 2H, C6H4), 4.74 (s, 2H, COCH2), 3.75 (s, 3H, OCH3).

[0046] Example 5

[0047] Antitumor activity of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives

[0048] 1. Principle of antitumor activity experiment

[0049] In living cells, mitochondria contain succinate dehydrogenase, which reduces exogenous MTT to insoluble blue-purple crystalline formazan, which then deposits within the cell. Dead cells lack this ability. Dimethyl sulfoxide (DMSO) can dissolve the purple crystals in cells; the absorbance at 490 nm using an enzyme-linked immunosorbent assay (ELISA) scanner indirectly reflects cell number. Within a certain cell number range, the amount of MTT crystals formed is directly proportional to the cell number.

[0050] 2. Experimental methods for antitumor activity

[0051] Cell lines: 4T1 (mouse breast cancer cells) and TPC-1 (human papilloma thyroid cancer cells), donated by the Laboratory of Modern Engineering and Applied Science, Nanjing University.

[0052] Reagents: Thiazol blue (MTT), RPMI 1640 culture medium containing antibiotics (Nanjing Kaiji Biotechnology Development Co., Ltd.), fetal bovine serum (Zhejiang Tianhang Biotechnology Co., Ltd.), trypsin (Nanjing Kaiji Biotechnology Development Co., Ltd.), 96-well culture plate (Wuxi Nais Life Science Co., Ltd.), dimethyl sulfoxide (Sigma (Shanghai) Co., Ltd.).

[0053] Instruments: 1300 series A2 biosafety cabinet (Thermo Scientific, USA), CLM-170B-8-CN CO2 incubator (ESCO), BDS400 inverted microscope (Chongqing Aote Optical Instrument Co., Ltd.), Multiskan GO microplate reader (Thermo Scientific, USA), ultrapure water preparation system (Milli-Q, USA).

[0054] Experimental Procedure: The samples were tested against 4T1 (mouse breast cancer cells) and TPC-1 (human papilloma-thyroid cancer cells). In one experiment, seven concentration gradients were set for each sample (2500 ng / L, 1250 ng / L, 625 ng / L, 312.5 ng / L, 156 ng / L, 78 ng / L, and 39 ng / L). The drugs were dissolved in DMSO and incubated for 72 hours. Four parallel samples were used for each concentration, and each experiment was repeated in triplicate. A blank control was used for the conclusion. The OD value of each well was measured using a microplate reader at a wavelength of 490 nm.

[0055] 3. Sample to be tested: Compound 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate

[0056] 4. Evaluation of antitumor activity

[0057] 4T1 (mouse breast cancer cells) and TPC-1 (human papillomathyroid carcinoma cells) cells were incubated with the drug dissolved in DMSO for 72 hours. Cell viability was detected by the MTT assay. The results showed that compound 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate had significant cytotoxicity to cancer cells, with an IC50 of [missing value] against both 4T1 (mouse breast cancer cells) and TPC-1 (human papillomathyroid carcinoma cells). 50 The values ​​are listed in Table 1.

[0058] Table 1. IC50 of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives on 4T1 and TPC-1 cells 50

[0059]

[0060]

[0061] Activity test results showed that the 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative had good inhibitory activity against breast cancer 4T1 cells and human papillomatous thyroid carcinoma TPC-1 cells, and could be used to prepare antitumor drugs.

Claims

1. A class of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives of chemical structural formula I and their pharmaceutically acceptable salts: in, R is selected from: 2-methoxy, 3-methoxy, 4-methoxy, 2,3-dimethoxy, 2,4-dimethoxy, 2,5-dimethoxy, 2,6-dimethoxy, 3,4-dimethoxy, 3,5-dimethoxy, 2-hydroxy-3-methoxy, 2-hydroxy-4-methoxy, 2-hydroxy-5-methoxy, 2-hydroxy-6-methoxy, 3-hydroxy-2-methoxy, 3-hydroxy-4-methoxy, 3-hydroxy-5-methoxy, 3-hydroxy-6-methoxy, 4-hydroxy-2-methoxy, 4-hydroxy-3-methoxy, 4-hydroxy-3,5-dimethoxy, 2,3,4-trimethoxy, or 3,4,5-trimethoxy.

2. A class of 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivatives and their pharmaceutically acceptable salts, selected from the following compounds: 2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) acetate, 3-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) acetate, 4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) acetate, 2,3-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-yl) acetate, 2,4-dimethoxyphenyl-2-(5-fluoro- 2,4-Dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 2,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 2,6-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 3,4-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 2-hydroxy-3-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3)-yl) acetate 4-Dihydropyrimidin-1(2H)-yl) acetate, 2-hydroxy-4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 2-hydroxy-5-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 2-hydroxy-6-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 3-hydroxy-2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 3-hydroxy-4-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate -dihydropyrimidin-1(2H)-yl) acetate, 3-hydroxy-5-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 3-hydroxy-6-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 4-hydroxy-2-methoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 4-hydroxy-3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 4-hydroxy-3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, 4-hydroxy-3,5-dimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate4-Dihydropyrimidin-1(2H)-yl) acetate, 2,3,4-trimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate, or 3,4,5-trimethoxyphenyl-2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) acetate.

3. The method for preparing the 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative according to claim 1, characterized in that, Its preparation reaction is as follows: In the formula, R is defined as described in claim 1.

4. The use of the 5-fluoro-2,4-dioxo-3,4-dihydropyrimidine acetate derivative of claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of an antitumor drug.

5. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically usable carrier.

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