Compound based on 6-methylfuro [2, 3-d] pyrimidine-4 (3H)-ketone structure and preparation method and application thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a compound based on a 6-methylfuro [2, 3-d] pyrimidine-4 (3H)-ketone structure and a preparation method and application thereof. According to the compound based on the 6-methylfuro [2, 3-d] pyrimidine-4 (3H)-one structure, a pharmacophore of a DNA methyltransferase 3A inhibitor is spliced with a hydroxamic acid fragment, the chelation of the compound and zinc ions in histone deacetylase is increased, and the compound shows a relatively strong HDAC inhibition effect while keeping the inhibition effect on DNMT3A. The inhibitory activity of the compound provided by the invention on human non-small cell lung cancer cells H460 is far higher than that of H460DNMT3A-HDAC6 double knockout cells, and the compound shows the activity of resisting human non-small cell lung cancer in vivo, and has application value as a drug therapeutic agent for treating diseases and disorders related to DNMT3A and HADC6.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and specifically relates to a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure, a preparation method and an application thereof. Background Art

[0002] Epigenetic regulation is closely related to the occurrence, progression and drug resistance of tumors. Currently, a variety of drugs targeting epigenetic enzymes have been approved by the FDA and used for cancer treatment. For example, the DNA methyltransferase inhibitor 5-Azacytidine (5-AzaC) is used to treat myelodysplastic syndrome and acute myeloid leukemia, and histone deacetylase (HDAC) inhibitors (such as Vorinostat, Belinostat and Romidepsin) have been approved for the treatment of cutaneous and peripheral T-cell lymphomas.

[0003] In 2022, researchers found that the non-nucleoside DNA methyltransferase 3A (DNMT3A) inhibitor DY-46 has high activity (IC 50 =1.3±0.22 μM) and high selectivity, which can occupy the SAM-cofactor pocket and cytosine pocket of DNMT3A. Its analog DY-46-2 has an IC of 1. 50 The concentration of DY-46-2 in the 24-nitropropene molecule was 0.39±0.23 μM, showing excellent selectivity relative to DNMT1 (33.3 times), DNMT3B (269 times) and G9a (more than 1000 times). DY-46 and DY-46-2 significantly inhibited cancer cell proliferation [Zhang J, et al. Cancers (Basel), 2020, 12 (8). 11-16].

[0004] In cells lacking DNMT3A, histone deacetylase 6 (HDAC6) is significantly upregulated, which may be one of the reasons why single DNMT inhibitors are mainly used to treat leukemia and are accompanied by more adverse reactions. How to develop dual-target inhibitors that selectively target DNMT3A and HDAC6 to provide a synergistic effect for therapeutic applications is still a blank. Summary of the invention

[0005] The object of the present invention is to provide a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure and a preparation method and application thereof. The compound provided by the present invention has a strong DMNT3A inhibitory effect and HDAC6 inhibitory effect.

[0006] In order to achieve the above object, the present invention provides the following technical solutions:

[0007] The present invention provides a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure, the structure of which is shown in Formula I:

[0008]

[0009] In formula I, R is amino, substituted amino, hydroxyl or alkoxy; L is a benzene ring, a substituted benzene ring, an aromatic heterocycle, a substituted aromatic heterocycle or an alkyl chain; and n is 1, 2, 3 or 4.

[0010] Preferably, in R described in Formula I, the substituted amino group includes any one of the following structural groups;

[0011]

[0012] The alkoxy group includes a methoxy group or an ethoxy group.

[0013] Preferably, in L described in Formula I, the substituted benzene ring is:

[0014]

[0015] The aromatic heterocycle is:

[0016]

[0017] The substituted aromatic heterocycles include:

[0018]

[0019] The alkyl chain is:

[0020]

[0021] Preferably, the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure includes any one of the following structural compounds:

[0022]

[0023]

[0024] The present invention also provides a method for preparing the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure described in the above scheme, comprising the following steps:

[0025] (1) mixing 2-chloro-3-oxobutyric acid acetic acid and malononitrile to carry out a cyclization reaction to obtain a compound with a structure shown in Formula II;

[0026] (2) mixing the compound of formula II with formic acid and acetic anhydride to carry out a cyclization reaction to obtain a compound of formula III;

[0027] (3) mixing the compound having a structure represented by Formula III with a substituted alkane, a first basic compound and a first organic solvent to carry out a substitution reaction to obtain a compound having a structure represented by Formula IV;

[0028] (4) mixing the compound of formula IV with a substituted amine, a second basic compound and a second organic solvent to carry out a substitution reaction to obtain a compound of formula V;

[0029] The structural formula of the substituted amine is shown in Formula VIII:

[0030] RH type VIII;

[0031] (5) mixing the compound of formula V with a third basic compound and a third solvent to carry out a hydrolysis reaction to obtain a compound of formula VI;

[0032] (6) mixing the compound of formula VI with an amino-substituted carboxylic acid ester, a condensing agent and a fourth organic solvent to carry out a condensation reaction to obtain a compound of formula VII;

[0033] (7) mixing the compound of the structure represented by Formula VII with hydroxylamine, water, a fourth basic compound and a fifth organic solvent to carry out a hydroxylamine reaction to obtain the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure;

[0034]

[0035] Preferably, the molar ratio of the compound of the structure represented by formula II to formic acid is 1:10-30; the molar ratio of the compound of the structure represented by formula II to acetic anhydride is 1:5-10.

[0036] Preferably, the molar ratio of the compound of formula III to the substituted alkane is 1:3-10; the molar ratio of the compound of formula III to the first basic compound is 1:1.2-5; the mass volume ratio of the compound of formula III to the first organic solvent is 1:5-30.

[0037] Preferably, the molar ratio of the compound of formula VI to the amino-substituted carboxylate is 1:0.8-1.2; the molar ratio of the compound of formula VI to the condensing agent is 1:1-2; the mass volume ratio of the compound of formula VI to the fourth organic solvent is 1:5-50.

[0038] Preferably, the mass ratio of hydroxylamine to water is 1:1-10; the molar ratio of the compound of the structure represented by formula VII to hydroxylamine is 1:20-100; the molar ratio of the compound of the structure represented by formula VII to the fourth basic compound is 1:5-20; the mass volume ratio of the compound of the structure represented by formula VII to the fifth organic solvent is 1:5-50.

[0039] The present invention also provides the use of the compound based on the 6-methylfurano[2,3-d]pyrimidine-4(3H)-one structure described in the above scheme or the compound based on the 6-methylfurano[2,3-d]pyrimidine-4(3H)-one structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases related to DNA methyltransferase 3A or histone deacetylase.

[0040] The present invention provides a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure. The compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure provided by the present invention combines the pharmacophore of a DNA methyltransferase 3A (DNMT3A) inhibitor with a hydroxamic acid fragment to increase the chelation of the compound with zinc ions in histone deacetylase (HDAC), thereby maintaining an inhibitory effect on DNMT3A while exhibiting a strong HDAC inhibitory effect.

[0041] The present invention also provides a method for preparing the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure described in the above scheme. The preparation method provided by the present invention has simple steps, convenient operation, high feasibility, and has the prospect of large-scale industrialization.

[0042] The present invention also provides the use of the compound based on the 6-methylfurano[2,3-d]pyrimidine-4(3H)-one structure described in the above scheme in the preparation of a drug for treating diseases related to DNA methyltransferase 3A or histone deacetylase. The compound provided by the present invention exhibits selectivity for DNMT3A and HDAC6, and has strong DMNT3A inhibition and HDAC6 inhibition. The inhibitory activity on human non-small cell lung cancer cells H460 is much higher than that on H460 DNMT3A-HDAC6 double knockout cells, and exhibits anti-human non-small cell lung cancer activity in vivo, and has application value as a drug therapeutic agent for treating diseases and disorders related to DNMT3A and HADC6. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings required for use in the embodiments will be briefly introduced below. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying creative work.

[0044] Figure 1 Cellular thermal shift analysis of compound FQX-1D;

[0045] Figure 2 Methylation dot blot analysis of compound FQX-1D;

[0046] Figure 3 is the expression level of Ac-α-tubulin in H460 cells treated with compound FQX-1D;

[0047] Figure 4 This is the enzyme activity test of compound FQX-1D. DETAILED DESCRIPTION

[0048] The present invention provides a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure, the structure of which is shown in Formula I:

[0049]

[0050] Wherein, R is amino, substituted amino, hydroxyl or alkoxy; L is a benzene ring, substituted benzene ring, aromatic heterocycle, substituted aromatic heterocycle or alkyl chain; and n is 1, 2, 3 or 4.

[0051] In the present invention, in R described in formula I, the structure of the substituted amino group is preferably -NR1R2; the R1 and R2 independently preferably include C1~C6 alkyl, substituted C1~C6 alkyl, C1~C6 alkenyl, substituted C1~C6 alkenyl, C3~C20 cycloalkyl, substituted C3~C20 cycloalkyl, 3~20-membered heterocyclic group or substituted 3~20-membered heterocyclic group, or the R1 and R2 preferably jointly form C3~C20 cycloalkyl, substituted C3~C20 cycloalkyl, 3~20-membered heterocyclic group or substituted 3~20-membered heterocyclic group.

[0052] In the present invention, the C1-C6 alkyl in R1 and R2 preferably includes methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl or isopentyl; the C1-C6 alkenyl preferably includes allyl; the structure of the C3-C20 cycloalkyl is preferably monocyclic, polycyclic, spirocyclic or bridged; the C3-C20 cycloalkyl preferably includes cyclopentyl, cyclohexyl, methyl-substituted cyclohexyl, cycloheptyl or cyclooctyl; the structure of the 3-20 membered heterocyclic group is preferably monocyclic, polycyclic, spirocyclic or bridged; the heteroatoms in the 3-20 membered heterocyclic group preferably include one or more of N, O and S; the number of heteroatoms in the 3-20 membered heterocyclic group is preferably 1-5, specifically 1, 2, 3, 4 or 5; the 3-20 membered heterocyclic group preferably includes pyrrolidinyl, morpholinyl, piperazinyl, methyl-substituted piperazinyl or azacycloheptyl.

[0053] In the present invention, the number of substituents (substitution means that one or more hydrogen atoms on the group are replaced by a substituent) of the substituted C1-C6 alkyl, substituted C1-C6 alkenyl, substituted C3-C20 cycloalkyl and substituted 3-20 membered heterocyclic group in R1 and R2 is preferably 1 or more, specifically 1, 2 or 3; the number of substituents of the substituted C1-C6 alkyl, substituted C1-C6 alkenyl, substituted C3-C20 cycloalkyl and substituted 3-20 membered heterocyclic group is independently Preferred groups include halogen, cyano, oxygen (i.e., two hydrogen atoms on the same carbon atom in the group are replaced by =O), C1~C6 alkyl, halogenated C1~C6 alkyl, C1~C6 alkoxy, C6~C10 aryl, C6~C10 aryloxy, C2~C10 ester, C2~C10 acyl, C2~C10 amide, carboxyl, nitro, hydroxyl, amino, one C1~C6 alkyl-substituted amino, two C1~C6 alkyl-substituted aminos or a C1~C6 alkyl-substituted thiol.

[0054] In the present invention, the halogen preferably includes fluorine, chlorine or bromine; the C1~C6 alkyl preferably includes methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, n-butyl, n-pentyl or isopentyl; the halogenated C1~C6 alkyl preferably includes trifluoromethyl, 2-chloroethyl or 3-chloropropyl; the C1~C6 alkoxy preferably includes methoxy, ethoxy, isopropoxy or trifluoromethoxy; the C6~C10 aryl preferably includes phenyl; the C6~C10 aryloxy preferably includes phenoxy; the C2~C10 ester group preferably includes alkyl-COO- or alkyl-OOC-; the alkyl-COO- preferably includes -CH2COO- or -CH2CH2COO-; the alkyl-OOC- preferably includes CH3COO- or CH3CH2COO-; the The C2~C10 acyl group is preferably an alkyl-CO- group; the alkyl-CO- group preferably includes CH3CO- or CH3CH2CO-; the C2~C10 amide group preferably includes an alkyl NHC(O)- or an aryl NHC(O)- group; the alkyl NHC(O)- group preferably includes CH3NHCO-, (CH3)2NCO- or CH3CH2NHCO-; the aryl NHC(O)- group preferably includes PhNHCO- or PhCH3NCO-; the one C1~C6 alkyl-substituted amino group preferably includes methylamino, ethylamino or isopropylamino; the two C1~C6 alkyl-substituted amino groups preferably include dimethylamino or diethylamino; the C1~C6 alkyl-substituted thiol group (C1~C6 alkyl-S-) preferably includes methylthio, ethylthio or isopropylthio.

[0055] In a specific embodiment of the present invention, in R described in Formula I, the substituted amino group preferably includes any one of the following structural groups;

[0056]

[0057] In the present invention, in R of Formula I, the alkoxy group preferably includes a methoxy group or an ethoxy group.

[0058] In the present invention, in L described in Formula I, the substituted benzene ring is preferably an alkyl substituted benzene ring; the alkyl substituted benzene ring is preferably a C1-C10 alkyl substituted benzene ring; the C1-C10 alkyl substituted benzene ring is preferably a methyl substituted benzene ring; the structural formula of the methyl substituted benzene ring is preferably:

[0059]

[0060] In the present invention, in L described in Formula I, the aromatic heterocycle is preferably a nitrogen-substituted aromatic heterocycle; the structural formula of the nitrogen-substituted aromatic heterocycle is preferably:

[0061]

[0062] In the present invention, in L described in Formula I, the substituted aromatic heterocycle is preferably an alkyl substituted aromatic heterocycle; the alkyl substituted aromatic heterocycle is preferably a C1-C8 alkyl substituted aromatic heterocycle, the C1-C8 alkyl substituted aromatic heterocycle is preferably a methyl substituted aromatic heterocycle; the structural formula of the methyl substituted aromatic heterocycle is preferably:

[0063]

[0064] In the present invention, in L described in Formula I, the alkyl chain is preferably a C1-C30 alkyl chain; the C1-C30 alkyl chain is preferably a C1-C8 alkyl chain; the C1-C8 alkyl chain is preferably a hexane chain; the structural formula of the hexane chain is:

[0065]

[0066] In the present invention, in Formula I, n is preferably 1, 2 or 3.

[0067] In the present invention, the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure preferably includes any one of the following structural compounds:

[0068]

[0069]

[0070] The present invention also provides a method for preparing the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure described in the above scheme, comprising the following steps:

[0071] (1) mixing 2-chloro-3-oxobutyric acid acetic acid and malononitrile to carry out a cyclization reaction to obtain a compound with a structure shown in Formula II;

[0072] (2) mixing the compound of formula II with formic acid and acetic anhydride to carry out a cyclization reaction to obtain a compound of formula III;

[0073] (3) mixing the compound of formula III with a substituted alkane, a basic compound and an organic solvent to carry out a substitution reaction to obtain a compound of formula IV;

[0074] (4) mixing the compound represented by the structure of Formula IV with a substituted amine, a basic compound and an organic solvent to carry out a substitution reaction to obtain a compound represented by the structure of Formula V;

[0075] The structural formula of the substituted amine is shown in Formula VIII:

[0076] RH type VIII;

[0077] (5) mixing the compound of formula V with a basic compound and a solvent to carry out a hydrolysis reaction to obtain a compound of formula VI;

[0078] (6) mixing the compound of formula VI with an amino-substituted carboxylic acid ester, a condensing agent and an organic solvent to carry out a condensation reaction to obtain a compound of formula VII;

[0079] (7) mixing the compound of the structure represented by Formula VII with hydroxylamine, water, an alkaline compound and an organic solvent to carry out a hydroxylamine reaction to obtain the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure;

[0080]

[0081] In the present invention, the meanings of the substituent groups (R and L) and the degree of polymerization (n) in each structural formula are consistent and will not be repeated here.

[0082] The present invention mixes 2-chloro-3-oxobutyric acid acetic acid and malononitrile (referred to as the first mixing) and performs a cyclization reaction (referred to as the first cyclization reaction) to obtain a compound having a structure shown in formula II. In the present invention, the molar ratio of the 2-chloro-3-oxobutyric acid acetic acid to malononitrile is preferably 1 to 1.1:1 to 1.5, and specifically can be 1:1, 1:1.2, 1:1.4, 1:1.5, 1.05:1, 1.05:1.2, 1.05:1.4, 1.05:1.5, 1.1:1, 1.1:1.1, 1.1:1.3 or 1.1:1.5.

[0083] In the present invention, the temperature of the first cyclization reaction is preferably room temperature, and the reaction time is preferably 4.5 to 8 hours, specifically 4.5 hours, 5 hours, 6 hours, 6.5 hours or 7 hours.

[0084] In the present invention, the first cyclization reaction is preferably carried out in the presence of an alcohol solvent and sodium ethoxide; the alcohol solvent is preferably ethanol; the volume mass ratio of the alcohol solvent to 2-chloro-3-oxobutyric acid acetic acid is preferably (5-20) mL:1 g, specifically 5 mL:1 g, 6 mL:1 g, 10 mL:1 g or 15 mL:1 g; the molar ratio of sodium ethoxide to 2-chloro-3-oxobutyric acid acetic acid is preferably 1-1.2:1-3, specifically 1:1, 1:2, 1:3, 1.1:3, 1.1:2, 1.1:1, 1:1.2, 1.2:1, 1.2:2 or 1.2:3.

[0085] In the present invention, after the first cyclization reaction, the reaction solution is preferably concentrated in sequence, the residue is redissolved and the solid-liquid separation is performed; the reagent used for the redissolution preferably includes petroleum ether and ethyl acetate; the volume ratio of petroleum ether and ethyl acetate is preferably 3:1; and the solid-liquid separation is preferably suction filtration.

[0086] In a specific embodiment of the present invention, the first mixing is preferably: ethyl 2-chloro-3-oxobutyrate, malononitrile and an alcohol solvent are premixed at -5 to -20°C to obtain a premixed solution, and then sodium ethoxide solution is added dropwise to the premixed solution while stirring; the concentration of the sodium ethoxide solution is preferably 5% to 18%, specifically 5%, 8%, 10%, 15% or 18%; the solvent of the sodium ethoxide solution preferably includes ethanol; the dropping rate of the stirring and dropping is preferably 20 to 60 drops / minute, specifically 30 drops / minute or 50 drops / minute.

[0087] After obtaining the compound of formula II, the present invention mixes the compound of formula II with formic acid and acetic anhydride to perform a cyclization reaction (referred to as the second cyclization reaction) to obtain a compound of formula III. In the present invention, the molar ratio of the compound of formula II to formic acid is preferably 1:10 to 30, specifically 1:12, 1:15, 1:20, 1:25 or 1:28.

[0088] In the present invention, the molar ratio of the compound of the structure represented by Formula II to acetic anhydride is preferably 1:5-10, specifically 1:6, 1:7, 1:8 or 1:9.

[0089] In the present invention, the second cyclization reaction is preferably carried out under reflux conditions, and the insulation time is preferably 36 to 60 hours, specifically 36 hours, 40 hours, 48 ​​hours, 52 hours or 56 hours.

[0090] In the present invention, after the second cyclization reaction, the steps preferably include sequentially concentrating the reaction solution, redissolving the residue, adjusting the pH value to 7, stirring and solid-liquid separation; the redissolving agent is preferably water; the pH adjusting agent is preferably a saturated sodium carbonate aqueous solution; the stirring temperature is preferably room temperature, and the stirring time is preferably 2 hours; the solid-liquid separation is preferably suction filtration.

[0091] After obtaining the compound of the structure shown in formula III, the present invention mixes the compound of the structure shown in formula III with a substituted alkane, a basic compound (referred to as the first basic compound) and an organic solvent (referred to as the first organic solvent) to carry out a substitution reaction (referred to as the first substitution reaction) to obtain a compound of the structure shown in formula IV. In the present invention, the substituted alkane preferably includes a dibromo-substituted alkane or a bromo-chloro-substituted alkane; the dibromo-substituted alkane preferably includes 1,2-dibromoethane or 1,3-dibromopropane; the bromo-chloro-substituted alkane preferably includes 1-bromo-2-chloroethane or 1-bromo-3-chloropropane; the molar ratio of the compound of the structure shown in formula III to the substituted alkane is preferably 1:3 to 10, specifically 1:4, 1:5, 1:6, 1:7 or 1:9.

[0092] In the present invention, the first alkaline compound preferably includes cesium carbonate or potassium carbonate; the molar ratio of the compound of the structure represented by formula III to the first alkaline compound is preferably 1:1.2-5, specifically 1:1.2, 1:1.5, 1:2, 1:3, 1:4 or 1:5.

[0093] In the present invention, the first organic solvent preferably includes DMF; the mass volume ratio of the compound represented by the structure of Formula III to the first organic solvent is preferably 1g:(5-30)mL, specifically 1g:7mL, 1g:10mL, 1g:15mL, 1g:18mL, 1g:21mL, 1g:25mL or 1g:28mL.

[0094] In the present invention, the temperature of the first substitution reaction is preferably 20-50°C, specifically 20°C, 30°C, 40°C or 50°C, and the insulation time is preferably 6-12h, specifically 8h or 10h.

[0095] In the present invention, after the first substitution reaction, the steps preferably include sequentially concentrating the reaction solution, redissolving the residue, washing the organic layer with water, washing with saturated brine, drying, solid-liquid separation, concentration and purification; the reagent used for the redissolution is preferably ethyl acetate; the number of water washings is preferably more than 3 times; the number of saturated brine washings is preferably more than 1 time; the drying is preferably drying with anhydrous sodium sulfate; the solid-liquid separation is preferably filtration; and the purification is preferably column chromatography purification.

[0096] After obtaining the compound of formula IV, the present invention mixes the compound of formula IV with a substituted amine, a basic compound (referred to as the second basic compound) and an organic solvent (referred to as the second organic solvent) to carry out a substitution reaction (referred to as the second substitution reaction) to obtain a compound of formula V. In the present invention, the substituted amine preferably includes one or more of dimethylamine, diethylamine, morpholine, piperidine, pyrrolidine, N-methylpiperazine, N-ethylpiperazine and isopropylamine; the molar ratio of the compound of formula IV to the substituted amine is preferably 1:1 to 3, specifically 1:1.1, 1:1.3, 1:1.7, 1:2.1 or 1:2.7.

[0097] In the present invention, the second alkaline compound preferably includes cesium carbonate or potassium carbonate; the molar ratio of the compound having the structure represented by formula IV to the second alkaline compound is preferably 1:2-5, specifically 1:3 or 1:4.

[0098] In the present invention, the second organic solvent preferably includes one or more of DMF, acetonitrile and tetrahydrofuran; the mass volume ratio of the compound with the structure represented by formula IV to the second organic solvent is preferably 1g:(10-50)mL, specifically 1g:20mL, 1g:30mL or 1g:40mL.

[0099] In the present invention, the temperature of the second substitution reaction is preferably 20-80°C, specifically 20°C, 40°C, 60°C or 70°C, and the insulation time is preferably 4-8h, specifically 5h or 6h.

[0100] In the present invention, after the second substitution reaction, the steps of concentrating the reaction solution, redissolving the residue, washing with water, washing with saturated brine, drying, solid-liquid separation and concentration are preferably performed in sequence; the reagent used for the redissolution is preferably dichloromethane; the number of water washings is preferably more than 2 times; the number of saturated brine washings is preferably more than 1 time; the drying is preferably drying with anhydrous sodium sulfate; and the solid-liquid separation is preferably suction filtration.

[0101] After obtaining the compound of the structure shown in formula V, the present invention mixes the compound of the structure shown in formula V with an alkaline compound (referred to as the third alkaline compound) and a solvent (referred to as the third solvent) for hydrolysis reaction to obtain a compound of the structure shown in formula VI. In the present invention, the third alkaline compound preferably includes one or more of sodium hydroxide and potassium hydroxide; the molar ratio of the compound of the structure shown in formula V to the third alkaline compound is preferably 1:5 to 10, specifically 1:6, 1:7, 1:8 or 1:9.

[0102] In the present invention, the third solvent preferably includes one or more of water, ethanol and methanol; the mass volume ratio of the compound with the structure represented by formula V to the third solvent is preferably 1g:(10-50)mL, specifically 1g:15mL, 1g:20mL, 1g:25mL, 1g:35mL or 1g:45mL.

[0103] In the present invention, the temperature of the hydrolysis reaction is preferably 20-50°C, specifically 20°C, 30°C or 40°C, and the insulation time is preferably 0.5-2h, specifically 1h or 1.5h.

[0104] In the present invention, after the hydrolysis reaction, the steps preferably include adjusting the pH value of the reaction solution to 5-6, standing and solid-liquid separation in sequence; the reagent used to adjust the pH value of the reaction solution is preferably dilute hydrochloric acid with a mass concentration of 5% to 20%; the standing time is preferably 1 hour, and a white solid is precipitated; the solid-liquid separation is preferably suction filtration.

[0105] After obtaining the compound of the structure shown in Formula VI, the present invention mixes the compound of the structure shown in Formula VI with an amino-substituted carboxylic acid ester, a condensing agent and an organic solvent (referred to as the fourth organic solvent) for a condensation reaction to obtain a compound of the structure shown in Formula VII. In the present invention, the amino-substituted carboxylic acid ester preferably includes one or more of methyl p-aminobenzoate, methyl p-aminomethylbenzoate, methyl 5-aminopyridine-2-carboxylate, methyl 7-aminoheptanoate and methyl 5-aminopyridine-2-carboxylate; the molar ratio of the compound of the structure shown in Formula VI to the amino-substituted carboxylic acid ester is preferably 1:0.8 to 1.2, and can specifically be 1:1.

[0106] In the present invention, the condensing agent preferably includes one or more of HOBt, EDCI and HATU; the molar ratio of the compound of the structure represented by formula VI to the condensing agent is preferably 1:1-3, specifically 1:1.5, 1:2 or 1:3.

[0107] In the present invention, the fourth organic solvent preferably includes one or both of acetonitrile and tetrahydrofuran; the mass volume ratio of the compound with the structure represented by formula VI to the fourth organic solvent is preferably 1g:(5-50)mL, specifically 1g:10mL, 1g:15mL, 1g:25mL, 1g:30mL or 1g:40mL.

[0108] In the present invention, the temperature of the condensation reaction is preferably room temperature, and the reaction time is preferably 6 to 10 hours, specifically 8 hours.

[0109] In the present invention, after the condensation reaction, the steps of sequentially concentrating the reaction solution, redissolving the residue, washing the organic layer with water, washing with saturated brine, drying, solid-liquid separation and purification are preferably further performed; the reagents used for the redissolution are preferably water and ethyl acetate; the volume ratio of water to ethyl acetate is preferably 3:2; the number of times the organic layer is washed with water is preferably more than 2 times; the number of times the saturated brine is washed is preferably more than 1 time; the drying is preferably drying with anhydrous sodium sulfate; the solid-liquid separation is preferably suction filtration; and the purification is preferably column chromatography purification.

[0110] After obtaining the compound of the structure shown in Formula VII, the present invention mixes the compound of the structure shown in Formula VII with hydroxylamine, water, an alkaline compound (referred to as the fourth alkaline compound) and an organic solvent (referred to as the fifth organic solvent) to perform a hydroxylamine reaction to obtain the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure. In the present invention, the hydroxylamine and water are preferably used as a hydroxylamine aqueous solution; the mass ratio of the hydroxylamine to water is preferably 1:1 to 10, specifically 1:1, 1:2, 1:4, 1:6 or 1:8.

[0111] In the present invention, the molar ratio of the compound of the structure represented by Formula VII to hydroxylamine is preferably 1:20 to 100, specifically 1:40, 1:60 or 1:80.

[0112] In the present invention, the fourth alkaline compound preferably includes one or more of sodium hydroxide and potassium hydroxide; the molar ratio of the compound of the structure represented by formula VII to the fourth alkaline compound is preferably 1:5 to 20, specifically 1:6, 1:8, 1:10, 1:12, 1:15 or 1:18.

[0113] In the present invention, the fifth organic solvent is preferably an alcohol; the alcohol includes one or more of methanol and ethanol; the mass volume ratio of the compound with the structure represented by formula VII to the fifth organic solvent is preferably 1g:(5-50)mL, specifically 1g:5mL, 1g:15mL, 1g:25mL, 1g:30mL, 1g:35mL or 1g:45mL.

[0114] In the present invention, the temperature of the hydroxylamine reaction is preferably room temperature, and the reaction time is preferably 0.5 to 5 h, specifically 0.5 h, 1 h, 3 h or 4 h.

[0115] In the present invention, after the hydroxylamine reaction, the steps of removing methanol from the reaction solution, adjusting the pH value of the reaction solution to 7-8, standing and solid-liquid separation are preferably performed in sequence; the removal of methanol from the reaction solution is preferably performed by vacuum distillation; the reagent used for adjusting the pH value of the reaction solution is preferably diluted hydrochloric acid with a mass concentration of 5% to 10%; and the solid-liquid separation is preferably performed by suction filtration.

[0116] The present invention also provides the use of the compound based on the 6-methylfurano[2,3-d]pyrimidine-4(3H)-one structure described in the above scheme or the compound based on the 6-methylfurano[2,3-d]pyrimidine-4(3H)-one structure obtained by the preparation method described in the above scheme in the preparation of drugs for treating diseases related to DNA methyltransferase 3A or histone deacetylase.

[0117] In the present invention, the disease associated with DNA methyltransferase 3A or histone deacetylase preferably includes cancer.

[0118] In order to further illustrate the present invention, the scheme of the present invention is described in detail below in conjunction with embodiments, but they should not be understood as limiting the scope of protection of the present invention.

[0119] Example 1 Synthesis of N-[6-(hydroxycarbamoyl)pyridin-3-yl]-6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-1A), the synthetic route is as follows:

[0120]

[0121] At -10°C, ethyl 2-chloro-3-oxobutyrate (20 g, 121.32 mmol), malononitrile (8 g, 121.32 mmol), and 120 mL of ethanol were added to a three-necked flask, and then 10% sodium ethoxide solution (24 mL, 133.45 mmol) was slowly added dropwise under stirring. After the addition was completed, the reaction was allowed to react at room temperature for 6 h. The reaction solution was concentrated, and 12 mL of petroleum ether and 4 mL of ethyl acetate were added to the residue. The mixture was stirred for 1 h and filtered to obtain ethyl 5-amino-4-cyano-2-methylfuran-3-carboxylate (II). 19.6 g of light yellow solid was obtained, with a yield of 85.21%; mp: 78-79°C; ESI-MS (m / z): 194.07 [M+Na] + .

[0122] At room temperature, 5-amino-4-cyano-2-methylfuran-3-carboxylic acid ethyl ester (II) (5.3 g, 27.29 mmol) and formic acid (18 mL, 500 mmol) were added to a three-necked flask, and then acetic anhydride (15 mL, 168 mmol) was slowly added dropwise to the reaction solution under stirring. After the addition was completed, the reaction solution was refluxed for 48 h. The reaction solution was concentrated, water (30 mL) was added to the residue, and the pH was adjusted to 7 with a saturated sodium carbonate aqueous solution, and a large amount of black solid appeared. The reaction solution was stirred at room temperature for 2 h, and filtered to obtain 6-methyl-4-oxo-1,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (III), 4.6 g of black crude product, and a yield of 75.41%; mp: 129-134°C; 1H NMR (400MHz, DMSO-d6) δ12.58(s,1H),8.11(s,1H),4.27(q,J=7.1Hz,2H),2.58(s,3H),1.30(t,J=7.1Hz,3H).

[0123] At room temperature, 6-methyl-4-oxo-1,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (III) (1.3 g, 5.90 mmol), 1,2-dibromoethane (6.62 g, 35.40 mmol), cesium carbonate (2.88 g, 8.85 mmol), and DMF (15 mL) were added to a three-necked flask and reacted at 25°C for 8 h; the reaction solution was concentrated, ethyl acetate (20 mL) was added, the ethyl acetate layer was washed with water (20 mL×3), washed once with saturated brine (25 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 4.2 g of a viscous black solid, which was purified by column chromatography to obtain 3-(2-bromoethyl)-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (IV), 1.1 g of a white solid, with a yield of 55%; mp: 45-46°C.

[0124] At room temperature, 3-(2-bromoethyl)-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (IV) (0.3 g, 0.91 mmol), piperidine (0.08 mL, 1.00 mmol), potassium carbonate (0.37 g, 2.73 mmol), and acetonitrile (10 mL) were added to a three-necked flask and reacted at 25°C for 5 h; the reaction solution was concentrated, dissolved in dichloromethane (15 mL), washed twice with water (10 mL×2), washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (V), 0.27 g of white solid, yield 85.71%; mp: 97~100°C.

[0125] At room temperature, 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid ethyl ester (V) (0.2 g, 0.62 mmol) and 1M NaOH aqueous solution (5 mL) were added to a three-necked flask and reacted at 50°C for 1 h. 10% dilute hydrochloric acid was slowly added dropwise to the reaction solution until the pH was 5-6. The reaction solution was allowed to stand for 1 h to precipitate a white solid, which was filtered to obtain 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid (VI), 0.14 g, with a yield of 82.35%; mp: 119-123°C.

[0126] At room temperature, 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid (VI) (0.3 g, 0.94 mmol), 5-aminopyridine-2-carboxylic acid methyl ester (0.14 g, 0.94 mmol), EDCI (0.27 g, 1.41 mmol), HOBt (0.19 g, 1.41 mmol), acetonitrile (10 mL) were added to an eggplant-shaped bottle, and then TEA (0.29 mL, 2.07 mmol) was added dropwise at 0°C. After the addition, the mixture was moved to room temperature for reaction for 8 h. The reaction solution was concentrated, 15 mL of water and 10 mL of EA were added. mL, the EA layer was separated, washed twice with water (15 mL×2), washed once with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated by suction to obtain 0.38 g of an oily crude product, which was purified by column chromatography to obtain 5-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}pyridine-2-carboxylic acid methyl ester (VII) as a white solid, 0.15 g in a yield of 35.71%.

[0127] At room temperature, 5-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}picolinic acid methyl ester (VII) (0.15 g, 0.33 mmol) and methanol (5 mL) were added to a single-necked bottle, and a 50% mass fraction hydroxylamine aqueous solution (2 mL) was slowly added dropwise at 0°C, followed by a 1M NaOH aqueous solution (2 mL). After the addition was completed, the mixture was transferred to room temperature for reaction for 0.5 h; the reaction mixture was evaporated under reduced pressure. The methanol in the solution was added, and 10% dilute hydrochloric acid was added to adjust the pH of the reaction solution to 7-8. The reaction solution was allowed to stand, and the precipitated white solid was filtered to obtain N-[6-(hydroxycarbamoyl)pyridin-3-yl]-6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-1A), 0.04 g, yield 28.57%; mp: 181-184°C; ESI-MS (m / z): 455.2 [M+H] + .

[0128] 1H NMR (400MHz, DMSO-d6) δ12.70(s,1H),11.32(s,1H),9.03(s,1H),8.92(d,J=2.4Hz,1H),8.62(s,1H),8.20(dd,J=8.6,2.5Hz,1H), 8.02(d,J=8.5Hz,1H),4.18(t,J=6.6Hz,2H),2.79(s,3H),2.29(dd,J=17.1,10.8Hz,6H),1.93(t,J=6.5Hz,2H),1.48-1.28(m,6H).

[0129] 13 C NMR(101MHz,DMSO-d6)δ162.95,161.58,160.70,160.33,159.92,150.42,145.51,139.44, 138.08,127.15,123.15,112.29,103.87,55.73,54.24,46.49,25.94,25.12,24.54,14.19.

[0130] Example 2 Synthesis of N-[6-(hydroxycarbamoyl)pyridin-3-yl]-6-methyl-4-oxo-3-[3-(pyrrolidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-2A)

[0131] The preparation method of this example is the same as that of Example 1, except that piperidine is replaced by pyrrolidine to obtain the target compound YQ-2A; 0.06 g of white solid, yield 34.29%; mp: 190-192°C; ESI-MS (m / z): 441.2 [M+H] + .

[0132] 1 H NMR (400MHz, DMSO-d6) δ12.68(s,1H),11.33(s,1H),9.04(s,1H),8.93(d,J=2.4Hz,1H),8.62(s,1H),8.22(dd,J=8.5,2.5Hz,1H) ,8.03(d,J=8.5Hz,1H),4.20(t,J=6.9Hz,2H),2.80(s,3H),2.48-2.36(m,6H),1.94(p,J=7.0Hz,2H),1.64(q,J=4.0,3.3Hz,4H).

[0133] 13C NMR (101MHz, DMSO-d6) δ162.95,161.59,160.71,160.29,159.95,150.35,145.53,139. 47,138.07,127.19,123.17,112.30,103.87,53.75,52.73,46.37,27.42,23.57,14.20.

[0134] Example 3 Synthesis of N-[6-(hydroxycarbamoyl)pyridin-3-yl]-6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-2A)

[0135] The preparation method of this example is the same as that of Example 1, except that piperidine is replaced by pyrrolidine, and 1,3-dibromopropane is replaced by 1,2-dibromoethane to obtain the target compound FQX-2A; 0.06 g of white solid, yield 34.29%; mp: 228-230°C; ESI-MS (m / z): 425.0 [MH] - .

[0136] 1 H NMR (400MHz, DMSO-d6) δ12.61(s,1H),11.30(s,1H),8.92(s,1H),9.00-8.80(m,1H),8.56(s,1H),8.20(dd,J=8.8,2.3Hz,1H ), 8.01 (d, J = 8.6Hz, 1H), 4.23 (d, J = 6.9Hz, 2H), 2.80 (d, J = 4.7Hz, 5H), 2.54 (s, 2H), 1.86 (s, 2H), 1.67 (q, J = 4.3, 2.6Hz, 4H).

[0137] 13 C NMR(101MHz,DMSO-d6)δ161.80,160.43,159.55,158.94,158.88,149.23,144.44,1 38.34,136.91,126.06,122.01,111.19,102.78,52.98,52.95,44.99,22.61,13.11.

[0138] Example 4 Synthesis of 3-[3-(diethylamino)propyl]-N-[6-(hydroxycarbamoyl)pyridin-3-yl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-7A)

[0139] The preparation method of this example is the same as that of Example 1, except that piperidine is replaced by diethylamine to obtain the target compound YQ-7A; 0.05 g of white solid, yield 30.69%; mp: 215-217°C; ESI-MS (m / z): 443.2 [M+H] + .

[0140] 1 H NMR (400MHz, DMSO-d6) δ12.64(s,1H),11.32(s,1H),9.04(s,1H),8.92(d,J=2.4Hz,1H),8.66(s,1H),8.22(dd,J=8.6,2. 5Hz, 1H), 8.02 (d, J = 8.5Hz, 1H), 4.20 (t, J = 7.0Hz, 2H), 2.90-2.63 (m, 9H), 2.00 (d, J = 20.0Hz, 2H), 1.03 (d, J = 8.8Hz, 6H).

[0141] 13 C NMR (101MHz, DMSO-d6) δ162.92,161.58,160.68,160.26,160.01,150.21,145.54,139. 47,138.05,127.15,123.16,112.33,104.02,49.14,46.46,45.77,40.68,14.21,10.64.

[0142] Example 5 Synthesis of N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-1B)

[0143] The preparation method of this embodiment is the same as that of Example 1, and 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is obtained, and then condensed with methyl 4-aminobenzoate to obtain methyl 4-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamidobenzoate, and then subjected to hydroxylamine hydrolysis reaction to obtain the target compound YQ-1B. The specific steps are as follows:

[0144] At room temperature, 6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid (0.3 g, 0.94 mmol), methyl 4-aminobenzoate (0.14 g, 0.94 mmol), EDCI (0.27 g, 1.41 mmol), HOBt (0.19 g, 1.41 mmol) and ACN (10 mL) were added into an eggplant shaped flask. TEA (0.29 mL, 2.07 mmol) was added dropwise at 0°C, and the mixture was moved to room temperature for reaction for 8 h. The reaction solution was concentrated, and 15 mL of water and 10 mL of EA were added. The EA layer was separated, washed with water twice (15 mL×2), washed once with saturated brine (15 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated by suction to obtain 0.32 g of an oily substance. After PTLC purification, 4-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamidobenzoic acid methyl ester was obtained as a white solid, 0.25 g, and the yield was 59.52%.

[0145] At room temperature, methyl 4-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}benzoate (0.25 g, 0.55 mmol) and methanol (5 mL) were added to an eggplant-shaped bottle, 50% hydroxylamine aqueous solution (2 mL) was slowly added dropwise at 0°C, and then 1M NaOH aqueous solution (2 mL) was slowly added dropwise, and the mixture was moved to room temperature for reaction for 0.5 h; methanol in the reaction solution was evaporated under reduced pressure, and 10% dilute hydrochloric acid was added to adjust the pH of the reaction solution to 7-8, and the reaction solution was allowed to stand for 3 h to precipitate a white solid, which was filtered to obtain the target compound YQ-1B, 0.18 g, with a yield of 72.29%; mp: 184-188°C; ESI-MS (m / z): 454.1 [M+H] + .

[0146] 1 H NMR(400MHz,DMSO-d6)δ12.53(s,1H),11.15(s,1H),8.97(s,1H),8.60(s,1H),7.88-7.68(m,4H),4.18 (t,J=6.7Hz,2H),2.79(s,3H),2.29(dd,J=16.5,10.1Hz,6H),1.93(t,J=6.6Hz,2H),1.45-1.28(m,6H).

[0147] 13C NMR(101MHz,DMSO-d6)δ164.26,162.92,160.33,159.54,150.31,141.79,128.51,128 .22,118.95,112.67,103.90,82.77,55.72,54.25,46.43,25.94,25.13,24.55,14.19.

[0148] Example 6 Synthesis of N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3-[3-(pyrrolidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-2B)

[0149] The preparation method of this example is the same as that of Example 5, except that piperidine is replaced by pyrrolidine to obtain the target compound YQ-2B; 0.12 g of white solid, yield 47.26%; mp: 187-190°C; ESI-MS (m / z): 440.2 [M+H] + .

[0150] 1 H NMR(400MHz,DMSO-d6)δ12.63-12.27(m,1H),11.17(s,1H),9.00(s,1H),8.61(s,1H),7.84-7.69(m,4H), 4.20(t,J=6.8Hz,2H),2.98-2.81(m,6H),2.79(d,J=1.9Hz,3H),2.14-2.00(m,2H),1.77(d,J=6.0Hz,4H).

[0151] 13 C NMR (101MHz, DMSO-d6) δ164.17,162.91,160.28,159.55,150.24,141.60,129.19,128. 42,118.96,118.77,112.68,103.87,53.75,52.75,46.33,29.45,27.47,23.58,14.19.

[0152] Example 7 Synthesis of 3-[3-(dimethylamino)propyl]-N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-9B)

[0153] The preparation method of this example is the same as that of Example 5, except that piperidine is replaced by dimethylamine to obtain the target compound YQ-9B; 0.09 g of white solid, yield 43.96%; mp: 159-162°C; ESI-MS (m / z): 414.1 [M+H] + .

[0154] 1 H NMR(400MHz,DMSO-d6)δ12.41(s,1H),10.04(s,1H),8.57(s,1H),7.86-7.60(m,4H),4.14 (t,J=7.1Hz,2H),2.77(s,3H),2.26(t,J=6.7Hz,2H),2.13(s,6H),1.89(p,J=6.8Hz,2H).

[0155] 13 C NMR(101MHz,DMSO-d6)δ164.09,162.84,160.21,160.18,159.51,150.10,141.2 9,129.04,128.25,118.89,112.70,103.93,56.15,46.02,45.43,26.47,14.18.

[0156] Example 8 Synthesis of 3-[3-(diethylamino)propyl]-N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-7B)

[0157] The preparation method of this example is the same as that of Example 5, except that piperidine is replaced by diethylamine to obtain the target compound YQ-7B; 0.12 g of white solid, yield 46.30%; mp: 151-152°C; ESI-MS (m / z): 442.1 [M+H] + .

[0158] 1 H NMR(400MHz,DMSO-d6)δ12.49(s,1H),11.16(s,1H),9.02(s,1H),8.59(s,1H),7.82-7.74(m,4H) ,4.15(t,J=7.0Hz,2H),2.78(s,3H),2.48-2.40(m,6H),1.92-1.87(m,2H),0.92(t,J=7.1Hz,6H).

[0159] Example 9 Synthesis of 3-[4-(diethylamino)butyl]-N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (WZ-7B)

[0160] The preparation method of this example is the same as that of Example 5, except that piperidine is replaced by diethylamine, and 1,3-dibromopropane is replaced by 1,4-dibromobutane to obtain the target compound WZ-7B; 0.06 g of white solid, yield 34.26%; mp: 134-136°C; ESI-MS (m / z): 456.2 [M+H] + .

[0161] 1 H NMR (400MHz, DMSO-d6) δ12.46(s,1H),11.11(s,1H),9.04(s,1H),8.63(s,1H),7.78(q,J=8.7Hz,4H),4.13(t,J=7.2H z, 2H), 2.78 (s, 3H), 2.41 (dq, J = 13.5, 7.1Hz, 6H), 1.75 (p, J = 7.2Hz, 2H), 1.43 (p, J = 7.2Hz, 2H), 0.93 (t, J = 7.1Hz, 6H).

[0162] 13 C NMR (101MHz, DMSO-d6) δ164.24,162.82,160.27,160.13,159.66,149.87,141.75,128. 48,128.22,118.95,112.67,104.01,52.24,47.40,46.75,27.30,24.25,14.20,12.23.

[0163] Example 10 Synthesis of N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3-[4-(piperidin-1-yl)butyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (WZ-1B)

[0164] The preparation method of this example is the same as that of Example 5, except that 1,3-dibromopropane is replaced by 1,4-dibromobutane to obtain the target compound WZ-1B; 0.07 g of white solid, yield 39.33%; mp: 177-179°C; ESI-MS (m / z): 468.2 [M+H] + .

[0165] 1H NMR(400MHz,DMSO-d6)δ12.40(s,1H),11.19(s,1H),8.99(s,1H),8.68(s,1H),7.88-7.50(m,4H), 4.14(d,J=8.1Hz,2H),3.20-2.87(m,6H),2.77(s,3H),1.75(dd,J=12.1,6.2Hz,8H),1.51(s,2H).

[0166] 13 C NMR(101MHz,DMSO-d6)δ164.23,162.81,160.22,159.67,149.94,141.71,131.14,128.51, 128.22,118.93,112.67,104.03,55.83,52.54,46.77,26.38,23.03,22.12,20.86,14.19.

[0167] Example 11 Synthesis of N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-1B)

[0168] The preparation method of this example is the same as that of Example 1, and 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is obtained, and then condensed with 4-amino-N-(benzyloxy)benzamide to obtain N-{4-[(benzyloxy)carbamoyl]phenyl}-6-methyl-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide, and then subjected to hydroxylamine reaction to obtain the target compound FQX-1B. The specific steps are as follows:

[0169] At room temperature, 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuro[2,3-d]pyrimidine-5-carboxylic acid (0.26 g, 0.91 mmol), 4-amino-N-(benzyloxy)benzamide (0.25 g, 0.91 mmol), HATU (0.52 g, 1.37 mmol), and acetonitrile (10 mL) were added to a three-necked flask, and then DIPEA (0.47 mL, 2.73 mmol) was slowly added dropwise at 0°C. After the addition was completed, the mixture was transferred to a hot magnetic stirrer and reacted at 50°C. 10h; concentrated the reaction solution, added 15mL of ethyl acetate, washed the ethyl acetate layer with water (15mL×2), washed once with saturated brine (15mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 0.25g of crude product, which was purified by column chromatography to obtain N-{4-[(benzyloxy)carbamoyl]phenyl}-6-methyl-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide; 0.12g of white solid, yield 38.71%; mp: 189~193℃.

[0170] At room temperature, N-{4-[(benzyloxy)carbamoyl]phenyl}-6-methyl-4-oxo-3-(2-(pyrrolidin-1-yl)ethyl)-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (0.1 g, 0.29 mmol), palladium carbon (0.01 g, 0.029 mmol), 6 mL of a mixed solution of methanol and ethyl acetate (v / v, 1:1) were added to a 50 mL eggplant-shaped flask, and hydrogen was passed through for 4 h. The reaction solution was filtered to remove palladium carbon, and the filtrate was concentrated under reduced pressure to obtain the target compound FQX-1B; 0.05 g of white solid, yield 62.50%; mp: 209-211°C; ESI-MS (m / z): 426.2 [M+H] + .

[0171] 1 H NMR(400MHz,DMSO-d6)δ12.43(s,1H),11.16(s,1H),8.97(s,1H),8.54(s,1H),7.84-7.7 3(m,4H),4.24(t,J=6.1Hz,2H),2.84-2.79(m,5H),2.55(d,J=17.7Hz,4H),1.69(s,4H).

[0172] 13C NMR(101MHz,DMSO-d6)δ163.21,161.77,159.20,158.99,158.58,149.13,140.6 6,127.44,127.16,117.89,111.58,102.83,52.96,39.45,30.62,22.59,13.13.

[0173] Example 12 Synthesis of N-[4-(hydroxycarbamoyl)phenyl]-6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-2B)

[0174] The preparation method of this example is the same as that of Example 11, except that pyrrolidine is replaced by piperidine to obtain the target compound FQX-2B; 0.04 g of white solid, yield 44.09%; mp: 183-185°C; ESI-MS (m / z): 440.1 [M+H] + .

[0175] 1 H NMR(400MHz,DMSO-d6)δ12.44(s,1H),11.16(s,1H),8.96(s,1H),8.49(s,1H),7 .86-7.71(m,4H),4.23(s,2H),2.78(s,3H),2.43(s,6H),1.42(d,J=32.9Hz,6H).

[0176] 13 C NMR(101MHz,DMSO-d6)δ164.31,162.85,160.29,160.07,159.59,150.34,141.76,1 28.52,128.22,118.96,118.76,112.67,103.77,56.64,54.36,26.02,24.24,14.20.

[0177] Example 13 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-1C)

[0178] The preparation method of this embodiment is the same as that of Example 1, and 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is obtained, and then condensed with methyl 4-(aminomethyl)benzoate to obtain methyl 4-({6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}methyl)benzoate, and then subjected to hydroxylamine reaction to obtain the target compound FQX-1C. The specific steps are as follows:

[0179] At room temperature, 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid (0.3 g, 0.94 mmol), methyl 4-(aminomethyl)benzoate (0.16 g, 0.94 mmol), EDCI (0.27 g, 1.41 mmol), HOBt (0.19 g, 1.41 mmol), and ACN (10 mL) were added to an eggplant-shaped bottle, and TEA (0.29 mL, 2.07 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature for reaction for 8 h. The reaction solution was concentrated, 15 mL of water was added, and EA 10mL, separate the EA layer, wash twice with water (15mL×2), wash once with 15mL saturated brine (15mL), dry over anhydrous sodium sulfate, and concentrate the filtrate to obtain 0.43g of oily crude product, which was purified by column chromatography to obtain methyl 4-({6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}methyl)benzoate as a white solid, 0.35g, with a yield of 85.37%.

[0180] At room temperature, methyl 4-({6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}methyl)benzoate (0.35 g, 0.80 mmol) and methanol (5 mL) were added to an eggplant-shaped bottle, 50% hydroxylamine aqueous solution (2 mL) was slowly added dropwise at 0°C, and then 1M NaOH aqueous solution (2 mL) was slowly added dropwise. After the addition was completed, the mixture was transferred to room temperature for reaction for 0.5 h. Methanol in the reaction solution was evaporated under reduced pressure at 30°C, and the pH of the reaction solution was adjusted to 7-8 by adding 10% dilute hydrochloric acid. The reaction solution was allowed to stand for 3 h, and a large amount of white solid was precipitated. The target compound FQX-1C was obtained by suction filtration, 0.30 g, and the yield was 85.71%; mp: 206-209°C; ESI-MS (m / z): 440.2 [M+H] + .

[0181] 1H NMR(400MHz,DMSO-d6)δ11.16(s,1H),10.54(t,J=5.8Hz,1H),9.00(s,1H),8.47(s,1H),7.75-7.68(m,2H),7 .43-7.37(m,2H),4.58(d,J=5.8Hz,2H),4.14(t,J=6.1Hz,2H),2.72(d,J=11.3Hz,5H),1.65(p,J=3.1Hz,4H).

[0182] Example 14 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-2C)

[0183] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by piperidine to obtain the target compound FQX-2C; 0.26 g of white solid, yield 89.35%; mp: 180-182°C; ESI-MS (m / z): 454.2 [M+H] + .

[0184] 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),10.54(s,1H),8.99(s,1H),8.43(s,1H),7.74-7.68(m,2H),7.43-7.3 7(m,2H),4.57(d,J=5.7Hz,2H),4.14(s,2H),2.74(s,3H),2.57(s,2H),2.38(s,4H),1.39(d,J=26.3Hz,6H).

[0185] Example 15 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-3-[2-(isopropylamino)ethyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-3C)

[0186] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by isopropylamine to obtain the target compound FQX-3C; 0.16 g of white solid, yield 65.23%; mp: 222-224°C; ESI-MS (m / z): 426.0 [MH] - .

[0187] 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.45(s,1H),7.75-7.66(m,2H),7.38(d,J=8.1Hz,2H),4.56(d,J=5.8 Hz, 2H), 4.05 (t, J = 6.0Hz, 2H), 2.78 (t, J = 6.0Hz, 2H), 2.73 (s, 3H), 2.68-2.64 (m, 1H), 0.90 (d, J = 6.2Hz, 6H).

[0188] Example 16 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-3-[2-(4-methylpiperazin-1-yl)ethyl]-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-5C)

[0189] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by N-methylpiperazine to obtain the target compound FQX-5C; 0.27 g of white solid, yield 80.97%; mp: 155-157°C; ESI-MS (m / z): 469.2 [M+H] + .

[0190] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.55(t,J=5.8Hz,1H),9.01(s,1H),8.43(s,1H),7.72(d,J=8.1Hz,2H),7.39(d,J=8.1 Hz, 2H), 4.57 (d, J = 5.7Hz, 2H), 4.13 (t, J = 5.9Hz, 2H), 2.73 (s, 3H), 2.56 (t, J = 6.0Hz, 2H), 2.33 (d, J = 73.3Hz, 8H), 2.12 (s, 3H).

[0191] 13 C NMR(101MHz,DMSO-d6)δ162.25,161.08,158.85,157.56,149.06,141.73,130.87, 126.57,126.45,111.97,102.93,54.99,54.13,51.88,45.07,42.91,41.29,12.92.

[0192] Example 17 Synthesis of 3-[2-(diethylamino)ethyl]-N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-7C)

[0193] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by diethylamine to obtain the target compound FQX-7C; 0.19 g of white solid, yield 72.69%; mp: 205-207°C; ESI-MS (m / z): 442.1 [M+H] + .

[0194] 1 H NMR (400MHz, DMSO-d6) δ11.15(s,1H),10.58(t,J=5.8Hz,1H),9.01(s,1H),8.41(s,1H),7.71(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2 H), 4.57 (d, J = 5.7Hz, 2H), 4.07 (t, J = 5.8Hz, 2H), 2.73 (s, 3H), 2.63 (t, J = 5.8Hz, 2H), 2.44 (q, J = 7.1Hz, 4H), 0.80 (t, J = 7.0Hz, 6H).

[0195] 13 C NMR(101MHz,DMSO-d6)δ164.49,162.99,161.80,159.62,158.23,150.26,142.78,1 31.99,127.58,127.52,112.08,103.89,50.76,47.08,45.57,42.38,14.00,12.46.

[0196] Example 18 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-3-[3-(4-methylpiperazin-1-yl)propyl]-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-5C)

[0197] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by N-methylpiperazine, and 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-5C; 0.19 g of white solid, yield 69.63%; mp: 189-190°C; ESI-MS (m / z): 483.3 [M+H] + .

[0198] 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.60(t,J=5.8Hz,1H),9.02(s,1H),8.53(s,1H),7.75-7.67(m,2H),7.39(d, J=8.1Hz,2H),4.57(d,J=5.8Hz,2H),4.08(t,J=6.7Hz,2H),2.73(s,3H),2.49-1.96(m,13H),1.85(p,J=6.6Hz,2H).

[0199] 13 C NMR(101MHz,DMSO-d6)δ164.44,162.92,161.82,159.90,158.11,149.96,142.83,131.95, 127.58,127.53,112.18,104.23,54.99,54.84,52.51,46.23,45.87,42.35,25.00,13.98.

[0200] Example 19 Synthesis of 3-[3-(diethylamino)propyl]-N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-7C)

[0201] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by diethylamine, and 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-7C; 0.14 g of white solid, yield 56.77%; mp: 129-132°C; ESI-MS (m / z): 456.3 [M+H] + .

[0202] 1 H NMR (400MHz, DMSO-d6) δ10.93(s,1H),10.58(t,J=5.8Hz,1H),9.08(s,1H),8.53(s,1H),7.78-7.63(m,2H),7.40(d,J=8.3Hz,2 H), 4.57 (d, J = 5.7Hz, 2H), 4.06 (t, J = 7.1Hz, 2H), 2.73 (s, 3H), 2.47-2.33 (m, 6H), 1.82 (p, J = 6.9Hz, 2H), 0.89 (t, J = 7.1Hz, 6H).

[0203] 13C NMR (101MHz, DMSO-d6) δ164.42,162.89,161.80,159.71,158.22,149.98,142.77,132. 01,127.59,127.51,112.12,104.15,49.68,46.31,46.17,42.37,26.11,13.99,11.80.

[0204] Example 20 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-3-(2-hydroxyethyl)-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-8C)

[0205] The preparation method of this example is the same as that of Example 13, except that 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is replaced with 3-(2-hydroxyethyl)-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid to obtain the target compound YQ-8C; white solid 0.06 g, yield 25.63%; mp: 208-212°C; ESI-MS (m / z): 387.1 [M+H] + .

[0206] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),10.56(t,J=5.8Hz,1H),9.00(s,1H),8.42(s,1H),7.72(d,J=8.0Hz,2H),7.40(d ,J=8.0Hz,2H),4.96(t,J=5.6Hz,1H),4.57(d,J=5.8Hz,2H),4.11(t,J=5.2Hz,2H),3.65(q,J=5.4Hz,2H),2.74(s,3H).

[0207] 13 C NMR(101MHz,DMSO-d6)δ164.57,163.01,161.78,159.73,158.22,150.30,14 2.81,132.01,127.65,127.57,112.11,104.16,58.40,49.76,42.39,14.00.

[0208] Example 21 Synthesis of 3-(2-(dimethylamino)ethyl)-N-(4-(hydroxycarbamoyl)benzyl)-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-9C)

[0209] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by dimethylamine to obtain the target compound FQX-9C; 0.14 g of white solid, yield 51.63%; mp: 210-212°C; ESI-MS (m / z): 414.1 [M+H] + .

[0210] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),10.54(t,J=5.9Hz,1H),9.00(s,1H),8.45(s,1H),7.71(d,J=8.0Hz,2H),7. 40(d,J=8.0Hz,2H), 4.57(d,J=5.7Hz,2H), 4.12(t,J=6.0Hz,2H), 2.73(s,3H), 2.53(d,J=5.7Hz,2H), 2.17(s,6H).

[0211] 13 C NMR(101MHz,DMSO-d6)δ164.53,162.85,161.80,159.57,158.28,150.04,142.8 4,131.97,127.63,127.54,112.11,104.10,57.54,45.69,44.62,42.36,14.01.

[0212] Example 22 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3-[3-(pyrrolidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-1C)

[0213] The preparation method of this example is the same as that of Example 13, except that 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-1C; 0.21 g of white solid, yield 79.88%; mp: 128-131°C; ESI-MS (m / z): 454.1 [M+H] + .

[0214] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),10.59(t,J=5.8Hz,1H),9.06(s,1H),8.53(s,1H),7.72(d,J=7.9Hz,2H),7.39(d,J=8.0Hz,2H),4. 57(d,J=5.8Hz,2H),4.09(t,J=7.0Hz,2H),2.73(s,3H),2.38(dt,J=22.8,6.3Hz,6H),1.85(p,J=6.9Hz,2H),1.61(q,J=3.8,3.3Hz,4H).

[0215] 13 C NMR (101MHz, DMSO-d6) δ164.41,162.91,161.81,159.76,158.20,150.00,142.75,132. 02,127.60,127.49,112.10,104.10,53.73,52.76,46.17,42.36,27.52,23.55,14.00.

[0216] Example 23 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-2C)

[0217] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by piperidine, and 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-2C; 0.20 g of white solid, yield 74.98%; mp: 130-133°C; ESI-MS (m / z): 468.2 [M+H] + .

[0218] 1 H NMR (400MHz, DMSO-d6) δ11.14(s,1H),10.61(t,J=5.8Hz,1H),9.02(s,1H),8.53(s,1H),7.71(d,J=8.0Hz,2H),7.39(d,J=8.0Hz,2H),4.5 7(d,J=5.8Hz,2H),4.07(t,J=6.7Hz,2H),2.73(s,3H),2.24(dd,J=16.1,9.7Hz,6H),1.84(p,J=6.7Hz,2H),1.33(tt,J=13.5,5.7Hz,6H).

[0219] 13C NMR(101MHz,DMSO-d6)δ164.43,162.94,161.83,159.85,158.15,150.07,142.80,132.00, 127.56,127.50,112.13,104.14,55.82,54.24,46.34,42.35,25.95,25.11,24.55,14.00.

[0220] Example 24 Synthesis of N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-3-(3-morpholinopropyl)-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-4C)

[0221] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by morpholine, and 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-4C; 0.16 g of white solid, yield 51.79%; mp: 127-129°C; ESI-MS (m / z): 470.2 [M+H] + .

[0222] 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.59(t,J=5.8Hz,1H),9.02(d,J=22.8Hz,1H),8.55(s,1H),7.80-7.64(m,2H),7.39(d,J=8.1Hz,2 H), 4.57 (d, J = 5.8Hz, 2H), 4.09 (t, J = 6.8Hz, 2H), 3.43 (t, J = 4.6Hz, 4H), 2.73 (s, 3H), 2.28 (dt, J = 19.6, 5.6Hz, 6H), 1.86 (p, J = 6.7Hz, 2H).

[0223] 13 C NMR (101MHz, DMSO-d6) δ164.49,162.94,161.80,159.86,158.21,150.04,142.83,131. 96,127.61,127.52,112.13,104.17,66.55,55.48,53.49,46.19,42.36,24.79,14.00.

[0224] Example 25 Synthesis of 3-[3-(4-ethylpiperazin-1-yl)propyl]-N-[4-(hydroxycarbamoyl)benzyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-6C)

[0225] The preparation method of this example is the same as that of Example 13, except that pyrrolidine is replaced by N-ethylpiperazine, and 1,2-dibromoethane is replaced by 1,3-dibromopropane to obtain the target compound YQ-6C; 0.17 g of white solid, yield 54.38%; mp: 108-110°C; ESI-MS (m / z): 497.3 [M+H] + .

[0226] 1 H NMR (400MHz, DMSO-d6) δ11.16(s,1H),10.61(t,J=5.8Hz,1H),9.00(s,1H),8.52(s,1H),7.85-7.66(m,2H),7.49-7.31(m,2H) ,4.57(d,J=5.8Hz,2H),4.08(t,J=6.7Hz,2H),2.73(s,3H),2.43-1.98(m,12H),1.85(p,J=6.6Hz,2H),0.92(t,J=7.2Hz,3H).

[0227] 13 C NMR(101MHz,DMSO-d6)δ164.45,162.94,161.83,159.94,158.10,149.97,142.86,131.94,127 .57,127.51,112.19,104.24,55.20,52.95,52.61,52.03,46.33,42.34,24.96,13.97,12.23.

[0228] Example 26 Synthesis of N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-1D)

[0229] The preparation method of this embodiment is the same as that of Example 1, and 6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is obtained, and then condensed with 7-aminoheptanoic acid methyl ester hydrochloride to obtain 7-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}heptanoic acid methyl ester, and then subjected to hydroxylamine hydrolysis reaction to obtain the target compound YQ-1D. The specific steps are as follows:

[0230] At room temperature, 6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid (0.3 g, 0.86 mmol), 7-aminoheptanoic acid methyl ester hydrochloride (0.17 g, 0.86 mmol), EDCI (0.25 g, 1.29 mmol), HOBt (0.17 g, 1.29 mmol) and ACN (10 mL) were added to an eggplant-shaped bottle, and TEA (0.39 mL, 2.75 mmol) was added dropwise at 0°C. After the addition was completed, the mixture was moved to room temperature for reaction for 8 h. The reaction solution was concentrated, 15 mL of water was added, and EA was added dropwise. 10mL, separate the EA layer, wash twice with water (15mL×2), wash once with saturated brine (15mL), dry over anhydrous sodium sulfate, and concentrate the filtrate to obtain 0.56g of oily crude product, which was purified by column chromatography to obtain 7-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}heptanoic acid methyl ester as a light yellow solid, 0.36g, with a yield of 91.14%.

[0231] At room temperature, methyl 7-{6-methyl-4-oxo-3-[3-(piperidin-1-yl)propyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide}heptanoate (0.36 g, 0.78 mmol) and methanol (5 mL) were added to an eggplant-shaped bottle, 50% hydroxylamine aqueous solution (3 mL) was slowly added dropwise at 0°C, and then 1M NaOH aqueous solution (2 mL) was slowly added dropwise, and the mixture was moved to room temperature for reaction for 0.5 h; the methanol in the reaction solution was evaporated under reduced pressure, and the pH of the reaction solution was adjusted to 7-8 by adding 10% dilute hydrochloric acid, and the reaction solution was allowed to stand for 3 h to precipitate a white solid, which was filtered to obtain a filter cake of 0.32 g, with a yield of 88.89%; mp: 94-96°C; ESI-MS (m / z): 462.2 [M+H] + .

[0232] 1 H NMR (400MHz, DMSO-d6) δ10.30(s,1H),10.10(t,J=5.4Hz,1H),8.71-8.60(m,1H),8.51(s,1H),4.09(t,J=6.7Hz,2H),3.26(dd,J=7.1,5.5H z,2H),2.71(s,3H),2.25(dd,J=15.5,9.0Hz,6H),1.90(dt,J=30.1,7.0Hz,4H),1.50(h,J=7.6Hz,4H),1.31(dq,J=29.6,6.6,6.2Hz,10H).

[0233] 13C NMR(101MHz,DMSO-d6)δ169.55,162.88,161.50,159.80,157.63,149.98,112.44,104.14,5 5.80,54.23,46.31,38.96,32.69,29.32,28.72,26.63,25.94,25.52,25.12,24.55,13.93.

[0234] Example 27 Synthesis of N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3-[2-(piperidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-1D)

[0235] The preparation method of this example is the same as that of Example 26, except that 1,3-dibromopropane is replaced by 1,2-dibromoethane to obtain the target compound FQX-1D; 0.30 g of white solid, yield 79.58%; mp: 88-89°C; ESI-MS (m / z): 448.2 [M+H] + .

[0236] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.04(t,J=5.4Hz,1H),8.63(s,1H),8.41(s,1H),4.14(t,J=6.0Hz,2H),3.29 -3.24(m,2H),2.71(s,3H),2.54(t,J=6.0Hz,2H),2.37(d,J=5.9Hz,4H),1.94(t,J=7.4Hz,2H),1.52-1.23(m,14H).

[0237] 13 C NMR(101MHz,DMSO-d6)δ169.56,162.83,161.47,159.52,157.71,150.05,112.43,103.98,56.80,54.44,44.21,39.00,32.68,29.33, 28.72,26.64,26.11,25.52,24.34,13.93.),2.54(t,J=6.0Hz,2H),2.37(d,J=5.9Hz,4H),1.94(t,J=7.4Hz,2H),1.52-1.23(m,14H).

[0238] Example 28 Synthesis of 3-[3-(diethylamino)propyl]-N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-7D)

[0239] The preparation method of this example is the same as that of Example 26, except that piperidine is replaced by ethylenediamine to obtain the target compound YQ-7D; 0.20 g of white solid, yield 65.81%; mp: 115-117°C; ESI-MS (m / z): 450.3 [M+H] + .

[0240] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.08(t,J=5.3Hz,1H),8.66(s,1H),8.51(s,1H),4.07(t,J=7.0Hz,2H),3.27(td,J=6.9,5.3Hz,2H),2 .71(s,3H),2.47-2.34(m,6H),1.94(t,J=7.4Hz,2H),1.83(p,J=6.9Hz,2H),1.50(h,J=7.5Hz,4H),1.38-1.23(m,4H),0.90(t,J=7.1Hz,6H).

[0241] 13 C NMR(101MHz,DMSO-d6)δ169.54,162.84,161.47,159.67,157.70,149.89,112.43,104.1 5,49.69,46.32,46.16,38.98,32.69,29.32,28.73,26.64,26.09,25.51,13.92,11.82.

[0242] Example 29 Synthesis of 3-[3-(diethylamino)propyl]-N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (YQ-9D)

[0243] The preparation method of this example is the same as that of Example 26, except that piperidine is replaced by ethylmethylamine to obtain the target compound YQ-9D; 0.21 g of white solid, yield 69.34%; mp: 155-156°C; ESI-MS (m / z): 422.2 [M+H] + .

[0244] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.06(t,J=5.3Hz,1H),8.67(s,1H),8.51(s,1H),4.07(t,J=7.1Hz,2H),3.26(s,2H),2.71(s,3H), 2.24(t,J=6.7Hz,2H),2.12(s,6H),1.94(t,J=7.4Hz,2H),1.84(p,J=6.9Hz,2H),1.50(h,J=7.6Hz,4H),1.30(dq,J=24.8,8.9,8.1Hz,4H).

[0245] 13 C NMR(101MHz,DMSO-d6)δ169.51,162.84,161.47,159.67,157.73,149.82,112.44,10 4.18,56.16,45.86,45.38,38.98,32.67,29.33,28.72,26.64,26.49,25.52,13.93.

[0246] Example 30 Synthesis of 3-[3-(diethylamino)propyl]-N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (WZ-1D)

[0247] The preparation method of this example is the same as that of Example 26, except that 1,3-dibromopropane is replaced by 1,4-dibromobutane to obtain the target compound WZ-1D; 0.15 g of white solid, yield 56.39%; mp: 108-109°C; ESI-MS (m / z): 476.2 [M+H] + .

[0248] 1 H NMR (400MHz, DMSO-d6) δ10.31(s,1H),10.06(t,J=5.4Hz,1H),8.71(s,1H),8.55(s,1H),4.05(t,J=7.2Hz,2H),3.29-3. 21(m,2H),2.71(s,3H),2.25(dt,J=18.6,6.2Hz,6H),1.94(t,J=7.4Hz,2H),1.69(p,J=7.3Hz,2H),1.54-1.24(m,16H).

[0249] 13C NMR(101MHz,DMSO-d6)δ169.54,162.81,161.45,159.60,157.77,149.60,112.44,104.24,58.4 0,54.46,47.23,38.97,32.69,29.34,28.72,27.22,26.62,26.02,25.52,24.60,23.76,13.93.

[0250] Example 31 Synthesis of N-[7-(hydroxyamino)-7-oxoheptyl]-6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxamide (FQX-2D)

[0251] The preparation method of this example is the same as that of Example 26, except that: piperidine is replaced by pyrrolidine, 1,3-dibromopropane is replaced by 1,2-dibromoethane, and the target compound FQX-2D is obtained; 6-methyl-4-oxo-3-[2-(pyrrolidin-1-yl)ethyl]-3,4-dihydrofuran[2,3-d]pyrimidine-5-carboxylic acid is used as a raw material, and the target compound FQX-2D is obtained through two steps of reaction; white solid 0.33 g, yield 94.10%; mp: 183-185°C; ESI-MS (m / z): 434.2 [M+H] + .

[0252] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),10.03(t,J=5.4Hz,1H),8.65(s,1H),8.46(s,1H),4.15(t,J=6.1Hz,2H),3.27(q,J=6.8Hz ,2H),2.72(d,J=7.1Hz,5H),2.51(s,4H),1.94(t,J=7.4Hz,2H),1.67(h,J=3.1Hz,4H),1.49(p,J=7.4Hz,4H),1.38-1.24(m,4H).

[0253] 13 C NMR(101MHz,DMSO-d6)δ169.56,162.81,161.43,159.50,157.76,149.89,112.41,10 4.10,54.15,54.03,45.86,39.00,32.69,29.32,28.72,26.64,25.52,23.69,13.93.

[0254] Test Example: Inhibitory activity test of compounds based on the structure of 6-methylfurano[2,3-d]pyrimidin-4(3H)-one on human non-small cell lung cancer cells H460 and H460 DNMT3A-HDAC6 double knockout cells

[0255] H460 DNMT3AHDAC6 double knockout cells were constructed using CRISPR-Cas9 technology. RPMI 1640 medium was used as the basic culture medium to prepare a cell culture medium containing 10% fetal bovine serum. Culture was carried out in a 37°C incubator containing 5% CO2. The culture medium was replaced once a day. When the cells grew to 80% to 90%, the original culture medium was discarded, the cells were rinsed once with PBS, and the cells were digested with 0.25% trypsin. The cells were subcultured according to the experimental requirements.

[0256] Use an analytical balance to weigh some of the compound powders prepared in Examples 1 to 31, calculate the required volume of DMSO based on the molecular weight of the compound and the weighed mass, prepare a mother solution of the same concentration (100 mM / L), use a vortex instrument to oscillate, fully dissolve and mix, and dispense into 200 μL centrifuge tubes to avoid repeated freezing and thawing. Store in a refrigerator at -40°C, and use the working solution freshly prepared.

[0257] Take cells in good growth condition in the logarithmic growth phase, digest the cells with 0.25% trypsin, and then disperse them into a single cell suspension by blowing with culture medium. After counting, inoculate them in a 96-well plate with an appropriate density (H460 Vector, H460DNMT3AHDAC6-KO2500 / well), 100 μL / well, and culture them in a 37°C incubator with a CO2 concentration of 5%.

[0258] Initial drug screening: After the cells have grown overnight, cells in good growth condition in the logarithmic growth phase are taken and dispersed into a single cell suspension. The cells are plated at a density of 2500 cells / well (H460 Vector, H460 DNMT3AHDAC6-KO). After 18 hours of plating, 31 test compounds at a concentration of 10 μM are added to the two types of cells, with six replicate wells for each compound, and the effect is 96 hours.

[0259] Drug rescreening: After the cells were cultured overnight, 5 drugs with different concentration gradients were set according to the experimental needs. Each group includes 6 replicate wells, and each plate also has a blank group. In the experiment, the drug was diluted to a concentration gradient of 100μM, 10μM, 1μM, 0.1μM, and 0.01μM for drug addition, and the continuous action time was 96 hours. After drug addition, the cells were cultured in a constant temperature cell culture incubator with a CO2 concentration of 5% and 37°C for the corresponding time, and the cell state was observed using an inverted microscope.

[0260] After the drug action time is over, 10 μL of 2.5 mg / mL MTT solution is added to each well and incubated in a 37°C incubator for 4 hours. Then, the supernatant is removed, 100 μL of dimethyl sulfoxide is added to each well, and shaken at an appropriate speed for 5 minutes to dissolve the purple crystals. The 96-well plate is placed in an ELISA reader, the optical density value of each well at a wavelength of 492 nm is detected, and the effect of the drug on cell proliferation is calculated.

[0261] The cell proliferation rate, inhibition rate and drug resistance index of each group were calculated.

[0262] Cell survival rate % = (OD value of drug group / OD value of blank group) × 100%;

[0263] Inhibition rate % = (1-OD value of drug administration group / OD value of blank group) × 100%;

[0264] GraphPadPrism 8.0 software was used to draw a graph based on the drug concentration and the inhibition rate of cell growth, and then SPSS20.0 was used to perform regression-Probit method to calculate the half effective inhibitory concentration (IC 50 )value.

[0265] The inhibition rates of the compounds of the present invention on H460 Vector and H460 DNMT3A-HDAC6 double knockout cells are shown in Table 1.

[0266] Table 1 Inhibition rate of the compounds of the present invention (%)

[0267]

[0268]

[0269] Furthermore, FQX-1B, FQX-3C, YQ-1C, FQX-1D, FQX-2B, YQ-1B, and YQ-2A were diluted to 100 μM, 10 μM, 1 μM, 0.1 μM, and 0.01 μM concentration gradients for inhibition test, and the IC 50 The results are shown in Table 2.

[0270] Table 2 IC of the compounds of the present invention 50 Value (μM)

[0271]

[0272] According to Tables 1 and 2, it can be seen that the inhibition rates of compounds FQX-1B, FQX-3C, YQ-1C, FQX-1D, and FQX-2D on human non-small cell lung cancer cells H460 Vector were significantly higher than those on H460-DNMT3A / HDAC6 double knockout cells; the inhibition rates of compounds FQX-1B, FQX-2B, YQ-1B, YQ-2A, YQ-7A, and FQX-1D on H460 Vector and H460-DNMT3A / HDAC6 double knockout cells were all strong; and compound FQX-1D showed a stronger selective inhibitory effect on DNMT3A and HDAC6.

[0273] In order to determine the interaction of the compounds of the present invention with DNMT3A and HDAC6, a cell thermal shift assay (CETSA) was performed on compound FQX-1D. Figure 1 As shown. Figure 1 It can be seen that after treatment with compound FQX-1D, the thermal stability of DNMT3A and HDAC6 was significantly enhanced compared with the control group, indicating that there is a direct interaction between compound FQX-1D and DNMT3A and HDAC6 in cells.

[0274] The effect of compound FQX-1D on the global methylation status of genomic DNA in H460 vector cells was evaluated using methylation dot blot analysis. Figure 2 As shown. Figure 2 As can be seen, cells treated with the DNMT inhibitor 5-Aza or the compound FQX-1D showed a clear concentration-dependent reduction in global methylation.

[0275] Acetylated α-tubulin (Ac-α-tubulin) is the main cytoplasmic substrate of HDAC6 and has a significant impact on tumorigenesis. It is usually used as an indicator of HDAC6 deacetylase activity. The expression level of Ac-α-tubulin in H460 cells was detected. The results are as follows Figure 3 As shown. Figure 3 It can be seen that, consistent with the HDAC6 inhibitor WT-161, compound FQX-1D significantly increased the level of Ac-α-tubulin in a dose-dependent manner by inhibiting HDAC6 activity, and the effect was better than WT-161 used as a positive control at a high dose.

[0276] The enzyme activity of compound FQX-1D was tested, and the results were as follows: Figure 4 As shown. Figure 4 It can be seen that compound FQX-1D exhibits concentration-dependent inhibitory effects on both DNMT and HDAC6 enzymes, with IC 50 The value is close to the IC of the positive drug 50The above results indicate that compound FQX-1D has a strong binding affinity to DNMT3A and HDAC6 and effectively inhibits their respective activities.

[0277] The effects of the test compound FQX-1D on the proliferation, migration and self-renewal ability of H460 vector cells were compared with DNMT3A-HDAC6 double knockout (Double KO) cells. The results showed that the proliferation and migration ability of Double KO cells were partially impaired compared with vector cells, indicating the role of DNMT3A and HDAC6 in tumorigenesis. The clone formation experiment and sphere formation assay showed that the compound FQX-1D significantly inhibited the number of colonies and tumor spheres formed by vector cells in a concentration-dependent manner, but had no significant inhibitory effect on Double KO cells. Similarly, the well migration assay confirmed that the compound FQX-1D inhibited the migration ability of vector cells in a concentration-dependent manner, while the inhibitory effect on Double KO cells was very small.

[0278] The targeting activity of compound FQX-1D in vivo was detected in a subcutaneous xenograft model established with H460 vector and DNMT3AHDAC6 double knockout cells. The results showed that, consistent with the results of in vitro experiments, knockout of DNMT3A and HDAC6 in mice showed a more than 60% reduction in tumor volume compared with the Vector group. Treatment with compound FQX-1D (20 mg / kg) resulted in tumor regression in H460 vector cell xenograft mice, while showing minimal inhibitory effect on double KO cell-derived tumor growth. The inhibition rates of endpoint tumor weights were 67.83% and 27.48%, respectively. The above results can demonstrate that compound FQX-1D can inhibit the proliferation of human non-small cell lung cancer cells in vivo by specifically inhibiting DNMT3A and HDAC6.

[0279] It can be seen from the above examples that the compounds provided by the present invention are selective for DNMT3A and HDAC6, and have strong DMNT3A inhibitory effect and HDAC6 inhibitory effect. The inhibitory activity on human non-small cell lung cancer cells H460 is much higher than that on H460 DNMT3A-HDAC6 double knockout cells, and has application value as a drug therapeutic agent for the treatment of diseases and disorders related to DNMT3A and HADC6.

[0280] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. Other embodiments can be obtained based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A compound based on the structure of 6-methylfurano[2,3-d]pyrimidin-4(3H)-one, characterized in that: The structure is shown in Formula I: In formula I, R is amino, substituted amino, hydroxyl or alkoxy; L is a benzene ring, a substituted benzene ring, an aromatic heterocycle, a substituted aromatic heterocycle or an alkyl chain; and n is 1, 2, 3 or 4.

2. The compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure according to claim 1, characterized in that: In R of Formula I, the substituted amino group includes any one of the following structural groups: The alkoxy group includes a methoxy group or an ethoxy group.

3. The compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure according to claim 1 or 2, characterized in that In L of Formula I, the substituted benzene ring is: The aromatic heterocycle is: The substituted aromatic heterocycles include: The alkyl chain is:

4. The compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure according to claim 1 or 2, characterized in that The compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure includes any one of the following structural compounds:

5. The method for preparing a compound based on a 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure according to any one of claims 1 to 4, characterized in that: The following steps are involved: (1) mixing 2-chloro-3-oxobutyric acid acetic acid and malononitrile to carry out a cyclization reaction to obtain a compound with a structure shown in Formula II; (2) mixing the compound of formula II with formic acid and acetic anhydride to carry out a cyclization reaction to obtain a compound of formula III; (3) mixing the compound having a structure represented by Formula III with a substituted alkane, a first basic compound and a first organic solvent to carry out a substitution reaction to obtain a compound having a structure represented by Formula IV; (4) mixing the compound of formula IV with a substituted amine, a second basic compound and a second organic solvent to carry out a substitution reaction to obtain a compound of formula V; The structural formula of the substituted amine is shown in Formula VIII: RH type VIII; (5) mixing the compound of formula V with a third basic compound and a third solvent to carry out a hydrolysis reaction to obtain a compound of formula VI; (6) mixing the compound of formula VI with an amino-substituted carboxylic acid ester, a condensing agent and a fourth organic solvent to carry out a condensation reaction to obtain a compound of formula VII; (7) mixing the compound of the structure represented by Formula VII with hydroxylamine, water, a fourth basic compound and a fifth organic solvent to carry out a hydroxylamine reaction to obtain the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure; 6. The preparation method according to claim 5, characterized in that: The molar ratio of the compound represented by the formula II to formic acid is 1:10-30; The molar ratio of the compound represented by the formula II to acetic anhydride is 1:5-10.

7. The preparation method according to claim 5 or 6, characterized in that: The molar ratio of the compound represented by the structure of formula III to the substituted alkane is 1:3-10; The molar ratio of the compound of formula III to the first basic compound is 1:1.2-5; The mass volume ratio of the compound represented by the structure of formula III to the first organic solvent is 1:5-30.

8. The preparation method according to claim 5, characterized in that: The molar ratio of the compound represented by the formula VI to the amino-substituted carboxylic acid ester is 1:0.8-1.2; The molar ratio of the compound of the structure represented by formula VI to the condensing agent is 1:1-2; The mass volume ratio of the compound represented by the structure of Formula VI to the fourth organic solvent is 1:5-50.

9. The preparation method according to claim 5 or 8, characterized in that: The mass ratio of hydroxylamine to water is 1:1-10; The molar ratio of the compound of the structure represented by Formula VII to hydroxylamine is 1:20-100; The molar ratio of the compound of the structure represented by Formula VII to the fourth basic compound is 1:5-20; The mass volume ratio of the compound represented by the structure of Formula VII to the fifth organic solvent is 1:5-50.

10. Use of the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure according to any one of claims 1 to 4 or the compound based on the 6-methylfurano[2,3-d]pyrimidin-4(3H)-one structure obtained by the preparation method according to any one of claims 5 to 9 in the preparation of drugs for treating diseases related to DNA methyltransferase 3A or histone deacetylase.

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