Imidazo tetrahydropyrimidone derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of medicinal chemistry, in particular to an imidazo tetrahydropyrimidone derivative as well as a preparation method and application thereof. The imidazo tetrahydropyrimidone derivative provided by the invention has strong inhibitory activity to HDAC1, and compared with SAHA, part of the imidazo tetrahydropyrimidone derivative has stronger inhibitory activity to HDAC1.

Description

Technical Field

[0001] The present invention relates to the technical field of medicinal chemistry, and in particular to an imidazotetrahydropyrimidinone derivative, a preparation method and application thereof. Background Art

[0002] Histone deacetylases (HDACs) are important epigenetic regulators that regulate key biological processes such as gene transcription, translation, apoptosis, and chromatin remodeling by catalyzing the deacetylation of lysine on histone and non-histone substrates. HDACs can be divided into four subclasses (classes I, II, III, and IV). Class I, II, and IV HDACs share highly homologous catalytic core domains, and their catalytic activity depends on the participation of zinc ions. Class III HDACs are a family of nicotinamide adenine dinucleotide-dependent Sirtuins, including SIRT1-7. Among class I HDACs, HDAC1, 2, and 3 primarily deacetylate lysine in the nucleus, while HDAC8 is involved in the deacetylation of fatty acids. Class II HDACs can be further divided into subclass IIa (HDAC4, 5, 7, 9) and subclass IIb (HDAC6, 10). Class IIa is primarily responsible for recognizing acetylated lysine, with HDAC6 acting on the deacetylation of cytoplasmic lysine and HDAC10 involved in the deacetylation of polyamines. HDAC11, the only member of class IV, has a fatty acid deacetylation function. In recent years, numerous studies have demonstrated that HDACs are overactivated in a variety of diseases, including cancer, heart disease, and inflammation, and have become an important target for drug discovery. Currently, several HDAC inhibitors have been approved for the treatment of hematological malignancies, such as sidamistat, vorinostat, panobinostat, and romidepsin. However, most of these drugs are broad-spectrum HDAC inhibitors, and their use inevitably leads to potential side effects, such as hepatotoxicity and nephrotoxicity. Therefore, the development of novel, highly effective, and low-toxic HDAC inhibitors remains of great significance and value. Summary of the Invention

[0003] The purpose of the present invention is to provide an imidazotetrahydropyrimidinone derivative and a preparation method and application thereof, wherein the imidazotetrahydropyrimidinone derivative has a potent inhibitory activity on HDAC1 protein.

[0004] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0005] The present invention provides an imidazotetrahydropyrimidinone derivative having the structure shown in Formula I:

[0006]

[0007] Among them, R1 is

[0008] R2 is

[0009] Preferably, the imidazotetrahydropyrimidinone derivative is a compound represented by any one of Formulas 1 to 10:

[0010]

[0011]

[0012] The present invention also provides a method for preparing the imidazotetrahydropyrimidinone derivative described in the above technical solution, comprising the following steps:

[0013] (1) a compound having a structure represented by formula a is subjected to a first substitution reaction with carbon disulfide and DABCO (1,4-diazabicyclo[2.2.2]octane) to obtain a compound having a structure represented by formula b;

[0014] (2) subjecting the compound having the structure shown in formula b to a Boc removal reaction with 4-dimethylaminopyridine and di-tert-butyl dicarbonate to obtain a compound having the structure shown in formula c;

[0015] (3) subjecting the compound having the structure shown in Formula C to a cyclization reaction with aminoacetonitrile hydrochloride under alkaline conditions to obtain a compound having the structure shown in Formula D;

[0016] (4) subjecting the compound having the structure shown in Formula d to a second substitution reaction with X-R1 under alkaline conditions to obtain a compound having the structure shown in Formula e, wherein X is a halogen, such as Br, Cl, etc.;

[0017] (5) reacting the compound having the structure shown in formula e with X-R2-CO-O-CH3 under alkaline conditions to undergo a third substitution reaction to obtain a compound having the structure shown in formula f, wherein X is a halogen, such as Br, Cl, etc.;

[0018] (6) hydrolyzing the compound having the structure represented by Formula F under alkaline conditions, and reacting the hydrolyzed compound with an aqueous solution of hydroxylamine to obtain a compound having the structure represented by Formula I, wherein Formula I is the imidazotetrahydropyrimidinone derivative;

[0019]

[0020] Preferably, in step (1), the molar ratio of the compound having the structure represented by formula a to carbon disulfide and DABCO is 1:(1-4):(0.5-1);

[0021] The temperature of the first substitution reaction is 20-50°C.

[0022] Preferably, in step (2), the molar ratio of the compound having the structure shown in formula b to the compound of 4-dimethylaminopyridine and di-tert-butyl dicarbonate is 1:(0.5-3):(1-10);

[0023] The temperature of the Boc removal reaction is 25-50°C.

[0024] Preferably, in step (3), the molar ratio of the compound having the structure shown in formula C to aminoacetonitrile hydrochloride and the substance providing alkaline conditions is 1: (0.5-3): (1-2.5) respectively;

[0025] The temperature of the cyclization reaction is -5 to 15°C.

[0026] Preferably, in step (4), the molar ratio of the compound having the structure shown in formula d, X-R1 and the substance providing alkaline conditions is 1:(1-3):(1-3);

[0027] The temperature of the second substitution reaction is 0-25°C.

[0028] Preferably, in step (5), the molar ratio of the compound having the structure shown in formula e, X-R2-CO-O-CH3 and the substance providing alkaline conditions is 1:(1-3):(1-3);

[0029] The temperature of the third substitution reaction is 25-50°C.

[0030] Preferably, in step (6), the molar ratio of the compound having the structure represented by formula f, hydroxylamine and the substance providing alkaline conditions is 1:(1-10):(1-3).

[0031] Preferably, in steps (3)-(6), the substance providing alkaline conditions is one or more of triethylamine, sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium bicarbonate.

[0032] Application of the imidazotetrahydropyrimidinone derivative in the preparation of HDAC1 inhibitors.

[0033] Beneficial effects of the present invention:

[0034] The present invention provides an imidazotetrahydropyrimidinone derivative having good inhibitory activity against HDAC1. Some of the imidazotetrahydropyrimidinone derivatives described in the present invention have stronger inhibitory activity against HDAC1 protein than SAHA. DETAILED DESCRIPTION

[0035] In the present invention, unless otherwise specified, all raw material components are commercially available products well known to those skilled in the art.

[0036] In the present invention, the substitution reaction between the compound having the structure represented by Formula (a) and carbon disulfide and DABCO is preferably carried out by mixing carbon disulfide, DABCO, the compound having the structure represented by Formula (a), and a polar organic solvent, and conducting a first substitution reaction at room temperature. In the present invention, the polar organic solvent is preferably one or more of methanol, ethanol, acetonitrile, and dioxane. When the solvent is two or more of the above-mentioned specific selections, the present invention does not have any particular limitation on the ratio of the above-mentioned specific solvent components, and they can be mixed in any ratio.

[0037] In the present invention, the mixing of carbon disulfide, DABCO, the compound having the structure shown in formula a, and the polar organic solvent is preferably carried out under stirring conditions; the present invention does not have any special restrictions on the stirring conditions, and the stirring conditions can be carried out using a process well known to those skilled in the art. In the present invention, the mixing of carbon disulfide, DABCO, the compound having the structure shown in formula a, and the polar organic solvent is preferably carried out by mixing the compound having the structure shown in formula a with the polar organic solvent, and then mixing with the carbon disulfide and DABCO. In the present invention, the mixing method with carbon disulfide and DABCO is preferably to add carbon disulfide dropwise to the mixed solution of DABCO, the compound having the structure shown in formula a, and the polar organic solvent; the present invention does not have any special restrictions on the dropping process, and the stirring conditions can be carried out using a process well known to those skilled in the art.

[0038] In the present invention, the molar ratio of the compound having the structure represented by Formula a to carbon disulfide and DABCO is preferably 1:(1-4):(0.5-1), more preferably 1:(1-3):(0.5-1), and most preferably 1:(2-3):(0.8-1). In the present invention, the volume ratio of the amount of the compound having the structure represented by Formula a to the solvent is preferably 1 mmol:(2-4) mL, such as 1 mmol:2 mL, 1 mmol:3 mL, and the like.

[0039] In the present invention, the temperature of the first substitution reaction is preferably 20-50°C, more preferably 25-40°C, and most preferably 25-30°C; the time of the first substitution reaction is preferably 2-10h, more preferably 3-9h, and most preferably 4-6h.

[0040] After the first substitution reaction is completed, the present invention further preferably includes post-processing the product system obtained by the first substitution reaction, and the post-processing preferably includes cooling and filtration performed in sequence; in the present invention, the cooling is preferably performed under stirring conditions, and the present invention has no special restrictions on the stirring, and the stirring is performed using a process well known to those skilled in the art and ensures that the product system can be cooled to room temperature and solids are precipitated. In the present invention, the filtration method is preferably suction filtration; the present invention has no special restrictions on the suction filtration, and the filtration is performed using a process well known to those skilled in the art.

[0041] After obtaining the compound having the structure shown in formula b, the present invention performs a de-Boc reaction on the compound having the structure shown in formula b with 4-dimethylaminopyridine and di-tert-butyl dicarbonate to obtain a compound having the structure shown in formula c. In the present invention, the de-Boc reaction is preferably carried out by mixing the compound having the structure shown in formula b, 4-dimethylaminopyridine, di-tert-butyl dicarbonate and a polar organic solvent at room temperature. In the present invention, the polar organic solvent is preferably one or more of ethanol, methanol, acetonitrile, dichloromethane and dioxane; when the polar organic solvent is two or more of the above-mentioned specific selections, the present invention does not have any special restrictions on the ratio of the above-mentioned specific substances, and can be mixed in any ratio. In the present invention, the mixture of the 4-dimethylaminopyridine, di-tert-butyl dicarbonate, the compound having the structure shown in formula b and the polar organic solvent is preferably 4-dimethylaminopyridine, the compound having the structure shown in formula b and the polar organic solvent are mixed, and then mixed with the di-tert-butyl dicarbonate.

[0042] In the present invention, the molar ratio of the compound having the structure represented by formula b to 4-dimethylaminopyridine and di-tert-butyl dicarbonate is preferably 1:(0.5-3):(1-10). The mass ratio of the compound having the structure represented by formula b to the solvent is preferably 1 mmol:(2-4) mL, more preferably 1 mmol:3 mL.

[0043] In the present invention, the temperature of the de-Boc reaction is preferably 25-50°C, more preferably 28-40°C, and most preferably 28-35°C; the time of the de-Boc reaction is preferably 0.5-3h, more preferably 0.5-2h, and most preferably 0.5-1h.

[0044] After the de-Boc reaction is completed, the present invention further preferably includes post-processing the product system obtained by the de-Boc reaction, and the post-processing preferably includes purification; in the present invention, the purification is preferably performed using a chromatographic column; the present invention does not have any special limitations on the purification process, and the purification process can be performed using a process well known to those skilled in the art.

[0045] After obtaining the compound having the structure shown in Formula C, the present invention conducts a cyclization reaction between the compound having the structure shown in Formula C and aminoacetonitrile hydrochloride under alkaline conditions to obtain a compound having the structure shown in Formula D. In the present invention, the cyclization reaction process is preferably: mixing the compound having the structure shown in Formula C, aminoacetonitrile hydrochloride, a substance providing the alkaline conditions, and a polar solvent, and conducting a cyclization reaction. In the present invention, the substance providing the alkaline conditions is preferably one or more of triethylamine, potassium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate. When the substance providing the alkaline conditions is two or more of the above-mentioned specific selections, the present invention has no particular restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio. In the present invention, the polar solvent is preferably one or more of water, methanol, ethanol, acetone, acetonitrile, and dioxane. When the polar solvent is two or more of the above-mentioned specific selections, the present invention has no particular restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0046] In the present invention, the mixing is preferably carried out under stirring conditions. The present invention does not have any particular limitations on the stirring, and the stirring can be carried out using a process well known to those skilled in the art. In the present invention, the order of the mixing is preferably: after mixing the compound having the structure represented by Formula C, aminoacetonitrile hydrochloride, and a polar solvent, adding a substance providing alkaline conditions. In the present invention, the substance providing alkaline conditions is preferably added dropwise in the form of a solution; the present invention does not have any particular limitations on the dropping, and the dropping process well known to those skilled in the art can be used.

[0047] In the present invention, the molar ratio of the compound having the structure represented by formula c, aminoacetonitrile hydrochloride and the substance providing alkaline conditions is preferably 1: (0.5-3): (1-2.5); in the present invention, the volume ratio of the mass of the compound having the structure represented by formula d to the polar solvent is preferably 1 mmol: (2-6) mL, such as 1 mmol: 3 mL, 1 mmol: 5 mL, and the like.

[0048] In the present invention, the cyclization reaction is preferably carried out under low temperature conditions; the temperature of the cyclization reaction is preferably -5 to 15°C, more preferably -5 to 5°C, and most preferably -5 to 0°C; the time of the cyclization reaction is preferably 1 to 3 hours, more preferably 1 to 2 hours, and most preferably 1.5 to 2 hours.

[0049] In the present invention, whether the cyclization reaction is complete is preferably determined by TLC to determine whether the compound having the structure shown in Formula C disappears.

[0050] After the cyclization reaction is completed, the present invention further preferably includes post-processing the product system obtained after the cyclization reaction, and the post-processing preferably includes extraction and purification performed sequentially. In the present invention, the extraction is preferably performed three times sequentially using ethyl acetate and water. The present invention does not have any particular limitations on the amounts of ethyl acetate and water used, and amounts familiar to those skilled in the art can be used. In the present invention, the purification is preferably performed using a chromatographic column. The present invention does not have any particular limitations on the purification process, and a process familiar to those skilled in the art can be used.

[0051] After obtaining the compound having the structure shown in formula d, the present invention conducts a second substitution reaction between the compound having the structure shown in formula d and X-R1 under alkaline conditions to obtain a compound having the structure shown in formula e. In the present invention, the process of the substitution reaction is preferably: mixing the compound having the structure shown in formula d, X-R1, the substance providing the alkaline conditions and a polar solvent to carry out a substitution reaction. In the present invention, the substance providing the alkaline conditions is preferably one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium bicarbonate; when the substance providing the alkaline conditions is two or more of the above-mentioned specific selections, the present invention has no special restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio. In the present invention, the polar solvent is preferably one or more of water, methanol, ethanol, acetone, acetonitrile and dioxane. When the polar solvent is two or more of the above-mentioned specific selections, the present invention has no special restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0052] In the present invention, the mixing is preferably carried out under stirring conditions. The present invention does not have any particular limitation on the stirring and can be carried out using a process well known to those skilled in the art. In the present invention, the order of the mixing is preferably: after mixing the compound having the structure shown in Formula d, X-R1 and a polar solvent, adding a substance that provides alkaline conditions. In the present invention, the substance that provides alkaline conditions is preferably added in the form of a solid.

[0053] In the present invention, the molar ratio of the compound having the structure represented by formula d, X-R1 and the substance providing alkaline conditions is preferably 1:(1~3):(1~3); in the present invention, the volume ratio of the mass of the compound having the structure represented by formula d to the polar solvent is preferably 1mmol:(2~4)mL, such as 1mmol:3mL, 1mmol:4mL and the like.

[0054] In the present invention, the second substitution reaction is preferably carried out under low temperature conditions; the temperature of the substitution reaction is preferably 0-25°C, more preferably 0-15°C, and most preferably 5-15°C; the time of the substitution reaction is preferably 0.5-2h, more preferably 0.5-1.5h, and most preferably 0.5-1h.

[0055] In the present invention, whether the substitution reaction is completed is preferably determined by TLC to determine whether the compound having the structure shown in Formula d disappears.

[0056] After the substitution reaction is completed, the present invention further preferably includes post-processing the product system obtained after the substitution reaction, and the post-processing preferably includes extraction and purification performed sequentially. In the present invention, the extraction is preferably performed three times sequentially using ethyl acetate and water. The present invention does not have any particular restrictions on the amounts of ethyl acetate and water used, and amounts familiar to those skilled in the art can be used. In the present invention, the purification is preferably performed using a chromatographic column. The present invention does not have any particular restrictions on the purification process, and a process familiar to those skilled in the art can be used.

[0057] After obtaining the compound having the structure shown in Formula e, the present invention conducts a third substitution reaction between the compound having the structure shown in Formula e and X-R2-CO-O-CH3 under alkaline conditions to obtain a compound having the structure shown in Formula f. In the present invention, the process of the substitution reaction is preferably: mixing the compound having the structure shown in Formula e, X-R2-CO-O-CH3, a substance providing the alkaline conditions and a polar solvent to conduct a third substitution reaction. In the present invention, the substance providing the alkaline conditions is preferably one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate and potassium bicarbonate; when the substance providing the alkaline conditions is two or more of the above-mentioned specific selections, the present invention has no special limitation on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio. In the present invention, the polar solvent is preferably one or more of N,N-dimethylformamide, water, methanol, ethanol, acetone, acetonitrile and dioxane. When the polar solvent is two or more of the above-mentioned specific selections, the present invention has no special restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0058] In the present invention, the mixing is preferably carried out under stirring. The present invention does not have any particular limitation on the stirring and can be carried out using a process well known to those skilled in the art. In the present invention, the order of the mixing is preferably: after mixing the compound having the structure shown in formula e, X-R2-CO-O-CH3 and a polar solvent, adding a substance providing alkaline conditions. In the present invention, the substance providing the alkaline conditions is preferably added in the form of a solid.

[0059] In the present invention, the molar ratio of the compound having the structure represented by formula e, X-R2-CO-O-CH3 and the substance providing alkaline conditions is preferably 1:(1-3):(1-3); in the present invention, the volume ratio of the mass of the compound having the structure represented by formula e to the polar solvent is preferably 1 mmol:(2-4) mL.

[0060] In the present invention, the temperature of the third substitution reaction is preferably 25-50°C, more preferably 30-50°C, most preferably 35-45°C; the time of the substitution reaction is preferably 2-6h, more preferably 3-5h, most preferably 3-4h.

[0061] In the present invention, whether the substitution reaction is completed is preferably determined by TLC to determine whether the compound having the structure represented by Formula e disappears.

[0062] After the substitution reaction is completed, the present invention further preferably includes post-processing the product system obtained after the substitution reaction, and the post-processing preferably includes extraction and purification performed sequentially. In the present invention, the extraction is preferably performed three times sequentially using ethyl acetate and water. The present invention does not have any particular restrictions on the amounts of ethyl acetate and water used, and amounts familiar to those skilled in the art can be used. In the present invention, the purification is preferably performed using a chromatographic column. The present invention does not have any particular restrictions on the purification process, and a process familiar to those skilled in the art can be used.

[0063] After obtaining the compound having the structure shown in Formula f, the present invention hydrolyzes the compound having the structure shown in Formula f with an aqueous solution of hydroxylamine under alkaline conditions to obtain a compound having the structure shown in Formula I. In the present invention, the process of the substitution reaction is preferably: mixing the compound having the structure shown in Formula f, an aqueous solution of hydroxylamine, a substance providing the alkaline conditions, and a polar solvent to carry out a substitution reaction. In the present invention, the substance providing the alkaline conditions is preferably one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, potassium phosphate, sodium carbonate, sodium bicarbonate, and potassium bicarbonate; when the substance providing the alkaline conditions is two or more of the above-mentioned specific selections, the present invention has no special restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio. In the present invention, the polar solvent is preferably one or more of water, methanol, ethanol, acetone, acetonitrile, dichloromethane, and dioxane. When the polar solvent is two or more of the above-mentioned specific selections, the present invention has no special restrictions on the ratio of the above-mentioned specific substances, and they can be mixed in any ratio.

[0064] In the present invention, the mixing is preferably carried out under stirring conditions. The present invention does not have any particular limitations on the stirring and can be carried out using a process well known to those skilled in the art. In the present invention, the order of the mixing is preferably: after mixing the compound having the structure represented by Formula f, the hydroxylamine aqueous solution and the polar solvent, adding the substance providing alkaline conditions. In the present invention, the substance providing alkaline conditions is preferably added in the form of a solid.

[0065] In the present invention, the molar ratio of the compound having the structure represented by formula f, hydroxylamine and the substance providing alkaline conditions is preferably 1: (1 to 10): (1 to 3); in the present invention, the volume ratio of the mass of the compound having the structure represented by formula f to the polar solvent is preferably 1 mmol: (2 to 5) mL, such as 1 mmol: 3 mL, 1 mmol: 5 mL and the like.

[0066] In the present invention, the specific method of the hydrolysis reaction is as follows: a compound having a structure shown in formula f is dispersed in a solvent, and then a hydroxylamine aqueous solution is added, the temperature is 20-30°C, and the reaction is stirred for 0.5-2 hours; then the mixture is placed in an ice bath, a substance providing alkaline conditions is added, and stirring is continued for 0.5-1 hour.

[0067] In the present invention, whether the substitution reaction is completed is preferably determined by TLC to determine whether the compound having the structure represented by formula f disappears.

[0068] After the hydrolysis reaction is completed, the present invention preferably further includes post-processing the product system obtained after the hydrolysis reaction; the post-processing preferably includes cooling, adjusting the pH, filtration, and recrystallization in sequence. In the present invention, the cooling is preferably carried out under stirring conditions; the present invention does not have any specific restrictions on the stirring; a process familiar to those skilled in the art can be used to ensure that the product system is cooled to room temperature. In the present invention, the reagent used for adjusting the pH is preferably a 0.1M formic acid solution; the product system after pH adjustment is preferably neutral. In the present invention, the purpose of adjusting the pH to neutral is to precipitate the solid product in the product system. In the present invention, the filtration method is preferably suction filtration; the present invention does not have any specific restrictions on the suction filtration; a process familiar to those skilled in the art can be used. In the present invention, the reagent used for recrystallization is preferably ethanol; the present invention does not have any specific restrictions on the amount of ethanol used and the recrystallization process; the use of an amount and a recrystallization process familiar to those skilled in the art can ensure that the compound having the structure represented by Formula H is achieved.

[0069] The present invention also provides the use of the imidazotetrahydropyrimidinone derivative described in the above technical solution or the imidazotetrahydropyrimidinone derivative prepared by the preparation method described in the above technical solution in the preparation of a drug, wherein the drug is an HDAC1 inhibitor.

[0070] In the present invention, the application is preferably to use the imidazotetrahydropyrimidinone derivative as an HDAC1 inhibitor; the present invention has no special limitation on the method of the application, and methods well known to those skilled in the art can be used.

[0071] The imidazotetrahydropyrimidinone derivatives provided by the present invention, their preparation methods and applications are described in detail below with reference to the examples, but they should not be construed as limiting the scope of protection of the present invention.

[0072] Example 1

[0073] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0074] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0075] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0076] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0077] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0078] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane: methanol = 1:2 by volume, sonicate, add a 50% hydroxylamine aqueous solution (10mmol), stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as formula 1);

[0079] The compound having the structure of Formula 1 was subjected to NMR testing, and the characterization results were: Yield 68%. White solid. Mp: 193.7-194.4 ℃. 1 H NMR (500MHz, DMSO-d6) δ11.17(s,1H),9.02(s,1H),7.71(d,J=8.0Hz,2H),7.32(d,J=8.2Hz,2H),7.27-7.20(m ,3H),7.13-7.03(m,2H),6.59(s,1H),4.90(s,2H),4.04(s,2H),3.76(t,J=6.8Hz,2H),2.62(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO)δ164.81,163.92,139.66,137.87,133.80,133.21,131.83 ,128.71,128.38,127.22,127.03,126.99,112.11,45.23,38.90,38.41,30.48.

[0080] Example 2

[0081] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0082] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0083] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0084] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0085] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0086] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 2);

[0087] The compound having the structure of Formula 2 was subjected to NMR testing, and the characterization results were: Yield 68%. White solid. Mp: 209.4-210.8 ℃. 1 HNMR(400MHz,DMSO-d6)δ11.19(s,1H),9.02(s,1H),7.71(d,J=8.2Hz,2H),7.45(dd,J=8.0,1.3Hz,1H),7.35-7.27(m,3H),7.13(td, J=7.5,1.3Hz,1H),7.04(dd,J=7.6,1.7Hz,1H),6.59(s,1H),4.90(s,2H),4.11(s,2H),3.79(t,J=6.8Hz,2H),2.66(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO)δ164.77,163.88,139.60,135.27,134.05,132.87,132.52,131.81 ,131.04,129.44,129.31,127.12,127.00,126.96,112.27,45.20,38.41,37.25,30.48.

[0088] Example 3

[0089] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0090] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0091] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0092] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0093] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0094] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (Recorded as Equation 3);

[0095] The compound having the structure of Formula 3 was subjected to NMR testing, and the characterization results were: Yield 78%. White solid. Mp: 150.5-151.9 ℃. 1H NMR (400MHz, DMSO-d6) δ10.36(s,1H),7.30(dd,J=4.6,2.2Hz,2H),7.17-7.09(m,2H),6.71(s,1H),4.07(s,2H),3.79(t,J=6.8H z,2H),3.61(t,J=7.3Hz,2H),2.55(t,J=6.8Hz,2H),1.93(t,J=7.4Hz,2H),1.51(dt,J=15.3,7.8Hz,4H),1.24(q,J=8.0Hz,2H). 13 CNMR(101MHz,DMSO)δ168.83,164.29,140.60,134.21,132.78,132.58,130.20,128. 48,127.40,127.05,111.58,42.51,38.50,38.40,32.07,30.49,26.56,25.66,24.76.

[0096] Example 4

[0097] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0098] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0099] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0100] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0101] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0102] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 4);

[0103] The compound having the structure of Formula 4 was subjected to NMR testing, and the characterization results were: Yield 83%. White solid. Mp: 176.5-178.9 ℃. 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),9.02(s,1H),7.70(d,J=8.2Hz,2H),7.37-7.27(m,3H),7.26(t,J=7.7Hz,1H),7.18(t,J =1.8Hz,1H),7.09(dt,J=7.5,1.5Hz,1H),6.59(s,1H),4.90(s,2H),4.06(s,2H),3.88(t,J=6.8Hz,2H),2.69(t,J=6.8Hz,2H). 13CNMR(101MHz,DMSO)δ164.76,163.81,140.55,139.59,133.99,132.94,132.81,131.80 ,130.17,128.49,127.37,127.06,127.00,126.96,112.04,45.34,38.45,38.35,30.45.

[0104] Example 5

[0105] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0106] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0107] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0108] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0109] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0110] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 5);

[0111] The compound having the structure of Formula 5 was subjected to NMR testing, and the characterization results were: Yield 71%. White solid. Mp: 203.4-204.7 ℃. 1 HNMR(500MHz,DMSO-d6)δ7.71(d,J=8.1Hz,2H),7.33(d,J=8.1Hz,2H),7.28(d,J=8.4Hz,2H), 7.14(d,J=8.4Hz,2H),6.57(s,1H),4.05(s,2H),3.88(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO)δ165.37,164.48,140.19,137.59,134.45,133.59,132 .38,131.10,128.84,127.59,127.55,112.61,45.81,39.02,38.76,31.05.

[0112] Example 6

[0113] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0114] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0115] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0116] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0117] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0118] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 6);

[0119] The compound having the structure of Formula 6 was subjected to NMR testing, and the characterization results were: Yield 59%. White solid. Mp: 181.5-182.7 ℃. 1 HNMR(400MHz,DMSO-d6)δ11.19(s,1H),9.04(s,1H),7.71(d,J=8.2Hz,2H),7.34(d,J=8.1Hz,2H),7.06-6.98(m,2H), 6.81-6.75(m,2H),6.58(s,1H),4.91(s,2H),4.00(s,2H),3.83(t,J=6.8Hz,2H),3.71(s,3H),2.67(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO)δ164.80,163.79,158.50,139.62,133.76,133.48,131.84,12 9.89,129.59,127.01,126.98,113.77,112.02,55.08,45.24,38.82,38.41,30.50.

[0120] Example 7

[0121] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0122] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0123] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0124] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0125] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0126] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane: methanol = 1:2 by volume, sonicate, add 20mmol of 50% hydroxylamine aqueous solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 7);

[0127] The compound having the structure of Formula 7 was subjected to NMR testing, and the characterization results were: Yield 67%. White solid. Mp: 200.1-201.1 ℃. 1 HNMR (400MHz, DMSO-d6) δ11.18(s,1H),9.02(s,1H),7.71(d,J=7.9Hz,2H),7.42(d,J=8.1Hz,2H),7.33(d,J=8.0H z,2H),7.08(d,J=8.2Hz,2H),6.57(s,1H),4.90(s,2H),4.04(s,2H),3.88(t,J=6.8Hz,2H),2.70(t,J=6.7Hz,2H). 13CNMR(101MHz,DMSO)δ164.84,163.91,139.67,137.52,133.91,133.00,131.84 ,131.25,130.94,127.06,127.02,120.35,112.10,45.26,38.48,38.30,30.51.

[0128] Example 8

[0129] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0130] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0131] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0132] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0133] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0134] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane: methanol = 1:2 by volume, sonicate, add 20mmol of 50% hydroxylamine aqueous solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 8);

[0135] The compound having the structure of Formula 8 was subjected to NMR testing, and the characterization results were: Yield 70%. White solid. Mp: 163.4-165.1 ℃. 1 HNMR (400MHz, DMSO-d6) δ11.18(s,1H),9.02(s,1H),7.70(d,J=8.0Hz,2H),7.44(d,J=6.4Hz,1H),7.34(d,J=8.1Hz,2H),7.29(d,J=1.9H z,1H),7.20(t,J=7.8Hz,1H),7.14(d,J=7.7Hz,1H),6.59(s,1H),4.91(s,2H),4.05(s,2H),3.87(t,J=6.8Hz,2H),2.68(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO)δ164.82,163.89,140.89,139.66,134.03,132.93,131.82,131 .40,130.55,130.00,127.82,127.05,121.43,112.13,45.39,38.50,38.45,30.49.

[0136] Example 9

[0137] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0138] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0139] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0140] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0141] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0142] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane: methanol = 1:2 by volume, sonicate, add 20mmol of 50% hydroxylamine aqueous solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 9);

[0143] The compound having the structure of Formula 9 was subjected to NMR testing, and the characterization results were: Yield 61%. White solid. Mp: 177.6-178.1 ℃. 1 HNMR(400MHz,DMSO-d6)δ11.19(s,1H),7.74-7.67(m,2H),7.33(d,J=8.1Hz,2H),7.30-7.23(m,1H),7.11(dd,J=16.4,6.5Hz,1H), 7.01(d,J=10.2Hz,1H),6.94(d,J=7.6Hz,1H),6.58(s,1H),4.91(s,2H),4.07(s,2H),3.89(t,J=6.8Hz,2H),2.70(t,J=6.8Hz,2H). 13 CNMR(101MHz,DMSO-d6)δ164.86,163.87,163.18,160.76,140.93,140.85,139.68,134.00,133.04,131.85,1 30.34,130.26,127.07,127.00,124.87,115.61,115.40,114.17,113.97,112.10,45.31,38.51,38.46,30.53.

[0144] Example 10

[0145] Under stirring, 50 mmol of carbon disulfide and 25 mmol of DABCO were added to 50 mL of (25mmol) in ethanol solution, react at room temperature for 4 to 6 hours, under stirring, solid precipitated, filtered, the obtained solid is

[0146] 20 mmol 15mmol of 4-dimethylaminopyridine, 30mmol of di-tert-butyl dicarbonate and 60mL of ethanol were mixed and reacted at room temperature for 1h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 4:1) to obtain

[0147] 10mmol 8mmol of aminoacetonitrile hydrochloride and 50mL of ethanol were mixed, and 10mmol of triethylamine was added under stirring. The mixture was reacted at 0℃ for 1h. The reaction was detected by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:2) to obtain

[0148] 5mmol 5mmol 10mmol sodium hydroxide and 20mL ethanol were mixed and stirred at room temperature for 0.5h. The obtained product system was extracted three times with ethyl acetate and water, and then purified by chromatography (methylene chloride / methanol mass ratio of 50:1) to obtain

[0149] 3mmol 3.6mmol Mix 6mmol potassium carbonate and 10ml N,N-dimethylformamide, stir at room temperature for 3-4h, and detect by TLC. The product system was extracted three times with ethyl acetate and water, and then purified by chromatographic column (petroleum ether / ethyl acetate mass ratio of 1:1) to obtain

[0150] 1mmol Place in a 25ml reaction flask, add 5ml of a mixed solvent of dichloromethane:methanol = 1:2 by volume, sonicate, add 20mmol of a 50% aqueous hydroxylamine solution, stir at room temperature for 0.5h, place the reaction system in an ice bath, slowly add 1.25mmol of lithium hydroxide, and continue stirring for 0.5h-1h. TLC detection The solution completely disappeared, the organic solvent was removed by distillation under reduced pressure, water was added to dissolve the residue, and the mixture was placed in an ice bath. Formic acid was slowly added dropwise under stirring until a large amount of white solid was generated. The addition was continued dropwise to adjust the pH of the solution to about 6, and stirring was continued for 5 minutes. The stirring was turned off and the mixture was allowed to stand for crystallization. The mixture was filtered, the solid was rinsed with water, and dried to obtain (denoted as Equation 10);

[0151] The compound having the structure of Formula 10 was subjected to NMR testing, and the characterization results were: Yield 72%. White solid. Mp: 186.8-188.7 ℃. 1H NMR (400MHz, DMSO-d6) δ7.69(d,J=7.9Hz,2H),7.36(d,J=7.9Hz,2H),6.48( s,1H),4.90(s,2H),4.15(t,J=6.8Hz,2H),2.90(t,J=6.8Hz,2H),2.79(d,J =6.8Hz,2H),1.76(d,J=12.6Hz,2H),1.69-1.54(m,3H),1.42(ddt,J=11.0, 7.4, 3.6Hz, 1H), 1.14 (h, J=11.8, 11.4Hz, 3H), 0.92 (q, J=10.2, 8.6Hz, 2H). 13 C NMR (101MHz, DMSO) δ164.90,163.79,139.71,134.82,133.66,131.88,127.1 1,127.01,111.29,45.41,40.85,38.40,37.26,31.71,30.67,25.82,25.39.

[0152] Test Case

[0153] The imidazotetrahydropyrimidone derivatives prepared in Examples 1 to 10 were subjected to HDAC1 inhibitory activity assay, and the test process was as follows:

[0154] Assay buffer: 0.01% Tween-20 (%), 50 mM Tris-HCl (pH 7.5), 50 mM NaCl. Compounds were dissolved in dimethyl sulfoxide (DMSO) and diluted with DMSO to a final concentration of 100 nM. 12 μL of HDAC1 protein (1 nM) was added to the reaction mixture. The mixture was incubated at room temperature for 15 minutes, followed by the addition of 8 μL of the substrate GL-8 (AC-Leu-Gly-Lys(Ac)-AMC). The concentration was read on an EnVision microplate reader (PerkinElmer) using the Ex355 / Em460 scale. % Inhibition = (1 - (experimental group value - blank group value) / (control group value - blank group value) × 100).

[0155] The test results are shown in Table 1:

[0156] Table 1 Inhibitory activity data of compounds in Examples 1 to 10 on HDAC1 protein

[0157]

[0158] As shown in Table 1, the imidazotetrahydropyrimidinone derivatives provided by the present invention have potent HDAC1 inhibitory activity, especially Example 10, which exhibits more potent activity than the positive control SAHA.

[0159] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principles of the present invention. These improvements and modifications should also be regarded as within the scope of protection of the present invention.

Claims

1. An imidazotetrahydropyrimidinone derivative, characterized in that: It has the structure shown in formula I: Among them, R1 is R2 is 2. An imidazotetrahydropyrimidinone derivative according to claim 1, characterized in that A compound represented by any one of formulas 1 to 10:

3. The method for preparing the imidazotetrahydropyrimidinone derivative according to claim 1 or 2, characterized in that: The following steps are involved: (1) subjecting the compound having the structure represented by formula a to a first substitution reaction with carbon disulfide and DABCO to obtain a compound having the structure represented by formula b; (2) subjecting the compound having the structure shown in formula b to a Boc removal reaction with 4-dimethylaminopyridine and di-tert-butyl dicarbonate to obtain a compound having the structure shown in formula c; (3) subjecting the compound having the structure shown in Formula C to a cyclization reaction with aminoacetonitrile hydrochloride under alkaline conditions to obtain a compound having the structure shown in Formula D; (4) subjecting the compound having the structure shown in Formula d to a second substitution reaction with X-R1 under alkaline conditions to obtain a compound having the structure shown in Formula e, wherein X is a halogen; (5) reacting the compound having the structure shown in Formula e with X-R2-CO-O-CH3 under alkaline conditions to undergo a third substitution reaction to obtain a compound having the structure shown in Formula f, wherein X is a halogen; (6) hydrolyzing the compound having the structure represented by Formula F under alkaline conditions, and reacting the hydrolyzed compound with an aqueous solution of hydroxylamine to obtain a compound having the structure represented by Formula I, wherein Formula I is the imidazotetrahydropyrimidinone derivative; 4. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (1), the molar ratio of the compound having the structure shown in formula a to carbon disulfide and DABCO is 1:(1-4):(0.5-1); the temperature of the first substitution reaction is 20-50°C.

5. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (2), the molar ratio of the compound having the structure shown in formula b to the compound of 4-dimethylaminopyridine and di-tert-butyl dicarbonate is 1:(0.5-3):(1-10); the temperature of the de-Boc reaction is 25-50°C.

6. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (3), the molar ratio of the compound having the structure shown in formula C to aminoacetonitrile hydrochloride and the substance providing alkaline conditions is 1:(0.5-3):(1-2.5), respectively; the temperature of the cyclization reaction is -5-15°C.

7. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (4), the molar ratio of the compound having the structure shown in formula d, X-R1 and the substance providing alkaline conditions is 1:(1~3):(1~3); the temperature of the second substitution reaction is 0~25°C.

8. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (5), the molar ratio of the compound having the structure shown in formula e, X-R2-CO-O-CH3 and the substance providing alkaline conditions is 1:(1~3):(1~3); the temperature of the third substitution reaction is 25~50°C.

9. The method for preparing an imidazotetrahydropyrimidinone derivative according to claim 3, wherein: In step (6), the molar ratio of the compound having the structure represented by formula f, hydroxylamine and the substance providing alkaline conditions is 1:(1-10):(1-3).

10. Use of the imidazotetrahydropyrimidinone derivative according to claim 1 or 2 in the preparation of an HDAC1 inhibitor.

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