Pyrimidine dione compounds, their preparation methods and applications

Abstract

This invention discloses a pyrimidine dione compound, its preparation method, and its applications, belonging to the field of pharmaceutical chemistry. Existing hypertrophic cardiomyopathy treatments, such as Avkaite, suffer from long half-life, easy accumulation in vivo, high drug risk, and poor safety. The pyrimidine dione compound provided by this invention is prepared by using (S)-1-(3-bromophenyl)ethylamine or its isomer as a starting material, introducing an aromatic heterocycle containing a borate ester group via a Suzuki coupling reaction, followed by a nucleophilic substitution reaction with a 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione. This compound effectively inhibits cardiac myosin ATPase activity, significantly reduces cardiomyocyte contractility, has a significantly shorter half-life than Avkaite, lower risk of accumulation in vivo, and superior safety. The compound of this invention can be used to prepare drugs for treating hypertrophic cardiomyopathy, especially suitable for feline hypertrophic cardiomyopathy, and can also be used for human hypertrophic cardiomyopathy.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical chemistry. More specifically, this invention relates to pyrimidine dione compounds, their preparation methods, and applications. Background Technology

[0002] Hypertrophic cardiomyopathy (HCM) is a primary cardiomyopathy characterized by asymmetric thickening of the ventricular walls. Its pathophysiological mechanisms are complex, and its clinical phenotypes are diverse. First systematically described by Teare in 1958, the disease is typically characterized by asymmetric thickening of the left ventricular wall, particularly the interventricular septum, often accompanied by ventricular cavity reduction, decreased left ventricular diastolic function, and left ventricular outflow tract obstruction (oHCM). Epidemiological studies show that the prevalence of HCM in the general population is approximately 1 / 500, and it is the leading cause of sudden cardiac death in adolescents and athletes.

[0003] Current treatment strategies for hemorrhagic muscular tract infection (HCM) primarily focus on symptom relief and complication prevention, lacking radical treatments targeting the underlying cause. First-line drug therapy includes beta-blockers (such as metoprolol), non-dihydropyridine calcium channel blockers (such as verapamil), and disopyramide. These drugs alleviate outflow tract obstruction by slowing heart rate and reducing myocardial contractility; however, approximately 30% of HCM patients do not respond well to drug therapy. For drug-resistant cases, invasive treatments such as septal alcohol ablation and surgical septal myocardectomy can effectively relieve obstruction, but they have limitations such as high surgical risks and numerous postoperative complications. In recent years, breakthroughs have been made in the development of novel targeted therapies. Among them, Mavacamten, as the first selective myosin ATPase inhibitor, inhibits excessive myocardial contraction by binding to the myosin-actin complex, significantly improving outflow tract pressure gradient and cardiac function in HCM patients. However, clinical application has shown that Avkaitide has pharmacokinetic defects: its plasma half-life is as long as 60-80 hours, leading to a prolonged dose adjustment cycle; and it has significant interactions with other drugs (such as strong CYP2C19 inhibitors), increasing the risk of adverse reactions. Moreover, some patients require frequent monitoring of creatine kinase levels due to the narrow therapeutic window, limiting its convenience for clinical application.

[0004] Based on the aforementioned clinical needs, the development of afucate analogues with superior pharmacokinetic properties and safety has become a research hotspot. The development of afucate analogues can not only fill the current clinical gaps in HCM treatment but also is expected to improve long-term patient outcomes by delaying myocardial remodeling and reducing the risk of sudden cardiac death. Therefore, research on afucate analogues has significant theoretical and clinical value, opening new avenues for the precision treatment of hypertrophic cardiomyopathy. Summary of the Invention

[0005] This invention provides a pyrimidine dione compound or its pharmaceutically acceptable salt, solvate, or prodrug molecule, addressing the technical problems of existing hypertrophic cardiomyopathy treatment drugs such as afukaitai, including long half-life, easy accumulation in vivo, high drug risk, and poor safety. The pyrimidine dione compound provided by this invention is prepared by introducing an aromatic heterocycle containing a borate ester group via a Suzuki coupling reaction using (1S)-1-(3-bromophenyl)ethylamine, (1S)-1-(4-bromophenyl)ethylamine, or (1S)-1-(2-bromophenyl)ethylamine as a starting material, followed by a nucleophilic substitution reaction with a 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione. This type of compound can effectively inhibit cardiac myosin ATPase activity, significantly reduce cardiomyocyte contractility, and has a significantly shorter half-life than afukaitai, with lower risk of accumulation in vivo and superior safety. The compound of this invention can be used to prepare drugs for the treatment of hypertrophic cardiomyopathy.

[0006] The compounds of this invention are particularly well-suited to the pharmacokinetic characteristics of pet cats and can be used as preferred therapeutic agents for feline hypertrophic cardiomyopathy; at the same time, they also have good inhibitory effects on human hypertrophic cardiomyopathy and have the potential for development for human use.

[0007] To achieve these objectives and other advantages according to the invention, a pyrimidine dione compound having the structure shown in general formula (I), (II), (III) or (IV) is provided, as well as a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug molecule thereof. (I); (II); (III); (IV); Among them, R1 is selected independently from hydrogen, , C1-C5 alkyl or C3-C5 cycloalkyl; R2, R3, R4, R5, R6, R7, R8, and R9 are each individually selected from hydrogen, C1-C2 alkyl, and R 10 R 11 R 12 R 13 Each is individually selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or C3-C6 cycloalkyl.

[0008] Preferably, in formula (I), R1 is selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, ... , R2 and R3 are each individually selected from hydrogen or methyl, R 10R4 and R5 are each individually selected from ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, isopentyl, cyclopentyl, cyclohexyl, and vinyl; in formula (II), R4 and R5 are each individually selected from hydrogen or methyl, R 11 Selected from isopropyl; in formula (III), R6 is selected from methyl, R 12 Selected from isopropyl; in formula (III), R7, R8, and R9 are each individually selected from hydrogen, R 13 Selected from isopropyl.

[0009] Preferably, the pyrimidine dione compounds with the structure shown in formula (I) are compounds of formulas 1 to 34 as follows: Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 Formula 9 Formula 10 Formula 11 Formula 12 Formula 13 Formula 14 Formula 15 Formula 16 Formula 17 Formula 18 Formula 19 Formula 20 Formula 21 Equation 22 Formula 23 Formula 24 Formula 25 Formula 26 Equation 27 Formula 28 Formula 29 Formula 30 Formula 31 Formula 32 Formula 33 Equation 34.

[0010] Preferably, the pyrimidine dione compounds with the structure shown in formula (II) are compounds of formulas 35 to 40 as follows: Formula 35 Formula 36 Formula 37 Formula 38 Formula 39 Formula 40.

[0011] Preferably, the pyrimidine dione compound with the structure shown in formula (III) is a compound of formula 41 or formula 42 as follows: Formula 41 Equation 42.

[0012] Preferably, the pyrimidine dione compound with the structure shown in formula (IV) is a compound of formula 43 or formula 44 as follows: Formula 43 Equation 44.

[0013] The present invention also provides a method for preparing the pyrimidine dione compound, comprising the following steps: S1. Using (1S)-1-(3-bromophenyl)ethylamine, (1S)-1-(4-bromophenyl)ethylamine or (1S)-1-(2-bromophenyl)ethylamine as raw materials, an aromatic heterocyclic compound containing a boron ester group is subjected to a Suzuki coupling reaction in the presence of a catalyst and a base, and heated to obtain the corresponding intermediate amine. S2. The intermediate amine and 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione undergo a nucleophilic substitution reaction in the presence of a base and upon heating. The reaction solution is then concentrated and purified by column chromatography to obtain pyrimidine dione compounds represented by general formulas (I), (II), (III) or (IV).

[0014] Preferably, in step S1, the catalyst is tetrakis(triphenylphosphine)palladium, the molar ratio of the raw material to the aromatic heterocyclic compound containing borate ester groups is 1:1 to 2, the base is potassium carbonate, the heating temperature is 80 to 85°C, the reaction time is 5 to 6 hours, the reaction solvent is a mixed solvent of 1,4-dioxane and water, and the volume ratio of 1,4-dioxane to water in the mixed solvent is 5:1; the aromatic heterocyclic compound containing borate ester groups is 4-(4,4,5,5-tetramethyl-1,3,2-dioxane). Oxaborane-2-yl)isoxazole and its derivatives, 1-alkyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole and its derivatives, 1-alkyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-imidazolium and its derivatives, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrimidine and its derivatives.

[0015] Preferably, in step S2, the base is triethylamine, the molar ratio of the intermediate amine to 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione is (1-2):1, the reaction temperature is 80-85°C, the reaction time is 20-24 h, and the reaction solvent is 1,4-dioxane.

[0016] The present invention also provides the use of the pyrimidine dione compounds or pharmaceutically acceptable salts thereof or solvates thereof or prodrug molecules thereof in the preparation of medicaments for treating hypertrophic cardiomyopathy.

[0017] The present invention has at least the following beneficial effects: 1. The pyrimidine dione compounds of this invention exhibit excellent inhibitory activity against myosin ATPase, with an IC50 as low as 0.12 μM. They significantly inhibit cardiomyocyte contraction, achieving an inhibition rate of over 66% on cardiomyocyte shortening fraction at a concentration of 0.5 μM, which is superior to or equivalent to the existing drug Avkaite (MYK-461). Furthermore, the pharmacokinetic properties of these compounds are significantly improved, with half-lives (T1 / 2) of 3.5–4.3 hours in mice and 16.5–20.3 hours in cats, significantly shorter than Avkaite (4.75 hours in mice but with high bioavailability, 155 hours in cats). This effectively avoids the risk of long-term drug accumulation in vivo, reducing the complexity of clinical dosage adjustments and the incidence of adverse reactions. Furthermore, the concentration of this compound in rat myocardial tissue can reach 712 ng / mg; the no-adverse-effect level (NOAEL) after repeated administration to rats for 14 days is 15 mg / kg, while Avkaite caused the death of all animals after continuous administration at a dose of 10 mg / kg for 7 days, indicating that the safety of the compound of the present invention is significantly better than that of the prior art.

[0018] 2. The method for preparing pyrimidine dione compounds of the present invention uses (S)-1-(3-bromophenyl)ethylamine, (S)-1-(4-bromophenyl)ethylamine, or (S)-1-(2-bromophenyl)ethylamine as starting materials. An aromatic heterocyclic compound containing a borate ester group is introduced via Suzuki coupling reaction, followed by nucleophilic substitution with a 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione. The target product can be obtained in only two steps. This method uses mild reaction conditions (80–85°C), conventional solvents (1,4-dioxane / water), and common bases (potassium carbonate, triethylamine). The amount of the tetra-triphenylphosphine palladium catalyst is controllable (approximately 0.18 eq). The operation is simple, and post-processing only requires extraction and column chromatography purification, with good yields. This preparation method is highly versatile. By selecting bromophenylethylamine at different positions (meta or para) and boronic esters with different structures, it can efficiently synthesize compounds of general formulas (I) to (IV). It is suitable for the large-scale preparation of pyrimidine dione compounds with various substituent modifications.

[0019] 3. The pyrimidine dione compounds of this invention can be used to prepare drugs for treating hypertrophic cardiomyopathy, particularly for the treatment of hypertrophic cardiomyopathy in animals such as cats and dogs. Animal pharmacodynamic experiments show that a single intravenous injection of 0.1 mg / kg of the compounds of this invention (such as A001-A004) into naturally occurring hypertrophic cardiomyopathy cats can reduce interventricular septal thickness by 0.32-0.73 mm and decrease short-axis contraction rate (FS) by 13.07%-14.29%, which is superior to the same dose of avkaite (interventricular septal thickness reduction of 0.27 mm, FS reduction of 10.8%), and no adverse reactions such as death occurred. Acute pharmacodynamic experiments in mice further confirmed that intravenous injection of 1 mg / kg of the compounds of this invention can reduce the cardiac short-axis contraction rate from baseline 36.3% to 19.0%-25.5%, a significantly greater reduction than avkaite (reduced to 26.7%), and at a dose of 5 mg / kg, all mice in the compound group survived, while mice in the avkaite group died. Therefore, the compounds of this invention can achieve better cardiac contractile inhibition at lower doses and have a wider safety window, and are expected to become safer and more effective treatments for hypertrophic cardiomyopathy, especially suitable for clinical treatment in companion animals (cats and dogs).

[0020] Other advantages, objectives and features of the present invention will become apparent in part from the following description, and in part from those skilled in the art through study and practice of the invention. Attached Figure Description

[0021] Figure 1 The figure shows the experimental results of detecting the contents of compounds A003 and MYK-461 in myocardial tissue using the LC-MS / MS method of this invention; Figure 2 This diagram illustrates the interaction between compounds A003 and MYK-461 of this invention and cardiac myosin. Detailed Implementation

[0022] The present invention will now be described in further detail so that those skilled in the art can implement it based on the description.

[0023] It should be noted that, unless otherwise specified, the experimental methods described in the following implementation plan are all conventional methods, and the reagents and materials described are all commercially available unless otherwise specified.

[0024] Example 1 (S)-3-Isopropyl-6-((1-(3-(isoxazo-4-yl)phenyl)ethyl)amino)pyrimidine-4(1H,3H)-dione (A001), which has the following structure: Its synthetic route is as follows: The specific synthesis steps include: Preparation of S1, (S)-1-(3-(isoxazo-4-yl)phenyl)ethane-1-amine: Add 2.5 g of (S)-1-(3-bromophenyl)ethylamine, 4.87 g of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)isoxazolate, 5.18 g of potassium carbonate, and 48 mL of 1,4-dioxane aqueous solution (1,4-dioxane to water volume ratio: 5:1) to a 50 mL reaction flask. Sonicate for 5 min, add 2.6 g of tetrakis(triphenylphosphine)palladium, purge with nitrogen three times, heat to 85 °C, and maintain the temperature for 5 h. Perform TLC; after the reaction is complete, add 100 mL of water and 100 mL of... mL of dichloromethane (DCM) was stirred and filtered. The aqueous phase was then extracted with DCM (100 mL × 2) until colorless. The organic phases were combined, washed with saturated brine, dried, and purified by column chromatography (eluent: DCM:MeOH = 40:1, yielding 2.11 g of a yellow solid, namely (S)-1-(3-(isoxazo-4-yl)phenyl)ethane-1-amine). Preparation of S2 and (S)-3-isopropyl-6-((1-(3-(isoxazol-4-yl)phenyl)ethyl)amino)pyrimidine-4(1H,3H)-dione (A001): 1.0 g of 6-chloro-3-isopropyl-pyrimidine-2,4(1H,3H)-dione, 2.11 g of (S)-1-(3-(isoxazol-4-yl)phenyl)ethane-1-amine, 1.61 g of triethylamine, and 40 mL of 1,4-dioxane were added to a 50 mL reaction flask. The mixture was heated to 80 °C and maintained at this temperature for 24 h. The solution was spotted onto a TLC plate, concentrated, and purified by column chromatography (eluent: DCM : MeOH = 50:1) to obtain compound A001 in 45% yield. 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.57 (s, 1H), 7.76 (td, J=1.9, 0.9 Hz, 1H), 7.65 (d, J = 8.5 Hz, 2H), 7.47 (dt, J = 7.3, 2.2 Hz, 1H),7.43-7.31 (m, 2H), 4.98 (q, J = 0.8 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 152.72, 151.07,148.06, 141.21, 135.76, 135.43, 127.76, 127.42, 126.66, 126.02, 125.50,77.41, 55.51, 49.72, 22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 20 N4O3:341.1535, found: 341.1616. Example 2 (S)-6-((1-(3-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A002), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(3,5-dimethylisoxazol-4-yl)phenyl)ethylamine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)isoxazole (1.67 g, 7.5 mmol) dissolved in 12 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and tetrakis(triphenylphosphine)palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a light red solid intermediate (S)-1-(3-(3,5-dimethylisoxazol-4-yl)phenyl)ethylamine (972.9 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(3-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A002): (S)-1-(3-(3,5-dimethylisoxazol-4-yl)phenyl)ethylamine (972.9 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (565.6 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (606.9 mg, 6 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A002 was obtained by purification with MeOH = 50:1, with a yield of 43%.

[0025] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.85 (td, J = 2.0, 1.0 Hz,1H), 7.64 (s, 1H), 7.46 (t, J = 7.5 Hz,1H), 7.36 (dtd, J = 7.5, 2.0, 0.9 Hz,1H), 7.27 (dt, J = 7.5, 2.1 Hz, 1H), 4.98 (q, J = 0.8 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 2.36 (s, 3H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 159.75, 156.56, 152.72, 151.07, 141.58, 135.60, 128.06, 127.42,123.29, 122.93, 121.13, 77.41, 55.51, 49.72, 22.15, 21.41,12.40, 12.38. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 24 N4O3: 369.1848, found: 369.1928. Example 3 (S)-3-isopropyl-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (A003), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol (1.56 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine (895.3 mg, 4.45 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A003): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine (895.3 mg, 4.45 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (559.3 mg, 2.97 mmol) was added and stirred until dissolved. Triethylamine (600.17 mg, 5.93 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A003 was obtained by purification with MeOH = 40:1, with a yield of 48%.

[0026] 1 H NMR (400 MHz, DMSO- d6) δ 9.80 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.15 (d, J =7.8 Hz, 1H), 6.53 (d, J = 7.0 Hz, 1H), 4.92 (p, J = 7.0 Hz, 1H), 4.48 (t, J =6.8 Hz, 1H), 4.40 (s, 1H), 3.87 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.28 (dd, J= 6.9, 2.8 Hz, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 163.20, 151.46, 150.42,144.26, 136.06, 132.93, 129.18, 127.87, 123.85, 123.13,122.49, 121.78, 74.42,54.91, 51.13, 42.35, 38.66, 23.46, 19.39. HRMS (ESI-MS) m / z:[M+H] + calcd forC 19 H 23 N5O2: 354.1852, found: 354.1934. Example 4 (S)-6-((1-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A004), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazol (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine (946.9 mg, 4.4 mmol). Preparation of S2, (S)-6-((1-(3-(1-ethyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A004): (S)-1-(3-(1-ethyl-1H-pyrazole-4-yl)phenyl)ethane-1-amine (946.9 mg, 4.4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (553.1 mg, 2.93 mmol) was added and stirred until dissolved. Triethylamine (593.4 mg, 5.86 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A004 was obtained by purification with MeOH = 50:1, with a yield of 46%.

[0027] 1 H NMR (400 MHz, DMSO- d6) δ 9.78 (s, 1H), 8.17 (s, 1H), 7.86 (s, 1H), 7.55 (d, J = 2.0 Hz, 1H), 7.45 (d, J = 7.8Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 7.14 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 7.0 Hz, 1H), 4.91 (p, J = 6.9 Hz, 1H), 4.47 (t, J = 6.8 Hz, 1H), 4.39 (s, 1H), 4.15(q, J = 7.3 Hz, 2H), 1.46 – 1.36(m, 6H), 1.27 (dd, J = 7.0, 2.8 Hz, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 163.19,151.47, 150.41, 144.26, 135.90,133.03, 129.17, 126.41, 123.84, 123.07,122.52, 121.55, 74.39, 51.15, 46.40, 42.33, 23.48, 19.36, 15.44. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 25 N5O2: 368.2008, found: 368.2088. Example 5 (S)-6-((1-(3-(1-butyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A005), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-butyl-1H-pyrazole-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxoborane-2-yl)-1H-pyrazole (1.88 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-butyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine (1.03 g, 4.25 mmol). Preparation of S2, (S)-6-((1-(3-(1-butyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A005): (S)-1-(3-(1-butyl-1H-pyrazole-4-yl)phenyl)ethane-1-amine (1.03 g, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (532.2 mg, 2.82 mmol) was added and stirred until dissolved. Triethylamine (856 mg, 8.47 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A005 was obtained by purification with MeOH = 50:1, with a yield of 43%.

[0028] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.82 (td, J =2.0, 1.0 Hz, 1H), 7.69 (s, 1H), 7.66 – 7.56 (m, 2H), 7.45 – 7.31(m, 2H), 4.98(q, J = 0.9 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.87 (s, 2H), 1.76 (s, 2H), 1.50 (s, 3H), 1.36 (s, 2H), 1.26 (s, 6H), 0.89 (s, 3H).13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 140.57, 139.17, 137.04, 127.82, 127.66, 127.61,127.43,126.68, 125.88, 77.41, 55.51, 50.13, 49.72, 30.22, 22.15, 21.41,19.96, 13.74. HRMS (ESI-MS) m / z:[M+H] + calcd for C 22 H 29 N5O2: 396.2321, found:396.2399. Example 6 (S)-3-isopropyl-6-((1-(3-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A006), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol), 1-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (2.01 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) was added, along with the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethane-1-amine (1.17 g, 4.5 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(3-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A006): (S)-1-(3-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethane-1-amine (1.17 g, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (567.2 mg, 3.01 mmol) was added and stirred until dissolved. Triethylamine (913 mg, 9.02 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM). The compound A006 was obtained by purification with a ratio of MeOH = 50:1, with a yield of 47%.

[0029] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.82 (td, J =2.0, 1.0 Hz, 1H), 7.71 – 7.56 (m, 3H), 7.45 – 7.31(m, 2H), 4.98 (q, J = 0.9Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.99 (s, 2H), 3.45 (s, 2H), 1.82 (s,2H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72,151.07, 140.97, 139.17, 137.04, 127.82, 127.69, 127.61, 127.43,126.97,125.88, 77.41, 70.46, 58.06, 55.51, 49.72, 48.81, 28.91, 22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 22 H 29 N5O3: 412.2270, found: 412.2345. Example 7 (S)-6-((1-(3-(1-cyclopentyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A007), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.97 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-cyclopentyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.10 g, 4.3 mmol). Preparation of S2, (S)-6-((1-(3-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A007): (S)-1-(3-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.10 g, 4.3 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (541.6 mg, 2.87 mmol) was added and stirred until dissolved. Triethylamine (871.8 mg, 8.62 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A007 was obtained by purification with MeOH = 50:1, with a yield of 41%.

[0030] 1 H NMR (400 MHz, DMSO- d6) δ 9.74 (s, 1H), 8.21 (s, 1H), 7.82 (td, J =2.0, 1.0 Hz, 1H), 7.69 (s, 1H), 7.66 – 7.56 (m, 2H), 7.45 – 7.31(m, 2H), 4.98(q, J = 0.9 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 4.40 (s, 1H), 2.10 (d, J =12.9 Hz, 2H), 1.85 (d, J = 13.0 Hz, 2H), 1.79 (d, J = 12.9 Hz, 2H),1.66 (d, J= 13.0 Hz, 2H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ165.20, 152.72, 151.07, 140.72, 139.17, 137.74, 129.11, 127.82, 127.43,126.09,125.88, 77.41, 59.30, 55.51, 49.72, 33.22, 23.87, 22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 23 H 29 N5O2: 408.2321, found: 408.2401. Example 8 (S)-6-((1-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A008), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (968.4 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A008): (S)-1-(3-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (968.4 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (565.7 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910.3 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A008 was obtained by purification with MeOH = 50:1, with a yield of 46%.

[0031] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.64 (s, 1H), 7.55 (td, J =2.0, 1.0 Hz, 1H), 7.47 (t, J = 7.4 Hz,1H), 7.39 – 7.30 (m, 2H), 4.98 (q, J =0.9 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 2.33 (s, 3H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO-d 6) δ 165.20, 152.72, 151.07, 146.19, 142.10,140.91, 135.32, 128.16, 127.43, 124.24,123.46, 122.62, 77.41, 55.51, 49.72,22.15, 21.41, 15.95, 12.72. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 25 N5O2:368.2008, found: 368.2083. Example 9 (S)-6-((1-(3-(1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidin-2,4(1H,3H)-dione (A009), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.45 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (1.38 g, 10 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine (851 mg, 4.55 mmol). Preparation of S2, (S)-6-((1-(3-(1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidine-2,4(1H,3H)-dione (A009): (S)-1-(3-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine (851 mg, 4.55 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (571.8 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (920.4 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to obtain compound A009, with a yield of 52%.

[0032] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.30 (s, 1H), 8.01 (s, 1H), 7.82 (td, J = 2.0, 1.0 Hz, 1H), 7.66 – 7.56 (m, 2H), 7.45 – 7.31(m, 2H), 4.98(q, J = 0.8 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 139.17, 137.27, 135.51,127.71, 127.54, 127.43, 125.87, 125.77, 124.61, 77.41, 55.51, 49.72, 22.15,21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 21 N5O2: 340.1695, found: 340.1775. Example 10 (S)-3-isopropyl-6-((1-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A010), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-isopropyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.77 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.03 g, 4.5 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(3-(1-isopropyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A010): (S)-1-(3-(1-isopropyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.03 g, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (564.7 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (909 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A010 was obtained by purification with MeOH = 50:1, with a yield of 43%.

[0033] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.32 (s, 1H), 7.85-7.76 (m,2H), 7.66-7.56 (m, 2H), 7.45-7.31 (m, 2H), 4.98 (q, J = 0.8 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 4.32 (s, 1H), 1.50 (s, 3H), 1.27 (d, J = 9.6 Hz, 12H). 13 CNMR (100 MHz, DMSO- d6) δ 165.20, 152.72, 151.07, 141.14, 139.17,137.26,128.70, 127.82, 127.43, 126.32, 125.88, 77.41, 55.51, 55.25, 49.72, 23.19,22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 21 H 27 N5O2: 382.2165, found:382.2247. Example 11 (S)-6-((1-(3-(1-(tert-butyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H, 3H)-dione (A011), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-tert-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.88 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-tert-butyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1 g, 4.25 mmol). Preparation of S2, (S)-6-((1-(3-(1-(tert-butyl)-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (A011): (S)-1-(3-(1-tert-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1 g, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (516.7 mg, 2.74 mmol) was added and stirred until dissolved. Triethylamine (831.6 mg, 8.22 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A011 was obtained by purification with MeOH = 50:1, with a yield of 45%.

[0034] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.29 (s, 1H), 7.82 – 7.78 (m, 2H), 7.66 – 7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 4.98 (q, J = 1.0 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.50 (d, J = 0.9 Hz, 12H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO-) d 6) δ 165.20, 152.72, 151.07, 140.25, 139.17, 137.00, 128.25,127.82, 127.43, 125.88,123.93, 77.41, 59.64, 55.51, 49.72, 29.79, 22.15,21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 22 H 29 N5O2: 396.2321, found: 396.2401. Example 12 (S)-3-isopropyl-6-((1-(3-(1-propyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A012), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.77 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-propyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (974.2 mg, 4.25 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(3-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A012): (S)-1-(3-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (974.2 mg, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (516.7 mg, 2.74 mmol) was added and stirred until dissolved. Triethylamine (831.6 mg, 8.22 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A012 was obtained by purification with MeOH = 50:1, with a yield of 45%.

[0035] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.82 (td, J =2.0, 1.0 Hz, 1H), 7.69 – 7.56 (m, 3H), 7.45 – 7.31(m, 2H), 4.98 (q, J = 0.9Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.84 (s, 2H), 1.72 (s, 2H), 1.50 (s,3H), 1.26 (s, 6H), 0.90 (s, 3H).13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72,151.07, 140.57, 139.17, 137.04, 127.82, 127.66, 127.61, 127.43,126.67,125.88, 77.41, 55.51, 49.87, 49.72, 22.15, 21.74, 21.41, 11.63. HRMS (ESI-MS) m / z:[M+H] + calcd for C 21 H 27 N5O2: 382.2165, found: 382.2246. Example 13 (S)-3-isopropyl-6-((1-(3-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A013), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.77 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine (865.1 mg, 4.3 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(3-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (A013): (S)-1-(3-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine (538.1 mg, 2.85 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (516.7 mg, 2.74 mmol) was added and stirred until dissolved. Triethylamine (866.1 mg, 8.56 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound A013 was obtained by purification with MeOH = 50:1, with a yield of 50%.

[0036] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.31 (s, 1H), 7.87 (q, J =0.7 Hz, 1H), 7.79 (td, J = 1.9, 0.9 Hz,1H), 7.65 (s, 1H), 7.56 (ddd, J = 6.0,3.4, 2.1 Hz, 1H), 7.39 – 7.30 (m, 2H), 4.98 (d, J = 0.9 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 3.68 (d, J = 0.7 Hz, 3H), 1.50 (s, 3H), 1.26 (s, 6H). 13 CNMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 139.27, 138.71, 137.87,136.05, 132.34, 127.70, 127.42,124.79, 124.64, 77.41, 55.51, 49.72, 31.92,22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 23 N5O2: 354.1852, found:354.1931. Example 14 (S)-3-isopropyl-6-((1-(3-(pyrimidin-5-yl)phenyl)ethyl)amino)pyrimidin-2,4(1H,3H)-dione (A014), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(pyrimidin-5-yl)phenyl)ethyl-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrimidine (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) was added, along with the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(pyrimidin-5-yl)phenyl)ethyl-1-amine (896.3 mg, 4.5 mmol). Preparation of S2 and (S)-3-isopropyl-6-((1-(3-(pyrimidin-5-yl)phenyl)ethyl)amino)pyrimidin-2,4(1H,3H)-dione (A014): (S)-1-(3-(pyrimidin-5-yl)phenyl)ethyl-1-amine (896.3 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidin-2,4(1H,3H)-dione (565.6 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910.3 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound A014, with a yield of 51%.

[0037] 1 H NMR (400 MHz, DMSO- d6) δ 9.74 (s, 1H), 9.12 (s, 1H), 8.99 (s, 2H), 7.78 (td, J = 1.9, 0.9 Hz, 1H), 7.66 – 7.55 (m, 2H), 7.45 – 7.31(m, 2H), 4.98(q, J = 0.8 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.50 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 156.90, 152.72, 151.22, 151.07, 139.39,135.75, 132.10, 127.71, 127.49, 127.43, 125.63, 77.41, 55.51, 49.72, 22.15,21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 21 N5O2: 352.1695, found: 352.1774. Example 15 (S)-3-isopropyl-6-((1-(4-(isoxazo-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (B001), which has the following structure: Its synthetic route is as follows: The specific synthesis steps include: Preparation of S1, (S)-1-(4-(isoxazo-4-yl)phenyl)ethane-1-amine: Add 2.5 g (S)-1-(4-bromophenyl)ethylamine, 4.87 g 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)isoxazolate, 5.18 g potassium carbonate, and 48 mL of 1,4-dioxane aqueous solution (volume ratio: 5:1) to a 50 mL reaction flask. Sonicate for 5 min, add 2.6 g tetraphenylphosphine palladium catalyst, purge with nitrogen three times, heat to 85℃, and maintain the reaction temperature for 5 h. Spot the reaction on a TLC plate. After the reaction is complete, add 100 mL water and 100 mL DCM. Stir and filter. Extract the aqueous phase with DCM (100 mL × 2) until colorless. Combine the organic phases, wash with saturated brine, dry, and purify by column chromatography (eluent: DCM). MeOH = 40:1, yielding 2.11 g of a yellow solid, namely (S)-1-(4-(isoxazo-4-yl)phenyl)ethane-1-amine; Preparation of S2, (S)-3-isopropyl-6-((1-(4-(isoxazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (B001): 1.0 g of 6-chloro-3-isopropyl-pyrimidine-2,4(1H,3H)-dione, 2.11 g of (S)-1-(4-(isoxazol-4-yl)phenyl)ethane-1-amine, 1.61 g of triethylamine, and 40 mL of 1,4-dioxane were added to a 50 mL reaction flask. The mixture was heated to 80 °C and maintained at this temperature for 24 h. The solution was spotted onto a TLC plate, concentrated, and purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B001, yield 46%.

[0038] 1 H NMR (400 MHz, DMSO- d 6) δ 9.73 (s, 1H), 8.56 (s, 1H), 7.75 (td, J =1.9, 0.9 Hz, 1H), 7.66 (d, J = 8.5 Hz,2H), 7.46 (dt, J = 7.3, 2.2 Hz, 1H),7.44 – 7.30 (m, 2H), 4.97 (q, J = 0.8 Hz, 1H), 4.87 (s, 1H), 4.59 (s, 1H), 1.51 (s, 3H), 1.25 (s, 6H). 13 C NMR (100 MHz, DMSO- d6) δ 165.22, 152.70, 151.07,148.05, 141.23, 135.76, 135.45, 127.77, 127.42, 126.67, 126.02, 125.50,77.42, 55.51, 49.73, 22.15, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 20 N4O3:341.1538, found: 341.1616. Example 16 (S)-6-((1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H, 3H)-dione (B002), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(3,5-dimethylisoxazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl-1-amine (972.89 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B002): (S)-1-(4-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl-1-amine (972.89 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (565.6 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910.3 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (eluent: dichloromethane and methanol, v / v: DCM). The compound B002 was obtained by purification with a ratio of 50:1 (MeOH = 50:1), with a yield of 49%.

[0039] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.50 – 7.41 (m, 3H), 7.34 –7.27 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 2.36 (s, 3H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 160.73,155.41, 152.72, 151.07, 141.32, 135.11, 126.74, 126.47, 119.08,77.41, 53.70,49.72, 22.55, 21.41, 12.40, 12.38. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 24 N4O3:369.1848, found: 369.1928. Example 17 (S)-3-isopropyl-6-((1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (B003), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.56 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (972.89 mg, 4.5 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (B003): (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (972.89 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H, 3H)-dione (565.6 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910.3 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound B003 was obtained by purification with MeOH = 50:1, with a yield of 45%.

[0040] 1 H NMR (400 MHz, DMSO- d6) δ 9.80 (s, 1H), 8.12 (s, 1H), 7.86 (s, 1H), 7.55 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.34 (t, J = 7.7 Hz, 1H), 7.15 (d, J =7.8 Hz, 1H), 6.53 (d, J = 7.0 Hz, 1H), 4.92 (p, J = 7.0 Hz, 1H), 4.48 (t, J =6.8 Hz, 1H), 4.40 (s, 1H), 3.87 (s, 3H), 1.43 (d, J = 6.7 Hz, 3H), 1.28 (dd, J= 6.9, 2.8 Hz, 6H). 13 C NMR (100MHz, DMSO- d 6) δ 163.20, 151.46, 150.42, 144.26,136.06, 132.93, 129.18, 127.87, 123.85, 123.13,122.49, 121.78, 74.42, 54.91,51.13, 42.35, 38.66, 23.46, 19.39. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 23 N5O2:354.1852, found: 354.1934. Example 18 (S)-6-((1-(4-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B004), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.56 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(3-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (957.7 mg, 4.45 mmol). Preparation of S2, (S)-6-((1-(4-(1-ethyl-1H-pyrazole-phenyl)ethyl)amino)-3-isopropylpyrimidine-4(1H,3H)-dione (B004): (S)-1-(3-(1-ethyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (957.7 mg, 4.45 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (559.3 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (900.1 mg, 8.9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B004, with a yield of 44%.

[0041] 1 H NMR (400 MHz, DMSO- d6) δ 9.78 (s, 1H), 8.14 (s, 1H), 7.83 (s, 1H), 7.53 (d, J = 8.2 Hz, 2H), 7.30 (d, J = 8.3Hz, 2H), 6.49 (d, J = 6.8 Hz, 1H), 4.94 – 4.86 (m, 1H), 4.47 (t, J = 6.9 Hz, 1H), 4.36 (d, J = 2.4 Hz, 1H), 4.14(q, J = 7.3Hz, 2H), 1.44 – 1.36 (m, 6H), 1.26 (dd, J = 6.9, 2.3 Hz, 6H). 13 CNMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 141.08, 140.60, 137.59,127.80, 127.19, 126.56, 125.47, 77.41, 53.70, 49.72, 48.59, 22.55, 21.41,14.42. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 25 N5O2: 368.2008, found: 368.2086. Example 19 (S)-6-((1-(4-(1-butyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B005), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.88 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(1-butyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.1 g, 4.5 mmol). Preparation of S2, (S)-6-((1-(4-(1-butyl-1H-pyrazole-phenyl)ethyl)amino)-3-isopropylpyrimidine-4(1H,3H)-dione (B005): (S)-1-(4-(1-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.1 g, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (563.2 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (906.5 mg, 8.96 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B005, with a yield of 48%.

[0042] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.75 – 7.67 (m, 3H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.87 (s, 2H), 1.76 (s, 2H), 1.46 (s, 3H), 1.36 (s, 2H), 1.26 (s, 6H), 0.89 (s, 3H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 152.72,151.07, 141.08, 140.54, 137.59, 128.19, 127.19, 126.66, 126.56, 77.41,53.70,50.13, 49.72, 30.22, 22.55, 21.41, 19.96, 13.74. HRMS (ESI-MS) m / z:[M+H] + calcdfor C 22 H 29 N5O2: 396.2321, found: 396.2403. Example 20 (S)-3-isopropyl-6-((1-(4-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (B006), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-(3-methoxypropyl)-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-(3-methoxypropyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (2 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.1 g, 4.25 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(4-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-4(1H,3H)-dione (B006): (S)-1-(4-(1-(3-methoxypropyl)-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.1 g, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (533 mg, 2.83 mmol) was added and stirred until dissolved. Triethylamine (858.3 mg, 8.48 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: Compound B006 was obtained by purification with MeOH = 50:1, with a yield of 53%.

[0043] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.75 – 7.67(m, 3H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 3.99 (s, 2H), 3.45 (s, 2H), 1.82 (s, 2H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 141.08,140.54, 137.98, 127.79, 127.19, 126.90, 126.56, 77.41, 70.46,58.06, 53.70,49.72, 48.81, 28.91, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 22 H 29 N5O3:412.2270, found: 412.2351. Example 21 (S)-6-((1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B007), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-cyclopentyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.97 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(1-cyclopentyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.08 g, 4.23 mmol). Preparation of S2, (S)-6-((1-(4-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B007): (S)-1-(4-(1-cyclopentyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.08 g, 4.23 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (532 mg, 2.83 mmol) was added and stirred until dissolved. Triethylamine (856 mg, 8.48 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound B007 was obtained by purification with MeOH = 50:1, with a yield of 47%.

[0044] 1 H NMR (400 MHz, DMSO- d6) δ 9.74 (s, 1H), 8.20 (s, 1H), 7.76 – 7.67(m, 3H), 7.48 (s, 1H), 7.30 – 7.23 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 4.40 (s, 1H), 2.10 (d, J= 12.9 Hz, 2H), 1.85 (d, J = 13.0Hz, 2H), 1.79 (d, J = 12.9 Hz, 2H), 1.66 (d, J = 13.0 Hz, 2H), 1.46 (s, 3H),1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 141.11,141.09, 138.51, 127.97, 127.19, 126.56, 126.18, 77.41, 59.29,53.70, 49.72,33.22, 23.87, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 23 H 29 N5O2:408.2321, found: 408.2400. Example 22 (S)-6-((1-(4-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidine-2,4(1H,3H)-dione (B008), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (968.5 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(4-3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidine-2,4(1H,3H)-dione (B008): (S)-1-(4-(3,5-dimethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (968.5 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (565.6 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910.4 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound B008 was obtained by purification with MeOH = 50:1, with a yield of 42%.

[0045] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 7.55 – 7.46 (m, 3H), 7.37 –7.29 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 2.33 (s, 3H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 152.72,151.07, 145.20, 141.70, 141.52, 135.97, 126.74, 125.39, 122.82,77.41, 53.70,49.72, 22.55, 21.41, 16.53, 12.72. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 25 N5O2:368.2008, found: 368.2087. Example 23 (S)-6-((1-(4-(1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidine-2,4(1H,3H)-dione (B009), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.45 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine (842.2 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(4-(1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropyl-pyrimidine-2,4(1H,3H)-dione (B009): (S)-1-(4-(1H-pyrazol-4-yl)phenyl)ethyl-1-amine (842.2 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (630.5 mg, 3.34 mmol) was added and stirred until dissolved. Triethylamine (910.4 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B009, with a yield of 49%.

[0046] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.21 (s, 1H), 8.01 (s, 1H),7.75-7.67 (m, 2H), 7.48 (s, 1H), 7.30-7.22(m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 141.08, 136.68, 135.12, 127.29, 126.56, 126.05,125.15, 77.41, 53.70, 49.72, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd forC 18 H 21 N5O2: 340.1695, found: 340.1774. Example 24 (S)-3-isopropyl-6-((1-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (BO10), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-isopropyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-isopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.77 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (974.2 mg, 4.25 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (BO10): (S)-1-(4-(1-isopropyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (974.2 mg, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (534.1 mg, 2.83 mmol) was added and stirred until dissolved. Triethylamine (860 mg, 8.5 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, v / v: DCM). The compound B010 was obtained by purification with a ratio of 50:1 (MeOH = 50:1), with a yield of 43%.

[0047] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.34 (s, 1H), 7.86 (s, 1H),7.75-7.67 (m, 2H), 7.48 (s, 1H), 7.30-7.22(m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 4.32 (s, 1H), 1.46 (s, 3H), 1.27 (d, J = 9.6 Hz, 12H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 152.72, 151.07, 141.08, 140.99,138.84, 128.00, 127.19, 126.56, 126.47, 77.41, 55.25, 53.70, 49.72, 23.19,22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 21 H 27 N5O2: 382.2165, found:382.2247. Example 25 (S)-6-((1-(4-(1-(tert-butyl)-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B011), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-tert-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.88 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(1-tert-butyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.09 g, 4.48 mmol). Preparation of S2, (S)-6-((1-(4-(1-(tert-butyl)-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (B011): (S)-1-(4-(1-tert-butyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.09 g, 4.48 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (563 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (906.5 mg, 8.96 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, v / v: DCM). The compound B011 was obtained by purification with a ratio of 50:1 (MeOH = 50:1), with a yield of 50%.

[0048] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.26 (s, 1H), 7.79 – 7.67(m, 3H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 1.48 (d, J = 14.1 Hz, 12H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07, 141.08, 140.12, 137.37, 128.23, 127.17,126.56, 123.40, 77.41, 59.64, 53.70, 49.72, 29.79, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 22 H 29 N5O2: 396.2321, found: 396.2401. Example 26 (S)-3-isopropyl-6-((1-(4-(1-propyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (BO12), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-propyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazole (1.77 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) was added, followed by the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 50:1) to give a yellow solid intermediate (S)-1-(4-(1-propyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (1.03 g, 4.5 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(4-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (BO12): (S)-1-(4-(1-propyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (1.03 g, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H, 3H)-dione (564.7 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (909 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound B012 was obtained by purification with MeOH = 50:1, with a yield of 55%.

[0049] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.75 – 7.67(m, 3H), 7.48 (s, 1H), 7.30 – 7.23 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s,1H), 4.58 (s, 1H), 3.84 (s, 2H), 1.72 (s, 2H), 1.46 (s, 3H), 1.26 (s, 6H), 0.90 (s, 3H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 152.72, 151.07, 141.08,140.49, 137.59, 127.99, 127.19, 126.67, 126.56, 77.41, 53.70,49.87, 49.72,22.55, 21.74, 21.41, 11.63. HRMS (ESI-MS) m / z:[M+H] + calcd for C 21 H 27 N5O2:382.2165, found: 382.2235. Example 27 (S)-3-isopropyl-6-((1-(4-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (BO13), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-imidazolium (1.56 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2 and (S)-3-isopropyl-6-((1-(4-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (B013): (S)-1-(4-(1-methyl-1H-imidazol-5-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (565.4 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B013, with a yield of 53%.

[0050] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.20 (s, 1H), 7.87 (q, J =0.7 Hz, 1H), 7.72 – 7.65 (m, 2H), 7.48 (s, 1H), 7.35 – 7.27 (m, 2H), 5.11 (d,J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.68 (d, J = 0.7 Hz, 3H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 152.72, 151.07,141.87, 138.71, 138.07, 133.88, 132.96, 126.77, 125.36,77.41, 53.70, 49.72,31.92, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 23 N5O2: 354.1852, found: 354.1931. Example 28 (S)-3-isopropyl-6-((1-(4-(pyrimidin-5-yl)phenyl)ethyl)amino)pyrimidin-2,4(1H, 3H)-dione (BO14), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)pyrimidine (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) was added, followed by the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl-1-amine (866.4 mg, 4.35 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(4-(pyrimidin-5-yl)phenyl)ethyl)amino)pyrimidin-2,4(1H,3H)-dione (B014): (S)-1-(4-(pyrimidin-5-yl)phenyl)ethyl-1-amine (866.4 mg, 4.35 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidin-2,4(1H,3H)-dione (546.7 mg, 2.9 mmol) was added and stirred until dissolved. Triethylamine (880 mg, 8.7 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound B014, with a yield of 58%.

[0051] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 9.12 (s, 1H), 8.97 (s, 2H), 7.73 – 7.66 (m, 2H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H), 5.11 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.46 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d6) δ 165.20, 156.83, 152.72, 151.07, 150.78, 141.08, 136.66, 131.52,127.24, 126.56, 77.41, 53.70, 49.72, 22.55, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 21 N5O2: 352.1695, found: 352.1776. Example 29 (S)-3-isopropyl-6-((1-(2-(isoxazo-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (C001), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(isoxazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole (1.46 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) was added, followed by the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(2-(isoxazol-4-yl)phenyl)ethyl-1-amine (837.3 mg, 4.45 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(2-(isoxazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (C001): (S)-1-(2-(isoxazol-4-yl)phenyl)ethyl-1-amine (837.3 mg, 4.45 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (559.3 mg, 2.9 mmol) was added and stirred until dissolved. Triethylamine (900 mg, 8.9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound C001, with a yield of 65%.

[0052] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.56 (s, 1H), 8.11 (s, 1H), 7.73 (s, 1H), 7.54 (dd, J = 7.2, 2.3 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.24 (ddd, J =7.2, 2.3, 1.0 Hz, 1H), 5.09 (d, J = 1.2 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 1.49 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 153.35,151.07, 148.13, 138.87, 137.43, 134.34, 128.22, 127.80, 126.73,125.68,124.78, 76.86, 53.92, 49.72, 21.92, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd forC 18 H 20 N4O3: 341.1535, found: 341.1616. Example 30 (S)-6-((1-(2-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (C002), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)isoxazole (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) was added, followed by the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol). After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(2-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl-1-amine (951 mg, 4.4 mmol). Preparation of S2, (S)-6-((1-(2-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (C002): (S)-1-(2-(3,5-dimethylisoxazol-4-yl)phenyl)ethyl-1-amine (951 mg, 4.4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (553 mg, 2.9 mmol) was added and stirred until dissolved. Triethylamine (890 mg, 8.8 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). The compound C002 was obtained by purification with MeOH = 50:1, with a yield of 67%.

[0053] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.11 (s, 1H), 7.60 (dd, J =7.5, 2.1 Hz, 1H), 7.46 (td, J= 7.4, 2.1 Hz, 1H), 7.41 – 7.27 (m, 2H), 5.13 (d, J = 1.2 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 2.35 (s, 3H), 1.49 (s, 3H), 1.26(s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20, 161.76, 156.28, 153.35, 151.07,139.56, 139.35, 128.59, 127.80, 126.62, 126.51, 119.62, 76.86, 52.81, 49.72,21.92, 21.41,12.50, 12.24. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 24 N4O3:369.1848, found: 369.1927. Example 31 (S)-3-isopropyl-6-((1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (C003), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.56 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885 mg, 4.4 mmol). Preparation of S2, (S)-3-isopropyl-6-((1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (C003): (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885 mg, 4.4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (552.8 mg, 2.9 mmol) was added and stirred until dissolved. Triethylamine (890 mg, 8.8 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). The compound C003 was obtained by purification with MeOH = 50:1, with a yield of 65%.

[0054] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.71 (dd, J = 7.1, 2.3 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.24 (ddd, J =7.1, 2.3, 1.0 Hz, 1H), 5.09 (d, J = 1.2 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.73 (s, 3H), 1.49 (s, 3H), 1.26 (s, 6H). 13 C NMR (100 MHz, DMSO- d 6) δ 165.20,153.35, 151.07, 139.85, 139.35, 136.08, 128.33, 127.67, 127.53, 127.49,127.11, 126.65, 76.86, 53.92, 49.72, 39.04, 21.92, 21.41. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 23 N5O2: 354.1852, found: 354.1934. Example 32 (S)-6-((1-(2-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (C004), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.67 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=50:1) to give a yellow solid intermediate (S)-1-(2-(1-ethyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (990 mg, 4.6 mmol). Preparation of S2, (S)-6-((1-(2-(1-ethyl-1H-pyrazole-4-yl)phenyl)ethyl)amino)-3-isopropylpyrimidine-2,4(1H,3H)-dione (C004): (S)-1-(2-(1-ethyl-1H-pyrazole-4-yl)phenyl)ethyl-1-amine (990 mg, 4.6 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-isopropylpyrimidine-2,4(1H,3H)-dione (578.2 mg, 3.1 mmol) was added and stirred until dissolved. Triethylamine (930.6 mg, 9.2 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). The compound C004 was obtained by purification with MeOH (50:1), with a yield of 70%.

[0055] 1 H NMR (400 MHz, DMSO- d 6) δ 9.74 (s, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 7.85 (s, 1H), 7.71 (dd, J= 7.1, 2.3 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.24 (ddd, J =7.1, 2.3, 1.0 Hz, 1H), 5.09 (d, J = 1.1 Hz, 1H), 4.88 (s, 1H), 4.58 (s, 1H), 3.88 (s, 2H), 1.49 (s, 3H), 1.26 (d, J = 2.1 Hz, 9H). 13 C NMR (100 MHz, DMSO- d 6)δ 165.20, 153.35, 151.07, 139.85, 139.45, 137.05, 128.33, 127.67, 127.49,127.08, 126.65, 125.48, 76.86, 53.92, 49.72, 48.59, 21.92,21.41, 14.42. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 25 N5O2: 368.2008, found: 368.2085. Example 33 (S)-3-ethyl-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D001), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (865.1 mg, 4.3 mmol). Preparation of S2, (S)-3-ethyl-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D001): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (865.1 mg, 4.3 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-ethylpyrimidine-2,4(1H,3H)-dione (500.3 mg, 2.87 mmol) was added and stirred until dissolved. Triethylamine (869.9 mg, 8.6 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D001 was obtained by purification with MeOH = 50:1, with a yield of 70%.

[0056] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.28 (s, 1H), 7.86 – 7.79 (m, 2H), 7.66 – 7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.39 (s, 1H), 4.98 (q, J =1.0 Hz, 1H), 3.74 (d, J = 1.8 Hz, 5H), 1.50 (s, 3H), 1.27 (s, 3H). 13C NMR (100MHz, DMSO-d6) δ 164.69, 152.01, 151.68, 140.63, 139.17,136.35, 128.76,127.82, 127.61, 127.43, 126.41, 125.88, 77.22, 55.51, 39.04, 35.83, 22.15,13.34. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 21 N5O2: 340.1695, found: 340.1774. Example 34 (S)-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione (D002), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885.2 mg, 4.4 mmol). Preparation of S2, (S)-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-propylpyrimidine-2,4(1H,3H)-dione (D002): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885.2 mg, 4.4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (553.1 mg, 2.93 mmol) was added and stirred until dissolved. Triethylamine (890 mg, 8.8 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM). The compound D002 was obtained by purification with a ratio of 50:1 (MeOH = 50:1), with a yield of 68%.

[0057] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.66 –7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.33 (s, 1H), 4.98 (q, J = 0.9 Hz, 1H),3.73 (s, 3H), 3.67 (s, 2H),1.77 (s, 2H), 1.50 (s, 3H), 0.88 (s, 3H). 13 C NMR(100 MHz, DMSO-d6) δ 164.72, 152.52, 152.01, 140.63, 139.17,136.35, 128.76,127.82, 127.52 (d, J = 18.3 Hz), 126.41, 125.88, 77.66, 55.51, 41.28, 39.04,22.15, 21.79, 10.84. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 23 N5O2: 354.1852, found: 354.1912. Example 35 (S)-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-(3-pentyl)pyrimidin-2,4(1H,3H)-dione (D003), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2, (S)-6-((1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-(3-pentyl)pyrimidine-2,4(1H,3H)-dione (D003): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-(pent-3-yl)pyrimidine-2,4(1H,3H)-dione (649.5 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D003 was obtained by purification with MeOH = 50:1, with a yield of 65%.

[0058] 1 H NMR (400 MHz, DMSO-d6) δ 7.86 – 7.79 (m, 1H), 7.66 – 7.56(m, 1H), 7.45 – 7.31 (m, 1H), 5.00 – 4.94 (m, 1H), 3.73 (s, 2H), 1.78 (d, J = 12.4 Hz,1H), 1.57 – 1.47 (m, 3H), 0.88 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 166.23,152.72,152.30, 140.63, 139.17, 136.35, 128.76, 127.82, 127.61, 127.43,126.41, 125.88, 76.81, 55.51, 50.39, 39.04, 25.81, 22.15, 10.31. HRMS (ESI-MS) m / z:[M+H] + calcd for C 21 H 27 N5O2: 382.2165, found: 382.2246. Example 36 (S)-3-cyclopentyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D004), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2, (S)-3-cyclopentyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D004): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-cyclopentylpyrimidine-2,4(1H, 3H)-dione (643.4 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound D004, with a yield of 71%.

[0059] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.66 –7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.00 – 4.94 (m, 2H), 4.48 (s, 1H), 3.73(s,3H), 1.79 (d, J = 13.0 Hz, 2H), 1.64 (d, J = 13.0 Hz, 2H), 1.58 – 1.50 (m,4H), 1.50 (s, 6H). 13 C NMR (100 MHz, DMSO-d6) δ 166.08, 152.72, 152.15, 140.63,139.17,136.35, 128.76, 127.82, 127.61, 127.43, 126.41, 125.88, 76.81, 55.51,54.85, 39.04, 31.12, 26.30, 23.95, 22.15. HRMS (ESI-MS) m / z:[M+H] + calcd forC 21 H 25 N5O2: 380.2008, found: 380.2089. Example 37 (S)-3-cyclopropyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D005), has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885.3 mg, 4.4 mmol). Preparation of S2, (S)-3-cyclopropyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D005): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (885.3 mg, 4.4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-cyclopropylpyrimidine-2,4(1H,3H)-dione (547 mg, 2.93 mmol) was added and stirred until dissolved. Triethylamine (890 mg, 8.79 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D005 was obtained by purification with MeOH = 50:1, with a yield of 65%.

[0060] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.66 –7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.00 – 4.94 (m, 2H), 3.73 (s, 3H), 3.68(s,1H), 1.50 (s, 3H), 1.36 (d, J = 5.1 Hz, 2H), 1.11 (d, J = 5.0 Hz, 2H). 13CNMR (100 MHz, DMSO-d6) δ 165.72, 152.72,151.83, 140.63, 139.17, 136.35,128.76, 127.82, 127.61, 127.43, 126.41, 125.88, 76.81, 55.51, 46.11, 39.04,22.15, 9.13. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 21 N5O2: 352.1695, found:352.1775. Example 38 (S)-3-cyclobutyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D006), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, v / v: DCM:MeOH = 40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (855 mg, 4.25 mmol). Preparation of S2, (S)-3-cyclobutyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D006): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (855 mg, 4.25 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-cyclobutylpyrimidine-2,4(1H, 3H)-dione (568.2 mg, 2.83 mmol) was added and stirred until dissolved. Triethylamine (859.7 mg, 8.5 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D006 was obtained by purification with MeOH = 50:1, with a yield of 72%.

[0061] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.66 –7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.00 – 4.94 (m, 2H), 4.27 (s, 1H), 3.73(s,3H), 1.89 (d, J = 12.9 Hz, 2H), 1.76 (s, 2H), 1.64 (d, J = 13.0 Hz, 2H), 1.50 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ 165.85, 152.72, 152.03, 140.63,139.17, 136.35, 128.76, 127.82, 127.61, 127.43,126.41, 125.88, 76.81, 55.51,54.03, 39.04, 30.22, 22.15, 20.11. HRMS (ESI-MS) m / z:[M+H] + calcd for C 20 H 23 N5O2:366.1852, found: 366.1933. Example 39 (S)-3-cyclohexyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D007), has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2 and (S)-3-cyclohexyl-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D007): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-cyclohexylpyrimidine-2,4(1H, 3H)-dione (685.5 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound D007, with a yield of 71%.

[0062] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.66 –7.56 (m, 2H), 7.45 – 7.31 (m, 2H), 5.00 – 4.94 (m, 2H), 4.48 (s, 1H), 3.73(s,3H), 1.79 (d, J = 13.0 Hz, 2H), 1.64 (d, J = 13.0 Hz, 2H), 1.58 – 1.50 (m,4H), 1.50 (s, 6H). 13C NMR (100 MHz, DMSO-d6) δ 166.08, 152.72, 152.15, 140.63,139.17,136.35, 128.76, 127.82, 127.61, 127.43, 126.41, 125.88, 76.81, 55.51,54.85, 39.04, 31.12, 26.30, 23.95, 22.15. HRMS (ESI-MS) m / z:[M+H] + calcd forC 22 H 27 N5O2: 394.2165, found: 394.2244. Example 40 (S)-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-vinylpyrimidine-2,4(1H,3H)-dione (D008), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethane-1-amine: (S)-1-(3-bromophenyl)ethylamine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2, (S)-6-(1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)-3-vinylpyrimidine-2,4(1H, 3H)-dione (D008): (S)-1-(3-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-vinylpyrimidine-2,4(1H, 3H)-dione (517.3 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound D008, with a yield of 63%.

[0063] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H),7.86 – 7.79 (m, 2H), 7.59(dt, J = 7.5, 2.1 Hz, 1H), 7.54 (s, 1H), 7.45 – 7.31 (m, 2H),7.14 (s, 1H), 5.71 (d, J = 12.3 Hz, 1H), 5.46 (d, J = 12.3 Hz, 1H), 5.20 (s, 1H), 4.98 (q,J = 0.9 Hz, 1H), 3.73 (s, 3H), 1.50 (s, 3H). 13 C NMR (100 MHz, DMSO-d6) δ164.33, 152.56,150.83, 140.63, 139.17, 136.35, 135.00, 128.76, 127.82,127.61, 127.43, 126.41, 125.88, 102.75, 77.27, 55.51, 39.04, 22.15. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 19 N5O2:338.1539, found: 338.1620. Example 41 (S)-3-ethyl-6-((1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D009), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol). Preparation of S2, (S)-3-ethyl-6-((1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D009): (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (905 mg, 4.5 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-ethylpyrimidine-2,4(1H, 3H)-dione (523.3 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound D009, with a yield of 75%.

[0064] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H),8.24 (s, 1H), 7.83 (s, 1H),7.75 – 7.67 (m, 2H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H),5.39 (s, 1H), 5.11 (d,J = 1.1 Hz, 1H), 3.74 (d, J = 1.8 Hz, 5H), 1.46 (s, 3H), 1.27 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.69, 152.01, 151.68, 141.08, 140.24, 137.21, 127.50,127.19, 126.64, 126.56, 77.22, 53.70, 39.04, 35.83, 22.55, 13.34. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 21 N5O2:340.1695 found: 340.1776. Example 42 (S)-3-cyclopropyl-6-(1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D010), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(4-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (925.5 mg, 4.6 mmol). Preparation of S2 and (S)-3-cyclopropyl-6-(1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D010): (S)-1-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (925 mg, 4.6 mmol) was dissolved in 10 mL of 1,4-dioxane, and 6-chloro-3-cyclopropylpyrimidine-2,4(1H, 3H)-dione (572 mg, 3 mmol) was added and stirred until dissolved. Triethylamine (910 mg, 9 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the residue was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: MeOH = 50:1) to obtain compound D010, with a yield of 68%.

[0065] 1 H NMR (400 MHz, DMSO-d6) δ 8.24 (s, 1H),7.83 (s, 1H), 7.75 – 7.67(m, 2H), 7.48 (s, 1H), 7.30 – 7.22 (m, 2H),5.11 (d, J = 1.1 Hz, 1H), 4.96 (s,1H), 3.73 (s, 3H), 3.68 (s, 1H), 1.46 (s, 3H), 1.36 (d, J = 5.1 Hz, 2H), 1.11(d, J = 5.0 Hz, 2H). 13 C NMR (100 MHz, DMSO-d6) δ 165.72, 152.72,151.83,141.08, 140.24, 137.21, 127.50, 127.19, 126.64, 126.56, 76.81, 53.70, 46.11,39.04, 22.55, 9.13. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 21 N5O2: 352.1695 found: 352.1773. Example 43 (S)-3-ethyl-6-((1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D011), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (804.7 mg, 4 mmol). Preparation of S2, (S)-3-ethyl-6-((1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D011): (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (804.7 mg, 4 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-ethylpyrimidine-2,4(1H, 3H)-dione (465.3 mg, 2.67 mmol) was added and stirred until dissolved. Triethylamine (809.1 mg, 8 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D011 was obtained by purification with MeOH = 50:1, with a yield of 65%.

[0066] 1 H NMR (400 MHz, DMSO-d6) δ 9.94 (s, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.71 (dd, J = 7.1, 2.3 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.24 (ddd,J = 7.1, 2.3, 1.0 Hz, 1H), 5.39 (s, 1H), 5.09 (d, J = 1.1 Hz, 1H), 3.74 (d, J= 1.8 Hz, 5H), 1.49 (s, 3H), 1.27(s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 164.69,153.51, 151.68, 139.85, 139.35, 136.08, 128.33, 127.67, 127.53, 127.49,127.11, 126.65, 77.22, 53.92, 39.04, 35.83, 21.92, 13.34. HRMS (ESI-MS) m / z:[M+H] + calcd for C 18 H 21 N5O2:340.1695 found: 340.1775. Example 44 (S)-3-cyclopropyl-6-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H,3H)-dione (D012), which has the following structure: The specific synthesis steps include: Preparation of S1 and (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine: (S)-1-(2-bromophenyl)ethyl-1-amine (1 g, 5 mmol) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborane-2-yl)-1H-pyrazol (1.54 g, 7.5 mmol) dissolved in 15 mL of 1,4-dioxane aqueous solution (volume ratio of 1,4-dioxane to water: 5:1) were added to a 50 mL reaction flask. Potassium carbonate (2.07 g, 15 mmol) and the catalyst tetra-triphenylphosphine palladium (231 mg, 199.92 μmol) were added. After purging with nitrogen three times, the temperature was raised to 85 °C, and the reaction was stirred for 6 h until completion. The crude product was purified by column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM:MeOH=40:1) to give a yellow solid intermediate (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (824.9 mg, 4.1 mmol). Preparation of S2, (S)-3-cyclopropyl-6-(1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl)amino)pyrimidine-2,4(1H, 3H)-dione (D012): (S)-1-(2-(1-methyl-1H-pyrazol-4-yl)phenyl)ethyl-1-amine (824.9 mg, 4.1 mmol) was dissolved in 10 mL of 1,4-dioxane. 6-chloro-3-cyclopropylpyrimidine-2,4(1H, 3H)-dione (509.8 mg, 2.73 mmol) was added and stirred until dissolved. Triethylamine (829.5 mg, 8.2 mmol) was added, and the mixture was heated to 80 °C and reacted for 12 h. The reaction solution was concentrated, and the resulting residue was subjected to column chromatography (eluent: dichloromethane and methanol, volume ratio: DCM: ). Compound D012 was obtained by purification with MeOH = 50:1, with a yield of 70%.

[0067] 1 H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H),8.11 (s, 1H), 7.84 (s, 1H),7.71 (dd, J = 7.1, 2.3 Hz, 1H), 7.45 – 7.32 (m, 2H), 7.24 (ddd, J = 7.1, 2.3,1.0 Hz, 1H), 5.09 (d, J = 1.2 Hz, 1H), 4.96 (s, 1H), 3.73 (s, 3H), 3.68 (s,1H), 1.49 (s, 3H),1.36 (d, J = 5.1 Hz, 2H), 1.11 (d, J = 5.0 Hz, 2H). 13 C NMR(100 MHz, DMSO-d6) δ 165.72, 153.35, 151.83, 139.85, 139.35,136.08, 128.33,127.67, 127.53, 127.49, 127.11, 126.65, 76.81, 53.92, 46.11, 39.04, 21.92,9.13. HRMS (ESI-MS) m / z:[M+H] + calcd for C 19 H 21 N5O2: 352.1695 found:352.1775. Example 45 Determination of myosin inhibitory activity: To evaluate the effects of the compounds of this invention on the ATP (adenosine triphosphate) enzyme activity of full-length myofibrils in the context of natural sarcomeres, peeled myofibrils analysis was performed. Rat cardiac myofibrils were obtained by homogenizing left ventricular tissue from rats (SPF grade, 200-220 g, male) in the presence of a detergent (such as Triton X-100). This treatment removed the membrane and most soluble cytoplasmic proteins, but preserved the myofibril actomyosin structure intact. The myofibril formulation retained Ca2+. 2+ The ability to regulate ATP hydrolysis. At the threshold fractions of activation to the maximum rate (i.e., 25%, 75%), Ca... 2+ At various concentrations, the ATPase activity of the myofibril formulation was analyzed in the presence and absence of the compound. The ability of the compound to inhibit the homeostasis of ATPase activity in rat cardiac myofibrils was evaluated using a pyruvate kinase / lactate dehydrogenase (PK / LDH) coupled enzyme system. This analysis was performed by oxidizing NADH (nicotinamide adenine dinucleotide), which regenerates ADP produced by myosin into ATP, resulting in absorbance changes at 340 nm. Prior to testing the compound, the calcium reactivity of rat cardiac myofibrils was evaluated, and calcium concentrations achieving 50% (pCa50) or 75% (pCa75) activation of the myofibril system were selected as the conditions for evaluating the inhibitory activity of the compound. All enzyme activities were measured in a pH 6.8 buffer solution containing 12 mM PIPES (piperazine-N,N'-bis(2-ethanesulfonic acid)) and 2 mM magnesium chloride. The final analytical conditions were 1 mg / mL rat cardiac myofibrils, 4 U / mL pyruvate kinase, 6 U / mL lactate dehydrogenase, 50 μM ATP, 0.1 mg / mL BSA (rat serum albumin), 10 ppm antifoaming agent, 1 mM DTT (dithiothreitol), 0.5 mM NADH (nicotinamide adenine dinucleotide), 1.5 mM PEP, 0.6 mM EGTA, and an amount of CaCl2 sufficient to achieve 50% or 75% activation of myofibril ATPase activity.

[0068] The compound was serially diluted 3-fold with DMSO to 11 different concentrations, starting at 0.1 mM. 2 μL of each concentration was added to a 96-well plate, followed by 100 μL of rat cardiac myofibrils, 40 μL of a solution containing PK / LDH, BSA, and DTT (2.4 U / μL PK / LDH, 0.1% BSA, 1 mM DTT), and 40 μL of BSA containing ATP, NADH, and PEP (5 mM ATP, 0.2 mM NADH, 2 mM PEP). Finally, 20 μL of calcium solution (the free calcium concentration required for 50% activation of the myofibril system) was added to initiate the enzymatic reaction. The absorbance was read at 340 nm using an Infinite® M200 PRO-grating multi-functional microplate reader at 25°C, with readings every 30 seconds for 15 minutes. The data were recorded as the slope of the absorbance response versus time. The slope of the absorbance response as a function of time was normalized to the slope on the DMSO-containing plate. This normalized ratio was then plotted as a function of drug concentration, and the data were fitted to a curve using Graph PadPrism. The midpoint of this curve was the IC50, which represents the drug concentration at which 50% of the total response was inhibited. The results for the tested compounds are shown in Table 1. These compounds were prepared according to the synthetic method described herein.

[0069] Table 1. Myosin inhibitory activity of the compounds of the present invention Experimental results show that the compound of the present invention has an inhibitory effect on myosin ATPase.

[0070] Example 46 Measurement of cardiomyocyte contractility in adult rats: Adult male rats were anesthetized and their hearts were rapidly removed, flushed, and a cannula was inserted into the ascending aorta. Continuous retrograde perfusion was initiated on the heart at a perfusion pressure of 60 cm H2O. Initially, a nominally Ca-free solution with the following composition was used. 2+The heart was perfused with a modified Krebs solution: 113 mM NaCl, 4.7 mM KCl, 0.6 mM KH₂PO₄, 0.6 mM Na₂HPO₄, 1.2 mM MgSO₄, 12 mM NaHCO₃, 10 mM KHCO₃, 30 mM taurine, 5.5 mM glucose, and 10 mM Hepes (Sigma). This medium was continuously aerated with a mixture of 95% O₂ and 5% CO₂. The heart was perfused with modified Krebs buffer supplemented with collagenase and a final calcium concentration of 12.5 μM. After the heart appeared white and soft, it was removed from the cannula. The atria and vessels were removed, and the ventricles were gently cut into smaller pieces with forceps. The tissue was homogenized by repeated pipetting, and the collagenase reaction was stopped by 10% fetal bovine serum (BCS). The tissue was then settled and resuspended in perfusion buffer containing 5% BCS and 12.5 μM CaCl₂. Myocytes were conditioned to calcium tolerance by gradually adding CaCl2 solution to a final concentration of 1.2 mM. Cells were then washed and resuspended in Tyrode's buffer (137 mM NaCl, 3.7 mM KCl, 0.5 mM MgCl, 11 mM glucose, 4 mM Hepes, and 1.2 mM CaCl2, pH 7.4). Cells were incubated at 37°C for 60 min before initiating experiments and used within 5 hours of separation. Cell formulations were only used if cells first passed QC standards (by demonstrating a contractile response to treatment with standards (>150% basal) and isoproterenol (ISO; >250% basal). Furthermore, in subsequent experiments with the compounds, only cells with a basal contractile rate between 3% and 8% were used.

[0071] Aliquots of myocytes in Tyrode buffer were placed in a perfusion chamber equipped with a heated stage. Myocytes were allowed to attach, the chamber was heated to 37°C, and the cells were perfused with 37°C Tyrode buffer. Myocytes were stimulated with a 1 Hz electric field (20% above the threshold) using platinum electrodes. Only cells with clear striations and at rest before pacing were used for contractility assays. To determine the baseline contractility, myocytes were imaged via a 40x objective. Images were digitized using a variable frame rate (60 Hz–240 Hz) charge-coupled device (CCD) camera and displayed on a computer screen at a sampling rate of 240 Hz (IonOptix Milton). Once cell contraction stabilized over time, the test compound (0.01 µM–15 µM) was perfused into the myocyte chamber for 5 minutes. Edge detection was then used to record the myocyte contractility and contraction and relaxation rates. Data were continuously recorded using IonOptix software. Contractility data were analyzed using Ionwizard software (IonOptix). For each cell, 10–20 transient contractile states were averaged, and baseline (no compound) conditions were compared with compound-treated conditions. The effect of the compound was measured by the fractional shortening (FS), which is the ratio of the maximum cell length at contraction to the baseline cell length, normalized relative to 100% for untreated cells. The test results are shown in Table 2.

[0072] Table 2. Inhibition of cardiomyocyte contraction by the selected compounds + indicates a fractional inhibition value of less than 33%; ++ indicates a fractional inhibition value of 33% to 66%; +++ indicates a fractional inhibition value of greater than 66%. nd indicates no inhibition.

[0073] Experimental results showed that all compounds effectively inhibited cardiomyocyte contraction. At the same molar concentration, compounds A001, A002, A003, and A004 exhibited significantly better inhibitory effects than MYK-461, while compounds A007, A008, A009, B003, and B004 showed inhibitory effects comparable to MYK-461.

[0074] Example 47 Pharmacokinetic studies in mice: Thirty male BalB / c mice were randomly divided into six groups of five each. Each group received the test compounds A001, A002, A003, A004, and MYK-461 via gavage at a dose of 2.5 mg / kg. Mice were fasted for 12 hours prior to gavage but had free access to water throughout the experiment. Following administration, 0.1 mL of blood was collected via the orbital venous plexus at time points (before administration, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, and 24 h) and placed in labeled EDTA-K2 anticoagulant tubes. The tubes were gently inverted to thoroughly mix the anticoagulant (EDTA-K2) with the blood, and immediately placed on wet ice. Plasma was separated by centrifugation within one hour of blood collection at 4°C, 6800 g, and for 5 minutes. The separated plasma was then placed in labeled EP tubes and stored in an ultra-low temperature freezer as soon as possible until sample analysis. The concentrations of compounds in plasma samples were determined by LC-MS / MS using an AB Sciex 5500 Q-Trap mass spectrometer with an ESI ion source in positive ion MRM mode. The parent-daughter ion pairs for A001, A002, A003, A004, and MYK-461 were 342.2 / 185, 372.1 / 171.4, 354.3 / 185, 368.2 / 171.4, and 274.0 / 128.0, respectively. The ion pair for the internal standard Carbamazepine was 237.3 / 194.2. The chromatographic column was an AQ-C18 (2.1 x 50 mm, 5 μm). Mobile phase A was an aqueous solution containing 0.1% formic acid, and mobile phase B was acetonitrile, using gradient elution mode. The sample preparation procedure was as follows: 300 μL of precipitant containing internal standard was added to a 96-well plate containing 20 μL of the unknown sample; the mixture was vortexed; centrifuged at 4°C for 5 minutes; 150 μL of supernatant was transferred to a new 96-well plate, and 150 μL of ultrapure water was added and mixed; LC-MS / MS was then performed. The peak areas of the analyte and internal standard were obtained using Analyst 1.6.3 software, and weighted averages (W=1 / x) were calculated. 2 The least squares method was used to perform linear regression on the plasma analyte concentration (X) and peak area ratio (Y), and the resulting regression equation (Y=a+bX) served as the standard curve. The concentration of the compound in plasma was calculated based on the standard curve of the analytical batch; the linear range in this study was 5–5000 ng / mL. Pharmacokinetic parameters were calculated using the statistical moment method with a non-compartmental model selected using Phoenix® WinNonlin® 6.3 software. The experimental results are shown in Table 3.

[0075] Table 3. Blood drug concentrations and p-kJ parameters of the corresponding compounds after oral administration of A001, A002, A003, A004 and MYK-461 to mice (n=5) Experimental results show that compounds A003 and A004 of the present invention are well absorbed pharmacokinetically in C57 mice. Furthermore, compounds A001, A002, A003, and A004 of the present invention have a lower T than compound MYK-461. 1 / 2 There is a significant shortening. Compound MYK-461 has a shortening due to T 1 / 2 The duration of T is relatively long (consistent with the literature), leading to significant accumulation in clinical practice. This necessitates constant adjustments to clinical dosing, increasing the risk of adverse drug reactions. Shortening T... 1 / 2 This can reduce or avoid drug accumulation in the body during clinical practice, which is beneficial for determining clinical dosage and avoiding the risks caused by accumulation. Clearly, compounds A001, A002, A003, and A004 of this invention have significant pharmacokinetic advantages over compound MYK-461.

[0076] Example 48 Pharmacokinetics of the compound in cats Twenty male domestic cats were divided into 5 groups (n=4 per group) and administered the test compounds A001, A002, A003, and A004 by gavage at a dose of 5 mg / kg. Cats were fasted overnight before gavage and resumed feeding 4 hours afterward. Water was available freely throughout the experiment. Following gavage, 1 mL of blood was collected from the venous plexus of each limb at time points (before administration, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h, 48 h, 96 h, 120 h, 144 h, and 168 h after administration). The collected blood was placed in anticoagulant tubes containing 2 μL of 20% EDTA-K2 and stored on moist ice. The plasma was centrifuged at 6000 rpm for 10 min at low temperature (4-10℃) within 1 hour to obtain the supernatant plasma, which was then stored in an ultra-low temperature freezer (below -60℃) for analysis. The concentrations of compounds A001, A002, A003, and A004 in plasma samples were determined using LC-MS / MS, following the same method as for compound concentration determination in mouse plasma. Pharmacokinetic parameters were calculated using Phoenix® WinNonlin® 6.3 software. The experimental results are shown in Table 4.

[0077] Table 4. Pharmacokinetic parameters of cats orally administered compounds A001, A002, A003, and A004 Experimental results showed that after administration, cats in groups A001, A002, A003, and A004 did not die, exhibited no obvious abnormal clinical symptoms (no decreased activity, arched back, or ruffled hair), had normal appetite and water intake, and showed no significant weight loss. At this dose, there was no acute toxicity in cats, and the cats were well tolerated. Compounds A003 and A004 of this invention were well absorbed pharmacologically in cats. Furthermore, compound T of compounds A003 and A004 of this invention… 1 / 2Within 20 hours, a daily gavage interval can be designed, resulting in a low risk of accumulation in clinical practice. The compounds A001, A002, A003, and A004 of this invention are rapidly absorbed and metabolized in cats, exhibiting high safety.

[0078] Example 49 Acute efficacy experiment in mice First, a standardized method for echocardiography in mice was established by optimizing anesthesia time, anesthesia degree, and post-anesthesia echocardiography time, eliminating the influence of anesthesia degree and time on the accuracy of echocardiography. This method was applied to echocardiography in 348 mice to obtain the baseline value of short-axis contractility (FS, %), an indicator of cardiac contractility evaluation in this study. Mice were intravenously injected with 1 mg / kg and 5 mg / kg of A001-A006, intravenously injected with blank solvent, and orally administered 2.5 mg / kg of MYK-461 while awake. Each group had at least six mice in each replicate. Mice in the A001-A006 and blank solvent groups were anesthetized immediately after administration, and echocardiography was performed to obtain FS values. Mice in the MYK-461 group were anesthetized 3 hours after oral administration, and echocardiography was performed to obtain FS values. Difference analysis was performed between the mean and baseline values ​​for each group, identifying compounds that significantly reduced the baseline value. The experimental results are shown in Table 5.

[0079] Table 5. Mean FS values ​​in mice after a single intravenous injection of different doses of the compound The experimental results showed that in this study, the mean baseline short-axis contraction rate (FS%, an indicator of cardiac systolic function) of 348 mice was 36.3% ± 5.5. After intravenous injection of blank solvent, the mean FS value was 33.8%, which was not significantly different from the baseline group. According to the literature, after a single gavage administration of MYK-461 to mice, the FS value decreased to 28.8% 3 hours later, indicating that the system of this study was reliable. When compounds A001-A006 were administered intravenously at a single dose of 5 mg / kg, all mice survived. After intravenous injection of 1 mg / kg A001-A006, the mean free fibrosis (FS) values ​​decreased sequentially to 24.5%, 22.2%, 19.0%, 23.4%, 25.5%, and 23.2%. After intravenous injection of 5 mg / kg A001-A006, the mean FS values ​​decreased sequentially to 19.3%, 19.7%, 17.6%, 19.8%, 20.4%, and 18.2%, all significantly lower than the baseline group (p < 0.05). Furthermore, with increasing dose, the ability of A001-A006 to reduce cardiac contractility in mice increased (FS value).

[0080] Example 50 Acute efficacy study in HCM cats: Twenty male cats diagnosed with hypertrophic cardiomyopathy by veterinary echocardiography were selected; all were naturally occurring cases. A001, A002, A003, and A004 were administered as single intravenous injections at a dose of 1 mg / kg. Baseline data were obtained from echocardiography of each cat before injection. Echocardiography was performed immediately after injection while the cat was awake, and animated images were obtained. The long axis was captured, and left ventricular septal thickness and short-axis contractility (FS, an indicator of cardiac contractility) were measured in both 2D and M-mode. The effects of the compounds on hypertrophic cardiomyopathy were compared by examining the echocardiographic parameters before and after injection. The experimental results are shown in Table 6.

[0081] Table 6. Echocardiographic results of cats with spontaneous hypertrophic acute disease following a single intravenous injection of a series of compounds As shown in Table 6, after a single intravenous injection of A001, A002, A003 and A004, the interventricular septal thickness and short-axis contraction rate (FS) of HCM cats decreased, indicating that the compounds of the present invention have the ability to improve the heart contraction of cats with hypertrophic cardiomyopathy.

[0082] Example 51 Distribution experiment of compounds in rat myocardial tissue Six male SD rats were divided into two groups of three each. Each group was administered the test compound A003 by gavage at a dose of 2.5 mg / kg. Two hours after administration, the rats were sacrificed, and their hearts were rapidly dissected. 0.1 g of heart tissue was collected and homogenized at a 1:100 ratio. 0.5 mL of homogenate was placed in a 10 mL stoppered centrifuge tube. 0.5 mL of 1 mol / L HCl was added to acidify the sample, followed by two shakes with 5 mL of hexane to defatt the tissue. The aqueous phase was then removed, and 0.5 mL of 1 mol / L NaOH and 0.5 mL of 0.2 M phosphate buffer were added to adjust the pH to 7. Ethyl acetate was then added for extraction. The content of compound A003 in the myocardial tissue was detected using LC-MS / MS. The experimental results are as follows: Figure 1 As shown.

[0083] Experimental results showed that the content of compound A003 of the present invention in the myocardial tissue of SD rats was 712 ng / mg.

[0084] Example 52 Toxicity test of rats after repeated gavage for 14 days: One hundred SD rats were divided into 8 groups of 20 each, with half males and half females. The groups were: control solvent group, low-dose A003 group (3 mg / kg), medium-dose A003 group (6 mg / kg), and high-dose A003 group (15 mg / kg); low-dose A004 group (3 mg / kg), medium-dose A004 group (6 mg / kg), and high-dose A004 group (15 mg / kg); and MYK-461 (10 mg / kg). Administration was by gavage once daily for 14 consecutive days. General indicators were observed during the administration period, including animal condition, body weight, food intake, and mortality; organ indicators, including heart, liver, kidney, lung, and spleen organ coefficients; and histopathological examination (HE staining). The experimental results are shown in Table 7.

[0085] Table 7. Toxicity test of compounds A003, A004, and MYK-461 in rats after repeated gavage for 14 days. Experimental Results: After 7 consecutive days of gavage administration of 10 mg / kg MYK-461 solution to rats, irreversible damage to multiple organs was induced, resulting in the death of all animals. This suggests that MYK-461 is poorly tolerated in rats, and the no-analytical-effect level (NOAEL) in rats after 14 days was less than 10 mg / kg. Repeated gavage administration of compounds A003 and A004 for 14 days at concentrations of 3 mg / kg, 6 mg / kg, and 15 mg / kg did not show significant toxic reactions, with a NOAEL of 15.0 mg / kg. In conclusion, compounds A003 and A004 of this invention have a better safety profile than MYK-461.

[0086] Example 53 Molecular docking validates the inhibitory activity of the compound against cardiac myosin: Molecular docking was used to compare the docking performance of the preferred compound A003 with the control compound MYK-461. The molecular docking software used was AutoDock Vina, and the molecular docking diagrams were drawn using PyMOL 2.5. The three-dimensional crystal structure of cardiac myosin was downloaded from the PDB protein database (PDB ID: 8QYQ). Molecular docking studies were conducted on the two target compounds, and the specific docking steps are as follows: (1) Construction and pretreatment of two small molecule ligand conformations The structures of compound A003 and control compound MYK-461 were imported into AutoDock Tools (ADT) software for standardized preprocessing: hydrogenation, charge distribution (using Gasteiger charge), and nonpolar hydrogen merging were performed sequentially on the ligand structures. At the same time, the bond lengths and bond angles of the ligands were detected and corrected to complete the basic energy optimization. The preprocessed ligand structures were converted into the PDBQT format recognized by AutoDock Vina to obtain the standard docking ligand files of the two compounds, which served as the basic conformational source for subsequent docking studies with the 8QYQ protein molecule.

[0087] (2) Pretreatment of 8QYQ protein receptor and construction of docking box The three-dimensional crystal structure of the 8QYQ protein was downloaded from the PDB protein database (PDB ID: 8QYQ). The original PDB format file was imported into AutoDockTools (ADT) software for systematic preprocessing: First, a water molecule removal operation was performed to eliminate irrelevant water molecules in the crystal structure; then, co-crystallized ligands in the structure were extracted, and their binding regions were precisely labeled (as docking core sites); next, hydrogenation, charge distribution (Gasteiger charge), and nonpolar hydrogen merging were performed on the protein to repair missing amino acid residue side chains in the structure, completing the protein structure optimization; the preprocessed protein receptor structure was converted into PDBQT format recognized by AutoDock Vina and saved as a receptor docking file.

[0088] Centered on the three-dimensional spatial position of the original co-crystallized ligand of the protein, the docking box (Grid Box) of ADT software was constructed: according to the molecular size of the co-crystallized ligand, the length, width, height (x / y / z axes) and grid spacing of the docking box were reasonably set to ensure that the box completely covers the core binding region of the protein. The docking mode adopted semi-flexible docking (protein backbone fixed, amino acid side chain flexible adaptation). Except for the above-specified parameters, all other docking-related parameters adopted the default values ​​of the AutoDockVina software system.

[0089] (3) Molecular docking calculations and ligand-receptor interaction analysis Based on the AutoDock Vina software platform, the preprocessed 8QYQ protein receptor PDBQT file, the ligand PDBQT files of the two target compounds, and the constructed docking box parameter file (conf.txt) were placed in the same working directory. The AutoDock Vina docking algorithm was called through the command line / visual interface to perform molecular docking calculations between the two ligands and the protein, and the binding strength, spatial matching degree, and conformational fit between each compound and the 8QYQ protein were systematically evaluated.

[0090] Nine optimal conformations (Vina default output) were generated for each compound during docking. Binding affinity (binding free energy, unit: kcal / mol) was used as the core screening criterion. The conformation with the lowest binding affinity (strongest binding ability) was selected as the representative result of the docking of that compound with the 8QYQ protein. PyMOL software was used to integrate the docked ligand conformation with the protein receptor structure into a complex and save it as a PDB file. The obtained complex structure files were imported into PyMOL software for three-dimensional visualization analysis. This allowed for in-depth analysis of the hydrogen bonds, hydrophobic interactions, van der Waals forces, π-π stacking, and π-cation interactions between amino acid residues at the binding site of each target compound and the 8QYQ protein, including interaction sites and details. This completed the molecular docking mechanism analysis of the two compounds with the 8QYQ protein. The docking results are as follows: Figure 2 As shown.

[0091] The docking results showed that the binding free energy of compound A003 with cardiac myosin was -8.2 kcal / mol, while that of MYK-461 with cardiac myosin was -7.6 kcal / mol. According to molecular docking evaluation criteria, a more negative binding free energy (lower value) indicates a stronger affinity between the ligand and the target protein. Therefore, A003 exhibited significantly better binding ability than MYK-461, indicating that it formed a more stable binding complex with the target.

[0092] Protein-ligand interaction mode analysis ( Figure 2 It also reveals that, while retaining conventional hydrogen bonds, π-π stacking, and π-cation interactions, compound A003 introduces an alkyl-substituted imidazole structure at the 3-position of the benzene ring, which adds a strong interaction with the protein residue LYS146. At the same time, the π-alkyl interaction further enhances the binding with hydrophobic / basic amino acids such as ILE713 and ARG147.

[0093] Although the technical solutions of the present invention have been disclosed above, they are not limited to the applications listed in the specification and embodiments. They can be applied to various fields suitable for the present invention. For those skilled in the art, other modifications can be easily made. Therefore, without departing from the general concept defined by the claims and their equivalents, the present invention is not limited to the specific details and embodiments shown and described herein.

Claims

1. A pyrimidine dione compound having the structure shown in general formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, (I)) (II)) (III)) (IV)) in, R1 is selected independently from hydrogen, , C1-C5 alkyl or C3-C5 cycloalkyl; R2, R3, R4, R5, R6, R7, R8, and R9 are each individually selected from hydrogen, C1-C2 alkyl, and R 10 R 11 R 12 R 13 Each is individually selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl or C3-C6 cycloalkyl.

2. The pyrimidine dione compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, characterized in that, In formula (I), R1 is selected independently from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, cyclopentyl, , R2 and R3 are each individually selected from hydrogen or methyl, R 10 R4 and R5 are each individually selected from ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, isopentyl, cyclopentyl, cyclohexyl, and vinyl; in formula (II), R4 and R5 are each individually selected from hydrogen or methyl, R 11 Selected from isopropyl; in formula (III), R6 is selected from methyl, R 12 Selected from isopropyl; in formula (IV), R7, R8, and R9 are each individually selected from hydrogen, R 13 Selected from isopropyl.

3. The pyrimidine dione compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, characterized in that, The pyrimidine dione compounds with the structure shown in formula (I) are compounds of formulas 1 to 34 as follows: Formula 1 Formula 2 Formula 3 Formula 4 Formula 5 Formula 6 Formula 7 Formula 8 Formula 9 Formula 10 Formula 11 Formula 12 Formula 13 Formula 14 Formula 15 Formula 16 Formula 17 Formula 18 Formula 19 Formula 20 Formula 21 Equation 22 Formula 23 Formula 24 Formula 25 Formula 26 Equation 27 Formula 28 Formula 29 Formula 30 Formula 31 Formula 32 Formula 33 Equation 34.

4. The pyrimidine dione compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, characterized in that, The pyrimidine dione compounds with the structure shown in formula (II) are compounds of formulas 35 to 40 as follows: Formula 35 Formula 36 Formula 37 Formula 38 Formula 39 Formula 40.

5. The pyrimidine dione compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, characterized in that, The pyrimidine dione compounds with the structure shown in formula (III) are compounds of formula 41 or 42 as follows: Formula 41 Equation 42.

6. The pyrimidine dione compound of claim 1, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, characterized in that, The pyrimidine dione compounds with the structure shown in formula (IV) are compounds of formula 43 or 44 as follows: Formula 43 Equation 44.

7. A method for preparing a pyrimidine dione compound as described in any one of claims 1 to 6, characterized in that, Includes the following steps: S1. Using (1S)-1-(3-bromophenyl)ethylamine, (1S)-1-(4-bromophenyl)ethylamine or (1S)-1-(2-bromophenyl)ethylamine as raw materials, an aromatic heterocyclic compound containing a boron ester group is subjected to a Suzuki coupling reaction in the presence of a catalyst and a base, and heated to obtain the corresponding intermediate amine. S2. The intermediate amine and 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione undergo a nucleophilic substitution reaction in the presence of a base and upon heating. The reaction solution is then concentrated and purified by column chromatography to obtain pyrimidine dione compounds represented by general formulas (I), (II), (III) or (IV).

8. The method for preparing pyrimidine dione compounds according to claim 7, characterized in that, In step S1, the catalyst is tetraphenylphosphine palladium, the molar ratio of the reactant to the aromatic heterocyclic compound containing borate ester groups is 1:1-2, the base is potassium carbonate, the reaction temperature is 80-85℃, and the reaction time is 5-6 minutes. h, the reaction solvent is a mixed solvent of 1,4-dioxane and water, in which the volume ratio of 1,4-dioxane to water is 5:1; the aromatic heterocyclic compounds containing borate ester groups are 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)isoxazole and its derivatives, 1-alkyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-pyrazole and its derivatives, 1-alkyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H-imidazolium and its derivatives, and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)pyrimidine and its derivatives.

9. The method for preparing pyrimidine dione compounds according to claim 7, characterized in that, In step S2, the base is triethylamine, the molar ratio of the intermediate amine to 6-chloro-3-substituted pyrimidine-2,4(1H,3H)-dione is (1-2):1, the reaction temperature is 80-85℃, the reaction time is 20-24 h, and the reaction solvent is 1,4-dioxane.

10. The use of a pyrimidine dione compound as described in any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or a prodrug molecule thereof, in the preparation of a medicament for treating hypertrophic cardiomyopathy; said medicament is for human or veterinary use.

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