CN117430562A - 4-methyl-2-oxo-3, 6-dihydropyrimidine compound and preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a 4-methyl-2-oxo-3, 6-dihydropyrimidine compound, and a preparation method and application thereof. The invention provides a 4-methyl-2-oxo-3, 6-dihydropyrimidine compound with a novel structure, which shows good inhibition effect on phosphodiesterase type one (PDE 1) through experiments, and can be used for preparing phosphodiesterase type one inhibitor; meanwhile, the medicine prepared by using the compound as an active ingredient has better curative effects on liver fibrosis, idiopathic pulmonary fibrosis and pulmonary arterial hypertension, and has important medicinal value and wide application prospect in preparing medicines for liver fibrosis, pulmonary arterial hypertension and idiopathic pulmonary fibrosis; and the preparation method of the 4-methyl-2-oxo-3, 6-dihydropyrimidine compound is simple and is suitable for large-scale industrial production and application.

Description

A 4-methyl-2-oxo-3,6-dihydropyrimidine compound and its preparation method and application

Technical Field

The present invention belongs to the field of medical technology, and more specifically, relates to a 4-methyl-2-oxo-3,6-dihydropyrimidine compound, a preparation method and application thereof.

Background Art

Phosphodiesterase (PDE) is an enzyme that regulates the cellular levels of cAMP and cGMP by controlling the rate of cyclic nucleotide hydrolysis. It is a therapeutic target for many diseases, such as pulmonary hypertension, idiopathic pulmonary fibrosis, Alzheimer's disease, diabetes, and heart failure. PDE is widely distributed in the body and is divided into 11 isozyme families (PDE1 to PDE11) based on protein sequence similarity, enzyme kinetic characteristics, regulatory properties, cell tissue distribution, and pharmacological properties; and these 11 families have different distribution areas in the body and play different roles in different physiological or pathological processes. Among these 11 families, PDE1 was identified as Ca2 ⁺ calmodulin-dependent phosphodiesterase (CaM-PDE), which is activated by Ca2 ⁺ calmodulin and has been shown to mediate calcium and cyclic nucleotide signaling pathways. The three known CaM-PDE genes PDE1A, PDE1B, and PDE1C are all expressed in central nervous system tissues. Among them, PDE1A is expressed throughout the brain, with higher expression in the CA1 and CA3 layers of the hippocampus and cerebellum and lower expression in the striatum. PDE1A is also expressed in the lungs and heart; PDE1B is mainly expressed in the striatum, dentate gyrus, olfactory tract and cerebellum, and its expression is related to the brain areas innervated by dopaminergic nerves; although PDE1B is mainly expressed in the central nervous system, it may be detected in the heart; PDE1C is mainly expressed in the olfactory epithelium, cerebellar granule cells and striatum, but it is also expressed in the heart and vascular smooth muscle.

Studies have shown that changes in the signaling pathways regulated by PDE1 are associated with the central nervous system and can be used to regulate mental disorders, movement disorders, cognitive function, and Alzheimer's disease; some studies have also shown that PDE1 is related to heart failure and can be used to regulate heart failure, cardiac remodeling, and dysfunction; some studies have shown that PDE1 is associated with the lungs, kidneys, hematology, gastrointestinal tract, liver, fertility, cancer, and metabolic disorders. For example, Chinese patent application CN111747960A discloses a substituted pyrazole [3,4-d] pyrimidine compound as a PDE1 inhibitor, which has good efficacy in treating pulmonary hypertension and idiopathic pulmonary fibrosis. At present, PDE inhibitors with significant efficacy have been successfully marketed, but the number of PDE1 inhibitors that can be marketed for clinical treatment is still limited, and there is an urgent need to develop more PDE1 inhibitors for patients to choose from.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing PDE1 inhibitors that can be marketed for clinical treatment, and to provide a 4-methyl-2-oxo-3,6-dihydropyrimidine compound to provide patients with more optional drugs.

The purpose of the present invention is to provide a method for preparing the 4-methyl-2-oxo-3,6-dihydropyrimidine compounds.

Another object of the present invention is to provide the application of the 4-methyl-2-oxo-3,6-dihydropyrimidine compounds.

The above-mentioned purpose of the present invention is achieved through the following technical solutions:

The present invention protects a 4-methyl-2-oxo-3,6-dihydropyrimidine compound, characterized in that the structure of the compound is as shown in formula (I) or formula (II):

Wherein, _R1 is substituted or unsubstituted phenyl, substituted or unsubstituted pyridyl, substituted or unsubstituted indazolyl, substituted or unsubstituted piperonyl, the substituted substituent is one or more, the substituent of the substituted phenyl, substituted pyridyl, substituted indazolyl, substituted piperonyl is selected from one or more of _C1-4 alkyl, substituted or unsubstituted _C1-4 alkoxy, halogenated _C1-4 alkoxy, phenol or halogen, the substituent of the substituted _C1-4 alkoxy is _C3-6 cycloalkyl;

Q is an oxygen or sulfur atom; X is an oxygen or sulfur atom; Y is a carbon, oxygen, nitrogen or sulfur atom, which is connected to a hydrogen atom to form a saturated bond as required;

_R2 is _C3-6 cycloalkyl, substituted or unsubstituted _C1-4 alkyl, the substituted substituent is one or more, and the substituent of the substituted _C1-4 alkyl is selected from phenyl or _C3-6 cycloalkyl;

_R3 is hydrogen, _C1-4 alkyl, substituted benzyl or substituted _C2-4 alkenyl, the substituted substituent is one or more, and the substituent of the substituted benzyl or substituted _C2-4 alkenyl is selected from one or more of phenyl or halogen;

_R4 is hydrogen, phenyl, substituted or unsubstituted _C1-4 alkyl, the substituted substituent is one or more, and the substituent of the substituted _C1-4 alkyl is selected from one or more of phenyl, _C3-6 cycloalkyl, and halogen.

Preferably, the _R1 is a substituted or unsubstituted phenyl, a substituted or unsubstituted pyridyl, a substituted or unsubstituted indazolyl, or a substituted or unsubstituted piperonyl, the substituted substituent is one or more, the substituent of the substituted phenyl, substituted pyridyl, substituted indazolyl, or substituted piperonyl is selected from one or more of _C1-3 alkyl, substituted or unsubstituted _C1-4 alkoxy, halogenated _C1-3 alkoxy, phenol or halogen, and the substituent of the substituted _C1-4 alkoxy is _{C3-5 cycloalkyl} ;

_R2 is cyclohexyl or substituted or unsubstituted methyl, the substituted substituent is one or more, and the substituent substituted by _R2 is selected from phenyl or _C3-6 cycloalkyl;

_R3 is hydrogen, methyl, substituted benzyl or substituted propenyl, the substituted substituent is one or more, the substituent of the substituted benzyl or substituted propenyl is selected from phenyl or halogen;

_R4 is hydrogen, phenyl, substituted or unsubstituted _C1-3 alkyl, the substituted substituent is one or more, and the substituent of the substituted _C1-3 alkyl is selected from phenyl or _C3-6 cycloalkyl.

Preferably, the _R1 is a substituted phenyl group, a substituted pyridyl group, a substituted indazolyl group, or an unsubstituted piperonyl group, and the substituent of the substituted phenyl group, the substituted pyridyl group, or the substituted indazolyl group is selected from one or more of a methyl group, an unsubstituted or substituted methoxy group, a phenol group, or a halogen group, and the substituent of the substituted methoxy group is a cyclopropyl group;

_R2 is cyclohexyl or substituted or unsubstituted methyl, the substituted substituent is one or more, and the substituent of the substituted methyl is selected from phenyl, cyclohexyl or cyclopentyl;

_R4 is hydrogen, phenyl, substituted or unsubstituted _C1-3 alkyl, the substituted substituent is one or more, and the substituent of the substituted _C1-3 alkyl is selected from phenyl, cyclohexyl or cyclopentyl.

More preferably, _R1 is 3,4-difluoro-substituted phenyl, 3,4-dimethoxy-substituted phenyl, m-methoxy-substituted phenyl, p-methoxy-substituted phenyl, piperonyl, 1-methyl-1H-indazolyl, methoxypyridyl, chloropyridyl, 3-cyclopropylmethoxy-4-difluoromethoxyphenyl, 3,4-difluoromethoxyphenyl or diphenyl ether;

_R2 is methyl, cyclohexyl, benzyl, cyclohexylmethyl or cyclopentylmethyl;

_R3 is hydrogen, methyl, propenylbenzene or halogenated benzyl;

_R4 is hydrogen, _C1-3 alkyl, phenyl, benzyl, cyclohexylmethyl or cyclopentylmethyl.

More preferably, the R ₁ is

One of the following;

The _R2 is

One of the following;

The R ₃ is hydrogen,

One of the following;

The _R4 is: hydrogen,

One of them.

Furthermore, the 4-methyl-2-oxo-3,6-dihydropyrimidine compound also includes a pharmaceutically acceptable salt, hydrate or prodrug thereof.

The present invention also protects a method for preparing the 4-methyl-2-oxo-3,6-dihydropyrimidine compound, and the synthetic route is as follows:

The specific steps include:

S1, dissolving compound 1, compound 2 and urea in a polar organic solvent, reacting completely at 50-200° C. under the conditions of YB(OTF) ₃ catalysis and protective gas atmosphere, and post-treating to obtain a compound of formula (I-1);

S2, dissolving the compound of formula (I-1) and compound 3 in a polar organic solvent, reacting completely at room temperature under alkaline conditions, and post-treating to obtain compound (I-2);

S3, extracting hydrogen from the compound of formula (I-1) and mixing it with a polar organic solvent solution containing compound 4, reacting it completely at room temperature under a protective gas atmosphere, and post-treating it to obtain a compound of formula (II);

Wherein, in the above synthesis route, A is a halogen; the definitions of R ₁ to R ₄ , X, Y and Q are consistent with those described above.

Preferably, in step S1, the temperature at which the reaction is completed is 71°C.

Preferably, in step S1, the molar ratio of compound 1, compound 2 and urea is 1:1-2:1-2.

More preferably, in step S1, the molar ratio of compound 1, compound 2 and urea is 1:1.2:1.2.

Furthermore, in step S1 and step S3, the polar organic solvent is tetrahydrofuran, 1,4-dioxane or DMF (dimethylformamide).

Furthermore, in steps S1 and S3, the protective gas includes helium, neon, argon or nitrogen.

Preferably, the protective gas is argon.

Preferably, in step S1, the time required for the reaction to be complete is 20 to 30 hours. As the size of the group increases, the reaction time will be extended accordingly.

In detail, in steps S1 to S3, the post-treatment is that after the reaction is completed, ethyl acetate and water are added to the system for extraction, the aqueous layer is extracted again with ethyl acetate, the organic layers are combined, and the combined organic extracts are washed with brine. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which is purified by silica gel column chromatography (petroleum ether/EtOAc, petroleum ether/EtOAc, 3 to 5:1) to obtain a compound of formula (I-1), formula (I-2) or formula (II).

Furthermore, in step S2, the polar organic solvent is N,N-dimethylformamide, N,N-dimethylacetamide, THF or 1,4-dioxane.

Preferably, in step S2, the molar ratio of the compound of formula (I-1) to compound 3 is 1:1 to 1.5.

Preferably, in step S2, the time required for the reaction to be complete is 10 to 20 hours.

Preferably, in step S2, the alkaline reagent used in the alkaline condition is K ₂ CO ₃ , cesium carbonate, or sodium hydroxide.

Preferably, in step S3, the hydrogen extraction reagent is a 60% sodium hydride and tetrahydrofuran solution.

Preferably, in step S3, the molar ratio of the compound of formula (I-1) to compound 4 is 1:1 to 1.5.

Preferably, in step S3, the time required for the reaction to be complete is 10 to 20 hours.

The present invention protects the use of the 4-methyl-2-oxo-3,6-dihydropyrimidine compound in the preparation of a PDE1 inhibitor.

The present invention also protects the use of the 4-methyl-2-oxo-3,6-dihydropyrimidine compounds in the preparation of drugs for treating phosphodiesterase-related diseases.

Furthermore, the phosphodiesterase-related disease is any one or more of liver fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis.

The present invention has the following beneficial effects:

The invention provides a 4-methyl-2-oxo-3,6-dihydropyrimidine compound with a completely new structure. Experiments have shown that the 4-methyl-2-oxo-3,6-dihydropyrimidine compound has a good inhibitory effect on phosphodiesterase type 1 (PDE1), and can be used to prepare a phosphodiesterase type 1 inhibitor. At the same time, a drug prepared by using the compound as an active ingredient has a good therapeutic effect on pulmonary hypertension and idiopathic pulmonary fibrosis, and has important medicinal value and broad application prospects in the preparation of drugs for pulmonary hypertension and idiopathic pulmonary fibrosis. In addition, the preparation method of the 4-methyl-2-oxo-3,6-dihydropyrimidine compound is simple, and is suitable for large-scale industrial production and application.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows representative images of different groups of liver sections stained by H&E staining, Masson staining, and α-SMA immunohistochemistry.

FIG2 is a quantitative graph showing the results of H&E staining (a in FIG2 ), Masson staining (b in FIG2 ), and α-SMA immunohistochemical staining (c in FIG2 ) (compared with the control group, #p<0.05,

##p<0.01; compared with the model group, *p<0.05, **p<0.01; data are expressed as the mean ± SEM of independent determination data).

DETAILED DESCRIPTION

The present invention is further described below in conjunction with the accompanying drawings and specific examples, but the examples do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the art.

Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

Example 1 Preparation of Compound (I-1)

The synthetic route of the compound (I-1) is as follows:

The specific steps include:

Compound 1 (2.5 mM), compound 2 (2.5 mM) and urea (2.5 mM) were dissolved in THF (10 mL), YB (OTF) ₃ (0.25 mM) was added, inert gas Ar was purged for more than 3 times, and the mixture was heated under reflux at 71°C for 25 h. Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, the aqueous layer was extracted again with ethyl acetate (20 mL), the organic layers were combined, and washed with brine (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, petroleum ether/EtOAc, 50:1 to 1:1 gradient elution) to obtain compound (I-1).

Taking compound 17 as an example, the specific steps include:

Compound 4-(difluoromethoxy)-3-(cyclopropylmethoxy)benzaldehyde (CAS No. 151103-09-2, 1.21 g, 5 mM), compound cyclohexylmethyl 3-oxobutanoate (0.99 g, 5 mM) and urea 57-13-6 (300 mg, 5 mM) were dissolved in THF (20 mL), and YB(OTF) ₃ (310 mg, 0.5 mM) was added. The inert gas Ar was purged for more than 3 times, and the mixture was heated at 71°C for 21 h under reflux. Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, and the aqueous layer was extracted again with ethyl acetate (20 mL), and the organic layers were combined and washed with brine (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, gradient elution from 50:1 to 1:1) to give compound 17 (1.546 g, yield 66.6%).

Example 2 Preparation of Compound (I-2)

The synthetic route of the compound (I-2) is as follows:

The specific steps include:

Compound (I-1) (4 mM) obtained in Example 1 and compound 3 (4 mM) were dissolved in DMF (10 mL), K ₂ CO ₃ (8 mM) was added, and the mixture was reacted at room temperature overnight. Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, and the aqueous layer was extracted again with ethyl acetate (20 mL), and the organic layers were combined and washed with brine (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, 3:1) to obtain compound (I-2).

Taking compound 18 as an example, the specific steps include:

Compound 17 (50 mg, 0.108 mM) obtained in Example 1 and iodomethane (15.3 mg, 0.108 mM) were dissolved in DMF (0.27 mL), K ₂ CO ₃ (30 mg, 0.216 mM) was added, and the mixture was reacted at room temperature overnight (23 h). Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, and the aqueous layer was extracted again with ethyl acetate (20 mL), and the organic layers were combined and washed with brine (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to give a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, gradient elution from 50:1 to 2:1) to give compound 18 (23 mg, yield 30%).

Example 3 Preparation of Compound (II)

The synthetic route of the compound (II) is as follows:

The specific steps include:

Under ice bath conditions, the anhydrous THF solution (9 mL) of compound (I-1) (2.5 mM) obtained in Example 1 was slowly dripped into 60% NaH (2.75 mM) protected by inert gas, and the reaction was stirred for 30 min until no bubbles were generated in the system, and the anhydrous THF solution (1 mL) of compound 4 (2.75 mM) was slowly dripped, and the mixture was transferred to room temperature and stirred for overnight. Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, and the aqueous layer was extracted again with ethyl acetate (20 mL), and the organic layers were combined and washed with brine (3×100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, 3:1) to obtain compound (II).

Taking compound 26 as an example, the specific steps include:

Under ice bath conditions, the anhydrous THF solution (9 mL) of compound 17 (1.16 g, 2.5 mM) obtained in Example 1 was slowly dripped into 60% NaH (150 mg, 3.75 mM) protected by inert gas, and the reaction was stirred for 30 min until no bubbles were generated in the system, and the anhydrous THF solution (1 mL) of compound S-benzyl carbonochloridothioate (710 mg, 3.8 mM) was slowly dripped, and the reaction was transferred to room temperature and stirred overnight (18 h). Ethyl acetate (80 mL) and water (100 mL) were added to the system for extraction, and the aqueous layer was extracted again with ethyl acetate (20 mL), and the organic layers were combined and washed with brine (3 × 100 mL). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/EtOAc, 50:1 to 3:1 gradient elution) to obtain compound 26 (912 mg, yield 79%).

The above method can be used to synthesize and prepare compounds 1 to 39 of the following formulas.

The NMR data of compounds 1 to 39 synthesized by the above method are shown in Table 1.

Table 1 NMR data of 4-methyl-2-oxo-3,6-dihydropyrimidine compounds 1 to 39

Experimental Example 1 Compound Activity Test and Results

Compounds 1 to 39 prepared in the examples were used as test objects to determine their IC ₅₀ (half-maximal inhibitory concentration) or single-point inhibition rate against phosphodiesterase type 1. An IC ₅₀ below 50000 nM indicates that the compound exhibits an inhibitory effect on PDE1, and the smaller the IC ₅₀ , the better the inhibitory activity of the compound. An IC ₅₀ within 100 nM indicates excellent inhibitory activity; 50% @ 1000 nM indicates that when the compound concentration is 1000 nM, its inhibition rate against PDE1C is 50%, and other single-point inhibition rate data are similar.

The measured results are shown in Table 2.

Table 2 Inhibitory activity of 4-methyl-2-oxo-3,6-dihydropyrimidine compounds on PDE1C

As can be seen from the table, most of the compounds showed significant inhibitory effects on phosphodiesterase type 1, among which compounds 3, 4, 6, 9, 12-15, 24-27, 35, and 37 showed particularly significant inhibitory effects on phosphodiesterase type 1, with IC ₅₀ less than 200 nM or an inhibition rate of ≥50% on PDE1C when the compound concentration was 100 nM; in particular, compounds 9, 10, 14, 15, 26, and 27 had IC ₅₀ less than 25 nM, showing significant inhibitory effects on phosphodiesterase type 1. Existing studies (DOI: 10.1021/acs.jmedchem.0c00711, DOI: 10.1021/acs.jmedchem.2c00458) reported that PDE1 is a potential target for the treatment of idiopathic pulmonary fibrosis, and the compounds of the present application showed good inhibitory effects on PDE1, indicating that the compounds of the present application have potential prospects for the preparation of idiopathic pulmonary fibrosis drugs.

Experimental Example 2 Pharmacodynamic effects of compounds 26 and 35 on BDL-induced liver fibrosis rat model

1. Experimental Materials

All animal care and experimental protocols were in accordance with the Guide for the Care and Use of Laboratory Animals (National Institutes of Health publication, revised 1996, No. 86-23, Bethesda, MD) and approved by the Institutional Animal Research Ethics Committee of Sun Yat-sen University (SYSU-IACUC-2022-001792). 85 male SD rats (6-8 weeks old, weighing 180 to 200 g) were purchased from Guangdong Weitong Lihua Laboratory Animal Technology Co., Ltd.

2. Experimental methods

Animal grouping: Rats were kept at a temperature of 24±1 and a relative humidity of 60-70% with a 24-hour light/dark cycle (light on from 7:00 to 19:00). After one week of habituation, the animals were randomly divided into a control group (Sham, also known as a sham operation group), a model group (BDL), a drug-treated group: 26 groups, 35 groups, and a positive control group (PPC as a positive drug, i.e., polyene phosphatidylcholine), and the group numbers were Sham group, BDL group, BDL-26 group, BDL-35 group, and BDL-PPC group.

Treatment: Sterile food and water were provided according to institutional guidelines. The rats were anesthetized with sodium pentobarbital (45 mg/kg, Sigma). The common bile duct was freed and the bile duct was ligated with surgical suture. 24 hours after surgery, the sham-operated group and the BDL-treated model group were injected intraperitoneally with normal saline solution every day, and the drug-treated groups were given 2.5 mg/kg of compound 26, 2.5 mg/kg of compound 35 and 150 mg/kg of PPC every day, respectively. The sham-operated group served as a healthy control, and the number of mice in each group was ≥6.

After fasting overnight, the animals were killed with sodium pentobarbital (45 mg/kg) after blood was collected by abdominal aorta method. The serum was centrifuged at 3000 rpm and 4°C for 15 minutes and stored in a -80°C refrigerator. The ligated left lobe was harvested after euthanasia of the rats; the tissue was immersed in 4% buffered paraformaldehyde at room temperature overnight and then embedded in paraffin. The paraffin-embedded tissue sections were sliced to a thickness of 5 μm and mounted on slides. The paraffin sections of the liver tissue were stained with H&E, Masson staining and α-SMA (Servicebio, GB111364) immunohistochemistry, and the results are shown in Figure 1. Liver necrosis and bile duct proliferation were quantified in a blinded manner on a scale of 1 to 5 in H&E staining using a microscope, and the results are shown in Figure 2, Panel a; histological sections of all animals were observed at low magnification (10× objective lens, Life Technologies, EVOS FL Auto) and analyzed using ImageJ to calculate the percentage of collagen area, and the results are shown in Figure 2, Panel b; histological sections of all animals were observed at low magnification (10× objective lens, Life Technologies, EVOS FL Auto) and analyzed using ImageJ to calculate the percentage of α-SMA-positive area, and the results are shown in Figure 2, Panel c.

3. Experimental results

The results of H&E staining, Masson staining and α-SMA immunohistochemical staining are shown in Figure 1, where the H&E staining results are used to observe the pathological conditions of liver tissue, the Masson staining results are used to observe the collagen deposition in liver tissue; and the α-SMA immunohistochemical staining results are used to observe the expression level of α-SMA in liver tissue.

The H&E staining score results are shown in Figure 2a. Combined with Figures 1 and 2, it can be seen that compared with the control group Sham group, the BDL-induced rat liver had obvious pathological changes such as bile duct hyperplasia and fibrosis, and some even had hepatocyte necrosis and fibrosis. When compound 26 and 35 were treated with drugs, the structural damage of the liver was reduced, and the fibrotic lesions were less.

Collagen deposition is a pathological feature of liver fibrosis, and its expression can be represented by blue staining after Masson staining. The quantification result is shown in Figure 2b. Combined with Figures 1 and 2, it can be seen that compared with the control group, there is a large area of collagen deposition and fibrosis around the portal vein area of the BDL-induced rat liver. Compounds 26 and 35 reduce collagen deposition to normal levels.

α-Smooth muscle actin (α-SMA) is the main marker of active hepatic stellate cells (HSCs). Immunofluorescence staining was used to detect its expression in the liver tissues of each group, as shown in Figure 2 c. Combined with Figures 1 and 2, it can be seen that the α-SMA level in the model group was significantly higher than that in the control group, and compounds 26 and 35 significantly reduced the level of α-SMA.

The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be equivalent replacement methods and are included in the protection scope of the present invention.

Claims (10)

1. A 4-methyl-2-oxo-3,6-dihydropyrimidine compound, characterized in that the structure of the compound is as shown in formula (I) or formula (II): Wherein, the R ₁ is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group, a substituted or unsubstituted indazolyl group, a substituted or unsubstituted piperonyl group, and the substituted substituent is one or more, so The substituents of the substituted phenyl, substituted pyridyl, substituted indazolyl, and substituted piperonyl groups are selected from C _{1 to 4} alkyl groups, substituted or unsubstituted C _{1 to 4} alkoxy groups, and halogenated C _{1 to 4} alkoxy groups. One or more of the group, phenol group or halogen, the substituent of the C _{1 to 4} alkoxy group is a C _{3 to 6} cycloalkyl group; Q is an oxygen or sulfur atom; X is an oxygen or sulfur atom; Y is a carbon, oxygen, nitrogen or sulfur atom; R ₂ is C _3-6 cycloalkyl, substituted or unsubstituted C _1-4 alkyl, the substituted substituent is one or more, and the substituent of the substituted C _1-4 alkyl is selected from phenyl Or C _3～6 cycloalkyl; R ₃ is hydrogen, C _{1 to 4} alkyl, substituted benzyl or substituted C _{2 to 4} alkenyl, the substituted substituent is one or more, the substituted benzyl or substituted C _{2 to 4} alkenyl The substituent is selected from one or more types of phenyl or halogen; R ₄ is hydrogen, phenyl, substituted or unsubstituted C _1-4 alkyl, the substituted substituent is one or more, and the substituent of the substituted C _1-4 alkyl is selected from phenyl, C _{3 ~6} One or more types of cycloalkyl and halogen. 2. 4-methyl-2-oxo-3,6-dihydropyrimidine compounds according to claim 1, characterized in that, said _R1 is a substituted or unsubstituted phenyl group, a substituted or unsubstituted pyridyl group , substituted or unsubstituted indazolyl, substituted or unsubstituted piperonyl, the substituted substituent is one or more, the substituted phenyl, substituted pyridyl, substituted indazolyl, substituted piperonyl The group is selected from one or more C _{1 to 3} alkyl groups, substituted or unsubstituted C _{1 to 4} alkoxy groups, halogenated C _{1 to 3} alkoxy groups, phenol groups or halogens, and the substituted C _{1 to 4 alkoxy groups are} The substituent of ₄ alkoxy is C _3~5 cycloalkyl; R ₂ is cyclohexyl or substituted or unsubstituted methyl, the substituted substituent is one or more, and the substituted substituent of R ₂ is selected from phenyl or C _{3 to 6} cycloalkyl; R ₃ is hydrogen, methyl, substituted benzyl or substituted propenyl, the substituted substituent is one or more, the substituent of the substituted benzyl or substituted propenyl is selected from phenyl or halogen; R ₄ is hydrogen, phenyl, substituted or unsubstituted C _1-3 alkyl, the substituted substituent is one or more, and the substituent of the substituted C _1-3 alkyl is selected from phenyl or C _{3 ~6} cycloalkyl. 3. 4-methyl-2-oxo-3,6-dihydropyrimidine compounds according to claim 2, characterized in that, said _R1 is substituted phenyl, substituted pyridyl, substituted indazolyl, Non-substituted piperonyl ring group, the substituent of the substituted phenyl group, substituted pyridyl group, substituted indazolyl group is selected from one or more of methyl, unsubstituted or substituted methoxy group, phenol group or halogen, the The substituent substituting the methoxy group is cyclopropyl; R ₂ is cyclohexyl or substituted or unsubstituted methyl, the substituted substituent is one or more, and the substituent of the substituted methyl is selected from phenyl, cyclohexyl or cyclopentyl; R ₄ is hydrogen, phenyl, substituted or unsubstituted C _1-3 alkyl, the substituted substituent is one or more, and the substituent of the substituted C _1-3 alkyl is selected from phenyl, cyclohexyl Or cyclopentyl. 4. 4-methyl-2-oxo-3,6-dihydropyrimidine compounds according to claim 3, characterized in that said _R1 is 3,4-difluoro-substituted phenyl, 3,4 -Dimethoxy substituted phenyl, m-methoxy substituted phenyl, p-methoxy substituted phenyl, piperonyl ring, 1-methyl-1H-indazolyl, methoxypyridyl, chloropyridyl, 3-cyclopropylmethoxy-4-difluoromethoxyphenyl, 3,4-difluoromethoxyphenyl or diphenyl ether; R ₂ is methyl, cyclohexyl, benzyl, cyclohexylmethyl or cyclopentylmethyl; R ₃ is hydrogen, methyl, propenylbenzene or halobenzyl; R ₄ is hydrogen, C _1-3 alkyl, phenyl, benzyl, cyclohexylmethyl or cyclopentylmethyl. 5. 4-methyl-2-oxo-3,6-dihydropyrimidine compound according to claim 4, characterized in that, said _R1 is one of; The R ₂ is one of; The R ₃ is hydrogen, one of; The R ₄ is: hydrogen, one of them. 6. The 4-methyl-2-oxo-3,6-dihydropyrimidine compound according to any one of claims 1 to 5, characterized in that, the 4-methyl-2-oxo-3, 6-Dihydropyrimidine compounds also include pharmaceutically acceptable salts, hydrates or prodrugs thereof. 7. The preparation method of 4-methyl-2-oxo-3,6-dihydropyrimidine compounds according to any one of claims 1 to 5, characterized in that the synthesis route is as follows: Specifically, it includes the following steps: S1. Dissolve compound 1, compound 2 and urea in a polar organic solvent, react completely at 50-200°C under the catalytic and protective gas atmosphere of YB(OTF) ₃ , and perform post-processing to obtain formula (I-1 ) compound; S2. Dissolve the compound of formula (I-1) and compound 3 in a polar organic solvent, react completely at room temperature under alkaline conditions, and perform post-processing to obtain compound (I-2); S3. Mix the hydrogen-extracted compound of formula (I-1) with the polar organic solvent solution containing compound 4, react completely at room temperature under protective gas atmosphere, and perform post-processing to obtain the compound of formula (II); In the above synthetic route, A is halogen; the definitions of R ₁ to R ₄ , X, Y and Q are consistent with any one of claims 1 to 5. 8. Use of the 4-methyl-2-oxo-3,6-dihydropyrimidine compound according to any one of claims 1 to 5 in the preparation of PDE1 inhibitors. 9. Application of the 4-methyl-2-oxo-3,6-dihydropyrimidine compound according to any one of claims 1 to 5 in the preparation of drugs for treating phosphodiesterase-related diseases. 10. The application according to claim 9, characterized in that the phosphodiesterase-related disease is any one or more of liver fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis.