6-oxo-1, 6-dihydropyrimidine-5-nitrile derivative as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of biological medicines, and particularly relates to a 6-oxo-1, 6-dihydropyrimidine-5-nitrile derivative as well as a preparation method and application thereof. The derivative has a good inhibition effect on phosphodiesterase type 1 (PDE1), and can be applied as a phosphodiesterase type 1 inhibitor; according to the research on phosphodiesterase type I related diseases in the prior art, the 6-oxo-1, 2, 4-triazole-3-carboxylic acid is used as a raw material. In addition, the 2, 6-dihydropyrimidine-5-nitrile derivative and the pharmaceutically acceptable salt thereof can be further applied to treatment of diseases related to phosphodiesterase I, such as pulmonary fibrosis, pulmonary arterial hypertension, hepatic fibrosis, pneumonia, vascular dementia, enteritis, Alzheimer's disease and the like, and more selectable medicines are provided; and the pharmaceutical composition has important medicinal value and clinical application prospect. Moreover, the 6-oxo-1, 6-dihydropyrimidine-5-nitrile derivative disclosed by the invention is novel in structure, simple in preparation method and very suitable for large-scale industrial production and application.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine technology, and more specifically, relates to a 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative, a preparation method and application thereof. Background Art

[0002] Phosphodiesterases (PDEs) have the function of hydrolyzing intracellular second messengers (cyclic adenosine monophosphate cAMP or cyclic guanosine monophosphate cGMP), and terminate the biochemical effects transmitted by these second messengers by degrading intracellular cAMP or cGMP. Studies have shown that cAMP and cGMP play an important regulatory role in cell activities. They are second messengers of substances such as neurotransmitters, hormones, light and odors, and widely act on intracellular target organs. The regulation of intracellular cAMP and cGMP concentrations is mainly determined by the balance between the synthesis of nucleotide cyclases and the hydrolysis of phosphodiesterases (PDEs).

[0003] PDEs are widely distributed in the body and are divided into 11 isozyme families (PDE1 to PDE11) based on their protein sequence similarity, enzyme kinetics, regulatory properties, cell tissue distribution, and pharmacological properties. Among them, phosphodiesterase type 1 (PDE1) was identified as Ca 2+ Calmodulin-dependent phosphodiesterase (CaM-pde), which is activated by Ca 2+Calmodulin activates and mediates calcium and cyclic nucleotide signaling pathways. Studies have found 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 also shown that PDE1 is associated with lung, kidney, hematology, gastrointestinal tract, liver, fertility, cancer and metabolic disorders. ([1] Ren, L.; Yang, C.; Dou, Y.; Zhan, R.; Sun, Y.; Yu, Y., MiR-541-5p Regulates Lung Fibrosis by Targeting CyclicNucleotide Phosphodiesterase 1A. Exp Lung Res 2017, 43(6-7), 249-258. [2] Xin, W.; Li, N.; Fernandes, VS; Chen, B.; Rovner, ES; Petkov, GV, BK Channel Regulation byPhosphodiesterase Type 1:ANovel Signaling Pathway Controlling Human DetrusorSmooth Muscle Function.Am J Physiol Renal Physiol 2016,310(10),F994-9.). It can be seen that PDE1 inhibitors play an important role in the field of disease treatment.

[0004] Currently, PDE1 inhibitors have been reported as drugs for treating pulmonary arterial hypertension (PAH), but the development and research on PDE1 inhibitors is still relatively limited, and there is still a need to provide more PDE1 inhibitors to expand the range of drug options for research and clinical applications. Summary of the invention

[0005] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the limited types of existing PDE1 inhibitors and provide a 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative.

[0006] The purpose of the present invention is to provide a method for preparing the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives.

[0007] Another object of the present invention is to provide the use of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives in the preparation of phosphodiesterase type I inhibitors.

[0008] Another object of the present invention is to provide the use of the phosphodiesterase type I inhibitor in the preparation of drugs for treating phosphodiesterase type I related diseases.

[0009] Another object of the present invention is to provide a phosphodiesterase type I inhibitor.

[0010] The above-mentioned purpose of the present invention is achieved through the following technical solutions:

[0011] A 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative, the structural formula of which is shown in formula (I) and (II):

[0012]

[0013] Wherein, R1 is selected from C 1～6 Alkyl, five-membered heteroaryl, C 3～8 One of the cycloalkyl groups; wherein the five-membered heteroaryl group is unsubstituted or substituted with one or more halogens, C 1～6 Alkyl substitution;

[0014] R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～6 Alkyl, C 3～8 Cycloalkyl C 1～6 Alkyl, phenyl C 2～6 Alkyl, phenyl C 1～6 Carbonyl, phenyl C 1～6 wherein the benzyl or phenyl group is unsubstituted or substituted with one or more halogens, C 1～6 Alkyl, C 1～6 Haloalkyl, six-membered halogenated heteroaryl substitution;

[0015] R3 is selected from benzyl, C 3～8 Cycloalkyl C 1～6 Alkyl, C 1～6 wherein the benzyl group is unsubstituted or substituted with one or more halogens.

[0016] Further, R1 is selected from C 3～6 Alkyl, five-membered heteroaryl, C 3～6 One of the cycloalkyl groups; wherein the five-membered heteroaryl group is unsubstituted or substituted with one or more halogens, C 1～3 Alkyl substituted; the heteroatom in the five-membered heteroaryl group is one or more of an oxygen atom, a sulfur atom, and a nitrogen atom;

[0017] R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～3 Alkyl, C 5～8 Cycloalkyl C 1～3 Alkyl, phenyl C 2～3 Alkyl, phenyl C 1～3 Carbonyl, phenyl C 1～3wherein the benzyl or phenyl group is unsubstituted or substituted with one or more halogens, C 1～3 Alkyl, C 1～3 The heteroatom in the six-membered halogenated heteroaryl group is a nitrogen atom;

[0018] R3 is selected from benzyl, C 3～5 Cycloalkyl C 1～3 Alkyl, C 1～3 wherein the benzyl group is unsubstituted or substituted with one or more halogens.

[0019] Furthermore, R1 is selected from C 3～5 Alkyl, five-membered heteroaryl, C 3～5 One of cycloalkyl; wherein the five-membered heteroaryl is unsubstituted or substituted by one or more halogens or methyl groups; the five-membered heteroaryl is one of furanyl, thiazolyl, pyrrolyl, and thienyl;

[0020] R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～2 Alkyl, C 5～6 Cycloalkyl C 1～3 Alkyl, phenyl C 2～3 Alkyl, phenyl C 1～3 Carbonyl, phenyl C 1～3 Amide; wherein the benzyl group and the phenyl group are unsubstituted or substituted with one or more halogen, methyl, trifluoromethyl, and six-membered halogenated heteroaryl groups; the heteroatom in the six-membered halogenated heteroaryl group is a nitrogen atom;

[0021] R3 is selected from benzyl, C 3～5 Cycloalkyl C 1～3 alkyl, methyl; wherein the benzyl group is unsubstituted or substituted with one or more halogens.

[0022] Preferably, R1 is selected from

[0023] One of;

[0024] R2 is selected from

[0025] One of;

[0026] R3 is selected from methyl, One of them.

[0027] In the present invention, C 1～6 Alkyl refers to an alkyl group with a total carbon number of 1 to 6, including C 1～6 Straight chain alkyl, C 1～6for example, a straight chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms, or a branched chain alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. 1～3 Alkyl, C 3～6 Alkyl, C 1～2 Alkyl groups have a similar interpretation, except that the number of carbon atoms is different.

[0028] C 3～8 Cycloalkyl refers to a cycloalkyl group having 1 to 8 carbon atoms. 3～6 Cycloalkyl, C 5～6 Cycloalkyl groups have a similar interpretation, except that the number of carbon atoms is different.

[0029] C 1～6 Amide group refers to an amide group containing 1 to 6 carbon atoms, including C 1～6 The straight chain amide group, C 1～6 Branched chain amide group; C 1～3 The amide group has a similar interpretation, except that the number of carbon atoms is different.

[0030] C 1～6 Carbonyl refers to a carbonyl group containing 1 to 6 carbon atoms, including C 1～6 The straight-chain carbonyl, C 1～6 The branched carbonyl group; C 1～3 The carbonyl group has a similar explanation, except that the number of carbon atoms is different.

[0031] The halogenated heteroaryl group means that the hydrogen on the heteroaryl group is replaced by a halogen, and the halogen refers to fluorine, chlorine, bromine and iodine.

[0032] Furthermore, the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives of the present invention also include pharmaceutically acceptable salts and solvates thereof.

[0033] At the same time, the present invention also provides a method for preparing the 6-oxo-1,6-dihydropyrimidine-5-nitrile derivatives, and the synthetic route is as follows:

[0034]

[0035] The specific steps include:

[0036] S1. Ethyl cyanoacetate, thiourea and R1-substituted aldehyde compound are placed in an organic solvent, an alkaline reagent is added, and the mixture is heated to reflux at 75-100° C. and reacted completely, and the precipitate is filtered and washed and dissolved in water, and acidified with acid, and filtered, and the precipitate is washed and dried to obtain compound b;

[0037] S2, dissolving compound b in an alkaline solution, adding compound c, reacting at 25-30°C until complete, and post-treating to obtain a compound of formula (I);

[0038] S3, dissolving the compound of formula (I) in an alkaline solution, adding compound d, reacting at 25-60°C until complete, and post-treating to obtain the compound of formula (II);

[0039] Wherein, R1, R2, and R3 are consistent with any of the definitions of R1, R2, and R3 in the present invention.

[0040] Further, in step S1, the alkaline agent is selected from one or more of potassium carbonate, cesium carbonate, sodium carbonate, pyridine, sodium hydroxide, potassium hydroxide, sodium hydride, potassium tert-butoxide, sodium ethoxide, sodium methoxide, and sodium. Preferably, the alkaline agent is potassium carbonate.

[0041] Furthermore, in step S1, the organic solvent is selected from one or more of ethanol, acetonitrile, N,N-dimethylformamide (DMF), methanol, and acetone. Preferably, the organic solvent is anhydrous ethanol.

[0042] Furthermore, in step S1, the heating reflux time is 8 to 48 hours; preferably, the heating reflux time is 8 to 36 hours; more preferably, the heating reflux time is 12 to 24 hours.

[0043] Furthermore, in step S1, the acidification is performed to neutralize the solution and precipitate the compound.

[0044] Further, in step S2, the solute in the alkaline solution is selected from one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, and N,N-diisopropylethylamine (DIPEA). Preferably, the solute in the alkaline solution is potassium carbonate.

[0045] Furthermore, in step S2, the solvent in the alkaline solution is selected from one or more of water, ethanol, acetonitrile, N,N-dimethylformamide, methanol, and acetone. Preferably, the solvent in the alkaline solution is one or both of water and acetone.

[0046] In a further embodiment, in step S2, the post-treatment is filtering after the reaction is completed, washing the filter cake with water, and drying to obtain the compound of formula (I).

[0047] Furthermore, in step S2, the reaction time is 1 to 48 hours; preferably, in step S2, the reaction time is 12 to 48 hours; more preferably, in step S2, the reaction time is 24 to 48 hours.

[0048] In a further embodiment, in step S3, the solute in the alkaline solution is selected from one or more of potassium hydroxide, sodium hydroxide, potassium carbonate, triethylamine, and N,N-diisopropylethylamine (DIPEA). Preferably, the solute in the alkaline solution is potassium carbonate.

[0049] Furthermore, in step S3, the solvent in the alkaline solution is selected from one or more of N,N-dimethylformamide and acetone. Preferably, the solvent in the alkaline solution is acetone.

[0050] Furthermore, in step S3, the post-treatment is to cool after the reaction is completed, add ethyl acetate or diethyl ether for extraction, wash with saturated brine, combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure, and purify the residue by column chromatography (solvent is petroleum ether / ethyl acetate = 5:1) to obtain a compound of formula (II).

[0051] In addition, the present invention also claims to protect the use of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives in the preparation of phosphodiesterase type I inhibitors.

[0052] At the same time, the present invention also claims to protect the use of the phosphodiesterase type I inhibitor in the preparation of drugs for treating phosphodiesterase type I related diseases.

[0053] Furthermore, the phosphodiesterase type I related diseases include pulmonary fibrosis, pulmonary hypertension, liver fibrosis, pneumonia, vascular dementia, enteritis, and Alzheimer's disease.

[0054] The present invention provides a phosphodiesterase type I inhibitor, comprising any one of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives of the present invention.

[0055] The present invention has the following beneficial effects:

[0056] The present invention provides a 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative. Experimental results show that 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives generally exhibit good inhibitory effects on phosphodiesterase type 1 (PDE1) and can be used as phosphodiesterase type 1 inhibitors. Generally speaking, IC 50 The concentration below 50000 nM indicates that the compound exhibits an inhibitory effect on PDE1. In the specific experiment of the present invention, the compound has a particularly significant inhibitory effect on phosphodiesterase type 1. 50 Less than 500 nM; among them, IC of compounds 6-7, 13, 16, 28, 39, 41, 43 50Less than 50nM. This means that the compounds of the present invention have a good inhibitory effect as PDE1 inhibitors. At the same time, according to the prior art research on phosphodiesterase type I related diseases, the 6-oxo-1,6-dihydropyrimidine-5-nitrile derivatives of the present invention can also be further applied to the treatment of phosphodiesterase type I related diseases such as pulmonary fibrosis, pulmonary hypertension, liver fibrosis, pneumonia, vascular dementia, enteritis, Alzheimer's disease, etc., providing more optional drugs, and having important medicinal value and clinical application prospects. In addition, the 6-oxo-1,6-dihydropyrimidine-5-nitrile derivatives of the present invention have a novel structure and a simple preparation method, and are very suitable for large-scale industrial production and application. DETAILED DESCRIPTION

[0057] The present invention is further described below with reference to 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.

[0058] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0059] Example 1 Preparation of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative compound 6

[0060] The synthetic route of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative compound 6 is as follows:

[0061]

[0062] The specific steps include:

[0063] S1. Ethyl cyanoacetate (11.3 g, 100 mmol), thiourea (7.75 g, 100 mmol), 5-chlorothiophene-2-carboxaldehyde (14.7 g, 100 mmol) and K2CO3 (13.8 g, 100 mmol) were mixed in 250 mL, reacted at reflux temperature (75°C) for 16 hours, cooled, filtered to obtain the precipitate, and washed with EtOH (ethanol) three times; then, dissolved it in hot water; 2.0 M hydrochloric acid was added dropwise to neutralize the solution while stirring until a large amount of precipitate was observed; the precipitate was filtered, washed with water and dried to obtain a gray-green solid, which was compound 6-1 (12.7 g), with a yield of 47%;

[0064] S2, 6-1 (540 mg, 2 mmol) was suspended and stirred in 30 mL of water, and KOH (224 mg, 4 mmol) was added. After 30 minutes, a clear solution was obtained, and then 3-chlorobenzyl bromide (410 mg, 2 mmol) was added. The reaction mixture was stirred at room temperature (room temperature was 25-30° C.) for 48 hours, the precipitate was filtered, and washed three times with water (3 mL×3), and dried to obtain a yellow powder, which was compound 6 (275 mg), with a yield of 35%.

[0065] Example 2 Preparation of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative compound 7

[0066]

[0067] S3, the compound 6 (75mg, 0.19mmol) prepared in Example 1, (bromomethyl) cyclopropane (116mg, 0.86mmol) and K2CO3 (53mg, 0.38mmol) were stirred in 1.5mL N, N-dimethylformamide. The reaction mixture was heated to 60 ° C for 16 hours. After cooling, ethyl acetate (10mL×3) was added and extracted three times, and washed five times with saturated brine (50mL×5), the organic layer was combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by column chromatography (solvent is petroleum ether / ethyl acetate=5:1) elution to obtain a white solid, which is compound 7 (12mg), and the yield is 14%.

[0068] Example 3 Preparation, Molecular Structure and NMR Data of 6-Oxo-1,6-dihydropyrimidine-5-carbonitrile Derivatives

[0069] The synthetic route of the 6-oxo-1,6-dihydropyrimidine-5-nitrile derivatives is as follows:

[0070]

[0071] Referring to the preparation method of Example 1 or 2 and the above-mentioned synthetic route, 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative compounds 1 to 46 were prepared. The specific structure is as follows:

[0072]

[0073] The NMR data of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative compounds 1 to 46 are shown in Table 1.

[0074] Table 1 NMR data of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives 1 to 46

[0075]

[0076]

[0077]

[0078]

[0079]

[0080]

[0081]

[0082] Note: In Table 1, DMSO-d6 is deuterated dimethyl sulfoxide; CDCl3 is deuterated chloroform; Acetone-d6 is deuterated acetone.

[0083] Example 4 Activity Test of 6-Oxo-1,6-dihydropyrimidine-5-carbonitrile Derivatives

[0084] The compounds prepared in the examples were used as test objects to determine their IC values ​​for phosphodiesterase type 1. 50 , which is the half inhibitory concentration. IC 50 The concentration below 50000 nM indicates that the compound exhibits an inhibitory effect on PDE1. The test results are shown in Table 2.

[0085] The compounds prepared in the examples were used as test objects to measure their inhibitory activity against phosphodiesterase type 1 (PDE1), and the test concentrations were 1000 nM and 100 nM. The inhibition rate of the test compound against phosphodiesterase type 1 under these two concentration conditions refers to the inhibition rate of phosphodiesterase type 1 enzyme obtained at 1000 nanomolar and 100 nanomolar concentrations of the compound. The measured results are shown in Tables 3 and 4.

[0086] Table 2 Inhibitory activity of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives against PDE1

[0087]

[0088]

[0089] Table 3 Inhibition rate of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives on PDE1 at 1000 nM

[0090] Compound Inhibition rate Compound Inhibition rate 21 76％ 25 13％ 22 59％ 27 65％

[0091] Table 4 Inhibition rate of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives on PDE1 at 100 nM

[0092] Compound Inhibition rate Compound Inhibition rate 29 38％ 37 56％ 30 37％ 38 66％ 31 23％ 40 16％ 33 33％ 42 89％ 34 63％

[0093] As shown in Tables 2, 3, and 4, most of the compounds showed significant inhibitory effects on phosphodiesterase type 1, among which compounds 3-5, 8-9, 11-12, 14-15, 17, 26, 32, 35-36, and 44-46 had particularly significant inhibitory effects on phosphodiesterase type 1, with IC 50 Less than 500 nM; especially compounds 6-7, 13, 16, 28, 39, 41, 43, 45, 46, IC 50 The inhibition rates of compounds 21, 22, and 27 on PDE1 at a concentration of 1000 nM were all greater than 59%; compounds 29-30 and 33 had a certain inhibitory effect on PDE1 at a concentration of 100 nM, and the inhibition rates of compounds 34, 37, 38, 40, and 42 on PDE1 at a concentration of 100 nM were all greater than 50%, indicating that their IC 50 Less than 100 nM. From the above results, it can be seen that the compounds prepared by the present invention all show significant inhibitory effect on phosphodiesterase type 1.

[0094] 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

1. A 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative, characterized in that: The structural formula is shown in formula (I) and (II): Wherein, R1 is selected from C 1～6 Alkyl, five-membered heteroaryl, C 3～8 One of the cycloalkyl groups; wherein the five-membered heteroaryl group is unsubstituted or substituted with one or more halogens, C 1～6 Alkyl substitution; R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～6 Alkyl, C 3～8 Cycloalkyl C 1～6 Alkyl, phenyl C 2～6 Alkyl, phenyl C 1～6 Carbonyl, phenyl C 1～6 wherein the benzyl or phenyl group is unsubstituted or substituted with one or more halogens, C 1～6 Alkyl, C 1～6 Haloalkyl, six-membered halogenated heteroaryl substitution; R3 is selected from benzyl, C 3～8 Cycloalkyl C 1～6 Alkyl, C 1～6 wherein the benzyl group is unsubstituted or substituted with one or more halogens.

2. The 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to claim 1, characterized in that: R1 is selected from C 3～6 Alkyl, five-membered heteroaryl, C 3～6 One of the cycloalkyl groups; wherein the five-membered heteroaryl group is unsubstituted or substituted with one or more halogens, C 1～3 Alkyl substituted; the heteroatom in the five-membered heteroaryl group is one or more of an oxygen atom, a sulfur atom, and a nitrogen atom; R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～3 Alkyl, C 5～8 Cycloalkyl C 1～3 Alkyl, phenyl C 2～3 Alkyl, phenyl C 1～3 Carbonyl, phenyl C 1～3 wherein the benzyl or phenyl group is unsubstituted or substituted with one or more halogens, C 1～3 Alkyl, C 1～3 The heteroatom in the six-membered halogenated heteroaryl group is a nitrogen atom; R3 is selected from benzyl, C 3～5 Cycloalkyl C 1～3 Alkyl, C 1～3 wherein the benzyl group is unsubstituted or substituted with one or more halogens.

3. The 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to claim 2, characterized in that: R1 is selected from C 3～5 Alkyl, five-membered heteroaryl, C 3～5 One of cycloalkyl; wherein the five-membered heteroaryl is unsubstituted or substituted by one or more halogens or methyl groups; the five-membered heteroaryl is one of furanyl, thiazolyl, pyrrolyl, and thienyl; R2 is selected from benzyl, six-membered halogenated heteroaryl C 1～2 Alkyl, C 5～6 Cycloalkyl C 1～3 Alkyl, phenyl C 2～3 Alkyl, phenyl C 1～3 Carbonyl, phenyl C 1～3 Amide; wherein the benzyl group and the phenyl group are unsubstituted or substituted with one or more halogen, methyl, trifluoromethyl, and six-membered halogenated heteroaryl groups; the heteroatom in the six-membered halogenated heteroaryl group is a nitrogen atom; R3 is selected from benzyl, C 3～5 Cycloalkyl C 1～3 Alkyl, methyl; wherein benzyl is unsubstituted or substituted by one or more halogens.

4. The 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to claim 3, characterized in that: R1 is selected from One of; R2 is selected from One of; R3 is selected from methyl, One of them.

5. The 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to any one of claims 1 to 4, characterized in that: The 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives also include pharmaceutically acceptable salts and solvates thereof.

6. The method for preparing the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to any one of claims 1 to 5, characterized in that: The synthetic route is as follows: The specific steps include: S1. Ethyl cyanoacetate, thiourea and R1-substituted aldehyde compound are placed in an organic solvent, an alkaline reagent is added, and the mixture is heated to reflux at 75-100° C. and reacted completely, and the precipitate is filtered and washed and dissolved in water, and acidified with acid, and filtered, and the precipitate is washed and dried to obtain compound b; S2, dissolving compound b in an alkaline solution, adding compound c, reacting at 25-30°C until complete, and post-treating to obtain a compound of formula (I); S3, dissolving the compound of formula (I) in an alkaline solution, adding compound d, reacting at 25-60°C until complete, and post-treating to obtain the compound of formula (II); Wherein, R1, R2, and R3 are consistent with any definition of claims 1 to 5.

7. Use of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to any one of claims 1 to 5 in the preparation of phosphodiesterase type I inhibitors.

8. Use of the 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to any one of claims 1 to 5 in the preparation of a drug for treating phosphodiesterase type I related diseases.

9. The use according to claim 8, characterized in that: The phosphodiesterase type I related diseases include pulmonary fibrosis, pulmonary hypertension, liver fibrosis, pneumonia, vascular dementia, enteritis, and Alzheimer's disease.

10. A phosphodiesterase type I inhibitor, characterized in that: A 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivative according to any one of claims 1 to 4.

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