A pyrazole compound, a preparation method and use thereof

Abstract

The application belongs to the technical field of chemical drugs, and particularly relates to a pyrazole compound and a preparation method and application thereof. The application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which not only has good myeloperoxidase (MPO) inhibitory activity, but also can be used for treating and / or preventing cardiovascular diseases. (I)

Description

Technical Field

[0001] This invention belongs to the field of chemical pharmaceutical technology, specifically relating to a pyrazole compound, its preparation method, and its uses. Background Technology

[0002] Myeloperoxidase (MPO), also known as myeloperoxidase, is a heme protease of the heme cofactor and a member of the heme peroxidase superfamily. MPO is found in the aniline blue granules of myeloid cells (mainly neutrophils and monocytes) and is a specific marker of myeloid cells. The main function of MPO is to utilize hydrogen peroxide and chloride ions to produce hypochlorite, forming the MPO-H₂O₂-halogen system, which kills microorganisms within phagocytes. In addition, MPO can be released extracellularly, damaging various target substances such as tumor cells, platelets, NK cells, protozoa, and toxins, playing a role in the production and regulation of inflammatory responses in the body. However, under certain conditions, the MPO-catalyzed reaction generates excessive oxidation products (hypochlorous acid, 3-chlorotyrosine, nitrotyrosine, etc.), exceeding the defense response of local antioxidants, leading to oxidative stress and oxidative tissue damage. Currently, excessive activation of MPO has been found to be closely related to cardiovascular disease, neurodegenerative diseases, tumors, and inflammation.

[0003] Currently, MPO is considered the most promising cardiovascular biomarker. Elevated MPO levels in the body indicate a risk of arteriosclerosis and coronary heart disease, serving as an early warning sign of myocardial infarction. It is more sensitive than other indicators such as troponin T, CK-MB, and CRP, allowing for earlier diagnosis and risk assessment. MPO levels can significantly increase within 2 hours of the onset of chest pain. Therefore, for patients with chest pain, MPO will have greater clinical significance in diagnosing acute coronary syndrome (ACS).

[0004] Although small molecule MPO inhibitors have been reported, such as CN115403584B, CN107001374B, CN100379737C, and CN120265633A, none are currently marketed. The main MPO covalent inhibitors in clinical development are Bioheeaven's BHV3241 (purchased from AstraZeneca, formerly designated AZD3241) and AstraZeneca's AZD4831. BHV3241 is in Phase III clinical trials for the treatment of multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS). AZD4831 is in Phase II clinical trials for the treatment of cardiovascular diseases such as heart failure.

[0005] Therefore, the present invention aims to provide a novel small molecule MPO inhibitor, particularly a small molecule MPO inhibitor with good biological activity that can be used for the prevention and / or treatment of cardiovascular-related diseases. Summary of the Invention

[0006] This invention provides a pyrazole compound, its preparation method, and its uses.

[0007] Specifically, the present invention provides a pyrazole compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, characterized in that the structural formula of the pyrazole compound is shown in formula (I):

[0008] (I)

[0009] Wherein: R1 is independently selected from: H, C1-C8 alkyl, C1-C8 haloalkyl, C3-C8 cycloalkyl, 3-10 membered heterocyclic alkyl;

[0010] The n is independently selected from an integer of 0, 1, 2 or 3.

[0011] Furthermore, as a preferred embodiment of the present invention, R1 is independently selected from: C1-C3 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic alkyl;

[0012] The n is independently selected from an integer of 1 or 2.

[0013] Furthermore, the present invention also provides a pyrazole compound, its stereoisomers, tautomers, or pharmaceutically acceptable salts thereof, characterized in that the structural formula of the pyrazole compound is as shown in formula (II) or formula (III):

[0014] (II) or (III);

[0015] R1 is independently selected from: C1-C3 alkyl, C3-C6 cycloalkyl, and 3-6 membered heterocyclic alkyl.

[0016] Furthermore, as a preferred embodiment of the present invention, R1 is independently selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, ... .

[0017] Furthermore, as a preferred embodiment of the present invention, the pyrazole compound or a pharmaceutically acceptable salt thereof is selected from the following compounds:

[0018] .

[0019] Furthermore, as a preferred embodiment of the present invention, the pharmaceutically acceptable salt refers to a pyrazole compound prepared with a pharmaceutically acceptable acid or base.

[0020] Furthermore, the present invention also provides a pharmaceutical composition comprising a compound of formula (I), formula (II) or formula (III) as described in the present invention, its stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

[0021] Furthermore, the present invention also provides the use of the compound of formula (I), formula (II) or formula (III) of the present invention, or its stereoisomers, tautomers or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment and / or prevention of diseases related to MPO enzymes.

[0022] Furthermore, as a preferred embodiment of the present invention, the MPO enzyme-related diseases are selected from cardiovascular-related diseases.

[0023] Furthermore, as a preferred embodiment of the present invention, the cardiovascular-related diseases are selected from: hypertension, heart failure, and atherosclerosis.

[0024] Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0025] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of the present invention, prepared by reacting a compound having specific substituents discovered in the present invention with a pharmaceutically acceptable acid or base.

[0026] In addition to the salt form, the compounds provided by this invention also exist in prodrug form. The prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to be converted into the compounds of this invention. Furthermore, the prodrugs can be converted into the compounds of this invention in the in vivo environment via chemical or biochemical methods.

[0027] Some compounds of this invention may exist in non-solventized or solvated forms, including hydrated forms. Generally, solvated and non-solventized forms are equivalent and both are included within the scope of this invention.

[0028] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0029] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0030] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 20 carbon atoms. Preferably, it contains alkyl groups with 1 to 8 carbon atoms, more preferably alkyl groups with 1 to 6 carbon atoms, and most preferably alkyl groups with 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, and various branched isomers thereof.

[0031] The term "haloalkyl" indicates that at least one of the hydrogen atoms in an alkyl group has been replaced by the same or a different halogen atom. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, and pentafluoroethyl. Particularly noteworthy haloalkyl groups are trifluoromethyl and trifluoroethyl.

[0032] The terms "cycloalkyl" or "carbocyclic" refer to a saturated monocyclic or polycyclic cyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms, preferably 3 to 8 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.; polycyclic cycloalkyl includes spirocyclic, fused-ring, and bridged-ring cycloalkyl.

[0033] The term "heterocyclic alkyl" refers to a monovalent saturated or partially unsaturated monocyclic or bicyclic system with 3 to 8 ring atoms, comprising 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. In a particular embodiment, a heterocyclic alkyl is a monovalent saturated monocyclic system with 4 to 7 ring atoms, comprising 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic saturated heterocyclic alkyl groups are aziridine propane, ethylene oxide, aziridine butane, oxacyclobutane, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, aziridine heptane, diaziridine heptane, homopiperazinyl, oxazidine heptane, and thiazoyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxa-9-aza-bicyclo[3.3.1]nonyl, 3-thia-9-aza-bicyclo[3.3.1]nonyl, and 2,6-diaza-spiro[3.3]heptyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, dihydrooxazolyl, tetrahydropyridyl, or dihydropyranyl. More specific examples of heterocyclic alkyl groups are pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirheptanyl, diazaheptanyl, high-piperazinyl, oxazheptanyl, thiazinyl, and 2,6-diaza-spiro[3.3]heptyl. More specific examples of heterocyclic alkyl groups are pyrrolyl, piperidinyl, thiomorpholinyl, thiazinyl, and 2,6-diaza-spiro[3.3]heptyl.

[0034] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. Detailed Implementation

[0035] The present invention will be further described in detail below with reference to embodiments, but the implementation of the invention is not limited thereto.

[0036] Example 1: Preparation of Compound 1

[0037]

[0038] Step A: Synthesize compound 1B

[0039] Compound 1A (1.80 g, 10 mmol) was dissolved in 50 mL of DMF, followed by the addition of bromocyclopropane (1.45 g, 12 mmol) and potassium carbonate (4.15 g, 30 mmol). The mixture was heated to 60 °C and stirred for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate (100 mL x 3). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by rapid preparative chromatography to obtain 1.1 g of compound 1B. ESI-MS: [M+H] + =221.1.

[0040] Step B: Synthesize compound 1C

[0041] Compound 1B (0.88 g, 4 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (3.9 mL, 1 M) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, water was added to eliminate the free radical, the mixture was filtered, the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by rapid preparative chromatography to obtain 0.57 g of compound 1C. ESI-MS: [M+H] + =179.1.

[0042] Step C: Synthesize compound 1D

[0043] Compound 1C (0.36 g, 2 mmol) was dissolved in dichloromethane (10 mL), and Dys-Martin oxidant (1.0 g, 2.4 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was added to 50 mL of dichloromethane and washed with 20 mL of saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 0.29 g of compound 1D. ESI-MS: [M+H] + =177.1.

[0044] Step D: Synthesize compound 1F

[0045] Compound 1E (0.28 g, 1.5 mmol) was dissolved in 10 mL of anhydrous ethanol. Then, N,N-diisopropylethylamine (0.19 g, 1.5 mmol) and glacial acetic acid (4 mmol) were added to the mixture. After stirring at room temperature for 10 minutes, compound 1D (0.26 g, 1.5 mmol) was added to the mixture. After stirring at room temperature for 2 hours, sodium cyanoborohydride (0.1 g, 1.65 mmol) was added to the mixture, and the reaction was carried out at room temperature for 12 hours.

[0046] After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was extracted with 10 mL of water and two 30 mL solutions of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (eluent: 0.1% ammonia solution) to give 0.34 g of compound 1F. ESI-MS: [M+H] + =315.2.

[0047] Step E: Synthesize compound 1

[0048] Compound 1F (0.31 g, 1 mmol) and benzoyl isothiocyanate (0.20 g, 1.2 mmol) were dissolved in 5 mL of methanol and stirred at room temperature for 3 hours. Then, cesium carbonate (1.3 g, 4 mmol) was added, and the reaction solution was heated to 65°C. o C reaction takes 2 hours.

[0049] After the reaction was complete, the solvent was evaporated to dryness, and then extracted with 20 mL of water and 30 mL*2 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (eluent: 0.1% ammonia solution) to give 0.26 g of compound 1. ESI-MS: [M+H] + =328.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.20 (s, 1H), 12.08 (s, 1H), 7.44 (d, 1H), 6.22 (d, 1H), 4.84 (s, 2 H), 2.78-2.96 (m, 4H), 2.32-2.54 (m, 3H), 0.86-1.21 (m, 4H).

[0050] Example 2 Preparation of Compound 4

[0051]

[0052] Step A: Synthesize compound 4B

[0053] Compound 1A (1.81 g, 10 mmol) was dissolved in 50 mL of DMF, followed by the addition of 3-bromoepoxide (1.64 g, 12 mmol) and potassium carbonate (4.16 g, 30 mmol). The mixture was heated to 60 °C and stirred for 5 h. After the reaction was complete, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate (100 mL * 3). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by rapid preparative chromatography to obtain 1.3 g of compound 4B. ESI-MS: [M+H] + =237.1.

[0054] Step B: Synthesize compound 4C

[0055] Compound 4B (0.95 g, 4 mmol) was dissolved in tetrahydrofuran (50 mL), and lithium aluminum hydride (3.9 mL, 1 M) was added at 0 °C. After the addition was complete, the reaction mixture was stirred at 0 °C for 1 hour. After the reaction was complete, water was added to eliminate the free radical, the mixture was filtered, the filtrate was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by rapid preparative chromatography to obtain 0.66 g of compound 4C. ESI-MS: [M+H] + =195.1.

[0056] Step C: Synthesize compound 4D

[0057] Compound 4C (0.39 g, 2 mmol) was dissolved in dichloromethane (10 mL), and Dys-Martin oxidant (1.0 g, 2.4 mmol) was added. The reaction was carried out at room temperature for 1 hour. After the reaction was completed, the mixture was filtered, and the filtrate was added to 50 mL of dichloromethane and washed with 20 mL of saturated sodium bicarbonate aqueous solution. The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to give 0.33 g of compound 4D. ESI-MS: [M+H] + =193.1.

[0058] Step D: Synthesize compound 4F

[0059] Compound 1E (0.28 g, 1.5 mmol) was dissolved in 10 mL of anhydrous ethanol. Then, N,N-diisopropylethylamine (0.19 g, 1.5 mmol) and glacial acetic acid (4 mmol) were added to the mixture. After stirring at room temperature for 10 minutes, compound 4D (0.29 g, 1.5 mmol) was added to the mixture. After stirring at room temperature for 2 hours, sodium cyanoborohydride (0.1 g, 1.65 mmol) was added to the mixture, and the reaction was carried out at room temperature for 12 hours.

[0060] After the reaction was complete, the solvent was evaporated under reduced pressure, and the mixture was extracted with 10 mL of water and 30 mL x 2 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (eluent: 0.1% ammonia solution) to give 0.37 g of compound 4F. ESI-MS: [M+H] + =331.2.

[0061] Step E: Synthesize compound 4

[0062] Compound 4F (0.33 g, 1 mmol) and benzoyl isothiocyanate (0.20 g, 1.2 mmol) were dissolved in 5 mL of methanol and stirred at room temperature for 3 hours. Then, cesium carbonate (1.3 g, 4 mmol) was added, and the reaction solution was heated to 65 °C.o C reaction takes 2 hours.

[0063] After the reaction was complete, the solvent was evaporated to dryness, and then extracted with 20 mL of water and 30 mL*2 of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was purified by reverse-phase column chromatography (eluent: 0.1% ammonia solution) to give 0.27 g of compound 4. ESI-MS: [M+H] + =344.1. 1 H NMR (400 MHz, DMSO-d6) δ 12.23 (s, 1H), 12.10 (s, 1H), 7.54 (d, 1H), 6.42 (d, 1H), 5.04-5.22 (m, 5 H), 4.88 (s, 2 H), 2.80-2.97 (m, 4H), 2.32-2.54 (m, 2H).

[0064] Example 3-15

[0065] Compounds 2-3 and 5-15 were prepared according to the method in Example 1 or 2. The structural and characterization data of compounds 1-15 are as follows:

[0066]

[0067] Example 16: Evaluation experiment on the inhibitory effect of the compound of the present invention on human myeloperoxidase (hMPO) activity.

[0068] Add 50 μL of 2X substrate (Amplex® MLtraRed and 10 μM H2O2) to an opaque 96-well plate with low protein adsorption. Then add 45 μL of different concentrations of 2X compound, ensuring the final concentration of DMSO is 1%. Mix thoroughly by pipetting, then add 5 μL of 2 μg / mL human myeloperoxidase and mix well. Immediately read the fluorescence values ​​from 0 to 30 min using a microplate reader at Ex / Em: 530 / 590 nm. Calculate the IC50. 50 The values ​​are shown in Table 1.

[0069] Table 1. Inhibitory activity of compounds against human myeloperoxidase (hMPO)

[0070]

[0071] The positive control compound is compound 89 from Example 78 of patent CN115403584B, and its structural formula is as follows: .

[0072] As can be seen from the results in Table 1, the compounds of the present invention have a good inhibitory effect on hMPO activity, which is significantly better than the positive control, especially compounds 4, 5 and 6, which have better inhibitory activity on hMPO.

[0073] Example 17: Pharmacokinetic Study of the Compounds of the Invention in Mice

[0074] 17.1 Experimental Materials

[0075] CD-1 mice: male, 200-350g, 3 mice per group.

[0076] Reagents: DMSO (dimethyl sulfoxide), PEG-400 (polyethylene glycol 400), physiological saline, acetonitrile, formic acid, and propranolol (internal standard) are all commercially available.

[0077] 17.2 Experimental Methods

[0078] A certain amount of the compound was weighed and dissolved in a mixture of 5% DMSO, 60% PEG-400, and 35% physiological saline. Mice were administered the compound by gavage. Venous blood samples of 30 μL were collected at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h in EDTA-K2 anticoagulant tubes. The tubes were centrifuged at 10000 rpm for 2 min, and the plasma was stored at -80℃ for later analysis. A certain amount of the test sample was accurately weighed and dissolved in DMSO to a concentration of 2 mg / mL to prepare a stock solution. An appropriate amount of the stock solution was accurately pipetted and diluted with acetonitrile to prepare a series of standard solutions.

[0079] 17.3 Data Processing

[0080] After LC-MS determination of blood drug concentration, pharmacokinetic parameters were calculated using WinNonlin 6.1 software and a non-compartmental model method. Specific test results are shown in Table 2.

[0081] Table 2. Pharmacokinetic results of the compounds of this invention in mice.

[0082]

[0083] As can be seen from the results in Table 2, the compounds of the present invention have a higher oral exposure in mice, which is significantly better than that of the positive control.

[0084] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A pyrazole compound or a pharmaceutically acceptable salt thereof, characterized in that, The structural formula of the pyrazole compound is shown in formula (I): (I)； Wherein: R1 is independently selected from: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl contains one cyclic heteroatom selected from O, and the remaining cyclic atom is carbon; The n is independently selected from an integer of 1 or 2.

2. The pyrazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The structural formulas of the pyrazole compounds are shown in formula (II) or formula (III): (II) or (III); R1 is independently selected from: C1-C3 alkyl, C3-C6 cycloalkyl, 3-6 membered heterocyclic alkyl, wherein the heterocyclic alkyl contains one cyclic heteroatom selected from O, and the remaining cyclic atom is carbon.

3. The pyrazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, R1 is independently selected from: methyl, ethyl, isopropyl, cyclopropyl, cyclopentyl, cyclohexyl, .

4. The pyrazole compound or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that, The pyrazole compounds are selected from: 。 5. The pyrazole compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-4, characterized in that, The pharmaceutically acceptable salt refers to a salt prepared by reacting a pyrazole compound with a pharmaceutically acceptable acid or base.

6. A pharmaceutical composition, characterized in that, It comprises a pyrazole compound as described in any one of claims 1-5 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

7. Use of the pyrazole compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-5, or the pharmaceutical composition according to claim 6, in the preparation of a medicament for the prevention and / or treatment of myeloperoxidase-related diseases.

8. The use according to claim 7, characterized in that, The diseases related to myeloperoxidase mentioned are selected from: cardiovascular-related diseases.

9. The use according to claim 8, characterized in that, The cardiovascular-related diseases mentioned are selected from: hypertension, heart failure, and atherosclerosis.

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