Novel deuterium-containing pyrazolone compound as well as pharmaceutical composition and application thereof

Abstract

The invention discloses a novel deuterium-containing pyrazolone compound as well as a pharmaceutical composition and application thereof, the novel deuterium-containing pyrazolone compound is shown as a formula (I) and / or a formula (II), and the definition of each substituent is shown in the specification. The compound can be used for preparing medicines for preventing or treating neurodegenerative diseases and cardiovascular and cerebrovascular diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of pharmaceutical chemistry, and particularly relates to a novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof, and a pharmaceutical composition and use thereof. BACKGROUND

[0002] Neurodegenerative diseases (NDDs) are a group of nervous system diseases characterized by progressive loss of neurons in the central nervous system (CNS) or peripheral nervous system (PNS), and are a kind of chronic and progressive neurological diseases. Such diseases mainly include senile dementia, Parkinson's disease, Huntington's disease, different types of spinocerebellar ataxia, multiple sclerosis, cerebellar atrophy and amyotrophic lateral sclerosis, etc. Studies have found that neurodegenerative diseases are caused by a variety of different reasons, including insufficient nutrition provided by neurons or glial cells, excessive glutamate receptor activity, excessive active oxygen level, impaired metabolic pathways, reduced mitochondrial energy production, inflammation, viral infection, and mutations in nuclear or mitochondrial DNA, etc., which interact with each other and eventually lead to neurological dysfunction and cell death. Due to the complex and diverse mechanisms of action, there is no effective and mature method and drug to prevent and treat the disease so far. Therefore, it is of great social significance and economic value to find a highly efficient and multi-target drug. SUMMARY

[0003] The present inventors have developed a novel deuterium-containing pyrazolone compound, which has better L-glutamic acid-induced PC12 cell damage protection effect, better ischemic stroke improvement effect, is more easily passed through the blood-brain barrier, and has a longer residence time in the brain tissue and spinal fluid. Unexpectedly, it has a shorter half-life, which can effectively avoid in vivo enrichment and thus reduce the side effects of liver toxicity.

[0004] In one aspect, the present application provides a novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof as shown in formula (I) and / or formula (II):

[0005]

[0006] In formula (I) and / or formula (II),

[0007] R1 is selected from hydrogen, deuterium, C1-C8 alkyl substituted with one or more substituents or unsubstituted, phenyl substituted with one or more substituents or unsubstituted, or pyridyl substituted with one or more substituents or unsubstituted, wherein the above-mentioned substituents are selected from deuterium or halogen;

[0008] R2is selected from hydrogen, deuterium, C1-C8alkyl substituted with one or more substituents or unsubstituted, phenyl substituted with one or more substituents or unsubstituted, or pyridyl substituted with one or more substituents or unsubstituted, wherein the aforementioned substituents are selected from deuterium, or halogen;

[0009] R3is selected from hydrogen, or deuterium;

[0010] R4is selected from cyclohexyl substituted with one or more substituents or unsubstituted, benzyl substituted with one or more substituents or unsubstituted, naphthyl substituted with one or more substituents or unsubstituted, heterocyclyl substituted with one or more substituents or unsubstituted, or wherein,

[0011] the aforementioned substituents are selected from deuterium, or halogen;

[0012] R X1 is selected from halogen, or C1-C8alkyl substituted with one or more substituents or unsubstituted, wherein the aforementioned substituents are selected from deuterium, or halogen;

[0013] R X2 is selected from halogen, or C1-C8alkyl substituted with one or more substituents or unsubstituted, wherein the aforementioned substituents are selected from deuterium, or halogen;

[0014] R X3 is selected from halogen, C1-C8alkyl substituted with one or more substituents or unsubstituted, C1-C8alkoxy substituted with one or more substituents or unsubstituted, wherein,

[0015] the aforementioned substituents are selected from deuterium, hydroxyl;

[0016] the aforementioned R X4 is selected from C1-C8alkyl substituted with one or more substituents or unsubstituted, or C1-C8alkoxy substituted with one or more substituents or unsubstituted, wherein the aforementioned substituents are selected from deuterium, or halogen;

[0017] In particular,

[0018] R1, R2, R3and R4are at least one of deuterium or substituted with deuterium.

[0019] In some embodiments, the present application provides a novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salts thereof as shown in formula (III) and / or formula (IV):

[0020]

[0021] The definitions of the substituents in formula (III) and / or formula (IV) are as defined above for formula (I) and / or formula (II).

[0022] In some embodiments, in the above formulae (I)-(IV), R1is selected from hydrogen, deuterium, C1-C8alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the above substituents are selected from deuterium, or halogen; preferably, R1is selected from methyl, trideuteromethyl, phenyl, or propyl.

[0023] In some embodiments, in the above formulae (I)-(IV), R2is selected from hydrogen, deuterium, C1-C8alkyl substituted or unsubstituted with one or more substituents, phenyl substituted or unsubstituted with one or more substituents, or pyridyl substituted or unsubstituted with one or more substituents, wherein the above substituents are selected from deuterium, or halogen; preferably, R2is selected from hydrogen, deuterium, or isobutyl.

[0024] In some embodiments, in the above formulae (I) and / or (III), R3is selected from hydrogen, or deuterium;

[0025] In some embodiments, in the above formulae (I) and / or (II), R4is selected from cyclohexyl substituted or unsubstituted with one or more substituents, benzyl substituted or unsubstituted with one or more substituents, naphthyl substituted or unsubstituted with one or more substituents, heterocyclyl substituted or unsubstituted with one or more substituents, or wherein the above substituents are selected from deuterium, or halogen; preferably, R4is selected from cyclohexyl, benzyl, naphthyl, pyridyl, benzothiophenyl, or wherein,

[0026] The above R X1 is selected from halogen, or C1-C8alkyl substituted or unsubstituted with one or more substituents, wherein the above substituents are selected from deuterium, or halogen; preferably, R X1 is selected from chloro, methyl, trideuteromethyl;

[0027] The above R X2 is selected from halogen, or C1-C8alkyl substituted or unsubstituted with one or more substituents, wherein the above substituents are selected from deuterium, or halogen; preferably, R X2 is selected from methyl, trideuteromethyl;

[0028] The above R X3 is selected from halogen, C1-C8alkyl substituted or unsubstituted with one or more substituents, C1-C8alkoxy substituted or unsubstituted with one or more substituents, wherein,

[0029] The above substituents are selected from deuterium, hydroxyl;

[0030] The above R X4selected from the group consisting of deuterium, or halogen; preferably, R

[0031] R is preferably selected from the group consisting of deuterium, or halogen; X3 R is preferably selected from the group consisting of deuterium, or halogen;

[0032] R4is preferably selected from the group consisting of deuterium, or halogen; wherein,

[0033] R is preferably selected from the group consisting of deuterium, or halogen; X1 R is preferably selected from the group consisting of deuterium, or halogen; preferably, R X1 R is preferably selected from the group consisting of deuterium, or halogen;

[0034] R is preferably selected from the group consisting of deuterium, or halogen; X2 R is preferably selected from the group consisting of deuterium, or halogen; preferably, R X2 R is preferably selected from the group consisting of deuterium, or halogen;

[0035] R is preferably selected from the group consisting of deuterium, or halogen; X3 R is preferably selected from the group consisting of deuterium, or halogen; wherein,

[0036] R is preferably selected from the group consisting of deuterium, or halogen;

[0037] R is preferably selected from the group consisting of deuterium, or halogen; X4 R is preferably selected from the group consisting of deuterium, or halogen;

[0038] R is preferably selected from the group consisting of deuterium, or halogen; X3 R is preferably selected from the group consisting of deuterium, or halogen;

[0039] In particular,

[0040] R1, R2, R3and R4are at least one of deuterium or substituted with deuterium.

[0041] In some embodiments, the present application provides the above novel deuterium-containing pyrazolone compounds, tautomers, stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, selected from the following compounds:

[0042]

[0043]

[0044]

[0045] In another aspect, the present application provides a pharmaceutical composition comprising the above-mentioned novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof.

[0046] The present application discloses a pharmaceutical composition, which takes the compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof as the active ingredient or main active ingredient, and is supplemented with a pharmaceutically acceptable carrier.

[0047] In another aspect, the present application provides the use of the above-mentioned novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for preparing a neuroprotective drug.

[0048] In a third aspect, the present application provides the use of the above-mentioned novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition for preparing a drug for preventing or treating cardiovascular and cerebrovascular diseases.

[0049] The present application provides the use of the above-mentioned pharmaceutical composition for preparing a neuroprotective drug, wherein the neuroprotective drug is a drug for treating neurodegenerative diseases, and the neurodegenerative diseases are Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, multiple sclerosis, cerebellar atrophy, different types of spinocerebellar ataxia, spinal muscular atrophy, cerebral ischemia, and primary lateral sclerosis.

[0050] The present application provides the use of the above-mentioned pharmaceutical composition for preparing a drug for preventing or treating cardiovascular and cerebrovascular diseases, wherein the drug for preventing or treating cardiovascular and cerebrovascular diseases is a drug for treating cardiovascular and cerebrovascular diseases, and the cardiovascular and cerebrovascular diseases are hypertension, coronary heart disease, stroke, diabetic heart failure, heart failure, diastolic heart failure, systolic heart failure, postoperative volume overload, idiopathic edema, pulmonary hypertension, pulmonary arterial hypertension, acute decompensated heart failure, cardiac insufficiency, acute renal insufficiency, and nephrotic syndrome.

[0051] In some embodiments, the novel compounds of the present application can be formulated into pharmaceutical compositions for administration to patients in a variety of suitable selected modes of administration, including systemic, such as oral or parenteral, intravenous, intramuscular, transdermal or subcutaneous, etc.

[0052] The present inventors have developed a novel deuterium-containing pyrazolone compound, which has better L-glutamic acid-induced PC12 cell damage protection effect, better ischemic stroke improvement effect, is more easily passed through the blood-brain barrier, and has a longer residence time in brain tissue and spinal fluid, and unexpectedly, has a shorter half-life, which can effectively avoid in vivo enrichment and thus reduce the side effects of hepatotoxicity.

[0053] Definitions:

[0054] The following terms and phrases, as used herein, are intended to have the following meanings unless otherwise indicated. A particular term or phrase should not be construed as indefinite or unclear in the absence of a specific definition, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding product or active ingredient thereof.

[0055] Certain compounds of the present application can exist in unsolvated as well as solvated forms, such as, for example, hydrates, ethanolates. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present application.

[0056] The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0057] The term "pharmaceutically acceptable salt" means a salt of a compound of this application which is found to be suitable for use in pharmaceutical administration from among the salts of the compounds of this application having specific substituents discovered by the inventors. When the compounds of this application contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base to produce the salt. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, manganese, iron, ammonium, organic amino, or magnesium salts or similar salts. When compounds of this application contain relatively basic functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid to produce the salt. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids, such as hydrochloric, hydrobromic, nitric, carbonic, boric, sulfuric, sulfamic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, and the like; and organic acids such as acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like; also salts of amino acids such as arginine and the like, and salts of organic acids like glucuronic, and the like. Certain specific compounds of this application contain both basic and acidic functionalities, allowing the compounds to be converted into either base or acid addition salts.

[0058] The term "alkyl" denotes a saturated aliphatic group, including straight chain and branched chain groups. Alkyl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two substituents.

[0059] The term "alkenyl" denotes an aliphatic group containing an unsaturated carbon-carbon double bond, including straight chain and branched chain groups. Alkenyl groups can be substituted or unsubstituted. The carbon-carbon double bond can be one or more.

[0060] The term "cycloalkyl" denotes a monocyclic or fused ring ("fused" rings mean that each ring in the system shares a pair of adjacent carbon atoms with another ring in the system) group of all carbon, in which one or more rings do not have a fully conjugated pi-electron system. Examples of cycloalkyl groups (without limitation) are cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane, and cycloheptatriene. Cycloalkyl groups can be substituted and unsubstituted.

[0061] The term "aryl" denotes a monocyclic or fused polycyclic group of all carbon, having a fully conjugated pi-electron system, of from 1 to 12 carbon atoms. Non-limiting examples of aryl groups are phenyl, naphthyl, and anthryl. Aryl groups can be substituted or unsubstituted. When substituted, the substituents are preferably one or more, more preferably one, two or three, and still more preferably one or two.

[0062] The term "arylalkyl" means an alkyl group substituted with an aryl group.

[0063] The term "heteroaryl" means a monocyclic or fused ring group of atoms containing one, two, three or four ring heteroatoms selected from N, O or S, with the remaining ring atoms being C, and additionally having a fully conjugated pi-electron system. Non-limiting examples of unsubstituted heteroaryl groups are pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyrimidine, quinoline, isoquinoline, purine, tetrazole, triazine and carbazole.

[0064] The term "alkoxy" means an alkyl group attached to an oxygen atom, where the alkyl group can be straight chain, branched or cyclic.

[0065] The term "hydroxy" means an -OH group.

[0066] The term "amino" means an -NH2 group.

[0067] The term "carboxyl" means a -COOH group.

[0068] The term "halogen" means fluorine, chlorine, bromine or iodine.

[0069] The term "pharmaceutically acceptable carrier" means any formulation or carrier medium that is capable of delivering an effective amount of an active substance of the present application, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient. Representative carriers include water, oils, vegetable and mineral, ointment bases, lotion bases, ointment bases, and the like. These bases include suspending agents, viscosity increasing agents, transdermal enhancers, and the like.

[0070] The term "stereoisomer" means a compound having the same chemical constitution, but differing in the arrangement of the atoms or groups in space.

[0071] The term "C1-C8" as used in the present application means that the group can contain 1 carbon atom, 2 carbon atoms, 3 carbon atoms, and so on, up to and including 8 carbon atoms. DETAILED DESCRIPTION

[0072] A number of exemplary methods for preparing compounds of the present application are provided in the examples that follow. The present application is described in detail below by way of examples, but not intended to be limited to the examples. The present application has been described in detail by specific embodiments, and it also discloses specific modes for its concrete implementation, to those skilled in the art, without departing from the spirit and scope of the present application, it will be obvious to make various changes and improvements to the specific implementation of the present application. Some of the compounds of the present application can be used as intermediates for preparing other compounds of the present application, and the structures of all the compounds are determined by liquid chromatography-mass spectrometry.

[0073] Unless otherwise indicated, the materials in the examples of the present application are available from commercial suppliers.

[0074] Example 1: Synthesis of compound ZJT1

[0075] Reaction formula:

[0076]

[0077] Preparation method:

[0078] Under nitrogen, 2,3,5-trimethylpyrazine (3.5 g, 28.6 mmol) was added to heavy water (35 mL), and then 5 mL of 40% sodium deuterate hydroxide solution was added, and refluxed for five days. Liquid chromatography-mass spectrometry showed that the reaction was complete.

[0079] The reaction solution was extracted with dichloromethane (DCM, 50 mL x 3), and the organic phase was combined, dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain a liquid 3.0 g (yield: 79.9%). ESI-MS(+): m / z = 132.07 [M+1].

[0080] Example 2: Synthesis of compound ZJT2

[0081] Reaction formula:

[0082]

[0083] Preparation method:

[0084] Step 1: Preparation of compound ZJT-2-1

[0085] ZJT-2-SM (880 mg, 10 mmol, 1 eq) was cooled to -78°C, and then lithium bis(trimethylsilyl)amide (1.0 mol / L in tetrahydrofuran) (11 mL, 11 mmol, 1.1 eq) was added, and the reaction was continued for 10 min. Then acetyl chloride-3d (815 mg, 10 mml, 1.0 eq) was added, and the system was kept at -78°C, and the reaction was continued for 2 hours. Liquid chromatography showed that the reaction was complete.

[0086] The system was poured into water (25 mL) to quench, and the aqueous phase was extracted with ethyl acetate (30 mL x 3), and the organic phase was combined and dried with anhydrous sodium sulfate. Filtration, concentration, obtained residue 1 g. Without purification for the next step. ESI-MS(+): m / z = 134.13 [M+1].

[0087] Step 2: Preparation of compound ZJT-2

[0088] The above ZJT-2-1 (1 g) was added to hydrazine hydrate (10 ml), and the system was heated to 120°C, and the reaction was continued for 3 hours. Thin layer chromatography showed that the reaction was complete. The system was cooled to room temperature, and concentrated to obtain a crude product.

[0089] Column chromatography (petroleum ether: ethyl acetate = 30: 1) to get solid 653 mg (yield: 86.1%). ESI-MS (+): m / z = 102.09 [M+1].

[0090] Example 3: Synthesis of compound ZJT3

[0091] Reaction formula:

[0092]

[0093] Preparation method:

[0094] Step 1: Preparation of compound ZJT-3-1

[0095] Mitsunobu acid (2.88 g, 20 mmol, 1 eq) was added to heavy water (30 ml), and then potassium carbonate (5.52 g, 40 mmol, 2 eq) was added, and the reaction was continued for 1 hour. Liquid phase monitoring, the reaction was complete.

[0096] Filtering, concentrating to dryness, the residue was dissolved in ethyl acetate (60 mL) and dried over anhydrous sodium sulfate. Filtering, concentrating, the target 2.84 g (yield: 97.2%) was obtained. ESI-MS (+): m / z = 147.23 [M+1].

[0097] Step 2: Preparation of compound ZJT-3-2

[0098] ZJT-3-1 (2.8 g, 19.2 mol, 1 eq) was added to DCM (80 ml), and then pyridine (1.7 g, 21.1 mmol, 1.1 eq) was added, and the system was cooled to -10 ℃, and acetyl chloride-3d (1.7 g, 21.1 mmol, 1.1 eq) was added, and the reaction was continued for 2 hours. Liquid phase monitoring, the reaction was complete.

[0099] The system was poured into water (70 mL) to quench, and the aqueous phase was extracted with ethyl acetate (50 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate. Filtering, concentrating, the target 3.41 g was obtained. (yield: 93.5%). ESI-MS (+): m / z = 191.13 [M+1].

[0100] Step 3: Preparation of compound ZJT-3-3

[0101] ZJT-3-2 (2.8 g, 20.0 mmol) was added to deuterated ethanol-1d (20 ml), and the system was heated to reflux, and the reaction was continued for 4 hours. Liquid quality monitoring, no starting material molecular weight, the reaction was complete.

[0102] The system was cooled to room temperature, concentrated, and the target 2.4 g (yield: 88.9%) was obtained. ESI-MS(+): m / z = 136.09 [M+1].

[0103] Step 4: Preparation of compound ZJT-3

[0104] ZJT-3-3 (1.35 g, 10 mmol) was added to hydrazine hydrate (15 ml), and the system was heated to 120°C for 1 hour. Thin layer detection showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain a crude product. Column chromatography (petroleum ether: ethyl acetate = 30:1) of the crude product gave 800 mg of white solid (yield: 77.6%). ESI-MS(+): m / z = 104.19 [M+1].

[0105] Example 4: Synthesis of compound DSC207-01

[0106] Reaction formula:

[0107]

[0108] Preparation method:

[0109] Step 1: Preparation of compound DSC207-01-1

[0110] ZJT-1 (25.0 g, 190.5 mmol, 1.0 eq) (5 g, 38.1 mmol, 1 eq) was added to DCM (250 ml), and the system was cooled to -10°C. m-CPBA (36.2 g, 209.5 mmol, 1.1 eq) was added in portions, and the reaction was continued for 40 min.

[0111] Thin layer detection showed that the reaction was complete. The system was warmed to 25°C, poured into an aqueous sodium sulfite solution (250 ml), and separated. The aqueous phase was extracted with DCM (150 mL x 3), and the combined organic phases were dried over sodium sulfate and concentrated to obtain the target DSC207-01-1 25.0 g (yield: 89.2%). ESI-MS(+): m / z = 148.89 [M+1].

[0112] Step 2: Preparation of compound DSC207-01-2

[0113] DSC207-01-1 (25.0 g, 170.0 mmol, 1 eq) was added to toluene (250 ml), and the system was cooled to -10°C. Phosphorus oxychloride (31.3 g, 20.4 mmol, 1.2 eq) was added, and the system was warmed to 90°C for 16 hours.

[0114] Thin layer test showed the reaction was complete. Concentrate, the residue was dissolved in DCM (100 ml), adjust pH = 8-9 with aqueous sodium bicarbonate solution, separate, the aqueous phase was extracted with DCM (150 ml x 3), the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated to give the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 20: 1) to give a solid 13.5 g (yield: 47.9%). ESI-MS(+): m / z = 166.19 [M+1].

[0115] Step 3: Preparation of compound DSC207-01-3

[0116] DSC207-01-2 (10 g, 60.4 mmol) was added to hydrazine hydrate (100 ml), the system was heated to 120 °C, and reacted for 6 hours. Thin layer test showed that the reaction was complete. The system was cooled to room temperature and concentrated to give the crude product. The crude product was column chromatographed (dichloromethane: methanol = 50: 1) to give a white solid 8.1 g,

[0117] (yield: 83.2%). ESI-MS(+): m / z = 162.01 [M+1].

[0118] Step 4: Preparation of compound DSC207-01-4

[0119] DSC207-01-3 (4.0 g, 24.8 mmol, 1 eq) was added to acetic acid (30 ml), and then ethyl acetoacetate (3.54 g, 27.28 mmol, 1.1 eq) was added. The system was heated to 90 °C and reacted for 1.5 hours. Thin layer test showed that the reaction was complete. The system was cooled to room temperature and concentrated to give the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 10: 1) to give a yellow solid 3.7 g (yield: 65.6%).

[0120] ESI-MS(+): m / z = 228.79 [M+1].

[0121] Step 5: Preparation of compound DSC207-01-5

[0122] DSC207-01-4 (7.0 g, 30.8 mmol, 1 eq) was added to acetic anhydride (70 ml), and the system was heated to 130 °C and reacted for 3 hours. Thin layer test showed that the reaction was complete. The system was cooled to room temperature and concentrated to give the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 20: 1) to give an oil 6.4 g, (yield: 77.1%). ESI-MS(+): m / z = 270.39 [M+1].

[0123] Step 6: Preparation of compound DSC207-01-6

[0124] DSC207-01-5 (4.0 g, 14.9 mmol, 1 eq) was added to DCM (40 ml), the system was cooled to -10 °C, m-CPBA (5.13 g, 29.7 mmol, 2 eq) was added in portions, and the reaction was allowed to proceed for 30 min after the addition was completed. TLC detection showed that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 mL), and separated. The aqueous phase was extracted with DCM (50 mL x 3), the combined organic phases were dried over sodium sulfate, and concentrated to obtain the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1) to obtain 3.5 g of a solid (yield: 82.5%). ESI-MS(+): m / z = 286.29 [M+1].

[0125] Step 7: Preparation of compound DSC207-01-7

[0126] DSC207-01-6 (3.0 g, 10.5 mmol, 1 eq) was added to acetic anhydride (30 mL), and the system was heated to 130 °C for 5 h. TLC detection showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1) to obtain 1.9 g of the target product (yield: 55.8%). ESI-MS(+): m / z = 327.89 [M+1].

[0127] Step 8: Preparation of compound DSC207-01

[0128] Into a 25 ml single-neck flask was added DSC207-01-7 (1.5 g, 4.6 mmol, 1 eq), methanol (15 mL), lithium hydroxide (220 mg, 9.2 mmol, 2.5 eq), and the reaction was allowed to proceed at room temperature for 16 h. TLC detection showed that the starting material was consumed. The reaction was concentrated, the residue was added to water (15 ml), the pH was adjusted to 6-7 with 4N hydrochloric acid, the aqueous phase was extracted with DCM (20 ml x 3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product.

[0129] The crude product was column chromatographed (dichloromethane:methanol = 30:1) to obtain 640 mg of the target product (yield: 57.5%). ESI-MS(+): m / z = 243.14 [M+1].

[0130] Example 5: Synthesis of compound DSC207-03

[0131] Reaction scheme:

[0132]

[0133] Preparation method:

[0134] Step 1: Preparation of compound DSC207-03-1

[0135] Compound DSC207-03-SM (8.0 g, 52.6 mmol) was dissolved in methanol (80 mL), the system was cooled to 0 °C, 2 drops of sulfuric acid was added, the system was warmed to room temperature for 3 hours, thin layer test showed that the reaction was substantially complete. The system was concentrated, the residue was poured into water, extracted with ethyl acetate (100 ml x 3), the combined organic phase was dried over anhydrous sodium sulfate, and concentrated to give a yellow oil 7.0 g, (yield: 80.1%).

[0136] ESI-MS(+): m / z = 167.18 [M+1].

[0137] Step 2: Preparation of compound DSC207-03-2

[0138] DSC207-03-1 (7.0 g, 42.1 mmol, 1 eq) was added to DCM (70 ml), the system was cooled to -10 °C, m-CPBA (8.7 g, 50.5 mmol, 1.2 eq) was added in portions, after addition, the system was reacted at room temperature for 8 hours. Thin layer test showed that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 mL), separated, the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phase was dried over sodium sulfate, and concentrated to give a white solid 7.0 g, (yield: 91.3%).

[0139] ESI-MS(+): m / z = 183.59 [M+1].

[0140] Step 3: Preparation of compound DSC207-03-3

[0141] DSC207-03-2 (5.0 g, 27.4 mmol, 1 eq) was added to toluene (25 ml), the system was cooled to -10 °C, phosphorus oxychloride (5.0 g, 32.9 mmol, 1.2 eq) was added, after addition, the system was warmed to 90 °C, and reacted for 16 hours. Thin layer test showed that the reaction was complete. Concentration, the residue was dissolved in DCM (20 mL), the pH was adjusted to 8-9 with an aqueous sodium bicarbonate solution, separated, the aqueous phase was extracted with DCM (50 ml x 3), the combined organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give a crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 20:1) to give the target 4.7 g, (yield 85.4%). ESI-MS(+): m / z = 201.09 [M+1].

[0142] Step 4: Preparation of compound DSC207-03-4

[0143] DSC207-03-4 (1.0 g, 3.8 mmol, 1 eq) was added to tetrahydrofuran (THF, 10 mL), the system was cooled to -10 °C, lithium aluminum hydride-4d (1 mol / L in THF, 4.19 mL, 4.19 mmol, 1.1 eq) was added, after addition, it was raised to room temperature and reacted for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 ml), the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phase was dried over sodium sulfate, concentrated to give an oil 720 mg, (yield: 80.0%). ESI-MS(+): m / z = 237.29 [M+1].

[0144] Column chromatography (petroleum ether: ethyl acetate = 10:1) of the crude product gave 2.0 g of white solid (yield: 76.9%). ESI-MS(+): m / z = 263.29 [M+1].

[0145] Step 5: Preparation of compound DSC207-03

[0146] DSC207-03-4 (1.0 g, 3.8 mmol, 1 eq) was added to tetrahydrofuran (THF, 10 mL), the system was cooled to -10 °C, lithium aluminum hydride-4d (1 mol / L in THF, 4.19 mL, 4.19 mmol, 1.1 eq) was added, after addition, it was raised to room temperature and reacted for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 ml), the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phase was dried over sodium sulfate, concentrated to give an oil 720 mg, (yield: 80.0%). ESI-MS(+): m / z = 237.29 [M+1].

[0147] Example 6: Synthesis of compound DSC207-04

[0148] Reaction scheme:

[0149]

[0150] Preparation method:

[0151] DSC207-03-4 (1.0 g, 3.8 mmol, 1 eq) was added to tetrahydrofuran (THF, 10 mL), the system was cooled to -10 °C, lithium aluminum hydride-4d (1 mol / L in THF, 4.19 mL, 4.19 mmol, 1.1 eq) was added, after addition, it was raised to room temperature and reacted for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 ml), the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phase was dried over sodium sulfate, concentrated to give an oil 720 mg, (yield: 80.0%). ESI-MS(+): m / z = 237.29 [M+1].

[0152] The thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phases were dried over sodium sulfate, concentrated, and purified by column to obtain the target compound 494 mg (yield: 55.3%). ESI-MS(+): m / z = 236.49 [M+1].

[0153] Example 7: Synthesis of compound DSC207-05

[0154] Reaction formula:

[0155]

[0156] Preparation method:

[0157] Step 1: Preparation of compound DSC207-05-1

[0158] ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), the system was cooled to -10°C, and then potassium carbonate (2.75 g, 20.0 mmol, 2 eq) was added, and after the addition, it was stirred at room temperature for ten minutes, and then DSC207-03-3 (2.0 g, 10.0 mmol, 1 eq) was added, and after the addition, it was reacted at room temperature for 3 hours.

[0159] The thin layer detection showed that the reaction was complete. The system was poured into water, the pH was adjusted to 3-4 with 1N hydrochloric acid, and ethyl acetate was extracted (15 ml x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the organic phase was concentrated to obtain the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1) to obtain the target compound 1.3 g (yield: 49.0%). ESI-MS(+): m / z = 266.29 [M+1].

[0160] Step 2: Preparation of compound DSC207-05

[0161] DSC207-05-1 (1.0 g, 3.8 mmol, 1 eq) was added to methanol (10 mL), the system was cooled to -10°C, and sodium borohydride-4d (0.64 g, 15.2 mmol, 4 eq) was added, and after the addition, it was allowed to react at room temperature for 4 hours.

[0162] The thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phases were dried over sodium sulfate, concentrated, and purified by column to obtain the target compound 494 mg (yield: 55.3%). ESI-MS(+): m / z = 236.49 [M+1].

[0163] Example 8: Synthesis of compound DSC207-06

[0164] Reaction Scheme:

[0165]

[0166] Preparation Method:

[0167] Step 1: Preparation of compound DSC207-06-3

[0168] ZJT-2 (1.46 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), the system was cooled to -10 °C, and then potassium carbonate (2.75 g, 19.9 mmol, 2 eq) was added. After the addition was completed, the system was stirred at room temperature for 10 minutes, and then DSC207-01-2 (1.65 g, 9.96 mmol, 1 eq) was added. After the addition was completed, the system was reacted at room temperature for 3 hours.

[0169] Thin layer detection showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1N hydrochloric acid. Ethyl acetate (15 ml x 3) was used for extraction, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography was used to purify the target compound 1.5 g (yield: 65.5%). ESI-MS(+): m / z = 231.33 [M+1].

[0170] Step 2: Preparation of compound DSC207-06-2

[0171] DSC207-06-3 (4.0 g, 17.4 mmol, 1 eq) was added to DCM (40 ml), and the system was cooled to -10 °C. m-CPBA (6.0 g, 34.8 mmol, 2 eq) was added in batches, and the system was reacted for 30 min after the addition was completed.

[0172] Thin layer detection showed that the reaction was complete. The system was warmed to 25 °C and poured into an aqueous sodium sulfite solution (50 mL). The system was separated, and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was dried over sodium sulfate and concentrated to obtain the crude product. Column chromatography was used to purify the target compound 3.1 g (yield: 72.3%). ESI-MS(+): m / z = 247.42 [M+1].

[0173] Step 3: Preparation of compound DSC207-06-1

[0174] DSC207-06-2 (3.0 g, 12.2 mmol, 1 eq) was added to acetic anhydride (30 mL), and the system was heated to 130 °C and reacted for 5 hours. Thin layer detection showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain the crude product. Column chromatography was used to purify the target compound 2.0 g (yield: 57.3%).

[0175] ESI-MS(+): m / z=288.45[M+1].

[0176] Step 4: Preparation of compound DSC207-06

[0177] To a 50 mL single-necked flask, add the raw material DSC207-06-1 (1.32 g, 4.6 mmol, 1 eq), methanol (15 mL), and lithium hydroxide (220 mg, 9.2 mmol, 2.0 eq). The mixture was allowed to react at room temperature for 16 hours. TLC confirmed the disappearance of the starting material. The residue was concentrated, and water (15 mL) was added. The pH was adjusted to 6-7 with 4N hydrochloric acid. The aqueous phase was extracted with DCM (20 mL x 3). The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to yield 610 mg of the desired compound (yield: 54.1%). ESI-MS (+): m / z = 246.19 [M+1].

[0178] Example 9: Synthesis of Compound DSC207-07

[0179] Reaction formula:

[0180]

[0181] Preparation method:

[0182] DSC207-05-1 (1 g, 3.77 mmol, 1 eq) was added to methanol (10 mL). The system was cooled to -10°C and lithium aluminum hydroxide-4d (174.1 mg, 4.15 mmol, 1.1 eq) was added. After the addition was complete, the mixture was allowed to warm to room temperature and react for 4 hours. Thin layer chromatography indicated that the reaction was complete. The system was poured into an aqueous solution (50 mL). The aqueous phase was extracted with DCM (50 mL x 3). The organic phases were combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain 462.7 mg of the desired product (yield: 51.3%). ESI-MS (+): m / z = 240.21 [M+1]

[0183] Example 10: Synthesis of Compound DSC207-08

[0184] Reaction formula:

[0185]

[0186] Preparation method:

[0187] Step 1: Preparation of compound DSC207-08-1

[0188] ZJT-3 (1.5 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), the system was cooled to -10 °C, and then potassium carbonate (2.76 g, 20.0 mmol, 2 eq) was added. After the addition was completed, the system was stirred at room temperature for 10 min, and then DSC207-03-3 (2.0 g, 10.0 mmol, 1 eq) was added. After the addition was completed, the system was stirred at room temperature for 3 h.

[0189] Thin layer detection showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1N hydrochloric acid. Ethyl acetate (25 ml x 3) was used for extraction, and the organic phase was combined and washed with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 1.3 g (yield: 48.6%). ESI-MS (+): m / z = 268.26 [M+1].

[0190] Step 2: Preparation of compound DSC207-08

[0191] DSC207-08-1 (1.0 g, 3.74 mmol, 1 eq) was added to methanol (10 ml), and the system was cooled to -10 °C. Sodium borohydride (566.0 mg, 15.0 mmol, 4 eq) was added, and the system was stirred at room temperature for 4 h. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), and the aqueous phase was extracted with DCM (50 mL x 3). The organic phase was combined, dried over sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the target compound 418 mg (yield: 46.7%). ESI-MS (+): m / z = 240.36 [M+1].

[0192] Example 11: Synthesis of compound DSC207-09

[0193] Reaction formula:

[0194]

[0195] Preparation method:

[0196] Step 1: Preparation of compound ZJT-4

[0197] Under nitrogen, 3-methyl-2-pyrazolin-5-one (2.8 g, 28.6 mmol, 1 eq) was added to heavy water (30 mL), and then potassium carbonate (4.0 g, 28.6 mml, 1 eq) was added. The system was stirred at room temperature for 15 min. Liquid chromatography showed that the reaction was complete. The reaction solution was extracted with DCM (50 mL x 3), and the organic phase was combined and dried over anhydrous magnesium sulfate. The filtrate was concentrated to obtain the target compound 2.1 g (yield: 73.3%).

[0198] ESI-MS (+): m / z = 101.11 [M+1]

[0199] Step 2: Preparation of compound DSC207-09-1

[0200] ZJT-4 (1.45 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), the system was cooled to -10 °C, and then potassium carbonate (2.76 g, 20.0 mmol, 2 eq) was added. After the addition was completed, the system was stirred at room temperature for 10 minutes, and then DSC207-03-3 (2.0 g, 10.0 mmol, 1 eq) was added. After the addition was completed, the system was reacted at room temperature for 3 hours. Thin layer detection showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1N hydrochloric acid. Ethyl acetate (20 ml x 3) was used for extraction, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the target product 1.2 g (yield: 45.4%).

[0201] ESI-MS(+): m / z = 265.34 [M+1].

[0202] Step 3: Preparation of compound DSC207-09

[0203] DSC207-09-1 (988 mg, 3.74 mmol, 1 eq) was added to methanol (10 mL), and the system was cooled to -10 °C. Sodium borohydride (566 mg, 15 mmol, 4 eq) was added, and after the addition was completed, the system was allowed to react at room temperature for 4 hours.

[0204] Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic phase was dried over sodium sulfate and concentrated to obtain 473 mg of colorless oil (yield: 53.5%). ESI-MS(+): m / z = 237.41 [M+1].

[0205] Example 12: Synthesis of compound DSC207-10

[0206] Reaction formula:

[0207]

[0208] Preparation method:

[0209] Step 1: Preparation of compound DSC207-10-3

[0210] ZJT-3 (6.0 g, 58.2 mmol, 1.45 eq) was added to DMSO (120 mL), the system was cooled to -10 °C, and then potassium carbonate (11.1 g, 80.0 mmol, 2.0 eq) was added. After the addition was completed, the system was stirred at room temperature for 10 minutes, and then DSC207-01-2 (6.6 g, 40.0 mmol, 1 eq) was added. After the addition was completed, the system was reacted at room temperature for 3 hours.

[0211] Thin layer detection showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1N hydrochloric acid. Ethyl acetate (100 mL x 3) was used for extraction, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to obtain the target product 6.1 g (yield: 65.6%).

[0212] ESI-MS(+): m / z = 233.22 [M+1].

[0213] Step 2: Preparation of compound DSC207-10-2

[0214] DSC207-10-3 (4.0 g, 17.4 mmol, 1 eq) was added to DCM (40 ml), and the system was cooled to -10 °C. m-CPBA (6.0 g, 34.8 mmol, 2 eq) was added in batches, and the system was reacted for 30 min after the addition was completed.

[0215] Thin layer detection showed that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 mL), and separated. The aqueous phase was extracted with DCM (50 mL x 3), and the combined organic phase was dried over sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target product 3.02 g (yield: 69.9%).

[0216] ESI-MS(+): m / z = 249.11 [M+1].

[0217] Step 3: Preparation of compound DSC207-10-1

[0218] DSC207-10-2 (3.0 g, 12.1 mmol, 1 eq) was added to acetic anhydride (30 mL), and the system was heated to 130 °C and reacted for 5 hours. Thin layer detection showed that the reaction was complete. The system was cooled to room temperature and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target product 2.1 g (yield: 60.1%).

[0219] ESI-MS(+): m / z = 290.39 [M+1].

[0220] Step 4: Preparation of compound DSC207-10

[0221] Into a single neck flask was placed DSC207-10-1 (1.33 g, 4.6 mmol, 1 eq), methanol (15 mL), lithium hydroxide (220 mg, 9.2 mmol, 2.0 eq), and the reaction was stirred at room temperature for 16 hours. TLC indicated the disappearance of starting material. The reaction was concentrated, the residue was added to water (15 mL), the pH was adjusted to 6-7 with 4N hydrochloric acid, the aqueous phase was extracted with DCM (20 mL x 3), the organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give the target compound 481 mg (yield: 42.3%). ESI-MS(+): m / z = 248.72 [M+1].

[0222] Example 13: Synthesis of compound DSC207-11

[0223] Reaction scheme:

[0224]

[0225] Preparation method:

[0226] Step 1: Preparation of compound DSC207-11-1

[0227] Into a single neck flask was placed DSC207-11-SM (4.12 g, 38.16 mmol, 1 eq), DCM (50 mL), the system was cooled to -10 °C, m-CPBA (7.24 g, 41.97 mmol, 1.1 eq) was added in portions, and the reaction was stirred for 40 minutes after the addition was completed. TLC indicated that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 mL), the phases were separated, the aqueous phase was extracted with DCM (50 mL x 3), the organic phases were combined, dried over sodium sulfate, and concentrated to give the target compound 4.3 g (yield: 90.8%). ESI-MS(+): m / z = 125.19 [M+1].

[0228] Step 2: Preparation of compound DSC207-11-2

[0229] DSC207-11-1 (4.22 g, 34.0 mmol, 1 eq) was added to toluene (50 mL), the system was cooled to -10 °C, and then phosphorus oxychloride (6.25 g, 40.8 mmol, 1.2 eq) was added. After the addition was completed, the system was raised to 90 °C and reacted for 16 hours. Thin layer detection showed that the reaction was complete. Concentration was performed, and the residue was dissolved in DCM (20 mL), and the pH was adjusted to 8-9 with an aqueous sodium bicarbonate solution. The mixture was separated, and the aqueous phase was extracted with DCM (50 mL x 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography (petroleum ether: ethyl acetate = 20: 1) of the crude product yielded 2.2 g of the target compound (yield: 45.4%). ESI-MS(+): m / z = 143.13 [M+1].

[0230] Step 3: Preparation of compound DSC207-11-3

[0231] ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added to DMSO (30 mL), and the system was cooled to -10 °C. Potassium carbonate (2.75 g, 20 mmol, 2 eq) was then added, and after the addition was completed, the system was stirred at room temperature for ten minutes. DSC207-11-2 (1.43 g, 10.0 mmol, 1 eq) was then added, and after the addition was completed, the system was reacted at room temperature for 3 hours. Thin layer detection showed that the reaction was complete. The system was poured into water, and the pH was adjusted to 3-4 with 1N hydrochloric acid. Ethyl acetate (20 mL x 3) was used to extract the mixture, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Column chromatography purification of the crude product yielded 1.63 g of the target compound (yield: 78.7%). ESI-MS(+): m / z = 208.21 [M+1].

[0232] Step 4: Preparation of compound DSC207-11-4

[0233] DSC207-11-3 (1.6 g, 7.72 mmol, 1 eq) was added to DCM (40 mL), and the system was cooled to -10 °C. m-CPBA (2.66 g, 15.44 mmol, 2 eq) was then added in portions, and after the addition was completed, the system was reacted for 30 minutes. Thin layer detection showed that the reaction was complete. The system was then warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 mL), and separated. The aqueous phase was extracted with DCM (50 mL x 3), and the combined organic phases were dried over sodium sulfate and concentrated to obtain the crude product. Column chromatography purification of the crude product yielded 1.02 g of the target compound (yield: 59.2%). ESI-MS(+): m / z = 224.31 [M+1].

[0234] Step 5: Preparation of compound DSC207-11-5

[0235] DSC207-11-4 (1.0 g, 4.18 mmol, 1 eq) was added to toluene (25 mL), the system was cooled to -10 °C, and then phosphorus oxychloride (0.77 g, 5.02 mmol, 2 eq) was added. After the addition was completed, the system was raised to 90 °C and reacted for 16 h. Thin layer detection showed that the reaction was complete. Concentration was performed, and the residue was dissolved in DCM (20 mL), adjusted to pH = 8-9 with an aqueous sodium bicarbonate solution, separated, and the aqueous phase was extracted with DCM (30 mL x 3). The combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 0.52 g (yield: 51.5%). ESI-MS(+): m / z = 242.23 [M+1].

[0236] Step 6: Preparation of compound DSC207-11

[0237] DSC207-11-5 (0.5 g, 2.07 mmol, 1 eq) (2.41 g, 10 mmol, 1 eq) was added to ethanol (25 mL), the system was cooled to -10 °C, and sodium ethoxide (0.16 g, 2.35 mmol, 1.1 eq) (748.5 mg, 11 mmol, 1.1 eq) was added. After the addition was completed, the system was reacted for 50 min. Thin layer detection showed that the reaction was complete. The system was poured into 1 N aqueous hydrochloric acid (35 mL), and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phases were dried over sodium sulfate and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound 0.22 g (yield 42.3%). ESI-MS(+): m / z = 252.26 [M+1].

[0238] Example 14: Synthesis of compound DSC207-16

[0239] Reaction scheme:

[0240]

[0241] Step 1: Preparation of compound DSC207-16-1

[0242] Compound DSC207-16-SM (16.0 g, 105.2 mmol) was dissolved in ethanol (250 mL), the system was cooled to 0 °C, and 2 drops of sulfuric acid were added. After the addition was completed, the system was raised to room temperature and reacted for 3 h. Thin layer detection showed that the reaction was substantially complete. The system was concentrated, the residue was poured into water, and ethyl acetate was added (150 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain the target compound 14.4 g (yield: 76.5%).

[0243] ESI-MS(+): m / z = 181.78 [M+1]

[0244] Step 2: Preparation of compound DSC207-16-2

[0245] DSC207-16-1 (7.58 g, 42.12 mmol, 1 eq) was added into dichloromethane (150 mL), the system was cooled to -10 °C, m-CPBA (8.72 g, 50.54 mmol, 1.2 eq) was added in batches, after addition, the system was reacted at room temperature for 8 hours. Thin layer detection showed that the reaction was complete. The system was warmed to 25 °C, poured into aqueous sodium sulfite solution (50 mL), separated, the aqueous phase was extracted with dichloromethane (80 mL x 3), the combined organic phase was dried with sodium sulfate, concentrated to obtain the target product 7.0 g, (yield: 84.7%).

[0246] ESI-MS(+): m / z = 197.41 [M+1].

[0247] Step 3: Preparation of compound DSC207-16-3

[0248] DSC207-16-2 (5.38 g, 27.44 mmol, 1 eq) was added into toluene (50 mL), the system was cooled to -10 °C, phosphorus oxychloride (5.1 g, 32.93 mmol, 1.2 eq) was added, after addition, the system was warmed to 90 °C, reacted for 16 hours. Thin layer detection showed that the reaction was complete. Concentration, the residue was dissolved in DCM (25 mL), the pH was adjusted to 8-9 with aqueous sodium bicarbonate solution, separated, the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phase was washed once with saturated brine, dried with anhydrous sodium sulfate, concentrated to obtain the target product 4.8 g, (yield 81.5%). ESI-MS(+): m / z = 215.17 [M+1].

[0249] Step 4: Preparation of compound DSC207-16

[0250] ZJT-2 (1.47 g, 14.5 mmol, 1.45 eq) was added into DMSO (50 mL), the system was cooled to -10 °C, potassium carbonate (2.75 g, 20.0 mmol, 2 eq) was added, after addition, the system was stirred at room temperature for ten minutes, then DSC207-16-3 (2.15 g, 10.0 mmol, 1 eq) was added, after addition, the system was reacted at room temperature for 3 hours. Thin layer detection showed that the reaction was complete. The system was poured into water, 1N hydrochloric acid was used to adjust the pH to 3-4, ethyl acetate was used for extraction (50 mL x 3), the combined organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, the organic phase was concentrated, the residue was purified by column to obtain the target product 1.3 g (yield: 46.5%).

[0251] ESI-MS(+): m / z = 280.33 [M+1].

[0252] Example 15: Synthesis of compound DSC207-20

[0253] Reaction Scheme:

[0254]

[0255] Preparation Method:

[0256] Step 1: Preparation of compound DSC207-20-1

[0257] ZJT-3 (2.32 g, 22.5 mmol, 1.5 eq) was added to DMSO (100 mL), the system was cooled to -10 °C, and then potassium carbonate (4.1 g, 30 mmol, 2 eq) was added. After the addition was completed, the system was stirred at room temperature for ten minutes, and then DSC207-03-3 (3.0 g, 15 mmol, 1 eq) was added. After the addition was completed, the system was reacted at room temperature for 3 hours. Thin layer detection showed that the reaction was complete. The system was poured into water, and 1N hydrochloric acid was used to adjust the pH to 3-4. Ethyl acetate (80 mL x 3) was used for extraction, and the combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Column purification obtained the target product 1.79 g (yield: 44.7%). ESI-MS(+): m / z = 268.29 [M+1]

[0258] Step 2: Preparation of compound DSC207-20

[0259] DSC207-20-1 (1.0 g, 3.74 mmol, 1 eq) was added to tetrahydrofuran (10 mL), and the system was cooled to -10 °C. Lithium aluminum hydride-4d (172 mg, 4.11 mmol, 1.1 eq) was added, and after the addition was completed, the system was allowed to warm to room temperature and reacted for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), and the aqueous phase was extracted with DCM (40 mL x 3). The combined organic phase was dried over sodium sulfate, concentrated, and the residue was purified by column to obtain the target product 359.2 mg (yield: 39.8%). ESI-MS(+): m / z = 242.36 [M+1].

[0260] Example 16: Synthesis of compound DSC207-21

[0261] Reaction Scheme:

[0262]

[0263] Preparation Method:

[0264] Step 1: Preparation of compound DSC207-21-1

[0265] DSC207-03-4 (1.0 g, 3.81 mmol, 1 eq) was added to DCM (10 mL), the system was cooled to -10 °C, DIBAL-H (1 mol / L in DCM) (4.2 mL, 4.2 mmol, 1.1 eq) was added, after addition, it was raised to room temperature for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), the aqueous phase was extracted with DCM (40 mL x 3), the combined organic phase was dried with sodium sulfate, concentrated, and the residue was purified by column to obtain the target compound 521 mg (yield: 58.9%).

[0266] ESI-MS(+): m / z = 233.45 [M+1].

[0267] Step 2: Preparation of compound DSC207-21

[0268] DSC207-21-1 (0.5 g, 2.15 mmol, 1 eq) was added to ethanol (10 mL), and then DSC207-21-SM (316 mg, 3.22 mmol, 1.5 eq) was added, the system was warmed to 80 °C, and then reacted for 4 hours. Thin layer detection showed that the reaction was complete. The concentrated system was concentrated to obtain a crude product. Column purification obtained the target compound 250.5 mg (yield: 37.3%). ESI-MS(+): m / z = 313.27 [M+1].

[0269] Example 17: Synthesis of compound DSC207-22

[0270] Reaction formula:

[0271]

[0272] Preparation method:

[0273] Step 1: Preparation of compound DSC207-22-1

[0274] DSC207-16 (1.0 g, 3.58 mmol, 1 eq) was added to DCM (30 mL), the system was cooled to -10 °C, DIBAL-H (1 mol / L in DCM) (4.14 mL, 4.14 mmol, 1.1 eq) was added, after addition, it was raised to room temperature for 4 hours. Thin layer detection showed that the reaction was complete. The system was poured into an aqueous solution (50 mL), the aqueous phase was extracted with DCM (30 mL x 3), the combined organic phase was dried with sodium sulfate, concentrated, and the residue was purified by column to obtain the target compound 526 mg (yield: 62.4%). ESI-MS(+): m / z = 236.36 [M+1].

[0275] Step 2: Preparation of compound DSC207-22

[0276] DSC207-22-1 (505 mg, 2.15 mmol, 1 eq) was added to ethanol (20 mL), and DSC207-21-SM (0.319 mg, 3.25 mmol, 1.5 eq) was added, and the system was warmed to 80 °C and reacted for 4 hours. Thin layer detection showed that the reaction was complete. The system was concentrated, and the residue was purified by column to obtain 215 mg of the target compound (yield: 31.7%). ESI-MS(+): m / z = 316.37 [M+1].

[0277] Example 18: Synthesis of compound DSC207-02

[0278] Reaction formula:

[0279]

[0280] Preparation method:

[0281] Step 1: Preparation of compound DSC207-02-1

[0282] Under nitrogen, 2,5-dimethylpyrazine (12.36 g, 114.4 mmol) was added to heavy water (120 mL), and 20 ml of 40% sodium deuterate hydroxide solution was added, and refluxed for five days. Liquid chromatography showed that the reaction was complete.

[0283] The reaction solution was extracted with DCM (150 mL x 3), and the organic phase was combined, dried with anhydrous magnesium sulfate, filtered, and concentrated to obtain a light yellow oily liquid 9.04 g (yield: 69.3%)

[0284] ESI-MS(+): m / z = 115.17 [M+1]

[0285] Step 2: Preparation of compound DSC207-02-2

[0286] DSC207-02-1 (8.7 g, 76.32 mmol, 1 eq) was added to DCM (50 ml), and the system was cooled to -10 °C, and m-CPBA (14.48 g, 83.94 mmol, 1.1 eq) was added in batches, and reacted for 40 min.

[0287] Thin layer detection showed that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 ml), and separated, and the aqueous phase was extracted with DCM (50 mL x 3), and the combined organic phase was dried with sodium sulfate and concentrated to obtain a yellow oily liquid (8.4 g, 84.6%).

[0288] ESI-MS(+): m / z = 131.18 [M+1].

[0289] Step 3: Preparation of compound DSC207-02-3

[0290] DSC207-02-2 (4.42 g, 34 mmol, 1 eq) was added to toluene (25 ml), the system was cooled to -10 °C, and then phosphorus oxychloride (6.25 g, 40.8 mmol, 1.2 eq) was added. After the addition was completed, the system was raised to 90 °C, and the reaction was carried out for 16 h.

[0291] Thin layer detection showed that the reaction was complete. The residue was dissolved in DCM (20 ml), the pH was adjusted to 8-9 with an aqueous sodium bicarbonate solution, the phases were separated, the aqueous phase was extracted with DCM (50 ml*3), the combined organic phases were washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product.

[0292] The crude product was column chromatographed (petroleum ether: ethyl acetate = 20:1) to give 3.7 g of a yellow solid (yield: 73.2%).

[0293] ESI-MS(+): m / z = 149.29 [M+1].

[0294] Step 4: Preparation of compound DSC207-02-4

[0295] ZJT-2 (2.92 g, 29 mmol, 1.45 eq) was added to DMSO (30 ml), the system was cooled to -10 °C, and then potassium carbonate (5.5 g, 39.8 mmol, 2 eq) was added. After the addition was completed, the system was stirred at room temperature for 10 min, and then DSC207-02-3 (2.96 g, 19.92 mmol, 1 eq) was added. After the addition was completed, the system was stirred at room temperature for 3 h.

[0296] Thin layer detection showed that the reaction was complete. The system was poured into water, the pH was adjusted to 3-4 with 1N hydrochloric acid, and the product was extracted with ethyl acetate (50 ml*3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the crude product.

[0297] The crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1) to give 3.93 g of a white solid (yield: 92.7%).

[0298] ESI-MS(+): m / z = 214.29 [M+1].

[0299] Step 5: Preparation of compound DSC207-02-5

[0300] DSC207-02-4 (3.7 g, 17.36 mmol, 1 eq) was added into DCM (40 ml), the system was cooled to -10 °C, m-CPBA (5.13 g, 34.73 mmol, 2 eq) was added in batches, and the reaction was carried out for 30 min after the addition was completed.

[0301] Thin layer detection showed that the reaction was complete. The system was warmed to 25 °C, poured into an aqueous sodium sulfite solution (50 ml), separated, the aqueous phase was extracted with DCM (50 mL x 3), the combined organic phases were dried over sodium sulfate, concentrated to give the crude product.

[0302] The crude product was column chromatographed (petroleum ether: ethyl acetate = 10:1) to give a yellow solid (3.1 g, 77.8%).

[0303] ESI-MS(+): m / z = 230.39 [M+1].

[0304] Step 6: Preparation of compound DSC207-02

[0305] DSC207-02-5 (3 g, 13.08 mmol, 1 eq) was added into acetic anhydride (30 ml), the system was heated to 130 °C, and the reaction was carried out for 5 h. Thin layer detection showed that the reaction was complete. The system was cooled to room temperature and concentrated to give a residue. The residue was added into 30 ml of 2N hydrochloric acid aqueous solution, stirred at room temperature for 2 h, and thin layer detection showed that the reaction was complete. The aqueous phase was extracted with DCM (50 mL x 3), the combined organic phases were dried over sodium sulfate, concentrated to give the crude product. The crude product was column chromatographed (petroleum ether: ethyl acetate = 20:1) to give a yellow solid (3.1 g, 77.8%).

[0306] ESI-MS(+): m / z = 241.3 [M+1].

[0307] The following example compounds were synthesized according to the same method as the above examples, using commercially available compounds or intermediate compounds synthesized appropriately from commercially available compounds.

[0308]

[0309]

[0310] Example 19: Test of protective effect of L-glutamic acid-induced PC12 cell damage on structure X1901

[0311]

[0312] Cell: Rat adrenal pheochromocytoma cell PC-12 (highly differentiated), also known as PC-12 Adh (National Model and Characteristic Experimental Cell Resource Bank / Chinese Academy of Sciences Cell Bank Stem Cell Bank, Catalog No. SCSP-5259)

[0313] Environment: The cell culture box environment is kept at a temperature of 37°C and 5% CO2. Culture medium (RPMI1640, Gibco Company): fetal bovine serum (FBS) (10091-148, Gibco Company) (v:v) = 9:1.

[0314] Main instruments and equipment:

[0315] Instrument Manufacturer Model CO2 cell incubator Thermo Fisher 3111 Microplate reader Thermo scientific MULTISKAN Sky Cell counter Invitrogen by Thermo Fisher Countess 3 Inverted microscope OLYMPUS CKX41

[0316] Main reagents:

[0317] Name Source / Brand Lot number L-Glutamic acid Shanghai TargetMol 117997 RPMI 1640 Gibco 2916962 PBS pH7.4 Gibco 2902929 DMSO SIGMA SHBJ7916 Fetal bovine serum (FBS) Gibco 10091-148

[0318] Preparation of modeling agent solution (L-glutamic acid): weigh an appropriate amount of L-glutamic acid powder, dissolve in RPMI1640 complete medium (containing 10% FBS) to 10 mmol / L, ultrasonic for 15 min, and ultrasonic for 15 min in a 37°C water bath until completely dissolved. Prepare fresh before use.

[0319] Preparation of test substance series solution: dissolve an appropriate amount of sample in DMSO to 100 mmol / L as a stock solution, and store at -20°C for standby. Before use, dilute 1000 times in RPMI1640 complete medium (containing 10% FBS) prepared above (L-glutamic acid final concentration is 10 mmol / L), mix well, and then dilute to 50 μmol / L in the modeling agent solution prepared above, and then continue to dilute by half to form test substance series concentrations (25, 12.5, 6.25, 3.125, 1.6, 0.8, 0.4, 0.2 μmol / L) solution.

[0320] Test method:

[0321] Take the logarithmic growth phase PC12 cells cultured in vitro (96-well cell culture plate, 5×10 3The experiment was performed on PC12 cells in 96-well plates (100 μL / well, 24 h after cell inoculation). Blank control, model, comparative compound (X1901), and test compound groups were set up. After removing the original culture medium, 100 μL / well of RPMI 1640 complete medium (containing 10% FBS) was added to the control group, 100 μL / well of the above-mentioned model agent solution was added to the model group, and 100 μL / well of the above-mentioned test compound solution at various concentrations (0.2, 0.4, 0.8, 1.6, 3.125, 6.25, 12.5, 25, 50, 100 μmmol / L, a total of 10 concentration groups) was added to the test compound group. Each group had five replicate wells. After adding the solutions, the plates were immediately placed in a 37°C, 5% CO2 incubator for culture. After 24 h of culture, the survival rate of PC12 cells was detected by the CCK-8 method. The cell death inhibition rate of the test compound at different concentrations was calculated, and the cell death inhibition rate = (OD 给药组 -OD 模型组 ) / (OD 空白对照组 -OD 模型组 ) x 100%, and OD represents the absorbance at 450 nm measured by the enzyme marker. The EC 50 (50% effective concentration) of the corresponding test compound was calculated by using the software graphpad prism 6.0.

[0322] The test results are shown in Table 1.

[0323] Table 1 Protective effect of the compound of the present application on L-glutamic acid-induced PC12 cell damage

[0324]

[0325]

[0326] The data show that the protective activity of the compound of the present application on L-glutamic acid-induced PC12 cell damage is very strong compared with the comparative compound, and the protective activity of DSC207-L01, DSC207-L02, DSC207-L03, DSC207-L04, and DSC207-L05 is stronger, and the protective activity of compound DSC207-L05 is the strongest, which is about 7.5 times the protective activity of the comparative compound X1901.

[0327] Example 20: Pharmacodynamic test on a rat model of cerebral ischemia-reperfusion

[0328] Animals: SD rats, SPF level, male, from Shanghai Slac Laboratory Animal Limited Liability Company.

[0329] Number of animals enrolled: 72, animal weight at the start of the experiment: about 180-200 g.

[0330] Test method:

[0331] Grouping: The rats were adaptively fed for 7 days, and the behavior training (balance beam, rotating rod) was performed on all rats three days before the operation in each group. The SD rats were evenly divided into 9 groups according to the body weight, namely, the sham operation group, the model group, the positive drug (Xinbixin, i.e. edaravone dexpanthenol injection) group, the control group (X1901 group), the DSC207-01 group, the DSC207-02 group, the DSC207-03 group, the DSC207-04 group and the DSC207-05 group, with 8 rats in each group.

[0332] Modeling: The rats were fasted for 12-14 h before the operation and were allowed to drink water freely. The animals in each group were anesthetized with isoflurane before the operation, and the spontaneous respiration was maintained. The rats were fixed on the mouse plate in the supine position, the neck was depilated in the middle, and was disinfected with 75% alcohol. The abdominal side of the neck was incised, the muscle and fascia were separated along the inner edge of the sternocleidomastoid muscle, and the right common carotid artery, external carotid artery and internal carotid artery were separated. A small inclined mouth was cut on the external carotid artery about 0.5 cm from the ligation site towards the heart with a blood vessel scissors, and the proximal end of the external carotid artery was pulled to be in line with the internal carotid artery. The rat wire plug was slowly pushed into the intracranial direction of the internal carotid artery through the right external carotid artery main incision for 1.8 cm. The bifurcation of the common carotid artery was used as a marker, and when the slight resistance was felt during the pushing, the middle cerebral artery was blocked. The wire plug was removed 2 h after the infarction to complete the cerebral ischemia-reperfusion injury model. The sham operation group was only treated with blood vessel separation. After 20 min of infarction, the cerebral blood flow was investigated by Doppler flowmeter, and the model was determined to be successful according to the left and right brain blood flow difference (ROI%) higher than 48%, and the experiment was entered. The anal temperature was maintained by heating with an incandescent lamp during the operation.

[0333] Drug administration: The drugs in each group were intravenously injected at 0.5 h after the cerebral infarction of the animals, and the sham operation group and the model group were given the same volume of blank solvent (8% propylene glycol + 92% normal saline). The grouping and detailed drug administration information are shown in Table 2.

[0334] Table 2 Test grouping and drug administration information

[0335]

[0336] Zea-longa neurological function score was performed on each animal at 24 h after reperfusion; the change of cerebral blood flow of all animals was determined by Doppler flowmeter at the end of the experiment (24 h after reperfusion) to evaluate the improvement effect of the tested substance on ischemic stroke; the behavior function test (balance beam) was performed; the animals in each group were euthanized after 1 h, and the whole brain was continuously coronally sectioned for TTC staining, photographing, measurement of infarct area by using Image-J software, calculation of the percentage of infarct area to whole brain area, and calculation of the infarction improvement rate.

[0337] Zea-Longa score criteria: no neurological deficits: 0 points; paralyzed side of the forepaw cannot fully extend: 1 point; walking to the paralyzed side of the circle: 2 points; walking to the paralyzed side of the fall: 3 points; unable to walk automatically, there is a loss of consciousness phenomenon: 4 points.

[0338] Infarct area ratio = total infarct area ÷ total brain section area × 100%;

[0339] Infarct improvement rate = (model group infarct area ratio - drug administration group infarct area ratio) ÷ model group infarct area ratio × 100%

[0340] The experimental data is expressed as Mean ± SD, and the corresponding statistical analysis is performed by SPSS21.0 software, and if p < 0.05, it is considered to have statistically significant difference.

[0341] The pharmacodynamic test of ischemic stroke rats is shown in Table 3.

[0342] Table 3 Pharmacodynamic test results of ischemic stroke rats

[0343]

[0344] ## p < 0.01 vs. sham operation group; *p < 0.05, **p < 0.01 vs. model group

[0345] The above data show that in the single intravenous injection of the test substance on the MCAO rat model pharmacodynamic experiment, the test substance group (DSC207-01 group, DSC207-02 group, DSC207-03 group, DSC207-04 group and DSC207-05 group) and the positive drug group (Xinbixin) and the control group (X1901 group) can effectively improve the Zea-Longa score, the balance wood passing time of the behavior of the MCAO rats, can significantly improve the blood flow difference of the left and right sides of the brain of the MCAO rats, can significantly reduce the cerebral infarction area of the MCAO rats, and can improve the cerebral infarction improvement rate of the rats, and DSC207-05 performs the best.

[0346] Example 21: Rat gavage brain and spinal cord tissue distribution test

[0347] Animals: SD rats, SPF level, male, from Beijing Vantoll Life Co., Ltd,

[0348] The number of animals enrolled was 36, and the body weight of the animals at the beginning of the experiment was about 200 ± 20 g.

[0349] Test method:

[0350] Male SD rats were randomly divided into 4 groups according to body weight, which were control group (X1901 group), DSC207-02 group, DSC207-03 group and DSC207-05 group, each group had 9 rats. The animals were fasted for 12-14h before administration, but not water. According to the weight of the animals, 13.40mg / kg was respectively administered by gavage (gavage volume 5mL / kg, gavage solvent 5% DMSO+95% 0.5% MC solution) on the test day. 3 animals in each group were euthanized at each time point of 10min, 60min, 3h after single oral gavage administration, and brain and spinal cord tissue samples were collected (note that the bloodstains were wiped off with filter paper, and the blood vessels were removed as much as possible), and stored in-80℃ refrigerator for testing.

[0351] During the whole experiment, the general state of the experimental animals was observed, and the observation contents included: the change of food and water intake of rats, the change of body weight, the abnormality of fur color, the abnormality of behavior and mental state, the abnormal secretion of eyes, ears, mouth and nose, and the abnormality of stool and urine. If abnormality appeared, it was recorded immediately, and the reason for the abnormality was analyzed.

[0352] Detection method: LC / MS / MS method for detecting the content of drug prototype in brain and spinal cord.

[0353] The results of brain and spinal cord tissue distribution test after gavage administration of rats are shown in Table 4.

[0354] Table 4 Average concentration of prototype drug in brain and spinal cord tissue after single gavage administration (ng / g)

[0355]

[0356] The data showed that after oral administration in rats, the compound of the application and X1901 could quickly distribute in brain and spinal cord tissues; compared with X1901, the distribution amount of the compound of the application in brain and spinal cord tissues was significantly greater than that of X1901; after administration of the compound of the application, the exposure amount in brain and spinal cord tissues remained very high at 3h, and was significantly higher than that of X1901. In summary, the compound of the application has higher exposure amount in brain and spinal cord tissues, and stays longer in these two tissues, especially DSC207-05 is the best.

[0357] Example 22: Pharmacokinetic test of rats

[0358] Grouping and administration: 18 male SD rats were divided into 6 groups, 3 rats in each group, and the animals were fasted for 12-14 h before administration, but not water-restricted. The control group (X1901 group), DSC207-01 group, DSC207-02 group, DSC207-03 group, DSC207-04 group and DSC207-05 group were all administered by tail vein injection, and the animals were administered according to the weight of 5 mg / kg (the administration volume was 5 mL / kg) on the experimental day.

[0359] Plasma collection: within 0.5 h (0 h) before single intravenous injection administration, and at 0.083 h, 0.25 h, 0.50 h, 1.0 h, 3.0 h, 6.0 h, 9.0 h, 24.0 h after administration, 200 μL of blood was taken from the orbital vein of the rat into an EDTA-K2 anticoagulant tube, and placed in an ice bath, centrifuged at 4000 rpm for 10 min, the plasma was transferred to a 1.5 mL centrifuge tube, and stored in a-80℃ refrigerator for testing. The animals were fed 4 h after administration, and the whole process was not water-restricted.

[0360] Data calculation: the drug concentration was analyzed by LC-MS / MS method, and the pharmacokinetic parameters were calculated by DAS3.2.7 software.

[0361] The pharmacokinetic parameters of intravenous administration of rats are shown in Table 5

[0362] Table 5 Average value of pharmacokinetic parameters of intravenous administration of rats

[0363]

[0364]

[0365] The data show that, compared with X1901, the half-life of the compound of the present application is significantly shorter than that of X1901 under the condition of similar exposure and clearance in vivo, which is unexpected. Commonly, the half-life of a drug is often significantly prolonged after the hydrogen in the drug structure is replaced by a deuterium atom, but the half-life of the compound of the present application shows the characteristic of shortening, which is very advantageous in treating cardiovascular and cerebrovascular diseases, can reduce the accumulation of the drug in the body, and thus significantly reduce or avoid the side effects of damage to liver function and kidney function of such drugs.

[0366] Although the present application has been disclosed with the preferred embodiments as above, it is not intended to limit the present application, and any person skilled in the art can make some modifications and improvements without departing from the spirit and scope of the present application, therefore the protection scope of the present application is defined by the claims.

Claims

1. A novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof as shown in formula (I) and / or formula (II): ###0001### (I) (II) wherein, in formula (I) and / or formula (II), R1 is selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl substituted with one or more substituents, phenyl substituted with one or more substituents, or pyridyl substituted with one or more substituents, wherein the substituents are selected from the group consisting of deuterium, or halogen; R2 is selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl substituted with one or more substituents, phenyl substituted with one or more substituents, or pyridyl substituted with one or more substituents, wherein the substituents are selected from the group consisting of deuterium, or halogen; R3 is selected from the group consisting of hydrogen, or deuterium; R4 is selected from the group consisting of hydrogen, deuterium, C1-C8 alkyl substituted with one or more substituents, phenyl substituted with one or more substituents, or pyridyl substituted with one or more substituents, wherein the substituents are selected from the group consisting of deuterium, or halogen; and wherein at least one of R1, R2, R3 and R4 is deuterium or substituted with deuterium.

2. The novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof according to claim 1, having a structure as shown in formula (III) and / or formula (IV): ###0002### (III) (IV) wherein the substituents in formula (III) and / or formula (IV) are defined as in claim 1. R1is selected from hydrogen, deuterium, C1-C8alkyl substituted with one or more substituents or unsubstituted, phenyl substituted with one or more substituents or unsubstituted, or pyridyl substituted with one or more substituents or unsubstituted, wherein, 3. The novel deuterium-containing pyrazolone compound, tautomer, stereoisomer, prodrug and pharmaceutically acceptable salt thereof according to claims 1-2, wherein the compound includes but is not limited to the following compounds: ###0003### ###0004### ###0005### ###0006### ###0007### ###0008### ###0009### ###0010### ###0011### ###0012### ###0013### ###0014### ###0015### ###0016### ###0017### ###0018### ###0019### ###0020### ###0021### ###0022### ###0023### ###0024### ###0025### ###0026### ###0027### ###0028### ###0029### ###0030### ###0031### ###0032### ###0033### ###0034### ###0035### ###0036### ###0037### ###0038### ###0039### ###0040### ###0041### ###0042### ###0043### ###0044### ###0045### ###0046### ###0047### ###0048### ###0049### ###0050### ###0051### ###0052### ###0053### ###0054### ###0055### ###0056### ###0057### ###0058### ###0059### ###0060### ###0061### ###0062### ###0063### ###0064### ###0065### ###0066### ###0067### ###0068### ###0069### ###0070### ###0071### ###0072### ###0073### ###0074### ###0075### ###0076### ###0077### ###0078### ###0079### ###0080### ###0081### ###0082### ###0083### ###0084### ###0085### ###0086### ###0087### ###0088### ###0089### ###0090### ###0091### ###0092### ###0093### ###0094### ###0095### ###0096### ###0097### ###0098### ###0099### ###0100### ###0101### ###0102### ###0103### ###0104### ###0105### ###0106### ###0107### ###0108### ###0109### ###0110### ###0111### ###0112### ###0113### ###0114### ###0115### ###0116### ###0117### ###0118### ###0119### ###0120### ###0121### ###0122### ###0123### ###0124### ###0125### ###0126### ###0127### ###0128### ###0129### ###0130### ###0131### ###0132### ###0133### ###0134### ###0135### ###0136### ###0137### ###0138### ###0139### ###0140### ###0141### ###0142### ###0143### ###0144### ###0145### ###0146### ###0147### ###0148### ###0149### ###0150### ###0151### ###0152### ###0153### ###0154### ###0155### ###0156### ###0157### ###0158### ###0159### ###0160### ###0161### ###0162### ###0163### ###0164### ###0165### ###0166### ###0167### ###0168### ###0169### ###0170### ###0171### ###0172### ###0173### ###0174### ###0175### ###0176### ###0177### ###0178### ###0179### ###0180### ###0181### ###0182### ###0183### ###0184### ###0185### ###0186### ###0187### ###0188### ###0189### ###0190### ###0191### ###0192### ###0193### ###0194### ###0195### ###0196### ###0197### ###0198### ###0199### ###0200### ###0201### ###0202### ###0203### ###0204### ###0205### ###0206### ###0207### ###0208### ###0209### ###0210### ###0211### ###0212### ###0213### ###0214### ###0215### ###0216### ###0217### ###0218### ###0219### ###0220### ###0221### ###0222### ###0223### ###0224### ###0225### ###0226### ###0227### ###0228### ###0229### ###0230### ###0231### ###0232### ###0233### ###0234### ###0235### ###0236### ###0237### ###0238### ###0239### ###0240### ###0241### ###0242### ###0243### ###0244### ###0245### ###0246### ###0247### ###0248### ###0249### ###0250### ###0251### ###0252### ###0253### ###0254### ###0255### ###0256### ###0257### ###0258### ###0259### ###0260### ###0261### ###0262### ###0263### ###0264### ###0265### ###0266### ###0267### ###0268### ###0269### ###0270### ###0271### ###0272### ###0273### ###0274### ###0275### ###0276### ###0277### ###0278### ###0279### ###0280### ###0281### ###0282### ###0283### ###0284### ###0285### ###0286### ###0287### ###0288### ###0289### ###0290### ###0291### ###0292### ###0293### ###0294### ###0295### ###0296### ###0297### ###0298### ###0299### ###0300### ###0301### ###0302### ###0303### ###0304### ###0305### ###0306### ###0307### ###0308### ###0309### ###0310### ###0311### ###0312### ###0313### ###0314### ###0315### ###0316### ###0317### ###0318### ###0319### ###0320### ###0321### ###0322### ###0323### ###0324### ###0325### ###0326### ###0327### ###0328### ###0329### ###0330### ###0331### ###0332### ###0333### ###0334### ###0335### ###0336### ###0337### ###0338### ###0339### ###0340### ###0341### ###0342### ###0343### ###0344### ###0345### ###0346### ###0347### ###0348### ###0349### ###0350### ###0351### ###0352### ###0353### ###0354### ###0355### ###0356### ###0357### ###0358### ###0359### ###0360### ###0361### ###0362### ###0363### ###0364### ###0365### ###0366### ###0367### ###0368### ###0369### ###0370### ###0371### ###0372### ###0373### ###0374### ###0375### ###0376### ###0377### ###0378### ###0379### ###0380### ###0381### ###0382### ###0383### ###0384### ###0385### ###0386### ###0387### ###0388### ###0389### ###0390### ###0391### ###0392### ###0393### ###0394### ###0395### ###0396### ​ ​ R4is selected from cyclohexyl substituted with one or more substituents, or unsubstituted, benzyl substituted with one or more substituents, or unsubstituted, naphthyl substituted with one or more substituents, or unsubstituted, heterocyclyl substituted with one or more substituents, or unsubstituted, or wherein the above substituents are selected from deuterium, or halogen; R X1 selected from halogen, or C1-C8 alkyl, which is unsubstituted or substituted by one or more substituents selected from deuterium, or halogen; R X2 selected from halogen, or C1-C8 alkyl, which is unsubstituted or substituted by one or more substituents selected from deuterium, or halogen; R X3 selected from halogen, Ci-C8alkyl which is unsubstituted or substituted by one or more substituents, Ci-C8alkoxy which is unsubstituted or substituted by one or more substituents, wherein the above substituents are selected from the group consisting of deuterium, hydroxyl; R is selected from the group consisting of C1-C8alkyl, or C1-C8alkoxy, wherein the alkyl and alkoxy groups are unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, or halogen; and X4 R is selected from the group consisting of C1-C8alkyl, or C1-C8alkoxy, wherein the alkyl and alkoxy groups are unsubstituted or substituted with one or more substituents selected from the group consisting of deuterium, or halogen; and ​ ​ ​ ​ ​ ​ ​ ​ ​ ​

Images