Sulfonamide compound for therapeutic use, enantiomer thereof, preparation method, and uses

Abstract

The present invention relates to the technical field of biomedicine, and in particular to a sulfonamide compound for therapeutic use, an enantiomer thereof, a preparation method, and uses. The present invention provides the following beneficial effects: the provided sulfonamide compound and the enantiomer thereof have the characteristics of high stability, a prolonged duration of action, superior efficacy, and the like, thereby serving as a superior diuretic and a novel anti-cerebral edema drug.

Description

Sulfonamide compounds for use in therapy and enantiomers thereof, and methods of preparation and use TECHNICAL FIELD

[0001] The present application relates to the technical field of biological medicine, in particular to a sulfonamide compound for use in therapy and enantiomers thereof, and methods of preparation and use. BACKGROUND

[0002] Torasemide is a new generation of high efficiency loop diuretics, which is l-[4-(3-methylphenyl) amino pyridine-3-yl] sulfonamide-3-isopropyl urea. It is mainly used in the treatment of congestive heart failure, hypertension and other diseases in the cardiovascular department. In clinical practice, torasemide has a wide range of indications, rapid, strong and long-lasting diuretic effect, and low incidence of adverse reactions. It is a high efficiency diuretic commonly used in clinical practice, which can inhibit the reabsorption of sodium and chlorine, and has diuretic and natriuretic effects.

[0003] At present, the marketed dosage forms of torasemide include injection, tablet and capsule. Since torasemide is almost insoluble in water, a large amount of solubilizer needs to be added in the preparation process of injection, which brings great hidden danger to the safety of patients.

[0004] Chinese patent CN110606860A discloses a pyridine sulfonamide phosphate compound, a preparation method thereof and a use thereof. The method is to phosphorylate the active metabolite of torasemide in vivo to improve the water solubility, and the in vivo effect is basically the same as that of torasemide.

[0005] Through retrieval, it is found that the half-life of torasemide in vivo is about 4 hours, the in vivo action time is short, and the water solubility is poor. Therefore, it is necessary to develop a more optimal diuretic and anti-cerebral edema new drug. SUMMARY

[0006] The purpose of the present application is to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer, the structure of which is shown as formula I:

[0007] X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl;

[0008] R1 is cyclopropyl or

[0009] R2 is hydrogen, PE is or PE is absent, R3 and R4 are independently hydrogen or a metal element, the metal element includes an alkali metal or an alkaline earth metal; when R3 or R4 is hydrogen, R3 or R4 can be salted with an organic base or an alkaline amino acid; Y is an O atom or Y is absent, and Z is CH2 or Z is absent.

[0010] when R2 is and PE is when Y and Z are both absent, the O atom in the group R2O in formula I is directly linked to PE;

[0011] when R2 is and PE is when Y is O, Z is CH2;

[0012] The organic base is selected from trimethylamine, meglumine or diisopropylethylamine, and the basic amino acid includes lysine or arginine salt.

[0013] When one of R3 and R4 is a hydrogen atom and the other is a metal element, the basicity of the entire compound is closer to human tolerance, and the drug property is better.

[0014] The present application also provides a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer.

[0015] Preferably, the sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer is selected from the following compounds:

[0016] Control compound

[0017] The second aspect of the present application provides a preparation method of a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer, comprising the following steps:

[0018] Preparation of M1 compound: 4-chloropyridine-3-sulfonamide, 2-fluoro-4-aminophenol, triethylamine, n-butanol are added into a three-necked flask, and the reaction is carried out under reflux at elevated temperature for 20 h. The solvent is removed by evaporation under reduced pressure. Dichloromethane is added to the residue for extraction. Filtration is performed, and the filtrate is dried with anhydrous sodium sulfate. The solvent is removed by evaporation under reduced pressure to obtain M1.

[0019] Preparation of M2 compound: the preparation method of M1 compound is used, and 2-fluoro-4-aminophenol is changed to 3-fluoro-5-aminophenol.

[0020] Preparation of M3 compound: the preparation method of M1 compound is used, and 2-fluoro-4-aminophenol is changed to 2-amino-4-fluorophenol.

[0021] M4 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 2-chloro-4-aminophenol.

[0022] M5 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 2-amino-4-chlorophenol.

[0023] M6 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-fluoro-4-aminophenol.

[0024] M7 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-amino-4-fluorophenol.

[0025] M8 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-chloro-4-aminophenol.

[0026] M9 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 2-amino-4-bromophenol.

[0027] M10 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-trifluoromethyl-4-aminophenol.

[0028] M11 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-difluoromethyl-4-aminophenol.

[0029] M12 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 3-fluoromethyl-4-aminophenol.

[0030] M13 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 2-trifluoromethyl-4-aminophenol.

[0031] M14 compound preparation: same as Ml compound preparation method, 2-fluoro-4- aminophenol is changed to 2-difluoromethyl-4-aminophenol.

[0032] M15 compound preparation: the same as the preparation method of Ml compound, 2-fluoro-4-aminophenol is changed to 2-fluoromethyl-4-aminophenol.

[0033] M16 compound preparation: the same as the preparation method of Ml compound, 2-fluoro-4-aminophenol is changed to 2-methyl-4-aminophenol

[0034] M17 compound preparation: the same as the preparation method of Ml compound, 2-fluoro-4-aminophenol is changed to 3-methyl-4-aminophenol

[0035] M18 compound preparation: the same as the preparation method of Ml compound, 2-fluoro-4-aminophenol is changed to 3-bromo-4-aminophenol

[0036] Preparation of the compound of the present application

[0037] Ml, M2, M4, M8, M10, M11, M12, M13, M14, M15, M16, M17, M18 intermediate is respectively added with methyl cyclopropyl carbamate or 1-cyclopropyl isopropyl carbamate or R-1-cyclopropyl isopropyl carbamate or S-1-cyclopropyl isopropyl carbamate, potassium carbonate, ethylene glycol diethyl ether, pyridine in a three-necked flask, and refluxed. After the reaction is completed, it is cooled to room temperature, filtered, the filter cake is dissolved in water, acetic acid is used to adjust the pH, and a solid is precipitated, filtered, and compound 109 to compound 139 is obtained.

[0038] The corresponding compound 109 to compound 139 is further reacted with phosphorus oxychloride to prepare the corresponding phosphate compound, and the corresponding phosphate compound is further reacted with sodium hydroxide or arginine or meglumine or choline to form a salt to prepare the corresponding compound 1 to compound 66.

[0039] Compound 109 to compound 139 is further chloromethylated with chlorobromomethane, phosphated, and salted to prepare compound 67 to compound 108.

[0040] The third aspect of the present application is to provide a pharmaceutical composition comprising a therapeutic amount of a sulfamide compound or a pharmaceutically acceptable salt or a pharmaceutically acceptable stereoisomer thereof and other pharmaceutically acceptable excipients.

[0041] The carrier refers to a carrier commonly used in the pharmaceutical field, such as diluent, excipient, binder, filler, disintegrant, flavoring agent and sweetening agent.

[0042] The various dosage forms of the composition of the present application can be prepared by conventional methods in the medical field, and the content of the active ingredient is 0.10% to 99.5% (weight ratio).

[0043] The application amount of the present application can be varied depending on the administration route, the age and weight of the patient, the type and severity of the disease to be treated, etc., and the daily dose is 0.001-30 mg / kg of body weight (oral) or 0.005-40 mg / kg of body weight (injection).

[0044] The fourth aspect of the present application provides the use of the sulfamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer in the preparation of a diuretic drug.

[0045] The present application has the advantages of providing the sulfamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer, which has the characteristics of high stability, longer action time, and better drug efficacy, and is superior to torsemide in anti-cerebral edema and diuretic effect, and is a new type of diuretic. DETAILED DESCRIPTION

[0046] The present application is further described below in conjunction with examples, but is not limited thereto.

[0047] Example 1: Preparation of M1 compound

[0048] 4-chloropyridine-3-sulfonamide 50 g (259.6 mmol), 2-fluoro-4-aminophenol 33.0 g (259.6 mmol), triethylamine 26.2 g (259.6 mmol), n-butanol 250 ml were added into a 500 ml three-necked flask, and the reaction was carried out by heating and refluxing. After 20 h of reaction, the solvent was removed by evaporation under reduced pressure at 60°C. 200 ml of dichloromethane was added to extract the residue, and then filtered and dried with anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure at 40°C to obtain 61.9 g of M1 compound with a yield of 84.2%, MS (ESI): m / s [M+H] + = 284.

[0049] Example 2: Preparation of M2 compound

[0050] The preparation method of M1 compound in Example 1 was used, and 2-fluoro-4-aminophenol was changed to 3-fluoro-5-aminophenol, MS (ESI): m / s [M+H] + = 284.

[0051] Example 3: Preparation of M3 compound

[0052] The preparation method of M1 compound in Example 1 was used, and 2-fluoro-4-aminophenol was changed to 2-amino-4-fluorophenol, MS (ESI): m / s [M+H] + = 284.

[0053] Example 4: Preparation of M4 compound

[0054] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 2-chloro-4-aminophenol, MS (ESI): m / s [M+H]+=301.

[0055] Example 5: Preparation of compound M5

[0056] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 2-chloro-4-aminophenol, MS (ESI): m / s [M+H]+=301.

[0057] Example 6: Preparation of compound M6

[0058] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0059] Example 7: Preparation of compound M7

[0060] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0061] Example 8: Preparation of compound M8

[0062] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0063] Example 9: Preparation of compound M9

[0064] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0065] Example 10: Preparation of compound M10

[0066] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0067] Example 11: Preparation of compound M11

[0068] The same as the preparation method of compound M1 in example 1, 2-fluoro-4-aminophenol was changed to 3-fluoro-4-aminophenol, MS (ESI): m / s [M+H]+=284.

[0069] Example 12: Preparation of compound M12

[0070] The compound M12 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 3- fluoromethyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 316. + = 298.

[0071] Example 13: Preparation of compound M13

[0072] The compound M13 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 2- trifluoromethyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 334. + = 334.

[0073] Example 14: Preparation of compound M14

[0074] The compound M14 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 2- difluoromethyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 316.

[0075] Example 15: Preparation of compound M15

[0076] The compound M15 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 2- fluoromethyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 298. + = 298.

[0077] Example 16: Preparation of compound M16

[0078] The compound M16 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 2- methyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 280. + = 280.

[0079] Example 17: Preparation of compound M17

[0080] The compound M17 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 3- methyl-4-aminophenol, MS (ESI): m / s [M+H]+ = 280. + = 280.

[0081] Example 18: Preparation of compound M18

[0082] The compound M18 was prepared according to the procedure described in Example 1 for the preparation of compound M1 by replacing 2-fluoro-4-aminophenol with 3- bromo-4-aminophenol, MS (ESI): m / s [M+H]+ = 345. + = 345.

[0083] Example 19: Preparation of compound 1

[0084] Ml compound 50 g (176.5 mmol), 1-cyclopropyl isopropyl carbamate 31.58 g (220.6 mmol), potassium carbonate 30.48 g (220.6 mol), ethylene glycol diethyl ether 500 ml, pyridine 30 ml were added into 1000 ml three-necked flask, refluxed for 30 h. Cooled to room temperature, filtered, the filter cake was dissolved in 100 ml water, adjusted pH to 5 with acetic acid, solid precipitated, filtered, vacuum dried at 50-60 °C, to obtain intermediate (compound 112) 59.87 g, yield 86%, MS (ESI): m / s [M+H] + = 395.

[0085] Dry 1000 ml three-necked flask was added acetonitrile 300 ml, intermediate 150 g (126.7 mmol), stirred to dissolve, then cooled to 0-5 °C, and then slowly added phosphorus oxychloride 58.3 g (380.1 mmol) dropwise. After the dropwise addition was completed, the temperature was raised to 40 °C and the reaction was maintained for 5 h. After the reaction was completed, 10 ml of water was slowly added dropwise for hydrolysis, and 20% sodium hydroxide solution was used to adjust the pH of the solution to 7-8. The solution was concentrated to dryness at 50 °C under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography, and the effective fraction was concentrated and dried at 40-45 °C under reduced pressure to obtain compound 137.4 g, yield 57%. MS (ESI): m / s [M+H] + = 519.

[0086] Example 20: Preparation of compound 2

[0087] The preparation method of compound 1 in Example 19 was used, except that 1-cyclopropyl isopropyl carbamate was changed to S-1-cyclopropyl isopropyl carbamate, to obtain compound 2, MS (ESI): m / s [M+H] + = 519.

[0088] Example 21: Preparation of compound 3

[0089] The preparation method of compound 1 in Example 19 was used, except that 1-cyclopropyl isopropyl carbamate was changed to R-1-cyclopropyl isopropyl carbamate, to obtain compound 3, MS (ESI): m / s [M+H] + = 519.

[0090] Example 22: Preparation of compound 4

[0091] The preparation method of compound 1 in Example 19 was used, except that M1 was changed to M2, to obtain compound 4, MS (ESI): m / s [M+H] + = 519.

[0092] Example 23: Preparation of compound 5

[0093] The compound 5 was prepared according to the procedure for compound 4 of Example 22, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1-cyclopropylisopropylcarbamic acid methyl ester. MS (ESI): m / s [M+H] + = 519.

[0094] Example 24: Preparation of compound 6

[0095] The compound 6 was prepared according to the procedure for compound 4 of Example 22, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to R-1-cyclopropylisopropylcarbamic acid methyl ester. MS (ESI): m / s [M+H] + = 519.

[0096] Example 25: Preparation of compound 7

[0097] The compound 7 was prepared according to the procedure for compound 1 of Example 19, by changing M1 to M3. MS (ESI): m / s [M+H] + = 519.

[0098] Example 26: Preparation of compound 8

[0099] The compound 8 was prepared according to the procedure for compound 7 of Example 25, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1-cyclopropylisopropylcarbamic acid methyl ester. MS (ESI): m / s [M+H] + = 519.

[0100] Example 27: Preparation of compound 9

[0101] The compound 9 was prepared according to the procedure for compound 7 of Example 25, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to R-1-cyclopropylisopropylcarbamic acid methyl ester. MS (ESI): m / s [M+H] + = 519.

[0102] Example 28: Preparation of compound 10

[0103] The compound 10 was prepared according to the procedure for compound 1 of Example 19, by changing M1 to M4. MS (ESI): m / s [M+H] + = 535.

[0104] Example 29: Preparation of compound 11

[0105] The compound 11 was prepared according to the procedure for compound 10 of Example 28, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1-cyclopropylisopropylcarbamic acid methyl ester. MS (ESI): m / s [M+H] + = 535.

[0106] Example 30: Preparation of compound 12

[0107] The compound 12 was prepared according to the method described in example 28 for the preparation of compound 10, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl R-1-cyclopropylisopropylcarbamate. MS (ESI): m / s [M+H] + = 535.

[0108] Example 31: Preparation of compound 13

[0109] The compound 13 was prepared according to the method described in example 19 for the preparation of compound 1, by changing M1 to M5. MS (ESI): m / s [M+H] + = 535.

[0110] Example 32: Preparation of compound 14

[0111] The compound 14 was prepared according to the method described in example 31 for the preparation of compound 13, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl S-1-cyclopropylisopropylcarbamate. MS (ESI): m / s [M+H] + = 535.

[0112] Example 33: Preparation of compound 15

[0113] The compound 15 was prepared according to the method described in example 31 for the preparation of compound 13, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl R-1-cyclopropylisopropylcarbamate. MS (ESI): m / s [M+H] + = 535.

[0114] Example 34: Preparation of compound 16

[0115] The compound 16 was prepared according to the method described in example 19 for the preparation of compound 1, by changing M1 to M6. MS (ESI): m / s [M+H] + = 519.

[0116] Example 35: Preparation of compound 17

[0117] The compound 17 was prepared according to the method described in example 34 for the preparation of compound 16, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl S-1-cyclopropylisopropylcarbamate. MS (ESI): m / s [M+H] + = 519.

[0118] Example 36: Preparation of compound 18

[0119] The compound 18 was prepared according to the method described in example 34 for the preparation of compound 16, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl R-1-cyclopropylisopropylcarbamate. MS (ESI): m / s [M+H]+ = 519.

[0120] Example 37: Preparation of compound 19

[0121] The compound 19 was prepared according to the method described in Example 19 for the preparation of compound 1, by changing M1 to M7, MS (ESI): m / s [M+H] + = 519.

[0122] Example 38: Preparation of compound 20

[0123] The compound 20 was prepared according to the method described in Example 37 for the preparation of compound 19, by changing 1-cyclopropyl isopropyl carbamic acid methyl ester to S-1-cyclopropyl isopropyl carbamic acid methyl ester, MS (ESI): m / s [M+H] + = 519.

[0124] Example 39: Preparation of compound 21

[0125] The compound 21 was prepared according to the method described in Example 37 for the preparation of compound 19, by changing 1-cyclopropyl isopropyl carbamic acid methyl ester to R-1-cyclopropyl isopropyl carbamic acid methyl ester, MS (ESI): m / s [M+H] + = 519.

[0126] Example 40: Preparation of compound 22

[0127] The compound 22 was prepared according to the method described in Example 19 for the preparation of compound 1, by changing M1 to M9, MS (ESI): m / s [M+H] + = 580.

[0128] Example 41: Preparation of compound 23

[0129] The compound 23 was prepared according to the method described in Example 40 for the preparation of compound 22, by changing 1-cyclopropyl isopropyl carbamic acid methyl ester to S-1-cyclopropyl isopropyl carbamic acid methyl ester, MS (ESI): m / s [M+H] + = 580.

[0130] Example 42: Preparation of compound 24

[0131] The compound 24 was prepared according to the method described in Example 40 for the preparation of compound 22, by changing 1-cyclopropyl isopropyl carbamic acid methyl ester to R-1-cyclopropyl isopropyl carbamic acid methyl ester, MS (ESI): m / s [M+H] + = 580.

[0132] Example 43: Preparation of compound 25

[0133] The compound 25 was prepared according to the method for preparing compound 1 in Example 19, except that the reaction material and reaction conditions were not changed, after the intermediate 1 was reacted with phosphorus oxychloride for hydrolysis, the solution was not adjusted with alkali, and the solution was concentrated to dryness at 50°C under reduced pressure. The residue was purified by silica gel column, and the effective fraction was concentrated and dried at 40-45°C under reduced pressure to obtain the compound 25. MS (ESI): m / z [M+H] + = 475.

[0134] Example 44: Preparation of compound 26

[0135] The compound 26 was prepared according to the method for preparing compound 25 in Example 43, except that the 1-cyclopropyl isopropyl carbamate was changed to S-1-cyclopropyl isopropyl carbamate. MS (ESI): m / z [M+H] + = 475.

[0136] Example 45: Preparation of compound 27

[0137] The compound 27 was prepared according to the method for preparing compound 25 in Example 43, except that the 1-cyclopropyl isopropyl carbamate was changed to R-1-cyclopropyl isopropyl carbamate. MS (ESI): m / z [M+H] + = 475.

[0138] Example 46: Preparation of compound 28

[0139] The compound 28 was prepared according to the method for preparing compound 25 in Example 43, except that M1 was changed to M8. MS (ESI): m / z [M+H] + = 491.

[0140] Example 47: Preparation of compound 29

[0141] The compound 29 was prepared according to the method for preparing compound 28 in Example 46, except that the 1-cyclopropyl isopropyl carbamate was changed to S-1-cyclopropyl isopropyl carbamate. MS (ESI): m / z [M+H] + = 491.

[0142] Example 48: Preparation of compound 30

[0143] The compound 30 was prepared according to the method for preparing compound 28 in Example 46, except that the 1-cyclopropyl isopropyl carbamate was changed to R-1-cyclopropyl isopropyl carbamate. MS (ESI): m / z [M+H] + = 491.

[0144] Example 49: Preparation of compound 31

[0145] The compound 31 was prepared according to the method for preparing compound 31 in Example 49, by changing methyl 1-cyclopropylisopropylcarbamate into methyl S-1- cyclopropylisopropylcarbamate. Compound 31, MS (ESI): m / z [M+H] + = 525.

[0146] Example 50: Preparation of compound 32

[0147] The compound 32 was prepared according to the method for preparing compound 31 in Example 49, by changing methyl 1-cyclopropylisopropylcarbamate into methyl S-1- cyclopropylisopropylcarbamate. Compound 32, MS (ESI): m / z [M+H] + = 525.

[0148] Example 51: Preparation of compound 33

[0149] The compound 33 was prepared according to the method for preparing compound 31 in Example 49, by changing methyl 1-cyclopropylisopropylcarbamate into methyl R-1- cyclopropylisopropylcarbamate. Compound 33, MS (ESI): m / z [M+H] + = 525.

[0150] Example 52: Preparation of compound 34

[0151] The compound 34 was prepared according to the method for preparing compound 1 in Example 19, by changing M1 into M13. Compound 34, MS (ESI): m / z [M+H] + = 569.

[0152] Example 53: Preparation of compound 35

[0153] The compound 35 was prepared according to the method for preparing compound 34 in Example 52, by changing methyl 1-cyclopropylisopropylcarbamate into methyl S-1- cyclopropylisopropylcarbamate. Compound 35, MS (ESI): m / z [M+H] + = 569.

[0154] Example 54: Preparation of compound 36

[0155] The compound 36 was prepared according to the method for preparing compound 34 in Example 52, by changing methyl 1-cyclopropylisopropylcarbamate into methyl R-1- cyclopropylisopropylcarbamate. Compound 36, MS (ESI): m / z [M+H] + = 569.

[0156] Example 55: Preparation of compound 37

[0157] The compound 37 was prepared according to the method for preparing compound 25 in Example 43, by changing M1 into M14. Compound 37, MS (ESI): m / z [M+H] + = 507.

[0158] Example 56: Preparation of compound 38

[0159] Compound 38 was prepared according to the procedure for Compound 37 in Example 55, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1- cyclopropylisopropylcarbamic acid methyl ester, MS (ESI): m / s [M+H] + = 507.

[0160] Example 57: Preparation of Compound 39

[0161] Compound 39 was prepared according to the procedure for Compound 37 in Example 55, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to R-1- cyclopropylisopropylcarbamic acid methyl ester, MS (ESI): m / s [M+H] + = 507.

[0162] Example 58: Preparation of Compound 40

[0163] Compound 40 was prepared according to the procedure for Compound 1 in Example 19, by changing M1 to M14, MS (ESI): m / s [M+H] + = 551.

[0164] Example 59: Preparation of Compound 41

[0165] Compound 41 was prepared according to the procedure for Compound 40 in Example 58, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1- cyclopropylisopropylcarbamic acid methyl ester, MS (ESI): m / s [M+H] + = 551.

[0166] Example 60: Preparation of Compound 42

[0167] Compound 42 was prepared according to the procedure for Compound 40 in Example 58, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to R-1- cyclopropylisopropylcarbamic acid methyl ester, MS (ESI): m / s [M+H] + = 551.

[0168] Example 61: Preparation of Compound 43

[0169] Compound 43 was prepared according to the procedure for Compound 1 in Example 19, by changing M1 to M15, MS (ESI): m / s [M+H] + = 533.

[0170] Example 62: Preparation of Compound 44

[0171] Compound 44 was prepared according to the procedure for Compound 43 in Example 61, by changing 1-cyclopropylisopropylcarbamic acid methyl ester to S-1- cyclopropylisopropylcarbamic acid methyl ester, MS (ESI): m / s [M+H] += 533.

[0172] Example 63: Preparation of compound 45

[0173] The compound 45 was prepared according to the procedure for compound 43 in Example 61, using methyl 1-cyclopropylisopropylcarbamate instead of methyl 1- cyclopropylallylcarbamate. MS (ESI): m / s [M+H] + = 533.

[0174] Example 64: Preparation of compound 46

[0175] The compound 46 was prepared according to the procedure for compound 25 in Example 43, using M1 instead of M2. MS (ESI): m / s [M+H] + = 489.

[0176] Example 65: Preparation of compound 47

[0177] The compound 47 was prepared according to the procedure for compound 46 in Example 64, using methyl 1-cyclopropylisopropylcarbamate instead of methyl 1- cyclopropylallylcarbamate. MS (ESI): m / s [M+H] + = 489.

[0178] Example 66: Preparation of compound 48

[0179] The compound 48 was prepared according to the procedure for compound 46 in Example 64, using methyl 1-cyclopropylisopropylcarbamate instead of methyl 1- cyclopropylallylcarbamate. MS (ESI): m / s [M+H] + = 489.

[0180] Example 67: Preparation of compound 49

[0181] The compound 49 was prepared according to the procedure for compound 25 in Example 43, using M1 instead of M16. MS (ESI): m / s [M+H] + = 471.

[0182] Example 68: Preparation of compound 50

[0183] The compound 50 was prepared according to the procedure for compound 49 in Example 67, using methyl 1-cyclopropylisopropylcarbamate instead of methyl 1- cyclopropylallylcarbamate. MS (ESI): m / s [M+H] + = 471.

[0184] Example 69: Preparation of compound 51

[0185] The compound 51 was prepared according to the method for preparing the compound 49 of Example 67, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl R-1- cyclopropylisopropylcarbamate. MS (ESI): m / z [M+H] + = 471.

[0186] Example 70: Preparation of compound 52

[0187] The compound 52 was prepared according to the method for preparing the compound 1 of Example 19, by changing M1 to M16. MS (ESI): m / z [M+H] + = 515.

[0188] Example 71: Preparation of compound 53

[0189] The compound 53 was prepared according to the method for preparing the compound 52 of Example 70, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl S-1- cyclopropylisopropylcarbamate. MS (ESI): m / z [M+H] + = 515.

[0190] Example 72: Preparation of compound 54

[0191] The compound 54 was prepared according to the method for preparing the compound 52 of Example 70, by changing the methyl 1-cyclopropylisopropylcarbamate to methyl R-1- cyclopropylisopropylcarbamate. MS (ESI): m / z [M+H] + = 515.

[0192] Example 73: Preparation of compound 55

[0193] M16 compound 50g (179.0 mmol), methyl cyclopropylcarbamate 25.75 g (223.7 mmol), potassium carbonate 30.91 g (223.7 mol), ethylene glycol diethyl ether 500 ml, pyridine 30 ml were added into a 1000 ml three-necked flask, and the reaction was carried out under reflux for 30 h. After cooling to room temperature, the mixture was filtered, and the filter cake was dissolved in 100 ml of water, and the pH was adjusted to 5 with acetic acid. A solid was precipitated, which was filtered and dried under vacuum at 50-60 °C to obtain the intermediate Y (compound 127) 57.73 g in a yield of 89%, MS (ESI): m / z [M+H] + = 363.

[0194] Into a dry 1000ml three-necked flask, add acetonitrile 300ml, intermediate Y 50g (138.0mmol), stir to dissolve, then cool to 0-5°C, start to slowly add phosphorus oxychloride 63.5g (414.0mmol), after the addition is completed, warm to 40°C and keep for 5h, after the reaction is completed, slowly add water 10ml to hydrolyze, adjust the solution pH to 7-8 with 20% sodium hydroxide solution, concentrate the solution to dryness at 50°C under reduced pressure, obtain a residue, purify the residue by silica gel column, concentrate the effective fraction, dry at 40-45°C under reduced pressure, obtain compound 55 35.6g with a yield of 53%. MS (ESI): m / s [M+H] + = 487.

[0195] Example 74: Preparation of compound 56

[0196] Into a dry 1000ml three-necked flask, add acetonitrile 300ml, intermediate Y (prepared according to the method of Example 73) 50g (138.0mmol), stir to dissolve, then cool to 0-5°C, start to slowly add phosphorus oxychloride 63.5g (414.0mmol), after the addition is completed, warm to 40°C and keep for 5h, after the reaction is completed, slowly add water 10ml to hydrolyze, adjust the solution pH to 1-2 with 20% sodium hydroxide solution, concentrate the solution to dryness at 50°C under reduced pressure, obtain a residue, purify the residue by silica gel column, concentrate the effective fraction, dry at 40-45°C under reduced pressure, obtain compound 56 35.4g with a yield of 58%. MS (ESI): m / s [M+H] + = 443.

[0197] Example 75: Preparation of compound 57

[0198] Prepare compound 57 according to the method for preparing compound 55 in Example 73, with M16 changed to M1, MS (ESI): m / s [M+H] + = 491.

[0199] Example 76: Preparation of compound 58

[0200] Prepare compound 57 according to the method for preparing compound 56 in Example 74, with M16 changed to M1, MS (ESI): m / s [M+H] + = 447.

[0201] Example 77: Preparation of compound 59

[0202] Prepare compound 59 according to the method for preparing compound 55 in Example 73, with M16 changed to M4, MS (ESI): m / s [M+H] + = 507.

[0203] Example 78: Preparation of compound 60

[0204] The compound 60 was prepared according to the procedure described for compound 56 in example 74, by changing M16 to M4, MS (ESI): m / s [M+H] + = 463.

[0205] Example 79: Preparation of compound 61

[0206] The compound 61 was prepared according to the procedure described for compound 55 in example 73, by changing M16 to M13, MS (ESI): m / s [M+H] + = 541.

[0207] Example 80: Preparation of compound 62

[0208] The compound 62 was prepared according to the procedure described for compound 56 in example 74, by changing M16 to M13, MS (ESI): m / s [M+H] + = 497.

[0209] Example 81: Preparation of compound 63

[0210] The compound 63 was prepared according to the procedure described for compound 55 in example 73, by changing M16 to M14, MS (ESI): m / s [M+H] + = 523.

[0211] Example 82: Preparation of compound 64

[0212] The compound 64 was prepared according to the procedure described for compound 56 in example 74, by changing M16 to M14, MS (ESI): m / s [M+H] + = 479.

[0213] Example 83: Preparation of compound 65

[0214] The compound 65 was prepared according to the procedure described for compound 55 in example 73, by changing M16 to M15, MS (ESI): m / s [M+H] + = 505.

[0215] Example 84: Preparation of compound 66

[0216] The compound 66 was prepared according to the procedure described for compound 56 in example 74, by changing M16 to M15, MS (ESI): m / s [M+H] + = 461.

[0217] Example 85: Preparation of compound 67

[0218] Step 1: Preparation of chloromethyl ether intermediate

[0219] 250ml reaction bottle was added 100ml tetrahydrofuran, sodium hydroxide 4.37g (109.2mmol) and chlorobromomethane 56.5g (436.8mmol) was stirred and heated, compound 12820g (54.6mmol) was added to the reaction bottle, and the reaction was stirred at 60°C for 4h, the reaction was stopped, the solid in the reaction liquid was filtered, the filtrate was evaporated under reduced pressure at 60°C, the residue was purified by silica gel column, the effective fraction was concentrated, and dried under reduced pressure at 40-45°C to obtain chloromethyl ether intermediate 14.7g with a yield of 65%.

[0220] Step 2: Preparation of compound 67

[0221] A 50ml acetonitrile was taken in a 250ml reaction bottle, triethylamine 8.94g (88.5mmol) was added, and phosphoric acid 10.20g (88.5mmol) was stirred until dissolved, chloromethyl ether intermediate 14.7g (35.4mmol) was slowly added, and after the addition was completed, the reaction was carried out at 60°C for 6h, the reaction was stopped, and the solvent was evaporated under reduced pressure at 60°C, after evaporation, 50ml water was added and stirred, concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 1.5, 50ml (25ml x 2 times) ethyl acetate was added to extract the water layer, the water layer was removed, the ethyl acetate layer was washed with 20ml (10ml x 2 times) water, and the ethyl acetate layer was dried with anhydrous sodium sulfate, then the ethyl acetate was evaporated under reduced pressure at 50°C, 20ml methanol was added to the residue, and the pH was adjusted to 9.0 with saturated sodium hydroxide solution, then 60ml isopropyl alcohol was added, and the mixture was stirred at 0°C for 12h, then filtered, and the filter cake was washed with 25ml acetone to obtain white solid 13.43g with a yield of 73%, which was compound 67. MS (ESI): m / s [M+H] =521. +

[0222] Example 86: Preparation of compound 68

[0223] Step 1: Preparation of chloromethyl ether intermediate

[0224] Prepared according to the method of Example 85

[0225] Step 2: Preparation of compound 68

[0226] ​Into a 250 mL reaction flask, 50 mL of acetonitrile was taken, to this was added triethylamine 8.94 g (88.5 mmol), phosphoric acid 10.20 g (88.5 mmol) was stirred to dissolve, to this was slowly added chloromethyl ether intermediate 14.7 g (35.4 mmol), after completion of addition, the reaction was carried out at 60 °C for 6 h, the reaction was stopped, the solvent was distilled off under reduced pressure at 60 °C, after distillation, 50 mL of water was added and stirred, concentrated hydrochloric acid was added dropwise to adjust the pH to 1.5, 50 mL (25 mL x 2 times) of ethyl acetate was added to extract the aqueous layer, the aqueous layer was removed, the ethyl acetate layer was washed with 20 mL (10 mL x 2 times) of water, the ethyl acetate layer was dried over anhydrous sodium sulfate, then the ethyl acetate was distilled off under reduced pressure at 50 °C, the residue was purified by silica gel column, the effective fraction was concentrated, dried under reduced pressure at 40 °C to 45 °C, to obtain compound 68 10.44 g, yield 62%. MS (ESI): m / s [M+H] + = 477.

[0227] Example 87: Preparation of compound 69

[0228] The compound 69 was obtained by the same method as in the preparation of compound 67 in Example 85, by changing compound 128 to compound 127, MS (ESI): m / s [M+H] + = 517.

[0229] Example 88: Preparation of compound 70

[0230] The compound 70 was obtained by the same method as in the preparation of compound 68 in Example 86, by changing compound 128 to compound 127, MS (ESI): m / s [M+H] + = 473.

[0231] Example 89: Preparation of compound 71

[0232] The compound 71 was obtained by the same method as in the preparation of compound 67 in Example 85, by changing compound 128 to compound 129, MS (ESI): m / s [M+H] + = 537.

[0233] Example 90: Preparation of compound 72

[0234] The compound 72 was obtained by the same method as in the preparation of compound 68 in Example 86, by changing compound 128 to compound 129, MS (ESI): m / s [M+H] + = 493.

[0235] Example 91: Preparation of compound 73

[0236] The compound 73 was obtained by the same method as in the preparation of compound 67 in Example 85, by changing compound 128 to compound 130, MS (ESI): m / s [M+H]+ = 571.

[0237] Example 92: Preparation of compound 74

[0238] The compound 74 was obtained by the same method as the preparation of compound 68 in Example 86, using compound 128 instead of compound 130, MS (ESI): m / s [M+H]+ = 527. + = 527.

[0239] Example 93: Preparation of compound 75

[0240] The compound 75 was obtained by the same method as the preparation of compound 67 in Example 85, using compound 128 instead of compound 131, MS (ESI): m / s [M+H]+ = 553.

[0241] Example 94: Preparation of compound 76

[0242] The compound 76 was obtained by the same method as the preparation of compound 68 in Example 86, using compound 128 instead of compound 131, MS (ESI): m / s [M+H]+ = 509.

[0243] Example 95: Preparation of compound 77

[0244] The compound 77 was obtained by the same method as the preparation of compound 67 in Example 85, using compound 128 instead of compound 132, MS (ESI): m / s [M+H]+ = 535.

[0245] Example 96: Preparation of compound 78

[0246] The compound 78 was obtained by the same method as the preparation of compound 68 in Example 86, using compound 128 instead of compound 132, MS (ESI): m / s [M+H]+ = 491.

[0247] Example 97: Preparation of compound 79

[0248] The compound 79 was obtained by the same method as the preparation of compound 67 in Example 85, using compound 128 instead of compound 133, MS (ESI): m / s [M+H]+ = 517.

[0249] Example 98: Preparation of compound 80

[0250] The compound 80 was obtained by the same method as the preparation of compound 68 in Example 86, using compound 128 instead of compound 133, MS (ESI): m / s [M+H]+ = 473.

[0251] Example 99: Preparation of compound 81

[0252] Following the same procedure as described in Example 85 for the preparation of compound 67, except substituting compound 128 with compound 134, to afford compound 81, MS (ESI): m / s [M+H]+=521.

[0253] Example 100: Preparation of compound 82

[0254] Following the same procedure as described in Example 86 for the preparation of compound 68, except substituting compound 128 with compound 134, to afford compound 82, MS (ESI): m / s [M+H]+=477.

[0255] Example 101: Preparation of compound 83

[0256] Following the same procedure as described in Example 85 for the preparation of compound 67, except substituting compound 128 with compound 135, to afford compound 83, MS (ESI): m / s [M+H]+=537.

[0257] Example 102: Preparation of compound 84

[0258] Following the same procedure as described in Example 86 for the preparation of compound 68, except substituting compound 128 with compound 135, to afford compound 84, MS (ESI): m / s [M+H]+=493.

[0259] Example 103: Preparation of compound 85

[0260] Following the same procedure as described in Example 85 for the preparation of compound 67, except substituting compound 128 with compound 136, to afford compound 85, MS (ESI): m / s [M+H]+=571.

[0261] Example 104: Preparation of compound 86

[0262] Following the same procedure as described in Example 86 for the preparation of compound 68, except substituting compound 128 with compound 136, to afford compound 86, MS (ESI): m / s [M+H]+=527.

[0263] Example 105: Preparation of compound 87

[0264] Following the same procedure as described in Example 85 for the preparation of compound 67, except substituting compound 128 with compound 137, to afford compound 87, MS (ESI): m / s [M+H]+=553.

[0265] Example 106: Preparation of compound 88

[0266] Following the same procedure as described in Example 86 for the preparation of compound 68, except substituting compound 128 with compound 137, to afford compound 88, MS (ESI): m / s [M+H]+=509.

[0267] Example 107: Preparation of compound 89

[0268] The compound 89 was obtained by the same method described in Example 85 for the preparation of compound 67, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=535.

[0269] Example 108: Preparation of compound 90

[0270] The compound 90 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=491.

[0271] Example 109: Preparation of compound 91

[0272] The compound 91 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=501.

[0273] Example 110: Preparation of compound 92

[0274] The compound 92 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=501.

[0275] Example 111: Preparation of compound 93

[0276] The compound 93 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=501.

[0277] Example 112: Preparation of compound 94

[0278] The compound 94 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=505.

[0279] Example 113: Preparation of compound 95

[0280] The compound 95 was obtained by the same method described in Example 86 for the preparation of compound 68, using compound 128 instead of compound 67, MS (ESI): m / z [M+H]+=505.

[0281] Example 114: Preparation of compound 96

[0282] The preparation method of compound 68 of example 86, compound 128 was changed to compound 114, compound 96 was obtained, MS (ESI): m / s [M+H]+=505.

[0283] Example 115: Preparation of compound 97

[0284] The preparation method of compound 68 of example 86, compound 128 was changed to compound 124, compound 97 was obtained, MS (ESI): m / s [M+H]+=521.

[0285] Example 116: Preparation of compound 98

[0286] The preparation method of compound 68 of example 86, compound 128 was changed to compound 125, compound 98 was obtained, MS (ESI): m / s [M+H]+=521.

[0287] Example 117: Preparation of compound 99

[0288] The preparation method of compound 68 of example 86, compound 128 was changed to compound 126, compound 99 was obtained, MS (ESI): m / s [M+H]+=521.

[0289] Example 118: Preparation of compound 100

[0290] The preparation method of compound 68 of example 86, compound 128 was changed to compound 115, compound 100 was obtained, MS (ESI): m / s [M+H]+=555.

[0291] Example 119: Preparation of compound 101

[0292] The preparation method of compound 68 of example 86, compound 128 was changed to compound 116, compound 101 was obtained, MS (ESI): m / s [M+H]+=555.

[0293] Example 120: Preparation of compound 102

[0294] The preparation method of compound 68 of example 86, compound 128 was changed to compound 117, compound 102 was obtained, MS (ESI): m / s [M+H]+=555.

[0295] Example 121: Preparation of compound 103

[0296] The preparation method of compound 68 of example 86, compound 128 was changed to compound 118, compound 103 was obtained, MS (ESI): m / s [M+H]+=537.

[0297] Example 122: Preparation of compound 104

[0298] The compound 104 was obtained by the same method as the preparation of compound 68 in example 86, using compound 128 instead of compound 119, MS (ESI): m / z [M+H]+= 537.

[0299] Example 123: Preparation of compound 105

[0300] The compound 105 was obtained by the same method as the preparation of compound 68 in example 86, using compound 128 instead of compound 120, MS (ESI): m / z [M+H]+= 537.

[0301] Example 124: Preparation of compound 106

[0302] The compound 106 was obtained by the same method as the preparation of compound 68 in example 86, using compound 128 instead of compound 121, MS (ESI): m / z [M+H]+= 519.

[0303] Example 125: Preparation of compound 107

[0304] The compound 107 was obtained by the same method as the preparation of compound 68 in example 86, using compound 128 instead of compound 122, MS (ESI): m / z [M+H]+= 519.

[0305] Example 126: Preparation of compound 108

[0306] The compound 108 was obtained by the same method as the preparation of compound 68 in example 86, using compound 128 instead of compound 123, MS (ESI): m / z [M+H]+= 519.

[0307] Example 127: Preparation of compound 109

[0308] The compound 109 was obtained by the same method as the preparation of the intermediate in the first step of compound 1 in example 19, using M1 instead of 16, MS (ESI): m / z [M+H]+= 391.

[0309] Example 128: Preparation of compound 110

[0310] The compound 110 was obtained by the same method as the preparation of compound 109 in example 127, using methyl 1-cyclopropylisopropylcarbamate instead of methyl S-1- cyclopropylisopropylcarbamate, MS (ESI): m / z [M+H]+= 391. +

[0311] Example 129: Preparation of compound 111 ​

[0312] Compound 109 using the similar method for preparing Compound 109 in Example 127 except for using R-1-cyclopropylisopropylammonium methyl carbonate instead of 1- cyclopropylisopropylammonium methyl carbonate to give Compound 111, MS (ESI): m / z [M+H]+ = 391. +

[0313] Example 130: Preparation of Compound 112

[0314] Compound 112 using the similar method for preparing Compound 1 in Example 19 except for using Ml instead of M2 to give Compound 112, MS (ESI): m / z [M+H]+ = 395. +

[0315] Example 131: Preparation of Compound 113

[0316] Compound 113 using the similar method for preparing Compound 112 in Example 130 except for using S-1-cyclopropylisopropylammonium methyl carbonate instead of 1- cyclopropylisopropylammonium methyl carbonate to give Compound 113, MS (ESI): m / z [M+H]+ = 395. +

[0317] Example 132: Preparation of Compound 114

[0318] Compound 114 using the similar method for preparing Compound 112 in Example 130 except for using R-1-cyclopropylisopropylammonium methyl carbonate instead of 1- cyclopropylisopropylammonium methyl carbonate to give Compound 114, MS (ESI): m / z [M+H]+ = 395. +

[0319] Example 133: Preparation of Compound 115

[0320] Compound 115 using the similar method for preparing Compound 1 in Example 19 except for using Ml instead of M2 to give Compound 115, MS (ESI): m / z [M+H]+ = 445.

[0321] Example 134: Preparation of Compound 116

[0322] Compound 116 using the similar method for preparing Compound 115 in Example 133 except for using S-1-cyclopropylisopropylammonium methyl carbonate instead of 1- cyclopropylisopropylammonium methyl carbonate to give Compound 116, MS (ESI): m / z [M+H]+ = 445. +

[0323] Example 135: Preparation of Compound 117

[0324] Compound 117 using the similar method for preparing Compound 115 in Example 133 except for using R-1-cyclopropylisopropylammonium methyl carbonate instead of 1- cyclopropylisopropylammonium methyl carbonate to give Compound 117, MS (ESI): m / z [M+H]+ = 445.​​​​​+ = 445.

[0325] Example 136: Preparation of Compound 118

[0326] The compound 118 was obtained by the same method as in the preparation of the intermediate of the first step of Compound 1 in Example 19, changing M1 to 14, MS (ESI): m / z [M+H]+= 427.

[0327] Example 137: Preparation of Compound 119

[0328] The compound 427 was obtained by the same method as in the preparation of Compound 118 in Example 136, changing methyl 1-cyclopropylisopropylcarbamate to methyl S-1- cyclopropylisopropylcarbamate, MS (ESI): m / z [M+H]+= 427. + = 391.

[0329] Example 138: Preparation of Compound 120

[0330] The compound 120 was obtained by the same method as in the preparation of Compound 118 in Example 136, changing methyl 1-cyclopropylisopropylcarbamate to methyl R-1- cyclopropylisopropylcarbamate, MS (ESI): m / z [M+H]+= 427. + = 427.

[0331] Example 139: Preparation of Compound 121

[0332] The compound 121 was obtained by the same method as in the preparation of the intermediate of the first step of Compound 1 in Example 19, changing M1 to 15, MS (ESI): m / z [M+H]+= 409.

[0333] Example 140: Preparation of Compound 122

[0334] The compound 122 was obtained by the same method as in the preparation of Compound 121 in Example 139, changing methyl 1-cyclopropylisopropylcarbamate to methyl S-1- cyclopropylisopropylcarbamate, MS (ESI): m / z [M+H]+= 409. + = 409.

[0335] Example 141: Preparation of Compound 123

[0336] The compound 123 was obtained by the same method as in the preparation of Compound 121 in Example 139, changing methyl 1-cyclopropylisopropylcarbamate to methyl R-1- cyclopropylisopropylcarbamate, MS (ESI): m / z [M+H]+= 409. + = 409.

[0337] Example 142: Preparation of Compound 124

[0338] The preparation method of the intermediate in the first step of compound 1 in example 19 is adopted, M1 is changed into M4, compound 124 is obtained, MS (ESI): m / s [M+H]+=411.

[0339] Example 143: Preparation of compound 125

[0340] The preparation method of compound 124 in example 142 is adopted, 1-cyclopropyl isopropyl carbamic acid methyl ester is changed into S-1-cyclopropyl isopropyl carbamic acid methyl ester, compound 125 is obtained, MS (ESI): m / s [M+H]+=411. +

[0341] Example 144: Preparation of compound 126

[0342] The preparation method of compound 124 in example 142 is adopted, 1-cyclopropyl isopropyl carbamic acid methyl ester is changed into R-1-cyclopropyl isopropyl carbamic acid methyl ester, compound 126 is obtained, MS (ESI): m / s [M+H]+=411. +

[0343] Example 145: Preparation of compound 127

[0344] The preparation method of the intermediate in the first step of compound 55 in example 73 is adopted, compound 127 is obtained, MS (ESI): m / s [M+H]+=363. +

[0345] Example 146: Preparation of compound 128

[0346] The preparation method of the intermediate in the first step of compound 55 in example 73 is adopted, M16 is changed into M1, compound 128 is obtained, MS (ESI): m / s [M+H]+=367.

[0347] Example 147: Preparation of compound 129

[0348] The preparation method of the intermediate in the first step of compound 55 in example 73 is adopted, M16 is changed into M4, compound 129 is obtained, MS (ESI): m / s [M+H]+=383.

[0349] Example 148: Preparation of compound 130

[0350] The preparation method of the intermediate in the first step of compound 55 in example 73 is adopted, M16 is changed into M13, compound 130 is obtained, MS (ESI): m / s [M+H]+=417.

[0351] Example 149: Preparation of compound 131

[0352] ​​​The compound 131 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M14, MS (ESI): m / s [M+H]+= 399.

[0353] Example 150: Preparation of compound 132

[0354] The compound 132 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M15, MS (ESI): m / s [M+H]+= 381.

[0355] Example 151: Preparation of compound 133

[0356] The compound 133 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M17, MS (ESI): m / s [M+H]+= 363.

[0357] Example 152: Preparation of compound 134

[0358] The compound 134 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M6, MS (ESI): m / s [M+H]+= 367.

[0359] Example 153: Preparation of compound 135

[0360] The compound 135 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M8, MS (ESI): m / s [M+H]+= 383.

[0361] Example 154: Preparation of compound 136

[0362] The compound 136 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M10, MS (ESI): m / s [M+H]+= 417.

[0363] Example 155: Preparation of compound 137

[0364] The compound 137 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M11, MS (ESI): m / s [M+H]+= 399.

[0365] Example 156: Preparation of compound 138

[0366] The compound 138 was obtained using the same method as the preparation of the intermediate in the first step of compound 55 in example 73, by changing M16 to M12, MS (ESI): m / s [M+H]+= 381.

[0367] Example 157: Preparation of compound 139

[0368] The compound 139 was obtained by the same method as described in the preparation of the intermediate of compound 55 in example 73, except that M16 was replaced by M18, MS (ESI): m / z [M+H]+=428.

[0369] Example 158: Preparation of compound 140

[0370] The compound 140 was obtained by the same method as described in the preparation of compound 140 in example 158, except that compound 56 was replaced by compound 58, and the molar ratio of the raw materials was unchanged.

[0371] Example 159: Preparation of compound 141

[0372] The compound 141 was obtained by the same method as described in the preparation of compound 140 in example 158, except that compound 56 was replaced by compound 58, and the molar ratio of the raw materials was unchanged.

[0373] Example 160: Preparation of compound 142

[0374] The compound 142 was obtained by the same method as described in the preparation of compound 140 in example 158, except that compound 56 was replaced by compound 60, and the molar ratio of the raw materials was unchanged.

[0375] Example 161: Preparation of compound 143

[0376] The compound 143 was obtained by the same method as described in the preparation of compound 140 in example 158, except that compound 56 was replaced by compound 62, and the molar ratio of the raw materials was unchanged.

[0377] Example 162: Preparation of compound 144

[0378] The compound 144 was obtained by the same method as described in the preparation of compound 144 in example 162, except that compound 56 was replaced by compound 58, and the molar ratio of the raw materials was unchanged.

[0379] Example 163: Preparation of compound 145

[0380] The compound 145 was obtained by the same method as described in the preparation of compound 144 in example 162, except that compound 56 was replaced by compound 58, and the molar ratio of the raw materials was unchanged.

[0381] Example 164: Preparation of compound 146

[0382] The compound 146 was prepared according to the method for preparing the compound 144 in Example 162, with the exception that the compound 56 was replaced by the compound 60, and the molar ratio of the feed was unchanged.

[0383] Example 165: Preparation of compound 147

[0384] The compound 147 was prepared according to the method for preparing the compound 146 in Example 162, with the exception that the compound 56 was replaced by the compound 62, and the molar ratio of the feed was unchanged.

[0385] Example 166: Preparation of compound 148

[0386] The compound 148 was prepared according to the method for preparing the compound 148 in Example 166, with the exception that the compound 56 was replaced by the compound 58, and the molar ratio of the feed was unchanged.

[0387] Example 167: Preparation of compound 149

[0388] The compound 149 was prepared according to the method for preparing the compound 148 in Example 166, with the exception that the compound 56 was replaced by the compound 60, and the molar ratio of the feed was unchanged.

[0389] Example 168: Preparation of compound 150

[0390] The compound 150 was prepared according to the method for preparing the compound 148 in Example 166, with the exception that the compound 56 was replaced by the compound 62, and the molar ratio of the feed was unchanged.

[0391] Example 169: Preparation of compound 151

[0392] The compound 151 was prepared according to the method for preparing the compound 148 in Example 166, with the exception that the compound 56 was replaced by the compound 62, and the molar ratio of the feed was unchanged.

[0393] Example 170: Preparation of compound 152

[0394] The compound 152 was prepared according to the method for preparing the compound 148 in Example 166, with the exception that the compound 56 was replaced by the compound 49, and the molar ratio of the feed was unchanged.

[0395] Example 171: Preparation of compound 1 injection

[0396] Formulation composition: compound 10.4 g, sodium chloride 18 g, water for injection 2000 mL.

[0397] Preparation method:

[0398] (1) Take 1500 mL of water for injection, add compound 10.4 g and sodium chloride 18 g, stir until dissolved, adjust the pH of the solution to 4-9 with a pH adjuster, pre-filter through a titanium rod filter to obtain a concentrated solution;

[0399] (2) Add water for injection to the concentrated solution in step (1) to the full amount, stir well, and filter through two 0.22 um polyether sulfone filter cartridges to obtain an intermediate;

[0400] (3) After determining the content of the intermediate, it is filled, capped, and packaged to obtain the product.

[0401] Example 172: Preparation of Compound 52 lyophilized powder

[0402] Formulation composition: compound 5210 g, mannitol 10 g, and water for injection 1000 mL.

[0403] The preparation process is as follows:

[0404] (1) Take 70% by volume of water for injection, add compound 5210 g and mannitol 10 g, stir until dissolved, to obtain a concentrated solution;

[0405] (2) Adjust the pH of the above concentrated solution to 4.0-9.0 with a pH adjuster under stirring, pre-filter through a titanium rod filter to obtain solution 1;

[0406] (3) Filter solution 1 in step (2) through two 0.22 um polyether sulfone filter cartridges to obtain solution 2, fill, semi-press the plug, and obtain intermediate 1;

[0407] (4) Freeze-dry the intermediate 1 using the following program:

[0408] (a) Set the temperature to -45℃ to -40℃, pre-freeze for 4.0 h;

[0409] (b) Increase the temperature to -20℃ to -10℃, sublimate at a vacuum degree of 1-10 Pa for 4.0 h;

[0410] (c) Increase the temperature to -10℃ to -0℃, sublimate at a vacuum degree of 1-10 Pa for 4.0 h;

[0411] (d) Increase the temperature to 0℃ to 5℃, sublimate at a vacuum degree of 1-10 Pa for 2.0 h;

[0412] (e) warming to a temperature of 15-25℃ and a vacuum of 1-10 Pa for 2.0 h;

[0413] After the holding, the plug is pressed, the box is taken out, and the cap is tied, so as to obtain the freeze-dried powder injection of compound 52.

[0414] Example 173: Comparison of diuretic effect

[0415] SD male rats (weight 270±20g) are randomly divided into groups, and each group is given 30mL / kg of normal saline by gavage. After the normal saline is given by gavage, each group is given one drug (10mg / kg) by gavage except the blank control group, and 4h urine collection is performed, and the results are shown in Table 2:

[0416] Table 2, comparison of urine output of different compounds

[0417] The diuretic effect experiment results show that the compound of the present application has better diuretic effect compared with the control compound, and has better drug-making advantages.

[0418] Example 174: Pharmacokinetic study

[0419] 1. Test dose

[0420] SD rats are respectively given 10mg / kg by single tail intravenous injection (i.v.).

[0421] 2. Test animals

[0422] SD rats are taken, the weight is 200±10g, half male and half female, and are randomly divided into groups, 6 rats in each group, half male and half female. An environmental adaptation period of 2-4 days is given before the experiment.

[0423] 3. Test sample

[0424] The compound of the present application.

[0425] 4. Experimental process

[0426] The test group rats were fasted for 8-12 hours, then each group was given 10 mg / kg by i.v. administration. The blood was collected from the orbital venous plexus of the rats before administration and 4 min, 10 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 12 h and 24 h after administration, about 0.1 mL to 0.2 mL of the blood was collected into a blood collection tube, and 20 μL of 60 mg / mL EDTA disodium (prepared with normal saline) was added to the blood collection tube in advance. After centrifugation of the whole blood at 8000 rpm for 5 min, 50 μL of the upper plasma was transferred, 500 μL of protein precipitation agent was added, and the protein was precipitated by oscillation for 3 min. After two times of centrifugation (18000 rpm for 10 min), 100 μL of the supernatant was transferred to a sample injection bottle, and 5 μL was injected for analysis. The concentration of the active metabolite drug in the plasma was determined by LC-MS / MS.

[0427] The measured plasma drug concentration over time was calculated by fitting using Phoenix Winnolin 6.3, the model was selected as NAC and Toolbox→NAC model, and the weight coefficient was selected as 1 / Y. The results are shown in Table 3.

[0428] Table 3 Pharmacokinetic half-life results of the compound of the present application and the control compound

[0429] The results show that the pharmacokinetic half-life of the compound of the present application is significantly better than that of the control compound, indicating that the compound of the present application has a long pharmacodynamic effect and good drug-making advantages.

[0430] Example 175: Continuous 2-week repeated dose toxicity study of SD rats injected with the compound of the present application via the tail vein

[0431] SD rats were taken, half male and half female, and divided into solvent, control compound, low-dose compound of the present application (50 mg / kg), medium-dose compound of the present application (100 mg / kg), and high-dose compound of the present application (200 mg / kg) groups. The rats were given 20 mL / kg of the compound by tail vein injection once a day, 7 days a week, and continuously for 2 weeks. The drug toxicity was observed.

[0432] The administered compounds are as follows

[0433] Compound 1-24, compound 34-36, compound 40-45, compound 52-55, compound 57, compound 59, compound 61, compound 63, compound 65, compound 67, compound 69, compound 71, compound 73, compound 75, compound 79, compound 81, compound 83, compound 85, compound 87, compound 89, compound 91, compound 109-140, compound 144, compound 148.

[0434] The results show that the SD rats are continuously injected with the compound of the present application through the tail vein for 2 weeks, and no obvious accumulation of the drug in the SD rats is found. After 2 weeks of drug withdrawal, the drug can be completely cleared in the body. It can cause increased urination and electrolyte disturbance in animals, which can recover after 2 weeks of drug withdrawal. The no-observed-adverse-effect level (NOAEL) is 60 mg / kg, and no serious adverse reactions and liver and kidney damage are found in animals.

[0435] Example 176: Activity study of the compound of the present application on a rabbit intracranial hypertension model induced by nitroglycerin

[0436] Male experimental rabbits are grouped according to body weight, and are divided into the following groups: normal control group, model control group, mannitol group (1000 mg / kg), control compound group (10 mg / kg), and compound of the present application group (10 mg / kg), with 4 rabbits in each group. After anesthesia, the animals in each group are fixed, and the normal control group is intravenously injected with 0.9% sodium chloride injection 5 mL / kg. The remaining groups are first continuously intravenously infused with nitroglycerin (0.04 mg / kg / min) for 10 min for modeling. Except for the model control group, the remaining groups are then intravenously injected with the corresponding drugs. The mannitol injection is an aqueous solution with a concentration of 20% (weight ratio), and the control compound and the compound of the present application are both prepared into 10 mg / ml injection solutions with physiological saline (i.e., 0.9% sodium chloride injection). The animals are administered according to their body weight, and the specific dosages are as follows: the mannitol group is administered at a dosage of 1000 mg / kg, the control compound group is administered at a dosage of 10 mg / kg, and the compound of the present application group is administered at a dosage of 10 mg / kg. The intracranial pressure of the experimental rabbits is detected before modeling (before intravenous infusion of nitroglycerin), after modeling (10 min after intravenous infusion of nitroglycerin), 10 min, 20 min, 30 min, 60 min, 90 min, 120 min, 150 min, and 180 min after administration. The results are shown in Table 4.

[0437] Table 4 Effect of the compound on the intracranial pressure reduction percentage of the experimental rabbit intracranial hypertension model induced by nitroglycerin

[0438] Example 176: Activity study of the compound of the present application on a rabbit intracranial hypertension model induced by nitroglycerin

[0439] The experimental rabbits were randomly grouped according to gender and weight, and were respectively normal control group, model control group, mannitol injection group, compound of the present application group, and combined administration group. The normal control group was intravenously injected with 0.9% sodium chloride injection 5 mL / kg, and the rest of the animals were all subdurally injected with 0.9% sodium chloride injection 1 μL containing collagenase IV 0.5 μg / μL to make a model. Except that the model control group was not given drug treatment, the rest of the groups were respectively intravenously injected with corresponding drugs. The mannitol injection used an aqueous solution with a concentration of 20% (weight ratio), and the compound of the present application all used 0.9% sodium chloride injection to prepare an injection with a concentration of 10 mg / ml. The animals were administered according to the animal weight, and the specific administration dose was: the administration dose of the mannitol group was 1000 mg / kg, the administration dose of the compound of the present application group was all 3.0 mg / kg, and the administration dose of the combined administration group was 1000 mg / kg of mannitol injection plus 3.0 mg / kg of the compound of the present application. The administration speed was 6 mL / min, and the animals were treated at the time points of 24 h, 48 h and 72 h after modeling according to the administration frequency set in the experiment. The animals were sacrificed after femoral artery blood sampling under propofol emulsion anesthesia, and the brain lesions around were immediately weighed, dried in an incubator, and then weighed again to calculate the brain water content. The results are shown in Table 5.

[0440] Table 5 Effect of the compound of the present application on brain water content of the collagenase IV-induced experimental rabbit brain hemorrhage model

[0441] The experimental results show that the compound of the present application can obviously reduce the increase of brain water content caused by experimental rabbit brain hemorrhage, and the activity of reducing brain water content is better than that of mannitol injection and the control compound.

[0442] Example 177: Study on the inhibitory activity of the compound of the present application on Na + , K + , Cl － pump

[0443] The activity of the control compound and the compound of the present application in a series of concentrations on the Na + -K + -2Cl - pump transport model of pig kidney was detected. The rubidium ion concentration in each group of buffers was detected by atomic absorption spectrometry, the activity of each test / control on Na + -K + -2Cl - pump was calculated according to the original concentration of RbCl, and the activity was expressed as half effective concentration (EC50).

[0444] Table 6 Activity of the compound on Na + -K+ -2Cl - Pump activity

[0445] The results show that the control compounds and the compounds of the present application have different degrees of inhibitory activity on Na + -K + -2Cl - Pump activity, and the compounds of the present application are superior to the control compounds.

[0446] The above-described examples only express some specific embodiments of the present application, which are described in more detail and in more detail, but cannot be understood as limiting the scope of the patent of the present application. It should be noted that for ordinary skilled in the art, without departing from the concept of the present application, a number of modifications and improvements can be made, which are within the scope of protection of the present application. Therefore, the scope of protection of the patent of the present application should be subject to the appended claims.

Claims

A sulfonamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof, having a structure represented by Formula I: wherein X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl; R1is cyclopropyl or R2is hydrogen, wherein, PE is or PE is absent, R3and R4are independently hydrogen or a metal element, the metal element includes an alkali metal or an alkaline earth metal; when R3or R4is hydrogen, R3or R4may be salified with an organic base or a basic amino acid; Y is an O atom or Y is absent, Z is CH2or Z is absent; when R2 is and PE is when Y and Z are both absent, the O atom in the group R2O in formula I is directly connected to PE; when R2 is and PE is when Y is O, Z is CH2. The sulfamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof according to claim 1, wherein The pharmaceutical salt includes a salt formed with an inorganic / organic base. The sulfamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof according to claim 2, wherein The organic base is selected from trimethylamine, meglumine or diisopropyl ethylamine. The sulfamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof according to claim 1, wherein The pharmaceutical salt includes a metal salt or a basic amino acid salt formed with a basic amino acid. The sulfonamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof according to claim 4, characterized in that, The metal salt is selected from an alkali metal, an alkaline earth metal, the alkali metal is selected from a sodium salt or a potassium salt, the alkaline earth metal is selected from a calcium salt, a magnesium salt or a barium salt, the basic amino acid salt is selected from a lysine salt, an arginine salt. The sulfamide compound or a pharmaceutically acceptable salt thereof according to Claim 1, wherein selected from the group consisting of: A pharmaceutical composition comprising a therapeutic amount of the sulfamide compound and / or the pharmaceutical salt thereof according to any one of claims 1-5 and other pharmaceutically acceptable excipients. Use of the sulfamide compound or the pharmaceutical salt thereof or the enantiomer thereof according to any one of claims 1-5 in the preparation of a diuretic drug. Use of the sulfamide compound or the pharmaceutical salt thereof or the enantiomer thereof according to any one of claims 1-5 in the preparation of an anti-cerebral edema drug.

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