Sulfonamide compound for treatment, enantiomer of sulfonamide compound, preparation method of enantiomer and application of enantiomer

Abstract

The invention relates to the technical field of biological medicines, in particular to a sulfonamide compound for treatment and an enantiomer thereof as well as a preparation method and application thereof, and has the beneficial effects that the provided sulfonamide compound and the enantiomer thereof have the characteristics of strong stability, longer action effect, better drug effect and the like; the compound is a better diuretic and new anti-encephaledema medicine.

Description

Technical Field

[0001] The present invention relates to the field of biomedicine technology, and in particular to a sulfonamide compound and its enantiomer for treatment, as well as a preparation method and use thereof. Background Art

[0002] Torsemide, whose chemical name is l-[4-(3-methylphenyl)aminopyridin-3-yl]sulfonyl-3-isopropylurea, is a new generation of highly effective loop diuretics. It is mainly used in the cardiovascular department to treat congestive heart failure, hypertension and other diseases. In clinical practice, torsemide has a wide range of indications, rapid, strong and long-lasting diuretic effects, and a low incidence of adverse reactions. It is a commonly used highly effective diuretic in clinical practice today, which can inhibit the reabsorption of sodium and chloride, and has diuretic and natriuretic effects.

[0003] Currently, the marketed dosage forms of torasemide include injection, tablets and capsules. Since torasemide is almost insoluble in water, a large amount of co-solvent needs to be added during the preparation of injection, which poses a great hidden danger to the safety of patients' medication.

[0004] Chinese patent CN110606860A discloses a pyridine sulfonamide phosphate compound, its preparation method and its use. The method utilizes the active metabolite of torsemide in vivo for phosphate esterification to achieve the purpose of improving water solubility. Its in vivo effect is basically consistent with torsemide.

[0005] It was found through searching that torasemide has the disadvantages of having a half-life of about 4 hours in vivo, a short duration of action in vivo, and poor water solubility. Our company has been continuously researching this type of drug and surprisingly found that the compound of the present invention has the characteristics of longer effect and better efficacy, and is superior to torasemide in anti-cerebral edema and diuretic effects, and is a better diuretic and anti-cerebral edema new drug. Summary of the invention

[0006] The object of the present invention is to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer, the structure of which is shown in Formula I: Ⅰ wherein X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl; R 1 is cyclopropyl or ; R 2 For hydrogen, .

[0007] When R 2 for When Y and Z are both absent, O is directly connected to P; when Y is O, Z is CH 2; When R is hydrogen, it can form a salt with an organic base or a basic amino acid; the organic base includes trimethylamine, meglumine or diisopropylethylamine, and the basic amino acid includes lysine or arginine.

[0008] The present invention also aims to provide a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer.

[0009] Preferably, the sulfonamide compound or its pharmaceutically acceptable salt and pharmaceutically acceptable stereoisomer are selected from the following compounds:

[0010]

[0011]

[0012]

[0013]

[0014]

[0015]

[0016]

[0017]

[0018]

[0019]

[0020]

[0021]

[0022]

[0023]

[0024]

[0025]

[0026]

[0027] Control compound

[0028]

[0029]

[0030] The second aspect of the present invention is to provide a method for preparing a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer thereof, comprising the following steps: Preparation of compound M1: 4-chloropyridine-3-sulfonamide, 2-fluoro-4-aminophenol, triethylamine and n-butanol were added into a three-necked flask, the temperature was raised to reflux for reaction, the reaction was carried out for 20 hours, the solvent was evaporated under reduced pressure, dichloromethane was added to the residue for extraction, the residue was filtered, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain M1.

[0031]

[0032] Preparation of compound M2: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-fluoro-5-aminophenol.

[0033]

[0034] Preparation of compound M3: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-amino-4-fluorophenol.

[0035]

[0036] Preparation of compound M4: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-chloro-4-aminophenol.

[0037]

[0038] Preparation of compound M5: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-amino-4-chlorophenol.

[0039]

[0040] Preparation of compound M6: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-fluoro-4-aminophenol.

[0041]

[0042] Preparation of compound M7: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-amino-4-fluorophenol.

[0043]

[0044] Preparation of compound M8: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-chloro-4-aminophenol.

[0045]

[0046] Preparation of compound M9: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-amino-4-bromophenol.

[0047]

[0048] Preparation of compound M10: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-trifluoromethyl-4-aminophenol.

[0049]

[0050] Preparation of compound M11: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-difluoromethyl-4-aminophenol.

[0051]

[0052] Preparation of compound M12: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 3-fluoromethyl-4-aminophenol.

[0053]

[0054] Preparation of compound M13: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-trifluoromethyl-4-aminophenol.

[0055]

[0056] Preparation of compound M14: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-difluoromethyl-4-aminophenol.

[0057]

[0058] Preparation of compound M15: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol is replaced by 2-fluoromethyl-4-aminophenol.

[0059]

[0060] Preparation of compound M16: Same as the preparation of compound M1, except that 2-fluoro-4-aminophenol was replaced by 2-methyl-4-aminophenol

[0061] Preparation of compound M17: Same as the preparation method of compound M1, except that 2-fluoro-4-aminophenol was replaced by 3-methyl-4-aminophenol

[0062] Preparation of compound M18: Same as the preparation of compound M1, except that 2-fluoro-4-aminophenol was replaced by 3-bromo-4-aminophenol

[0063] Preparation of the compounds of the present invention The intermediates M1, M2, M4, M8, M10, M11, M12, M13, M14, M15, M16, M17, and M18 were added to a three-necked flask with cyclopropylcarbamic acid methyl ester or 1-cyclopropylisopropylcarbamic acid methyl ester or R-1-cyclopropylisopropylcarbamic acid methyl ester or S-1-cyclopropylisopropylcarbamic acid methyl ester, potassium carbonate, ethylene glycol diethyl ether, and pyridine, respectively, and refluxed. After the reaction was completed, it was cooled to room temperature and filtered, and the filter cake was dissolved in water, and the pH was adjusted with acetic acid. Solids precipitated and filtered to obtain compounds 109 to 139.

[0064] The corresponding compounds 109 to 139 are then reacted with phosphorus oxychloride to obtain corresponding phosphate compounds, and the corresponding phosphate compounds are then salted with sodium hydroxide or arginine or meglumine or choline to obtain corresponding compounds 1 to 66.

[0065] Compounds 109 to 139 were further treated with chlorobromomethane and subjected to chloromethylation, phosphorylation and salt formation to obtain compounds 67 to 108.

[0066] The third aspect of the present invention is to provide a pharmaceutical composition comprising a therapeutic amount of a sulfonamide compound or a pharmaceutically acceptable salt or pharmaceutically acceptable stereoisomer thereof and other pharmaceutically acceptable excipients.

[0067] The carrier refers to a conventional carrier in the pharmaceutical field, such as a diluent, an excipient, a binder, a filler, a disintegrant, a flavoring agent, and a sweetener.

[0068] Various dosage forms of the composition of the present invention can be prepared by conventional methods in the medical field, wherein the content of the active ingredient is 0.10% to 99.5% (by weight).

[0069] The dosage of the present invention can be varied according to the route of administration, the patient's age, body weight, the type and severity of the disease being treated, etc. The daily dose is 0.001-30 mg / kg body weight (oral) or 0.005-40 mg / kg body weight (injection).

[0070] The fourth aspect of the present invention provides use of a sulfonamide compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable stereoisomer thereof in the preparation of a diuretic drug.

[0071] The beneficial effect of the present invention is that the provided sulfonamide compound or its pharmaceutically acceptable salt and pharmaceutically acceptable stereoisomer have the characteristics of high stability, longer action time, better drug efficacy, etc., and is a new type of diuretic. DETAILED DESCRIPTION

[0072] The present invention is further described in detail below with reference to the embodiments, but is not limited thereto.

[0073] Example 1: Preparation of Compound M1 4-Chloropyridine-3-sulfonamide 50g (259.6mmol), 2-fluoro-4-aminophenol 33.0g (259.6mmol), triethylamine 26.2g (259.6mmol), and n-butanol 250ml were added to a 500ml three-necked flask, and the temperature was raised to reflux for reaction. The reaction was continued for 20h, and the solvent was evaporated at 60℃ under reduced pressure. 200ml of dichloromethane was added to the residue for extraction, filtered, and dried over anhydrous sodium sulfate. The solvent was evaporated at 40℃ under reduced pressure to obtain 61.9g of M1 compound with a yield of 84.2%. MS (ESI): m / s[M+H] + =284.

[0074] Example 2: Preparation of M2 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 3-fluoro-5-aminophenol. MS (ESI): m / s [M+H] + =284.

[0075] Example 3: Preparation of M3 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 2-amino-4-fluorophenol. MS (ESI): m / s [M+H] + =284.

[0076] Example 4: Preparation of M4 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 2-chloro-4-aminophenol. MS (ESI): m / s [M+H] + =301.

[0077] Example 5: Preparation of Compound M5 The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 2-amino-4-chlorophenol. MS (ESI): m / s [M+H] + =301.

[0078] Example 6: Preparation of M6 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 3-fluoro-4-aminophenol. MS (ESI): m / s [M+H] + =284.

[0079] Example 7: Preparation of M7 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 3-amino-4-fluorophenol. MS (ESI): m / s [M+H] + =284.

[0080] Example 8: Preparation of M8 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 3-chloro-4-aminophenol. MS (ESI): m / s [M+H] + =301.

[0081] Example 9: Preparation of M9 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 2-amino-4-bromophenol. MS (ESI): m / s [M+H] + =345.

[0082] Example 10: Preparation of M10 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 3-trifluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =334.

[0083] Example 11: Preparation of M11 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 3-difluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =316.

[0084] Example 12: Preparation of M12 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 3-fluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =298.

[0085] Example 13: Preparation of M13 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 2-trifluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =334.

[0086] Example 14: Preparation of Compound M14 The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 2-difluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =316.

[0087] Example 15: Preparation of M15 compound The same preparation method as Example 1 M1 compound was used, except that 2-fluoro-4-aminophenol was replaced with 2-fluoromethyl-4-aminophenol. MS (ESI): m / s [M+H] + =298.

[0088] Example 16: Preparation of M16 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 2-methyl-4-aminophenol. MS (ESI): m / s [M+H] + =280.

[0089] Example 17: Preparation of M17 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 3-methyl-4-aminophenol. MS (ESI): m / s [M+H] + =280.

[0090] Example 18: Preparation of M18 compound The same preparation method as Example 1 M1 was used, except that 2-fluoro-4-aminophenol was replaced with 3-bromo-4-aminophenol. MS (ESI): m / s [M+H] + =345.

[0091] Example 19: Preparation of Compound 1 Add 50g (176.5mmol) of M1 compound, 31.58g (220.6mmol) of 1-cyclopropylisopropylcarbamate, 30.48g (220.6mol) of potassium carbonate, 500ml of ethylene glycol diethyl ether, and 30ml of pyridine into a 1000ml three-necked flask and reflux for 30h. Cool to room temperature, filter, dissolve the filter cake in 100ml of water, adjust the pH to 5 with acetic acid, filter solids precipitate, and dry under vacuum at 50℃~60℃ to obtain 59.87g of intermediate (Compound 112), with a yield of 86%, MS (ESI): m / s[M+H] +=395.

[0092] Add 300 ml of acetonitrile and 50 g (126.7 mmol) of intermediate 1 to a dry 1000 ml three-necked flask, stir to dissolve, then cool to 0°C to 5°C, slowly add 58.3 g (380.1 mmol) of phosphorus oxychloride, and after the addition is complete, heat to 40°C and keep warm for 5 hours. After the reaction is complete, slowly add 10 ml of water for hydrolysis, adjust the pH of the solution to 7-8 with 20% sodium hydroxide solution, and concentrate the solution at 50°C to dryness to obtain a residue. The residue is purified by silica gel column, the effective fraction is concentrated, and dried at 40°C to 45°C under reduced pressure to obtain 37.4 g of compound 1, with a yield of 57%. MS (ESI): m / s[M+H] + =519.

[0093] Example 20: Preparation of Compound 2 The same preparation method as in Example 19 was used for compound 1, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 2. MS (ESI): m / s[M+H] + =519.

[0094] Example 21: Preparation of Compound 3 The same preparation method as in Example 19 was used for compound 1, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 3. MS (ESI): m / s[M+H] + =519.

[0095] Example 22: Preparation of Compound 4 The same preparation method as Example 19, compound 1, was used, except that M1 was replaced by M2 to obtain compound 4. MS (ESI): m / s [M+H] + =519.

[0096] Example 23: Preparation of Compound 5 The same preparation method as in Example 22, compound 4, was used to obtain compound 5, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate. MS (ESI): m / s[M+H] + =519.

[0097] Example 24: Preparation of Compound 6 The same preparation method as in Example 22, compound 4, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 6, MS (ESI): m / s[M+H] + =519.

[0098] Example 25: Preparation of Compound 7 The same preparation method as Example 19, compound 1, was used, except that M1 was replaced by M3 to obtain compound 7. MS (ESI): m / s [M+H] + =519.

[0099] Example 26: Preparation of Compound 8 The same preparation method as in Example 25, compound 7, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 8, MS (ESI): m / s [M+H] + =519.

[0100] Example 27: Preparation of Compound 9 The same preparation method as in Example 25, compound 7, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 9. MS (ESI): m / s [M+H] + =519.

[0101] Example 28: Preparation of Compound 10 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M4 to obtain compound 10. MS (ESI): m / s[M+H] + =535.

[0102] Example 29: Preparation of Compound 11 The same preparation method as in Example 28 for compound 10 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 11. MS (ESI): m / s[M+H] + =535.

[0103] Example 30: Preparation of Compound 12 The same preparation method as Example 28, Compound 10, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 12. MS (ESI): m / s [M+H] + =535.

[0104] Example 31: Preparation of Compound 13 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M5 to obtain compound 13, MS (ESI): m / s [M+H] + =535.

[0105] Example 32: Preparation of Compound 14 The same preparation method as in Example 31 for compound 13 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 14. MS (ESI): m / s[M+H]+ =535.

[0106] Example 33: Preparation of Compound 15 The same preparation method as in Example 31 for compound 13 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 15. MS (ESI): m / s[M+H] + =535.

[0107] Example 34: Preparation of Compound 16 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M6 to obtain compound 16. MS (ESI): m / s [M+H] + =519.

[0108] Example 35: Preparation of Compound 17 The same preparation method as in Example 34 for compound 16 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 17. MS (ESI): m / s[M+H] + =519.

[0109] Example 36: Preparation of Compound 18 The same preparation method as in Example 34 for compound 16 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 18. MS (ESI): m / s[M+H] + =519.

[0110] Example 37: Preparation of Compound 19 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M7 to obtain compound 19. MS (ESI): m / s [M+H] + =519.

[0111] Example 38: Preparation of Compound 20 The same preparation method as in Example 37, compound 19, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 20. MS (ESI): m / s [M+H] + =519.

[0112] Example 39: Preparation of Compound 21 The same preparation method as Example 37, Compound 19, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 21, MS (ESI): m / s [M+H] + =519.

[0113] Example 40: Preparation of Compound 22 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M9 to obtain compound 22, MS (ESI): m / s [M+H] + =580.

[0114] Example 41: Preparation of Compound 23 The same preparation method as in Example 40 for compound 22 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 23. MS (ESI): m / s[M+H] + =580.

[0115] Example 42: Preparation of Compound 24 The same preparation method as in Example 40, Compound 22, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 24, MS (ESI): m / s [M+H] + =580.

[0116] Example 43: Preparation of Compound 25 The same preparation method of compound 1 as in Example 19 was used, except that the reactants and reaction conditions remained unchanged. After the intermediate 1 was hydrolyzed with phosphorus oxychloride, the base was not adjusted, and the solution was concentrated to dryness under reduced pressure at 50°C to obtain a residue. The residue was purified by silica gel column, and the effective fraction was concentrated and dried under reduced pressure at 40°C to 45°C to obtain compound 25. MS (ESI): m / s[M+H] + =475.

[0117] Example 44: Preparation of Compound 26 The same preparation method as in Example 43 for compound 25 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 26. MS (ESI): m / s[M+H] + =475.

[0118] Example 45: Preparation of Compound 27 The same preparation method as in Example 43, Compound 25, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 27. MS (ESI): m / s [M+H] + =475.

[0119] Example 46: Preparation of Compound 28 The same preparation method as Example 43, compound 25, was used, except that M1 was replaced by M8 to obtain compound 28. MS (ESI): m / s [M+H] + =491.

[0120] Example 47: Preparation of Compound 29 The same preparation method as Example 46, Compound 28, was used to obtain Compound 29, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate. MS (ESI): m / s[M+H] + =491.

[0121] Example 48: Preparation of Compound 30 The same preparation method as Example 46, Compound 28, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 30, MS (ESI): m / s [M+H] + =491.

[0122] Example 49: Preparation of Compound 31 The same preparation method as Example 43, compound 25, was used, except that M1 was replaced by M13 to obtain compound 31. MS (ESI): m / s [M+H] + =525.

[0123] Example 50: Preparation of Compound 32 The same preparation method as in Example 49 for compound 31 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 32. MS (ESI): m / s[M+H] + =525.

[0124] Example 51: Preparation of Compound 33 The same preparation method as Example 49, compound 31, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 33. MS (ESI): m / s [M+H] + =525.

[0125] Example 52: Preparation of Compound 34 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M13 to obtain compound 34. MS (ESI): m / s [M+H] + =569.

[0126] Example 53: Preparation of Compound 35 The same preparation method as in Example 52, compound 34, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 35. MS (ESI): m / s [M+H] + =569.

[0127] Example 54: Preparation of Compound 36 The same preparation method as in Example 52, compound 34, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 36. MS (ESI): m / s [M+H] + =569.

[0128] Example 55: Preparation of Compound 37 The same preparation method as Example 43, compound 25, was used, except that M1 was replaced by M14 to obtain compound 37. MS (ESI): m / s [M+H] + =507.

[0129] Example 56: Preparation of Compound 38 The same preparation method as Example 55, Compound 37, was used to obtain Compound 38, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate. MS (ESI): m / s[M+H] + =507.

[0130] Example 57: Preparation of Compound 39 The same preparation method as Example 55, Compound 37, was used to obtain Compound 39, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate. MS (ESI): m / s[M+H] + =507.

[0131] Example 58: Preparation of Compound 40 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M14 to obtain compound 40. MS (ESI): m / s [M+H] + =551.

[0132] Example 59: Preparation of Compound 41 The same preparation method as in Example 58, compound 40, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 41. MS (ESI): m / s [M+H] + =551.

[0133] Example 60: Preparation of Compound 42 The same preparation method as in Example 58, compound 40, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 42. MS (ESI): m / s [M+H] + =551.

[0134] Example 61: Preparation of Compound 43 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M15 to obtain compound 43. MS (ESI): m / s [M+H] + =533.

[0135] Example 62: Preparation of Compound 44 The same preparation method as in Example 61, compound 43, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 44. MS (ESI): m / s [M+H] + =533.

[0136] Example 63: Preparation of Compound 45 The same preparation method as in Example 61, compound 43, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 45. MS (ESI): m / s [M+H] + =533.

[0137] Example 64: Preparation of Compound 46 The same preparation method as Example 43, compound 25, was used, except that M1 was replaced by M15 to obtain compound 46. MS (ESI): m / s [M+H] + =489.

[0138] Example 65: Preparation of Compound 47 The same preparation method as in Example 64, compound 46, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain compound 47. MS (ESI): m / s [M+H] + =489.

[0139] Example 66: Preparation of Compound 48 The same preparation method as in Example 64, compound 46, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain compound 48. MS (ESI): m / s [M+H] + =489.

[0140] Example 67: Preparation of Compound 49 The same preparation method as Example 43, compound 25, was used, except that M1 was replaced by M16 to obtain compound 49. MS (ESI): m / s [M+H] + =471.

[0141] Example 68: Preparation of Compound 50 The same preparation method as Example 67, Compound 49, was used to replace 1-cyclopropylisopropylcarbamate with S-1-cyclopropylisopropylcarbamate to obtain Compound 50. MS (ESI): m / s [M+H] + =471.

[0142] Example 69: Preparation of Compound 51 The same preparation method as Example 67, Compound 49, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 51. MS (ESI): m / s [M+H] + =471.

[0143] Example 70: Preparation of Compound 52 The same preparation method as in Example 19, compound 1, was used, except that M1 was replaced by M16 to obtain compound 52. MS (ESI): m / s [M+H] + =515.

[0144] Example 71: Preparation of Compound 53 The same preparation method as in Example 70 for compound 52 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 53. MS (ESI): m / s[M+H] + =515.

[0145] Example 72: Preparation of Compound 54 The same preparation method as in Example 70, Compound 52, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 54. MS (ESI): m / s [M+H] + =515.

[0146] Example 73: Preparation of Compound 55 Add 50g (179.0mmol) of M16 compound, 25.75g (223.7mmol) of methyl cyclopropylcarbamate, 30.91g (223.7mol) of potassium carbonate, 500ml of ethylene glycol diethyl ether, and 30ml of pyridine into a 1000ml three-necked flask and reflux for 30h. Cool to room temperature, filter, dissolve the filter cake in 100ml of water, adjust the pH to 5 with acetic acid, and solid precipitate. Filter and dry under vacuum at 50℃~60℃ to obtain 57.73g of intermediate Y (compound 127), with a yield of 89%, MS (ESI): m / s[M+H] + =363.

[0147] Add 300 ml of acetonitrile and 50 g (138.0 mmol) of intermediate Y to a dry 1000 ml three-necked flask, stir and dissolve, then cool to 0°C to 5°C, slowly add 63.5 g (414.0 mmol) of phosphorus oxychloride, and after the addition is complete, heat to 40°C and keep warm for 5 hours. After the reaction is complete, slowly add 10 ml of water for hydrolysis, adjust the pH of the solution to 7-8 with 20% sodium hydroxide solution, and concentrate the solution to dryness at 50°C under reduced pressure to obtain a residue. The residue is purified by silica gel column, the effective fraction is concentrated, and dried under reduced pressure at 40°C to 45°C to obtain 35.6 g of compound 55, with a yield of 53%. MS (ESI): m / s[M+H] + =487.

[0148] Example 74: Preparation of Compound 56 Add 300 ml of acetonitrile and 50 g (138.0 mmol) of intermediate Y (prepared according to the method of Example 73) to a dry 1000 ml three-necked flask, stir and dissolve, then cool to 0°C to 5°C, slowly add 63.5 g (414.0 mmol) of phosphorus oxychloride, and after the addition is complete, heat to 40°C and keep warm for 5 hours. After the reaction is complete, slowly add 10 ml of water to hydrolyze, adjust the pH of the solution to 1-2 with 20% sodium hydroxide solution, and concentrate the solution at 50°C to dryness under reduced pressure to obtain a residue. The residue is purified by silica gel column, the effective fraction is concentrated, and dried under reduced pressure at 40°C to 45°C to obtain 35.4 g of compound 56, with a yield of 58%. MS (ESI): m / s[M+H] + =443.

[0149] Example 75: Preparation of Compound 57 The same preparation method as Example 73, Compound 55, was used, except that M16 was replaced by M1 to obtain Compound 57. MS (ESI): m / s [M+H] + =491.

[0150] Example 76: Preparation of Compound 58 The same preparation method as Example 74, compound 56, was used, except that M16 was replaced by M1 to obtain compound 57. MS (ESI): m / s [M+H] + =447.

[0151] Example 77: Preparation of Compound 59 The same preparation method as Example 73, Compound 55, was used, except that M16 was replaced by M4 to obtain Compound 59. MS (ESI): m / s [M+H] + =507.

[0152] Example 78: Preparation of Compound 60 The same preparation method as Example 74, compound 56, was used, except that M16 was replaced by M4 to obtain compound 60. MS (ESI): m / s [M+H] + =463.

[0153] Example 79: Preparation of Compound 61 The same preparation method as Example 73, compound 55, was used to obtain compound 61, except that M16 was replaced by M13. MS (ESI): m / s [M+H] + =541.

[0154] Example 80: Preparation of Compound 62 The same preparation method as Example 74, compound 56, was used, except that M16 was replaced by M13 to obtain compound 62. MS (ESI): m / s [M+H] + =497.

[0155] Example 81: Preparation of Compound 63 The same preparation method as Example 73, compound 55, was used to obtain compound 63, except that M16 was replaced by M14. MS (ESI): m / s [M+H] + =523.

[0156] Example 82: Preparation of Compound 64 The same preparation method as Example 74, compound 56, was used, except that M16 was replaced by M14 to obtain compound 64. MS (ESI): m / s [M+H] + =479.

[0157] Example 83: Preparation of Compound 65 The same preparation method as Example 73, compound 55, was used to obtain compound 65, except that M16 was replaced by M15. MS (ESI): m / s [M+H] + =505.

[0158] Example 84: Preparation of Compound 66 The same preparation method as Example 74, compound 56, was used, except that M16 was replaced by M15 to obtain compound 66. MS (ESI): m / s [M+H] + =461.

[0159] Example 85: Preparation of Compound 67 Step 1: Preparation of chloromethyl ether intermediate In a 250 ml reaction bottle, 100 ml of tetrahydrofuran, 4.37 g (109.2 mmol) of sodium hydroxide and 56.5 g (436.8 mmol) of chlorobromomethane were added, stirred and heated. 20 g (54.6 mmol) of compound 128 was added to the reaction bottle, and the reaction was stirred at 60 ° C for 4 h. The reaction was stopped, and the solid in the reaction solution was filtered. The filtrate was evaporated under reduced pressure at 60 ° C to remove the solvent. The residue was purified by silica gel column, the effective fraction was concentrated, and dried under reduced pressure at 40 ° C to 45 ° C to obtain 14.7 g of chloromethyl ether intermediate (yield 65%).

[0160] Step 2: Preparation of compound 67 50 mL of acetonitrile was placed in a 250 mL reaction bottle, and 8.94 g (88.5 mmol) of triethylamine and 10.20 g (88.5 mmol) of phosphoric acid were added and stirred until dissolved. 14.7 g (35.4 mmol) of chloromethyl ether intermediate was slowly added. After the addition was complete, the reaction was carried out at 60 ° C for 6 h. The reaction was stopped and the solvent was evaporated at 60 ° C under reduced pressure. After evaporation to dryness, 50 mL of water was added and stirred. Concentrated hydrochloric acid was slowly added dropwise to adjust the pH to 1.5. 50 mL (25 mL × 2 times) of ethyl acetate was added to extract the water layer. The water layer was removed, and the ethyl acetate layer was washed with 20 mL (10 mL × 2 times) of water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then ethyl acetate was evaporated under reduced pressure at 50 ° C. 20 mL of methanol was added to the residue, and the pH was adjusted to 9.0 with saturated sodium hydroxide solution. 60 mL of isopropanol was added, and the mixture was stirred at 0 ° C for 12 hours. Filtered, the filter cake was washed with 25 mL of acetone to obtain 13.43 g of white solid with a yield of 73%, i.e., compound 67. MS (ESI): m / s [M+H] + =521.

[0161] Example 86: Preparation of Compound 68 Step 1: Preparation of chloromethyl ether intermediate Prepared in the same manner as Example 85 Step 2: Preparation of compound 68 Take 50mL of acetonitrile and place it in a 250mL reaction bottle. Add 8.94g (88.5mmol) of triethylamine and 10.20g (88.5mmol) of phosphoric acid and stir until dissolved. Slowly add 14.7g (35.4mmol) of chloromethyl ether intermediate. After addition, react at 60℃ for 6h. Stop the reaction. Distill off the solvent under reduced pressure at 60℃. After evaporation, add 50mL of water and stir. Slowly drop concentrated hydrochloric acid to adjust the pH to 1.5. Add 50mL (25mL×2 times) of ethyl acetate to extract the water layer. Remove the water layer. Wash the ethyl acetate layer with 20mL (10mL×2 times) of water. Dry the ethyl acetate layer with anhydrous sodium sulfate. Then distill off the ethyl acetate under reduced pressure at 50℃. The residue is purified by silica gel column. The effective fraction is concentrated and dried under reduced pressure at 40℃~45℃ to obtain 10.44g of compound 68 with a yield of 62%. MS (ESI): m / s[M+H] + =477.

[0162] Example 87: Preparation of Compound 69 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 127 to obtain Compound 69. MS (ESI): m / s [M+H] + =517.

[0163] Example 88: Preparation of Compound 70 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 127, to obtain Compound 70, MS (ESI): m / s [M+H] + =473.

[0164] Example 89: Preparation of Compound 71 The same preparation method as in Example 85, compound 67, was used to replace compound 128 with compound 129 to obtain compound 71. MS (ESI): m / s [M+H] + =537.

[0165] Example 90: Preparation of Compound 72 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 129 to obtain Compound 72. MS (ESI): m / s [M+H] + =493.

[0166] Example 91: Preparation of Compound 73 The same preparation method as in Example 85, Compound 67, except that Compound 128 was replaced by Compound 130, to obtain Compound 73, MS (ESI): m / s [M+H] + =571.

[0167] Example 92: Preparation of Compound 74 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 130 to obtain Compound 74. MS (ESI): m / s [M+H] + =527.

[0168] Example 93: Preparation of Compound 75 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 131 to obtain Compound 75. MS (ESI): m / s [M+H] + =553.

[0169] Example 94: Preparation of Compound 76 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 131, to obtain Compound 76, MS (ESI): m / s [M+H] + =509.

[0170] Example 95: Preparation of Compound 77 The same preparation method as in Example 85, Compound 67, except that Compound 128 was replaced by Compound 132, to obtain Compound 77, MS (ESI): m / s [M+H] + =535.

[0171] Example 96: Preparation of Compound 78 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 132 to obtain Compound 78, MS (ESI): m / s [M+H] + =491.

[0172] Example 97: Preparation of Compound 79 The same preparation method as in Example 85, Compound 67, except that Compound 128 was replaced by Compound 133, to obtain Compound 79, MS (ESI): m / s [M+H] + =517.

[0173] Example 98: Preparation of Compound 80 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 133 to obtain Compound 80. MS (ESI): m / s [M+H] + =473.

[0174] Example 99: Preparation of Compound 81 The same preparation method as in Example 85, compound 67, was used to replace compound 128 with compound 134 to obtain compound 81. MS (ESI): m / s [M+H] + =521.

[0175] Example 100: Preparation of Compound 82 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 134 to obtain Compound 82. MS (ESI): m / s [M+H] + =477.

[0176] Example 101: Preparation of Compound 83 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 135 to obtain Compound 83. MS (ESI): m / s [M+H] + =537.

[0177] Example 102: Preparation of Compound 84 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 135 to obtain Compound 84. MS (ESI): m / s [M+H] + =493.

[0178] Example 103: Preparation of Compound 85 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 136 to obtain Compound 85. MS (ESI): m / s [M+H] + =571.

[0179] Example 104: Preparation of Compound 86 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 136 to obtain Compound 86, MS (ESI): m / s [M+H] + =527.

[0180] Example 105: Preparation of Compound 87 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 137 to obtain Compound 87. MS (ESI): m / s [M+H] + =553.

[0181] Example 106: Preparation of Compound 88 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 137 to obtain Compound 88, MS (ESI): m / s [M+H] + =509.

[0182] Example 107: Preparation of Compound 89 The same preparation method as in Example 85, Compound 67, was used to replace Compound 128 with Compound 138 to obtain Compound 89. MS (ESI): m / s [M+H] +=535.

[0183] Example 108: Preparation of Compound 90 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 138 to obtain Compound 90. MS (ESI): m / s [M+H] + =491.

[0184] Example 109: Preparation of Compound 91 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 109 to obtain Compound 91. MS (ESI): m / s [M+H] + =501.

[0185] Example 110: Preparation of Compound 92 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 110 to obtain Compound 92, MS (ESI): m / s [M+H] + =501.

[0186] Example 111: Preparation of Compound 93 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 111 to obtain Compound 93. MS (ESI): m / s [M+H] + =501.

[0187] Example 112: Preparation of Compound 94 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 112 to obtain Compound 94, MS (ESI): m / s [M+H] + =505.

[0188] Example 113: Preparation of Compound 95 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 113 to obtain Compound 95, MS (ESI): m / s [M+H] + =505.

[0189] Example 114: Preparation of Compound 96 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 114 to obtain Compound 96, MS (ESI): m / s [M+H] + =505.

[0190] Example 115: Preparation of Compound 97 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 124 to obtain Compound 97, MS (ESI): m / s [M+H] + =521.

[0191] Example 116: Preparation of Compound 98 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 125, to obtain Compound 98, MS (ESI): m / s [M+H] + =521.

[0192] Example 117: Preparation of Compound 99 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 126, to obtain Compound 99, MS (ESI): m / s [M+H] + =521.

[0193] Example 118: Preparation of Compound 100 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 115 to obtain Compound 100. MS (ESI): m / s [M+H] + =555.

[0194] Example 119: Preparation of Compound 101 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 116 to obtain Compound 101. MS (ESI): m / s [M+H] + =555.

[0195] Example 120: Preparation of Compound 102 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 117 to obtain Compound 102. MS (ESI): m / s [M+H] + =555.

[0196] Example 121: Preparation of Compound 103 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 118 to obtain Compound 103. MS (ESI): m / s [M+H] + =537.

[0197] Example 122: Preparation of Compound 104 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 119 to obtain Compound 104. MS (ESI): m / s [M+H] + =537.

[0198] Example 123: Preparation of Compound 105 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 120 to obtain Compound 105. MS (ESI): m / s [M+H] + =537.

[0199] Example 124: Preparation of Compound 106 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 121 to obtain Compound 106, MS (ESI): m / s [M+H] + =519.

[0200] Example 125: Preparation of Compound 107 The same preparation method as in Example 86, Compound 68, was used to replace Compound 128 with Compound 122 to obtain Compound 107. MS (ESI): m / s [M+H] + =519.

[0201] Example 126: Preparation of Compound 108 The same preparation method as in Example 86, Compound 68, except that Compound 128 was replaced by Compound 123 to obtain Compound 108, MS (ESI): m / s [M+H] + =519.

[0202] Example 127: Preparation of Compound 109 The same preparation method as the first step intermediate of compound 1 in Example 19 was used, except that M1 was changed to 16 to obtain compound 109. MS (ESI): m / s [M+H] + =391.

[0203] Example 128: Preparation of Compound 110 The same preparation method as in Example 127 for compound 109 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 110. MS (ESI): m / s [M+H] + =391.

[0204] Example 129: Preparation of Compound 111 The same preparation method as in Example 127 for compound 109 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 111. MS (ESI): m / s [M+H] + =391.

[0205] Example 130: Preparation of Compound 112 The same preparation method as the first step intermediate of compound 1 in Example 19 was used to obtain compound 112, MS (ESI): m / s [M+H] + =395.

[0206] Example 131: Preparation of Compound 113 The same preparation method as in Example 130 for compound 112 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 113. MS (ESI): m / s[M+H] + =395.

[0207] Example 132: Preparation of Compound 114 The same preparation method as in Example 130 for compound 112 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 114. MS (ESI): m / s[M+H] + =395.

[0208] Example 133: Preparation of Compound 115 The same preparation method as the first step intermediate of compound 1 in Example 19 was used, except that M1 was changed to 13 to obtain compound 115. MS (ESI): m / s [M+H] + =445.

[0209] Example 134: Preparation of Compound 116 The same preparation method as in Example 133 for compound 115 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 116. MS (ESI): m / s[M+H] + =445.

[0210] Example 135: Preparation of Compound 117 The same preparation method as in Example 133 for compound 115 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 117. MS (ESI): m / s [M+H] + =445.

[0211] Example 136: Preparation of Compound 118 The same preparation method as the first step intermediate of compound 1 in Example 19 was used, except that M1 was changed to 14 to obtain compound 118. MS (ESI): m / s [M+H] + =427.

[0212] Example 137: Preparation of Compound 119 The same preparation method as Example 136 Compound 118 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain Compound 427. MS (ESI): m / s [M+H] + =391.

[0213] Example 138: Preparation of Compound 120 The same preparation method as in Example 136, Compound 118, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 120. MS (ESI): m / s [M+H] + =427.

[0214] Example 139: Preparation of Compound 121 The same preparation method as the first step intermediate of compound 1 in Example 19 was used, except that M1 was changed to 15 to obtain compound 121. MS (ESI): m / s [M+H] + =409.

[0215] Example 140: Preparation of Compound 122 The same preparation method as in Example 139 for compound 121 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 122. MS (ESI): m / s[M+H] + =409.

[0216] Example 141: Preparation of Compound 123 The same preparation method as in Example 139 for compound 121 was used, except that 1-cyclopropylisopropylcarbamate was replaced with R-1-cyclopropylisopropylcarbamate to obtain compound 123. MS (ESI): m / s [M+H] + =409.

[0217] Example 142: Preparation of Compound 124 The same preparation method as the first step intermediate of compound 1 in Example 19 was used, except that M1 was changed to M4 to obtain compound 124. MS (ESI): m / s [M+H] + =411.

[0218] Example 143: Preparation of Compound 125 The same preparation method as in Example 142 for compound 124 was used, except that 1-cyclopropylisopropylcarbamate was replaced with S-1-cyclopropylisopropylcarbamate to obtain compound 125. MS (ESI): m / s[M+H] + =411.

[0219] Example 144: Preparation of Compound 126 The same preparation method as in Example 142, Compound 124, was used to replace 1-cyclopropylisopropylcarbamate with R-1-cyclopropylisopropylcarbamate to obtain Compound 126. MS (ESI): m / s [M+H] + =411.

[0220] Example 145: Preparation of Compound 127 The same preparation method as the first step intermediate of compound 55 in Example 73 was used to obtain compound 127, MS (ESI): m / s [M+H] + =363.

[0221] Example 146: Preparation of Compound 128 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M1 to obtain compound 128. MS (ESI): m / s [M+H] + =367.

[0222] Example 147: Preparation of Compound 129 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M4 to obtain compound 129. MS (ESI): m / s [M+H] + =383.

[0223] Example 148: Preparation of Compound 130 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M13 to obtain compound 130. MS (ESI): m / s [M+H] + =417.

[0224] Example 149: Preparation of Compound 131 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M14 to obtain compound 131. MS (ESI): m / s [M+H] + =399.

[0225] Example 150: Preparation of Compound 132 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M15 to obtain compound 132. MS (ESI): m / s [M+H] + =381.

[0226] Example 151: Preparation of Compound 133 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M17 to obtain compound 133. MS (ESI): m / s [M+H]+ =363.

[0227] Example 152: Preparation of Compound 134 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M6 to obtain compound 134. MS (ESI): m / s [M+H] + =367.

[0228] Example 153: Preparation of Compound 135 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M8 to obtain compound 135. MS (ESI): m / s [M+H] + =383.

[0229] Example 154: Preparation of Compound 136 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M10 to obtain compound 136. MS (ESI): m / s [M+H] + =417.

[0230] Example 155: Preparation of Compound 137 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M11 to obtain compound 137. MS (ESI): m / s [M+H] + =399.

[0231] Example 156: Preparation of Compound 138 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M12 to obtain compound 138. MS (ESI): m / s [M+H] + =381.

[0232] Example 157: Preparation of Compound 139 The same preparation method as the first step intermediate of compound 55 in Example 73 was used, except that M16 was replaced by M18 to obtain compound 139. MS (ESI): m / s [M+H] + =428.

[0233] Example 158: Preparation of Compound 140 Take 10 g (23.4 mmol / L) of compound 56 and 9.13 g (46.8 mmol / L) of meglumine, add them to 70% ethanol aqueous solution, stir and dissolve at 50°C, keep warm and stir for 10 minutes after the solution is clear, filter, cool the filtrate to 0°C for crystallization for 4 to 8 hours, filter, and dry the filter cake in a forced air drying oven at 40°C to obtain 13.6 g, namely compound 140, with a yield of 71%.

[0234] Example 159: Preparation of Compound 141 The same preparation method as Example 158 for Compound 140 was used, except that Compound 56 was replaced by Compound 58 and the molar ratio of the feed materials remained unchanged, to obtain Compound 141.

[0235] Example 160: Preparation of Compound 142 The same preparation method as in Example 158 for Compound 140 was used, except that Compound 56 was replaced by Compound 60 and the molar ratio of the feed materials remained unchanged, to obtain Compound 142.

[0236] Example 161: Preparation of Compound 143 The same preparation method as in Example 158 for Compound 140 was used, except that Compound 56 was replaced by Compound 62, and the molar ratio of the feed materials remained unchanged, to obtain Compound 143.

[0237] Example 162: Preparation of Compound 144 Take 10 g (23.4 mmol / L) of compound 56 and 8.15 g (46.8 mmol / L) of arginine, add them to 70% ethanol aqueous solution, stir and dissolve at 50°C, keep warm and stir for 10 minutes after the solution is clear, filter, cool the filtrate to 0°C for crystallization for 4 to 8 hours, filter, and dry the filter cake in a forced air drying oven at 40°C to obtain 14.0 g, namely compound 144, with a yield of 77%.

[0238] Example 163: Preparation of Compound 145 The same preparation method as Example 162, Compound 144, was used to obtain Compound 145, except that Compound 56 was replaced by Compound 58 and the molar ratio of the raw materials remained unchanged.

[0239] Example 164: Preparation of Compound 146 The same preparation method as Example 162, Compound 144, was used to obtain Compound 146, except that Compound 56 was replaced by Compound 60 and the molar ratio of the feed materials remained unchanged.

[0240] Example 165: Preparation of Compound 147 The same preparation method as Example 162 for Compound 146 was used, except that Compound 56 was replaced by Compound 62, and the molar ratio of the feed materials remained unchanged, to obtain Compound 147.

[0241] Example 166: Preparation of Compound 148 Take 10 g (23.4 mmol / L) of compound 56 and 14.18 g (46.8 mmol / L) of choline hydroxide (40%), add them to 80% ethanol aqueous solution, stir and dissolve at 50°C, keep warm and stir for 10 minutes after the solution is clear, filter, cool the filtrate to 0°C for crystallization for 4 to 8 hours, filter, and dry the filter cake in a forced air drying oven at 40°C to obtain 10.42 g, namely compound 148, with a yield of 74%.

[0242] Example 167: Preparation of Compound 149 The same preparation method as Example 166 Compound 148 was used to obtain Compound 149, except that Compound 56 was replaced by Compound 58 and the molar ratio of the raw materials remained unchanged.

[0243] Example 168: Preparation of Compound 150 The same preparation method as Example 166 Compound 148 was used, except that Compound 56 was replaced by Compound 60, and the molar ratio of the raw materials remained unchanged, to obtain Compound 150.

[0244] Example 169: Preparation of Compound 151 The same preparation method as Example 166 Compound 148 was used, except that Compound 56 was replaced by Compound 62, and the molar ratio of the raw materials remained unchanged, to obtain Compound 151.

[0245] Example 170: Preparation of Compound 152 The same preparation method as Example 166 Compound 148 was used, except that Compound 56 was replaced by Compound 49, and the molar ratio of the raw materials remained unchanged, to obtain Compound 152.

[0246] Example 171: Preparation of Compound 1 Injection Preparation composition: Compound 1 0.4 g, sodium chloride 18 g, water for injection 2000 mL.

[0247] Preparation method: (1) Measure 1500 mL of water for injection, add 0.4 g of compound 1 and 18 g of sodium chloride, stir evenly, adjust the pH of the solution to 4-9 with a pH adjuster, and pre-filter through a titanium rod filter to obtain a concentrated solution; (2) Adding water for injection to the concentrated solution prepared in step (1) to the full amount, stirring evenly, and sterilizing and filtering with two 0.22 μm polyethersulfone filter cartridges to obtain an intermediate; (3) After the content of the intermediate is determined, it is filled, capped and packaged to obtain the product.

[0248] Example 172: Preparation of lyophilized powder injection of compound 52 Preparation composition: Compound 52 10 g, mannitol 10 g and water for injection 1000 mL.

[0249] The preparation process is as follows: (1) Add 10 g of compound 52 and 10 g of mannitol to 70% volume of water for injection, and stir until dissolved to obtain a concentrated solution; (2) The pH value of the concentrated solution is adjusted to 4.0 to 9.0 with a pH adjuster while stirring, and pre-filtered through a titanium rod filter to obtain solution 1; (3) sterilizing and filtering the solution 1 in step (2) using two 0.22 μm polyethersulfone filter cartridges to obtain a solution 2, which is then filled and semi-stoppered to obtain an intermediate 1; (4) The intermediate 1 is freeze-dried using the following procedure: (a) Set the temperature to -45℃~-40℃ and pre-freeze for 4 hours; (b) Heating to -20°C to -10°C and vacuum degree of 1 to 10 Pa for sublimation 4.Oh; (c) heating to a temperature of -10°C to -0°C and a vacuum degree of 1 to 10 Pa for sublimation for 4.0 h; (d) heating to a temperature of 0°C to 5°C and a vacuum of 1 to 10 Pa for sublimation for 2.0 h; (e) Heating to a temperature of 15°C to 25°C and maintaining the temperature at a vacuum of 1 to 10 Pa for 2.0 h; After the insulation is completed, the plug is pressed, the product is taken out of the box, and the lid is sealed to obtain the freeze-dried powder injection of compound 52.

[0250] Example 173: Comparison of diuretic effect SD male rats (weight 270±20g) were randomly divided into groups, 3 in each group, and each rat was given 30mL / kg normal saline by gavage. After gavage with normal saline, each group, except the blank control group, was given a drug (10mg / kg) by gavage, and the urine was collected for 4 hours. The results are shown in Table 2: Table 2. Comparison of urine excretion of different compounds

[0251]

[0252]

[0253]

[0254] The results of the diuretic effect experiment show that the compound of the present invention has a better diuretic effect than the control compound and has a better drugability advantage.

[0255] Example 174: Pharmacokinetic Studies 1. Test amount SD rats were given a single tail vein injection (iv) of 10 mg / kg.

[0256] 2. Test animals SD rats weighing 200±10g, half male and half female, were randomly divided into groups, 6 rats in each group, half male and half female. They were given an environmental adaptation period of 2 to 4 days before the experiment.

[0257] 3. Test samples Example compounds of the present invention.

[0258] 4. Experimental process After fasting for 8-12h, rats in the test group were given 10mg / kg iv in each group. About 0.1mL of venous blood was collected from the orbital venous plexus before administration and 4min, 10min, 15min, 30min, 1h, 2h, 4h, 8h, 12h, and 24h after administration and put into a 0.2mL blood collection tube. 20μl of 60mg / ml EDTA disodium (prepared with saline) was added to the blood collection tube in advance. After centrifugation of whole blood at 8000rpm for 5min, 50μl of upper plasma was transferred, 500μl of protein precipitant was added, and protein was precipitated for 3min. After two centrifugations (18000rpm for 10min), 100μl of supernatant was transferred to the injection bottle, and 5μl was injected for analysis. LC-MS / MS was used to determine the concentration of active metabolites in plasma.

[0259] The measured plasma drug concentration over time was fitted and calculated 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 Table 3 Pharmacokinetic half-life results of the compounds of the present invention and the control compounds

[0260]

[0261]

[0262]

[0263] The results show that the pharmacokinetic half-life of the compound of the present invention is significantly better than that of the control compound, indicating that the compound of the present invention has a long-lasting pharmacodynamic effect and has a better drugability advantage.

[0264] Example 175: Toxicity study of repeated administration of the compounds of the present invention to SD rats via tail vein injection for 2 consecutive weeks SD rats, half male and half female, were divided into vehicle group, control compound group, low-dose group of the present compound (50 mg / kg), medium-dose group of the present compound (100 mg / kg), and high-dose group of the present compound (200 mg / kg). The rats were injected with 20 mL / kg via the tail vein, once a day, 7 days a week, for 2 consecutive weeks to observe drug toxicity.

[0265] The compounds administered were as follows 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.

[0266] The results of the study showed that the compound of the present invention was administered to SD rats via tail vein injection for 2 consecutive weeks. The drug had no obvious accumulation effect in the body of SD rats and could be completely cleared from the body after 2 weeks of drug withdrawal. It could cause increased urination and electrolyte disturbance in animals, which could be restored after 2 weeks of drug withdrawal. The no-observed-toxicity-effect-level (NOAEL) was 60 mg / kg, and no serious adverse reactions and liver and kidney damage were observed in the animals.

[0267] Example 176: Study on the activity of the compounds of the present invention on the experimental rabbit intracranial hypertension model induced by nitroglycerin Male experimental rabbits were divided into groups according to body weight, namely: normal control group, model control group, mannitol group (1000 mg / kg), control compound group (10 mg / kg), and compound of the present invention group (10 mg / kg), with 4 rabbits in each group. After anesthesia, the animals in each group were fixed, and the normal control group was intravenously injected with 0.9% sodium chloride injection 5 mL / kg, and the other groups were firstly continuously intravenously dripped with nitroglycerin (0.04 mg / kg / min) for 10 min to make models. Except that the model control group was not given drug treatment, the other groups were then intravenously injected with corresponding drugs, and the mannitol injection used a 20% (weight ratio) aqueous solution, and the control compound and the compound of the present invention were both prepared with physiological saline (i.e. 0.9% sodium chloride injection) to form a 10 mg / ml injection. The drugs were administered according to the weight of the animals, and the specific dosages were: the dosage of the mannitol group was 1000 mg / kg, the dosage of the control compound group was 10 mg / kg, and the dosage of the compound of the present invention group was 10 mg / kg. The changes of intracranial pressure of experimental rabbits were detected before modeling (before intravenous drip of nitroglycerin), after modeling (10 minutes after intravenous drip of nitroglycerin), and 10 minutes, 20 minutes, 30 minutes, 60 minutes, 90 minutes, 120 minutes, 150 minutes, and 180 minutes after administration. The results are shown in Table 4.

[0268] Table 4 Effects of compounds on the percentage of intracranial pressure reduction in the experimental rabbit intracranial hypertension model induced by nitroglycerin

[0269]

[0270]

[0271]

[0272]

[0273] Example 176: Study on the activity of the compounds of the present invention on the collagenase IV-induced experimental rabbit cerebral hemorrhage model The experimental rabbits were randomly divided into normal control group, model control group, mannitol injection group, compound of the present invention group and combined administration group according to sex and weight. The normal control group was intravenously injected with 5 mL / kg of 0.9% sodium chloride injection, and the animals in the other groups were injected with 1 μL of 0.9% sodium chloride injection containing 0.5 μg / μL of collagenase IV under the dura mater for modeling. Except for the model control group, which was not given drug treatment, the other groups were intravenously injected with corresponding drugs. Mannitol injection used a 20% (weight ratio) aqueous solution, and the compounds of the present invention were all prepared into 10 mg / ml injections with physiological saline (i.e., 0.9% sodium chloride injection), and the drugs were administered according to the weight of the animals. The specific dosages were: the dosage of the mannitol group was 1000 mg / kg, the dosage of the compound of the present invention group was 3.0 mg / kg, and the dosage of the combined administration group was 1000 mg / kg of mannitol injection plus 3.0 mg / kg of the compound of the present invention. The administration rate was 6 mL / min, and the animals were treated according to the administration frequency set in the experiment. The animals were treated at 24h, 48h and 72h after modeling. The animals were anesthetized with propofol emulsion injection and bled through the femoral artery to kill the animals. The area around the brain lesion was immediately weighed, dried in a constant temperature box, and weighed again to calculate the brain water content. The results are shown in Table 5.

[0274] Table 5 Effects of the compounds of the present invention on brain water content in the rabbit cerebral hemorrhage model induced by collagenase IV

[0275]

[0276]

[0277]

[0278]

[0279] The experimental results show that the compounds of the present invention can significantly reduce the increase in brain water content caused by cerebral hemorrhage in experimental rabbits, and their activity in reducing brain water content is better than that of mannitol injection and control compounds.

[0280] Example 177: Effect of the compounds of the present invention on Na + , K + , Cl － Study on the inhibitory activity of the pump The effects of the control compound and the compounds of the present invention at a series of concentrations on the Na + -K + -2Cl - The activity of the pump transport model. The concentration of rubidium ions in each group of buffers was detected by atomic absorption spectroscopy, and the activity of each test / reference substance on Na + -K + -2Cl - The activity of the pump is expressed as the half effective concentration (EC50).

[0281] Table 6 Compounds for Na + -K + -2Cl - Pump activity

[0282]

[0283]

[0284]

[0285]

[0286] The results showed that the control compound and the compound of the present invention had an effect on Na + -K + -2Cl - The pump activity was inhibited to varying degrees, and the compounds of the present invention were superior to the control compounds.

[0287] The above-mentioned embodiments only express some specific implementation methods of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the patent of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A sulfonamide compound or a pharmaceutically acceptable salt thereof or an enantiomer thereof, the structure of which is shown in Formula I: Ⅰ Wherein X is methyl, F, Cl, Br, trifluoromethyl, difluoromethyl or monofluoromethyl; R1 is cyclopropyl or ; R2 is hydrogen, ; When R2 is When Y and Z are both absent, O is directly connected to P; when Y is O, Z is CH2; when R is hydrogen, it can form a salt with an organic base or a basic amino acid.

2. The sulfonamide compound or its pharmaceutically acceptable salt or its enantiomer according to claim 1, characterized in that: The pharmaceutically acceptable salts include salts formed with inorganic / organic bases.

3. The sulfonamide compound or its pharmaceutically acceptable salt or its enantiomer according to claim 2, characterized in that: The organic base is selected from trimethylamine, meglumine or diisopropylethylamine.

4. The sulfonamide compound or its pharmaceutically acceptable salt or its enantiomer according to claim 1, characterized in that: The pharmaceutically acceptable salts include metal salts or salts formed with basic amino acids.

5. The sulfonamide compound or the pharmaceutically acceptable salt thereof or the enantiomer thereof according to claim 4, characterized in that: The metal salt is selected from alkali metals and alkaline earth metals, the alkali metal is selected from sodium salts or potassium salts, the alkaline earth metal is selected from calcium salts, magnesium salts or barium salts, and the basic amino acid salt is selected from lysine and arginine.

6. The sulfonamide compound or pharmaceutically acceptable salt thereof or enantiomer thereof according to claim 1, characterized in that Selected from the following compounds: 。 7. A pharmaceutical composition comprising a therapeutic amount of a sulfonamide compound and / or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 5, and other pharmaceutically acceptable excipients.

8. The sulfonamide compound or the pharmaceutically acceptable salt thereof or the enantiomer thereof according to any one of claims 1 to 6, characterized in that: Use in the preparation of diuretic drugs.

9. The sulfonamide compound or the pharmaceutically acceptable salt thereof or the enantiomer thereof according to any one of claims 1 to 6, characterized in that: Use in the preparation of anti-cerebral edema drugs.

Images