Tetrahydroisoquinoline and pharmaceutical use thereof

Abstract

The present disclosure relates to tetrahydroisoquinoline and a pharmaceutical use thereof. Specifically, the present disclosure relates to a compound represented by formula I or a pharmaceutically acceptable salt thereof. The definition of each substituent is as defined in the description.

Description

Tetrahydroisoquinoline and its pharmaceutical use Technical Field

[0001] The present invention relates to the field of medicine and relates to tetrahydroisoquinoline and its pharmaceutical use. Background Art

[0002] Neuromuscular-blocking drugs (NMBDs) play an important role in anesthesiology and can be divided into two categories based on their mechanism of action and efficacy: nondepolarizing and depolarizing. Nondepolarizing drugs (such as vecuronium) competitively bind to cholinergic receptors at the neuromuscular junction, blocking the effects of acetylcholine and causing muscle paralysis. Depolarizing drugs (such as succinacaine) interfere with the electrical potential of nerve terminal cell membranes, preventing normal muscle contraction.

[0003] WO2014005122 discloses a series of non-depolarizing ultrashort-acting, short-acting, and intermediate-acting neuromuscular blockers, wherein the neuromuscular block (NMB) induced by the agents is reversible, for example, by administration of cysteine ​​or related compounds. Summary of the Invention

[0004] The present disclosure provides a compound represented by Formula I or a pharmaceutically acceptable salt thereof,

[0005] in:

[0006] W is selected from -C(R a R b R c )or

[0007] each independently selected from pharmaceutically acceptable anions;

[0008] R 3 、R 4 are each independently selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, the C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0009] L B 、L C Each independently selected from -C(R a R b R c) or alkylene, said alkylene being optionally substituted with one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, thiol, carboxyl, amino, or cyano groups;

[0010] When L B -C(R a R b R c ), then there is no B1 ~R B5 substituted phenyl groups;

[0011] When L C -C(R a R b R c ), then there is no D1 ~R D5 substituted phenyl groups;

[0012] R 1 、R 2 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、R W1 、R W2 、R W3 、R W4 、R W5 、R a 、R b 、R c Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0013] Or, R 1 and R 2 Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups.

[0014] Or, any two adjacent R A1 、R A2 、R A3 、R A4 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0015] Or, any two adjacent R B1 、R B2 、R B3 、R B4 、R B5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0016] Or, any two adjacent R D1 、R D2 、R D3 、R D4 、R D5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-,

[0017] Or, any two adjacent R W1 、R W2 、R W3 、R W4 、R W5 Together they form methylenedioxy, ethylenedioxy, -CH2-O-CH2-;

[0018] R 5 、R 6 cannot be hydrogen at the same time, and are independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0019] Or, R 5 and R 6 Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0020] x1 is selected from 1, 2, 3, 4, 5, 6;

[0021] x2 is selected from 1, 2, 3, 4, 5, 6;

[0022] x3 is selected from 0, 1, 2, 3, 4, 5;

[0023] x4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

[0024] In some embodiments, wherein L C is an alkylene group, wherein the alkylene group is optionally substituted by one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, mercapto, carboxyl, amino, or cyano groups.

[0025] In some embodiments, wherein L B is an alkylene group, wherein the alkylene group is optionally substituted by one or more halogen, hydroxyl, mercapto, nitro, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, oxo, thio or sulfonyl substituted, said C 1-6 Alkyl, C 1-6 The alkoxy group is optionally substituted with one or more halogen, hydroxy, mercapto, carboxyl, amino, or cyano groups.

[0026] In some embodiments, the compound represented by Formula I is selected from the compound represented by Formula II or a pharmaceutically acceptable salt thereof,

[0027] R d 、R e Each independently selected from hydrogen, halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, -C(O)-C 1-6 Alkyl, -C(O)-C 1-6 Alkoxy, methylsulfonyl, 3 to 10-membered carbocyclic ring, 3 to 10-membered heterocyclic ring, 6 to 10-membered aromatic ring or 5 to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino or cyano groups,

[0028] Or, R d and R e Together with the atoms to which it is attached, it forms an oxo group, a thioxo group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring, or a 5- to 10-membered heteroaromatic ring, wherein the carbocyclic ring, heterocyclic ring, aromatic ring, or heteroaromatic ring is optionally substituted with one or more halogen, hydroxyl, thiol, carboxyl, amino, cyano, C 1-6 Alkyl, C 1-6 Alkoxy is substituted, and the alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, thiol, carboxyl, amino, and cyano groups;

[0029] x5 is selected from 1, 2, 3, 4, 5, 6;

[0030] x6 is selected from 1, 2, 3, 4, 5, 6;

[0031] W. R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 , x1, x2, x3, x4 are as defined above.

[0032] In some embodiments, wherein x5 is 1.

[0033] In some embodiments, wherein x6 is 1.

[0034] In some embodiments, the compound represented by Formula I is selected from the compound represented by Formula III or a pharmaceutically acceptable salt thereof,

[0035] W. R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 , x1, x2, x3, x4, R d 、R e As defined above.

[0036] In some embodiments, wherein x3 is 0.

[0037] In some embodiments, wherein R A1 、R A4 All are hydrogen.

[0038] In some embodiments, wherein R B1 、R B2 、R B5 All are hydrogen.

[0039] In some embodiments, wherein R D1 、R D4 、R D5 All are hydrogen.

[0040] In some embodiments, the compound represented by Formula I is selected from the compound represented by Formula IV or a pharmaceutically acceptable salt thereof,

[0041] W. R 1 、R 2 、R 3 、R4 、R 5 、R 6 、R 7 、R A2 、R A3 、R B3 、R B4 、R D2 、R D3 , x1, x2, x4, R d 、R e As defined above.

[0042] In some embodiments, wherein R A2 、R A3 are each independently selected from hydrogen, C 1-6 In some embodiments, wherein R A2 、R A3 are each independently selected from hydrogen, methoxy, ethoxy, propoxy. In some embodiments, wherein R A2 、R A3 Each is independently selected from hydrogen and methoxy.

[0043] In some embodiments, wherein R B3 、R B4 are each independently selected from hydrogen, C 1-6 In some embodiments, wherein R B3 、R B4 are each independently selected from hydrogen, methoxy, ethoxy, propoxy. In some embodiments, wherein R B3 、R B4 Each is independently selected from hydrogen and methoxy.

[0044] In some embodiments, wherein R D2 、R D3 are independently selected from hydrogen, halogen, -C(O)-C 1-6 Alkyl, C 1-6 In some embodiments, wherein R D2 、R D3 Each is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -C(O)-methyl, -C(O)-ethyl, methoxy, ethoxy, methanesulfonyl. In some embodiments, wherein R D2 、R D3 Each is independently selected from hydrogen, fluorine, bromine, -C(O)-ethyl, methoxy, and methanesulfonyl.

[0045] In some embodiments, wherein R 1 、R 2 All are hydrogen.

[0046] In some embodiments, wherein R3 、R 4 All are hydrogen.

[0047] In some embodiments, wherein x1 is 3.

[0048] In some embodiments, wherein x2 is 3.

[0049] In some embodiments, wherein W is methyl.

[0050] In some embodiments, wherein R 5 、R 6 cannot be hydrogen at the same time, and are independently selected from hydrogen, halogen, C 1-6 In some embodiments, wherein R 5 、R 6 and R are not simultaneously hydrogen, and are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, and propoxy. 5 、R 6 It cannot be hydrogen at the same time, and each independently can be hydrogen, fluorine, chlorine, bromine, iodine, or methoxy.

[0051] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof, As defined above.

[0052] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof, As defined above.

[0053] In some embodiments, wherein Each is independently selected from the group consisting of halides, acetate, formate, benzoate, benzenesulfonate, camphorsulfonate, citrate, edisylate, fumarate, glucoheptanoate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, methanesulfonate, naphthoate, naphthylsulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogenphosphate, dihydrogenphosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, trifluoroacetate. In some embodiments, wherein are each independently selected from chloride, bromide, fluoride, iodide, trifluoroacetate, formate, methanesulfonate, and benzenesulfonate. Each is independently selected from chloride, bromide, trifluoroacetate, formate, methanesulfonate, and benzenesulfonate.

[0054] In some embodiments, the compound of Formula I or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof,

[0055] The present disclosure also provides isotopic substitutions of the aforementioned compounds or pharmaceutically acceptable salts thereof. In some embodiments, the isotopic substitutions are deuterated.

[0056] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0057] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0058] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0059] The present disclosure also provides use of the aforementioned compound or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in preparing a drug for neuromuscular blockade.

[0060] In certain embodiments, the neuromuscular blockade induced by the neuromuscular blocking agent can be reversed by a neuromuscular blocking agent antagonist, such as L-cysteine, D-cysteine, or a mixture thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or a combination thereof.

[0061] The present disclosure further provides a method for inducing neuromuscular blockade in a mammal for therapeutic purposes, comprising administering to the mammal an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same. The mammal may be a human or a non-human mammal, and the mammal may be subjected to general anesthesia. The therapeutic purpose may include surgical operation.

[0062] In certain embodiments, the method may further comprise the step of reversing neuromuscular blockade in the mammal, comprising administering to the mammal a neuromuscular blocker antagonist, such as L-cysteine, D-cysteine, or a mixture thereof; N-acetylcysteine; glutathione; homocysteine; methionine; S-adenosylmethionine; or penicillamine; or a combination thereof.

[0063] The present disclosure further provides a kit comprising the compound described herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition comprising the same. In certain embodiments, the kit may further comprise a neuromuscular blocker antagonist.

[0064] Pharmaceutically acceptable salts of the compounds disclosed herein may be selected from inorganic salts or organic salts. The inorganic salts may be selected from hydrochlorides, hydrobromides, phosphates, or sulfates; and the organic salts may be selected from acetates, trifluoroacetates, methanesulfonates, p-toluenesulfonates, citrates, maleates, tartrates, fumarates, citrates, or lactates.

[0065] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0066] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0067] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or or include both and Two configurations. For example, the compounds disclosed herein It can be any one of the following configurations, or it can contain both of the following configurations:

[0068] In the chemical structures of the compounds disclosed herein, the bond The configuration is not specified, that is, it can be Z configuration or E configuration, or contain both configurations. For example, the compounds disclosed in this invention It can be any one of the following configurations, or it can contain both of the following configurations:

[0069] Although all of the above formulae are drawn in certain isomeric forms for simplicity, the present disclosure may include all isomers, such as tautomers, geometric isomers, diastereomers, racemates, and enantiomers.

[0070] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine isomerizations. An example of a lactam-lactim equilibrium is between A and B as shown below.

[0071] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of this disclosure. The naming of the compounds does not exclude any tautomers.

[0072] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0073] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0074] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0075] Compared with the control compound, the disclosed compound has significant advantages in terms of in vivo efficacy and safety window.

[0076] Explanation of terms:

[0077] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0078] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or domestic animals.

[0079] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0080] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups of 1 to 6 carbon atoms. The alkyl group includes but is not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl and various branched isomers thereof. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, including but not limited to halogen, hydroxyl, oxo, amino, C 1-6 Alkyl, C 1-6 Alkoxy, 3 to 6 membered cycloalkyl, 3 to 6 membered heterocycloalkyl, 6 to 10 membered aryl or 5 to 10 membered heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group is optionally substituted by one or more halogen, hydroxyl, amino, C 1-6 Alkyl or C 1-6 Alkoxy substituted.

[0081] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 10 carbon atoms. Examples of monocyclic cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0082] The cycloalkyl or carbocyclic ring may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, including but not limited to halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0083] The term "heterocycloalkyl", "heterocyclyl" or "heterocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 6 to 10 ring atoms. Examples of monocyclic heterocycloalkyls include, but are not limited to, piperazine, piperidine, oxirane, thiophene, oxadiazine ... butyl ring, azetidine ring, thietidine ring, tetrahydropyrrole ring, tetrahydrofuran ring, tetrahydrothiophene ring, piperidine ring, tetrahydropyran ring, tetrahydrothiopyran ring, etc.; polycyclic cycloalkyl groups include spiro ring, condensed ring and bridged ring heterocycloalkyl groups.

[0084] Heterocycloalkyl, heterocyclyl or heterocycle may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0085] The term "aryl" or "aromatic ring" refers to any stable, monocyclic or bicyclic carbon ring of up to 7 atoms in each ring, wherein at least one ring is aromatic. Examples of such aryl groups include, but are not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl or binaphthyl. Unless otherwise specified, an aryl group or aromatic ring may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, hydroxyl, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0086] The term "heteroaryl" or "heteroaromatic ring" refers to a stable monocyclic or bicyclic ring of up to 7 atoms in each ring, wherein at least one ring is aromatic and at least one ring contains 1 to 4 heteroatoms selected from O, N and S. Heteroaromatic rings within the scope of this definition include, but are not limited to, pyridine, thiazine, pyrimidine, pyridazine, furan, pyrrole, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, benzofuran, isobenzofuran, isoindole, indole, benzothiophene, benzimidazole, indazole, benzoxazole, benzisoxazole, purine, benzothiazole, quinoline, isoquinoline, quinazoline, quinazolinone, and thioquinazolinone. Unless otherwise specified, heteroaryl or heteroaromatic rings may be substituted or unsubstituted.

[0087] Heteroaryl may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including but not limited to halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0088] The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined above. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy groups may be optionally substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups, including, but not limited to, halogen, hydroxy, thiol, carboxyl, amino, cyano, oxo, thio, C 1-6 Alkyl, C 1-6 The alkyl and alkoxy groups are optionally substituted by one or more halogen, hydroxy, mercapto, carboxyl, amino, and cyano groups.

[0089] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0090] The term "hydroxy" refers to -OH.

[0091] The term "amino" refers to -NH2.

[0092] The term "cyano" refers to -CN.

[0093] The term "nitro" refers to -NO2.

[0094] The term "oxo" or "oxo" refers to "=0".

[0095] The term "thio" or "thio" refers to "=S".

[0096] The term "carbonyl" refers to C=O.

[0097] The term "carboxy" refers to -C(O)OH.

[0098] The term "halo" refers to substitution with one or more atoms selected from fluorine, chlorine, bromine, and iodine.

[0099] The term "monovalent group" refers to a compound from which a univalent atom or group is "formally" eliminated.

[0100] The term "subunit" refers to an atom or group of atoms formed by "formally" eliminating two monovalent or one divalent atoms from a compound.

[0101] The term "alkylene" refers to the residue remaining after removing two hydrogen atoms from an alkane molecule, including straight-chain and branched subgroups of 1 to 20 carbon atoms. Examples of alkylene groups containing 1 to 6 carbon atoms include, but are not limited to, methylene (-CH2-) and ethylene (e.g., -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted.

[0102] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- atoms are replaced by a heteroatom selected from N, O and S, wherein the alkylene group is as defined above. Unless otherwise specified, a heteroalkylene group may be substituted or unsubstituted.

[0103] The term "cycloalkylene" refers to a group having two monovalent radical centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent cycloalkyl group. Examples of cycloalkylene groups include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. Cycloalkyl is as defined above.

[0104] The term "heterocyclylene" refers to a heterocyclic group having two monovalent radical centers, wherein the monovalent radical centers are derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent heterocyclic ring, by removing two hydrogen atoms from two nitrogen atoms of a parent heterocyclic ring, or by removing a hydrogen atom from a nitrogen atom and a hydrogen atom from a carbon atom of a parent heterocyclic ring. Examples of such heterocyclylene groups include, but are not limited to, piperidine-1,4-diyl, piperazine-1,4-diyl, tetrahydrofuran-2,4-diyl, tetrahydrofuran-3,4-diyl, azetidine-1,3-diyl, and pyrrolidine-1,3-diyl. Wherein, heterocyclyl is as defined above.

[0105] The term "arylene" refers to a monovalent radical having two centers derived by removing two hydrogen atoms from the same or two different carbon atoms of a parent aryl group. Examples of arylene groups include, but are not limited to Here, the aryl group is as defined above.

[0106] The term "heteroarylene" refers to a heteroaryl system having two points of attachment to the rest of the molecule. Examples of heteroarylene include, but are not limited to,

[0107] Here, heteroaryl is as defined above.

[0108] The term "substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. BRIEF DESCRIPTION OF THE DRAWINGS

[0109] Figure 1: Plasma histamine levels in rats before and after intravenous administration of 20 mg / kg (*P<0.05; **P<0.01) DETAILED DESCRIPTION

[0110] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure.

[0111] Experimental methods in the examples of this disclosure that do not specify specific conditions are generally based on conventional conditions or the conditions recommended by the raw material or product manufacturers. Reagents without specific sources are conventional reagents purchased from the market.

[0112] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (Methanol-d4). The internal standard was tetramethylsilane (TMS).

[0113] HPLC determination used Agilent1100 high pressure liquid chromatograph, GAS15B DAD UV detector, Water Vbridge C18 150*4.6mm 5um chromatographic column.

[0114] MS was determined using an Agilent 6120 triple quadrupole mass spectrometer, a G1315D DAD detector, and a Waters Xbridge C18 4.6*50mm, 5um column. The samples were scanned in positive / negative ion mode with a mass scan range of 80-1200.

[0115] The thin layer chromatography silica gel plate used was Yantai Huanghai HSGF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) was 0.2 mm ± 0.03 mm. The specification used for thin layer chromatography separation and purification products was 0.4 mm - 0.5 mm.

[0116] The flash column purification system used was Combiflash Rf150 (TELEDYNE ISCO) or Isolara one (Biotage).

[0117] Forward column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh or 300-400 mesh silica gel as the carrier, or uses Changzhou Santai pre-packed ultra-pure normal phase silica gel column (40-63μm, 60g, 24g, 40g, 120g or other specifications).

[0118] The known starting materials in the present disclosure can be synthesized by methods known in the art, or can be purchased from Shanghai Titan Technology, ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Bid Pharmaceuticals, etc.

[0119] Unless otherwise specified in the examples, all reactions were carried out under a nitrogen atmosphere.

[0120] Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a capacity of about 1L.

[0121] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0122] Hydrogen was produced by a QPH-1L hydrogen generator from Shanghai Quanpu Scientific Instrument Co., Ltd.

[0123] The nitrogen atmosphere or hydrogen atmosphere is usually evacuated and filled with nitrogen or hydrogen, and the operation is repeated three times.

[0124] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0125] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0126] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0127] Example 1 Preparation of Compound 1

[0128] Step 1)

[0129] Compound 1b (4.55 g, 28.89 mmol, purchased from Leyan) was weighed into a 250 mL reaction flask. Dichloromethane (90 mL), triethylamine (2.92 g, 28.89 mmol), compound 1a (3.2 g, 19.26 mmol, purchased from Leyan), and sodium triacetoxyborohydride (12.24 g, 57.77 mmol) were added and stirred at room temperature until the reaction was complete. Methanol (9 mL) was added to quench the reaction, followed by saturated sodium bicarbonate (NaHCO₃). The mixture was extracted with dichloromethane (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography (PE / EtOAc = 2:1) afforded 4.8 g of compound 1c (yield: 92%).

[0130] MS (ESI): m / z 272.3 [M+H] + .

[0131] 1 H NMR (400MHz, CDCl3) δ6.88(s,1H),6.84-6.74(m,2H),3.89(s,3H),3.87(s,3H),3.48(s,2H),2.53(t,4H),2.04-1.94(m,4H).

[0132] Step 2)

[0133] Compound 1c (2.4 g, 8.85 mmol) and propylene sulfate (3.67 g, 26.54 mmol) were weighed into a 100 mL reaction mixture. Acetonitrile (20 mL) was added and the mixture was heated in an oil bath until complete. Methyl tert-butyl ether (90 mL) was added to the mixture at room temperature, and the mixture was slurried. The mixture was filtered and dried to obtain 2.85 g of compound 1d (yield: 78.7%).

[0134] MS (ESI): m / z 410.3 [M+H] + .

[0135] 1 H NMR(400MHz,DMSO-d6)δ7.15(dd,1H),7.11(d,1H),7.05(d,1H),4.59(s,2H),3.89(t,2H),3.82( s,3H),3.80(s,3H),3.55-3.39(m,6H),2.60-2.53(m,1H),2.47-2.34(m,3H),2.19-2.15(m,2H).

[0136] Step 3)

[0137] Compound 1d (2.44 g, 5.96 mmol) was weighed into a 100 mL reaction mixture. MeOH (25 mL) and concentrated sulfuric acid (93.58 mg, 953.49 μmol) were added and heated until the reaction was complete. The mixture was cooled to room temperature and eluted with chloride ion exchange resin. The exchange solution was concentrated and lyophilized to obtain 2.4 g of compound 1e (yield: 122%).

[0138] MS (ESI): m / z 330.3 [M-Cl - ] + .

[0139] 1 H NMR(400MHz,DMSO-d6)δ7.20-7.18(m,2H),7.09(d,1H),4.65(s,2H),3.91(s,3H),3.90(s,3 H),3.75(t,2H),3.64-3.61(m,4H),3.54-3.50(m,2H),2.55-2.44(m,4H),2.20-2.14(m,2H).

[0140] Step 4)

[0141] In a 100 mL reaction vial, compound 1f (0.6 g, 1.24 mmol, prepared using the method disclosed in patent WO2014005122A2) was weighed, and N,N-dimethylformamide (8 mL), compound 1e (613.65 mg, 1.86 mmol), 4-methylpyridine (226.91 mg, 1.86 mmol), and HATU (706.22 mg, 1.86 mmol) were added. The mixture was reacted at room temperature until completion. The reaction solution was purified by HPLC (ammonium formate buffer) and lyophilized to obtain 390 mg of compound 1 (yield: 40%).

[0142] MS (ESI): m / z 398.4 [(M-2HCOO - / 2] + .

[0143] 1H NMR (400MHz, CDCl3) δ8.82(s,2H),7.30-7.25(m,1H),7.14(d,1H),6.88-6.79(m,5H),6.76-6.71(m,2H),6. 62(s,1H),5.61(s,1H),5.01-4.91(m,2H),4.69(d,1H),4.43-4.30(m,2H),4.22-4.17(m,1H),4.14-3.96(m, 4H),3.94-3.88(m,4H),3.85(s,3H),3.83(s,3H),3.76-3.70(m,4H),3.67-3.59(m,4H),3.57-3.45(m,3H), 3.38-3.30(m,6H),3.18-3.04(m,2H),2.80(t,1H),2.71-2.54(m,2H),2.46-2.30(m,4H),2.25-2.16(m,1H).

[0144] Example 2 Preparation of Compound 2

[0145] Step 1):

[0146] In a 100 mL reaction flask, compound 2a (2.00 g, 13.19 mmol, purchased from Leyan), potassium carbonate (5.47 g, 39.57 mmol), and potassium iodide (218 mg, 1.31 mmol) were weighed. Acetone (40 mL) was added, and 3-bromopropanol (1.65 g, 11.87 mmol) was added dropwise. The reaction was heated in an oil bath until the reaction was complete. The mixture was filtered, concentrated, and purified by column chromatography (MeOH / DCM = 1:10) to afford 2.17 g of compound 2b (94% yield).

[0147] MS (ESI): m / z 174.3 [M+H] + .

[0148] Step 2):

[0149] In a 100 mL reaction flask, compound 2b (1.00 g, 5.77 mmol) was weighed and dissolved in anhydrous acetonitrile (40 mL). 3,4-Dimethoxybenzyl bromide (1.33 g, 5.77 mmol) was added. Heat in an oil bath until the reaction was complete. The filtrate was concentrated and purified by column chromatography (MeOH / DCM = 1:10) to afford 1.29 g of compound 2c (yield: 55%).

[0150] MS (ESI): m / z 324.1 [M-Br - ] + .

[0151] 1 H NMR (400MHz, CD3OD) δ7.20-7.15(m,2H),7.10-7.05(m,1H),4.60(s,1H),4.52(s,1H),3.91-3.87(m,6H),3.76-3.67(m,2H),3.63 -3.58(m,1H),3.57-3.45(m,3H),3.45-3.38(m,4H),3.38-3.35(m,3H),2.39-2.26(m,1H),2.21-2.06(m,3H),2.05-1.92(m,2H).

[0152] Step 3):

[0153] In a 50 mL reaction flask, compound 1f (500 mg, 961.50 μmol), compound 2c (584 mg, 1.44 μmol), and HATU (549 mg, 1.44 mmol) were weighed and dissolved in anhydrous DMF (10 mL). 4-Methylpyridine (177 mg, 1.45 mmol) was added and the reaction was stirred at room temperature until the reaction was complete. The reaction solution was subjected to HPLC (trifluoroacetic acid buffer system) to obtain 513 mg of compound 2 (yield: 52%).

[0154] MS (ESI): m / z 395.4 [(M-2CF3COO - ) / 2] +

[0155] 1 H NMR(400MHz,DMSO-d6)δ7.14-6.95(m,5H),6.90-6.83(m,2H),6.82(s,1H),6.72-6.60(m,2H ),5.54(s,1H),4.64-4.58(m,1H),4.54-4.48(m,2H),4.30-4.23(m,2H),4.18-4.12(m,2H),3 .80-3.75(m,6H),3.74-3.69(m,6H),3.68-3.55(m,3H),3.52-3.27(m,11H),3.27-3.21(m,4 H),3.20(s,3H),3.14-3.05(m,2H),2.92-2.83(m,1H),2.26-2.15(m,4H),2.14-1.77(m,4H).

[0156] Example 3 Preparation of Compound 3

[0157] Step 1) Preparation of compound 3b

[0158] Compound 3a (2.18 g, 15.62 mmol, purchased from Bismuth), 3,4-dimethoxybenzaldehyde (2.00 g, 12.01 mmol), and triethylamine (1.22 g, 12.01 mmol) were dissolved in dichloromethane (40 mL) and stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (3.82 g, 18.02 mmol) was added and stirred at room temperature for 18 hours. The reaction mixture was adjusted to pH approximately 8 by adding saturated sodium carbonate solution. The layers were separated, and the aqueous phase was extracted once with dichloromethane (40 mL). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by normal phase purification (0-30% EA in PE) to afford compound 3b (2.68 g, 88% yield).

[0159] MS (ESI): m / z = 254.2 [M+H] + .

[0160] Step 2) Preparation of compound 3c

[0161] Compound 3b (1.10 g, 4.34 mmol) was weighed and dissolved in anhydrous acetonitrile (10 mL). Propylene sulfate (1.80 g, 13.03 mmol) was added. After complete addition, the mixture was stirred at 65°C for 16 hours. The reaction mixture was dried and purified by column chromatography (0-10% MeOH in DCM) to afford compound 3c (1.65 g, 97% yield).

[0162] MS (ESI): m / z = 392.3 [M+H] + .

[0163] Step 3) Preparation of compound 3d

[0164] Compound 3c (1.65 g, 4.22 mmol) was weighed and dissolved in methanol (16 mL). Concentrated sulfuric acid (42 mg, 428.26 μmol) was added and stirred at 60°C for 18 hours. The reaction mixture was passed through a chloride ion exchange resin (methanol as the eluent) three times, spin-dried, and lyophilized to afford compound 3d (1.28 g, 97% yield).

[0165] MS (ESI): m / z = 312.3 [M-Cl - ] + .

[0166] 1H NMR(400MHz,DMSO-d6)δ7.22-7.09(m,2H),7.08-7.02(m,1H),5.02-4.79(m,1H),4.61-4 .53(m,2H),3.84-3.75(m,6H),3.58-3.48(m,2H),3.47-3.28(m,6H),2.46-1.91(m,6H).

[0167] 19 F NMR (400MHz, DMSO-d6) δ-180.24,-183.73.

[0168] Step 4) Preparation of compound 3

[0169] Compound 1f (100 mg, 192.30 μmol) was weighed and dissolved in anhydrous DCM (2 mL). Oxalyl chloride (122 mg, 961.24 μmol) was added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane (10 mL), and then spin-dried to dryness. This was repeated twice, and then dissolved in anhydrous dichloromethane (2 mL). A solution of compound 3d (54 mg, 155.24 μmol) in anhydrous dichloromethane (2 mL) was slowly added dropwise and stirred at room temperature for 18 hours. Compound 3 (50.4 mg, 26% yield) was prepared using a reversed-phase trifluoroacetic acid system.

[0170] MS(ESI):m / z=389.4[(M-2Cl) / 2] + .

[0171] 1 H NMR(400MHz,DMSO-d6)δ7.17-6.95(m,5H),6.93-6.77(m,3H),6.75-6.59(m,2H ),5.55(s,1H),5.04-4.82(m,1H),4.66-4.52(m,3H),4.32-4.23(m,2H),4.21-4 .11(m,2H),3.98-3.86(m,1H),3.83-3.76(m,6H),3.75-3.69(m,6H),3.50-3.28 (m,13H),3.21(s,3H),3.14-3.05(m,2H),2.94-2.83(m,1H),2.44-1.96(m,8H).

[0172] 19 F NMR (400MHz, DMSO-d6) δ-180.11,-183.95.

[0173] Example 4 Preparation of Compound 4

[0174] Step 1) Preparation of compound 4b

[0175] Compound 4a (1.21 g, 7.82 mmol, purchased from Bismuth, lot number DTW951) and triethylamine (792 mg, 7.82 mmol) were dissolved in dichloromethane (150 mL) and stirred at room temperature for 10 minutes. 3,4-Dimethoxybenzaldehyde (1.0 g, 6.02 mmol, purchased from Adamas, lot number P2040957) was added, and the reaction was continued at room temperature for 2 hours. Sodium triacetylborohydride (1.91 g, 9.03 mmol) was added, and the reaction was allowed to continue overnight at room temperature to terminate the reaction. Saturated sodium carbonate solution (100 mL) was added, and the pH was adjusted to approximately 8. The organic phase was separated, and the aqueous phase was extracted twice with DCM (100 mL). The combined organic phases were dried, spin-dried, and purified by column chromatography (0-30% EA / PE) to afford compound 4b (1.1 g, yield: 67.76%).

[0176] MS (ESI): m / z = 270.2 [M+H] + .

[0177] Step 2) Preparation of compound 4c

[0178] Compound 4b (1.1 g, 4.08 mmol) and propylene sulfate (1.69 g, 12.23 mmol) were dissolved in acetonitrile (30 mL) and heated to 65°C overnight. The reaction was stopped, and the reaction solution was cooled to room temperature, concentrated under reduced pressure, and purified by column chromatography (0-25% MEOH / DCM) to obtain compound 4c (1.4 g, yield: 84.17%).

[0179] MS (ESI): m / z = 408.2 [M+H] + .

[0180] Step 3) Preparation of compound 4d

[0181] Compound 4c (1.4 g, 3.43 mmol) was dissolved in methanol (20 mL), and concentrated sulfuric acid (34 mg, 343 μmol) was added. After complete addition, the mixture was heated to 60°C and allowed to react overnight. The reaction was stopped, cooled to room temperature, and exchanged three times with chloride ion exchange resin (eluent: methanol). The entire methanol solution was collected and concentrated to dryness under reduced pressure to obtain compound 4d (1.05 g, yield: 93.03%).

[0182] MS (ESI): m / z = 328.3 [M-Cl - ] + .

[0183] Step 4) Preparation of Compound 4

[0184] Compound 4d (150 mg, 309 μmol) was dissolved in DMF (10 mL). HATU (177 mg, 464 μmol), compound 1f (101 mg, 309 μmol), and DIPEA (120 mg, 928.68 μmol) were added and stirred at room temperature overnight. The reaction mixture was purified by HPLC (0.3% TFA / MeCN) to afford compound 4 (38 mg, 15.44% yield).

[0185] MS (ESI): m / z = 397.2 [M-2Cl - ] + / 2.

[0186] 1 H NMR(400MHz,DMSO-d6)δ7.28-7.16(m,1H),7.11-6.98(m,5H),6.87-6.82(m,3H),6.6 7-6.66(m,2H),5.55(s,1H),4.63-4.60(m,3H),4.52(s,1H),4.31-4.25(m,3H),4.17 -4.12(m,2H),3.93-3.88(m,1H),3.78(s,6H),3.70(s,8H),3.39-3.33(m,10H),3.20 (s,3H),3.11-3.07(m,2H),2.91-2.85(m,1H),2.36-2.32(m,1H),2.22-2.08(m,6H).

[0187] Example 5 Preparation of Compound 5

[0188] Step 1) Preparation of compound 5b

[0189] Compound 5a (1.06 g, 7.82 mmol, purchased from Bismuth, lot number DQY244) and triethylamine (792 mg, 7.82 mmol) were dissolved in dichloromethane (150 mL) and stirred at room temperature for 10 minutes. 3,4-Dimethoxybenzaldehyde (1.00 g, 6.02 mmol, purchased from Adamas, lot number P2040957) was then added, and the reaction continued at room temperature for 2 hours. Sodium triacetylborohydride (1.91 g, 9.03 mmol) was then added, and the reaction continued at room temperature overnight. The reaction was stopped, and saturated sodium carbonate solution (100 mL) was added, adjusting the pH to approximately 8. The organic phase was separated, and the aqueous phase was extracted with dichloromethane (100 mL x 2). The combined organic phases were dried, concentrated, and purified by column chromatography (0-30% EA / PE) to afford compound 5b (1.2 g, 69.89% yield).

[0190] MS (ESI): m / z = 286.2 [M+1] + .

[0191] Step 2) Preparation of compound 5c

[0192] Compound 5b (1.2 g, 4.21 mmol) and propylene sulfate (1.74 g, 12.62 mmol) were dissolved in anhydrous acetonitrile (8 mL) and heated to 65°C for overnight reaction. The reaction solution was cooled to room temperature, stirred, concentrated, and purified by column chromatography (0-25% MEOH / DCM) to give compound 5c (1.23 g, yield: 69.06%).

[0193] MS (ESI): m / z = 424.3 [M+H] + .

[0194] Step 3) Preparation of compound 5d

[0195] Compound 5c (1.23 g, 2.90 mmol) was dissolved in methanol (15 mL), and concentrated sulfuric acid (29 mg, 290 μmol) was added. After complete addition, the mixture was heated to 60°C and stirred overnight. The reaction solution was cooled to room temperature and exchanged three times with chloride ion exchange resin (eluent: methanol). The entire methanol solution was collected and concentrated to dryness under reduced pressure to obtain compound 5d (1.0 g, yield: 99.96%).

[0196] MS (ESI): m / z = 344.3 [M-Cl - ] + .

[0197] Step 4) Preparation of Compound 5

[0198] Compound 5d (100 mg, 207 μmol) was dissolved in dichloromethane (8 mL), and oxalyl chloride (210 mg, 1.65 mmol) was added. The mixture was stirred at room temperature for 3 hours. The mixture was concentrated under reduced pressure, and 5 mL of dry dichloromethane and compound 1f (71 mg, 207 μmol) were added. The mixture was stirred at room temperature overnight. The reaction mixture was concentrated to dryness under reduced pressure and subjected to HPLC (0.3% TFA / MeCN) to afford compound 5 (32 mg, 19.12% yield).

[0199] MS (ESI): m / z = 405.2 [M-2Cl - ] + / 2.

[0200] 1 H NMR (400MHz, DMSO-d6) δ7.14-6.97(m,5H),6.87-6.82(m,4H),6.67(d,J=2.8Hz,1H ),6.64(s,1H),5.54(d,J=1.8Hz,1H),4.73-4.58(m,4H),4.31-4.10(m,6H),3.96- 3.85(m,3H),3.78-3.77(m,7H),3.71-3.70(m,9H),3.33-3.32(m,4H),3.32-3.18( m,4H),3.16-3.09(m,2H),2.91-2.85(m,2H),2.32-2.22(m,5H),1.03-1.00(m,2H).

[0201] 19 F NMR (400MHz, DMSO-d6) δ-104.60,-115.47.

[0202] Example 6 Preparation of Compound 6

[0203] Step 1) Preparation of compound 6b

[0204] Compound 6a (5.09 g, 23.00 mmol, purchased from Shanghai Bid Pharmaceutical Technology Co., Ltd.) was dissolved in pyridine (50 mL). DMAP (281 mg, 2.30 mmol) and triphenylmethane (7.69 g, 27.60 mmol) were added with stirring at room temperature. The mixture was stirred at room temperature for 4 hours. The reaction mixture was spin-dried and purified by normal phase purification (0-50% EA in PE) to afford compound 6b (6.59 g, 61% yield).

[0205] MS (ESI): m / z = 464.4 [M+1] + .

[0206] Step 2) Preparation of compound 6c

[0207] Oxalyl chloride (1.97 g, 15.53 mmol) was dissolved in dichloromethane (120 mL), and the atmosphere was replaced with nitrogen at -78°C with stirring. Dimethyl sulfoxide (2.43 g, 31.06 mmol) was added dropwise, and the mixture was stirred for 10 minutes. A solution of compound 6b (6 g, 12.94 mmol) in dichloromethane (60 mL) was then added dropwise, and the mixture was stirred for 15 minutes. Triethylamine (6.55 g, 64.71 mmol) was added, and the mixture was stirred at -78°C for 2 hours. The mixture was quenched with water (40 mL), stirred at room temperature, and the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The mixture was purified by column chromatography (0-25% EA in PE) to afford compound 6c (5.13 g, 85% yield).

[0208] MS (ESI): m / z = 462.4 [M+1] + .

[0209] 1 H NMR (400MHz, CDCl3) δ7.39-7.19(m,20H),3.68-3.51(m,3H),3.33-3.26(m,1H), 3.16(t,J=9.2Hz,1H),2.97-2.80(m,2H),2.57-2.40(m,2H),2.37-2.24(m,2H).

[0210] Step 3) Preparation of compound 6d

[0211] Compound 6c (5 g, 10.83 mmol) was dissolved in dichloromethane (100 mL), and diethylaminosulfur trifluoride (6.98 g, 43.33 mmol) was added. The mixture was stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate was added to adjust the pH to approximately 8, and the mixture was extracted with dichloromethane (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and dried. The mixture was then purified by column chromatography (0-20% EA in PE) to afford compound 6d (4.72 g, 90% yield).

[0212] MS (ESI): m / z = 484.4 [M+1] + .

[0213] 1 H NMR (400MHz, CDCl3) δ7.46-7.18(m,20H),3.62-3.44(m,3H),3.15-3.00(m,2H),2.72-2.64(m,1H),2.43-2.15(m,3H),1.98-1.84(m,2H).

[0214] 19 F NMR(400MHz, CDCl3)δ-98.35,-98.99.

[0215] Step 4) Preparation of compound 6e

[0216] Compound 6d (4.61 g, 9.53 mmol) was dissolved in methanol (46 mL), and 10% Pd / C (461 mg) was added. The mixture was replaced with hydrogen and stirred at room temperature. The reaction mixture was filtered, dried, and purified by column chromatography (0-100% ACN in water) to afford compound 6e (3.46 g, 92% yield).

[0217] 1 H NMR (400MHz, CDCl3) δ7.46-7.38(m,6H),7.34-7.19(m,9H),3.56-3.49(m,1H),3.39-3.30(m,1H),3.12-2. 96(m,2H),2.83-2.72(m,1H),2.67-2.56(m,1H),2.25-2.08(m,1H),1.97-1.86(m,1H),1.86-1.68(m,1H).

[0218] Step 5) Preparation of compound 6f

[0219] Compound 6e (3.24 g, 8.23 ​​mmol) was dissolved in acetonitrile (64 mL), and potassium carbonate (2.28 g, 16.47 mmol) and sodium iodide (124 mg, 827.25 μmol) were added. (3-bromopropoxy)(tert-butyl)diphenylsilane (3.11 g, 8.23 ​​mmol, obtained using the known method "Angewandte Chemie - International Edition, 2015, vol. 54, #51, pp. 15497–15500") was added with stirring at room temperature and stirred at 65°C for 1 hour. The reaction mixture was filtered, dried, and purified by column chromatography (0-10% EA in PE) to afford compound 6f (2.69 g, 47% yield).

[0220] MS (ESI): m / z = 690.5 [M+H] + .

[0221] 1H NMR (400MHz, CDCl3) δ7.70-7.64(m,4H),7.46-7.32(m,12H),7.32-7.17(m,9H),3.74-3.66(m,2H),3.53-3.46(m,1H),3.08-3.97(m,2H),2.74 -2.66(m,1H),2.58-2.38(m,2H),2.38-2.25(m,1H),2.21-2.10(m,1H) ,2.10-1.98(m,1H),1.96-1.82(m,2H),1.78-1.67(m,2H),1.05(s,9H).

[0222] Step 6) Preparation of compound 6g

[0223] Compound 6f (2.69 g, 3.90 mmol) and 3,4-dimethoxybenzyl bromide (1.80 g, 7.80 mmol) were dissolved in acetonitrile (54 mL) and stirred at 80°C for 1 hour. The reaction mixture was evaporated to dryness and purified by column chromatography (0-15% MEOH in DCM) to afford compound 6g (2.41 g, 91% yield).

[0224] MS (ESI): m / z = 598.3 [M-Br - ] + .

[0225] Step 7) Preparation of compound 6h

[0226] Compound 6g (300 mg, 500.99 μmol) was dissolved in methanol (3 mL), and 10 mL of 4.0 M HCl / Dioxane solution was added. The mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure and purified by column chromatography (0-10% ACN in water) to afford compound 6h (152 mg, 84% yield).

[0227] MS (ESI): m / z = 360.3 [M-Br - ] + .

[0228] 1H NMR (400MHz, CD3OD) δ7.24-7.14(m,2H),7.11-7.03(m,1H),4.73-4.54(m,2H),4.13-3.95(m,1H),3.89(s,3H),3.87(s,3H),3.81 -3.70(m,3H),3.70-3.57(m,4H),3.57-3.34(m,2H),2.96-2.69(m,1H),2.69-2.46(m,1H),2.46-2.29(m,1H),2.29-2.01(m,2H).

[0229] Step 8) Preparation of Compound 6

[0230] Compound 1f (150 mg, 288.45 μmol) and compound 6h (127 mg, 288.42 μmol) were dissolved in anhydrous DMF (2 mL). HATU (165 mg, 433.94 μmol) and DMAP (53 mg, 433.82 μmol) were added with stirring on an ice bath. The mixture was stirred at room temperature for 2 hours. The reaction mixture was treated with reversed-phase trifluoroacetic acid to yield compound 6 (63 mg, 20% yield).

[0231] MS(ESI):m / z=413.2[(M-2CF3COO - ) / 2] + .

[0232] 1 H NMR(400MHz,DMSO-d6)δ7.30-6.56(m,11H),5.55(s,1H),5.03-4.57(m,3H),4.57-4.37 (m,1H),4.37-4.26(m,1H),4.26-4.05(m,3H),4.05-3.83(m,4H),3.83-3.76(m,9H),3.6 2-3.42(m,9H),3.42-3.35(m,3H),3.34(s,3H),3.21(s,3H),3.17-2.99(m,3H),2.92-2 .83(m,1H),2.70-2.53(m,1H),2.44-2.32(m,1H),2.32-2.08(m,3H),2.07-1.93(m,1H).

[0233] 19 F NMR(400MHz, DMSO-d6)δ-69.19,-71.08,-103.63,-112.13.

[0234] Example 7 Preparation of Control Compound 1

[0235] Prepared by referring to the method disclosed in US4761418A.

[0236] Example 8 Preparation of Control Compound 2

[0237] Prepared by the method disclosed in reference patent WO2021115413.

[0238] Example 9 Preparation of Control Compound 3

[0239] The preparation method was disclosed in reference (Anesthesiology November 2018, Vol. 129, 970-988.).

[0240] Biological evaluation

[0241] Test Example 1 Pharmacodynamics Test

[0242] 1. Test compound

[0243] Samples: Compound 1, Compound 2, Control Compound 1, and Control Compound 2, all prepared with physiological saline.

[0244] 2. Experimental Animals

[0245] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0246] 3. Experimental steps

[0247] 1) Weigh the rat and anesthetize it by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the rat loses consciousness and is no longer reflexed, secure it in a prone position on a foam board. Depilate the right hind limb. Isolate the trachea and external jugular vein, intubate the trachea and intravenously, and prepare a ventilator.

[0248] 2) Behind the hip joint, make an incision in the skin at the mid-thigh, just outside the femur. Using a glass needle, bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the calf at the ankle joint, sever the anterior ankle ligament, separate the gastrocnemius muscle, and tie a ligature around the gastrocnemius tendon at the ankle. The tendon is severed distal to the ligature.

[0249] 3) Use a biofunctional experimental system to collect and record signals. Connect the gastrocnemius ligature to the tension transducer and the stimulator to the sciatic nerve. The experiment was set to investigate the effect of stimulation intensity on skeletal muscle contraction. The parameters were set to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms wave width, 10 ms wave interval, 8 Hz frequency, 0.350 V intensity, 0 intensity increment, 4 train lengths, and a 12 s main cycle. The muscle tension curve was recorded.

[0250] 4) After the signal stabilizes, inject 0.5 mg / kg of the different test compounds via the jugular vein and record the suppression of muscle tension after administration. During the measurement, keep the muscles and nerves moist with normal saline at all times, moistening every five minutes.

[0251] Experimental indicators:

[0252] Muscle tone inhibition %=(baseline muscle tone-muscle tone after drug administration) / baseline muscle tone*100%.

[0253] 4. Results

[0254] The inhibition rate of muscle tension of rats by 0.5 mg / kg of the disclosed compound is shown in Table 1 below.

[0255] Table 1

[0256] Compared with the control compound, Compound 1 of the present disclosure exhibits superior neuromuscular blocking efficacy.

[0257] Test Case 2: Security Testing

[0258] 1. Test compound

[0259] Samples: Compound 1, Compound 2, Control Compound 1, Control Compound 2, Control Compound 3, all prepared with physiological saline.

[0260] 2. Experimental Animals

[0261] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0262] 3. Experimental steps

[0263] 1) Rats were weighed and anesthetized by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the animals lost consciousness and were no longer reflexed, they were secured in a prone position on a foam board. The right hind limb was depilated. One jugular vein was cannulated for drug injection, and the other for blood collection.

[0264] 2) After stabilization for 15 minutes, draw 0.5 mL of venous blood into an EP tube containing sodium heparin saline (1:9), mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice. After stabilization for 15 minutes, administer a 20 mg / kg intravenous muscle relaxant. Immediately 1 minute after administration, draw 0.5 mL of venous blood, mix thoroughly, cool, and centrifuge at 4°C (1000 rpm, 10 minutes). Collect 0.2 mL of the upper plasma layer and freeze on dry ice.

[0265] 3) After the above plasma was processed, the histamine content in the rat plasma before and after administration was detected by LC-MS / MS.

[0266] 4. Results

[0267] The release of histamine in rats after intravenous administration of the disclosed compound at 20 mg / kg is shown in Figure 1. A common adverse reaction to the use of clinical muscle relaxants is histamine release. Histamine release after muscle relaxant injection can induce bronchospasm, increased heart rate, and decreased blood pressure, which endangers the health of patients. Under this test, the control compounds all had significant histamine release, while compound 1 described in the present disclosure did not show a significant increase in histamine. The safety of compound 1 described in the present disclosure is significantly better than that of control compound 1, control compound 2, and control compound 3.

[0268] Test Example 3 Pharmacodynamics Test

[0269] 1. Test compound

[0270] Samples: Compound 1, compounds 3-6, and control compound 3, all prepared with normal saline.

[0271] 2. Experimental Animals

[0272] SD rats (source: Beijing Huafukang Biotechnology Co., Ltd.), male, weighing 200-350 g before the experiment, were housed in an SPF-grade environment with 12 h of light per day.

[0273] 3. Experimental steps

[0274] 1) Weigh the rat and anesthetize it by intraperitoneal injection of 1 mL / 100 g of 25% urethane prepared with ethyl carbamate. After the rat loses consciousness and is no longer reflexed, secure it in a prone position on a foam board. Depilate the right hind limb. Isolate the trachea and external jugular vein, intubate the trachea and intravenously, and prepare a ventilator.

[0275] 2) Behind the hip joint, make an incision in the skin at the mid-thigh, just outside the femur. Using a glass needle, bluntly dissect the muscles to expose the sciatic nerve. Cut the skin of the calf at the ankle joint, sever the anterior ankle ligament, separate the gastrocnemius muscle, and tie a ligature around the gastrocnemius tendon at the ankle. The tendon is severed distal to the ligature.

[0276] 3) Use a biofunctional experimental system to collect and record signals. Connect the gastrocnemius ligature to the tension transducer and the stimulator to the sciatic nerve. The experiment was set to investigate the effect of stimulation intensity on skeletal muscle contraction. The parameters were set to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms wave width, 10 ms wave interval, 8 Hz frequency, 0.350 V intensity, 0 intensity increment, 4 train lengths, and a 12 s main cycle. The muscle tension curve was recorded.

[0277] 4) After the signal stabilizes, inject 0.5 mg / kg of the different test compounds via the jugular vein and record the suppression of muscle tension after administration. During the measurement, keep the muscles and nerves moist with normal saline at all times, moistening every five minutes.

[0278] Experimental indicators:

[0279] Muscle tone inhibition %=(baseline muscle tone-muscle tone after drug administration) / baseline muscle tone*100%.

[0280] 4. Results

[0281] The inhibition rate of muscle tension of rats by 0.5 mg / kg of the disclosed compound is shown in Table 1 below.

[0282] Table 1

[0283] Compared with the control compound, the compounds disclosed herein exhibit excellent neuromuscular blocking efficacy and are superior to the control compound 3.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt thereof, Wherein: W is selected from -C(R a R b R c ) or each independently selected from pharmaceutically acceptable anions; R 3 、R 4 each independently selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; L B and L C each independently selected from -C(R a R b R c ) or alkylene, said alkylene optionally substituted by one or more halogen, hydroxy, mercapto, nitro, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, oxo, thioxo or sulfonyl, said C 1-6 alkyl, C 1-6 alkoxy optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; When L B is -C(R a R b R c ), there is no phenyl group having R B1 ~R B5 substituents; When L C is -C(R a R b R c ), there is no phenyl group having R D1 ~R D5 substituents; R 1 、R 2 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、R W1 、R W2 、R W3 、R W4 、R W5 、R a 、R b 、R c each independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring are optionally substituted by one or more halogen, hydroxyl, mercapto, carboxyl, amino, cyano, Alternatively, R 1 and R 2 together with the atoms to which they are attached form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, said carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring being optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, said alkyl groups, alkoxy groups being optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, Alternatively, any two adjacent Rs A1 , R A2 , R A3 , R A4 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs B1 , Rs B2 , Rs B3 , Rs B4 , Rs B5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs D1 , Rs D2 , Rs D3 , Rs D4 , Rs D5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-, Alternatively, any two adjacent Rs W1 , Rs W2 , Rs W3 , Rs W4 , Rs W5 together form methylenedioxy, ethylenedioxy, -CH2-O-CH2-; R 5 and R 6 cannot both be hydrogen and are each independently selected from hydrogen, halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring are optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; Alternatively, R 5 and R 6 together with the atoms to which they are attached form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, and the carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring are optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, and the alkyl groups and alkoxy groups are optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups, cyano groups; x1 is selected from 1, 2, 3, 4, 5, 6; x2 is selected from 1, 2, 3, 4, 5, 6; x3 is selected from 0, 1, 2, 3, 4, 5; x4 is selected from 0, 1, 2, 3, 4, 5, 6, 7, 8.

2. The compound or its pharmaceutically acceptable salt according to claim 1, wherein L B , L C are each independently an alkylene group, and the alkylene group is optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, nitro groups, carboxyl groups, amino groups, cyano groups, C 1-6 alkyl groups, C 1-6 alkoxy groups, oxo groups, thio groups or sulfonyl groups, and the C 1-6 alkyl groups and C 1-6 alkoxy groups are optionally substituted by one or more halogen atoms, hydroxyl groups, mercapto groups, carboxyl groups, amino groups or cyano groups.

3. The compound or its pharmaceutically acceptable salt according to claim 1 or 2, wherein the compound represented by formula I is selected from the compounds represented by formula II or their pharmaceutically acceptable salts, R d 、R e are each independently selected from hydrogen, halogen, hydroxyl, mercapto, carboxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -C(O)-C 1-6 alkyl, -C(O)-C 1-6 alkoxy, mesyl, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, wherein the alkyl, alkoxy, carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring are optionally substituted by one or more halogen, hydroxyl, mercapto, carboxyl, amino, cyano; Alternatively, R d and R e together with the atom to which it is attached form an oxo group, a thio group, a 3- to 10-membered carbocyclic ring, a 3- to 10-membered heterocyclic ring, a 6- to 10-membered aromatic ring or a 5- to 10-membered heteroaromatic ring, said carbocyclic ring, heterocyclic ring, aromatic ring, heteroaromatic ring being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, said alkyl, alkoxy being optionally substituted by one or more halogen, hydroxy, mercapto, carboxy, amino, cyano; x5 is selected from 1, 2, 3, 4, 5, 6; x6 is selected from 1, 2, 3, 4, 5, 6; W、 R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、 x1, x2, x3, x4 are as defined in claim 1.

4. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein x5 and x6 are each independently 1.

5. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the compound represented by formula I is selected from the compounds represented by formula III or a pharmaceutically acceptable salt thereof, W、 R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R A1 、R A2 、R A3 、R A4 、R B1 、R B2 、R B3 、R B4 、R B5 、R C 、R D1 、R D2 、R D3 、R D4 、R D5 、x1, x2, x3, x4 are as defined in claim 1, R d 、R e as defined in claim 3.

6. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein x3 is 0.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein R A1 , R A4 , R B1 , R B2 , R D1 , R D4 , R D5 are each independently hydrogen.

8. The compound or its pharmaceutically acceptable salt according to any one of claims 1 to 7, wherein the compound represented by formula I is selected from the compounds represented by formula IV or their pharmaceutically acceptable salts, W、 R 1 、R 2 、R 3 、R 4 、R 5 、R 6 、R 7 、R A2 、R A3 、R B3 、R B4 、R D2 、R D3 、x1, x2, x4 are as defined in claim 1, R d 、R e as defined in claim 3.

9. The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R A2 , R A3 , R B3 , R B4 are each independently selected from hydrogen, C 1-6 alkoxy, preferably hydrogen, methoxy, ethoxy, propoxy, most preferably hydrogen, methoxy.

10. The compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof, wherein R D2 , R D3 are each independently selected from hydrogen, halogen, -C(O)-C 1-6 alkyl, C 1-6 alkoxy, mesyl, preferably hydrogen, fluorine, chlorine, bromine, iodine, -C(O)-methyl, -C(O)-ethyl, methoxy, ethoxy, mesyl, most preferably hydrogen, fluorine, bromine, -C(O)-ethyl, methoxy, mesyl.

11. The compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 are all hydrogen.

12. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, wherein x1 and x2 are each independently 3.

13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 12, wherein W is methyl.

14. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13, wherein R 5 , R 6 cannot both be hydrogen, and each independently is selected from hydrogen, halogen, C 1-6 alkoxy, preferably hydrogen, fluorine, chlorine, bromine, iodine, methoxy, ethoxy, propoxy, and most preferably hydrogen, fluorine, chlorine, bromine, iodine, methoxy.

15. The compound of formula I or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, As defined in claim 1.

16. The compound of formula I or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, As defined in claim 1.

17. The compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, wherein each independently selected from halide ions, acetate, formate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheptonate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, mesylate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, polygalacturonate, succinate, sulfate, sulfosalicylic acid, tartrate, toluenesulfonate, trifluoroacetate, preferably chloride, bromide, fluoride, iodide, trifluoroacetate, formate, mesylate, benzenesulfonate, most preferably chloride, bromide, trifluoroacetate, formate, mesylate, benzenesulfonate.

18. The compound of formula I or a pharmaceutically acceptable salt thereof, which is selected from the following compounds or pharmaceutically acceptable salts thereof, 19. An isotopically substituted compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, preferably, the isotopically substituted compound is a deuterated compound.

20. A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or an isotopically substituted compound according to claim 19, and a pharmaceutically acceptable excipient.

21. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 18, or an isotopically substituted compound according to claim 19, or a pharmaceutical composition according to claim 20 in the manufacture of a medicament for neuromuscular blockade.

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