Tetra-fused ring biquaternary ammonium salt compound and application thereof in medicine

Abstract

The invention relates to a tetra-fused ring biquaternary ammonium salt compound and application thereof in medicine, in particular to a compound shown in a general formula (I) or a stereoisomer, a racemate, a tautomer, a deuterated compound, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt or eutectic thereof, and an intermediate and a pharmaceutical composition thereof. The invention also relates to application in preparation of neuromuscular retardation drugs. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to a compound described by general formula (I) or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and intermediates and pharmaceutical compositions thereof, as well as use thereof in preparing neuromuscular blocking drugs. Background Art

[0002] Neuromuscular blockers (NMBs), also known as skeletalmuscular relaxants, are N2-cholinoceptor blocking drugs. After binding to the N2 choline receptors on the motor endplate membrane of skeletal muscle, muscle relaxants block the normal transmission of nerve impulses at the neuromuscular junction, leading to skeletal muscle relaxation. Based on whether the membrane is depolarized after binding to the receptor, it is divided into depolarizing blockers (non-competitive) and non-depolarizing blockers (competitive). Depolarizing blockers simulate Ach (acetylcholine) and bind to N receptors non-competitively and irreversibly, such as succinylcholine. Non-depolarizing blockers compete with Ach for binding to N receptors at the Ach recognition site (α subunit). The receptor configuration remains unchanged, the ion channel does not open, and depolarization cannot be produced, such as rocuronium bromide, cisatracurium, etc.

[0003] There are many benefits to using muscle relaxants during anesthesia: eliminating vocal cord activity to successfully complete endotracheal intubation; meeting the requirements for muscle relaxation in various surgeries or diagnosis and treatment; weakening or terminating muscle rigidity caused by certain skeletal muscle spasm diseases; and eliminating the asynchrony between the patient's spontaneous breathing and mechanical ventilation. Summary of the invention

[0004] The object of the present invention is to provide a compound or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a neuromuscular blocker, which has a fast onset time, a fast recovery time, good pharmacokinetic properties and good safety.

[0005] The compound of the invention has a good muscle relaxant effect and has a good inhibitory effect on the contraction of the sciatic nerve-extensor digitorum longus muscle.

[0006] The present invention provides a compound or its stereoisomer, racemate, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from the compounds represented by general formula (I),

[0007]

[0008] In some embodiments, the compound of formula (I) is selected from the compounds represented by formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f),

[0009]

[0010]

[0011] In some embodiments, B is selected from

[0012] In some embodiments, B is selected from

[0013] In some embodiments, B is selected from

[0014] In some embodiments, B is selected from

[0015] In some embodiments, n3, n6, and n7 are each independently selected from 2;

[0016] In some embodiments, L is selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace;

[0017] In some embodiments, L is selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace;

[0018] In some embodiments, L is selected from the group consisting of k substituted one of the following groups: methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene, pentenylene, ethynylene, propynylene, butynylene, pentynylene;

[0019] In some embodiments, R 1 , R 2 , R 3 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R kreplace;

[0020] In some embodiments, R 1 , R 2 , R 3 Each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0021] In some embodiments, R 1 , R 2 , R 3 Each independently selected from optionally 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0022] In some embodiments, R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0023] In some embodiments, R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl;

[0024] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 4- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0025] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is connected, it forms a 4-7-membered monoheterocyclic group, a 5-10-membered bridged heterocyclic group, a 7-10-membered heterocyclic group or a 7-10-membered spiro heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0026] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted R k One of the following groups substituted:

[0027]

[0028] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted:

[0029]

[0030] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted:

[0031]

[0032] In some embodiments, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms one of the following groups:

[0033] In some embodiments, R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0034] In some embodiments, R a1 , R a2 , R b1 , R b2 , R b3, R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0035] In some embodiments, R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0036] In some embodiments, R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0037] In some embodiments, R a1 , R a2 , R b1 , R b2 , Rb3 , R b4 , R b5 , R b6 , R b7 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NO2, COOH, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0038] In some embodiments, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently forms, together with the atoms to which it is attached, a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0039] In some embodiments, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently and together with the atoms to which it is attached form an optionally substituted R k One of the following groups substituted:

[0040] In some embodiments, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently and together with the atoms to which it is attached form an optionally substituted 1 to 2 R k One of the following groups substituted:

[0041] In some embodiments, R 3 , R b7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0042] In some embodiments, R 3 , R b7 Together with the atoms to which it is attached, it forms a k One of the following substituted groups: azacyclopentyl, azacyclohexenyl;

[0043] In some embodiments, R 3 , R b7 Together with the atoms to which it is attached, it forms a k One of the following groups substituted:

[0044]

[0045] In some embodiments, Selected from

[0046] In some embodiments, Selected from

[0047] In some embodiments, Selected from

[0048] In some embodiments, Selected from

[0049] In some embodiments, Selected from

[0050] In some embodiments, Selected from

[0051] In some embodiments, Selected from

[0052] In some embodiments, R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0053] In some embodiments, R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 substituted by an alkoxy substituent;

[0054] In some embodiments, R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0055] In some embodiments, Rk Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0056] In some embodiments, R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NH2, NO2, SF5, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0057] In some embodiments, X z- is a pharmaceutically acceptable anion;

[0058] In some embodiments, X z-Selected from halogen, acetate, benzoate, camphorsulfonate, citrate, glucoheptanoate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthylsulfonate, stearate, oleate, oxalate, dihydronaphthoate, nitrate, phosphate, sulfate, hydrogen phosphate alanine, arginine, lysine, cinnamate, propionate, valerate, triphenylacetate, L-proline, ferulate, mandelate, malonate, gentisate, salicylate, or glutarate;

[0059] In some embodiments, X - Selected from Cl-, Br - , I-, trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.

[0060] In some embodiments, m is 0.5, 2 / 3, 1 or 2;

[0061] In some embodiments, m is 1 or 2;

[0062] In some embodiments, m is 2;

[0063] In some embodiments, z is 1, 2, 3, 4;

[0064] In some embodiments, z is 1 or 2;

[0065] In some embodiments, z is 1;

[0066] In some embodiments, s1 or s2 are each independently selected from 0, 1, 2, 3, 4;

[0067] In some embodiments, s1 or s2 are each independently selected from 0, 1 or 2;

[0068] In some embodiments, s1 or s2 are each independently selected from 2;

[0069] In some embodiments, n1, n2, n3 or n7 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0070] In some embodiments, n4, n5 or n6 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0071] In some embodiments, n1, n2, n3 or n7 are each independently selected from 0, 1, 2 or 3;

[0072] In some embodiments, n4 and n5 are each independently selected from 1 or 2.

[0073] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0074] B is selected from

[0075] L is selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace;

[0076] R 1 , R 2 , R 3 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0077] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0078] Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 4- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0079] Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently forms, together with the atoms to which it is attached, a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0080] Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0081] X z - is a pharmaceutically acceptable anion;

[0082] m is 0.5, 2 / 3, 1 or 2;

[0083] z is 1, 2, 3, 4;

[0084] s1 or s2 are each independently selected from 0, 1, 2, 3 or 4;

[0085] n1, n2, n3 or n7 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0086] n4, n5 or n6 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8;

[0087] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

[0088] As a second embodiment of the present invention, the compound represented by the following general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0089] X z- Selected from halides, acetate, benzoate, camphorsulfonate, citrate, glucoheptanoate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthylsulfonate, stearate, oleate, oxalate, dihydronaphthoate, nitrate, phosphate, sulfate, phosphoric acid hydrogen, dihydrogen phosphate, polygalacturonate, succinate, sulfosalicylate, tartrate, trifluoroacetate, hippurate, D-glucuronate, glycolate, mucate, orotenate, pamoate, glycine, alanine, arginine, lysine, cinnamate, propionate, valerate, triphenylacetate, L-proline, ferulate, mandelate, malonate, gentisate, salicylate, or glutarate;

[0090] L is selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace;

[0091] R 1 , R 2 , R 3 Each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0092] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-4 Alkyl, -OC1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace;

[0093] Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is connected, it forms a 4- to 7-membered monoheterocyclic group, a 5- to 10-membered bridged heterocyclic group, a 7- to 10-membered heterocyclic group or a 7- to 10-membered spiro heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0094] Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently forms, together with the atoms to which it is attached, a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0095] Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace;

[0096] R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C1-6 substituted by an alkoxy substituent;

[0097] The remaining definitions are the same as those of the first embodiment of the present invention.

[0098] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0099] L is selected from 1 to 4 R k substituted one of the following groups: methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene, pentenylene, ethynylene, propynylene, butynylene, pentynylene;

[0100] R 1 , R 2 , R 3 Each independently selected from optionally 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0101] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0102] Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7Each independently and together with the atoms to which it is attached form an optionally substituted R k One of the following groups substituted:

[0103] Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted R k One of the following groups substituted:

[0104]

[0105] Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a k One of the following substituted groups: azacyclopentyl, azacyclohexenyl;

[0106] R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 substituted by an alkoxy substituent;

[0107] The remaining definitions are the same as those of the first or second embodiment of the present invention.

[0108] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0109] R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R kSubstituted one of the following groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0110] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0111] Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently and together with the atoms to which it is attached form an optionally substituted 1 to 2 R k One of the following groups substituted:

[0112] R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0113] m is 1 or 2;

[0114] z is 1 or 2;

[0115] s1 or s2 are each independently selected from 0, 1 or 2;

[0116] The remaining definitions are the same as those of the first, second or third embodiment of the present invention.

[0117] As a fifth embodiment of the present invention, the compound represented by the following general formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0118]

[0119] n4 and n5 are each independently selected from 1 or 2;

[0120] Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted:

[0121] R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NO2, COOH, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0122] Alternatively, B is selected from

[0123] R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NH2, NO2, SF5, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl;

[0124] X - Selected from Cl-, Br -, I-, trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate;

[0125] The remaining definitions are the same as those of the first, second, third or fourth embodiment of the present invention.

[0126] As a sixth embodiment of the present invention, the compound represented by the above general formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f) or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal,

[0127] B is selected from

[0128] R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl;

[0129] Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted:

[0130] Selected from

[0131] Selected from

[0132] Selected from

[0133] As an alternative, Selected from

[0134] As an alternative, Selected from Selected from

[0135] The remaining definitions are the same as those of the first, second, third, fourth or fifth embodiment of the present invention.

[0136] The present invention relates to the following compound or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein the compound is selected from one of the structures in Table S, X - Selected from Cl - Br - ,I - , trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.

[0137] The present invention relates to a pharmaceutical composition, comprising the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

[0138] The present invention relates to use of the above-mentioned compound of the present invention or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in preparing neuromuscular blocking drugs.

[0139] The present invention relates to a pharmaceutical composition or pharmaceutical preparation, which comprises a therapeutically effective amount of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal and a pharmaceutical excipient. The pharmaceutical composition can be in the form of a unit preparation (the amount of the main drug in the unit preparation is also referred to as "preparation specification").

[0140] The present invention also provides a method for treating a disease in a mammal, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal or pharmaceutical composition. In some embodiments, the mammal of the present invention includes a human.

[0141] "Effective amount" or "therapeutically effective amount" as used herein refers to administering a sufficient amount of a compound disclosed herein that will alleviate one or more symptoms of the disease or condition (e.g., neuromuscular blockade) being treated to some extent. In some embodiments, the result is a reduction and / or alleviation of the signs, symptoms, or causes of the disease, or any other desired changes in a biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising a compound disclosed herein required to provide a clinically significant reduction in disease symptoms.Examples of therapeutically effective amounts include, but are not limited to, 1-1500 mg, 1-600 mg, 2-600 mg, 3-600 mg, 4-600 mg, 5-600 mg, 6-600 mg, 10-600 mg, 20-600 mg, 25-600 mg, 30-600 mg, 40-600 mg, 50-600 mg, 60-600 mg, 70-600 mg, 75-600 mg, 80-600 mg, 90-600 mg, 100-600 mg, 200-600 mg, 1-500 mg, 2-500 mg, 3-500 mg, 4-500 mg, 5-5 00mg, 6-500mg, 10-500mg, 20-500mg, 25-500mg, 30-500mg, 40-500mg, 50-500mg, 60-500mg, 70-500mg, 75-500mg, 80-500mg, 90-500mg, 100-500mg, 125-500mg, 150-500mg, 200-500mg, 250-500mg, 300-500mg, 400-500mg, 5-400mg, 10-400mg, 20-400mg, 25-400mg, 30-400mg , 40-400mg, 50-400mg, 60-400mg, 70-400mg, 75-400mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400m g, 300-400mg, 1-300mg, 2-300mg, 5-300mg, 10-300mg, 20-300mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-30 0mg, 80-300mg, 90-300mg, 100-300mg, 125-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg , 25-200mg, 30-200mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;.

[0142] In some embodiments, the pharmaceutical composition includes but is not limited to 1-1500 mg, 1-600 mg, 20-400 mg, 25-200 mg, 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 300 mg of a compound of the invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof.

[0143] A method for treating a disease in a mammal, the method comprising administering to a subject a therapeutically effective amount of a compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, the therapeutically effective amount preferably being 1-1500 mg, and the disease preferably being a disease related to neuromuscular blockade.

[0144] A method for treating a disease in a mammal, the method comprising administering to a subject a drug compound of the present invention or a stereoisomer, racemate, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof at a daily dose of 1-1500 mg / day, the daily dose may be a single dose or divided doses, in some embodiments, the daily dose includes but is not limited to 10-1500 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, g / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in some embodiments, daily doses include but are not limited to 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1500 mg / day, 2000 mg / day.

[0145] The present invention relates to a kit, which may include a composition in a single-dose or multi-dose form, and the kit contains a compound of the present invention or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, and the amount of the compound of the present invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal is the same as that in the above-mentioned pharmaceutical composition.

[0146] The amount of the compound of the invention or its stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal in the present invention is in each case calculated as the free base.

[0147] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0148] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0149] The carbon, hydrogen, oxygen, sulfur, nitrogen or F, Cl, Br, I involved in the groups and compounds of the present invention include their isotopes, and the carbon, hydrogen, oxygen, sulfur or nitrogen involved in the groups and compounds of the present invention are optionally further replaced by one or more of their corresponding isotopes, wherein the carbon isotopes include 12 C. 13 C and 14 C, hydrogen isotopes include protium (H), deuterium (D, also called heavy hydrogen), tritium (T, also called super tritium), oxygen isotopes include 16 O. 17 O and 18 O, sulfur isotopes include 32 S. 33 S. 34 S and 36 S, isotopes of nitrogen include 14 N and 15 N, fluorine isotopes include 17 F and 19 F, chlorine isotopes include 35 Cl and 37 Isotopes of Cl and bromine include 79 Br and 81 Br.

[0150] "CN" refers to cyano.

[0151] "Halogen" refers to F, Cl, Br or I.

[0152] "Halogen substituted" refers to substitution with F, Cl, Br or I, including but not limited to substitution with 1 to 10 substituents selected from F, Cl, Br or I, substitution with 1 to 6 substituents selected from F, Cl, Br or I, and substitution with 1 to 4 substituents selected from F, Cl, Br or I. "Halogen substituted" is abbreviated as "halo".

[0153] "Alkyl" refers to a substituted or unsubstituted straight or branched chain saturated aliphatic hydrocarbon group, including but not limited to alkyl groups of 1 to 20 carbon atoms, alkyl groups of 1 to 8 carbon atoms, alkyl groups of 1 to 6 carbon atoms, and alkyl groups of 1 to 4 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, neobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and various branched chain isomers thereof; alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0154] "Alkylene" refers to substituted or unsubstituted straight-chain or branched divalent saturated hydrocarbon groups, including -(CH2) v -(v is an integer from 1 to 10), examples of alkylene include but are not limited to methylene, ethylene, propylene and butylene.

[0155] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon radical, typically having 3 to 12 carbon atoms, and the cycloalkyl radical can be a monocyclic, cyclic, bridged, and spirocyclic ring. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirocyclobutyl, adamantane, etc. The cycloalkyl radical can be monovalent, divalent, trivalent, or tetravalent.

[0156] "Heterocycloalkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms, 3 to 8 atoms, including 1 to 3 heteroatoms selected from N, O or S, and the C, N, S on the ring of the heterocycloalkyl can be oxidized to various oxidation states. Heterocycloalkyl can be a monocyclic, cyclic, bridged and spirocyclic. Heterocycloalkyl can be connected to a heteroatom or a carbon atom, and non-limiting examples include oxirane, aziridine, oxadiazole, azetidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxolane, dioxane, pyrrolidinyl, piperidinyl, imidazolidinyl, oxazolidinyl, oxazininyl, morpholinyl, hexahydropyrimidinyl, piperazinyl,

[0157] The heterocycloalkyl group may be monovalent, divalent, trivalent or tetravalent.

[0158] "Alkenyl" refers to a substituted or unsubstituted straight chain or branched unsaturated hydrocarbon group having at least one, typically one, two or three carbon-carbon double bonds, with a backbone of 2 to 10, 2 to 6 or 2 to 4 carbon atoms. Examples of alkenyl groups include but are not limited to vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-1-butenyl, 2-methyl-2 ... -methyl-3-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 1-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 1-octenyl, 3-octenyl, 1-nonenyl, 3-nonenyl, 1-decenyl, 4-decenyl, 1,3-butadiene, 1,3-pentadiene, 1,4-pentadiene and 1,4-hexadiene, etc.; the alkenyl group can be monovalent, divalent, trivalent or tetravalent.

[0159] "Alkynyl" refers to substituted or unsubstituted straight and branched unsaturated hydrocarbon groups having at least one, typically one, two or three carbon-carbon triple bonds, with a backbone comprising 2 to 10 carbon atoms, including but not limited to 2 to 6 carbon atoms in the backbone, 2 to 4 carbon atoms in the backbone, examples of alkynyl groups include but are not limited to ethynyl, propargyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-pentynyl, 6-pentynyl, 7-pentynyl, 8-pentynyl, 9-pentynyl, 10-pentynyl, 11-pentynyl, 12-pentynyl, 13-pentynyl, 14-pentynyl, 15-pentynyl, 16-pentynyl, 17-pentynyl, 18-pentynyl, 19-pentynyl, 20-pentynyl, 21-pentynyl, 22-pentynyl, 23-pentynyl, 24-pentynyl, 25-pentynyl, 26-pentynyl, 27-pentynyl, 28-pentynyl, 29-pentynyl, 30-pentynyl, 31-pentynyl, 32-pentynyl, 33-pentynyl, 34-pentynyl, 35-pentynyl, 36-pentynyl, 37-pentynyl, 38-pentynyl, 39-pentynyl, 40-pentynyl, 41-pentynyl, 42-pentynyl, 43-pentynyl, 44-pentynyl, 45-pentynyl, 46-pentynyl, 47-pentynyl, 48-pentynyl 1-methyl-1-butynyl, 2-methyl-1-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-methyl-1-pentynyl, 2-methyl-1-pentynyl, 1-heptynyl, 2-heptynyl, 3-heptynyl, 4-heptynyl, 1-octynyl, 3-octynyl, 1-nonynyl, 3-nonynyl, 1-decynyl, 4-decynyl and the like; the alkynyl group may be monovalent, divalent, trivalent or tetravalent.

[0160] "Alkoxy" refers to substituted or unsubstituted -O-alkyl. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropyloxy, and cyclobutyloxy.

[0161] "Carbocyclyl" or "carbocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8-membered monocyclic ring, a 4-12-membered bicyclic ring, a 10-15-membered tricyclic ring, or a 12-18-membered quaternary system. The carbocyclyl can be attached to an aromatic ring or a non-aromatic ring, and the ring can be optionally a monocyclic ring, a cyclic ring, a bridged ring, or a spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-alkenyl, 1-cyclopentyl-2-alkenyl, 1-cyclopentyl-3-alkenyl, cyclohexyl, 1-cyclohexyl-2-alkenyl, 1-cyclohexyl-3-alkenyl, cyclohexenyl, benzene ring, naphthalene ring, "Carbocyclyl" or "carbocycle" can be monovalent, divalent, trivalent or tetravalent.

[0162] "Heterocyclyl" or "heterocycle" refers to a substituted or unsubstituted aromatic or non-aromatic ring, which can be a 3-8 membered monocyclic ring, a 4-12 membered bicyclic ring, a 10-15 membered tricyclic ring, or a 12-18 membered quaternary system, and contains 1 or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O or S. The C, N, S selectively substituted in the heterocyclyl ring can be oxidized to various oxidation states. The heterocyclic group can be connected to a heteroatom or a carbon atom, and can be connected to an aromatic ring or a non-aromatic ring. The heterocyclic group is optionally a monocyclic, bridged, fused or spirocyclic ring. Non-limiting examples include oxirane, aziridine, oxetanyl, azetidinyl, 1,3-dioxolanyl, 1,4-dioxolanyl, 1,3-dioxhexacyclyl, azepanyl, pyridyl, furanyl, thienyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithianyl, dihydrofuranyl, dihydropyranyl, dithiolanyl, tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophenyl, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzopyridinyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonanyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptanyl,

[0163] "Heterocyclyl" or "heterocycle" may be monovalent, divalent, trivalent or tetravalent.

[0164] "Spiro" or "spirocyclyl" refers to a polycyclic group in which substituted or unsubstituted monocyclic rings share one atom (called spiro atom), and the number of ring atoms in the spiro system includes but is not limited to 5 to 20, 6 to 14, 6 to 12, 6 to 10, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds, and optionally may contain 0 to 5 selected from N, O or S (=O) n (n is 0, 1 or 2). Non-limiting examples include:

[0165]

[0166] "Spirocycle" or "spirocyclyl" can be monovalent, divalent, trivalent or tetravalent.

[0167] "Parallel ring" or "parallel ring group" refers to a polycyclic group in which each ring in the system shares a pair of adjacent atoms with other rings in the system, wherein one or more rings may contain 0 or more (including but not limited to 1, 2, 3 or 4) double bonds and may be substituted or unsubstituted, and each ring in the parallel ring system may contain 0 to 5 heteroatoms or groups containing heteroatoms (including but not limited to selected from N, S(=O) n or O, n is 0, 1 or 2). The number of ring atoms in the ring system includes, but is not limited to, 5 to 20, 5 to 14, 5 to 12, 5 to 10. Non-limiting examples include:

[0168] "Bicyclic" or "bicyclic group" may be monovalent, divalent, trivalent or tetravalent.

[0169] "Bridged ring" or "bridged ring group" refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, which may contain 0 or more double bonds, and any ring in the bridged ring system may contain 0 to 5 groups selected from heteroatoms or heteroatom-containing groups (including but not limited to N, S(=O)n or O, where n is 0, 1, 2). The number of ring atoms includes but is not limited to 5 to 20, 5 to 14, 5 to 12 or 5 to 10. Non-limiting examples include:

[0170] Cubane, adamantane. "Bridged ring" or "bridged ring group" may be monovalent, divalent, trivalent or tetravalent.

[0171] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a single ring or a fused ring, wherein the number of ring atoms in the aromatic ring includes, but is not limited to, 6 to 18, 6 to 12, or 6 to 10 carbon atoms. The aryl ring may be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring, non-limiting examples of which include benzene ring, naphthalene ring, "Aryl" or "aromatic ring" can be monovalent, divalent, trivalent or tetravalent. When divalent, trivalent or tetravalent, the point of attachment is on the aryl ring.

[0172] "Heteroaryl" or "heteroaromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or groups containing heteroatoms (including but not limited to N, O or S(=O)n, n is 0, 1, 2), and the number of ring atoms in the heteroaromatic ring includes but is not limited to 5 to 15, 5 to 10 or 5 to 6. The atoms C, N, and S on the ring are optionally oxidized (i.e., C(=O), NO, S(=O)n, n is 1, 2). Non-limiting examples of heteroaryl include but are not limited to pyridyl, furanyl, thienyl, pyridyl, pyranyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, benzopyrazolyl, benzimidazolyl, benzopyridinyl, pyrrolopyridinyl, pyridonyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbocyclic ring or heterocyclic ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include

[0173] The heteroaryl groups appearing in this article have the same definition as this definition. The heteroaryl group can be monovalent, divalent, trivalent or tetravalent. When it is divalent, trivalent or tetravalent, the attachment site is located on the aromatic ring.

[0174] "Substituted" or "substituted" means substituted by one or more (including but not limited to 2, 3, 4 or 5) substituents, including but not limited to H, F, Cl, Br, I, alkyl, cycloalkyl, alkoxy, haloalkyl, thiol, hydroxyl, nitro, mercapto, amino, cyano, isocyano, aryl, heteroaryl, heterocyclic, bridged, spiro, cycloalkyl, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, -(CH2) m -C(=O)-R a 、-O-(CH2) m -C(=O)-R a 、-(CH2) m -C(=O)-NR b R c 、-(CH2) m S(=O) n R a 、-(CH2) m -Alkenyl-R a , OR d or -(CH2) m -alkynyl-R a (wherein m and n are 0, 1 or 2), arylthio, thiocarbonyl, silane or -NR b R c etc., where Rb With R c is independently selected from the group consisting of H, hydroxy, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, and optionally, R b With R c It can form a five- or six-membered cycloalkyl or heterocyclic group, R a With R d Each is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclyl, carbonyl, ester, bridged, spiro or paracyclic groups.

[0175] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is selected from any integer between 1 and 10. For example, "1 to 4 R k "Substituted" means replaced by 1, 2, 3 or 4 R k For example, "1 to 5 substituents selected from..." means substituted by 1, 2, 3, 4 or 5 substituents selected from..." For example, "the heterobridged ring is optionally substituted by 1 to 4 substituents selected from H or F" means that the heterobridged ring is optionally substituted by 1, 2, 3 or 4 substituents selected from H or F.

[0176] The XY-membered ring (X, Y are integers, and 3≤X<Y, X<Y≤20 is selected from any integer between 4 and 20) includes X, X+1, X+2, X+3, X+4...Y-membered rings. The ring includes a heterocyclic ring, a carbocyclic ring, an aromatic ring, an aryl group, a heteroaryl group, a cycloalkyl group, a heteromonocyclic ring, a heterocyclic ring, a heterospirocyclic ring or a heterobridged ring. For example, "4-7-membered heteromonocyclic ring" refers to a 4-membered, 5-membered, 6-membered or 7-membered heteromonocyclic ring, and "5-10-membered heterocyclic ring" refers to a 5-membered, 6-membered, 7-membered, 8-membered, 9-membered or 10-membered heterocyclic ring.

[0177] C x-y Carbocycles (including aryl, cycloalkyl, monocyclic carbocycle, spirocyclic carbocycle, fused carbocycle or bridged carbocycle) include C x , C x+1 , C x+2 , C x+3 , C x+4 …C y A ring of 1-membered ring (x is an integer, and 3≤x<y, y is selected from any integer between 4 and 20), for example, C 3-6 "Cycloalkyl" means C3, C4, C5 or C6 cycloalkyl;

[0178] When a group has one or more connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection is non-positional and there are hydrogen atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease with the number of connected chemical bonds and become a group with the corresponding valence. For example It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Also included For example Indicates that the R group on the piperidinyl group can be located on C, can be located on N, and at least includes

[0179] When the listed linking groups do not specify their connection direction, their connection directions include connection from left to right and from right to left in reading order, for example, when ALB, L is selected from -MW-, it includes AMWB and AWMB.

[0180] "Optional" or "optionally" means that the event or circumstance described later may but need not occur, and the description includes situations where the event or circumstance occurs or does not occur. For example, "alkyl optionally substituted with F" means that alkyl may but need not be substituted with F, and the description includes situations where alkyl is substituted with F and situations where alkyl is not substituted with F.

[0181] "Pharmaceutically acceptable salt" or "pharmaceutically acceptable salt thereof" refers to a salt of the compound of the present invention that retains the biological effectiveness and properties of the free acid or free base, and the free acid is obtained by reacting with a non-toxic inorganic base or organic base, and the free base is obtained by reacting with a non-toxic inorganic acid or organic acid.

[0182] "Pharmaceutical composition" refers to a mixture of one or more compounds of the present invention, or stereoisomers, racemates, tautomers, deuterated forms, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals thereof and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients and / or one or more other therapeutic agents.

[0183] "Preparation specifications" refers to the weight of the main drug contained in each vial, tablet or other unit preparation.

[0184] "Carrier" refers to a material that does not cause significant irritation to an organism and does not abrogate the biological activity and properties of the administered compound.

[0185] "Prodrug" refers to a compound of the present invention that can be converted into a biologically active compound through in vivo metabolism. The prodrug of the present invention is prepared by modifying the amino or carboxyl group in the compound of the present invention, and the modification can be removed by conventional operations or in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free amino or carboxyl group.

[0186] "Co-crystal" refers to a crystal formed by the active pharmaceutical ingredient (API) and the co-crystal former (CCF) under the action of hydrogen bonds or other non-covalent bonds, in which the pure state of API and CCF are solid at room temperature and there is a fixed stoichiometric ratio between the components. Co-crystal is a multi-component crystal, including binary eutectics formed between two neutral solids and multi-component eutectics formed between neutral solids and salts or solvates.

[0187] "Animal" is meant to include mammals, such as humans, companion animals, zoo animals, and livestock, preferably humans, horses, or dogs.

[0188] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0189] "Tautomers" refer to functional group isomers produced by the rapid movement of an atom in a molecule between two positions, such as keto-enol isomerism and amide-imino alcohol isomerism.

[0190] “IC 50 ” is the concentration of a drug or inhibitor required to inhibit a specified biological process (or a component of the process such as an enzyme, receptor, cell, etc.) by half. DETAILED DESCRIPTION

[0191] The following embodiments illustrate the technical solutions of the present invention in detail, but the protection scope of the present invention includes but is not limited to them.

[0192] The structures of the compounds were determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). NMR shifts (δ) were measured in 10 -6 The unit of (ppm) is given. NMR measurements were performed using a (Bruker Avance III 400 and Bruker Avance 300) nuclear magnetic spectrometer, the measurement solvents were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS);

[0193] MS was measured using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0194] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Zorbax SB-C18 100×4.6 mm, 3.5 μM);

[0195] Thin layer chromatography silica gel plate using Yantai Huanghai HSGF 254 or Qingdao GF 254Silica gel plate: The silica gel plate used in thin layer chromatography (TLC) has a specification of 0.15mm-0.20mm, and the specification used for thin layer chromatography separation and purification of products is 0.4mm-0.5mm;

[0196] Column chromatography generally uses Yantai Huanghai Silica Gel 200-300 mesh silica gel as the carrier;

[0197] The negative ions of the quaternary ammonium salts in the following examples may be diverse, and the presence of other negative ions does not affect the reactions in the examples;

[0198] Boc: tert-butyloxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl.

[0199] Example 1: Preparation of Compound E1

[0200]

[0201] Step 1: Preparation of E1b

[0202] Dissolve E1a (5.00 g, 14.07 mmol), 3-bromo-1-propanol (2.50 mL, 27.70 mmol), potassium carbonate (3.89 g, 28.14 mmol), and sodium iodide (0.21 g, 1.42 mmol) in acetonitrile (30 mL) and react at 60 °C in a nitrogen atmosphere for 16 hours. Filter the reaction solution, concentrate the filtrate under reduced pressure, add 30 mL of water, extract with ethyl acetate (30 mL × 2), remove the organic phase, add sodium chloride to the aqueous phase until saturated, extract with chloroform (30 mL × 3), and combine the organic phases and concentrate to dryness to obtain E1b (2.90 g, yield: 45.81%). (Without chiral separation, the diastereomers are a mixture)

[0203] LCMS m / z=414.3

[0204] Step 2: Preparation of E1c

[0205] E1b (500 mg, 1.11 mmol) and maleic anhydride (117 mg, 1.19 mmol) were dissolved in acetonitrile (5 mL). Triethylamine (0.2 mL, 1.44 mmol) was added under ice bath condition. The mixture was reacted at room temperature under nitrogen atmosphere for 1 hour, and concentrated under reduced pressure. The pH was adjusted to 2 with 1N hydrochloric acid. Sodium chloride was added to the aqueous phase until saturated, and extracted with dichloromethane / acetonitrile (v / v=5 / 1, 15 mL×3). The organic phases were combined and concentrated to dryness to obtain E1c (577 mg, yield: 94.85%).

[0206] LCMS m / z=512.2

[0207] Step 3: Preparation of E1d

[0208] E1c (140 mg, 0.26 mmol) was dissolved in ultra-dry 1,2-dichloroethane (3 mL), and oxalyl chloride (0.15 mL, 1.77 mmol) was added under nitrogen atmosphere and reacted at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and then concentrated twice with ultra-dry 1,2-dichloroethane (5 mL×2) to obtain a crude product E1d (140 mg) which was directly used in subsequent reactions.

[0209] Step 4: Preparation of Compound E1

[0210] E1e (150 mg, 0.45 mmol, reference: US9156826B2) was dissolved in ultra-dry 1,2-dichloroethane / acetonitrile (v / v=1 / 1, 2 mL), 4A molecular sieves (100 mg) were added, stirred at room temperature for 10 minutes, E1d (140 mg) was added, and the reaction was carried out at room temperature for 16 hours under nitrogen atmosphere. The reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@PrepC18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% TFA) to obtain the target compound E1 (30 mg).

[0211] LCMS m / z=395.3

[0212] Example 2: Preparation of Compound E2-1

[0213]

[0214] Step 1: Preparation of E2b

[0215] E2a (9.45 g, 26.44 mmol) and 1,3,2-dioxathiazole-2,2-dioxide (7.3 g, 52.80 mmol) were dissolved in acetonitrile (120 mL) and reacted at 60°C for 16 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain E2b (13.08 g, yield 99.82%). (For the synthesis method of E2a, refer to CN107778234A)

[0216] Step 2: E2c-1 preparation

[0217] Under ice bath, acetyl chloride (18.99 mL, 266.11 mmol) was slowly added to anhydrous methanol (150 mL), reacted for 0.5 h, E2b (13.08 g, 26.4 mmol) was added, and reacted at room temperature for 3 hours under nitrogen atmosphere. Sodium bicarbonate was added to the reaction solution until no bubbles were generated, it was concentrated, and then extracted with ethyl acetate (100 mL × 3), sodium chloride solid was added to the aqueous phase until saturated, and then extracted with chloroform (100 mL × 3), the organic layers were combined and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography and prepared by pre-HPLC to obtain E2c-1 (4.48 g)

[0218] Preparation conditions:

[0219] Instrument: Waters 150Prep-SFC F; Column: Chiralcel IK column;

[0220] Mobile phase: A for CO2; B for 0.1% NH3·H2O in MeOH and ACN; Gradient: B 35%; Flow rate: 120 mL / min; Back pressure: 100 bar; Column temperature: 25°C; Wavelength: 220 nm; Cycle: 7.0 min; Sample preparation: Compound E2c was dissolved in acetonitrile to obtain 50 mg / ml; Injection: 2.0 ml / needle.

[0221] LCMS m / z=416.6

[0222] Step 3: Preparation of E2d-1

[0223] E2c-1 (4.48 g) and maleic anhydride (1.58 g, 16.14 mmol) were dissolved in acetonitrile (75 mL), triethylamine (1.64 mL, 11.84 mmol) was added under ice bath, and the mixture was reacted at 0°C for 1 hour under nitrogen atmosphere. 1N hydrochloric acid was added to the reaction solution to adjust the pH to below 2, and then saturated sodium chloride solution (100 mL) was added, and the mixture was extracted with DCM / ACN (v / v=5:1, 100 mL×3), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain E2d-1 (5.2 g).

[0224] LCMS m / z=514.2

[0225] Step 4: Preparation of E2e-1

[0226] E2d-1 (300 mg, 0.55 mmol) was dissolved in ultra-dry 1,2-dichloroethane (5 mL), and oxalyl chloride (0.24 mL, 2.84 mmol) was added under nitrogen atmosphere and reacted at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and then concentrated twice with ultra-dry 1,2-dichloroethane (5 mL×2) to obtain crude E2e-1 (300 mg) which was directly used in subsequent reactions.

[0227] Step 5: Preparation of compound E2-1

[0228] E1b (300 mg, 0.67 mmol) was dissolved in ultra-dry 1,2-dichloroethane / acetonitrile (v / v=1 / 1, 4 mL), 4A molecular sieves (150 mg) were added, and the mixture was stirred at room temperature for 10 minutes. The crude product E2e-1 (300 mg) from the previous step was added, and the mixture was reacted at room temperature for 16 hours under a nitrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% TFA) to obtain compound E2-1 (80 mg).

[0229] LCMS m / z=455.4

[0230] Example 3: Preparation of Compounds E3-1, E3-2

[0231]

[0232] In the chemical formula Represents a single stereo configuration, such as R or S configuration;

[0233] Step 1: Preparation of intermediates E1c-1 and E1c-2

[0234]

[0235] E1c (2.0 g) was separated to obtain two optical isomers:

[0236] Compound E1c-1 (retention time: 1.850 min, 749.7 mg, brown-yellow foamy solid, dr% = 100%), the structure of compound E1c-1 is one of the structures shown in E1c-A and E1c-B above);

[0237] Compound E1c-2 (retention time: 2.119 min, 605.7 mg, brown-yellow foamy solid, dr% = 100%), the structure of compound E1c-2 is one of the structures shown in the above E1c-A and E1c-B, and is a diastereomer with compound E1c-1, that is,

[0238] When the structural formula of compound E1c-1 is the structure of E1c-A, the structural formula of compound E1c-2 is the structure of E1c-B;

[0239] When the structural formula of compound E1c-1 is the structure of E1c-B, the structural formula of compound E1c-2 is the structure of E1c-A.

[0240] Analysis conditions:

[0241] Instrument: SHIMADZU LC-30AD sf; Column: Chiral OD column; Mobile phase: A for CO2; B for 0.05% DEA in methanol; Gradient: B for 5-40%; Flow rate: 3mL / min; Back pressure: 100bar; Column temperature: 35℃; Wavelength: 220nm

[0242] Separation conditions:

[0243] Instrument: Waters 150Prep-SFC; Column: Chiral OD column;

[0244] Mobile phase: A for CO2; B for 0.1% NH3·H2O in methanol; gradient: B for 35%; flow rate: 120mL / min; back pressure: 100bar; column temperature: room temperature; wavelength: 220nm.

[0245] LCMS m / z=512.7[M-Cl] +

[0246] Step 2: Preparation of compounds E3-1 and E3-2

[0247] E1c-1 (80 mg, 0.15 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (120 mg, 0.32 mmol), DIPEA (0.1 mL, 0.6 mmol), and E1e (64 mg, 0.19 mmol) were added and reacted at room temperature for 16 hours under nitrogen atmosphere. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% TFA) to obtain the target compound E3-1 (75 mg).

[0248] LCMS m / z=395.2[M-2CF3COO] 2+

[0249] Using E1c-2 as substrate, E3-2 (32 mg) was synthesized according to the above method.

[0250] LCMS m / z=395.3[M-2CF3COO] 2+

[0251] Example 4: Preparation of Compounds E4-1, E4-2

[0252]

[0253] Step 1: Preparation of E4b

[0254] E4a (3.32 g, 19.97 mmol) and 7-azabicyclo[2,2,1]heptane hydrochloride (4.0 g, 29.94 mmol) were dissolved in 1,2-dichloroethane (40 mL), reacted at 60 °C for 1 hour under nitrogen atmosphere and then cooled to room temperature, sodium triacetoxyborohydride (5.0 g, 23.54 mmol) was added and reacted for 16 hours under the same conditions, the reaction solution was concentrated, 50 mL of sodium bicarbonate aqueous solution was added, and the mixture was extracted with ethyl acetate (50 mL×2), the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by column chromatography to obtain E4b (4.0 g, yield 80.99%).

[0255] LCMS m / z=248.2[M+H] +

[0256] Step 2: Preparation of E4c

[0257] E4b (1.48 g, 5.98 mmol) and 1,3-propylene glycol cyclic sulfate (1.65 g, 11.96 mmol) were dissolved in acetonitrile (15 mL), and reacted at 70 °C for 16 hours under a nitrogen atmosphere. The system was concentrated to dryness, acetonitrile (5 mL) and tert-methyl ether (30 mL) were added, stirred at room temperature for 1 hour, and filtered. The filtered solid was washed with tert-methyl ether and dried to obtain E4c (1.619 g, yield 70.23%).

[0258] Step 3: Preparation of E4d

[0259] E4c (1.0 g, 2.59 mmol) was dissolved in anhydrous methanol (10 mL) and concentrated sulfuric acid (0.03 mL, 0.56 mmol) was added, and the mixture was reacted at 55° C. under nitrogen atmosphere for 20 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by column chromatography and eluted with Dowex 1X8-100 resin layer four times to obtain E4d (0.80 g, 90.35%).

[0260] LCMS m / z=306.2[M-Cl] +

[0261] Step 4: Preparation of compounds E4-1 and E4-2

[0262] E1c-1 (80 mg, 0.15 mmol) was dissolved in ultra-dry DMF (2 mL), and HATU (120 mg, 0.32 mmol), DIPEA (0.1 mL, 0.6 mmol), and E4d (65 mg, 0.19 mmol) were added and reacted at room temperature for 16 hours under nitrogen atmosphere. The filtrate was concentrated under reduced pressure, and the residue was separated and purified by preparative liquid chromatography (instrument: waters 2767 preparative liquid chromatography; chromatographic column: SunFire@Prep C18 (19 mm×150 mm); mobile phase composition: mobile phase A: acetonitrile mobile phase B: water (containing 0.1% TFA) to obtain the target compound E4-1 (55 mg).

[0263] LCMS m / z=400.5[M-2CF3COO] 2+

[0264] Using E1c-2 as substrate, E4-2 (30 mg) was synthesized according to the above method.

[0265] LCMS m / z=400.3[M-2CF3COO] 2+

[0266] Example 5: Preparation of Compounds E5-1 and E5-2

[0267]

[0268] Preparation of Compounds E5-1 and E5-2

[0269] Using 4-methoxy-3-methylbenzaldehyde and morpholine as substrates, refer to the first to third steps of Example 4 to obtain E5a. Using E5a and E1c-1 as substrates, refer to the fourth step of Example 4 to synthesize compound E5-1 (50 mg).

[0270] LCMS m / z=387.3[M-2CF3COO] 2+

[0271] Compound E5-2 (27 mg) was synthesized by using E5a and E1c-2 as substrates according to the fourth step of the synthesis method in Example 4.

[0272] LCMS m / z=387.3[M-2CF3COO] 2+

[0273] Example 6: Preparation of Compounds E6-1, E6-2

[0274]

[0275] Preparation of Compounds E6-1 and E6-2

[0276] Using 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde and morpholine as substrates, refer to the first to third steps of Example 4 to obtain E6a. Using E6a and E1c-1 as substrates, refer to the fourth step of Example 4 to synthesize compound E6-1 (60 mg).

[0277] LCMS m / z=405.2[M-2CF3COO] 2+

[0278] Compound E6-2 (30 mg) was synthesized by using E6a and E1c-2 as substrates according to the fourth step of the synthesis method in Example 4.

[0279] LCMS m / z=405.3[M-2CF3COO] 2+

[0280] Example 7: Preparation of Compounds E7-1 and E7-2

[0281]

[0282] Preparation of Compounds E7-1 and E7-2

[0283] Using 2,2-difluoro-1,3-benzodioxole-5-carboxaldehyde and 4,4-difluoropiperidine as substrates, refer to the first to third steps of Example 4 to obtain E7a. Using E7a and E1c-1 as substrates, refer to the fourth step of Example 4 to synthesize compound E7-1 (70 mg).

[0284] LCMS m / z=422.2[M-2CF3COO] 2+

[0285] Compound E7-2 (25 mg) was synthesized by using E7a and E1c-2 as substrates according to the fourth step of the synthesis method in Example 4.

[0286] LCMS m / z=422.3[M-2CF3COO] 2+

[0287] Example 8: Preparation of Compounds E8-1, E8-2

[0288]

[0289] Preparation of Compounds E8-1 and E8-2

[0290] Using 3,4-dimethoxybenzaldehyde and 2,2-difluoro-7-azaspiro[3.5]nonane hydrochloride as substrates, refer to the first to third steps of Example 4 to obtain E8a, and using E8a and E1c-1 as substrates, refer to the fourth step of Example 4 to synthesize compound E8-1 (66.6 mg).

[0291] LCMS m / z=432.3[M-2CF3COO] 2+

[0292] Compound E8-2 (29 mg) was synthesized by using E8a and E1c-2 as substrates according to the fourth step of the synthesis method in Example 4.

[0293] LCMS m / z=432.3[M-2CF3COO] 2+

[0294] Example 9: Preparation of Compounds E9-1, E9-2

[0295]

[0296] Preparation of Compounds E9-1 and E9-2

[0297] Using 4-methoxy-3-methylbenzaldehyde and 2,2-difluoro-7-azaspiro[3.5]nonane hydrochloride as substrates, refer to the first to third steps of Example 4 to obtain E9a, and using E9a and E1c-1 as substrates, refer to the fourth step of Example 4 to synthesize compound E9-1 (38 mg).

[0298] LCMS m / z=424.5[M-2CF3COO] 2+

[0299] Compound E9-2 (34 mg) was synthesized by using E9a and E1c-2 as substrates according to the fourth step of the synthesis method in Example 4.

[0300] LCMS m / z=424.3[M-2CF3COO] 2+

[0301] Biological test cases

[0302] 1. Experimental method for detecting the effective dose of muscle relaxants:

[0303] 1. Experimental preparation: After anesthetizing the rats with urethane intraperitoneally and inserting an intravenous indwelling needle sleeve through the throat, the rats were fixed in a supine position on the dissection table and connected to a small animal ventilator for mechanical ventilation. The rat tail vein was punctured with an indwelling needle and a cannula was placed for drug administration. The rat right hind leg ankle and outer calf hair was shaved with a shaver.

[0304] 2. Separation of the tibialis anterior tendon: Cut the skin along the right hind limb tibia at the ankle joint, with a 2 cm longitudinal incision to expose the transverse ligament of the ankle joint. Carefully separate the tibialis anterior tendon and ligate it with surgical suture silk thread, cut the tendon transversely at the distal end to free the tibialis anterior muscle. One end of the silk thread is fixed on the tension transducer.

[0305] 3. Sciatic nerve freeing and stimulating electrode connection: Make a longitudinal incision in the skin outside the knee joint (popliteal fossa), cut the fascia, separate the sciatic nerve with a glass needle, and connect the sciatic nerve to the stimulating electrode.

[0306] 4. TOF was used to stimulate the right sciatic nerve. The specific parameters were: voltage 2V, frequency 2Hz, wave width 200μs, and stimulation interval 10s. The tibialis anterior muscle tension curve was recorded, and medication was administered after the curve stabilized.

[0307] 5. Drug administration: The dosage is set as a gradient dose. When the drug administration is completed, TOF stimulation begins. The next dose can be given only when the fourth twitch T4 of TOF is equal to the first twitch, that is, T4 = T1. During the experiment, Krebs solution is sprayed on the exposed muscles and nerves intermittently to keep them moist and active.

[0308] 6. Index determination: Establish a dose-response curve based on the inhibition rate of T1 at different doses to calculate ED 50 and ED 95 .

[0309] 2. Detect the onset and recovery time of muscle relaxants:

[0310] 1. Experimental preparation: After anesthetizing rats with urethane intraperitoneally and inserting an intravenous indwelling needle sleeve through the throat, fix the rats in a supine position on the dissecting table and connect them to a small animal ventilator for mechanical ventilation. Puncture the rat's tail vein with an indwelling needle and place a cannula for drug administration. Use a shaver to remove the hair on the ankle joint and the outer side of the calf of the rat's right hind limb.

[0311] 2. Separation of the tibialis anterior tendon: Cut the skin along the right hind limb tibia at the ankle joint, with a 2 cm longitudinal incision to expose the transverse ligament of the ankle joint. Carefully separate the tibialis anterior tendon and ligate it with surgical suture silk thread, cut the tendon transversely at the distal end to free the tibialis anterior muscle. One end of the silk thread is fixed on the tension transducer.

[0312] 3. Sciatic nerve freeing and stimulating electrode connection: Make a longitudinal incision in the skin outside the knee joint (popliteal fossa), cut the fascia, separate the sciatic nerve with a glass needle, and connect the sciatic nerve to the stimulating electrode.

[0313] 4. TOF was used to stimulate the right sciatic nerve. The specific parameters were: voltage 2V, frequency 2Hz, wave width 200μs, and stimulation interval 10s. The tibialis anterior muscle tension curve was recorded, and medication was administered after the curve stabilized.

[0314] 5. Drug administration: The dosage is set as a gradient dose. When the drug administration is completed, TOF stimulation begins. The next dose can be given only when the fourth twitch T4 of TOF is equal to the first twitch, that is, T4 = T1. During the experiment, Krebs solution is sprayed on the exposed muscles and nerves intermittently to keep them moist and active.

[0315] 6. Index determination: Onset time: the time from the administration of a 2*ED95 dose to the maximum inhibition of T1; Recovery time: the time from the administration of a 2*ED95 dose to the recovery of T4 to 75% (TOFr75); the time from the administration of a 2*ED95 dose to the recovery of T4 to 90% (TOFr90).

[0316] Conclusion: The compounds of the present invention, such as the compounds in the examples, have good neuromuscular blocking effects in rats.

[0317] 3. Experimental Methods of Isolated Sciatic Nerve-Extensor Digitorum Longus Muscle in Rat

[0318] 1. Experimental Materials

[0319] Experimental animals: SD rats, male, 8 weeks old; isolated tissues: sciatic nerve-extensor digitorum longus muscle

[0320] 2. Experimental Methods

[0321] (1) Preparation of sciatic nerve-extensor digitorum longus muscle tissue: The animal was anesthetized with urethane. The sciatic nerve and extensor digitorum longus muscle were quickly isolated and placed in a modified Krebs solution with artificial mixed gas.

[0322] (2) Connection device: The sciatic nerve was placed on a stimulating electrode connected to a stimulator. One end of the extensor digitorum longus muscle was fixed and the other end was connected to a tension transducer. A PowerLab signal acquisition system was used to continuously record muscle tension.

[0323] (3) Baseline recording: 2 ms pulse stimulation was used to stimulate the sciatic nerve at a frequency of 0.1 Hz, and the stimulation intensity was gradually increased to induce the contraction amplitude of the extensor digitorum longus muscle. The stimulation intensity corresponding to 120% of the maximum contraction force of the extensor digitorum longus muscle was used as the stimulation intensity for subsequent experiments to ensure that the maximum contraction amplitude was obtained.

[0324] (4) Compound testing: Stimulate the sciatic nerve continuously at a frequency of 0.1 Hz and record the contraction of the extensor digitorum longus muscle. After stabilization for 8-10 min, add the test compound to the incubation solution and record the effect of the compound on the contraction of the extensor digitorum longus muscle. When the contraction amplitude stabilizes, replace the blank incubation solution for elution and test the next compound in the same manner as above.

[0325] 3. Data Analysis

[0326] The amplitude of the sciatic nerve-extensor digitorum longus muscle tension was analyzed, and the inhibition rate was statistically analyzed. All data were expressed as Mean.

[0327] The inhibition rate results are shown in Table 1:

[0328] Table 1 Inhibition rate of compounds on sciatic nerve-extensor digitorum longus contraction

[0329] Compound Inhibition rate (3μM) Compound E4-1 >60％ Compound E4-2 >90％ Compound E9-1 >60％ Control compound <20％

[0330] Structure of reference compound:

[0331] Conclusion: The compounds of the present invention, such as the example compounds, have better muscle relaxant effect than the control compounds. Specifically, the inhibition rate of compounds E4-1 and E9-1 on the contraction of the sciatic nerve-extensor digitorum longus muscle at 3 μM is greater than 60%, and the inhibition rate of compound E4-2 on the contraction of the sciatic nerve-extensor digitorum longus muscle at 3 μM is greater than 90%.

Claims

1. A compound represented by general formula (I) or a stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof, B is selected from L is selected from C 1-8 Alkylene, C 2-8 Alkenylene, C 2-8 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 Each independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 8 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace; Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms a 4- to 12-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently forms a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group with the atoms to which it is attached, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace; X z- is a pharmaceutically acceptable anion; m is 0.5, 2 / 3, 1 or 2; z is 1, 2, 3, 4; s1 or s2 are each independently selected from 0, 1, 2, 3 or 4; n1, n2, n3 or n7 are each independently selected from 0, 1, 2, 3, 4 or 5; n4, n5 or n6 are each independently selected from 0, 1, 2, 3, 4, 5, 6, 7 or 8; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic ring, -O-3 to 7 membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 7-membered heterocyclic ring, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 7 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 atoms selected from deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

2. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: X z- Selected from halides, acetate, benzoate, camphorsulfonate, citrate, glucoheptanoate, gluconate, glucuronate, isethionate, lactate, lactobionate, dodecylsulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthylsulfonate, stearate, oleate, oxalate, dihydronaphthoate, nitrate, phosphate, sulfate, phosphoric acid hydrogen, dihydrogen phosphate, polygalacturonate, succinate, sulfosalicylate, tartrate, trifluoroacetate, hippurate, D-glucuronate, glycolate, mucate, orotenate, pamoate, glycine, alanine, arginine, lysine, cinnamate, propionate, valerate, triphenylacetate, L-proline, ferulate, mandelate, malonate, gentisate, salicylate, or glutarate; L is selected from C 1-4 Alkylene, C 2-4 Alkenylene, C 2-4 Alkyne, wherein L is optionally substituted by 1 to 4 R k replace; R 1 , R 2 , R 3 Each independently selected from C 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, C 3-6 Carbocyclic group, 4 to 6 membered heterocyclic group, the alkyl, alkenyl, alkynyl, carbocyclic group, heterocyclic group are optionally substituted by 1 to 4 R k replace; Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is connected, it forms a 4- to 7-membered monoheterocyclic group, a 5- to 10-membered bridged heterocyclic group, a 7- to 10-membered heterocyclic group or a 7- to 10-membered spiro heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently forms a 4- to 6-membered carbocyclic group or a 4- to 6-membered heterocyclic group with the atoms to which it is attached, wherein the carbocyclic group or heterocyclic group is optionally substituted by 1 to 4 R k replace; Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a 4- to 8-membered heterocyclic group, wherein the heterocyclic group is optionally substituted by 1 to 4 R k replace; R k Each independently selected from deuterium, halogen, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, C 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 Alkenyl, C 2-4 Alkynyl, NHC 1-4 Alkyl, N(C 1-4 Alkyl)2, -OC 3-6 Carbocyclic ring, -O-3 to 6-membered heterocyclic ring, -NH-C 3-6 Carbocyclic ring, -NH-3 to 6-membered heterocyclic ring, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6 membered heterocyclic ring, C 3-6 carbocyclic ring, 3 to 6 membered heterocyclic ring, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic ring or heterocyclic ring is optionally substituted by 1 to 4 deuterium, halogen, CN, OH, NH2, C 1-6 Alkyl, C 1-6 The alkoxy group is substituted with an alkoxy substituent.

3. The compound according to claim 2 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: L is selected from 1 to 4 R k substituted one of the following groups: methylene, ethylene, propylene, butylene, pentylene, vinylene, propenylene, butenylene, pentenylene, ethynylene, propynylene, butynylene, pentynylene; R 1 , R 2 , R 3 Each independently selected from optionally 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 4 R k substituted with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently and together with the atoms to which it is attached form an optionally substituted R k One of the following groups substituted: Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted R k One of the following groups substituted: Alternatively, R 3 , R b7 Together with the atoms to which it is attached, it forms a k One of the following substituted groups: azacyclopentyl, azacyclohexenyl; R k each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally substituted by 1 to 4 selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is substituted with an alkoxy substituent.

4. The compound according to claim 3 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each independently selected from H, deuterium, halogen, CN, OH, =O, NH2, NO2, COOH or optionally substituted by 1 to 3 R k Substituted one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl; Alternatively, 2 R a1 , 2 R a2 , 2 R b1 , 2 R b6 , 2 R b7 Each independently and together with the atoms to which it is attached form an optionally substituted 1 to 2 R k One of the following groups substituted: R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrole Alkyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy; m is 1 or 2; z is 1 or 2; s1 and s2 are each independently selected from 0, 1 or 2.

5. The compound according to claim 4 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound represented by the general formula (I) is selected from the compounds represented by the general formula (II-a), (II-b), (II-c), (II-d), (II-e) or (II-f), n4 and n5 are each independently selected from 1 or 2; Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted: R a1 , R a2 , R b1 , R b2 , R b3 , R b4 , R b5 , R b6 , R b7 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, =O, NH2, NO2, COOH, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl; Alternatively, B is selected from R k Each independently selected from deuterium, F, Cl, Br, I, =O, CN, OH, SH, NH2, NO2, SF5, COOH, CONH2, NH(CH3), NH(CH2CH3), N(CH3)2, N(CH2CH3)2, CD3, OCD3, CF3, CH2F, CHF2, CH2OH, OCF3, OCHF2, OCH2F, methyl, ethyl, vinyl, ethynyl, methoxy, ethoxy, methylthio, -O-cyclopropyl, -NH-cyclopropyl, -CH2-cyclopropyl, -CH2-cyclobutyl, -CH2-cyclopentyl, -CH2-cyclohexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; X - Selected from Cl - Br - ,I - , trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.

6. The compound according to claim 5 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: B is selected from R 1 , R 2 , R 3 Each independently selected from optionally 1 to 3 R k One of the following substituted groups: methyl, ethyl, propyl; Alternatively, R 1 , R 2 Together with the nitrogen atom to which it is attached, it forms an optionally substituted 1 to 3 R k One of the following groups substituted: Selected from Selected from Selected from As an alternative, Selected from As an alternative, Selected from Selected from 7. The compound according to claim 1 or its stereoisomer, racemate, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, wherein: The compound is selected from one of the structures shown in Table S, X - Selected from Cl - Br - ,I - , trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate:

8. A pharmaceutical composition comprising the compound of any one of claims 1 to 7 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition or pharmaceutical preparation comprising 1-1500 mg of a compound according to any one of claims 1-7 or a stereoisomer, racemate, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal thereof and a pharmaceutical excipient.

10. Use of the compound according to any one of claims 1 to 7 or its stereoisomer, racemate, tautomer, deuterated form, solvate, prodrug, metabolite, pharmaceutically acceptable salt or cocrystal for preparing a neuromuscular blocking drug.

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