Benzopiperidine biquaternary ammonium salt compound and application thereof in medicine

Abstract

The invention relates to a benzopiperidine 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, pharmaceutically acceptable salt, an intermediate and a pharmaceutical composition of the compound, and application of the compound in preparation of neuromuscular blocking drugs.

Description

Technical Field

[0001] This invention relates to a compound of general formula (I) or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, intermediates and pharmaceutical compositions thereof, and its use in the preparation of neuromuscular blocking drugs. Background Technology

[0002] Neuromuscular blockers (NMBs), also known as skeletal muscular relaxants, are N2-cholinoceptor blocking drugs. After binding to N2 choline receptors on the motor endplate membrane of skeletal muscle, these blockers inhibit the normal transmission of nerve impulses at the neuromuscular junction, leading to skeletal muscle relaxation. Based on whether the membrane depolarizes after binding to the receptor, they are classified into depolarizing blockers (non-competitive) and non-depolarizing blockers (competitive). Depolarizing blockers mimic acetylcholine (Ach), binding irreversibly and non-competitively to N receptors, such as succinylcholine. Non-depolarizing blockers compete with Ach for binding to N receptors at the Ach recognition site (α subunit), maintaining receptor conformation, preventing ion channel opening, and thus preventing depolarization; examples include rocuronium bromide and cisatracurium.

[0003] The use of muscle relaxants during anesthesia has many benefits: eliminating vocal cord movement to facilitate endotracheal intubation; meeting the requirements for muscle relaxation in various surgeries, diagnoses, and treatments; reducing or terminating muscle rigidity caused by certain skeletal muscle spastic disorders; and eliminating asynchrony between spontaneous breathing and mechanical ventilation. Summary of the Invention

[0004] The purpose of this invention is to provide a compound or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts for the preparation of neuromuscular blocking agents, which have a rapid onset of action, a rapid recovery time, good pharmacokinetic properties, and good safety.

[0005] This invention provides a compound or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein the compound is selected from compounds represented by general formula (I).

[0006]

[0007] In some implementation schemes, L is selected from

[0008] In some implementation schemes, Selected from

[0009] In some implementations, L2 is selected from C 3-10 The L2 is optionally surrounded by 1 to 4 R groups, which are either carbocyclic or 4- to 10-membered heterocyclic groups. L 2 Replacement;

[0010] In some implementations, L2 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl or C 7-10 The L2 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L2 replace;

[0011] In some implementations, L2 is selected from 1 to 3 Rs. L2 The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0012] In some implementations, L2 is selected from 1 to 3 Rs. L2 One of the following groups is replaced:

[0013] In some implementations, L1 is selected from C 3-10 Carbocyclic or 4- to 10-membered heterocyclic groups, wherein the L1 is optionally divided by 1 to 4 R groups. L1 replace;

[0014] In some implementations, L1 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl or C 7-10 The L1 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L1 replace;

[0015] In some implementations, L1 is selected from 1 to 3 Rs. L1The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0016] In some implementations, L1 is selected from 1 to 3 Rs. L1 One of the following groups is replaced:

[0017] In some implementations, L5 is selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic groups, wherein the L5 is optionally surrounded by 1 to 4 R groups. L5 replace;

[0018] In some implementations, L5 is selected from C 3-6 Monocycloalkyl, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L5 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L5 replace;

[0019] In some implementations, L5 is selected from 1 to 3 Rs. L5 The substituted group is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0020] In some implementations, L5 is selected from 1 to 3 Rs. L5 One of the following groups is replaced:

[0021] In some implementation schemes, Selected from The Choose 1 to 2 Rs k replace;

[0022] In some implementation schemes, Selected from

[0023] In some implementation schemes, R L1 R L2 R L3 R L4 R L5 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0024] In some implementation schemes, R L3 R L4 Together with the carbon atoms attached thereto, they form carbon-carbon double bonds, =O, 3- to 6-membered carbocyclic groups, or 4- to 6-membered heterocyclic groups, wherein the carbon-carbon double bonds, carbocyclic groups, or heterocyclic groups are optionally surrounded by 1 to 4 R atoms. k replace;

[0025] In some implementation schemes, R L3 Selected from deuterium, halogens, CN, OH, NH2, NO2, COOH, C 2-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, methyl, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k The methyl group is replaced by 1 to 3 R groups. k replace;

[0026] In some implementation schemes, R L3 R L4 Each is independently selected from H and R 4a R 4b ;

[0027] In some implementation schemes, R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R k Substituted methyl groups, or optionally substituted with 1 to 4 R groups kThe substituted group may be one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0028] In some implementation schemes, R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, or optionally substituted with 1 to 4 Rs. k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrroleyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thiophenyl, thiazolyl; in some embodiments, R L3 Selected from F, Cl, Br, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, cyclopropyl, cyclobutyl, phenyl

[0029] In some implementation schemes, R L1 R L2 R L5 Each is independently selected from deuterium, halogens, =O, CN, OH, NH2, NO2, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0030] In some implementation schemes, R L1 R L2 R L5 Each is independently selected from deuterium, F, Cl, Br, I, ⁵O, CN, OH, NH₂, NO₂, or arbitrarily bound by 1 to 4 Rs. kThe substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolidine, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl;

[0031] In some implementation schemes, R 4a R 4b Each is independently selected from deuterium, halogens, CN, OH, NH2, NO2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0032] In some implementation schemes, R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or optionally by 1 to 4 R. k The substitution is made with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl;

[0033] In some implementation schemes, R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R. k Substituted methyl groups or optionally substituted with 1 to 4 R groups k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl;

[0034] In some implementation schemes, R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, and cyclopropyl.

[0035] In some implementations, ring A is selected from C. 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, wherein ring A is optionally surrounded by 1 to 4 R groups. k replace;

[0036] In some implementations, ring A is selected from 1 to 3 Rs. k The group that is substituted is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxacyclohexyl;

[0037] In some implementation schemes, Selected from 1 to 3 Rs k One of the following groups is replaced:

[0038] In some implementation schemes, R 1 R 2 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0039] In some implementation schemes, R 1 R 2 Each was independently selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0040] In some implementation schemes, R 1 R 2 Each is independently selected from 1 to 4 R's. k The substituted group may be one of the following: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0041] In some implementation schemes, R 1 R 2 Each is independently selected from 1 to 3 R's. k The substituted group is one of the following: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0042] In some implementation schemes, R a1 R a2 Ra3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0043] In some implementation schemes, R a1 R a2 R a3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0044] In some implementation schemes, R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 4 Rs. k The substituted group may be one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0045] In some implementation schemes, R a1 R a2 R a3 R b1 R b2 Rb3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 3 Rs. k The substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0046] In some implementation schemes, Selected from

[0047] In some implementation schemes, Selected from

[0048] In some implementation schemes, Selected from

[0049] In some implementation schemes, Selected from

[0050] In some implementation schemes, R k Each is independently selected from deuterium, halogens, =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 group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0051] In some implementation schemes, R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 6-membered heterocycles, -NH-C 3-6 Carbocyclic rings, -NH-3 to 6-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6-membered heterocycles, C 3-6 Carbocyclic rings, 3- to 6-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic rings are optionally selected from 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0052] In some implementation schemes, R k Each of the following groups is 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, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0053] In some implementation schemes, R kEach of these compounds is 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, aziridine, oxacyclobutyl, and pyrrole. Alkyl, piperidinyl, pyrazolyl, pyrrolithyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziroxybutyl, oxacyclobutyl, pyrrolithyl, piperidinyl, pyrazolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0054] In some implementation schemes, R k Each is 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;

[0055] In some implementation schemes, X z- It is a pharmaceutically acceptable anion;

[0056] In some implementation schemes, X z- Selected from halogens, acetate, benzoate, camphorsulfonate, citrate, gluconate, gluconate, glucuronate, ethanesulfonate, lactate, lacturonate, dodecyl sulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthalenesulfonate, stearate, oleate, oxalate, dihydronaphthalate, nitrate, phosphate, sulfate, hydrogen phosphate Radix, dihydrogen phosphate, polygalacturonic acid, succinate, sulfosalicylate, tartrate, trifluoroacetate, hippurate, D-glucuronide, glycolate, mucoacid, orotic acid, pamoate, glycine, alanine, arginine, lysine, cinnamic acid, propionate, valerate, triphenylacetic acid, L-proline, ferulic acid, mandelic acid, malonate, gentianate, salicylate, or glutarate;

[0057] In some implementation schemes, X - Selected from Cl - ,Br - I - Trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate.

[0058] In some implementations, m is 0.5, 2 / 3, 1, or 2; in some implementations, m is 1 or 2; in some implementations, m is 2.

[0059] In some implementations, z is 1, 2, 3, or 4; in some implementations, z is 1 or 2; in some implementations, z is 1.

[0060] In some implementations, s1 or s2 is independently selected from 0, 1, 2, 3, 4; in some implementations, s1 or s2 is independently selected from 0, 1, or 2; in some implementations, s1 or s2 is independently selected from 2.

[0061] In some implementations, n1 or n2 is independently selected from 0, 1, 2, 3, 4 or 5; in some implementations, n1 or n2 is independently selected from 0, 1, 2, 3.

[0062] In some implementation schemes, Selected from

[0063] Optionally, when s1 or s2 is both 0, and L is selected from... hour, Not selected Or, when both s1 and s2 are 1, L is selected from... hour, Not selected

[0064] As a first embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0065] L is selected from

[0066] L2 is selected from C 3-10 The L2 is optionally surrounded by 1 to 4 R groups, which are either carbocyclic or 4- to 10-membered heterocyclic groups. L2 replace;

[0067] L1 is selected from C 3-10 Carbocyclic or 4- to 10-membered heterocyclic groups, wherein the L1 is optionally divided by 1 to 4 R groups. L1 replace;

[0068] L5 is selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic groups, wherein the L5 is optionally surrounded by 1 to 4 R groups. L5 replace;

[0069] R 1 R 2 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0070] R L1 R L2 R L3 R L4 R L5 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0071] R a1 R a2 R a3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0072] As an option, R L3 R L4 Together with the carbon atoms attached to it, they form carbon-carbon double bonds, =O, 3- to 6-membered carbon cyclic groups, or 4- to 6-membered heterocyclic groups.

[0073] The carbon-carbon double bond, carbocyclic group, or heterocyclic group is optionally surrounded by 1 to 4 R...k replace;

[0074] X z- It is a pharmaceutically acceptable anion;

[0075] m can be 0.5, 2 / 3, 1, or 2;

[0076] z is 1, 2, 3, or 4;

[0077] s1 or s2 can be independently selected from 0, 1, 2, 3 or 4;

[0078] n1 or n2 are each independently selected from 0, 1, 2, 3, 4 or 5;

[0079] R k Each is independently selected from deuterium, halogens, =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 group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0080] The condition is that either s1 or s2 is 0 at the same time, and L is selected from... hour, Not selected Or, when both s1 and s2 are 1, L is selected from... hour, Not selected

[0081] As a second embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof

[0082] X z-Selected from halide ions, acetate, benzoate, camphorsulfonate, citrate, gluconate, glucuronate, ethanesulfonate, lactate, lacturonate, dodecyl sulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthalenesulfonate, stearate, oleate, oxalate, dihydronaphthyl acid, nitrate, phosphate, sulfate, and phosphoric acid. Hydrogen ions, dihydrogen phosphate ions, polygalacturonic acid ions, succinate ions, sulfosalicylate ions, tartrate ions, trifluoroacetate ions, hippurate ions, D-glucuronide ions, glycolate ions, mucoacid ions, orotic acid ions, pamoate ions, glycine ions, alanine ions, arginine ions, lysine ions, cinnamic acid ions, propionate ions, valerate ions, triphenylacetic acid ions, L-proline ions, ferulic acid ions, mandelic acid ions, malonate ions, gentianate ions, salicylate ions, or glutarate ions;

[0083] L2 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L2 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L2 replace;

[0084] L1 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L1 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L1 replace;

[0085] L5 is selected from C 3-6 Monocycloalkyl, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L5 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L5 replace;

[0086] R 1 R 2 Each was independently selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0087] R a1 R a2 R a3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0088] Selected from The Choose 1 to 2 Rs k replace;

[0089] Ring A is selected from C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, wherein ring A is optionally surrounded by 1 to 4 R groups. k replace;

[0090] R L3 Selected from deuterium, halogens, CN, OH, NH2, NO2, COOH, C 2-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, methyl, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k The methyl group is replaced by 1 to 3 R groups. k replace;

[0091] R L1 R L2 R L5 Each is independently selected from deuterium, halogens, =O, CN, OH, NH2, NO2, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0092] R 4a R 4b Each is independently selected from deuterium, halogens, CN, OH, NH2, NO2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace;

[0093] R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 6-membered heterocycles, -NH-C 3-6 Carbocyclic rings, -NH-3 to 6-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6-membered heterocycles, C 3-6 Carbocyclic rings, 3- to 6-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic, or heterocyclic rings are optionally selected from 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 Substituents of alkoxy groups;

[0094] The remaining definitions are the same as those in the first embodiment of the present invention.

[0095] As a third embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0096] R 1 R 2 Each is independently selected from 1 to 4 R's. kThe substituted group may be one of the following: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0097] R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R k Substituted methyl groups, or optionally substituted with 1 to 4 R groups k The substituted group may be one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0098] R L1 R L2 R L5 Each is independently selected from deuterium, F, Cl, Br, I, ⁵O, CN, OH, NH₂, NO₂, or arbitrarily bound by 1 to 4 Rs. k The substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolidine, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl;

[0099] R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or optionally by 1 to 4 R. k The substitution is made with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl;

[0100] R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 4 Rs. kThe substituted group may be one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0101] Ring A is selected from 1 to 3 R's. k The group that is substituted is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxacyclohexyl;

[0102] L2 is selected from 1 to 3 R's. L2 The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0103] L1 is selected from any 1 to 3 Rs. L1 The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0104] L5 is selected from any of 1 to 3 R's. L5 The substituted group is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl;

[0105] R kEach of the following groups is 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, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 Substituents of alkoxy groups;

[0106] The remaining definitions are the same as those in the first or second embodiment of the present invention.

[0107] As a fourth embodiment of the present invention, the compound represented by the aforementioned general formula (I), or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, are used.

[0108] R 1 R 2 Each is independently selected from 1 to 3 R's. k The substituted group is one of the following: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0109] R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 3 Rs. k The substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0110] R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, or optionally substituted with 1 to 4 Rs. kThe substituted group may be one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl;

[0111] R L1 R L2 R L5 Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, or arbitrarily selected by 1 to 3 Rs. k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl;

[0112] R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R. k Substituted methyl groups or optionally substituted with 1 to 4 R groups k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl;

[0113] R k Each of these compounds is 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, aziridine, oxacyclobutyl, and pyrrole. Alkyl, piperidinyl, pyrazolyl, pyrrolithyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziroxybutyl, oxacyclobutyl, pyrrolithyl, piperidinyl, pyrazolyl, morpholinyl are optionally substituted with 1 to 4 substituents selected from deuterium, F, Cl, Br, I, CN, OH, NH2, methyl, ethyl, methoxy, ethoxy;

[0114] m is 1 or 2;

[0115] z is 1 or 2;

[0116] s1 or s2 can be independently selected from 0, 1 or 2;

[0117] The remaining definitions are the same as those in the first, second, or third embodiments of the present invention.

[0118] As a fifth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof

[0119] Selected from 1 to 3 Rs k One of the following groups is replaced:

[0120] R L3 Selected from F, Cl, Br, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, cyclopropyl, cyclobutyl, phenyl

[0121] R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, and cyclopropyl.

[0122] R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl;

[0123] L2 is selected from 1 to 3 R's. L2 One of the following groups is replaced:

[0124] L1 is selected from any 1 to 3 Rs. L1 One of the following groups is replaced:

[0125] L5 is selected from any of 1 to 3 R's. L5 One of the following groups is replaced:

[0126] R k Each is 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;

[0127] X - Selected from Cl - ,Br - I - Trifluoroacetate, methanesulfonate, p-toluenesulfonate or benzenesulfonate;

[0128] Selected from Preferred from

[0129] n1 or n2 are each independently selected from 0, 1, 2, and 3;

[0130] The remaining definitions are the same as those in the first, second, third, or fourth embodiments of this invention.

[0131] As a sixth embodiment of the present invention, the compound represented by the above general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof...

[0132] Selected from

[0133] Selected from

[0134] Selected from

[0135] Selected from

[0136] Selected from

[0137] The remaining definitions are the same as those in the first, second, third, fourth, or fifth embodiments of this invention.

[0138] This invention relates to a compound or its stereoisomers, racemates, tautomers, deuterated derivatives, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals, 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.

[0139] This invention relates to a pharmaceutical composition comprising the above-described compound or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

[0140] This invention relates to the use of the above-mentioned compound or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts in the preparation of neuromuscular blocking agents, or in the preparation of drugs for assisting general anesthesia or muscle relaxation.

[0141] This invention relates to a pharmaceutical composition or pharmaceutical formulation comprising a therapeutically effective amount of the compound of the invention or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, and pharmaceutical excipients. The pharmaceutical composition may be in unit dosage form (the amount of the active ingredient in a unit dosage form is also referred to as a "dosage strength").

[0142] The present invention also provides a method for treating diseases in mammals, comprising administering to the mammal a therapeutically effective amount of the compound of the present invention or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, or pharmaceutical compositions. In some embodiments, the mammals described in the present invention include humans.

[0143] The term "effective amount" or "therapeutic effective amount" as used in this application means that administering a sufficient amount of the compound disclosed in this application will alleviate, to some extent, one or more symptoms of the treated disease or condition (e.g., neuromuscular blockade-related diseases). In some embodiments, the result is a reduction and / or mitigation of the signs, symptoms, or causes of the disease, or any other desired alteration of the biological system. For example, an "effective amount" for therapeutic use is the amount of a composition comprising the compound disclosed in this application required to provide a clinically significant reduction in disease symptoms. Examples of therapeutically effective doses include, but are not limited to, 1-1500 mg, 1-600 mg, 2-600 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, 20-500 mg, 25-500 mg, 30-500 mg, 40-500 mg, 50-500 mg, and 60-500 mg. , 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, 75-40 0mg, 80-400mg, 90-400mg, 100-400mg, 125-400mg, 150-400mg, 200-400mg, 250-400mg, 300-400mg, 10-300mg, 20-30 0mg, 25-300mg, 30-300mg, 40-300mg, 50-300mg, 60-300mg, 70-300mg, 75-300mg, 80-300mg, 90-300mg, 100-300mg, 1 25-300mg, 150-300mg, 200-300mg, 250-300mg, 1-200mg, 2-200mg, 5-200mg, 10-200mg, 20-200mg, 25-200mg, 30-200 mg, 40-200mg, 50-200mg, 60-200mg, 70-200mg, 75-200mg, 80-200mg, 90-200mg, 100-200mg, 125-200mg, 150-200mg;

[0144] 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 the compound of the present invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts.

[0145] A method for treating a disease in mammals, the method comprising administering to a subject a therapeutically effective amount of the compound of the present invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, preferably 1-1500 mg, wherein the disease is preferably a neuromuscular blockade-related disease.

[0146] A method for treating a disease in mammals, the method comprising administering a drug, a compound of the present invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, to a subject at a daily dose of 1-1500 mg / day, said daily dose being a single dose or multiple doses, and in some embodiments, the daily dose including but not limited to 10-1500 mg / day, 10-800 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200 mg / day, etc. -800mg / day, 25-400mg / day, 50-400mg / day, 100-400mg / day, 200-400mg / day, and in some embodiments, the daily dose includes, but is not limited to, 10mg / day, 20mg / day, 25mg / day, 50mg / day, 100mg / day, 125mg / day, 150mg / day, 200mg / day, 400mg / day, 600mg / day, 800mg / day, 1500mg / day, and 2000mg / day.

[0147] This invention relates to a kit that may include a single-dose or multi-dose composition comprising the compound of the present invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof, wherein the amount of the compound of the present invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof is the same as the amount in the aforementioned pharmaceutical composition.

[0148] In this invention, the amount of the compound of the invention or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts is converted in each case as a free base.

[0149] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0150] The compounds of this invention include their racemic, stereoisomer, tautomer, isotopic compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, or cocrystals.

[0151] The carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention include their isotopic forms. That is, the carbon, hydrogen, oxygen, sulfur, nitrogen, phosphorus, F, Cl, Br, I, etc. involved in the groups and compounds described in this invention may be optionally further replaced by one or more of their corresponding isotopes, wherein the isotopes of carbon include 11 C 12 C 13 C and 14 C, the isotopes of hydrogen include protium (H), deuterium (D, also called heavy hydrogen), and tritium (T, also called superheavy hydrogen), and the isotopes of oxygen include 15 O、 16 O、 17 O and 18 O, isotopes of sulfur include 32 S, 33 S, 34 S, 35 S and 36 S, nitrogen isotopes include 13 N、 14 N and 15 N, isotopes of fluorine include 17 F, 18 F and 19 F, isotopes of chlorine include 35 Cl、 36 Cl and 37 Cl, isotopes of bromine include 79 Br and 81 Br, an isotope of iodine, includes 123 I, 125 I, phosphorus isotopes include 31 P, 32 P.

[0152] “CN” refers to cyano.

[0153] "Halogen" refers to F, Cl, Br or I.

[0154] "Halogen-substituted" refers to substitution with F, Cl, Br, or I, including but not limited to 1 to 10 substituents selected from F, Cl, Br, or I, 1 to 6 substituents selected from F, Cl, Br, or I, and 1 to 4 substituents selected from F, Cl, Br, or I. "Halogen-substituted" is abbreviated as "halogenated".

[0155] "alkyl" refers to a substituted or unsubstituted straight-chain or branched saturated aliphatic hydrocarbon group, including but not limited to alkyl groups with 1 to 20 carbon atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 6 carbon atoms, and alkyl groups with 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 their various branched isomers; the alkyl group can be monovalent, divalent, trivalent, or tetravalent.

[0156] "Alkylene" refers to substituted or unsubstituted straight-chain and branched divalent saturated hydrocarbon groups, including -(CH2). v - (v is an integer from 1 to 10), alkylene examples include, but are not limited to, methylene, ethylene, propylene, and butylene.

[0157] "Cycloalkyl" refers to a substituted or unsubstituted saturated carbocyclic hydrocarbon group, typically having 3 to 12 carbon atoms. Cycloalkyl groups can be monocyclic, fused, bridged, or spirocyclic. Non-limiting examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclobutyl-cyclobutyl, cyclobutyl-spirobutyl, adamantane, etc. Cycloalkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0158] "Heterocyclic alkyl" refers to a substituted or unsubstituted saturated cyclic hydrocarbon group containing heteroatoms, including but not limited to 3 to 12 atoms or 3 to 8 atoms, containing 1 to 3 heteroatoms selected from N, O, S, or Se. The C, N, and S atoms on the ring of the heterocyclic alkyl group can be oxidized to various oxidation states. Heterocyclic alkyl groups can be monocyclic, fused, bridged, or spirocyclic. Heterocyclic alkyl groups can be attached to heteroatoms or carbon atoms. Non-limiting examples include epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, dioxopentyl, dioxohexyl, pyrrolylalkyl, piperidinyl, imidazoalkyl, oxazolidinyl, oxazinylalkyl, morpholinyl, hexahydropyrimidinyl, piperazineyl, etc. Heterocyclic alkyl groups can be monovalent, divalent, trivalent, or tetravalent.

[0159] "Alkenyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon double bonds. The main chain has, but is not limited to, 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-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.

[0160] "Alynyl" refers to a substituted or unsubstituted straight-chain and branched unsaturated hydrocarbon group having at least one, typically one, two, or three, carbon-carbon triple bonds. The main chain comprises 2 to 10 carbon atoms, including but not limited to having 2 to 6 carbon atoms on the main chain, or 2 to 4 carbon atoms on the main chain. Examples of alkynyl groups include, but are not limited to, ethynyl, propynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, and 4-pentynyl. The alkynyl group can be monovalent, divalent, trivalent, or tetravalent.

[0161] "Alkoxy" refers to a substituted or unsubstituted -O-alkyl group. Non-limiting examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, cyclopropoxy, and cyclobutoxy.

[0162] "Carbocyclic group" or "carbocyclic ring" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system. The carbocyclic group can be attached to an aromatic or non-aromatic ring, and the ring can be optionally a monocyclic, fused, bridged, or spirocyclic ring. Non-limiting examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, 1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl, cyclohexyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclohexenyl, benzene ring, naphthalene ring, etc. "Carbocyclic group" or "carbon ring" can be monovalent, divalent, trivalent or tetravalent.

[0163] "Heterocyclic group" or "heterocyclic" refers to a substituted or unsubstituted aromatic or non-aromatic ring. The aromatic or non-aromatic ring can be a 3- to 8-membered monocyclic ring, a 4- to 12-membered bicyclic ring, a 10- to 15-membered tricyclic ring, or a 12- to 18-membered quaternary system, and contains one or more (including but not limited to 2, 3, 4 or 5) heteroatoms selected from N, O, S or Se. The C, N, S or Se selectively substituted in the ring of the heterocyclic group can be oxidized to various oxidation states. The heterocyclic group can be attached to a heteroatom or a carbon atom, and can be attached 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 epoxyethyl, aziridinepropyl, oxacyclobutyl, aziridinebutyl, 1,3-dioxopentyl, 1,4-dioxopentyl, 1,3-dioxahexane, aziridineheptyl, pyridinyl, furanyl, thiophene, pyranyl, N-alkylpyrroleyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, piperidinyl, morpholinyl, thiomorpholinyl, 1,3-dithioyl, dihydrofuranyl, dihydropyranyl, dithiapentylcycloyl. Tetrahydrofuranyl, tetrahydropyrrolyl, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydropyranyl, benzimidazolyl, benzopyridyl, pyrrolopyridyl, benzodihydrofuranyl, pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyrazinyl, indazolyl, benzothiophene, benzofuranyl, benzopyrrolyl, benzimidazolyl, benzothiazolyl, benzooxazolyl, benzopyridyl, benzopyrimidinyl, benzopyrazinyl, piperazinyl, azabicyclo[3.2.1]octyl, azabicyclo[5.2.0]nonyl, oxatricyclo[5.3.1.1]dodecyl, azaadamantyl, oxaspiro[3.3]heptyl, "Heterocyclic group" or "heterocyclic" can be monovalent, divalent, trivalent or tetravalent.

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

[0165]

[0166] "Spirocyclic" or "spirocyclic group" can be monovalent, divalent, trivalent or tetravalent.

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

[0168] "Cyclone" or "cyclone base" can be monovalent, divalent, trivalent, or tetravalent.

[0169] A “bridged ring” or “bridged ring group” refers to a substituted or unsubstituted polycyclic group containing any two atoms that are not directly connected, and may contain zero or more double bonds. Any ring in a bridged ring system may contain 0 to 5 groups selected from heteroatoms or containing heteroatoms (including but not limited to N, S(=O)n, or O, where n is 0, 1, or 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] Cubicane, adamantane. "Bridged ring" or "bridged ring group" can be monovalent, divalent, trivalent, or tetravalent.

[0171] "Carbon spirocyclic", "spirocyclic carbon cyclic", "spirocarbon cyclic", or "carbon spirocyclic" refers to a spirocyclic system composed only of carbon atoms.

[0172] "Carbon fused ring", "fused cyclic carbon cyclic group", "fused carbon cyclic group" or "carbon fused cyclic group" refers to a ring system composed only of carbon atoms.

[0173] "Carbon bridged ring", "bridged ring carbon cyclo group", "bridged carbon cyclo group" or "carbon bridged ring group" refers to a ring system composed only of carbon atoms.

[0174] "Hybrid monocyclic", "monocyclic heterocyclic group" or "hybrid monocyclic group" refers to the "heterocyclic group" or "heterocyclic" in a monocyclic system.

[0175] "Hydrocyclic ring", "hydrocyclic cyclic group", "fused cyclic heterocyclic group" or "fused heterocyclic group" refers to a "fused ring" containing heteroatoms.

[0176] "Heterospirocyclic", "heterospirocyclic group", "spirocyclic heterocyclic group" or "spiroheterocyclic group" refers to a "spirocycle" containing heteroatoms.

[0177] "Hybrid-bridged ring", "hybrid-bridged ring group", "bridged ring heterocyclic group" or "bridged heterocyclic group" refers to a "bridged ring" containing heteroatoms.

[0178] "Aryl" or "aromatic ring" refers to a substituted or unsubstituted aromatic hydrocarbon group having a monocyclic or 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 can be fused to a saturated or unsaturated carbon ring, wherein the ring connected to the parent structure is the aryl ring. Non-limiting embodiments include benzene rings, naphthalene rings, etc. The "aryl" or "aryl ring" can be monovalent, divalent, trivalent, or tetravalent. When it is divalent, trivalent, or tetravalent, the linking site is located on the aryl ring.

[0179] "Heteroaryl" or "heteroary ring" refers to a substituted or unsubstituted aromatic hydrocarbon group containing 1 to 5 heteroatoms or a group containing heteroatoms (including but not limited to N, O, S(=O)n or Se(=O)n, where n is 0, 1, or 2). The number of ring atoms in the heteroaryl 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 may be optionally oxidized (i.e., C(=O), NO, S(=O)n, Se(=O)n, where n is 1 or 2). Non-limiting examples of heteroaryl groups include, but are not limited to, pyridyl, furanyl, thiophenyl, selenyl, pyridyl, pyranyl, N-alkylpyrrolithyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazoleyl, benzopyrazolyl, benzimidazoleyl, benzopyridyl, pyrrolopyridyl, pyridinoneyl, etc. The heteroaryl ring can be fused to a saturated or unsaturated carbon ring or heterocycle, wherein the ring connected to the parent structure is an aryl ring. Non-limiting embodiments include: The heteroaryl groups mentioned in this article are defined in accordance with this definition. Heteroaryl groups can be monovalent, divalent, trivalent, or tetravalent. When divalent, trivalent, or tetravalent, the linkage site is located on an aromatic ring.

[0180] "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 cyclic, spirocyclic, fused cyclic, hydroxyalkyl, =O, carbonyl, aldehyde, carboxylic acid, formate, and -(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 (where m and n are 0, 1, or 2), arylthio, thiocarbonyl, silyl, or -NR b R c Groups, wherein R b With R c Independently selected from H, hydroxyl, amino, carbonyl, alkyl, alkoxy, cycloalkyl, heterocyclic, aryl, heteroaryl, sulfonyl, trifluoromethanesulfonyl, R b With R c It can form five- or six-membered cycloalkyl or heterocyclic groups, R a With R d Each group is independently selected from aryl, heteroaryl, alkyl, alkoxy, cycloalkyl, heterocyclic, carbonyl, ester, bridged cyclic, spirocyclic, or fused cyclic groups.

[0181] "1 to X substituents selected from..." means substituted by 1, 2, 3...X substituents selected from..., where X is any integer between 1 and 10. For example, "1 to 4 R..." k "Replace" refers to being replaced by 1, 2, 3, or 4 Rs. k Substitution. For example, "1 to 5 substituents selected from ..." means that the ring is 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.

[0182] XY-membered rings (where X and Y are integers, and 3 ≤ X < Y, X < Y ≤ 20, selected from any integer between 4 and 20) include rings of the X, X+1, X+2, X+3, X+4…Y-membered types. These rings include heterocyclic rings, carbocyclic rings, aromatic rings, aryl groups, heteroaryl groups, cycloalkyl groups, heteromonocyclic rings, heterofused rings, heterospirocyclic rings, or heterobridged rings. For example, "4-7-membered heteromonocyclic rings" refers to heteromonocyclic rings of 4, 5, 6, or 7 members, and "5-10-membered heterofused rings" refers to heterofused rings of 5, 6, 7, 8, 9, or 10 members.

[0183] C x-y Carbocyclic rings (including aryl, cycloalkyl, monocyclic, spirocyclic, fused, or bridged carbocyclic rings) include C x C x+1 C x+2 C x+3 C x+4 …C y A ring of elements (x is an integer, and 3 ≤ x < y, where y is any integer between 4 and 20), for example, C. 3-6 "Cycloalkyl" refers to C3, C4, C5, or C6 cycloalkyl groups.

[0184] When a functional group has one or more connectable sites, any one or more of these sites can be linked to other functional groups via chemical bonds. When the chemical bond connection is non-directional and a hydrogen atom is present at the connectable site, the number of hydrogen atoms at that site decreases accordingly with the number of bonds being formed, resulting in a functional group with a corresponding valence. For example... This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... These four connection methods, even if an H atom is drawn on -N-, This also includes For example This indicates that the R group on the piperidinyl group can be located on C or N, and at least includes [missing information]. For example, the general formula segment is: When X is selected from CH2 or NH, it means that the R group on the general formula fragment can be located on C or X. When X is selected from CH2, the general formula fragment can be... When X is selected from NH, the general formula fragment can be:

[0185] When the listed linking groups do not specify their linking direction, the linking direction includes the direction of the reading order from left to right and from right to left. For example, when ALB is selected from -MW-, it includes AMWB and AWMB.

[0186] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the possibility or possibility that the event or environment may or may not occur. For example, "optionally substituted F alkyl" means that the alkyl group may but does not have to be substituted with F, and the description includes the case where the alkyl group is substituted with F and the case where the alkyl group is not substituted with F.

[0187] "Pharmaceutically acceptable salt" or "its pharmaceutically acceptable salt" means that the compound of the present invention retains the bioavailability and properties of a free acid or a free base, and that the free acid is obtained by reacting with a non-toxic inorganic or organic base, and the free base is obtained by reacting with a non-toxic inorganic or organic acid.

[0188] "Pharmaceutical composition" refers to a mixture of one or more compounds described in this invention, or stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts or cocrystals, and other chemical components, wherein "other chemical components" refers to pharmaceutically acceptable carriers, excipients, and / or one or more other therapeutic agents.

[0189] "Product specification" refers to the weight of the active pharmaceutical ingredient contained in each vial, tablet, or other unit of preparation.

[0190] "Carrier" refers to a material that does not cause significant stimulation to an organism and does not eliminate the biological activity and properties of the compound given.

[0191] "Prodrug" refers to a compound of the present invention that can be metabolized in vivo and converted into a biologically active compound. The prodrug of the present invention is prepared by modifying the amino or carboxyl groups in the compound of the present invention. This modification can be performed through conventional procedures or removed in vivo to obtain the parent compound. When the prodrug of the present invention is administered to a mammalian individual, the prodrug is cleaved to form free amino or carboxyl groups.

[0192] "Co-crystal" refers to a crystal formed by the bonding of an active pharmaceutical ingredient (API) and a co-crystal form (CCF) through hydrogen bonds or other non-covalent bonds. Both API and CCF are solids at room temperature in their pure states, and a fixed stoichiometric ratio exists between the components. Co-crystal is a multi-component crystal, encompassing both binary co-crystals formed between two neutral solids and multi-component co-crystals formed between a neutral solid and a salt or solvate.

[0193] "Animals" refers to mammals, such as humans, companion animals, zoo animals, and livestock, with humans, horses, or dogs being preferred.

[0194] "Stereoisomers" refer to isomers that are produced by different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers, and conformational isomers.

[0195] "Tautomers" refer to functional group isomers that are produced by the rapid movement of an atom in two positions within a molecule, such as keto-enol isomers and amide-imine alcohol isomers. Detailed Implementation

[0196] The following embodiments illustrate the technical solution of the present invention in detail, but the scope of protection of the present invention includes, but is not limited to, these embodiments.

[0197] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) were expressed in 10⁻¹⁰ increments. -6 The unit (ppm) is given. NMR measurements were performed using a Bruker Avance III 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0198] MS determination was performed using (Agilent 6120B (ESI) and Agilent 6120B (APCI));

[0199] HPLC determinations were performed using an Agilent 1260DAD high-performance liquid chromatograph (Zorbax SB-C18 100×4.6mm, 3.5μM).

[0200] Thin-layer chromatography silica gel plates used were from Yantai Huanghai HSGF. 254 Or Qingdao GF 254 Silica gel plates: The silica gel plates used in thin-layer chromatography (TLC) have a diameter of 0.15mm-0.20mm, while those used for TLC separation and purification of products have a diameter of 0.4mm-0.5mm.

[0201] Column chromatography typically uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier;

[0202] Boc: tert-butoxycarbonyl; Ts: p-toluenesulfonyl; Cbz: benzyloxycarbonyl; TMS: trimethylsilyl.

[0203] Synthesis Method 1:

[0204]

[0205] General formula (Z1) reacts with tert-butyl 3-bromopropionate under alkaline conditions to generate general formula (Z2). General formula (Z2) reacts with iodomethane under alkaline conditions to generate general formula (Z3). General formula (Z3) is deprotected under acidic conditions to generate general formula (Z4). General formula (Z4) reacts with oxalyl chloride to generate acyl chloride, which then immediately undergoes an acylation reaction with general formula (Z5) to generate general formula (I').

[0206] Example 1: Preparation of Compound 1

[0207]

[0208] 1-a (316 mg, 0.7 mmol, reference: US9156826 B2) was dissolved in ultra-dry DMF (5 mL). 1-b (54 mg, 0.35 mmol), HATU (266 mg, 0.7 mmol), and DIPEA (0.2 mL, 1.21 mmol) were added sequentially under ice bath conditions. The mixture was then transferred to room temperature and stirred for 16 hours. The system was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile / mobile phase B: water (containing 0.1% TFA) to obtain compound 1 (80 mg, yield 19.62%).

[0209] LCMS m / z = 476.1 [M-2CF3COO] 2+

[0210] Example 2: Preparation of Compound 2

[0211]

[0212] After separation, 2-a (71g, reference: WO2008132748) yielded two optical isomers:

[0213] Compound 2-b (retention time: 3.561 min, 20 g, white solid, dr% = 99%);

[0214] Compound 2-c (retention time: 3.626 min, 37 g, brownish-yellow foamy solid, dr% = 99%).

[0215] Analysis conditions:

[0216] Instrument: CAS-05-ANA-SFC-D; Column: Cellulose-2 column; Mobile phase: A for CO2; B for 0.05% DEA in methanol and acetonitrile (v / v = 3:1); Flow rate: 3 mL / min; Column temperature: 35℃; Wavelength: 220 nm

[0217] Separation conditions:

[0218] Instrument: CAS-05-Prep-HPLC-B; Column: Chiral OD column;

[0219] Mobile phase: A for CO2; B for methanol; Flow rate: 180 mL / min; Column temperature: room temperature; Wavelength: 220 nm.

[0220] Step 2: Preparation of 2-d

[0221] Dissolve 2-b (300 mg, 0.49 mmol) in dichloromethane (2 mL), add 4 M hydrochloric acid-dioxane solution (2 mL), react at room temperature for 2 hours, concentrate the system to dryness, and use it directly in the next step of the reaction.

[0222] Step 3: Preparation of Compound 2

[0223] 2-d (227 mg, 0.49 mmol) was dissolved in ultradry dichloromethane (2 mL), and a 2 M oxalyl chloride solution in dichloromethane (0.3 mL) was added. The mixture was stirred at room temperature for 2 hours, and then 12-f (35 mg, 0.24 mmol, reference: WO 2013 / 174736) was added. The mixture was reacted under a nitrogen atmosphere at room temperature for 16 hours. The reaction solution was concentrated to dryness, and the residue was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; 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 2 (15 mg, yield 5.15%).

[0224] LCMS m / z = 484.3 [M-2CF3COO] 2+

[0225] Example 3: Preparation of Compound 3

[0226]

[0227] Compound 3 was synthesized from 2-e,3-b using the synthesis method described in Example 2, with a yield of 6.92%.

[0228] LCMS m / z = 476.4 [M-2CF3COO] 2+1 H NMR(400MHz,DMSO-d6)δ6.90-6.81(m,4H),6.63-6.52(m,4H),5.76(s,2H),4.87-4.78(m,2H),4.20-4.11(m,4H),3. 95-3.69(m,20H),3.64(s,6H),3.55-3.45(m,2H),3.32-3.07(m,14H),2.97(s,6H),2.92-2.83(m,2H),1.72(s,6H).

[0229] Example 4: Preparation of Compound 4

[0230]

[0231] Compound 4 was synthesized from 4-a using the synthetic method described in Example 1, with a yield of 51.38%.

[0232] LCMS m / z = 476.1 [M-2CF3COO] 2+

[0233] Example 5: Preparation of Compound 5

[0234]

[0235] Compound 5 was synthesized from 2-e,5-b using the synthetic method described in Example 2, with a yield of 11.98%.

[0236] LCMS m / z = 470.3 [M-2CF3COO] 2+

[0237] Example 6: Preparation of Compound 6

[0238]

[0239] Compound 6 was synthesized using 2-d and 3-b as starting materials according to the synthesis method of Example 2, with a yield of 7.90%.

[0240] LCMS m / z = 476.3 [M-2CF3COO] 2+

[0241] Example 7: Preparation of Compound 7

[0242]

[0243] 7-a (440 mg, 1.04 mmol, reference: US9156826 B2) was dissolved in ultra-dry DMF (5 mL). 7-b (83 mg, 0.5 mmol), HATU (380 mg, 1 mmol), and DIPEA (0.3 mL, 1.82 mmol) were added sequentially under ice bath conditions. The mixture was then transferred to room temperature and stirred for 16 hours. The system was purified by preparative liquid chromatography (instrument: Waters 2767 preparative liquid chromatography; column: SunFire@Prep C18 (19 mm × 250 mm); mobile phase composition: mobile phase A: acetonitrile / mobile phase B: water (containing 0.1% TFA) to obtain compound 7 (87 mg, yield 14.78%).

[0244] LCMS m / z = 451.3 [M-2CF3COO]2+

[0245] Example 8: Preparation of Compound 8

[0246]

[0247] Compound 8 was synthesized from 1-a and 8-b using the synthesis method described in Example 1, with a yield of 8.90%.

[0248] LCMS m / z = 484.3 [M-2CF3COO] 2+1 H NMR(400MHz,DMSO-d6)δ7.80(s,2H),6.88-6.79(m,4H),6.68-6.62(m,2H),6.57-6.49(m,2H),5.65(s,2H),4.70-4.60(m,2H),4.17-4.07(m,4H ),3.95-3.83(m,2H),3.74-3.53(m,22H),3.43-3.35(m,4H),3.32(s,6H ),3.22(s,6H),3.14-3.01(m,4H),2.94-2.83(m,2H),2.29-2.12(m,4H).

[0249] Example 9: Preparation of Compound 9

[0250]

[0251] Compound 9 was synthesized from 9-a and 9-b using the synthetic method described in Example 1, with a yield of 15.87%.

[0252] LCMS m / z = 507.4 [M-2CF3COO] 2+1 H NMR(400MHz,DMSO-d6)δ6.85(s,2H),6.33(s,4H),5.72(s,2H),4.69-4.61(m,2H),4.06-3.78(m,8H),3.74-3 .50(m,28H),3.35-3.24(m,15H),3.17-2.96(m,4H),2.93-2.84(m,2H),2.18-2.04(m,7H),0.28-0.15(m,4H).

[0253] Example 10: Preparation of Compound 10

[0254]

[0255] Compound 10 was synthesized using 9-a and 1-b as raw materials according to the synthesis method of Example 1, with a yield of 24.60%.

[0256] LCMS m / z = 506.3 [M-2CF3COO] 2+1 H NMR(400MHz,DMSO-d6)δ6.87(s,2H),6.34(s,4H),5.73(s,2H),4.71-4.62(m,2H),4.07 -3.83(m,6H),3.76-3.50(m,28H),3.38-2.84(m,22H),2.20-2.06(m,4H),1.92(s,6H).

[0257] Example 11: Preparation of Compound 11

[0258]

[0259] Compound 11 was synthesized using 7-a and 8-b as raw materials according to the synthesis method of Example 1, with a yield of 6.25%.

[0260] LCMS m / z = 454.3 [M-2CF3COO] 2+1 H NMR(400MHz,DMSO-d6)δ7.81(s,2H),7.02-6.94(m,4H),6.90-6.76(m,6H),5.56(s,2H),4.67-4.58(m,2H),4.18-4.05(m,4H),3.96 -3.88(m,2H),3.75-3.65(m,14H),3.63-3.56(m,2H),3.43-3.27(m,10H),3.24-3.00(m,10H),2.94-2.82(m,2H),2.29-2.10(m,4H).

[0261] Example 12: Preparation of Compound 12

[0262]

[0263] Compound 12 was synthesized from 2-e,12-b using the synthesis method described in Example 2, with a yield of 5.85%.

[0264] LCMS m / z = 484.5 [M-2CF3COO] 2+

[0265] Compound 13-78 was synthesized according to the above method:

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Biological test cases

[0273] I. Experimental method for determining the effective dose of muscle relaxants:

[0274] 1. Experimental Preparation: Rats were anesthetized intraperitoneally with urethane, and an indwelling intravenous catheter was inserted through the larynx. The rats were then fixed in a supine position on the dissection table and mechanically ventilated using a small animal ventilator. The tail vein of the rat was punctured and a catheter was inserted for drug administration. Hair was removed from the right hind leg ankle joint and the outer side of the lower leg using a shaver.

[0275] 2. Tibialis anterior tendon separation: Make a 2cm longitudinal incision along the right tibia at the ankle joint to expose the transverse ankle ligament. Carefully separate the tibialis anterior tendon and ligate it with surgical sutures. Transversely cut the tendon at the distal end to free the tibialis anterior. Fix one end of the suture to a tension transverse ...

[0276] 3. Sciatic nerve dissection and electrode connection: A longitudinal incision is made in the skin outside the knee joint (popliteal fossa), the fascia is cut, and the sciatic nerve is separated using a glass needle. The sciatic nerve is then connected to the stimulation electrode.

[0277] 4. Administer TOF stimulation to the right sciatic nerve with the following parameters: voltage 2V, frequency 2Hz, pulse width 200μs, and interval stimulation 10s. Record the tibialis anterior muscle tension curve and administer the drug after the curve stabilizes.

[0278] 5. Drug administration: The dosage was set as a gradient. TOF stimulation was initiated upon completion of drug administration. The next dose was administered only when the fourth muscle twitch (T4) of TOF equaled the first muscle twitch (T4 = T1). Krebs solution was intermittently sprayed onto the exposed muscles and nerves during the experiment to maintain their moisture and activity.

[0279] 6. Index determination: Dose-response curves were established based on the inhibition rate of T1 at different doses to calculate ED. 50 and ED 95 .

[0280] II. Testing the onset and recovery time of muscle relaxants:

[0281] 1. Experimental Preparation: Rats were anesthetized intraperitoneally with urethane, and an indwelling intravenous catheter was inserted through the larynx. The rats were then fixed in a supine position on the dissection table and mechanically ventilated using a small animal ventilator. The tail vein of the rat was punctured and a catheter was inserted for drug administration. Hair was removed from the right hind leg ankle joint and the outer side of the lower leg using a shaver.

[0282] 2. Tibialis anterior tendon separation: Make a 2cm longitudinal incision along the right tibia at the ankle joint to expose the transverse ankle ligament. Carefully separate the tibialis anterior tendon and ligate it with surgical sutures. Transversely cut the tendon at the distal end to free the tibialis anterior. Fix one end of the suture to a tension transverse ...

[0283] 3. Sciatic nerve dissection and electrode connection: A longitudinal incision is made in the skin outside the knee joint (popliteal fossa), the fascia is cut, and the sciatic nerve is separated using a glass needle. The sciatic nerve is then connected to the stimulation electrode.

[0284] 4. Administer TOF stimulation to the right sciatic nerve with the following parameters: voltage 2V, frequency 2Hz, pulse width 200μs, and interval stimulation 10s. Record the tibialis anterior muscle tension curve and administer the drug after the curve stabilizes.

[0285] 5. Drug administration: The dosage was set as a gradient. TOF stimulation was initiated upon completion of drug administration. The next dose was administered only when the fourth muscle twitch (T4) of TOF equaled the first muscle twitch (T4 = T1). Krebs solution was intermittently sprayed onto the exposed muscles and nerves during the experiment to maintain their moisture and activity.

[0286] 6. Indicator determination: Onset time: the time from the administration of 2*ED95 dose to the production of maximum inhibition at T1; Recovery time: the time from the administration of 2*ED95 dose to the recovery to 75% at T4 (TOFr75); the time from the administration of 2*ED95 dose to the recovery to 90% at T4 (TOFr90).

[0287] Conclusion: The compounds of the present invention, such as those in the examples, have good neuromuscular blocking effects in rats.

[0288] III. Experimental Method for Isolated Sciatic Nerve-Extensor Phimorum Longus in Rats

[0289] 1. Experimental Materials

[0290] Experimental animals: SD rats, male, 8 weeks old; isolated tissues: sciatic nerve-extensor digitorum longus muscle

[0291] 2. Experimental Methods

[0292] (1) Preparation of sciatic nerve-extensor digitorum longus tissue: Animals were anesthetized with urethane. The sciatic nerve and extensor digitorum longus were rapidly separated and placed in a modified Krebs solution containing an artificial mixed gas.

[0293] (2) Connection device: The sciatic nerve is placed on the stimulation electrode connected to the stimulator. One end of the extensor digitorum longus muscle is fixed and the other end is connected to the tension transducer. The muscle tension is continuously recorded using the PowerLab signal acquisition system.

[0294] (3) Baseline recording: The sciatic nerve was stimulated with 2ms pulses at a frequency of 0.1Hz, and the stimulation intensity was gradually increased to induce the contraction amplitude of the extensor digitorum longus muscle. The stimulation intensity corresponding to 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.

[0295] (4) Compound test: The sciatic nerve was continuously stimulated at a frequency of 0.1 Hz and the contraction of the extensor digitorum longus muscle was recorded. After stabilizing for 8-10 min, the test compound was added to the incubation solution and the effect of the compound on the contraction of the extensor digitorum longus muscle was recorded. When the contraction amplitude stabilized, the blank incubation solution was replaced for elution, and the next compound was tested in the same way.

[0296] 3. Data Analysis

[0297] The amplitude values ​​of sciatic nerve-extensor digitorum longus muscle tone were analyzed, and the inhibition rate was statistically analyzed. All data are expressed as Mean.

[0298] Conclusion: The compounds of this invention, such as those in the examples, have good muscle relaxant effects and inhibit sciatic nerve-extensor digitorum longus contraction. IV. Patch-clamp technique for detecting the effect of the test substance on nAchα1β1δε receptor current.

[0299] 1. Cell Culture

[0300] In this study, we used the HEK293 cell line, which stably expresses the nAchα1β1δε receptor and was constructed by the laboratory of Beijing Aisiyipu Biotechnology Co., Ltd.

[0301] Cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum at 37°C and 5% carbon dioxide.

[0302] Cell passage: Remove the old culture medium and wash once with PBS, then add 1 mL of 0.25% Trypsin-EDTA solution and incubate at 37°C for approximately 1.5 min. When the cells detach from the bottom of the dish, add approximately 5 mL of preheated (37°C) complete culture medium. Gently pipette the cell suspension to separate aggregated cells. Transfer the cell suspension to sterile centrifuge tubes and centrifuge at 1000 rpm for 5 min to collect the cells. For expansion or maintenance culture, seed cells into 6 cm cell culture dishes, with a seeding density of 2.5 × 10⁵ cells per dish (final volume: 5 mL).

[0303] To maintain the electrophysiological activity of cells, the cell density must not exceed 80%.

[0304] Before patch-clamp assay, cells were separated with 0.25% Trypsin-EDTA, and 6.5 × 10³ cells were seeded onto coverslips and cultured in 24-well plates (final volume: 500 μL). Dox-tetoxin was added, and assays were performed after 24–72 hours.

[0305] All operations follow the standard operating procedures for cell culture of Beijing Aisiyipu Biotechnology Co., Ltd.

[0306] Record the liquid used

[0307] Extracellular fluid: 140mM NaCl, 3.5mM KCl, 1mM MgCl2·6H2O, 2mM CaCl2·2H2O, 10mM D-Glucose, 10mM HEPES, 1.25mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH.

[0308] Intracellular fluid: 50mM CsCl, 10mM NaCl, 10mM HEPES, 60mM CsF, 20mM EGTA, CsOH adjusted to pH 7.2.

[0309] 2. Experimental Methods:

[0310] The voltage stimulation protocol for whole-cell patch-clamp recording of nAchα1β1δε receptor currents is as follows: After whole-cell sealing, the cell membrane voltage is clamped at -70 mV. Current peaks are recorded by sequentially and rapidly administering the cell surface agonist Ach followed by an Ach+compound mixture. Each concentration is administered 2-3 times, and the current is measured only after stabilization. Extracellular fluid is used for elution between each administration.

[0311] The test data were acquired by the EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0312] The patch-clamp procedure begins by drawing a capillary glass tube into a recording electrode using a microelectrode drawing device. The electrode, filled with intracellular fluid, is then inserted into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid, and the electrode resistance (Rpip) is recorded. Next, the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to aspirate and create a high-resistance seal (GΩ). Fast capacitance compensation is then performed, and continued negative pressure is applied to rupture the cell membrane, establishing a whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is applied.

[0313] During electrophysiological recording, a coverslip containing cells was placed in a recording bath under an inverted microscope. Blank control solutions and working solutions of the test compounds were administered sequentially from low to high concentration via gravity perfusion, acting on the cells. A peristaltic pump was used for fluid replacement during recording. All electrophysiological experiments were performed at room temperature.

[0314] 3. Data Analysis:

[0315] First, the peak Ach receptor current after the treatment of each drug concentration and Ach mixture was measured. Ach+Compound ) and the peak receptor current excited by Ach Ach Normalized (%Normalized) the inhibition rate for each drug at each drug concentration was calculated. For each concentration-effect ratio, the mean (Mean), standard deviation (SD), and standard error (SEM) are calculated, and the data are expressed as Mean ± SEM.

[0316] 4. The test results are shown in Table 1:

[0317] compound <![CDATA[IC 50 ]]> compound <![CDATA[IC 50 ]]> Compound 1 A Compound 46 A Compound 2 A Compound 47 A Compound 3 A Compound 50 A Compound 5 A Compound 59 A Compound 6 A Compound 61 A Compound 8 A Compound 62 A Compound 10 A Compound 65 A Compound 11 A Compound 67 A Compound 12 A Compound 72 A Compound 15 A Compound 77 A Compound 16 A Compound 78 A Compound 45 A

[0318] A < 100nM

[0319] Conclusion: The compounds of the present invention, such as the compounds in the examples, have a good inhibitory effect on the nAchα1β1δε receptor.

[0320] V. Excitatory or inhibitory effects on the M1-M5 target sites

[0321] Second Messenger Detection

[0322] Cell line: Chinese hamster ovary (CHO) cell line stably expressing M1-M5 receptors

[0323] Experimental methods: Intracellular IP1 or Ca was measured using TR-FRET IP1 or FLIPR calcium flux assays. 2+ At the level of investigation, the activation / inhibition effects of the test substance on the target are studied.

[0324] In the TR-FRET IP1 assay, the positive compound and the analyte were first serially diluted. After cell counting, the treated cells were seeded into 384-well plates. Next, the diluted compound was added to the corresponding wells and incubated at 37°C for 30 min. After incubation, pre-prepared d2-IP1 and Anti-IP1-Cryptate were added to all wells. After centrifugation, the cells were incubated at room temperature for 1 h. Readings at 665 nm and 620 nm were detected using a microplate reader under excitation at 330 nm.

[0325] In the FLIPR calcium flow assay, cells were plated and incubated overnight for approximately 16-20 hours on the first day. On the second day, the culture medium was removed from the cell plates, and 1× loading buffer was quickly added to each well. After centrifugation, the cell plates were incubated at 37°C in the dark for 120 minutes. In activation mode, 20 μL / well of the prepared positive compound and analyte were transferred to a 384-well compound source plate. The cell plates, compound source plates, and pipette tips were placed in the corresponding positions on the FLIPR instrument. 10 μL of the compound diluted using FLIPR Tetra was added to each well, and data were collected at wavelengths of 515 nm-575 nm. In inhibition mode, 5 μL of the diluted compound was first added to the corresponding well, centrifuged, and incubated at 37°C for 30 minutes. The prepared agonist compound was then transferred in 20 μL / well to a 384-well compound source plate. 10 μL of the compound diluted with FLIPRTetra was added to each experimental well, and data were collected at wavelengths of 515 nm to 575 nm.

[0326] Data Analysis:

[0327] Data analysis and processing were performed using GraphPad Prism and Excel software. The activation levels of different compound concentrations on targets M1-M5 were calculated using the following formula:

[0328]

[0329] Here, Activation% / Inhibition% represents the percentage of the compound that activates or inhibits the receptor. The average value of the positive control group. The mean value of the negative control (DMSO).

[0330] Compound EC 50 / IC 50 The following equation was fitted and calculated using GraphPad Prism software:

[0331] Y=Bottom+(Top-Bottom) / (1+10^((LogEC 50 -X)*HillSlope))

[0332] Where X is the detection concentration of the test sample, Y is the activation / inhibition percentage at the corresponding concentration, and Bottom and Top are the minimum and maximum activation / inhibition percentages, respectively.

[0333] The test results are shown in Table 2:

[0334] compound M2 / nAchα1β1δεselectivity(fold) compound M2 / nAchα1β1δεselectivity(fold) Compound 1 A Compound 8 A Compound 3 A Compound 9 A Compound 4 A Compound 10 A Compound 6 A Compound 11 A

[0335] A: Multiple > 100

[0336] Conclusion: The compounds of the present invention, such as those in the examples, exhibit weak inhibitory activity against the M2 receptor but good inhibitory activity against the nAchα1β1δε receptor. The selectivity folds of compounds 1, 8, 10, and 11 for the M2 / nAchα1β1δε receptor are >468, 388, >546, and 290, respectively.

Claims

1. A compound of general formula (I) or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts thereof. L is selected from L2 is selected from C 3-10 The L2 is optionally surrounded by 1 to 4 R groups, which are either carbocyclic or 4- to 10-membered heterocyclic groups. L2 replace; L1 is selected from C 3-10 Carbocyclic or 4- to 10-membered heterocyclic groups, wherein the L1 is optionally divided by 1 to 4 R groups. L1 replace; L5 is selected from C 3-10 Cycloalkyl, 4- to 10-membered heterocyclic groups, wherein the L5 is optionally surrounded by 1 to 4 R groups. L5 replace; R 1 R 2 Each was independently selected from C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 8-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R L1 R L2 R L3 R L4 R L5 Each element is independently selected from H, deuterium, halogens, CN, OH, =O, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R a1 R a2 R a3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; As an option, R L3 R L4 Together with the carbon atoms attached thereto, they form carbon-carbon double bonds, =O, 3- to 6-membered carbocyclic groups, or 4- to 6-membered heterocyclic groups, wherein the carbon-carbon double bonds, carbocyclic groups, or heterocyclic groups are optionally surrounded by 1 to 4 R atoms. k replace; X z- It is a pharmaceutically acceptable anion; m can be 0.5, 2 / 3, 1, or 2; z is 1, 2, 3, or 4; s1 or s2 can be independently selected from 0, 1, 2, 3 or 4; n1 or n2 are each independently selected from 0, 1, 2, 3, 4 or 5; R k Each is independently selected from deuterium, halogens, =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 group, -OC 1-6 Alkyl, -SC 1-6 Alkyl, -OC 3-6 Carbocyclic rings, -O-3 to 7-membered heterocycles, -NH-C 3-6 Carbon rings, -NH-3 to 7-membered heterocycles, -C 1-4 Alkylene-C 3-6 Carbon ring, -C 1-4 Alkylene-3 to 7-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 7-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 deuterium, halogens, CN, OH, NH2, C 1-6 Alkyl, C 1-6 Substituents of alkoxy groups; The condition is that either s1 or s2 is 0 at the same time, and L is selected from... hour, Not selected Or, when both s1 and s2 are 1, L is selected from... hour, Not selected 2. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, X z- Selected from halide ions, acetate, benzoate, camphorsulfonate, citrate, gluconate, glucuronate, ethanesulfonate, lactate, lacturonate, dodecyl sulfate, malate, maleate, fumarate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthoate, naphthalenesulfonate, stearate, oleate, oxalate, dihydronaphthyl acid, nitrate, phosphate, sulfate, and phosphoric acid. Hydrogen ions, dihydrogen phosphate ions, polygalacturonic acid ions, succinate ions, sulfosalicylate ions, tartrate ions, trifluoroacetate ions, hippurate ions, D-glucuronide ions, glycolate ions, mucoacid ions, orotic acid ions, pamoate ions, glycine ions, alanine ions, arginine ions, lysine ions, cinnamic acid ions, propionate ions, valerate ions, triphenylacetic acid ions, L-proline ions, ferulic acid ions, mandelic acid ions, malonate ions, gentianate ions, salicylate ions, or glutarate ions; L2 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L2 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L2 replace; L1 is selected from C 3-6 Single carbon cyclo group, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L1 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L1 replace; L5 is selected from C 3-6 Monocycloalkyl, C 5-10 Bridged cycloalkyl, C 7-10 cycloalkyl, C 7-10 The L5 is optionally surrounded by 1 to 4 R groups: spirocycloalkyl, 4 to 7-membered monoheterocyclic, 6 to 10-membered bridged heterocyclic, 5 to 10-membered fused heterocyclic, 7 to 10-membered spiroheterocyclic, 5-6-membered heteroaryl. L5 replace; R 1 R 2 Each was independently selected from C 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R a1 R a2 R a3 R b1 R b2 R b3 Each element is independently selected from H, deuterium, halogens, CN, OH, NH2, NO2, COOH, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; Selected from The Choose 1 to 2 Rs k replace; Ring A is selected from C 3-6 Cycloalkyl or 4- to 6-membered heterocyclic groups, wherein ring A is optionally surrounded by 1 to 4 R groups. k replace; R L3 Selected from deuterium, halogens, CN, OH, NH2, NO2, COOH, C 2-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, methyl, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k The methyl group is replaced by 1 to 3 R groups. k replace; R L1 R L2 R L5 Each is independently selected from deuterium, halogens, =O, CN, OH, NH2, NO2, COOH, C 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R 4a R 4b Each is independently selected from deuterium, halogens, CN, OH, NH2, NO2, and C. 1-4 Alkyl, -OC 1-4 Alkyl, -SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 3-6 Carbocyclic, 4- to 6-membered heterocyclic, wherein the alkyl, alkenyl, alkynyl, carbocyclic, or heterocyclic group is optionally surrounded by 1 to 4 R groups. k replace; R k Each element is independently selected from deuterium, halogens, =O, CN, OH, SH, NO2, COOH, CONH2, NH2, SF5, and C. 1-4 Alkyl, OC 1-4 Alkyl, SC 1-4 Alkyl, C 2-4 alkenyl, C 2-4 Alkyne group, NHC 1-4 Alkyl, N(C) 1-4 Alkyl)2, -OC 3-6 Carbocyclic rings, -O-3 to 6-membered heterocycles, -NH-C 3-6 Carbocyclic rings, -NH-3 to 6-membered heterocycles, -C 1-2 Alkylene-C 3-6 Carbon ring, -C 1-2 Alkylene-3 to 6-membered heterocycles, C 3-6 Carbocyclic rings, 3 to 6-membered heterocycles, wherein the alkyl, alkylene, alkenyl, alkynyl, carbocyclic or heterocyclic rings are optionally selected from 1 to 4 elements selected from deuterium, halogens, CN, OH, NH2, C. 1-6 Alkyl, C 1-6 The alkoxy group is replaced by a substituent.

3. The compound according to claim 2, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, R 1 R 2 Each is independently selected from 1 to 4 R's. k The substituted group may be one of the following: methyl, ethyl, propyl, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R k Substituted methyl groups, or optionally substituted with 1 to 4 R groups k The substituted group may be one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; R L1 R L2 R L5 Each is independently selected from deuterium, F, Cl, Br, I, ⁵O, CN, OH, NH₂, NO₂, or arbitrarily bound by 1 to 4 Rs. k The substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolidine, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl; R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or optionally by 1 to 4 R. k The substitution is made with one of the following groups: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl; R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 4 Rs. k The substituted group may be one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazoleyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; Ring A is selected from any 1 to 3 Rs. k The group that is substituted is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, aziridine, oxacyclobutyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, oxacyclohexyl; L2 is selected from 1 to 3 Rs. L2 The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl; L1 is selected from any of 1 to 3 R's. L1 The substituted group is one of the following: phenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl; L5 is selected from any of 1 to 3 R's. L5 The substituted group is one of the following: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[1,1,1]pentyl, bicyclo[2,1,1]hexyl, bicyclo[2,2,1]heptyl, bicyclo[2,2,2]octyl, adamantyl, pyridyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrazolyl, imidazolyl, thiophene, furanyl, thiazolyl, oxazolyl, triazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl; R k Each of the following groups is 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, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propynyl, cyclopropyl, cyclobutyl, aziridine, oxacyclobutyl, pyrrolylyl, piperidinyl, pyrazolyl, pyrrolyl, morpholinyl is optionally selected from deuterium, F, Cl, Br, I, CN, OH, NH2, C 1-4 Alkyl, C 1-4 The alkoxy group is replaced by a substituent.

4. The compound according to claim 3, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, R 1 R 2 Each is independently selected from 1 to 3 R's. k The substituted group is one of the following: methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, COOH, or arbitrarily labeled with 1 to 3 Rs. k The substituted group is one of the following: methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl; R L3 Selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, or optionally substituted with 1 to 4 Rs. k The substituted group may be one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl; R L1 R L2 R L5 Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, or arbitrarily selected by 1 to 3 Rs. k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, aziridine, pyrrolyl, piperidinyl, morpholinyl, oxacyclobutyl, tetrahydrofuranyl, tetrahydropyranyl; R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, or by 1 to 3 R. k Substituted methyl groups or optionally substituted with 1 to 4 R groups k The substituted group is one of the following: ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl, cyclobutyl; R k Each of these compounds is 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, aziridine, oxacyclobutyl, and pyrrole. Alkyl, piperidinyl, pyrazolyl, pyrrolithyl, morpholinyl, wherein the methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, methylthio, vinyl, ethynyl, propynyl, propargyl, cyclopropyl, cyclobutyl, aziroxybutyl, oxacyclobutyl, pyrrolithyl, piperidinyl, pyrazolyl, 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 or s2 can be independently selected from 0, 1 or 2.

5. The compound according to claim 4, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, Selected from 1 to 3 Rs k One of the following groups is replaced: R L3 Selected from F, Cl, Br, CN, OH, NH2, NO2, CD3, CF3, CH2F, CHF2, CH2OH, CH2CN, CH2OCH3, CH2OCD3, cyclopropyl, cyclobutyl, phenyl R 4a R 4b Each is independently selected from deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, isopropoxy, and cyclopropyl. R a1 R a2 R a3 R b1 R b2 R b3 Each is independently selected from H, deuterium, F, Cl, Br, I, CN, OH, NH2, NO2, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, methyl, ethyl, propyl, methoxy, ethoxy, propoxy, vinyl, propenyl, ethynyl, propynyl, cyclopropyl; L2 is selected from 1 to 3 Rs. L2 One of the following groups is replaced: L1 is selected from any of 1 to 3 R's. L1 One of the following groups is replaced: L5 is selected from any of 1 to 3 R's. L5 One of the following groups is replaced: R k Each is 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; Selected from Preferred from n1 or n2 are each independently selected from 0, 1, 2, and 3.

6. The compound according to claim 5, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, wherein, Selected from Selected from Selected from Selected from Selected from 7. The compound according to claim 1, or its stereoisomers, racemates, tautomers, or pharmaceutically acceptable salts, 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: Table S 8. A pharmaceutical composition comprising the compound of any one of claims 1-7 or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, and a pharmaceutically acceptable carrier.

9. A pharmaceutical composition or pharmaceutical preparation comprising, in 1-1500 mg, a compound of any one of claims 1-7 or its stereoisomers, racemates, tautomers, pharmaceutically acceptable salts, and pharmaceutical excipients.

10. The use of the compound or its stereoisomer, racemate, tautomer, pharmaceutically acceptable salt, or the pharmaceutical composition of claim 8 in the preparation of a neuromuscular blocking drug according to any one of claims 1-7.

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