A quaternary amine salt compound, a preparation method and use thereof

Abstract

Provided are quaternary amine salt compounds, methods of making and uses thereof. The compounds are represented by Formula (I), or isomers, pharmaceutically acceptable salts thereof, and compositions thereof, which are useful in the preparation of anesthetic or analgesic medicaments. In Formula (I), each substituent is as defined herein.

Description

[0001] Related applications

[0002] This application claims priority to Chinese Patent Application No. CN202110587550.8, filed on May 27, 2021, entitled "A Quaternary Ammonium Salt Compound and Its Preparation Method and Use", the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application relates to, but is not limited to, the field of medicinal chemistry, and in particular to a quaternary ammonium salt compound and its preparation method and uses. Background Technology

[0004] Local anesthetics, also known as local anesthetics, are a class of drugs applied topically around nerve trunks or nerve endings to temporarily, completely, and reversibly block the generation and conduction of nerve impulses, thus temporarily eliminating local pain sensation. The mechanism of action of local anesthetics is through binding to sodium channels located on the nerve cell membrane, reducing the sodium content of the cell membrane. + Local anesthetics work by altering the membrane potential, thereby blocking the conduction of nerve impulses and achieving an anesthetic effect. Due to their advantages such as reliable efficacy, low risk of hyperalgesia, convenient local administration, low blood concentration, and few systemic side effects, local anesthetics remain a widely used pain management method in clinical practice.

[0005] Currently, the local anesthetics used in clinical practice are mainly compounds composed of aromatic and amino groups linked by ester or amide bonds, such as procaine, tetracaine, lidocaine, bupivacaine, and ropivacaine. Although bupivacaine and ropivacaine are considered to be new long-acting local anesthetics, their analgesic duration after a single dose is usually no more than 8 hours (“Localanesthetics: review of pharmacological considerations”, Becker D E. et al., Anesth Prog. 2012, 59(2):90-102.). While they can meet the needs of most surgeries or invasive procedures, they are far from fully meeting the needs of postoperative pain, chronic pain, etc.

[0006] Although lidocaine's quaternary ammonium derivative QX-314 can effectively block sodium ion currents after crossing the cell membrane, producing a relatively long-lasting anesthetic effect, it is difficult to actively cross the lipid-soluble cell membrane due to its permanently positive charge ("Mechanism of frequency-dependent inhibition of sodium currents in frogmyelinated nerve by the lidocaine derivative GEA", Courtney KR.J Pharmacol Exp Ther. 1975, 195:225-236). Studies have shown that QX-314, when used in combination with local anesthetics or transient receptor channel (TRP) agonists, can cross the cell membrane and produce a long-lasting local anesthetic effect, but this can lead to increased local neurotoxicity and systemic toxicity ("Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat", Allalem M. et al., BMC Pharmacol Toxicol. 2016, 17(1):31.). Invention Overview

[0008] The first aspect of this application provides a quaternary ammonium salt compound of formula (I), or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof:

[0009]

[0010] in:

[0011] R1 is selected from aryl and heteroaryl groups;

[0012] R2 is selected from C 1-18 Alkyl, C 3-12 cycloalkyl;

[0013] R3 is selected from C 1-8 Alkyl, C 3-12 Cycloalkyl, aryl, heteroaryl, and heterocycloalkyl;

[0014] X1 and X2 are each independently selected from O, S, and NR4, where R4 is hydrogen, deuterium, or C. 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Alkoxy C 1-8 Alkyl groups, or NR4 together with R1 or R3 attached thereto, form nitrogen-containing heterocyclic alkyl groups;

[0015] m and n are each independently selected from integers from 0 to 8. m and n can be the same or different.

[0016] L is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 etyne and C 3-8 Cycloalkylene;

[0017] S1, S2, Q1, and Q2 are each independently selected from single bonds (i.e., the atoms connected by these bonds are directly bonded together) and C. 1-6 Alkylene, wherein the C 1-6 The carbon atom in the alkylene backbone is optionally replaced by one heteroatom selected from O, S and N, wherein N can be replaced by R6 selected from hydrogen and deuterium, and it is stipulated that S1 and S2 are not simultaneously single bonds (i.e. the atoms they are connected to are directly bonded), and Q1 and Q2 are not simultaneously single bonds (i.e. the atoms they are connected to are directly bonded).

[0018] Y - This represents a pharmaceutically acceptable anion.

[0019] The second aspect of this application relates to a method for preparing compounds of general formula (I) described in this application, their tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, the preparation method comprising the following steps:

[0020]

[0021] The compound of formula (II) reacts with the compound of formula (III) to give the compound of formula (I);

[0022] Here, Z in formula (II) is an electron-withdrawing leaving group, optionally a bromine, chlorine or sulfonate ester, and the group definitions in formulas (II) and (III) are the same as in formula (I).

[0023] The third aspect of this application relates to pharmaceutical compositions comprising compounds of general formula (I) described in this application, or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, and pharmaceutically acceptable carrier excipients or diluents.

[0024] The fourth aspect of this application relates to compounds of general formula (I) described in this application, or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, for use in pharmaceuticals.

[0025] The fifth aspect of this application relates to the use of compounds of general formula (I) described herein, or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, in the preparation of anesthetic or analgesic medicaments.

[0026] The sixth aspect of this application relates to a method of anesthesia or analgesia, the method comprising administering to a patient in need a compound of general formula (I) of this application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0027] Detailed Explanation

[0028] Given the problems with QX-314, an increasing number of researchers are showing great interest in finding a novel, long-acting, and highly safe local anesthetic. For example, CN110156665B discloses a novel class of quaternary ammonium salt compounds that possess both long-acting and selective local anesthetic effects (sensory nerve block time is longer than motor nerve block time). Compared with existing QX314, QX314 compositions, and long-chain compounds with surfactant structures, it has the advantages of longer duration of local anesthetic action, better selectivity, less nerve damage, and higher safety. CN 110156666 A discloses a novel quaternary ammonium cationic compound that possesses both long-acting and selective local anesthetic effects (sensory nerve block time is longer than motor nerve block time). Compared with existing QX314, QX314 compositions, and long-chain compounds with surfactant structures, it has the advantages of longer duration of local anesthetic action, better selectivity, less nerve damage, and higher safety. CN101050200A discloses a class of alkene-substituted amide derivatives and their application in the field of local anesthesia. The results show that they have a certain local anesthetic effect and their acute toxicity is less than that of levobupivacaine hydrochloride.

[0029] This application provides a novel class of quaternary ammonium salt compounds, a method for preparing such compounds, and their uses. These compounds have the advantages of novel structure, long-lasting local anesthesia after a single dose, and no motor nerve damage.

[0030] The first aspect of this application provides a quaternary ammonium salt compound of formula (I), or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof:

[0031]

[0032] in:

[0033] R1 is selected from aryl and heteroaryl groups, wherein the aryl or heteroaryl group is optionally substituted by one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, cyano, halogen, hydroxyl, amino, nitro, ester, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0034] R2 is selected from C 1-18 Alkyl, C 3-12 cycloalkyl, here, the C 1-18 Alkyl, C 3-12 The cycloalkyl group may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino;

[0035] R3 is selected from C 1-8 Alkyl, C 3-12 cycloalkyl, aromatic, heteroaryl, and heterocycloalkyl, wherein, optionally, the C 1-8 Alkyl, C 3-12 Cycloalkyl, aryl, heteroaryl, and heterocycloalkyl groups may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 Alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic alkyl; here, the optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclic alkyl refers to an unsubstituted aryl, unsubstituted heteroaryl, unsubstituted heterocyclic alkyl, or an aryl, heteroaryl, or heterocyclic alkyl substituted by one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group;

[0036] X1 and X2 are each independently selected from O, S, and NR4, where R4 is hydrogen, deuterium, or C. 1-8 Alkyl, C 3-8 cycloalkyl, C 1-8 Alkoxy C 1-8 Alkyl groups, or NR4 together with R1 or R3 attached thereto, form nitrogen-containing heterocyclic alkyl groups;

[0037] m and n are each independently selected from integers from 0 to 8. m and n can be the same or different.

[0038] L is selected from C 1-8 Alkylene, C 2-8 imidene group, C 2-8 etyne and C 3-8 cycloalkylene compounds, wherein, optionally, here, the C 1-8 Alkylene, C 3-8 The carbon atoms in the cycloalkyl backbone are optionally replaced by 1-3 heteroatoms selected from O, S, and N, wherein N can be replaced by R5, which is selected from hydrogen, deuterium, and C. 1-4 Alkyl; the C 1-8 Alkylene, C 2-8 imidene group, C 2-8 etyne and C 3-8 The cycloalkylene group is optionally substituted with one or more of the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group;

[0039] S1, S2, Q1, and Q2 are each independently selected from single bonds (i.e., the atoms connected by these bonds are directly bonded together) and C. 1-6 Alkylene, here, the C 1-6 In the alkylene backbone, a carbon atom is optionally replaced by a heteroatom selected from O, S and N, wherein N can be replaced by R6 selected from hydrogen and deuterium, and it is stipulated that S1 and S2 are not simultaneously single bonds (i.e., the atoms they are connected to are directly bonded), and Q1 and Q2 are not simultaneously single bonds (i.e., the atoms they are connected to are directly bonded).

[0040] Y- This represents a pharmaceutically acceptable anion.

[0041] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided herein, wherein: R1 is phenyl or naphthyl; wherein the phenyl or naphthyl group is optionally substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, cyano, halogen, hydroxyl, amino, nitro, ester, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-6 Halogenated alkoxy groups.

[0042] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: R1 is phenyl, said phenyl being optionally substituted with one or more of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, ethyl ester; more preferably, R1 is phenyl, 2-methyl 2-Methoxyphenyl, 4-Methylphenyl, 4-Methoxyphenyl, 4-Fluorophenyl, 2-Chlorophenyl, 4-Chlorophenyl, 2-Bromophenyl, 3-Bromophenyl, 4-Bromophenyl, 3-Hydroxyphenyl, 4-Trifluoromethylphenyl, 2,6-Dimethylphenyl, 2,6-Dimethoxyphenyl, 3-Nitrophenyl, 2,6-Difluorophenyl, 3-Chloro-2-Methylphenyl, 2,3-Dichlorophenyl, 4-Hydroxyphenyl, 2,4,6-Trimethylphenyl, 2,4,6-Trimethoxyphenyl, 2,4,6-Trifluorophenyl.

[0043] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: R1 is phenyl, 2-methylphenyl, 2-methoxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl, 2,6-dimethylphenyl, 2,6-Dimethoxyphenyl, 3-nitrophenyl, 2,6-difluorophenyl, 3-chloro-2-methylphenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl, preferably, R1 is 4-fluorophenyl, 4-methylphenyl, 2,4,6-trimethylphenyl, 2,6-dimethylphenyl, 4-methoxyphenyl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, more preferably, 2,6-dimethylphenyl.

[0044] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided herein, wherein: R2 is C 1-8 Alkyl, C 3-8 cycloalkyl; the C 1-8 Alkyl or C 3-8 The cycloalkyl group may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino.

[0045] In some embodiments of this application, the compound of general formula (I) provided in this application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, n-octyl, n-heptyl, preferably ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, n-heptyl; more preferably n-butyl.

[0046] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided in this application, wherein: R3 is C 1-8 Alkyl, C 3-7Cycloalkyl, aryl, heteroaryl, ternary to octacyclic alkyl, or R3 together with X2 which is NR4 to form an azaheptacyclic alkyl group, wherein the C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, and ternary to octacyclic alkyl groups may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 Alkynyl, optionally substituted phenyl; here, the optionally substituted phenyl refers to an unsubstituted phenyl, or benzene substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 Alkyne group.

[0047] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: R3 is methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxypropyl, phenyl, phenethyl, benzyl, 4-fluorobenzyl, 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-hydroxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-trifluorophenyl Methylphenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dihydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl, or R3 and X2 being NR4 together form piperidine or pyrrolidine, preferably phenyl, 4-methylphenyl, 4-trifluoromethylphenyl, 2-hydroxyphenyl, ethyl, 2-methoxyethyl, 2-phenylethyl, 2,6-dimethylphenyl, cyclopropyl, benzyl, 4-fluorobenzyl, or R3 and X2 being NR4 together form piperidine or pyrrolidine.

[0048] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: m and n are each independently selected from 0, 1, and 2, and m and n may be the same or different.

[0049] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided in this application, wherein: L is selected from C 1-6 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene; here, the C 1-6 Alkylene, C 3-6 The carbon atoms in the main chain of the cycloalkyl group are optionally replaced by 1-3 heteroatoms selected from O, S, and N, wherein N can be replaced by R5, and R5 is selected from hydrogen, deuterium, and C. 1-4 Alkyl; the C 1-6 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6The cycloalkylene group may optionally be substituted with one or more of the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino, C 2-4 alkenyl, C 2-4 Alkyne group.

[0050] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: L is selected from: -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -O-, -CH2OCH2-, -OCH2-, -CH2O-, -OCH2O-, - O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2O-CH2O-, -CH2CH2OCH2C H2-, -S-, -CH2SCH2-, -SCH2-, -CH2S-, -CH2S-CH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH=CH-,

[0051] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: X1 and X2 are each independently O, NH, NCH3, NCH2CH3, N(CH2)2CH3, or when X2 is NR4, it forms piperidine together with R3.

[0052] In some embodiments of this application, the compound of general formula (I) provided in this application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutical salts, wherein: when one of S1 and S2 is a single bond (i.e., the atoms connected thereto are directly bonded together), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2OCH2CH2-, -CH2CH2OCH2-, or -CH2SCH2CH2-.

[0053] In some embodiments of this application, the compound of general formula (I) provided in this application, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or its pharmaceutical salts, wherein: when one of Q1 and Q2 is a single bond (i.e., the atoms connected thereto are directly bonded together), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0054] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein: Y - The ions are halide anions, sulfate anions, acetate anions, tartrate anions, p-toluenesulfonate anions, methanesulfonate anions, and citrate anions; preferably, Cl is a halogen anion. - ,Br - I - CH3COO - More preferably Br - .

[0055] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, provided herein, wherein:

[0056] R1 is selected from an aromatic group; the aromatic group is optionally substituted by one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, cyano, halogen, hydroxyl, amino, nitro, ester, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-4 Haloalkyl, C 1-6 Halogenated alkoxy groups;

[0057] R2 is selected from C 1-8 Alkyl, C 3-8 cycloalkyl; here, the C 1-8 Alkyl, C 3-8 The cycloalkyl group may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino;

[0058] R3 is selected from C 1-8 Alkyl, C 3-7Cycloalkyl, aryl, heteroaryl, ternary to octa-membered heterocycloalkyl, or R3 together with X2 which is NR4 to form an azaheptacycloalkyl, wherein the C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, and ternary to octacyclic alkyl groups may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 Alkynyl, optionally substituted phenyl; here, the optionally substituted phenyl is an unsubstituted phenyl, or the phenyl is substituted by one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino;

[0059] X1 and X2 are each independently selected from O, S, and NR4, where R4 is selected from hydrogen, deuterium, and C. 1-6 Alkyl, C 1-6 Alkoxy C 1-6 Alkyl, C 3-6 cycloalkyl;

[0060] m and n are each independently selected from integers between 0 and 4. m and n can be the same or different.

[0061] L is selected from C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, here, the C 1-4 Alkylene, C 3-6 The carbon atoms in the cycloalkyl backbone are optionally replaced by 1-2 heteroatoms selected from O, S, and N, wherein N can be replaced by R5, and R5 is selected from hydrogen, deuterium, and C. 1-4 Alkyl; wherein the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 The cycloalkylene group may optionally be substituted with one or more of the following groups: C 1-4 Alkyl, C1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-4 Alkylamino, diC 1-4 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group;

[0062] S1, S2, Q1, and Q2 are each independently selected from single bonds (i.e., the atoms connected by them are directly bonded together), C 1-6 Alkylene, C as described herein 1-6 The carbon atom in the alkylene backbone is optionally replaced by one heteroatom, which is selected from O or S; wherein S1 and S2 cannot be single bonds at the same time (i.e., the atoms they are connected to are directly bonded to each other), and Q1 and Q2 cannot be single bonds at the same time (i.e., the atoms they are connected to are directly bonded to each other).

[0063] Y - It consists of halide anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, and citrate.

[0064] In some embodiments of this application, the compound of general formula (I), or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, provided herein, wherein:

[0065] R1 is selected from phenyl, which may optionally be substituted by one or more of the following groups: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, ethyl ester.

[0066] R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclobutylmethylene, cyclopentylmethylene, n-octyl, and n-heptyl.

[0067] R3 is selected from C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, ternary to octa-membered heterocycloalkyl, or R3 together with X2 which is NR4 to form an azaheptacycloalkyl, wherein the C 1-8 Alkyl, C 3-7 Cycloalkyl, aryl, heteroaryl, and ternary to octacyclic alkyl groups may optionally be substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 Alkynyl, optionally substituted phenyl; here, the optionally substituted phenyl refers to an unsubstituted phenyl, or a phenyl substituted with one or more of the following groups: C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-6 Alkylamino, diC 1-6 Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group;

[0068] X1 and X2 are each independently selected from O, S, and NR4; wherein R4 is selected from hydrogen, deuterium, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopropylmethylene, cyclobutylmethylene, or NR4 together with R1 or R3 connected to it to form an azacycloalkyl group;

[0069] m and n are each independently selected from integers between 0 and 2. m and n can be the same or different.

[0070] L is selected from C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 Cycloalkylene, here, the C 1-4 Alkylene, C 3-6 The carbon atoms in the cycloalkyl backbone are optionally replaced by 1-2 heteroatoms selected from O, S, and N, wherein N can be replaced by R5, and R5 is selected from hydrogen, deuterium, and C. 1-4 Alkyl; wherein the C 1-4 Alkylene, C 2-4 imidene group, C 2-4 Ethyne group, C 3-6 The cycloalkylene group may optionally be substituted with one or more of the following groups: C 1-4 Alkyl, C 1-4 Alkoxy, C 1-4 Haloalkyl, C 1-4 Halogenated alkoxy groups, C 3-6 Cycloalkyl, halogen, hydroxyl, cyano, amino, ester, nitro, mono-C 1-4 Alkylamino, diC 1-4Alkylamino, C 2-4 alkenyl, C 2-4 alkynyl group;

[0071] When one of S1 and S2 is a single bond (i.e., the atoms connected to it are directly bonded together), the other one is selected from -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2SCH2CH2-;

[0072] When one of Q1 and Q2 is a single bond (i.e., the atoms connected to it are directly bonded together), the other one is selected from -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2OCH2CH2-, -CH2CH2OCH2-, -CH2SCH2CH2-;

[0073] Y is selected from halide anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, and citrate.

[0074] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein,

[0075] R1 is selected from phenyl, 2-methylphenyl, 2-methoxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 2-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl, 4-trifluoromethylphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 3-nitrophenyl, 2,6-difluorophenyl, 3-chloro-2-methylphenyl, 2,3-dichlorophenyl, 4-hydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl;

[0076] R2 is selected from methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-octyl, and n-heptyl.

[0077] R3 is selected from methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxyethyl, methoxypropyl, phenyl, 2-methylphenyl, phenethyl, benzyl, 4-fluorophenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-hydroxyphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4 -Hydroxyphenyl, 4-trifluoromethylphenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4-dihydroxyphenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dihydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl, or R3 together with X2 which is NR4 to form piperidine or pyrrolidine;

[0078] X1 and X2 are each independently selected from O, NH, NCH3, NCH2CH3, and N(CH2)2CH3;

[0079] m and n are each independently selected from integers between 0 and 2. m and n can be the same or different.

[0080] L is selected from: -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -O-, -CH2OCH2-, -OCH2-, -CH2O-, -OCH2O-, -O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O-, -CH2 OCH2CH2-, -CH2CH2OCH2-, -OCH2OCH2O-, -CH2CH2OCH2CH2-, -S-, -CH2SCH2-, -SCH2-, -CH2S-, -CH2SCH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH=CH-,

[0081] When one of S1 and S2 is a single bond (i.e., the atoms connected to it are directly bonded together), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CH2OCH2CH2-, -CH2 CH2OCH2-, or -CH2SCH2CH2-;

[0082] When one of Q1 and Q2 is a single bond (i.e., the atoms connected to it are directly bonded together), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0083] Y - It consists of halide anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, and citrate.

[0084] In some embodiments of this application, the compounds of general formula (I), or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided in this application, wherein the compounds of general formula (I) include, but are not limited to, the following compounds:

[0085]

[0086]

[0087]

[0088] In some embodiments of this application, the compounds of general formula (I), or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are provided in this application, wherein the compounds of general formula (I) include, but are not limited to, the following compounds:

[0089]

[0090] The second aspect of this application provides a method for preparing compounds of general formula (I) described in the first aspect of this application, their tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, wherein the preparation method comprises the following steps:

[0091]

[0092] The compound of formula (II) reacts with the compound of formula (III) to give the compound of formula (I);

[0093] Here, in formula (II), Z is an electron-withdrawing leaving group such as bromine, chlorine or sulfonate, and the group definitions in formula (II) and formula (III) are the same as in formula (I).

[0094] In the preparation method of this application, the compound of formula (II) can be prepared by the following method:

[0095]

[0096] The definitions of each group in formulas (II-1) and (II-2) are the same as above.

[0097] A third aspect of this application provides a pharmaceutical composition comprising a compound of general formula (I) as described in the first aspect of this application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

[0098] The fourth aspect of this application provides a compound of general formula (I) described herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, for use in a pharmaceutical remedy.

[0099] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are used for anesthetic or analgesic purposes.

[0100] In some embodiments of this application, the compound of general formula (I) provided herein, or its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are used for anesthetic or analgesic purposes.

[0101] The fifth aspect of this application provides the use of compounds of general formula (I) described in the first aspect of this application, or tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, or pharmaceutical compositions thereof, in the preparation of anesthetic or analgesic medicaments.

[0102] According to the use described in the fifth aspect of this application, the use is in the preparation of local anesthetic or analgesic drugs.

[0103] According to the use described in the fifth or fourth aspect of this application, the anesthesia is conduction anesthesia, surface anesthesia, or infiltration anesthesia; the analgesia is applicable to chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, or idiopathic pain.

[0104] According to the uses described in the fifth or fourth aspect of this application, the administration for anesthesia or analgesia is a local administration via a mucosal route, such as percutaneous, subcutaneous, intradermal, intramuscular, near nerve, intradental, intraspinal, epidural, intravenous, or ophthalmic drops.

[0105] The sixth aspect of this application provides a method of anesthesia or analgesia, the method comprising administering to a patient in need a compound of general formula (I) of this application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0106] According to the method described in the sixth aspect of this application, the anesthesia is local anesthesia, preferably conduction anesthesia, surface anesthesia or infiltration anesthesia; the analgesia is applicable to chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

[0107] According to the method described in the sixth aspect of this application, the administration is a local administration via a mucosal route, such as percutaneous, subcutaneous, intradermal, intramuscular, near nerves, intradental, intraspinal, epidural, intravenous, or ophthalmic drops.

[0108] The terms used to describe this application that appear in the specification and claims are defined as follows. If the meaning of a particular term defined in this application differs from the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail; if not defined in this application, it shall have the meaning commonly understood by those skilled in the art.

[0109] In this application, the names of compounds correspond to their structural formulas. When the names of compounds and their structural formulas are inconsistent, the structural formula shall prevail, or the names shall be inferred based on the specific circumstances of this application and the knowledge of those skilled in the art.

[0110] As used in this application, the term "alkyl" refers to a straight-chain or branched monovalent saturated hydrocarbon group.

[0111] Term "C" 1-8 "Alkyl" refers to a straight-chain or branched alkyl group having 1-8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7, or 8. Typical examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, pentyl or hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, etc. Similarly, the term "C"... 1-4 "Alkyl" refers to a straight-chain or branched alkyl group having 1, 2, 3, or 4 carbon atoms, namely methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl. The alkyl group in this application is preferably C10. 1-6 Alkyl, more preferably C 1-4 alkyl.

[0112] As used in this application, the term "alkylene" refers to a saturated straight-chain or branched aliphatic hydrocarbon group having two residues derived from the removal of two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane. It is a straight-chain or branched group containing 1 to 16 carbon atoms, preferably an alkylene group containing 1 to 6 carbon atoms. Non-limiting examples of "alkylene" include, but are not limited to, -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, etc.

[0113] -(CH2)5-, -(CH2)6-, -O-, -CH2O CH2-, -O CH2-, -CH2 O-,

[0114] -O CH2 O-, -O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O-,

[0115] -CH2O CH2 CH2-, -CH2 CH2 O CH2-, -O CH2 O CH2 O-,

[0116] -CH2 CH2 O CH2 CH2-, -S-, -CH2S CH2-, -S CH2-, -CH2 S-,

[0117] -CH2S CH2 CH2-, -CH2 CH2 S CH2-, -CH2 CH2 S CH2 CH2-.

[0118] As used in this application, the term "cycloalkylene" refers to a group formed by formally eliminating two hydrogen atoms from a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, comprising 3 to 8 carbon atoms. Non-limiting examples of "cycloalkylene" include, but are not limited to, [examples not specified in the original text].

[0119] As used in this application, the term "alkenyl" refers to a group formed by formally removing two hydrogen atoms from an olefin. Non-limiting examples of "alkenyl" include, but are not limited to, -CH=CH-.

[0120] As used in this application, the term "ynynyl" refers to a group formed by formally removing two hydrogen atoms from an alkyne. The term "ynynyl" is not a limiting concept and includes, but is not limited to, the following.

[0121] As used in this application, the term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), wherein alkyl is defined as described above. Non-limiting examples of "alkoxy" include, but are not limited to: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.

[0122] As used in this application, the term "alkoxyalkyl" refers to an alkyl group as defined above that is substituted with one or more alkoxy groups as defined above. Preferred alkoxyalkyl groups are alkoxy-C 1-3 Alkyl. Non-limiting examples of "alkoxyalkyl" include, but are not limited to, methoxymethyl, methoxyethyl, ethoxyethyl, etc.

[0123] The term "C" used in this application 2-4 "Alkenyl" refers to an alkenyl group having 2-4 carbon atoms, wherein the alkenyl group has 1, 2, or 3 carbon-carbon double bonds, and when it has more than one carbon-carbon double bond, the carbon-carbon double bonds may be conjugated or non-conjugated. "C" 2-4 The “alkenyl” non-limiting embodiments include, but are not limited to, vinyl and ethylenediene groups.

[0124] The term "C" used in this application 2-6 "Alynyl group" refers to an alkynyl group having 2-6 carbon atoms, wherein the alkynyl group has 1, 2, or 3 carbon-carbon triple bonds. When it has more than one carbon-carbon triple bond, the carbon-carbon triple bonds may be conjugated or non-conjugated. "C" 2-6 The “alkynyl” non-limiting examples include, but are not limited to, acetyleneyl.

[0125] As used in this application, the term "cycloalkyl" refers to a saturated carbocyclic group with 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group can be a monocyclic or polycyclic fused system and can be fused to an aromatic ring. Non-limiting examples of "cycloalkyl" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0126] As used in this application, the term "halogen" refers to fluorine, chlorine, bromine, and iodine atoms.

[0127] As used in this application, the term "aromatic group" refers to a monocyclic or bicyclic aromatic system containing at least one unsaturated aromatic ring, preferably an aryl group having 6-10, i.e., 6, 7, 8, 9, or 10 carbon atoms. Non-limiting examples of "aromatic group" include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and indenyl.

[0128] As used in this application, the term "heteroaryl" refers to a monocyclic or bicyclic unsaturated aromatic ring system optionally substituted with at least one heteroatom independently selected from N, O, or S, preferably having 5-10, i.e., 5, 6, 7, 8, 9, or 10 atoms. Non-limiting examples of "heteroaryl" include, but are not limited to, thiophene, 2-pyridinyl, 3-pyridinyl, thiazolyl, isothiazolyl, furanyl, pyrroleyl, triazolyl, imidazolyl, etc.

[0129] As used in this application, the term "heterocyclic alkyl" refers to a monocyclic or bicyclic saturated cyclic system optionally substituted with at least one and at most four heteroatoms independently selected from N, O, or S, preferably having 4-10, i.e., 4, 5, 6, 7, 8, 9, or 10 atoms, provided that the ring of the heterocyclic group does not contain two adjacent O or S atoms. Non-limiting examples of "heterocyclic alkyl" include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl, or piperazineyl.

[0130] As used in this application, the term "halogenated alkyl" refers to an alkyl group substituted with one or more halogens, wherein the alkyl group is as defined above.

[0131] As used in this application, the term "haloalkoxy" refers to an alkoxy group that is substituted with one or more halogens, wherein the alkoxy group is as defined above.

[0132] The term "hydroxyl" as used in this application refers to -OH.

[0133] The term "amino" as used in this application refers to -NH2.

[0134] The term "cyano" as used in this application refers to -CN.

[0135] The term "nitro" as used in this application refers to -NO2.

[0136] As used in this application, the term "ester group" refers to -C(O)O (alkyl) or -C(O)O (cycloalkyl), where alkyl and cycloalkyl are as defined above.

[0137] "Optional" or "optionally" means that the event or environment described below may but does not have to occur, and the description includes the cases in which the event or environment occurs or does not occur. For example, "optionally alkyl-substituted aryl" means that the alkyl group may but does not have to be present, and the description includes cases where the aryl group is substituted with an alkyl group and cases where the aryl group is not substituted with an alkyl group.

[0138] As used in this application, the term "mixtures thereof" refers to a mixture of tautomers, a mixture of geometric isomers (e.g., a mixture of trans and cis or E and Z), a mixture of enantiomers, or a mixture of diastereomers, or a mixture of at least two of tautomers, geometric isomers, enantiomers, and diastereomers.

[0139] As used in this application, the term "long-acting" refers to a single-drug anesthesia duration that is longer than that of a single-drug levobupivacaine hydrochloride at a standard concentration, which is considered long-acting.

[0140] This application provides a novel type of quaternary ammonium salt compound. Experiments have demonstrated that this compound, after a single dose, provides prolonged local anesthetic effects without causing motor nerve damage, exhibiting good safety, rapid onset of action, and high selectivity. This application provides a novel class of long-acting local anesthetics to overcome the shortcomings of existing clinical local anesthetics, such as short duration of action, tissue and neurotoxicity, and the inability to separate sensory and motor blockades, thus offering a new medical strategy for anesthesia and analgesia.

[0141] Other features and advantages of this application will be set forth in the following description, and will be apparent in part from the description, or may be learned by practicing the application. Other advantages of this application can be realized and obtained by means of the methods described in the description. Example

[0142] To make the objectives, technical solutions, and advantages of this application clearer, the embodiments of this application will be described in detail below. The following embodiments are for illustrative purposes only and should not be considered as limiting the scope of this application. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0143] TLC stands for thin layer chromatography.

[0144] HPLC stands for High Performance Liquid Chromatography.

[0145] MS: Mass Spectrometry;

[0146] 1 1H NMR: Nuclear Magnetic Resonance Spectroscopy.

[0147] 13 C1NMR: Carbon nuclear magnetic resonance spectrum;

[0148] TBTU: O-benzotriazole-N,N,N',N'-tetramethylureatetrafluoroboric acid;

[0149] NMM: N-methylmorpholine;

[0150] HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;

[0151] V / m: Volume-to-mass ratio, indicating that the preceding equivalent (eq) is the ratio of volume to mass;

[0152] m / m: mass-to-mass ratio, indicating that the preceding equivalent (eq) is the ratio of mass to mass.

[0153] This experiment used a Waters 2545-2767-2489 high-performance liquid chromatograph with an Epic Polar5u 120A column (25cm x 30mm) and a detection wavelength of 210nm. The elution was performed using a gradient of acetonitrile / 0.05% TFA / H2O (30% / 70%) at a flow rate of 15ml / min.

[0154] NMR was performed using a Bruker Ultrashied™ 400MHz Plus nuclear magnetic resonance spectrometer (TMS as internal standard, CDCl3 or CD3OD as solvent); LC-MS was performed using a Waters Qda MS KAD3195 portable mass spectrometer.

[0155] Example 1

[0156] Synthesis of compound 1b

[0157]

[0158] Weigh out 17.36 mmol (1.0 eq, 5 g) of bupivacaine 1a and add 2.0 eq of 1a (V / m, 10 mL). Stir and heat to 75 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give 1b (4.5 g, yield 59.1%, HPLC >90%), an orange-yellow oily liquid. MS m / z (ESI) = 437.22 [M] + 439.22 [M+2H] + .

[0159] Synthesis of Compound 1

[0160]

[0161] Compound 1b (1.14 mmol, 1.0 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq, V / m, 5.0 mL of compound 1b) by stirring. Analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g of compound 1b) was added, followed by N-(2',6'-xylyl)-2-piperidinecarboxamide 1c (1.34 mmol, 1.2 eq, 0.31 g). The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 1 (0.19 g, yield 24.9%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.48 (s, 1H), 9.39 (s, 1H), 7.15-6.97 (m, 6H), 4.10 (s, 2H), 3. 74-3.62(m, 2H), 3.46-3.24(m, 10H), 2.26-2.21(m, 6H), 2.18(s, 12H), 1.56-1.01(m, 17H). MSm / z(ESI)=589.37[M] + .

[0162] Example 2

[0163] Synthesis of compound 2c

[0164]

[0165] Take N-Boc-2-piperidinic acid 2a (4.37 mmol, 1.0 eq, 1.0 g), add analytical grade dichloromethane (25 eq of 2a, V / m, 25 mL), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add aniline (5.24 mmol, 1.2 eq, 0.48 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2.0 eq, 0.96 mL), and stir at 0 °C for about 1 hour. Then stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to give a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL for 2a). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL for N-Boc-2-piperidinic acid). The organic phase was collected and distilled under reduced pressure to give a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid compound 2c (1.21 g, yield 91.0%, HPLC >95%). MS m / z (ESI) = 305.18 [M+H] + .

[0166] Synthesis of compound 2d

[0167]

[0168] Compound 2c (3.28 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical grade dichloromethane (5 eq, V / m, 5 mL) with stirring. Trifluoroacetic acid (7.0 eq, V / m, 7 mL) was dissolved in analytical grade dichloromethane (10 eq, V / m, 10 mL) and added dropwise. After stirring for about 2 hours, the reaction was monitored by HPLC until complete. The reaction solution was distilled under reduced pressure, and analytical grade dichloromethane was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times). Analytical grade methanol was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times) to give a white solid compound 2d (0.62 g, yield 92.5%, HPLC >90%). MS m / z (ESI) = 205.13 [M+H] + .

[0169] Synthesis of Compound 2

[0170]

[0171] Weigh compound 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq, V / m, 5.0 mL of compound 1b), stir to dissolve, add analytical grade sodium bicarbonate (1 eq, m / m, 0.50 g of compound 1b), add compound 2d (1.34 mmol, 1.2 eq, 0.27 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq, V / m, 15 mL, three times), collect the filtrate, and obtain a white powdery solid compound 2 (0.13 g, yield 17.8%, HPLC >98%) by preparative separation. 1 HNMR (400MHz, CDCl3) δ (ppm): 10.58 (s, 1H), 9.21 (s, 1H), 7.32-7.11 (m, 8H), 4.20 (s, 2H), 3 .70-3.55(m, 2H), 3.48-3.00(m, 10H), 2.25-2.09(m, 6H), 1.81(s, 6H), 1.68-1.11(m, 17H). MS m / z(ESI)=561.40[M] + .

[0172] Example 3

[0173] Synthesis of compound 3b

[0174]

[0175] Take N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 min, add 4-fluoroaniline (5.24 mmol, 1.2 eq, 0.50 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL), and stir at 0 °C for about 1 h. Then stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid (1.33 g, yield 94.3%, HPLC >95%). MS m / z = 323.17 [M+H] + .

[0176] Synthesis of compound 3c

[0177]

[0178] Weigh 3.10 mmol (1 eq, 1.00 g) of compound 3b and dissolve it in analytical grade dichloromethane (5 eq, V / m, 5 mL) with stirring. Dissolve trifluoroacetic acid (7.0 eq, V / m, 7 mL) in analytical grade dichloromethane (10 eq, V / m, 10 mL) and add it dropwise. Stir for about 2 h and monitor the reaction by HPLC until complete. Distill the reaction solution under reduced pressure, add analytical grade dichloromethane and distill under reduced pressure (10 eq, V / m, 10 mL, three times), add analytical grade methanol and distill under reduced pressure (10 eq, V / m, 10 mL, three times), to give a white solid (0.64 g, yield 92.75%, HPLC >90%). MS m / z = 223.12 [M+H] + .

[0179] Synthesis of Compound 3

[0180]

[0181] Weigh compound 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq, V / m, 5.0 mL of compound 1b), stir to dissolve, add analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g of compound 1b), add 3c (1.34 mmol, 1.2 eq, 0.30 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq, V / m, 15 mL, three times), collect the filtrate and separate by preparative method to obtain white powdery solid compound 3 (0.15 g, yield 19.9%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.53 (s, 1H), 9.22 (s, 1H), 7.90-7.31 (m, 7H), 4.40-4.31 (m, 2H) , 3.72-3.50 (m, 2H), 3.48-3.20 (m, 10H), 2.15-2.09 (m, 6H), 1.90 (s, 6H), 1.44-1.11 (m, 17H). MS m / z(ESI)=579.41[M] + .

[0182] Example 4

[0183] Synthesis of compound 4b

[0184]

[0185] Take N-Boc-2-piperidinic acid 2a (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add 4-methylaniline (5.24 mmol, 1.2 eq, 0.58 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL), and stir at 0 °C for about 1 hour. Then stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid compound 4b (1.25 g, yield 91.9%, HPLC >95%). MS m / z (ESI) = 319.19 [M+H] + .

[0186] Synthesis of compound 4c

[0187]

[0188] Compound 4b (3.14 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical grade dichloromethane (5 eq, V / m, 5 mL). Trifluoroacetic acid (7.0 eq, V / m, 7 mL) was dissolved in analytical grade dichloromethane (10 eq, V / m, 10 mL) and added dropwise. After stirring for approximately 2 hours, the reaction was monitored by HPLC until complete. The reaction solution was distilled under reduced pressure, and analytical grade dichloromethane (10 eq, V / m, 10 mL, three times) was added and distilled under reduced pressure, followed by analytical grade methanol (10 eq, V / m, 10 mL, three times) to give a white solid, compound 4c (0.63 g, yield 92.6%, HPLC >90%). MS m / z (ESI) = 219.14 [M+H] + .

[0189] Synthesis of Compound 4

[0190]

[0191] Weigh compound 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq, V / m, 5.0 mL of compound 1b), stir to dissolve, add analytical grade sodium bicarbonate (1 eq, m / m, 0.50 g of compound 1b), add 4c (1.34 mmol, 1.2 eq, 0.29 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq, V / m, 15 mL, three times), collect the filtrate and separate by preparative method to obtain white powdery solid compound 4 (0.15 g, yield 20.0%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.57 (s, 1H), 9.28 (s, 1H), 7.54-7.29 (m, 7H), 4.38 (s, 2H), 3 .88-3.71(m, 2H), 3.44-3.19(m, 10H), 2.27-2.14(m, 6H), 2.01(s, 9H), 1.79-1.24(m, 17H). MS m / z(ESI)=575.35[M] + .

[0192] Example 5

[0193] Synthesis of compound 5b

[0194]

[0195] Weigh out N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add cyclopropylamine (5.24 mmol, 1.2 eq, 0.36 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL), and stir at 0 °C for about 1 hour. Then stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid compound 5b (1.03 g, yield 88.0%, HPLC >95%). MS m / z (ESI) = 269.18 [M+H] + .

[0196]

[0197] Compound 5b (3.72 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical grade dichloromethane (5 eq, V / m, 5 mL). Trifluoroacetic acid (7.0 eq, V / m, 7 mL) was dissolved in analytical grade dichloromethane (10 eq, V / m, 10 mL) and added dropwise. After stirring for approximately 2 hours, the reaction was monitored by HPLC until complete. The reaction solution was distilled under reduced pressure, and analytical grade dichloromethane was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times). Analytical grade methanol was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times) to give a white solid compound 5c (0.59 g, yield 93.7%, HPLC >90%). MS m / z (ESI) = 169.13 [M+H] + .

[0198] Synthesis of compound 5

[0199]

[0200] Weigh compound 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq, V / m, 5.0 mL of compound 1b), stir to dissolve, add analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g of compound 1b), add 5c (1.34 mmol, 1.2 eq, 0.22 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq, V / m, 15 mL, three times), collect the filtrate and separate by preparative method to obtain white powdery solid compound 5 (0.18 g, yield 26.1%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.58 (s, 1H), 8.95 (s, 1H), 7.14-7.07 (m, 3H), 4.28 (s, 1H), 4 .04-3.83(m, 4H), 3.44-3.19(m, 10H), 2.27-2.14(m, 6H), 2.22(s, 6H), 1.10-0.60(m, 21H). MS m / z(ESI)=525.40[M] +

[0201] Example 6

[0202] Synthesis of compound 6b

[0203]

[0204] Take N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add cyclohexylamine (5.24 mmol, 1.2 eq, 0.60 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL). After stirring at 0 °C for about 1 hour, stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to give a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was collected and distilled under reduced pressure to give a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid compound 6b (1.27 g, yield 93.4%, HPLC >95%). MS m / z (ESI) = 311.23 [M+H] + .

[0205] Synthesis of compound 6c

[0206]

[0207] Compound 6b (3.22 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical grade dichloromethane (5 eq, V / m, 5 mL) with stirring. Trifluoroacetic acid (7.0 eq, V / m, 7 mL) was dissolved in analytical grade dichloromethane (10 eq, V / m, 10 mL) and added dropwise. After stirring for about 2 hours, the reaction was monitored by HPLC until complete. The reaction solution was distilled under reduced pressure, and analytical grade dichloromethane was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times). Analytical grade methanol was added and distilled under reduced pressure (10 eq, V / m, 10 mL, three times) to give a white solid compound 6c (0.61 g, yield 91.0%, HPLC >90%). MS m / z (ESI) = 211.17 [M+H] + .

[0208] Synthesis of Compound 6

[0209]

[0210] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq, V / m, 5.0 mL). Analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g) and compound 6c (1.34 mmol, 1.2 eq, 0.28 g) were added. The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 6 (0.20 g, yield 27.1%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.59 (s, 1H), 8.95 (s, 1H), 7.14-7.07 (m, 3H), 5.14 (s, 1H) , 4.28(s, 2H), 4.04-3.11(m, 20H), 2.27-2.14(m, 8H), 2.22(s, 6H), 2.05-1.39(m, 17H). MS m / z(ESI)=567.38[M] + .

[0211] Example 7

[0212] Synthesis of compound 7a

[0213]

[0214] Weigh out 17.36 mmol (1.0 eq, 5 g) of bupivacaine and add 1,4-dibromobutane (2.0 eq of bupivacaine, V / m, 10 mL). Stir and heat to 75 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give an orange-yellow oily liquid compound 7a (4.3 g, yield 49.1%, HPLC >95%). MS m / z (ESI) = 423.20 [M] + 425.20 [M+2H] + .

[0215] Synthesis of Compound 7

[0216]

[0217] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq, V / m, 5.0 mL). Analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g) and compound 3c (1.41 mmol, 1.2 eq, 0.32 g) were added. The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 7 (0.13 g, yield 17.1%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.59 (s, 1H), 8.95 (s, 1H), 7.90-7.31 (m, 7H), 4.40-4.31 (m, 2H ), 3.72-3.50(m, 2H), 3.35-3.20(m, 8H), 2.15-2.10(m, 6H), 1.90(s, 6H), 1.44-1.11(m, 17H). MS m / z(ESI)=565.31[M] + .

[0218] Example 8

[0219] Synthesis of Compound 8

[0220]

[0221] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq, V / m, 6.0 mL). Analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g) and 2d (1.41 mmol, 1.2 eq, 0.29 g) were added. The mixture was heated to 75 °C and the reaction was monitored by HPLC until completion. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 8 (0.16 g, yield 21.6%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.61 (s, 1H), 9.90 (s, 1H), 7.33-7.10 (m, 8H), 4.94 (s, 1H), 4.16 (s , 1H), 3.70-3.55(m, 2H), 3.48-3.12(m, 8H), 2.25-2.09(m, 6H), 1.81(s, 6H), 1.68-1.11(m, 17H). MS m / z(ESI)=547.40[M] + .

[0222] Example 9

[0223] Synthesis of Compound 9

[0224]

[0225] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq, V / m, 6.0 mL). Analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g) and compound 6c (1.41 mmol, 1.2 eq, 0.30 g) were added. The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 9 (0.18 g, yield 24.1%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.56 (s, 1H), 8.54 (s, 1H), 7.16-7.09 (m, 3H), 4.65 (s, 1H), 4.27(s, 2H), 4.04-3.3.34(m, 18H), 2.27-2.14(m, 8H), 2.22(s, 6H), 2.05-1.39(m, 17H). MS m / z(ESI)=553.43[M] + .

[0226] Example 10

[0227] Synthesis of compound 10b

[0228]

[0229] Weigh 18.22 mmol (1.0 eq, 5 g) of ropivacaine and add 1,5-dibromopentane (2.0 eq of ropivacaine, V / m, 10 mL). Stir and heat to 75 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give 10b (5.1 g, yield 55.5%, HPLC >90%), an orange-yellow oily liquid. MS m / z (ESI) = 423.20 [M] + 425.20 [M+H] + .

[0230] Synthesis of Compound 10

[0231]

[0232] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq of 10b, V / m, 6.0 mL) by stirring. Analytical grade sodium bicarbonate (1 eq of 7a, m / m, 0.60 g) was added, followed by N-(2',6'-xylyl)-2-piperidinecarboxamide 1c (1.41 mmol, 1.2 eq, 0.33 g). The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of compound 10b, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 10 (0.21 g, yield 27.14%, HPLC >98%). 1 H NMR (400MHz, CDCl3) δ (ppm): 10.49 (s, 1H), 9.35 (s, 1H), 7.15-6.98 (m, 6H), 4.10 (s, 2H), 3. 74-3.59 (m, 2H), 3.44-3.20 (m, 10H), 2.26-2.21 (m, 6H), 2.19 (s, 12H), 1.56-1.01 (m, 15H). MSm / z(ESI)=575.45[M] + .

[0233] Example 11

[0234] Synthesis of Compound 11

[0235]

[0236] Weigh compound 10b (1.18 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq of compound 10b, V / m, 6.0 mL), stir to dissolve, add analytical grade sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g), add compound 6c (1.41 mmol, 1.2 eq, 0.30 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 10b, V / m, 15 mL, three times), collect the filtrate and use preparative separation to obtain a white powdery solid compound 11 (0.11 g, yield 14.7%, HPLC >98%). 1HNMR (400MHz, CDCl3) δ (ppm): 10.58 (s, 1H), 9.33 (s, 1H), 7.14-7.07 (m, 3H), 5.14 (s, 1H) ), 4.26 (s, 2H), 4.04-3.20 (m, 20H), 2.27-2.14 (m, 8H), 2.23 (s, 6H), 2.05-1.34 (m, 15H). MS m / z(ESI)=553.41[M] + .

[0237] Example 12

[0238] Synthesis of Compound 12

[0239]

[0240] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq of compound 10b, V / m, 6.0 mL) by stirring. Analytical grade sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g) and compound 4c (1.41 mmol, 1.2 eq, 0.31 g) were added. The mixture was heated to 75 °C and the reaction was monitored by HPLC until completion. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of 10b, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 12 (0.15 g, yield 19.8%, HPLC >98%). 1 HNMR (400MHz, CDCl3) δ (ppm): 10.57 (s, 1H), 9.30 (s, 1H), 7.56-7.31 (m, 7H), 4.36 (s, 2H), 3 .88-3.66(m, 2H), 3.51-3.15(m, 10H), 2.55-2.34(m, 6H), 2.24(s, 9H), 1.84-1.42(m, 15H). MS m / z(ESI)=561.48[M] + .

[0241] Example 13

[0242] Synthesis of Compound 13

[0243]

[0244] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical grade acetonitrile (10 eq of compound 10b, V / m, 6.0 mL) by stirring. Analytical grade sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g) was added, followed by compound 2d (1.41 mmol, 1.2 eq, 0.29 g). The mixture was heated to 75 °C and reacted by HPLC until complete. The reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of 10b, V / m, 15 mL, three times). The filtrate was collected and separated preparatively to obtain a white powdery solid compound 13 (0.18 g, yield 24.3%, HPLC >98%). 1 H NMR (400MHz, CDCl3)ClMHz%): 10.58 (s, 1H), 9.23 (s, 1H), 7.32-7.11 (m, 8H), 4.20 (s, 2H), 3 .70-3.55(m, 2H), 3.48-3.11(m, 10H), 2.25-2.09(m, 6H), 1.85(s, 6H), 1.68-1.23(m, 15H). MS m / z(ESI)=547.32[M] + .

[0245] Example 14

[0246] Synthesis of 8b

[0247]

[0248] Weigh out N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add diethylamine (5.24 mmol, 1.2 eq, 0.54 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL), and stir at 0 °C for about 1 hour. Then stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid 8b (1.12 g, yield 90.3%, HPLC >95%). MS m / z (ESI) = 285.21 [M+H] + .

[0249] Synthesis of 8c

[0250]

[0251] Weigh 8b (3.51 mmol, 1 eq, 1.00 g), add analytical grade dichloromethane (5 eq, V / m, 5 mL) and stir to dissolve. Dissolve trifluoroacetic acid (7.0 eq, V / m, 7 mL) in analytical grade dichloromethane (10 eq, V / m, 10 mL) and add dropwise. Stir for about 2 hours, and monitor the reaction by HPLC until complete. Distill the reaction solution under reduced pressure, add analytical grade dichloromethane and distill under reduced pressure (10 eq, V / m, 10 mL, three times), add analytical grade methanol and distill under reduced pressure (10 eq, V / m, 10 mL, three times), to obtain a white solid 8c (0.61 g, yield 93.8%, HPLC >90%). MS m / z (ESI) = 185.16 [M+H] + .

[0252] Synthesis of Compound 14

[0253]

[0254] Weigh 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq, V / m, 6.0 mL), stir to dissolve, add analytical grade sodium bicarbonate (1 eq, m / m, 0.60 g), add 8c (1.37 mmol, 1.2 eq, 0.25 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq, V / m, 15 mL, three times), collect the filtrate and separate by preparative method to obtain white powdery solid compound 14 (0.15 g, yield 21.1%, HPLC >98%). 1 H NMR (400MHz, CD3OD): 7.05 (s, 3H), 4.61-4.56 (m, 1H), 3.27-3.18 (m, 11H), 2 .51-2.41(m, 4H), 2.17-1.92(m, 8H), 1.86-1.08(m, 26H), 0.92-0.87(m, 3H). MS m / z(ESI)=541.45[M]+.

[0255] Example 15

[0256] Synthesis of 9b

[0257]

[0258] Weigh out N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 6.55 mmol, 1.5 eq, 2.10 g). After stirring at 0 °C for about 30 minutes, add 70% ethylamine aqueous solution (13.10 mmol, 3 eq, 1.06 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL). After stirring at 0 °C for about 1 hour, stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a white solid 9b (1.03 g, yield 92.0%, HPLC >95%). MS m / z (ESI) = 257.18 [M+H] + .

[0259] Synthesis of 9c

[0260]

[0261] Weigh 9b (3.90 mmol, 1 eq, 1.00 g), add analytical grade dichloromethane (5 eq, V / m, mL / g, 5 mL of 9b), and stir to dissolve. Dissolve trifluoroacetic acid (7.0 eq, V / m, mL / g, 7 mL of 9b) in analytical grade dichloromethane (10 eq, V / m, mL / g, 10 mL of 9b) and add it dropwise. Stir for about 2 hours, and monitor the reaction by HPLC until complete. Distill the reaction solution under reduced pressure, add analytical grade dichloromethane and distill under reduced pressure (10 eq, V / m, mL / g, 10 mL of 9b, three times), add analytical grade methanol and distill under reduced pressure (10 eq, V / m, mL / g, 10 mL of 9b, three times), to obtain a white solid 9c (0.57 g, yield 95.0%, HPLC >90%). MS m / z (ESI) = 157.13 [M+H] + .

[0262] Synthesis of Compound 15

[0263]

[0264] Weigh 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq of 1b, V / m, 6.0 mL), stir to dissolve, add analytical grade sodium bicarbonate (1 eq of 1b, m / m, 0.60 g), add 9c (1.34 mmol, 1.2 eq, 0.21 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), collect the filtrate and use preparative separation to obtain a white powdery solid compound 15 (0.11 g, yield 16.4%, HPLC >98%). 1 H NMR (400MHz, CD3OD) δ (ppm): 8.57 (s, 1H), 8.45 (s, 1H), 7.15-7.07 (m, 3H), 5.05-4.89 (m, 1H), 4.28 (s, 1H), 3. 87-3.84 (m, 2H), 3.67-3.23 (m, 10H), 2.21 (s, 6H), 1.92-1.86 (m, 9H), 1.48-1.37 (m, 8H), 1.16-0.98 (m, 11H). MS m / z(ESI)=513.34[M] + .

[0265] Example 16

[0266] Synthesis of 11b

[0267]

[0268] Take N-Boc-2-piperidinic acid (4.37 mmol, 1.0 eq, 1 g), add analytical grade dichloromethane (25 eq, V / m, 25 mL of N-Boc-2-piperidinic acid), stir to dissolve, and cool to 0 °C in an ice-water bath. Then add O-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboronic acid (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for about 30 minutes, add 2-methoxyethylamine (5.24 mmol, 1.2 eq, 0.46 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL). After stirring at 0 °C for about 1 hour, stir the mixture at room temperature and monitor the reaction by HPLC until completion. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid, which was dissolved in a mixed solvent of dichloromethane:methanol = 20:1 (70 eq, V / m, mL / g, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was washed three times with 5% NaHSO4 aqueous solution (70 eq, V / m, 70 mL of N-Boc-2-piperidinecarboxylic acid). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The liquid was purified by column chromatography using CH2Cl2:CH3OH = 40:1 as the eluent. The eluent was collected and distilled under reduced pressure to give a pale yellow solid 11b (1.11 g, yield 88.8%, HPLC >95%). MS m / z (ESI) = 287.19 [M+H] + .

[0269] Synthesis of 11c

[0270]

[0271] Weigh 11b (3.49 mmol, 1 eq, 1.00 g), add analytical grade dichloromethane (5 eq of 11b, V / m, 5 mL) and stir to dissolve. Dissolve trifluoroacetic acid (7.0 eq of 11b, V / m, 7 mL) in analytical grade dichloromethane (10 eq of 11b, V / m, 10 mL) and add dropwise. After stirring for about 2 hours, monitor the reaction by HPLC until complete. Distill the reaction solution under reduced pressure, add analytical grade dichloromethane and distill under reduced pressure (10 mL three times), add analytical grade methanol and distill under reduced pressure to obtain a white solid 11c (0.60 g, yield 92.3%, HPLC >90%). MS m / z (ESI) = 187.14 [M+H] + .

[0272] Synthesis of Compound 16

[0273]

[0274] Weigh 1b (1.14 mmol, 1 eq, 0.60 g), add analytical grade acetonitrile (10 eq of 1b, V / m, 6.0 mL), stir to dissolve, add analytical grade sodium bicarbonate (1 eq of 1b, m / m, 0.60 g), add 11c (1.37 mmol, 1.2 eq of 1b, 0.25 g), heat to 75 °C and react, monitoring by HPLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), collect the filtrate and use preparative separation to obtain a white powdery solid compound 16 (0.14 g, yield 19.7%, HPLC >98%). 1 H NMR (400MHz, CD3OD): 8.01 (s, 1H), 7.05 (s, 3H), 4.61-4.56 (m, 1H), 3.67 (m, 2H), 3.37-3. 17 (m, 12H), 2.51-2.41 (m, 4H), 2.17-1.92 (m, 8H), 1.86-1.20 (m, 20H), 0.92-0.87 (m, 3H). MS m / z(ESI)=543.43[M] + .

[0275] Example 17

[0276] Synthesis of 17e

[0277]

[0278] Weigh out Boc-N-proline 17a (10.0 mmol, 1.0 eq, 2.15 g), add analytical grade dichloromethane (10 eq of 17a, V / m, 20 mL) at 0 °C and stir to dissolve. Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 10.0 mmol, 7.6 g), stir at 0 °C for 1 h, then add 2,6-dimethylaniline (15 mL) and N-methylmorpholine (NMM, 8.6 mL), stir at 0 °C for 1 h, then move to room temperature. Detect the reaction by TLC until complete. Extract with 50 mL × 3 saturated NH4Cl solution, then extract with 50 mL × 3 saturated NaHCO3 solution, and collect the organic layer. Silica gel column chromatography, eluent: CH2Cl2:MeOH = 20:1. The eluent was collected and concentrated by rotary evaporation to give an orange-yellow oily liquid compound 17b (3.10 g, yield 98.0%, HPLC >90%). MS m / z (ESI) = 218.5 [M+H) + .

[0279] Weigh 17b (5.0 mmol, 1.0 eq, 1.59 g), add 16 mL of analytical grade dichloromethane, stir to dissolve, and add 2 mL of trifluoroacetic acid dropwise. Detect the reaction by TLC until complete. Concentrate by rotary evaporation to give an orange-yellow oily liquid compound 17c (1.2 g, yield 98%, HPLC >90%). MS m / z (ESI) = 218.5 [M+H] + .

[0280] Weigh 17c (5.0 mmol, 1.0 eq, 1.2 g) and add 12 mL of analytical grade acetonitrile, stirring to dissolve. Add 1.4 g of potassium carbonate and 1.4 g of bromobutane. React at 80 °C, monitoring with TLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), and concentrate by rotary evaporation to give a pale yellow solid compound 17d (1.3 g, yield 95%, HPLC >90%). MS m / z (ESI) = 275.5 [M+H) + .

[0281] Weigh 17d (5.0 mmol, 1.0 eq, 2.75 g), add 6 mL of 1,4-dibromobutane, stir and heat to 100 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give an orange-yellow oily liquid compound 17e (1.5 g, yield 73.17%, HPLC >90%). MS m / z (ESI) = 409.19 [M] + 410.99[M+2H] + .

[0282] Synthesis of Compound 17

[0283]

[0284] Weigh 17e (1.14 mmol, 1 eq, 0.56 g), add analytical grade acetonitrile (10 eq of 17e, V / m, 5.6 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 17e, m / m, 0.56 g), add 1c (2.28 mmol, 2 eq of 17e, 0.53 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 17 (0.36 g, yield 49.3%, HPLC > 98%) by preparative separation. 1H NMR (400MHz, CD3OD) δ (ppm): 10.51 (m, 1H), 9.35 (m, 1H), 7.15-6.98 (m, 6H), 4.10 (s, 2H), 3.74- 3.59(m, 2H), 3.43-3.21(m, 10H), 2.27-2.22(m, 6H), 2.18-2.01(m, 12H), 1.57-1.02(m, 13H), MS m / z(ESI)=561.41[M] + .

[0285] Example 18

[0286] Synthesis of Compound 18

[0287]

[0288] Weigh 17e (1.14 mmol, 1 eq, 0.56 g), add analytical grade acetonitrile (10 eq of 17e, V / m, 5.0 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 17e, m / m, 0.56 g), add 4c (2.28 mmol, 2 eq of 17e, 0.50 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 18 (0.43 g, yield 59.7%, HPLC >98%) by preparative separation. 1 H NMR (400MHz, CD3OD) δ (ppm): 10.53 (s, 1H), 9.32 (s, 1H), 7.45-7.27 (m, 7H), 4.25 (m, 2H), 3.80 -3.66(m, 2H), 3.49-3.11(m, 10H), 2.55-2.34(m, 6H), 2.20-2.10(m, 9H), 1.79-1.45(m, 13H). MS m / z(ESI)=547.38[M] + .

[0289] Example 19

[0290] Synthesis of 12c

[0291]

[0292] Weigh piperidineformyl chloride hydrochloride (2.0 mmol, 1 eq, 0.36 g), add 3.0 mL of analytical grade acetonitrile and stir to dissolve. Add 0.55 g of analytical grade potassium carbonate and p-methoxyaniline (4.0 mmol, 0.42 g). Heat to 80 °C and react, monitoring the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), collect the filtrate and concentrate by rotary evaporation. Perform silica gel column chromatography with CH2Cl2:MeOH = 40:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give a yellowish-brown solid compound 12c (0.40 g, yield 89.8%, HPLC >98%). MS m / z (ESI) = 235.2 [M+H] + .

[0293] Synthesis of Compound 19

[0294]

[0295] Weigh 17e (1.14 mmol, 1 eq, 0.56 g), add analytical grade acetonitrile (10 eq of 17e, V / m, 5.0 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 17e, m / m, 0.56 g), add 12c (2.28 mmol, 2 eq of 17e, 0.53 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 19 (0.49 g, yield 66.7%, HPLC > 98%) by preparative separation. 1 H NMR (400MHz, CD3OD) δ (ppm): 10.50 (s, 1H), 9.01 (s, 1H), 7.45-7.27 (m, 5H), 7.10-7.00 (m, 2H), 4.25-4.00 ( m, 2H), 3.79-3.66 (m, 2H), 3.50-3.10 (m, 10H), 2.54-2.33 (m, 6H), 2.19-2.10 (m, 9H), 1.79-1.45 (m, 13H), MS m / z(ESI)=563.32[M] + .

[0296] Example 20

[0297] Synthesis of 13c

[0298]

[0299] Weigh piperidinecarboxyl chloride (2.0 mmol, 1 eq, 0.36 g), add 3.0 mL of analytical grade acetonitrile and stir to dissolve. Add 0.55 g of analytical grade potassium carbonate and 4.0 mmol of p-trifluoromethylaniline (0.42 g). Heat to 80 °C and react, monitoring the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), collect the filtrate and concentrate by rotary evaporation. Perform silica gel column chromatography with CH2Cl2:MeOH = 40:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give a yellowish-brown solid compound 13c (0.41 g, yield 90.3%, HPLC >98%). MS m / z (ESI) = 273.2 [M+H] + .

[0300] Synthesis of Compound 20

[0301]

[0302] Weigh 17e (1.14 mmol, 1 eq, 0.56 g), add analytical grade acetonitrile (10 eq of 17e, V / m, 5.0 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 17e, m / m, 0.56 g), add 13c (2.28 mmol, 2 eq of 17e, 0.62 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 20 (0.30 g, yield 38.6%, HPLC >98%) by preparative separation. 1 H NMR (400MHz, CD3OD) δ (ppm): 10.54 (s, 1H), 9.47 (s, 1H), 7.78-7.30 (m, 7H), 4.26-4.01 (m, 2H), 3 .81-3.70(m, 2H), 3.53-3.14(m, 10H), 2.57-2.32(m, 6H), 2.25-2.10(m, 9H), 1.85-1.54(m, 13H). MS m / z(ESI)=601.29[M] + .

[0303] Example 21

[0304] Synthesis of Compound 21

[0305]

[0306] Weigh 17e (1.14 mmol, 1 eq, 0.56 g), add analytical grade acetonitrile (10 eq of 17e, V / m, 5.6 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 17e, m / m, 0.56 g), add 3c (2.28 mmol, 2 eq of 17e, 0.50 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 21 (0.36 g, yield 54.2%, HPLC >98%) by preparative separation. 1 H NMR (400MHz, CD3OD) δ (ppm): 10.53 (s, 1H), 9.41 (s, 1H), 7.68-7.26 (m, 7H), 4.25-4.00 (m, 2H), 3 .83-3.69(m, 2H), 3.55-3.20(m, 10H), 2.67-2.30(m, 6H), 2.23-2.10(m, 9H), 1.81-1.52(m, 13H). MS m / z(ESI)=551.48[M] + .

[0307] Example 22

[0308] Synthesis of 18e

[0309]

[0310] Weigh 17d (5.0 mmol, 1.0 eq, 1.37 g), add 6 mL of 1,5-dibromopentane, stir and heat to 100 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give a yellowish-brown oily liquid compound 18e (1.8 g, yield 71.4%, HPLC >90%). MS m / z (ESI) = 422.19 [M] + 424.28 [M+2H] + .

[0311] Synthesis of Compound 22

[0312]

[0313] Weigh 18e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 18e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 18e, m / m, 0.57 g), add 1c (2.28 mmol, 2 eq of 18e, 0.53 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 22 (0.38 g, yield 51.0%, HPLC >98%) by preparative separation. 1 H NMR(400MHz, CD3OD):7.05(s,6H),4.61-4.56(m,1H),3.47-3.42(m,1H),3.25-3.20(m,4H),2. 51-2.41(m,4H),2.20-2.13(m,14H),1.97-1.55(m,7H),1.49-1.29(m,11H),0.92-0.87(m,3H). MS m / z(ESI)=574.40[M] + .

[0314] Example 23

[0315] Synthesis of Compound 23

[0316]

[0317] Weigh 18e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 18e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 18e, m / m, 0.57 g), add 4c (2.28 mmol, 2 eq of 18e, 0.50 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 23 (0.45 g, yield 61.7%, HPLC >98%) by preparative separation. 1 H NMR(400MHz,CD3OD):9.70(s,1H),7.44(d,2H),7.10-7.05(m,5H),4.61-4.56(m,1H),3.47-3.42(m,1 H),3.25-3.20(m,4H),2.51-2.13(m,15H),1.97-1.45(m,7H),1.55-1.29(m,11H),0.92-0.87(m,3H). MS m / z(ESI)=561.38[M] + .

[0318] Example 24

[0319] Synthesis of Compound 24

[0320]

[0321] Weigh 18e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 18e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 18e, m / m, 0.57 g), add 12c (2.28 mmol, 2 eq of 18e, 0.55 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 24 (0.49 g, yield 65.4%, HPLC > 98%) by preparative separation. 1 H NMR(400MHz, CD3OD):7.41(d,2H),7.13-7.02(m,3H),6.86(d,2H),4.04-3 .94(m,1H),3.89-3.80(m,1H),3.79-3.62(m,5H),3.59-3.48(m,1H),3.44- 3.33(m,2H),3.30-3.14(m,3H),3.12-3.01(m,1H),2.77-2.60(m,1H),2.4 0-2.12(m,12H),1.97-1.48(m,10H),1.40-1.16(m,3H),0.92-0.87(m,3H). 13 C NMR (400MHz, CD3OD): δ172.0,158.9,137.1,130.8,130.7,127.7,126.8,122.6,114.5,83.9,68.6,64. 7,56.5,56.2,55.8,53.7,52.5,27.6,25.9,25.8,25.5,25.3,23.1,21.2,19.6,19.2,19.0,17.6,13.8. MS m / z(ESI)=577.39[M] + .

[0322] Example 25

[0323] Synthesis of Compound 25

[0324]

[0325] Weigh 18e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 18e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 18e, m / m, 0.57 g), add 13c (2.28 mmol, 2 eq of 18e, 0.62 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 25 (0.42 g, yield 53.2%, HPLC >98%) by preparative separation. 1 H NMR(400MHz,CD3OD):7.57(d,2H),7.46(d,2H),7.05(s,3H),4.61-4.56(m,1H),3.47-3.42(m,1H) ,3.27-3.17(m,6H),2.51-2.41(m,4H),2.17-1.92(m,9H),1.76-1.29(m,17H),0.92-0.87(m,3H). MS m / z(ESI)=615.41[M] + .

[0326] Example 26

[0327] Synthesis of Compound 26

[0328]

[0329] Weigh 18e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 18e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 18e, m / m, 0.57 g), add 3c (2.28 mmol, 2 eq of 2e, 0.51 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (18 mL, three times), collect the filtrate, and obtain a white solid compound 26 (0.30 g, yield 40.8%, HPLC >98%) by preparative separation. 1 H NMR(400MHz,CD3OD):7.59(dd,2H),7.17-7.12(m,2H),7.05(s,3H),4.61-4.56(m,1H),3.47-3.42(m, 1H),3.27-3.17(m,6H),2.51-2.41(m,4H),2.17-1.92(m,9H),1.76-1.29(m,17H),0.92-0.87(m,3H). MS m / z(ESI)

[0330] =565.39 [M] + .

[0331] Example 27

[0332] Synthesis of 19e

[0333]

[0334] Weigh out Boc-N-proline 17a (10.0 mmol, 1.0 eq, 2.15 g), add analytical grade dichloromethane (10 eq of 17a, V / m, 20 mL) at 0 °C and stir to dissolve. Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 20.0 mmol, 7.6 g), stir at 0 °C for 1 h, then add 2,4,6-trimethylaniline (15 mL), N-methyl... 8.6 mL of NMM (methylmorpholine) was stirred at 0 °C for 1 h and then cooled to room temperature. The reaction was monitored by TLC until complete. Extraction was performed with 50 mL × 3 saturated NH₄Cl solution, followed by 50 mL × 3 saturated NaHCO₃ solution. The organic layer was collected. Silica gel column chromatography was performed using CH₂Cl₂:MeOH = 20:1 as the eluent. The eluent was collected and concentrated by rotary evaporation to give an orange-yellow oily liquid compound 19b (3.10 g, yield 98%, HPLC > 90%). MS m / z (ESI) = 233.5 [M + H⁺). + .

[0335] Weigh 19b (5.0 mmol, 1.0 eq, 1.59 g), add 16 mL of analytical grade dichloromethane and stir to dissolve. Add 2 mL of trifluoroacetic acid dropwise, monitoring the reaction by TLC until complete. Concentrate by rotary evaporation to give an orange-yellow oily liquid compound 19c (1.2 g, yield 98%, HPLC >90%). MS m / z (ESI) = 233.5 [M+H) + .

[0336] Weigh 19c (5.0 mmol, 1.0 eq, 1.2 g) and add 12 mL of analytical grade acetonitrile, stirring to dissolve. Add 2.4 g of potassium carbonate and 1.4 g of bromobutane. React at 80 °C, monitoring with TLC until the reaction is complete. Filter the reaction solution, wash the filter cake with acetonitrile (15 mL, three times), and concentrate by rotary evaporation to give a pale yellow solid compound 19d (1.3 g, yield 95%, HPLC >90%). MS m / z (ESI) = 289.5 [M+H) + .

[0337] Weigh 19d (5.0 mmol, 1.0 eq, 2.75 g), add 6 mL of 1,4-dibromobutane, stir and heat to 100 °C, and monitor the reaction by TLC until complete. Perform silica gel column chromatography with CH2Cl2:MeOH = 20:1 as the eluent. Collect the eluent and concentrate by rotary evaporation to give an orange-yellow oily liquid compound 19e (1.5 g, yield 70.2%, HPLC >90%). MS m / z (ESI) = 422.79 [M] + 424.79 [M+2H] + .

[0338] Synthesis of Compound 27

[0339]

[0340] Weigh 19e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 19e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 19e, m / m, 0.57 g), add 1c (2.28 mmol, 2 eq of 19e, 0.53 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 19e, V / m, 18 mL, three times), and collect the filtrate. Use preparative separation to obtain a white solid compound 27 (0.39 g, yield 52.3%, HPLC >98%). 1 H NMR(400MHz,CD3OD):7.05(s,3H),6.90(s,2H),4.61-4.56(m,1H),3.47-3.42(m,1H),3.27- 3.17(m,6H),2.51-2.41(m,4H),2.26-1.92(m,18H),1.76-1.30(m,15H),0.92-0.87(m,3H). MS m / z(ESI)=575.35[M] + .

[0341] Example 28

[0342] Synthesis of Compound 28

[0343]

[0344] Weigh 19e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 19e, V / m, 5.07 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 19e, m / m, 0.57 g), add 4c (2.28 mmol, 2 eq of 1e, 0.50 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 19e, V / m, 18 mL, three times), and collect the filtrate. Use preparative separation to obtain a white solid compound 28 (0.40 g, yield 54.6%, HPLC >98%). 1 H NMR(400MHz, CD3OD):7.44(d,2H),7.10(d,2H),6.90(s,2H),4.61-4.56(m,1H),3.47-3. 42(m,1H),3.27-3.17(m,6H),2.51-1.92(m,19H),1.76-1.30(m,15H),0.92-0.87(m,3H). MS m / z(ESI)

[0345] =561.40 [M] + .

[0346] Example 29

[0347] Synthesis of Compound 29

[0348]

[0349] Weigh 19e (1.14 mmol, 1 eq, 0.57 g), add analytical grade acetonitrile (10 eq of 19e, V / m, 5.7 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 19e, m / m, 0.57 g), add 3c (2.28 mmol, 2 eq of 19e, 0.51 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 19e, V / m, 18 mL, three times), and collect the filtrate. Use preparative separation to obtain a white solid compound 29 (0.36 g, yield 48.9%, HPLC > 98%). 1H NMR (400MHz, CD3OD):7.59-7.52(m,2H),7.14-7.11(m,2H),6.90(s,2H),4.58-4.51(m,1H),3.44-3.37( m,1H),3.27-3.22(m,6H),2.43-2.41(m,4H),2.26-1.92(m,11H),1.97-1.30(m,16H),0.99-0.91(m,3H). MS m / z(ESI)=565.31[M] + .

[0350] Example 30

[0351] Synthesis of 20e

[0352]

[0353] Weigh 19d (5.0 mmol, 1.0 eq, 2.75 g), add 1,5-dibromopentane (2.0 eq of 19d, V / m, 6 mL), stir and heat to 100 °C, and monitor by TLC until the reaction is complete. Perform silica gel column chromatography, eluent: CH2Cl2:MeOH = 20:1, collect the eluent, and concentrate by rotary evaporation to give a yellowish-brown oily liquid compound 20e (1.8 g, yield 76.3%, HPLC >90%). MS m / z (ESI) = 437.22 [M] + ,439.21[M+2H].

[0354] Synthesis of Compound 30

[0355]

[0356] Weigh 20e (1.14 mmol, 1 eq, 0.59 g), add analytical grade acetonitrile (10 eq of 20e, V / m, 5.0 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 20e, m / m, 0.59 g), add 1c (2.28 mmol, 2 eq of 20e, 0.53 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 20e, V / m, 18 mL, three times), collect the filtrate, and obtain a white solid compound 30 (0.38 g, yield 50.0%, HPLC >98%) by preparative separation. 1H NMR (400MHz, CD3OD): δ10.02(s,2H),7.05(s,3H),6.90(s,2H),4.61-4.58(m,1H),3.44-3.39(m,1H),3.22-3 .16(m,4H),2.51-2.41(m,4H),2.26-2.13(m,17H),1.97-1.55(m,7H),1.49-1.29(m,11H),0.95-0.90(m,3H). MS m / z(ESI)=588.44[M] + .

[0357] Example 31

[0358] Synthesis of Compound 31

[0359]

[0360] Weigh 20e (1.14 mmol, 1 eq, 0.59 g), add analytical grade acetonitrile (10 eq of 20e, V / m, 5.9 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 20e, m / m, 0.59 g), add 4c (2.28 mmol, 2 eq of 20e, 0.50 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 20e, V / m, 18 mL, three times), and collect the filtrate. Use preparative separation to obtain a white solid compound 31 (0.45 g, yield 60.4%, HPLC >98%). 1 H NMR(400MHz,CD3OD):7.44(d,2H),7.10(d,2H),6.90(s,2H),4.58-4.51(m,1H),3.44-3.38(m,1H) ,3.22-3.10(m,4H),2.51-2.00(m,18H),1.97-1.55(m,7H),1.49-1.29(m,11H),0.98-0.93(m,3H). MS m / z(ESI)=575.37[M] + .

[0361] Example 32

[0362] Synthesis of Compound 32

[0363]

[0364] Weigh 20e (1.14 mmol, 1 eq, 0.59 g), add analytical grade acetonitrile (10 eq of 20e, V / m, 5.9 mL), stir to dissolve, add analytical grade potassium carbonate (1 eq of 20e, m / m, 0.59 g), add 3c (2.28 mmol, 2 eq of 20e, 0.51 g), heat to 80 °C, and monitor the reaction by thin-layer chromatography until completion. Filter the reaction solution, wash the filter cake with acetonitrile (30 eq of 20e, V / m, 18 mL, three times), and collect the filtrate. Use preparative separation to obtain a white solid compound 32 (0.31 g, yield 41.3%, HPLC >98%). 1 H NMR (400MHz, CD3OD):7.59-7.51(m,2H),7.14-7.10(m,2H),6.90(s,2H),4.58-4.53(m,1H),3.44-3.38( m,1H),3.27-3.17(m,6H),2.51-2.41(m,4H),1.26-1.92(m,12H),1.76-1.29(m,17H),0.89-0.85(m,3H). MS m / z(ESI)=579.39[M] + .

[0365] Biological testing

[0366] Unless otherwise specified, the experimental methods used in the following test examples are conventional experimental methods. Unless otherwise specified, the test materials used in the following test examples were all purchased from conventional biochemical reagent stores. Test Example 1: Nerve Blocking Local Anesthesia Effect of the Compounds of this Application

[0367] Three groups of fully adapted rats were given the compound from the example and the positive control group of levobupivacaine hydrochloride, with one rat in each group.

[0368] Solution preparation: 2 mg / mL Levobupivacaine Hydrochloride Injection: Pipette 2.670 mL of 7.5 mg / mL Levobupivacaine Hydrochloride Injection (batch number: 92S0702) into a 10 mL volumetric flask. Add 0.9% NaCl solution until the meniscus is level with the graduation mark. Invert and mix well to prepare a 2 mg / mL Levobupivacaine Hydrochloride Injection. 6 mg / mL Example Compound Solution (molar concentration range calculated based on the molecular weight of the compound in the examples: 8.6-10.1 mmol / L): Accurately weigh 19.80 mg of the example compound and add 3.3 mL of 0.9% NaCl solution to prepare a 6 mg / mL example compound solution.

[0369] Each rat was administered 5 mL / kg via injection, either as a drug or control, using a single dose along the right sciatic nerve. After administration, the rat was placed on a preheated (50±0.1℃) intelligent hot plate apparatus. The time required for the rat to exhibit obvious behaviors such as paw lifting and licking to avoid heat stimulation on the administered side was recorded as the heat latency. The maximum allowable heat latency was 60 seconds. If the rat did not lick its paw after 60 seconds, its hind paw was manually lifted to prevent tissue damage or hyperalgesia, and 60 seconds was recorded as the heat latency for that rat. After each measurement, any urine or feces on the hot plate were wiped clean and dried for subsequent tests.

[0370] Analytical methods

[0371] The result of the thermal latency is expressed as the maximum proportionality effect (MPE), calculated using the following equation:

[0372] MPE (%) = (CB) / (PB) * 100%

[0373] Where B represents the basal thermal latency of rats, P represents the maximum allowable thermal latency, and C represents the thermal latency at the detection time point.

[0374] If the measured time is less than 50% of the maximum proportional effect, the measurement is considered invalid. If the measured time is less than 50% of the maximum proportional effect after two consecutive measurements, the measurement should be stopped.

[0375] Test results:

[0376] Table 1 shows the local anesthetic effects of the compounds in this application.

[0377]

[0378]

[0379] Experimental results show that the compounds of this application can produce good local anesthetic effects in the sciatic nerve block model, and have a rapid onset of action. Within the range of molar concentrations of 8.6-10.1 mmol / L, the duration of single-drug anesthesia is greater than or equal to 11 hours, significantly longer than that of the positive control levobupivacaine hydrochloride. The duration of single-drug anesthesia for some compounds is greater than 24 hours, and the duration of single-drug local anesthesia for some compounds is greater than 48 hours, with an onset time of 1 minute.

[0380] Test Example 2: Subcutaneous infiltration local anesthetic effect of the compound of this application

[0381] SD rats weighing 190-210 grams (half male and half female) were shaved and disinfected on their backs. A circle with a diameter of approximately 1.5 cm was drawn on one side of the bare back. 0.5 mL of a drug-containing solution was subcutaneously injected into the center of the skin: physiological saline as the solvent, 2 mg / mL levobupivacaine hydrochloride, and 6 mg / mL of one of the nine compounds selected in this application (the molecular weight equivalent molar concentration of the compounds in the examples ranges from 8.6 to 10.1 mmol / L). Ten rats were used in each group. A 100-gram fiber from Von Frey fibers was bound to a needle for local skin stimulation. One minute after drug injection, the rats' response to the stinging stimulus was measured. The test sites were six different points along the circled area of ​​the drug injection site. Whether skin contraction or avoidance behaviors occurred after stimulation was observed and recorded. The number of times skin contraction or avoidance behaviors occurred was recorded as N / 6 after stimulating three points in the center and three points around the circle. In determining efficacy, the drug was considered ineffective if four or more rats exhibited avoidance or skin contraction behaviors; if there was a response over four weeks (≤3) with no response in between (≥1), the drug was considered still effective; and the drug was considered ineffective if there was a response only at the midpoint. Each compound was tested using 10 rats.

[0382] Test results:

[0383] Table 2 shows the local anesthetic effect of the compound (6 mg / mL) obtained by subcutaneous infiltration in this application.

[0384]

[0385] Experimental results show that the compounds of this application, at a concentration of 6 mg / mL (equivalent to a molar concentration range of 8.6-10.1 mmol / L), can produce local anesthesia for more than 48 hours in a rat subcutaneous infiltration model, with a rapid onset of action. Some of the compounds can produce local anesthesia for more than 72 hours, with an onset time of 1 minute.

[0386] Since local anesthesia lasting longer than 72 hours may cause irreversible nerve damage, we subsequently halved the dose of compounds with an action time exceeding 72 hours (3 mg / mL) and conducted an activity test to determine whether the local anesthetic effect in the skin infiltration model could be restored.

[0387] Table 3 shows the local anesthetic effect of the compound (3 mg / mL) obtained by subcutaneous infiltration in this application.

[0388] Compound 4 1 56 Compound 8 1 52 Compound 12 1 60 Compound 24 1 63 Levobupivacaine hydrochloride 3

[0389] Experimental results show that the compound of this application, at a concentration of 3 mg / mL (equivalent to a molar concentration range of 4.4-5.1 mmol / L), can still produce local anesthesia for more than 48 hours in a rat subcutaneous infiltration model, and the local anesthesia effect can be recovered.

[0390] Test Example 3: Neuropathological Damage Assessment of Compounds in this Application

[0391] Compounds 4, 8, 12, and 24 from the examples, along with the positive control group of levobupivacaine hydrochloride and the solvent control group, were administered to SD rats (half male and half female) weighing 190-210 grams that were fully adapted to the experimental environment. Eight rats were used in each group.

[0392] Dosage concentration: 2 mg / mL of levobupivacaine hydrochloride was administered using physiological saline as the solvent. The two concentrations of the compound in this application were 6 mg / mL and 12 mg / mL, respectively. The solvent control group was physiological saline.

[0393] The injection volume for each rat was 1.0 mL, injected near the sciatic nerve. On days 7 and 14 after the sciatic nerve injection, the rats were euthanized by cardiac injection of levobupivacaine hydrochloride under isoflurane anesthesia. Approximately 1.5 cm of the sciatic nerve at the injection site was harvested, preserved in 10% formaldehyde solution for 48 h, stained with hematoxylin and eosin (HE), and sectioned into 5 μm thick sections.

[0394] Compounds 4, 8, 12, and 24 prepared in the examples were selected. The positive control group and the solvent control group were 190-210 g SD rats (half male and half female) that were fully adapted to the experimental environment. Eight rats were given to each group.

[0395] Dosage concentration: Using physiological saline as solvent, levobupivacaine hydrochloride was administered at 2 mg / mL. Two concentrations of the compound in this application were also administered at 3 mg / mL and 6 mg / mL. The solvent control group was physiological saline.

[0396] The injection volume for each rat was 1 mL, injected subcutaneously into the back of the rat. On days 7 and 14 after subcutaneous injection, the experimental rats were euthanized by cardiac injection of levobupivacaine hydrochloride under isoflurane anesthesia. Skin tissue from the injection site was collected, preserved in 10% formaldehyde solution for 48 h, stained with hematoxylin and eosin (HE), and cut into 5 μm thick sections.

[0397] The neuropathological damage assessment results showed that the compound in the example had no significant differences in nerve damage, angiogenesis, degree of demyelination, muscle inflammation, and degree of connective tissue inflammation compared with the positive control group and the solvent control group, indicating good safety.

[0398] Test Example 4: Single-dose toxicity study of the compound in this application

[0399] Compounds 4, 8, 12, and 24 from the examples were administered to SD rats weighing 190-210 grams that were fully adapted to the experimental environment, with four rats in each group.

[0400] Dosage: Using physiological saline as a solvent, the concentration of compounds 4, 8, 12, and 24 in this application is 6 mg / kg.

[0401] Administration method: Each rat was administered via tail vein at a dose of 5 mL / kg.

[0402] Compounds 4, 8, 12, and 24 from the examples were selected. The positive control group of levobupivacaine hydrochloride was given to SD test rats weighing 190-210 grams that were fully adapted to the experimental environment, with 4 rats in each group.

[0403] Dosage: Using physiological saline as a solvent, the concentration of compounds 4, 8, 12, and 24 in this application is 30 mg / kg.

[0404] Administration method: Each rat was administered a subcutaneous injection at a dose of 5 mL / kg.

[0405] The results showed that after rats were administered the compound of this application at doses of 6 mg / kg via the tail vein and 30 mg / kg via the subcutaneous vein, there were no obvious abnormalities, and their behavior was active and not significantly different from that of normal rats.

[0406] In summary, this application provides a novel quaternary ammonium salt compound, its preparation method, and its uses. This compound has a rapid onset of action, provides a long-lasting local anesthetic effect after a single dose, and exhibits good safety.

[0407] This application describes several embodiments, but these descriptions are exemplary and not restrictive, and it will be apparent to those skilled in the art that there are many more embodiments and implementations within the scope of the embodiments described herein.

Claims

1. A quaternary ammonium salt compound of formula (I), or a pharmaceutical salt thereof: in: R1 is a phenyl group, which is reacted with one or more C atoms. 1-6 Alkyl substitution; R2 is selected from C 1-8 alkyl; R3 is selected from C 1-6 alkoxy-substituted C 1-8 Alkyl, C 3-7 cycloalkyl, phenyl or halogenated, C 1-6 Alkyl, C 1-6 Halogenated alkyl or C 1-6 Alkoxy-substituted phenyl; X1 and X2 are each independently NH; m and n are each independently selected from integers from 0 to 8, and m and n may be the same or different; L is selected from C 1-8 Alkylene; One of S1 and S2 is a single bond, and the other is -(CH2)3- or -(CH2)4-. One of Q1 and Q2 is a single bond, and the other is -(CH2)4-; Y - This represents a pharmaceutically acceptable anion.

2. The quaternary ammonium salt compound or its pharmaceutical salt according to claim 1, wherein, R1 is 2,6-dimethylphenyl or 2,4,6-trimethylphenyl; R2 is n-propyl or n-butyl; R3 is cyclohexyl, phenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-trifluoromethylphenyl or 2,6-dimethylphenyl; L is selected from: -(CH2)4- or -(CH2)5-; Y - It is a halide anion.

3. The quaternary ammonium salt compound or its pharmaceutical salt according to claim 1 or 2, wherein, In formula (I) Y - For Cl - ,Br - Or I - .

4. The quaternary ammonium salt compound or its pharmaceutical salt according to claim 1 or 2, wherein, In formula (I) Y - For Br - .

5. The quaternary ammonium salt compound or its pharmaceutical salt according to claim 1, wherein, In formula (I) Y - It can be a halogen anion, acetate, p-toluenesulfonate, or methanesulfonate.

6. A compound selected from the following: 、 、 、 、 、 、 、 、 、 。 7. A compound selected from the following: 。 8. A method for preparing the quaternary ammonium salt compound according to any one of claims 1 to 5, or its pharmaceutical salt, or the compound according to any one of claims 6 to 7, comprising the following steps: The compound of formula (II) reacts with the compound of formula (III) to give the compound of formula (I); In formula (II), Z is an electron-withdrawing leaving group, which is a bromine, chlorine or sulfonate ester. The group definitions in formula (II) and formula (III) are the same as in formula (I).

9. A pharmaceutical composition comprising a quaternary ammonium salt compound of any one of claims 1 to 5 or a pharmaceutical salt thereof, or a compound of any one of claims 6 to 7, and a pharmaceutically acceptable excipient.

10. Use of the quaternary ammonium salt compound of any one of claims 1 to 5 or its pharmaceutical salt, or the compound of any one of claims 6 to 7, or the pharmaceutical composition of claim 9 in the preparation of a medicament for anesthetic or analgesic purposes.

11. The use according to claim 10, wherein, The anesthesia is local anesthesia; the analgesia is applicable to chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, or idiopathic pain.

12. The use according to claim 10, wherein, The anesthesia is either conduction anesthesia, surface anesthesia, or infiltration anesthesia.

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