Quaternary ammonium salt compounds and their preparation and use

Abstract

The present application provides a quaternary ammonium salt compound and its preparation method and use. The compound is represented by the general formula (I), or its isomers, pharmaceutical salts, and compositions thereof can be used to prepare anesthetic or analgesic drugs. Each substituent in the general formula (I) is as defined in the specification. [Formula 1] TIFF2024519944000085.tif31143

Description

[Technical Field]

[0001] This application claims priority from a Chinese patent application for invention filed on May 27, 2021, entitled "Quaternary ammonium salt compounds and their preparation methods and uses" and bearing application number CN202110587550.8, the entire contents of which are incorporated herein by reference.

[0002] This application relates to the field of medicinal chemistry, but is not limited thereto, and more particularly to quaternary ammonium salt compounds and their preparation and use. [Background technology]

[0003] Local anesthetics, also known as regional anesthetics, are drugs applied locally to nerve trunks or around nerve endings to temporarily, completely, and reversibly inhibit the production and conduction of nerve impulses, thereby temporarily relieving local pain sensation. The mechanism of action of local anesthetics is to bind to binding sites located on sodium channels in the neuronal membrane, reducing Na+ influx across the cell membrane and altering the membrane potential, thereby inhibiting the conduction of nerve impulses and achieving an anesthetic effect. Due to their reliable efficacy, low risk of hyperalgesia, convenient local administration, low blood concentrations, and minimal systemic side effects, local anesthetics are a commonly used method of pain treatment in clinical practice.

[0004] Currently, local anesthetics used in clinical practice are primarily compounds in which the aromatic group and the amine group are linked via an ester or amide bond, such as procaine, tetracaine, lidocaine, bupivacaine, and ropivacaine. Among these, bupivacaine and ropivacaine are considered new long-acting local anesthetics, but the analgesic duration of a single dose usually does not exceed 8 hours ("Local anesthetics: review of pharmacological considerations," Becker D E. et al., Anesth Prog. 2012, 59(2): 90-102). While these drugs are suitable for most surgical or invasive procedures, they fall far short of satisfying the needs of postoperative pain, chronic pain, and other conditions.

[0005] QX-314, a quaternary ammonium salt derivative of lidocaine, can effectively inhibit sodium ion currents after crossing cell membranes, producing a prolonged anesthetic effect. However, because it has a permanent positive charge, it is difficult for it to actively cross lipid-soluble cell membranes ("Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA", Courtney KR. J Pharmacol Exp Ther. 1975, 195:225-236). Research has shown that combining QX-314 with local anesthetics or transient receptor potential channel (TRP) agonists can penetrate cell membranes and produce long-lasting local anesthetic effects, but also cause increased local neurotoxicity and systemic toxicity ("Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat", Alsalem M. et al., BMC Pharmacol Toxicol. 2016, 17(1): 31.). Summary of the Invention

[0006] In a first aspect of the present application, there is provided a quaternary ammonium salt compound represented by formula (I), or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof: [ka] During the ceremony, R1 is selected from aromatic hydrocarbon groups and heteroaryl groups; R2 is C 1-18 Alkyl group, C 3-12 cycloalkyl groups, R3 is C 1-8 Alkyl group, C 3-12 selected from a cycloalkyl group, an aromatic hydrocarbon group, a heteroaryl group, and a heterocycloalkyl group; X1 and X2 are each independently selected from O, S, and NR4, and R4 is hydrogen, deuterium, or C. 1-8 Alkyl group, C 3-8 Cycloalkyl groups, C 1-8 Alkoxy C 1-8 is an alkyl group, or NR4 together with the R1 or R3 to which it is attached forms a nitrogen heterocycloalkyl group; m and n are each independently selected from integers of 0 to 8, and m and n may be the same or different; L is C 1-8 Alkylene group, C 2-8 Alkenylene group, C 2-8 Alkynylene group and C 3-8 cycloalkylene groups, S1, S2, Q1 and Q2 are each independently a single bond (i.e., the connecting atoms are directly connected by a bond) and C 1-6 alkylene groups, 1-6 The carbon atoms in the main chain of the alkylene group are optionally replaced by one heteroatom, the heteroatom being selected from O, S and N, N being substituted by R6, R6 being selected from hydrogen and deuterium, and S1 and S2 are not simultaneously single bonds (i.e., the atoms connecting them are directly connected by a bond), and Q1 and Q2 are not simultaneously single bonds (i.e., the atoms connecting them are directly connected by a bond); Y- denotes a pharmaceutically acceptable anion.

[0007] In a second aspect, the present application provides a method for preparing a compound of general formula (I) as described herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, said method comprising: [ka] reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I), In formula (II), Z is an electron-withdrawing leaving group, optionally the leaving group is bromine, chlorine or sulfonate ester, and the definitions of the groups in formula (II) and formula (III) are the same as in formula (I).

[0008] A third aspect of the present application relates to a pharmaceutical composition comprising a compound of general formula (I) as described herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

[0009] In a fourth aspect, the present application relates to a compound of general formula (I) as described herein, its tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, for use in medicine.

[0010] A fifth aspect of the present application relates to the use of a compound of general formula (I) as described herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, in the manufacture of an anesthetic or analgesic drug.

[0011] A sixth aspect of the present application relates to a method of anesthesia or analgesia, said method comprising administering to a patient in need thereof a compound of general formula (I) as defined herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, or a pharmaceutical composition thereof. DETAILED DESCRIPTION OF THE INVENTION

[0012]

[0003] Due to the problems with QX-314, many researchers are interested in exploring new local anesthetics that have long-acting effects and high safety. For example, CN110156665B discloses a novel quaternary ammonium salt compound, which has both long-acting and selective local anesthetic effects (sensory nerve block duration longer than motor nerve block duration), and has the advantages of a longer local anesthetic duration, better local anesthetic selectivity, less nerve damage, and higher safety compared to conventional QX314, QX314 compositions, and long-chain compounds with surfactant structural characteristics. CN110156666A discloses a novel quaternary ammonium cation compound, which has both long-acting and selective local anesthetic effects (sensory nerve block duration longer than motor nerve block duration), and has the advantages of a longer local anesthetic duration, better local anesthetic selectivity, less nerve damage, and higher safety compared to conventional QX314, QX314 compositions, and long-chain compounds with surfactant structural characteristics. CN101050200A discloses alkene-substituted amide derivatives and their application in the field of local anesthesia, and the results show that they have a certain local anesthetic effect and their acute toxicity is less than that of levobupivacaine hydrochloride.

[0013] The present application provides novel quaternary ammonium salt compounds, including methods for preparing the compounds and their uses, which have the advantages of a novel structure, long-lasting local anesthesia after a single administration, and no motor nerve damage.

[0014] In a first aspect of the present application, there is provided a quaternary ammonium salt compound represented by formula (I), or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof: [ka] During the ceremony, R1 is selected from an aromatic hydrocarbon group and a heteroaryl group, and the aromatic hydrocarbon group and the heteroaryl group are optionally selected from C1-6 Alkyl group, C 1-6 Alkoxy group, cyano group, halogen, hydroxyl group, amino group, nitro group, ester group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-6 Haloalkyl group, C 1-6 substituted by one or more haloalkoxy groups; R2 is C 1-18 Alkyl group, C 3-12 cycloalkyl groups, 1-18 Alkyl group, C 3-12 The cycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 3-6 substituted with one or more of a cycloalkyl group, a halogen, a hydroxyl group, a cyano group, or an amino group; R3 is C 1-8 Alkyl group, C 3-12 is selected from a cycloalkyl group, an aromatic hydrocarbon group, a heteroaryl group, and a heterocycloalkyl group, 1-8 Alkyl group, C 3-12 The cycloalkyl group, aromatic hydrocarbon group, heteroaryl group, and heterocycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4and is substituted by one or more groups selected from the group consisting of an alkynyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heteroaryl group, and an optionally substituted heterocycloalkyl group, and the optionally substituted aromatic hydrocarbon group, the optionally substituted heteroaryl group, and the optionally substituted heterocycloalkyl group refer to an unsubstituted aromatic hydrocarbon group, an unsubstituted heteroaryl group, and an unsubstituted heterocycloalkyl group, or the aromatic hydrocarbon group, the heteroaryl group, and the heterocycloalkyl group are each selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 alkynyl groups, X1 and X2 are each independently selected from O, S, and NR4, and R4 is hydrogen, deuterium, or C. 1-8 Alkyl group, C 3-8 Cycloalkyl groups, C 1-8 Alkoxy C 1-8 is an alkyl group, or NR4 together with the R1 or R3 to which it is attached forms a nitrogen heterocycloalkyl group; m and n are each independently selected from integers of 0 to 8, and m and n may be the same or different; L is C 1-8 Alkylene group, C 2-8 Alkenylene group, C 2-8 Alkynylene group and C 3-8 cycloalkylene groups, 1-8 Alkylene group, C 3-8 The carbon atoms in the main chain of the cycloalkylene group are optionally substituted with 1 to 3 heteroatoms, which are selected from O, S, and N, and N can be substituted with R5, which can be hydrogen, deuterium, C 1-4 alkyl groups, 1-8 Alkylene group, C2-8 Alkenylene group, C 2-8 Alkynylene group and C 3-8 The cycloalkylene group may optionally be C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group, C 2-4 Alkenyl group, C 2-4 substituted by one or more alkynyl groups; S1, S2, Q1 and Q2 are each independently a single bond (i.e., the connecting atoms are directly connected by a bond) and C 1-6 alkylene groups, 1-6 One carbon atom in the main chain of the alkylene group is optionally replaced by one heteroatom, the heteroatom being selected from O, S and N, N being substituted by R6, R6 being selected from hydrogen and deuterium, and S1 and S2 are not simultaneously single bonds (i.e., the atoms connecting them are directly connected by a bond), and Q1 and Q2 are not simultaneously single bonds (i.e., the atoms connecting them are directly connected by a bond); Y - denotes a pharmaceutically acceptable anion.

[0015] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture form thereof, or pharmaceutical salt thereof, R1 is a phenyl group or a naphthyl group, and the phenyl group or naphthyl group is optionally C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group, halogen, hydroxyl group, amino group, nitro group, ester group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4Haloalkyl group, C 1-6 It is substituted by one or more haloalkoxy groups.

[0016] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture form thereof, or pharmaceutical salt thereof, R1 is a phenyl group, and the phenyl group is optionally substituted with one or more groups selected from the group consisting of methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, fluorine group, chlorine group, bromine group, iodine group, hydroxyl group, amino group, nitro group, methyl ester group, and ethyl ester group, and more preferably, R1 is a phenyl group, 2-methylphenyl group, group, 2-methoxyphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 2-chlorophenyl group, 4-chlorophenyl group, 2-bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 3-hydroxyphenyl group, 4-trifluoromethylphenyl group, 2,6-dimethylphenyl group, 2,6-dimethoxyphenyl group, 3-nitrophenyl group, 2,6-difluorophenyl group, 3-chloro-2-methylphenyl group, 2,3-dichlorophenyl group, 4-hydroxyphenyl group, 2,4,6-trimethylphenyl group, 2,4,6-trimethoxyphenyl group, and 2,4,6-trifluorophenyl group.

[0017] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R1 is a phenyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 3-hydroxylphenyl group, a 2,6-dimethylphenyl group, a 2,6-dimethoxyphenyl group, R1 is a phenyl group, a 3-nitrophenyl group, a 2,6-difluorophenyl group, a 3-chloro-2-methylphenyl group, a 2,3-dichlorophenyl group, a 4-hydroxyphenyl group, a 2,4,6-trimethylphenyl group, a 2,4,6-trimethoxyphenyl group, or a 2,4,6-trifluorophenyl group, preferably a 4-fluorophenyl group, a 4-methylphenyl group, a 2,4,6-trimethylphenyl group, a 2,6-dimethylphenyl group, a 4-methoxyphenyl group, a 4-trifluoromethylphenyl group, or a 3-hydroxylphenyl group, more preferably a 2,6-dimethylphenyl group.

[0018] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R2 is C 1-8 Alkyl group, C 3-8 is a cycloalkyl group, 1-8 Alkyl group or C 3-8 The cycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 3-6 It is substituted with one or more of the following groups: cycloalkyl groups, halogens, hydroxyl groups, cyano groups, and amino groups.

[0019] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, R2 is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopropylmethylene group, a cyclobutylmethylene group, a cyclopentylmethylene group, an n-octyl group, or an n-heptyl group, preferably an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-octyl group, or an n-heptyl group, more preferably an n-butyl group.

[0020] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R3 is C 1-8 Alkyl group, C 3-7 X2 is a cycloalkyl group, an aromatic hydrocarbon group, a heteroaryl group, a 3- to 8-membered heterocycloalkyl group, or R3 and NR4 together form a nitrogen heterocycloalkyl group, 1-8 Alkyl group, C 3-7 The cycloalkyl group, aromatic hydrocarbon group, heteroaryl group, and 3- to 8-membered heterocycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 alkynyl groups, optionally substituted phenyl groups, which refer to unsubstituted phenyl groups, or phenyl groups, which are selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 It refers to being substituted by one or more groups of alkynyl groups.

[0021] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, R3 is a methyl group, an ethyl group, a propyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a methoxyethyl group, a methoxypropyl group, a phenyl group, a phenylethyl group, a benzyl group, a 4-fluorophenylmethyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group, a 2-bromophenyl group, a 2-hydroxyphenyl group, a 3-methylphenyl group, a 3-methoxyphenyl group, a 3-fluorophenyl group, a 3-chlorophenyl group, a 3-bromophenyl group, a 3-hydroxyphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-chlorophenyl group, a 4-bromophenyl group, a 4-hydroxyphenyl group, a 4-tri ... X2 is a fluoromethylphenyl group, a 2,4-dimethylphenyl group, a 2,4-dimethoxyphenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,4-dihydroxyphenyl group, a 2,6-dimethylphenyl group, a 2,6-dimethoxyphenyl group, a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a 2,6-dihydroxyphenyl group, a 2,4,6-trimethylphenyl group, a 2,4,6-trimethoxyphenyl group, or a 2,4,6-trifluorophenyl group; or X2 when R3 and NR4 are taken together to form piperidine or pyrrolidine, preferably a phenyl group, a 4-methylphenyl group, a 4-trifluoromethylphenyl group, a 2-hydroxylphenyl group, an ethyl group, a 2-methoxyethyl group, a 2-phenylethyl group, a 2,6-dimethylphenyl group, a cyclopropyl group, a benzyl group, or a 4-fluorophenylmethyl group; or X2 when R3 and NR4 are taken together to form piperidine or pyrrolidine.

[0022] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, m and n are each independently selected from 0, 1, and 2, and m and n may be the same or different.

[0023] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, L is C 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 cycloalkylene groups, 1-6 Alkylene group, C 3-6 The carbon atoms in the main chain of the cycloalkylene group are optionally substituted with 1 to 3 heteroatoms, the heteroatoms being selected from O, S, and N, and N can be substituted with R5, where R5 is hydrogen, deuterium, or C. 1-4 alkyl groups, 1-6 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 The cycloalkylene group may optionally be C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group, C 2-4 Alkenyl group, C 2-4 It is substituted by one or more groups of alkynyl groups.

[0024] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, L is -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -O-, -CHOCH2-, -OCH2-, -CHO-, -OC H2O-, -O(CH2)2O-, -O(CH2)3O-, -O(CH2)4O-, -CH2OCH2CH2-, -CH2CH2OCH2-, -OCH2O-CH2O-, -CH2CH2OC H2CH2-, -S-, -CH2SCH2-, -SCH2-, -CH2S-, -CH2S-CH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH=CH-, [ka] Selected from.

[0025] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, X1 and X2 are each independently O, NH, NCH3, NCH2CH3, N(CH2)2CH3, or when X2 is NR4, form piperidine together with R3.

[0026] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or its tautomer, geometric isomer, enantiomer, diastereomer, or mixture form thereof, or pharmaceutical salt thereof, when one of S1 and S2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CHOCH2CH2-, -CH2CH2OCH2-, or -CH2SCH2CH2-.

[0027] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, when one of Q1 and Q2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-.

[0028] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, Y - is a halogen anion, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, or citrate, preferably Cl - , Br - , I - , CH3COO - and more preferably Br - is.

[0029] In some embodiments of the present application, the compound of general formula (I) according to the present application, or a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R1 is selected from aromatic hydrocarbon groups, and the aromatic hydrocarbon groups are optionally selected from C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group, halogen, hydroxyl group, amino group, nitro group, ester group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-4 Haloalkyl group, C 1-6 substituted by one or more haloalkoxy groups; R2 is C 1-8 Alkyl group, C 3-8 cycloalkyl groups, 1-8 Alkyl group, C 3-8 The cycloalkyl group may optionally be C1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 3-6 substituted with one or more of a cycloalkyl group, a halogen, a hydroxyl group, a cyano group, or an amino group; R3 is C 1-8 Alkyl group, C 3-7 X2 is selected from a cycloalkyl group, an aromatic hydrocarbon group, a heteroaryl group, and a 3- to 8-membered heterocycloalkyl group, or R3 and NR4 together form a nitrogen heterocycloalkyl group, 1-8 Alkyl group, C 3-7 The cycloalkyl group, aromatic hydrocarbon group, heteroaryl group, and 3- to 8-membered heterocycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 substituted with one or more groups selected from the group consisting of alkynyl groups, optionally substituted phenyl groups, and optionally substituted phenyl groups, which refers to unsubstituted phenyl groups, or phenyl groups selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 alkylamino groups, X1 and X2 are each independently selected from O, S, and NR4, and R4 is hydrogen, deuterium, or C. 1-6 Alkyl group, C 1-6 Alkoxy C 1-6 Alkyl group, C 3-6cycloalkyl groups, m and n are each independently selected from integers of 0 to 4, and m and n may be the same or different; L is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 cycloalkylene groups, 1-4 Alkylene group, C 3-6 The carbon atoms in the main chain of the cycloalkylene group are optionally substituted with 1 to 2 heteroatoms, the heteroatoms being selected from O, S, and N, and N can be substituted with R5, where R5 is hydrogen, deuterium, or C. 1-4 alkyl groups, 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 The cycloalkylene group may optionally be C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group, C 2-4 Alkenyl group, C 2-4 substituted by one or more alkynyl groups; S1, S2, Q1 and Q2 each independently represent a single bond (i.e., the atoms to be linked are directly connected by a bond), C 1-6 alkylene groups, 1-6 A carbon atom in the main chain of the alkylene group is optionally replaced by one heteroatom, the heteroatom being selected from O or S, S1 and S2 are not simultaneously a single bond (i.e., the atoms connecting them are directly connected by a bond), and Q1 and Q2 are not simultaneously a single bond (i.e., the atoms connecting them are directly connected by a bond); Y -are halogen anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, and citrate.

[0030] In some embodiments of the present application, the compound of general formula (I) according to the present application, or a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R1 is selected from phenyl groups, which are optionally substituted with one or more of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, trifluoromethyl, methoxy, trifluoromethoxy, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, and ethyl ester groups; R2 is selected from a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, an isopentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopropylmethylene group, a cyclobutylmethylene group, a cyclopentylmethylene group, an n-octyl group, and an n-heptyl group; R3 is C 1-8 Alkyl group, C 3-7 X2 is selected from a cycloalkyl group, an aromatic hydrocarbon group, a heteroaryl group, and a 3- to 8-membered heterocycloalkyl group, or R3 and NR4 together form a nitrogen heterocycloalkyl group, 1-8 Alkyl group, C 3-7 The cycloalkyl group, aromatic hydrocarbon group, heteroaryl group, and 3- to 8-membered heterocycloalkyl group may optionally be C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4alkynyl groups, optionally substituted phenyl groups, which refer to unsubstituted phenyl groups, or phenyl groups, which are selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 alkynyl groups, X1 and X2 are each independently selected from O, S, and NR4, where 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, and cyclobutylmethylene, or NR4 together with R1 or R3 to which it is attached forms a nitrogen heterocycloalkyl group; m and n are each independently selected from integers of 0 to 2, and m and n may be the same or different; L is C 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 cycloalkylene groups, 1-4 Alkylene group, C 3-6 The carbon atoms in the main chain of the cycloalkylene group are optionally substituted with 1 to 2 heteroatoms, the heteroatoms being selected from O, S, and N, and N can be substituted with R5, where R5 is hydrogen, deuterium, or C. 1-4 alkyl groups, 1-4 Alkylene group, C 2-4 Alkenylene group, C 2-4 Alkynylene group, C 3-6 The cycloalkylene group may optionally be C 1-4 Alkyl group, C 1-4Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono C 1-4 Alkylamino group, diC 1-4 Alkylamino group, C 2-4 Alkenyl group, C 2-4 substituted by one or more alkynyl groups; When one of S1 and S2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is selected from -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CHOCH2CH2-, -CH2CH2OCH2-, and -CH2SCH2CH2-; When one of Q1 and Q2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is selected from -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CHOCH2CH2-, -CH2CH2OCH2-, and -CH2SCH2CH2-; Y is selected from a halogen anion, a sulfate group, an acetate group, a tartrate group, a p-toluenesulfonate group, a methanesulfonate group, and a citrate group.

[0031] In some embodiments of the present application, the compound of general formula (I) according to the present application, or a tautomer, a geometric isomer, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutical salt thereof, R1 is selected from the group consisting of a phenyl group, a 2-methylphenyl group, a 2-methoxyphenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 3-hydroxyphenyl group, a 4-trifluoromethylphenyl group, a 2,6-dimethylphenyl group, a 2,6-dimethoxyphenyl group, a 3-nitrophenyl group, a 2,6-difluorophenyl group, a 3-chloro-2-methylphenyl group, a 2,3-dichlorophenyl group, a 4-hydroxyphenyl group, a 2,4,6-trimethylphenyl group, a 2,4,6-trimethoxyphenyl group, and a 2,4,6-trifluorophenyl group; R2 is selected from the group consisting of a methyl group, an ethyl group, an n-propyl group, an n-butyl group, an n-pentyl group, an n-hexyl group, an n-octyl group, and an n-heptyl group; R3 is a methyl group, ethyl group, propyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, methoxyethyl group, methoxypropyl group, phenyl group, 2-methylphenyl group, phenylethyl group, benzyl group, 4-fluorophenylmethyl group, 2-methoxyphenyl group, 2-fluorophenyl group, 2-chlorophenyl group, 2-bromophenyl group, 2-hydroxyphenyl group, 3-methylphenyl group, 3-methoxyphenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 3-bromophenyl group, 3-hydroxyphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, X2 is selected from the group consisting of a 4-bromophenyl group, a 4-hydroxyphenyl group, a 4-trifluoromethylphenyl group, a 2,4-dimethylphenyl group, a 2,4-dimethoxyphenyl group, a 2,4-difluorophenyl group, a 2,4-dichlorophenyl group, a 2,4-dihydroxyphenyl group, a 2,6-dimethylphenyl group, a 2,6-dimethoxyphenyl group, a 2,6-difluorophenyl group, a 2,6-dichlorophenyl group, a 2,6-dihydroxyphenyl group, a 2,4,6-trimethylphenyl group, a 2,4,6-trimethoxyphenyl group, and a 2,4,6-trifluorophenyl group, or X2, when R3 and NR4 are taken together, forms piperidine or pyrrolidine; X1 and X2 are each independently selected from O, NH, NCH3, NCH2CH3, and N(CH2)2CH3; m and n are each independently selected from integers of 0 to 2, and m and n may be the same or different; L is -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-, -CH2O CH2CH2-, -CH2CH2OCH2-, -OCH2OCH2O-, -CH2CH2OCH2CH2-, -S-, -CH2SCH2-, -SCH2-, -CH2S-, -CH2SCH2CH2-, -CH2CH2SCH2-, -CH2CH2SCH2CH2-, -CH=CH-, [ka] Selected from When one of S1 and S2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -CHOCH2CH2-, -CH2CH2OCH2-, or -CH2SCH2CH2-; When one of Q1 and Q2 is a single bond (i.e., the connecting atoms are directly connected by a bond), the other is -(CH2)3-, -(CH2)4-, -(CH2)5-, or -(CH2)6-; Y - are halogen anions, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate, and citrate.

[0032] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, the compound of general formula (I) includes, but is not limited to, the following compounds: [ka] TIFF0007787912000007.tif230166TIFF0007787912000008.tif249161

[0033] In some embodiments of the present application, in the compound of general formula (I) according to the present application, or in the form of a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, the compound of general formula (I) includes, but is not limited to, the following compounds: [ka]

[0034] In a second aspect of the present application, there is provided a method for preparing a compound of general formula (I) according to the first aspect of the present application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, said method comprising: [ka] reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I), In formula (II), Z is an electron-withdrawing leaving group such as bromine, chlorine or sulfonate ester, and the definitions of the groups in formula (II) and formula (III) are the same as in formula (I).

[0035] In the preparation process according to the present application, the compound of formula (II) may be prepared by the following method: [ka] The definitions of each group in formula (II-1) and formula (II-2) are the same as above.

[0036] In a third aspect of the present application, there is provided a pharmaceutical composition comprising a compound of general formula (I) as set forth in the first aspect of the present application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

[0037] In a fourth aspect of the present application, there is provided a compound of general formula (I) as described herein, its tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, for use in medicine.

[0038] In some embodiments of the present application, the compounds of general formula (I) according to the present application, or their tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are used for anesthetic or analgesic purposes.

[0039] In some embodiments of the present application, the compounds of general formula (I) according to the present application, or their tautomers, geometric isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutical salts thereof, are used for anesthetic or analgesic purposes.

[0040] In a fifth aspect of the present application, there is provided use of a compound of general formula (I) according to the first aspect of the present application, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, or a pharmaceutical composition thereof, in the manufacture of an anesthetic or analgesic medicament.

[0041] In the fifth aspect of the present application, the use is in the manufacture of a local anesthetic or analgesic medicament.

[0042] In the use according to the fifth or fourth aspect of the present application, the anesthesia is conduction anesthesia, topical anesthesia or infiltration anesthesia, and the pain suitable for analgesia is chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

[0043] In the use according to the fifth or fourth aspect of the present application, administration for anesthesia or analgesia is local administration by a transmucosal route such as transdermal, subcutaneous, intradermal, intramuscular, perineural, intrapulpal, intraspinal, epidural, intravenous or ophthalmic.

[0044] In a sixth aspect, the present application provides a method of anesthesia or analgesia, the method comprising administering to a patient in need thereof a compound of general formula (I) as defined herein, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, or a pharmaceutical composition thereof.

[0045] In the method according to the sixth aspect of the present application, the anesthesia is local anesthesia, preferably conduction anesthesia, topical anesthesia or infiltration anesthesia, and the pain suitable for analgesia is chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

[0046] In the method according to the sixth aspect of the present application, the administration is local administration by a transmucosal route such as transdermal, subcutaneous, intradermal, intramuscular, perineural, intrapulpal, intraspinal, epidural, intravenous or ophthalmic.

[0047] The definitions of terms used in the description of this application and in the claims are as follows: For a particular term, if the meaning defined in this application does not coincide with the meaning commonly understood by a person skilled in the art, the meaning defined in this application shall prevail, and if not defined in this application, the meaning commonly understood by a person skilled in the art shall prevail.

[0048] The compound names and their structural formulas in this application have a corresponding relationship, and if the compound names and structural formulas are not consistent, they shall be deduced based on the structural formulas or in combination with the knowledge of a person skilled in the art according to the specific circumstances of this application.

[0049] As used herein, the term "alkyl group" refers to a linear or branched monovalent saturated hydrocarbon group.

[0050] The term "C" 1-8"Alkyl group" means a straight or branched chain alkyl group having 1 to 8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and is typically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a neopentyl group, a pentyl group or a hexyl group, a 1-ethyl-2-methylpropyl group, a 1,1,2-trimethylpropyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, groups, 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. Correspondingly, the term "C 1-4 The alkyl group is 1, 2, 3 or 4 It means a straight or branched alkyl group having carbon atoms, i.e., a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group. In this application, the alkyl group is preferably a C 1-6 alkyl group, more preferably C 1-4 It is an alkyl group.

[0051] The term "alkylene group" as used herein refers to a saturated, straight-chain or branched-chain aliphatic hydrocarbon group, which has two residues derived by removing two hydrogen atoms from the same carbon atom or two different carbon atoms of a parent alkane, and is a straight-chain or branched-chain group containing 1 to 16 carbon atoms, with alkylene groups containing 1 to 6 carbon atoms being preferred. Non-limiting examples of "alkylene group" include -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2)5-, -(CH2)6-, -O -, -CH2O CH2-, -O CH2-, - CH2O -, - O CH2O -, - O (CH2)2O -, - O (CH2)3O -, - O (CH2)4O -, -CH2O CH2CH2-, -CH2CH2O CH2-, - O CH2O CH2O -, -CH2CH2O CH2CH2-, -S -, -CH2S CH2-, -S CH2-, - CH2S -, Including, but not limited to, -CH2S CH2CH2-, -CH2CH2S CH2-, -CH2CH2S CH2CH2-.

[0052] The term "cycloalkylene group" as used herein refers to a group obtained by formally removing two hydrogen atoms from a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon, and contains 3 to 8 carbon atoms. Non-limiting examples of "cycloalkylene group" include: [ka] Including, but not limited to:

[0053] The term "alkenylene group" as used herein refers to a group obtained by formally removing two hydrogen atoms from an alkene. Non-limiting examples of "alkenylene groups" include -CH=CH-, [ka] Including, but not limited to:

[0054] The term "alkynylene group" as used herein refers to a group formed by formally removing two hydrogen atoms from an alkyne; tree Non-limiting examples of the "nylene group" include: [ka] Including, but not limited to:

[0055] As used herein, the term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), where alkyl is defined above. Non-limiting examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy.

[0056] As used herein, the term "alkoxyalkyl group" refers to an alkyl group as defined above substituted with one or more alkoxy groups as defined above. Preferred alkoxyalkyl groups are alkoxy groups -C 1-3 Non-limiting examples of "alkoxyalkyl groups" include, but are not limited to, methoxymethyl groups, methoxyethyl groups, ethoxyethyl groups, and the like.

[0057] The term "C" as used in this application 2-4 The term "alkenyl group" refers to an alkenyl group having 2 to 4 carbon atoms, and the alkenyl group has 1, 2, or 3 carbon-carbon double bonds, and if the alkenyl group has one or more carbon-carbon double bonds, the carbon-carbon double bonds may or may not be conjugated. 2-4 Non-limiting examples of "alkenyl groups" include, but are not limited to, vinyl and vinylidene groups.

[0058] The term "C" as used in this application 2-6 The term "alkynyl group" refers to an alkynyl group having 2 to 6 carbon atoms, and the alkynyl group has 1, 2, or 3 carbon-carbon triple bonds, and if the alkynyl group has one or more carbon-carbon triple bonds, the carbon-carbon triple bonds may or may not be conjugated. 2-6 Non-limiting examples of an "alkynyl group" include, but are not limited to, an ethynyl group.

[0059] The term "cycloalkyl group" as used herein refers to a saturated carbocyclic group of 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. The cycloalkyl group may be a monocyclic or polycyclic fused system and may be fused to an aromatic ring. Non-limiting examples of "cycloalkyl group" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0060] As used herein, the term "halogen" refers to fluorine, chlorine, bromine, and iodine atoms.

[0061] The term "aromatic hydrocarbon group" as used herein refers to a monocyclic or bicyclic aromatic system containing at least one unsaturated aromatic ring, with aryl groups having 6 to 10 carbon atoms, i.e., 6, 7, 8, 9, or 10 carbon atoms, being preferred. Non-limiting examples of "aromatic hydrocarbon groups" include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and indenyl groups.

[0062] The term "heteroaryl group" as used herein refers to a monocyclic or bicyclic unsaturated aromatic ring system optionally substituted with at least one heteroatom independently selected from N, O, or S, with aromatic heterocyclic groups having 5 to 10 atoms, i.e., 5, 6, 7, 8, 9, or 10 atoms, being preferred. Non-limiting examples of "heteroaryl groups" include, but are not limited to, thienyl, 2-pyridinyl, 3-pyridinyl, thiazolyl, isothiazolyl, furanyl, pyrrolyl, triazolyl, imidazolyl, and the like.

[0063] The term "heterocycloalkyl group" as used herein refers to a monocyclic or bicyclic saturated ring system optionally substituted with at least one and at most four heteroatoms independently selected from N, O, or S, with heterocyclic groups having 4 to 10 atoms, i.e., 4, 5, 6, 7, 8, 9, or 10 atoms, being preferred, provided that the heterocyclic group does not contain two adjacent O or S atoms in any ring. Non-limiting examples of "heterocycloalkyl group" include, but are not limited to, pyrrolidinyl, piperidinyl, morpholino, or piperazinyl groups.

[0064] As used herein, the term "haloalkyl group" refers to an alkyl group substituted with one or more halogens, where alkyl group is defined above.

[0065] As used herein, the term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is defined above.

[0066] As used herein, the term "hydroxyl group" refers to --OH. As used herein, the term "amino group" refers to -NH2. As used herein, the term "cyano" refers to -CN. As used herein, the term "nitro group" refers to -NO2. The term "ester group" as used herein refers to an -C(O)O (alkyl group) or -C(O)O (cycloalkyl group), where alkyl and cycloalkyl groups are defined above.

[0067] "Optionally" or "optionally" means that the event or circumstance described below does not necessarily occur, and the statement includes cases where the event or circumstance occurs or does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group is not necessarily present, and the statement 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.

[0068] The term "mixtures thereof" as used herein 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 or more of tautomers, geometric isomers, enantiomers, and diastereomers.

[0069] With respect to the term "long-acting" as used herein, a single agent that provides a longer duration of anesthesia than a standard concentration of a single agent, levobupivacaine hydrochloride, is considered long-acting.

[0070] The present application provides a novel structural type of quaternary ammonium salt compound, which has been experimentally proven to have long-lasting local anesthetic effect after a single administration, without causing motor nerve damage, and has the effects of excellent safety, rapid onset, and high selectivity. The present application provides a long-acting local anesthetic with a novel structure, which overcomes the short duration, tissue and neurotoxicity, and inseparable sensory and motor blockade of conventional clinical local anesthetics, and provides a new medical solution for anesthesia and analgesic treatment.

[0071] Other features and advantages of the present application will be set forth in the description which follows, and in part will be obvious from the description, or may be learned by the practice of the present application. Other advantages of the present application will be realized and obtained by the solutions described in the description.

[0072] Example In order to clarify the purpose, technical solution and advantages of the present application, the following examples are provided in detail. The following examples are for illustrative purposes only and are not intended to limit the scope of the present application. Unless specific conditions are specified in the examples, the experiments are carried out under standard conditions or manufacturer's recommended conditions. Unless the manufacturer of the reagents or equipment used is specified, they are commercially available standard products.

[0073] TLC stands for thin layer chromatography. HPLC stands for High Performance Liquid Chromatography. MS stands for mass spectrum, 1 H NMR stands for Nuclear Magnetic Resonance Spectroscopy, 13 C NMR is carbon-13 nuclear magnetic resonance spectroscopy, TBTU is O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate; NMM is N-methylmorpholine HATU is 2-(7-azabenzotriazo)-N,N,N',N'-tetramethyluronium hexafluorophosphate; V / m is the volume to mass ratio, and the previous equivalent (eq) indicates the ratio of volume to mass. m / m is the mass-to-mass ratio, indicating that the previous equivalent (eq) is the ratio of mass to mass.

[0074] The HPLC used in this experiment was a Waters 2545-2767-2489 high performance liquid chromatograph, the column was an Epic Polar 5u 120A 25cm*30mm, the detection wavelength was 210nm, and the elution was with an acetonitrile / 0.05% TFA / H2O (30% / 70%) gradient, with a flow rate of 15ml / min. NMR was measured using a Bruker Ultrashied™ 400 MHz Plus nuclear magnetic resonance spectrometer (TMS was used as the internal standard, and CDCl 3 or CD 3 OD was used as the solvent), and LC-MS was measured using a Waters Qda MS KAD3195 portable mask spectrometer.

[0075] Example 1 Synthesis of compound 1b [ka] Bupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed and 1,5-dibromopentane (2.0 eq of 1a, V / m, 10 mL) was added. The temperature was raised to 75 °C under stirring and the temperature was increased until the reaction was complete. LC The compound was detected using a silica gel column chromatography eluent: CH₂Cl₂:MeOH = 20:1. The eluate was collected and concentrated by rotary evaporation to give compound 1b as an orange oily liquid (4.5 g, 59.1% yield, HPLC > 90%). MS m / z (ESI) = 437.22 [M]. + ,439.22[M+2H] + .

[0076] Synthesis of Compound 1 [ka] Compound 1b (1.14 mmol, 1.0 eq, 0.60 g) was weighed and dissolved in acetonitrile (10 eq of compound 1b, V / m, 5.0 mL). Analytical sodium bicarbonate (1 eq of compound 1b, m / m, 0.60 g) was added. N-(2',6'-xylyl)-2-piperidinecarboxamide 1c (1.34 mmol, 1.2 eq, 0.31 g) was added. The temperature was raised to 75 °C and the reaction was continued until completion. The reaction was monitored by HPLC. The reaction mixture was filtered and washed with acetonitrile (30 eq of 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 1 (0.19 g, 24.9% yield, 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). MS m / z(ESI)=589.37[M] + .

[0077] Example 2 Synthesis of compound 2c [ka] N-Boc-2-pipecolic acid 2a (4.37 mmol, 1.0 eq, 1.0 g) was dissolved in analytical reagent dichloromethane (25 eq of 2a, V / m, 25 mL) with stirring. The temperature was reduced to 0 °C in an ice-water bath, and then O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate was added. Boric acid To the reaction mixture was added 2a (TBTU, 5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for approximately 30 min, aniline (5.24 mmol, 1.2 eq, 0.48 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2.0 eq, 0.96 mL) were added. After stirring at 0 °C for approximately 1 h, the mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of 2a, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three times). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The mixture was purified by column chromatography (eluent: CH₂Cl₂:CH₃OH = 40:1). The collected eluate was distilled under reduced pressure to give compound 2c (1.21 g, 91.0% yield, HPLC > 95%) as a pale yellow solid. MS m / z (ESI) = 305.18 [M+H]. + .

[0078] Synthesis of compound 2d [ka] Compound 2c (3.28 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical dichloromethane (5 eq of 2c, V / m, 5 mL). Trifluoroacetic acid (7.0 eq of compound 2c, V / m, 7 mL) was dissolved in analytical dichloromethane (10 eq of 2c, V / m, 10 mL) and added dropwise. Stir for approximately 2 hours and then monitor by HPLC until the reaction was complete. The reaction mixture was vacuum distilled, and analytical dichloromethane was added (10 eq of compound 2c, V / m, 10 mL, in three portions). Analytical methanol was added (10 eq of compound 2c, V / m, 10 mL, in three portions) to obtain a white solid, compound 2d (0.62 g, 92.5% yield, HPLC >90%). MS m / z(ESI)=205.13[M+H] + .

[0079] Synthesis of compound 2 [ka] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 1b, V / m, 5.0 mL). The mixture was stirred to dissolve, and analytical reagent sodium bicarbonate (1 eq of compound 1b, m / m, 0.50 g) was added. Compound 2d (1.34 mmol, 1.2 eq, 0.27 g) was added. The temperature was raised to 75 °C and the reaction was continued until completion. The reaction mixture was filtered and the filter cake was washed with acetonitrile (30 eq of compound 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 2 (0.13 g, 17.8% yield, HPLC >98%). 1 H NMR(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] + .

[0080] Example 3 Synthesis of compound 3b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was dissolved in analytical reagent dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) and stirred. The temperature was reduced to 0°C in an ice-water bath, and then O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate was added. Boric acid To the reaction mixture was added TBTU (5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for approximately 30 min, 4-fluoroaniline (5.24 mmol, 1.2 eq, 0.50 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. After stirring at 0 °C for approximately 1 h, the mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three times). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. Purification by column chromatography (eluent: CH2Cl2:CH3OH = 40:1) gave a pale yellow solid (1.33 g, yield 94.3%, HPLC > 95%). MS m / z = 323.17 [M+H]. + .

[0081] Synthesis of compound 3c [ka] Compound 3b (3.10 mmol, 1 eq, 1.00 g) was weighed and added to analytical reagent dichloromethane (5 eq of compound 3b, V / m, 5 mL) and stirred to dissolve. Trifluoroacetic acid (7.0 eq of compound 3b, V / m, 7 mL) was dissolved in analytical reagent dichloromethane (10 eq of compound 3b, V / m, 10 mL) and added dropwise. Stir for approximately 2 h, then detect the reaction by HPLC until complete. The reaction mixture was vacuum distilled, and analytical reagent dichloromethane was added and vacuum distilled (10 eq of compound 3b, V / m, 10 mL, in three portions). Analytical reagent methanol was added and vacuum distilled (10 eq of compound 3b, V / m, 10 mL, in three portions) to give a white solid (0.64 g, 92.75% yield, HPLC >90%). MS m / z = 223.12 [M+H] + .

[0082] Synthesis of compound 3 [ka] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 1b, V / m, 5.0 mL). Stir to dissolve, then analytical reagent sodium bicarbonate (1 eq of compound 1b, m / m, 0.60 g) was added. 3c (1.34 mmol, 1.2 eq, 0.30 g) was added, and the reaction temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 3 (0.15 g, 19.9% ​​yield, 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] + .

[0083] Example 4 Synthesis of compound 4b [ka] N-Boc-2-pipecolic acid 2a (4.37 mmol, 1.0 eq, 1 g) was dissolved in analytical reagent dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) and stirred. The temperature was reduced to 0 °C in an ice-water bath, and then O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate was added. Boric acid To the reaction mixture was added TBTU (5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for approximately 30 min, 4-methylaniline (5.24 mmol, 1.2 eq, 0.58 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. After stirring at 0 °C for approximately 1 h, the mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three times). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The mixture was purified by column chromatography (eluent: CH₂Cl₂:CH₃OH = 40:1). The collected eluate was distilled under reduced pressure to give compound 4b (1.25 g, 91.9% yield, HPLC > 95%) as a pale yellow solid. MS m / z (ESI) = 319.19 [M+H]. + .

[0084] Synthesis of compound 4c [ka] Compound 4b (3.14 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical dichloromethane (5 eq of compound 4b, V / m, 5 mL). Trifluoroacetic acid (7.0 eq of compound 4b, V / m, 7 mL) was dissolved in analytical dichloromethane (10 eq of 4b, V / m, 10 mL) and added dropwise. Stir for approximately 2 hours and then monitor by HPLC until the reaction was complete. The reaction mixture was vacuum distilled, followed by the addition of analytical dichloromethane (10 eq of compound 4b, V / m, 10 mL, in three portions), and then the addition of analytical methanol (10 eq of 4b, V / m, 10 mL, in three portions) to obtain a white solid, compound 4c (0.63 g, 92.6% yield, HPLC >90%). MS m / z(ESI)=219.14[M+H] + .

[0085] Synthesis of compound 4 [ka] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 1b, V / m, 5.0 mL), stirred to dissolve, and then analytical reagent sodium bicarbonate (1 eq of compound 1b, m / m, 0.50 g) was added. 4c (1.34 mmol, 1.2 eq, 0.29 g) was added, and the reaction temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 4 (0.15 g, 20.0% yield, 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] + .

[0086] Example 5 Synthesis of compound 5b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was weighed and dissolved in analytical reagent dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) with stirring. The temperature was reduced to 0°C in an ice-water bath, and then O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate was added. Boric acid To the reaction mixture was added TBTU (5.24 mmol, 1.2 eq, 1.68 g). After stirring at 0 °C for approximately 30 min, cyclopropylamine (5.24 mmol, 1.2 eq, 0.36 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. After stirring at 0 °C for approximately 1 h, the mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three times). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The mixture was purified by column chromatography (eluent: CH2Cl2:CH3OH = 40:1). The eluate was collected and distilled under reduced pressure to give compound 5b as a pale yellow solid (1.03 g, yield 88.0%, HPLC > 95%). MS m / z (ESI) = 269.18 [M+H]. + .

[0087] Synthesis of 5c [ka] Compound 5b (3.72 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical dichloromethane (5 eq of compound 5b, V / m, 5 mL). Trifluoroacetic acid (7.0 eq of compound 5b, V / m, 7 mL) was dissolved in analytical dichloromethane (10 eq of compound 5b, V / m, 10 mL) and added dropwise. Stir for approximately 2 hours and then monitor by HPLC until the reaction was complete. The reaction mixture was vacuum distilled, and analytical dichloromethane was added (10 eq of compound 5b, V / m, 10 mL, in three portions). Analytical methanol was added (10 eq of compound 5b, V / m, 10 mL, in three portions) to obtain a white solid, compound 5c (0.59 g, 93.7% yield, HPLC >90%). MS m / z(ESI)=169.13[M+H] + .

[0088] Synthesis of compound 5 [ka] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 1b, V / m, 5.0 mL). Stir to dissolve, then analytical reagent sodium bicarbonate (1 eq of compound 1b, m / m, 0.60 g) was added. 5c (1.34 mmol, 1.2 eq, 0.22 g) was added, and the reaction temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of compound 1b, V / m, 15 mL, in three portions). The filtrate was collected and purified to give compound 5 (0.18 g, 26.1% yield, HPLC >98%) as a white powdery solid. 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] +

[0089] Example 6 Synthesis of compound 6b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was dissolved in analytical reagent dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) and stirred. The temperature was reduced to 0°C in an ice-water bath, and then O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate was added. Boric acid To the reaction mixture, TBTU (5.24 mmol, 1.2 eq, 1.68 g) was added. After stirring at 0 °C for approximately 30 min, cyclohexylamine (5.24 mmol, 1.2 eq, 0.60 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. After stirring at 0 °C for approximately 1 h, the mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was distilled under reduced pressure to obtain a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three times). The organic phase was collected and distilled under reduced pressure to obtain a yellow oily viscous liquid. The resulting mixture was purified by column chromatography using a 40:1 mixture of CH₂Cl₂:CH₃OH (eluent). The collected eluate was distilled under reduced pressure to give compound 6b (1.27 g, 93.4% yield, HPLC >95%) as a pale yellow solid. MS m / z (ESI) = 311.23 [M+H] + .

[0090] Synthesis of compound 6c [ka] Compound 6b (3.22 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical dichloromethane (5 eq of 6b, V / m, 5 mL). Trifluoroacetic acid (7.0 eq of 6b, V / m, 7 mL) was dissolved in analytical dichloromethane (10 eq of 6b, V / m, 10 mL) and added dropwise. Stir for approximately 2 hours and then monitor by HPLC until the reaction was complete. The reaction mixture was vacuum distilled, and analytical dichloromethane was added (10 eq of 6b, V / m, 10 mL, in three portions). Analytical methanol was added (10 eq of 6b, V / m, 10 mL, in three portions) to obtain a white solid, compound 6c (0.61 g, 91.0% yield, HPLC >90%). MS m / z(ESI)=211.17[M+H] + .

[0091] Synthesis of compound 6 [ka] Compound 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 1b, V / m, 5.0 mL). The mixture was stirred to dissolve, and analytical reagent sodium bicarbonate (1 eq of compound 1b, m / m, 0.60 g) was added. Compound 6c (1.34 mmol, 1.2 eq, 0.28 g) was added. The temperature was raised to 75 °C and the reaction was continued until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 6 (0.20 g, 27.1% yield, 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] + .

[0092] Example 7 Synthesis of compound 7a [ka] Weigh out bupivacaine (17.36 mmol, 1.0 eq, 5 g) and add 1,4-dibromobutane (2.0 eq of bupivacaine, V / m, 10 mL). Stir and raise the temperature to 75 °C until the reaction is complete. LC The compound was detected using a silica gel column chromatography eluent: CH₂Cl₂:MeOH = 20:1. The eluate was collected and concentrated by rotary evaporation to give compound 7a as an orange oily liquid (4.3 g, 49.1% yield, HPLC > 95%). MS m / z (ESI) = 423.20 [M]. + ,425.20[M+2H] + .

[0093] Synthesis of compound 7 [ka] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of 7a, V / m, 5.0 mL), stirred to dissolve, and analytical reagent sodium bicarbonate (1 eq of 7a, m / m, 0.60 g) was added. Compound 3c (1.41 mmol, 1.2 eq, 0.32 g) was added, and the temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 7a, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 7 (0.13 g, 17.1% yield, HPLC >98%). 1H 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] + .

[0094] Example 8 Synthesis of compound 8 [ka] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of 7a, V / m, 6.0 mL), stirred to dissolve, and analytical reagent sodium bicarbonate (1 eq of 7a, m / m, 0.60 g) and 2d (1.41 mmol, 1.2 eq, 0.29 g) were added. The temperature was raised to 75 °C and the reaction was continued until completion, followed by HPLC detection. The reaction mixture was filtered and the filter cake was washed with acetonitrile (30 eq of 7a, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 8 (0.16 g, 21.6% yield, 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] + .

[0095] Example 9 Synthesis of compound 9 [ka] Compound 7a (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical reagent acetonitrile (10 eq of 7a, V / m, 6.0 mL). Analytical reagent sodium bicarbonate (1 eq of 7a, m / m, 0.60 g) was added, followed by compound 6c (1.41 mmol, 1.2 eq, 0.30 g). The temperature was raised to 75 °C and the reaction was continued until completion, followed by HPLC analysis. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 7a, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 9 (0.18 g, 24.1% yield, 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] + .

[0096] Example 10 Synthesis of compound 10b [ka] Weigh out ropivacaine (18.22 mmol, 1.0 eq, 5 g) and add 1,5-dibromopentane (2.0 eq of ropivacaine, V / m, 10 mL). Stir and raise the temperature to 75 °C until the reaction is complete. LC The compound was detected using a silica gel column chromatography eluent: CH₂Cl₂:MeOH = 20:1. The eluate was collected and concentrated by rotary evaporation to give compound 10b as an orange oily liquid (5.1 g, 55.5% yield, HPLC > 90%). MS m / z (ESI) = 423.20 [M] + ,425.20[M+H] + .

[0097] Synthesis of compound 10 [ka] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical reagent acetonitrile (10 eq of 10b, V / m, 6.0 mL). Analytical reagent 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 temperature was raised to 75 °C and the reaction was continued until completion, followed by HPLC analysis. The reaction mixture was filtered and washed with acetonitrile (30 eq of 10b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 10 (0.21 g, 27.14% yield, 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). MS m / z(ESI) =575.45[M] + .

[0098] Example 11 Synthesis of compound 11 [ka] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 10b, V / m, 6.0 mL), stirred to dissolve, and then analytical reagent sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g) was added. Compound 6c (1.41 mmol, 1.2 eq, 0.30 g) was added, and the temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 10b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 11 (0.11 g, 14.7% yield, HPLC >98%). 1 H NMR(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] + .

[0099] Example 12 Synthesis of compound 12 [ka] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 10b, V / m, 6.0 mL), stirred to dissolve, and then analytical reagent sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g) was added. Compound 4c (1.41 mmol, 1.2 eq, 0.31 g) was added, and the reaction temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 10b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 12 (0.15 g, 19.8% yield, HPLC >98%). 1HNMR (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] + .

[0100] Example 13 Synthesis of compound 13 [ka] Compound 10b (1.18 mmol, 1 eq, 0.60 g) was weighed and added to analytical reagent acetonitrile (10 eq of compound 10b, V / m, 6.0 mL), stirred to dissolve, and then analytical reagent sodium bicarbonate (1 eq of compound 10b, m / m, 0.60 g) was added. Compound 2d (1.41 mmol, 1.2 eq, 0.29 g) was added, and the reaction temperature was raised to 75 °C. The reaction was monitored by HPLC until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (30 eq of 10b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 13 (0.18 g, 24.3% yield, 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] + .

[0101] Example 14 Synthesis of 8b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was weighed and dissolved in analytical dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) with stirring. The temperature was reduced to 0 °C in an ice-water bath, and O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 5.24 mmol, 1.2 eq, 1.68 g) was added. After stirring at 0 °C for approximately 30 min, diethylamine (5.24 mmol, 1.2 eq, 0.54 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. The mixture was stirred at 0 °C for approximately 1 h, and then the mixture was stirred at room temperature until the reaction was complete. Detected by HPLC. The reaction mixture was evaporated under reduced pressure to give a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three separate washes). The collected organic phase was evaporated under reduced pressure to give a yellow oily viscous liquid. The product was purified by column chromatography using a 40:1 CHCl:CHOH eluent. The collected eluate was evaporated under reduced pressure to give a pale yellow solid, 8b (1.12 g, 90.3% yield, HPLC >95%). MS m / z (ESI) = 285.21 [M+H]. + .

[0102] Synthesis of 8c [ka] 8b (3.51 mmol, 1 eq, 1.00 g) was weighed and dissolved in analytical dichloromethane (5 eq of 8b, V / m, 5 mL). Trifluoroacetic acid (7.0 eq of 8b, V / m, 7 mL) was dissolved in analytical dichloromethane (10 eq of 8b, V / m, 10 mL) and added dropwise. Stir for approximately 2 hours, then detect by HPLC until the reaction was complete. The reaction mixture was vacuum distilled, followed by the addition of analytical dichloromethane (10 eq of 8b, V / m, 10 mL, in three portions), and the addition of analytical methanol (10 eq of 8b, V / m, 10 mL, in three portions) to give a white solid, 8c (0.61 g, 93.8% yield, HPLC >90%). MS m / z (ESI) = 185.16 [M+H]. + .

[0103] Synthesis of compound 14 [ka] Weigh 1b (1.14 mmol, 1 eq, 0.60 g) and add analytical reagent acetonitrile (10 eq of 1b, V / m, 6.0 mL). Stir to dissolve. Add analytical reagent sodium bicarbonate (1 eq of 1b, m / m, 0.60 g). Add 8c (1.37 mmol, 1.2 eq, 0.25 g). Raise the temperature to 75 °C and react until complete. Monitor by HPLC. The reaction mixture was filtered and washed with acetonitrile (30 eq of 1b, V / m, 15 mL, in three portions). The filtrate was collected and used as a preparative white powder to obtain compound 14 (0.15 g, 21.1% yield, 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]+.

[0104] Example 15 Synthesis of 9b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was weighed and dissolved in analytical dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) with stirring. The temperature was reduced to 0 °C in an ice-water bath, and O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 6.55 mmol, 1.5 eq, 2.10 g) was added. After stirring at 0 °C for approximately 30 min, 70% aqueous ethylamine (13.10 mmol, 3 eq, 1.06 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. The mixture was stirred at 0 °C for approximately 1 h, and then the reaction was monitored by HPLC until completion. The reaction mixture was evaporated under reduced pressure to give a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL, three separate washes). The collected organic phase was evaporated under reduced pressure to give a yellow oily viscous liquid. The product was purified by column chromatography using a 40:1 CHCl:CHOH eluent. The collected eluate was evaporated under reduced pressure to give 9b (1.03 g, 92.0% yield, HPLC >95%) as a white solid. MS m / z (ESI) = 257.18 [M+H]. + .

[0105] Synthesis of 9c [ka] Weigh 9b (3.90 mmol, 1 eq, 1.00 g) and add analytical reagent dichloromethane (5 eq of 9b, V / m, mL / g, 5 mL) and stir to dissolve. Trifluoroacetic acid (7.0 eq of 9b, V / m, mL / g, 7 mL) dissolved in analytical reagent dichloromethane (10 eq of 9b, V / m, mL / g, 10 mL) was added dropwise and stirred for approximately 2 hours, followed by HPLC analysis until the reaction was complete. The reaction mixture was vacuum distilled, followed by vacuum distillation of analytical reagent dichloromethane (10 eq of 9b, V / m, mL / g, 10 mL, three portions), followed by vacuum distillation of analytical reagent methanol (10 eq of 9b, V / m, mL / g, 10 mL, three portions) to give a white solid, 9c (0.57 g, 95.0% yield, HPLC >90%). MS m / z(ESI)=157.13[M+H] + .

[0106] Synthesis of compound 15 [ka] Weigh 1b (1.14 mmol, 1 eq, 0.60 g) and add analytical reagent acetonitrile (10 eq of 1b, V / m, 6.0 mL). Stir to dissolve. Add analytical reagent sodium bicarbonate (1 eq of 1b, m / m, 0.60 g). Add 9c (1.34 mmol, 1.2 eq, 0.21 g). Raise the temperature to 75 °C and react until complete. Monitor by HPLC. The reaction mixture was filtered, washed with acetonitrile (15 mL, 3 portions), and the filtrate was collected to obtain compound 15 (0.11 g, 16.4% yield, HPLC >98%) as a white powdery solid. 1H 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] + .

[0107] Example 16 Synthesis of 11b [ka] N-Boc-2-pipecolic acid (4.37 mmol, 1.0 eq, 1 g) was dissolved in analytical dichloromethane (25 eq of N-Boc-2-pipecolic acid, V / m, 25 mL) and stirred. The temperature was reduced to 0 °C in an ice-water bath, and O-benzotriazolyl-N,N,N',N'-tetramethyluronium tetrafluoroborate (TBTU, 5.24 mmol, 1.2 eq, 1.68 g) was added. After stirring at 0 °C for approximately 30 minutes, 2-methoxyethylamine (5.24 mmol, 1.2 eq, 0.46 mL) and N-methylmorpholine (NMM, 8.74 mmol, 2 eq, 0.96 mL) were added. The mixture was stirred at room temperature for approximately 1 hour, and then the reaction was monitored by HPLC until completion. The reaction mixture was evaporated under reduced pressure to give a yellow oily liquid. This was dissolved in a 20:1 mixture of dichloromethane and methanol (70 eq of N-Boc-2-pipecolic acid, V / m, mL / g, 70 mL). The organic phase was washed with 5% aqueous NaHSO (70 eq of N-Boc-2-pipecolic acid, V / m, 70 mL, three separate washes). The collected organic phase was evaporated under reduced pressure to give a yellow oily viscous liquid. The product was purified by column chromatography using a 40:1 CHCl:CHOH eluent. The collected eluate was evaporated under reduced pressure to give a pale yellow solid, 11b (1.11 g, 88.8% yield, HPLC >95%). MS m / z (ESI) = 287.19 [M+H]. +.

[0108] Synthesis of 11c [ka] Weigh 11b (3.49 mmol, 1 eq, 1.00 g) and add analytical reagent dichloromethane (5 eq of 11b, V / m, 5 mL) and stir to dissolve. Trifluoroacetic acid (7.0 eq of 11b, V / m, 7 mL) dissolved in analytical reagent dichloromethane (10 eq of 11b, V / m, 10 mL) was added dropwise and stirred for approximately 2 hours, after which the reaction was monitored by HPLC until completion. The reaction mixture was evaporated under reduced pressure, and analytical reagent dichloromethane was added and evaporated under reduced pressure (10 mL, 3 portions). Analytical reagent methanol was added and evaporated under reduced pressure to give a white solid 11c (0.60 g, 92.3% yield, HPLC >90%). MS m / z (ESI) = 187.14 [M+H]. + .

[0109] Synthesis of compound 16 [ka] 1b (1.14 mmol, 1 eq, 0.60 g) was weighed and dissolved in analytical reagent acetonitrile (10 eq of 1b, V / m, 6.0 mL). Analytical reagent sodium bicarbonate (1 eq of 1b, m / m, 0.60 g) was added, followed by 11c (1.37 mmol, 1.2 eq of 1b, 0.25 g). The temperature was raised to 75 °C and the reaction was continued until completion, followed by HPLC analysis. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (15 mL, 3 portions). The filtrate was collected and used as a preparative solution to obtain compound 16 (0.14 g, 19.7% yield, HPLC >98%) as a white powdery solid. 1H 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] + .

[0110] Example 17 Synthesis of 17e [ka] Boc-N-proline 17a (10.0 mmol, 1.0 eq, 2.15 g) was weighed and dissolved in analytical reagent dichloromethane (10 eq of 17a, V / m, 20 mL) at 0 °C with stirring. 2-(7-azabenzotriazo)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 10.0 mmol, 7.6 g) was added and stirred at 0 °C for 1 h. Then, 2,6-dimethylaniline (15 mL) and N-methylmorpholine (NMM, 8.6 mL) were added and stirred at 0 °C for 1 h. The mixture was then transferred to room temperature and stirred until the reaction was complete. LC The mixture was detected using a HCl (HCl) detector and extracted with 50 mL of saturated NH4Cl solution three times, followed by 50 mL of saturated NaHCO3 solution three times. The organic layer was collected and subjected to silica gel column chromatography using a 20:1 CHCl:MeOH eluent. The collected eluate was concentrated by rotary evaporation to give compound 17b (3.10 g, 98.0% yield, HPLC >90%) as an orange oil. MS m / z (ESI) = 218.5 [M+H] + .

[0111] Weigh out 17b (5.0 mmol, 1.0 eq, 1.59 g), add 16 mL of analytical reagent dichloromethane, stir to dissolve, add 2 mL of trifluoroacetic acid dropwise, and continue stirring until the reaction is complete. LCThe compound was concentrated by rotary evaporation to give compound 17c (1.2 g, 98% yield, HPLC >90%) as an orange oil. MS m / z (ESI) = 218.5 [M+H] + .

[0112] Weigh out 17c (5.0 mmol, 1.0 eq, 1.2 g), add 12 mL of analytical reagent acetonitrile, stir to dissolve, add 1.4 g of potassium carbonate, add 1.4 g of bromobutane, and react at 80 °C until the reaction is complete. LC The reaction mixture was filtered, the filter cake was washed with acetonitrile (15 mL, 3 portions), and concentrated by rotary evaporation to give a pale yellow solid, compound 17d (1.3 g, 95% yield, HPLC >90%). MS m / z (ESI) = 275.5 [M+H]. + . Weigh 17d (5.0 mmol, 1.0 eq, 2.75 g), add 6 mL of 1,4-dibromobutane, stir, and raise the temperature to 100 °C until the reaction is complete. LC The compound was detected using a silica gel column chromatography using an eluent of CH₂Cl₂:MeOH=20:1. The eluate was collected and concentrated by rotary evaporation to give compound 17e as an orange oil (1.5 g, 73.17% yield, HPLC>90%). MS m / z (ESI)=409.19 [M] + ,410.99[M+2H] + .

[0113] Synthesis of compound 17 [ka] Weigh 17e (1.14 mmol, 1 eq, 0.56 g) and add analytical reagent acetonitrile (10 eq of 17e, V / m, 5.6 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 17e, m / m, 0.56 g). Add 1c (2.28 mmol, 2 eq of 17e, 0.53 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 17 (0.36 g, 49.3% yield, HPLC >98%) as a white solid. 1 H 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] + .

[0114] Example 18 Synthesis of compound 18 [ka] Weigh 17e (1.14 mmol, 1 eq, 0.56 g) and add analytical reagent acetonitrile (10 eq of 17e, V / m, 5.0 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 17e, m / m, 0.56 g). Add 4c (2.28 mmol, 2 eq of 17e, 0.50 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 18 (0.43 g, 59.7% yield, HPLC >98%) as a white solid. 1H 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] + .

[0115] Example 19 Synthesis of 12c [ka] Piperidine hydrochloride formyl chloride (2.0 mmol, 1 eq, 0.36 g) was weighed, added to 3.0 mL of analytical reagent acetonitrile, and stirred to dissolve. 0.55 g of analytical reagent potassium carbonate and p-methoxyaniline (4.0 mmol, 0.42 g) were added, and the temperature was raised to 80 °C. The reaction was monitored by thin-layer chromatography until completion. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (15 mL, 3 portions). The filtrate was collected and concentrated by rotary evaporation. This was then subjected to silica gel column chromatography using CHCl:MeOH (40:1) as the eluent. The eluate was collected and concentrated by rotary evaporation to give compound 12c (0.40 g, 89.8% yield, HPLC >98%) as a tan solid. MS m / z (ESI) = 235.2 [M+H] + .

[0116] Synthesis of compound 19 [ka] Weigh 17e (1.14 mmol, 1 eq, 0.56 g) and add analytical reagent acetonitrile (10 eq of 17e, V / m, 5.0 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 17e, m / m, 0.56 g). Add 12c (2.28 mmol, 2 eq of 17e, 0.53 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 19 (0.49 g, 66.7% yield, HPLC >98%) as a white solid. 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] + .

[0117] Example 20 Synthesis of 13c [ka] Piperidine hydrochloride formyl chloride (2.0 mmol, 1 eq, 0.36 g) was weighed, added to 3.0 mL of analytical reagent acetonitrile, and stirred to dissolve. 0.55 g of analytical reagent potassium carbonate and p-trifluoromethylaniline (4.0 mmol, 0.42 g) were added, and the temperature was raised to 80 °C. The reaction was monitored by thin-layer chromatography until complete. The reaction mixture was filtered, and the filter cake was washed with acetonitrile (15 mL, 3 portions). The filtrate was collected and concentrated by rotary evaporation. The resulting mixture was subjected to silica gel column chromatography using CHCl:MeOH (40:1) as an eluent. The collected eluate was concentrated by rotary evaporation to give compound 13c (0.41 g, 90.3% yield, HPLC >98%) as a tan solid. MS m / z (ESI) = 273.2 [M+H] + .

[0118] Synthesis of compound 20 [ka] Weigh 17e (1.14 mmol, 1 eq, 0.56 g) and add analytical reagent acetonitrile (10 eq of 17e, V / m, 5.0 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 17e, m / m, 0.56 g). Add 13c (2.28 mmol, 2 eq of 17e, 0.62 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 20 (0.30 g, 38.6% yield, HPLC >98%) as a white solid. 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] + .

[0119] Example 21 Synthesis of compound 21 [ka] Weigh 17e (1.14 mmol, 1 eq, 0.56 g) and add analytical reagent acetonitrile (10 eq of 17e, V / m, 5.6 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 17e, m / m, 0.56 g). Add 3c (2.28 mmol, 2 eq of 17e, 0.50 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 21 (0.36 g, 54.2% yield, HPLC >98%) as a white solid. 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] + .

[0120] Example 22 Synthesis of 18e [ka] 17d (5.0 mmol, 1.0 eq, 1.37 g) was weighed, 6 mL of 1,5-dibromopentane was added, and the mixture was stirred and the temperature was raised to 100 °C. The reaction was continued until completion. LC The compound was detected using a silica gel column chromatography using an eluent of CH₂Cl₂:MeOH=20:1. The eluate was collected and concentrated by rotary evaporation to give compound 18e (1.8 g, 71.4% yield, HPLC>90%) as a tan oily liquid. MS m / z (ESI) = 422.19 [M] +,424.28[M+2H] + .

[0121] Synthesis of compound 22 [ka] Weigh 18e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 18e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 18e, m / m, 0.57 g). Add 1c (2.28 mmol, 2 eq of 18e, 0.53 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 22 (0.38 g, 51.0% yield, HPLC >98%) as a white solid. 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] + .

[0122] Example 23 Synthesis of compound 23 [ka] Weigh 18e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 18e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 18e, m / m, 0.57 g). Add 4c (2.28 mmol, 2 eq of 18e, 0.50 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography (TLC). The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to give compound 23 (0.45 g, 61.7% yield, HPLC >98%) as a white solid. 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, 1H), 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] + .

[0123] Example 24 Synthesis of compound 24 [ka] Weigh 18e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 18e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 18e, m / m, 0.57 g). Add 12c (2.28 mmol, 2 eq of 18e, 0.55 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to obtain compound 24 (0.49 g, 65.4% yield, HPLC >98%) as a white solid. 1H 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), 2.40-2.12(m, 12H), 1.97-1.48(m, 10H), 1.40-1.16(m, 3H), 0.92-0.87(m, 3H). 13 C NMR (400 MHz, 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] + .

[0124] Example 25 Synthesis of compound 25 [ka] Weigh 18e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 18e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 18e, m / m, 0.57 g). Add 13c (2.28 mmol, 2 eq of 18e, 0.62 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography (TLC). The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to give compound 25 (0.42 g, 53.2% yield, HPLC >98%) as a white solid. 1H 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] + .

[0125] Example 26 Synthesis of compound 26 [ka] Weigh 18e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 18e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 18e, m / m, 0.57 g). Add 3c (2.28 mmol, 2 eq of 2e, 0.51 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered, washed with acetonitrile (18 mL, 3 portions), and the filtrate was collected to give compound 26 (0.30 g, 40.8% yield, HPLC >98%) as a white solid. 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) =565.39[M] + .

[0126] Example 27 Synthesis of 19e [ka] Boc-N-proline 17a (10.0 mmol, 1.0 eq, 2.15 g) was weighed and dissolved in analytical reagent dichloromethane (10 eq of 17a, V / m, 20 mL) at 0 °C with stirring. 2-(7-azabenzotriazo)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU, 20.0 mmol, 7.6 g) was added and stirred at 0 °C for 1 h. Then, 2,4,6-trimethylaniline (15 mL) and N-methylmorpholine (NMM, 8.6 mL) were added and stirred at 0 °C for 1 h. The mixture was then transferred to room temperature and stirred until the reaction was complete. LC The mixture was detected using a HCl (HCl) detector and extracted with 50 mL of saturated NH4Cl solution three times, followed by 50 mL of saturated NaHCO3 solution three times. The organic layer was collected and subjected to silica gel column chromatography using a 20:1 CHCl:MeOH eluent. The collected eluate was concentrated by rotary evaporation to give compound 19b (3.10 g, 98% yield, HPLC >90%) as an orange oil. MS m / z (ESI) = 233.5 [M+H] + .

[0127] Weigh 19b (5.0 mmol, 1.0 eq, 1.59 g), add 16 mL of analytical reagent dichloromethane, stir to dissolve, add 2 mL of trifluoroacetic acid dropwise, and continue stirring until the reaction is complete. LC The compound was concentrated by rotary evaporation to give compound 19c as an orange oil (1.2 g, 98% yield, HPLC >90%). MS m / z (ESI) = 233.5 [M+H]. + .

[0128] Weigh out 19c (5.0 mmol, 1.0 eq, 1.2 g), add 12 mL of analytical reagent acetonitrile, stir to dissolve, add 2.4 g of potassium carbonate, add 1.4 g of bromobutane, and react at 80 °C until the reaction is complete. LCThe reaction mixture was filtered, the filter cake was washed with acetonitrile (15 mL, 3 portions), and concentrated by rotary evaporation to give a pale yellow solid, compound 19d (1.3 g, 95% yield, HPLC >90%). MS m / z (ESI) = 289.5 [M+H]. + .

[0129] 19d (5.0 mmol, 1.0 eq, 2.75 g) was weighed, 6 mL of 1,4-dibromobutane was added, and the temperature was raised to 100 °C with stirring. LC The compound was detected using a silica gel column chromatography using an eluent of CH₂Cl₂:MeOH=20:1. The eluate was collected and concentrated by rotary evaporation to give compound 19e as an orange oil (1.5 g, 70.2% yield, HPLC>90%). MS m / z (ESI)=422.79 [M] + ,424.79[M+2H] + .

[0130] Synthesis of compound 27 [ka] Weigh 19e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 19e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 19e, m / m, 0.57 g). Add 1c (2.28 mmol, 2 eq of 19e, 0.53 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered and washed with acetonitrile (30 eq of 19e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 27 (0.39 g, 52.3% yield, HPLC >98%) as a white solid. 1H 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] + .

[0131] Example 28 Synthesis of compound 28 [ka] Weigh 19e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 19e, V / m, 5.07 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 19e, m / m, 0.57 g). Add 4c (2.28 mmol, 2 eq of 1e, 0.50 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered and washed with acetonitrile (30 eq of 19e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 28 (0.40 g, 54.6% yield, HPLC >98%) as a white solid. 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) =561.40[M] + .

[0132] Example 29 Synthesis of compound 29 [ka] Weigh 19e (1.14 mmol, 1 eq, 0.57 g) and add analytical reagent acetonitrile (10 eq of 19e, V / m, 5.7 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 19e, m / m, 0.57 g). Add 3c (2.28 mmol, 2 eq of 19e, 0.51 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography. The reaction mixture was filtered and washed with acetonitrile (30 eq of 19e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 29 (0.36 g, 48.9% yield, HPLC >98%) as a white solid. 1 H 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] + .

[0133] Example 30 Synthesis of 20e [ka] 19d (5.0 mmol, 1.0 eq, 2.75 g) was weighed, 1,5-dibromopentane (2.0 eq of 19d, V / m, 6 mL) was added, and the temperature was raised to 100 °C under stirring until the reaction was complete. LC The compound was detected using a silica gel column chromatography using an eluent of CH₂Cl₂:MeOH=20:1. The eluate was collected and concentrated by rotary evaporation to give compound 20e (1.8 g, 76.3% yield, HPLC>90%) as a tan oily liquid. MS m / z (ESI) = 437.22 [M] + ,439.21[M+2H].

[0134] Synthesis of compound 30 [ka] Weigh 20e (1.14 mmol, 1 eq, 0.59 g) and add analytical reagent acetonitrile (10 eq of 20e, V / m, 5.0 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 20e, m / m, 0.59 g). Add 1c (2.28 mmol, 2 eq of 20e, 0.53 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography (TLC). The reaction mixture was filtered and washed with acetonitrile (30 eq of 20e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 30 (0.38 g, 50.0% yield, HPLC >98%) as a white solid. 1 H 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] + .

[0135] Example 31 Synthesis of compound 31 [ka] Weigh 20e (1.14 mmol, 1 eq, 0.59 g) and add analytical reagent acetonitrile (10 eq of 20e, V / m, 5.9 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 20e, m / m, 0.59 g). Add 4c (2.28 mmol, 2 eq of 20e, 0.50 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography (TLC). The reaction mixture was filtered and washed with acetonitrile (30 eq of 20e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 31 (0.45 g, 60.4% yield, HPLC >98%) as a white solid. 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] + .

[0136] Example 32 Synthesis of compound 32 [ka] Weigh 20e (1.14 mmol, 1 eq, 0.59 g) and add analytical reagent acetonitrile (10 eq of 20e, V / m, 5.9 mL). Stir to dissolve. Add analytical reagent potassium carbonate (1 eq of 20e, m / m, 0.59 g). Add 3c (2.28 mmol, 2 eq of 20e, 0.51 g). Raise the temperature to 80 °C and react until complete. Monitor by thin-layer chromatography (TLC). The reaction mixture was filtered and washed with acetonitrile (30 eq of 20e, V / m, 18 mL, in three portions). The filtrate was collected and purified to give compound 32 (0.31 g, 41.3% yield, HPLC >98%) as a white solid. 1H 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] + .

[0137] Biological testing 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 purchased from ordinary biochemical reagent stores.

[0138] Test Example 1: Nerve block local anesthetic effect of the compound of the present invention The compound according to the embodiment and levobupivacaine hydrochloride positive control group were selected and administered to three groups of rats that had fully adapted to the environment, one rat per group. Solution formulation: 2 mg / mL levobupivacaine hydrochloride injection: 2.670 mL of 7.5 mg / mL levobupivacaine hydrochloride injection (batch number: 92S0702) was pipetted into a 10 mL volumetric flask, 0.9% NaCl solution was added until the concave meniscus was aligned with the graduated line, and the flask was inverted to mix uniformly to prepare a 2 mg / mL levobupivacaine hydrochloride injection. 6 mg / mL (molar concentration range calculated based on the molecular weight of the compound according to the example is 8.6 to 10.1 mmol / L) compound solution: 19.80 mg of the compound according to the example was accurately weighed, and 3.3 mL of 0.9% NaCl solution was added to prepare a 6 mg / mL compound solution. Each rat received a 5 mL / kg injection or control, administered as a single dose into the right sciatic nerve. After administration, the rat was placed on a preheated 50±0.1°C intelligent temperature-controlled board. The time required for the rat to demonstrate clear thermal avoidance behaviors, such as paw lifting and paw licking, on the administered side was recorded and used as the thermal latency period. The maximum allowable thermal latency period was controlled to 60 s. If the rat did not demonstrate paw licking after 60 s, the rat's hind paw was manually raised to avoid tissue damage or hyperalgesia, and the 60 s period was used as the thermal latency period for that rat. After each measurement, any urine or feces present on the board were promptly wiped dry before subsequent testing.

[0139] Analysis method The thermal incubation period results are expressed as maximum proportionality effect (MPE) and are calculated using the following equation: MPE(%)=(CB) / (PB)*100% In the formula, B represents the basal thermal latency of the rat, P represents the maximum allowable thermal latency, and C represents the thermal latency at the time of detection. A measurement time lower than 50% of the maximum proportional effect is defined as invalid, and if the results of two consecutive measurements are both lower than 50% of the maximum proportional effect, the measurement is stopped.

[0140] Test results: Table 1 shows the local anesthetic effect data of the compounds of the present application. [Table 1] TIFF0007787912000073.tif115157

[0141] Experimental results showed that the compounds of the present application can produce good local anesthetic effects in a sciatic nerve block model with rapid onset of action. In terms of molar concentration, within the range of 8.6 to 10.1 mmol / L, the anesthetic duration of each single agent was 11 hours or more, significantly longer than that of the positive control, levobupivacaine hydrochloride. Among these, the anesthetic duration of some compounds was longer than 24 hours, and that of others was longer than 48 hours with an onset time of 1 minute.

[0142] Test Example 2: Local anesthetic effect of the compound of the present invention after subcutaneous infiltration After shaving and disinfecting the backs of SD rats (half male and half female) weighing 190-210 grams, a circle approximately 1.5 cm in diameter was drawn on one side of the exposed back. 0.5 mL of a drug-containing solution (2 mg / mL levobupivacaine hydrochloride in saline) was subcutaneously injected into the center of the skin. Nine compounds were selected from the present invention at a concentration of 6 mg / mL (equivalent to a molar concentration range of 8.6-10.1 mmol / L depending on the molecular weight of the compounds). Each group contained 10 rats. Local skin stimulation was performed using a 100-gram strength Von Frey filament combined with a needle. One minute after drug injection, rats were measured for prick stimulation. Test sites were six different points around the injection site, and observations were made to record whether skin contraction, withdrawal, or other behaviors were observed after stimulation. Three points in the center of the circle and three points on the periphery of the circle are stimulated, and the number of times skin contractions and escape behaviors occur is recorded and recorded as N / 6. Regarding the judgment, if the number of escapes and skin contractions occurs is 4 or more, the drug is considered to have failed; if there is a reaction in the periphery (≦3) and no reaction in the middle (≧1), the drug is considered to be still effective; and if there is a reaction only in the middle point, the drug is considered to have failed. Experiments are conducted using 10 rats for each compound.

[0143] Test results: Table 2 shows the local anesthetic effect of the compound of the present invention (6 mg / mL) after subcutaneous infiltration. [Table 2] TIFF0007787912000075.tif73161

[0144] Experimental results showed that the compounds of the present application at a concentration of 6 mg / mL (equivalent to a molar concentration ranging from 8.6 to 10.1 mmol / L) can produce local anesthetic effects lasting for more than 48 hours in a rat subcutaneous infiltration model, with a rapid onset of action, and some compounds can produce local anesthetic effects lasting for more than 72 hours with an onset time of 1 minute.

[0145] Because irreversible nerve damage may occur if the local anesthesia duration is longer than 72 hours, the dose of compounds with a duration of action longer than 72 hours is subsequently halved (to 3 mg / mL) and activity tests are performed to determine whether the local anesthetic effect in the skin infiltration model can be restored.

[0146] Table 3 shows the local anesthetic effect of the compound of the present invention (3 mg / mL) after subcutaneous infiltration. [Table 3]

[0147] Experimental results showed that the compound of the present application, when administered at a concentration of 3 mg / mL (equivalent to a molar concentration ranging from 4.4 to 5.1 mmol / L), can still produce local anesthetic effects lasting for more than 48 hours in a rat subcutaneous infiltration model, and the local anesthetic effect can be recovered.

[0148] Test Example 3: Evaluation of neuropathological damage caused by the compounds of the present invention Compounds 4, 8, 12, and 24 according to the present invention, a levobupivacaine hydrochloride positive control group, and a solvent control group were selected and administered to test rats (half male and half female) weighing 190 to 210 grams that had fully adapted to the experimental environment, with eight rats per group. Administration concentration: 2 mg / mL levobupivacaine hydrochloride in saline. The compound of the present invention was administered in two concentrations of 6 mg / mL and 12 mg / mL, respectively. Vehicle control group: saline. Each rat received a 1.0 mL injection around the sciatic nerve. On days 7 and 14 after the sciatic nerve injection, the rats were euthanized by intracardiac injection of levobupivacaine hydrochloride under isoflurane anesthesia. Approximately 1.5 cm of the sciatic nerve was removed from the injection site and preserved in 10% formaldehyde for 48 hours. Then, HE staining was performed on the nerve sections, which were then sectioned at 5 μm thickness. Compounds 4, 8, 12, and 24 prepared in the examples, a levobupivacaine hydrochloride positive control group, and a solvent control group were selected and administered to test rats (half male and half female) weighing 190 to 210 grams that had fully adapted to the experimental environment, with eight rats per group. Administration concentration: 2 mg / mL levobupivacaine hydrochloride in saline. The compound of the present invention was administered in two concentrations, 3 mg / mL and 6 mg / mL, respectively. Vehicle control group: saline. Each rat received a 1 mL injection subcutaneously on its back. On days 7 and 14 after subcutaneous injection, the rats were euthanized by intracardiac injection of levobupivacaine hydrochloride under isoflurane anesthesia. Skin tissue from the injection site was removed and stored in 10% formaldehyde for 48 hours. Then, HE staining was performed on the tissue to prepare 5 μm-thick sections. According to the results of neuropathological damage evaluation, the compounds of the examples did not show significant differences in nerve damage, angiogenesis, the degree of demyelination, muscle inflammation, and connective tissue inflammation compared to the levobupivacaine hydrochloride positive control group and the solvent control group, and therefore have good safety.

[0149] Test Example 4: Single-dose toxicity study of the compound according to the present application Compounds 4, 8, 12 and 24 according to the examples were selected and administered to SD rats weighing 190-210 grams, which were fully adapted to the experimental environment, with four rats per group. Dosage: Using physiological saline as a solvent, the concentration of compounds 4, 8, 12, and 24 according to the present invention is 6 mg / kg. Administration route: administration via rat tail vein with a dose volume of 5 mL / kg for each rat. Compounds 4, 8, 12, and 24 according to the present invention and levobupivacaine hydrochloride positive control groups were selected and administered to SD rats weighing 190-210 g, which had fully adapted to the experimental environment, with four rats per group. Dosage: Using physiological saline as a solvent, the concentration of compounds 4, 8, 12, and 24 according to the present invention is 30 mg / kg. Administration method: Subcutaneous injection into rats with a dose volume of 5mL / kg for each rat. The results showed that after administration of the compound of the present invention at a dose of 6 mg / kg via the tail vein and 30 mg / kg subcutaneously, the rats showed no significant abnormalities and their behavior was active, with no significant difference from that of normal rats.

[0150] As described above, the present application provides a novel quaternary ammonium salt compound and its preparation and use, which has a fast onset of action, long-lasting local anesthetic effect after a single administration, and good safety.

[0151] Although several embodiments have been described herein, the description is for illustrative purposes only and is not intended to be limiting. It will be apparent to those skilled in the art that there may be many more embodiments and implementations within the scope of the embodiments described herein.

Claims

1. A quaternary ammonium salt compound represented by formula (I), or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, 【Chemistry 1】 During the ceremony, R 1 is a 2,6-dimethylphenyl group or a 2,4,6-trimethylphenyl group, R 2 is an n-propyl group or an n-butyl group, R 3 is a cyclohexyl group, a phenyl group, a 4-methylphenyl group, a 4-methoxyphenyl group, a 4-fluorophenyl group, a 4-trifluoromethylphenyl group, or a 2,6-dimethylphenyl group, X 1 and X 2 are each independently NH, m and n are each independently 1; L is -(CH 2 ) 2 - or -(CH 2 ) 3 -Selected from S 1 , S 2 One of the bonds is a single bond, and the other is -(CH 2 ) 3 - or -(CH 2 ) 4 - and Q 1 and Q 2 One of the bonds is a single bond, and the other is -(CH 2 ) 4 - and Y - is a halogen anion, The quaternary ammonium salt compound, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof.

2. In formula (I), Y - is Cl - , Br - , or I - 2. The compound of claim 1, wherein:

3. In formula (I), Y - Br - 3. The compound of claim 2, wherein:

4. 2. The compound of claim 1, wherein the compound of formula (I) is one selected from the following compounds: 【Chemistry 2】

5. 2. The compound of claim 1, wherein the compound of formula (I) is one selected from the following compounds: 【Transformation 3】

6. A method for preparing a compound according to any one of claims 1 to 5, comprising: 【Chemistry 4】 reacting a compound of formula (II) with a compound of formula (III) to obtain a compound of formula (I); In formula (II), Z is an electron-withdrawing leaving group, and the leaving group is bromine, chlorine, or sulfonate ester, and the definitions of the groups in formula (II) and formula (III) are the same as those in formula (I). The method.

7. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 5, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, and a pharmaceutically acceptable carrier excipient or diluent.

8. Use of a compound of formula (I) according to any one of claims 1 to 5, or a tautomer, geometric isomer, enantiomer, diastereomer, or mixture thereof, or a pharmaceutical salt thereof, in the manufacture of an anesthetic or analgesic drug.

9. 9. The use according to claim 8, wherein the anesthesia is local anesthesia and the pain suitable for analgesia is chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

10. The use according to claim 9, wherein the anesthesia is conduction anesthesia, topical anesthesia or infiltration anesthesia.

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