Cyclic quaternary ammonium salt compound, its preparation method and use

Abstract

The present application provides a cyclic quaternary ammonium salt compound represented by general formula (I) and its preparation method and use thereof, or its isomers, solvates, and compositions thereof and its use in the manufacture of anesthetics or analgesics, wherein each substituent in formula (I) is as defined in the specification.

Description

[Technical field]

[0001] (cross reference) This application claims the benefit of priority from a Chinese patent application filed with the State Intellectual Property Office of the People's Republic of China on May 18, 2022, bearing application number 202210551906.7 and entitled "Cyclic quaternary ammonium salt compounds and their preparation methods and uses," the contents of which are incorporated herein by reference.

[0002] The present application relates to the technical field of medicinal chemistry, but is not limited thereto, and in particular to cyclic quaternary ammonium salt compounds and their preparation methods and uses. [Background technology]

[0003] Local anasthetics, also called local anesthetics, are drugs that are applied locally around nerve trunks or nerve endings to temporarily, completely, and reversibly block the generation and transmission of nerve impulses, thereby temporarily eliminating localized pain sensation. Local anesthetics bind to the binding sites of sodium channels on the nerve cell membrane and block the Na + The mechanism of action of topical anesthetics is to inhibit the conduction of nerve impulses and exert an anesthetic effect by reducing the influx of serotonin into the cell membrane and changing the membrane potential. Topical anesthetics are one of the most widely used pain treatment methods in clinical practice, due to their advantages of reliable effectiveness, low risk of hyperalgesia, convenient local administration, low blood concentration, and few systemic side effects.

[0004] Currently, local anesthetics in clinical use are mainly compounds in which an aromatic group and an amine group are bonded via an ester bond or an amide bond, examples of which include procaine, buticaine, lidocaine, bupivacaine and ropivacaine. Among these, bupivacaine and ropivacaine are considered to be new long-acting local anesthetics, but the duration of the analgesic effect from a single dose usually does not exceed 8 hours ("Local anesthetics: review of pharmacological considerations", Becker DE.et al., Anesth Prog.2012,59(2):90-102.), and although they can be used until the end of most surgeries and invasive procedures, they may not be able to meet the needs of postoperative pain or chronic pain.

[0005] QX-314, a quaternary ammonium salt derivative of lidocaine, effectively blocks sodium ion currents when it passes through cell membranes, and can exert a relatively long-lasting anesthetic effect. However, since it is always positively charged, it has been difficult for it to freely pass through 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 when combined with local anesthetics or transient receptor potential (TRP) agonists, QX-314 can penetrate cell membranes and exert a long-lasting local anesthetic effect, but it may also lead to increased local neurotoxicity and systemic toxicity ("Anti-nociceptive and desensitizing effects of olvanil on capsaicin-induced thermal hyperalgesia in the rat", Alsalem M.etal., BMC Pharmacol Toxicol.2016,17(1):31.).

[0006] Currently, there are no new long-acting local anesthetics available in clinical practice that have strong local anesthetic effects, long duration, rapid onset of effects, high safety, and little skin irritation, so there is a strong demand for long-term, safe postoperative pain relief. Summary of the Invention

[0007] In view of this, the present application provides a novel cyclic quaternary ammonium salt compound, which has a novel structure, has a local anesthetic effect that can last for a long time after a single administration, and has the advantages of not causing damage to motor nerves and not causing neurotoxicity, as well as a method for preparing the same and uses thereof.

[0008] In a first aspect, the present application provides a method for producing a semiconductor device comprising: The following formula (I): [ka] [In the formula, R 1 is an aromatic hydrocarbon group or a heteroaryl group, or X 1 together with the nitrogen-containing heterocycloalkyl group, R 2 is C 1-8 Alkyl group or C 3-12 is a cycloalkyl group, R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group; or X 2 and forming a nitrogen-containing heterocycloalkyl group condensed with X 1 are O, S and NR A 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group, or R A 4 is N and R linked to itself 1together with a non-condensed or condensed nitrogen-containing heterocycloalkyl group, X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R B 4 is N and R linked to itself 3 together with the nitrogen-containing heterocycloalkyl group fused thereto, L is C 1-8 is an alkylene group, S 1 , S 2 are each independently a chemical bond and C 1-6 alkylene groups, and S 1 and S. 2 It is stipulated that both are not chemical bonds at the same time, Y - represents a pharma- ceutically acceptable anion. or a stereoisomer or solvate thereof.

[0009] In a second aspect, the present application relates to a method for preparing a compound represented by general formula (I) according to any one of the first aspects of the present application, or a stereoisomer or solvate thereof, comprising the step of reacting a compound represented by the following formula (II) with a compound represented by formula (III) to obtain compound (I): [ka] (wherein Z in formula (II) is an electron-withdrawing leaving group such as bromine, chlorine or sulfonate, and the definitions of the groups in formulas (II) and (III) are the same as in formula (I).)

[0010] In a third aspect, the present application relates to a pharmaceutical composition comprising a compound of general formula (I) as defined in any one of the first aspects of the present application, or a stereoisomer or solvate thereof, and a pharma- ceutically acceptable carrier excipient or diluent.

[0011] In a fourth aspect, the present application relates to the use of a compound of general formula (I) as defined in any one of the first aspect of the present application, or a stereoisomer or solvate thereof, or a pharmaceutical composition according to the third aspect of the present application, in the manufacture of a local anesthetic or analgesic medicament.

[0012] In a fifth aspect, the present application relates to a method for local anesthesia or analgesia, comprising administering to an individual in need thereof an effective amount of a compound of general formula (I) as described in any one of the first aspect of the present application, or a stereoisomer or solvate thereof, or a pharmaceutical composition according to the third aspect of the present application, said administration being local via a mucosal route, such as transdermal, subcutaneous, intradermal, intramuscular, paraneural, intrapulpal, intraspinal, epidural, intravenous, or eye drop.

[0013] Detailed Description According to a first aspect of the present application, The following formula (I): [ka] [In the formula, R 1 is an aromatic hydrocarbon group or a heteroaryl group, or X 1 together with the nitrogen-containing heterocycloalkyl group, R 2 is C 1-8 Alkyl group or C 3-12 is a cycloalkyl group, R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group; or X 2 and forming a nitrogen-containing heterocycloalkyl group condensed with X 1 are O, S and NRA 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R A 4 N and R linked to itself 1 together with a non-condensed or condensed nitrogen-containing heterocycloalkyl group, X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R B 4 is N and R linked to itself 3 together with the nitrogen-containing heterocycloalkyl group fused thereto, L is C 1-8 is an alkylene group, S 1 , S 2 are each independently a chemical bond and C 1-6 alkylene groups, and S 1 and S. 2 It is stipulated that both are not chemical bonds at the same time, Y - represents a pharma- ceutically acceptable anion. or a stereoisomer or solvate thereof.

[0014] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or solvate thereof, L is C 3 It is not an alkylene group.

[0015] In an embodiment of the first aspect of the present application, the present application provides a compound of formula (I): [ka] [In the formula, R 1 is an aromatic hydrocarbon group or a heteroaryl group, or X 1 and together form an unfused or fused nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the unfused nitrogen-containing heterocycloalkyl group, or the fused nitrogen-containing heterocycloalkyl group is optionally selected from the group consisting of 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 1-6 Haloalkyl groups and C 1-6 a haloalkoxy group, and the fused nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group; R 2 is C 1-8 Alkyl group or C 3-12 is a cycloalkyl group, 1-8 Alkyl group or C 3-12 The cycloalkyl group is optionally selected from the group consisting of 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 substituents selected from a cycloalkyl group, a halogen, a hydroxyl group, a cyano group, and an amino group; R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group; or X 2and forming a fused nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the heterocycloalkyl group, and the fused nitrogen-containing heterocycloalkyl group are optionally selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-4 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, sulfonyl groups, mercapto groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 and is substituted with one or more substituents selected from an alkynyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heteroaryl group, and an optionally substituted heterocycloalkyl group, wherein the optionally substituted aromatic hydrocarbon group, the optionally substituted heteroaryl group, and the optionally substituted heterocycloalkyl group are, respectively, an unsubstituted aromatic hydrocarbon group, an unsubstituted heteroaryl group, and an unsubstituted heterocycloalkyl group, or 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 The fused nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group; X 1 are O, S and NR A4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R A 4 is N and R linked to itself 1 together with each other to form a non-condensed or condensed nitrogen-containing heterocycloalkyl group, the condensed nitrogen-containing heterocycloalkyl group being condensed with an aromatic hydrocarbon group or a heteroaryl group; X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R B 4 is N and R linked to itself 3 together with a nitrogen-containing heterocycloalkyl group fused thereto, said nitrogen-containing heterocycloalkyl group being fused with an aromatic hydrocarbon group or a heteroaryl group; L is optionally 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 C substituted with one or more substituents selected from alkynyl groups 1-8 is an alkylene group, and L is C 3 It is specified that it is not an alkylene group, S1 , S 2 are each independently a chemical bond and C 1-6 alkylene groups, and S 1 and S. 2 are not chemical bonds at the same time, 1-6 The backbone of the alkylene group optionally contains one heteroatom, which may be O, S or NR 5 (However, R 5 is hydrogen or deuterium; Y - represents a pharma- ceutically acceptable anion. or a stereoisomer or solvate thereof.

[0016] In an embodiment of the first aspect of the present application, the present application provides a compound of formula (I): [ka] [In the formula, R 1 is an aromatic hydrocarbon group or a heteroaryl group, or X 1 and together form an unfused or fused nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the unfused nitrogen-containing heterocycloalkyl group, or the fused nitrogen-containing heterocycloalkyl group is optionally selected from the group consisting of 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 1-6 Haloalkyl groups and C 1-6 a haloalkoxy group, and the fused nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group; R2 is C 1-8 Alkyl group or C 3-12 is a cycloalkyl group, 1-8 Alkyl group or C 3-12 The cycloalkyl group is optionally selected from the group consisting of 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 substituents selected from a cycloalkyl group, a halogen, a hydroxyl group, a cyano group, and an amino group; R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group; or X 2 and forming a fused nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the heterocycloalkyl group, and the fused nitrogen-containing heterocycloalkyl group are optionally selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-4 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C 1-6 Alkanoyl group, ester group, nitro group, sulfonyl group, mercapto group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 and is substituted with one or more substituents selected from an alkynyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heteroaryl group, and an optionally substituted heterocycloalkyl group, wherein the optionally substituted aromatic hydrocarbon group, the optionally substituted heteroaryl group, and the optionally substituted heterocycloalkyl group are, respectively, an unsubstituted aromatic hydrocarbon group, an unsubstituted heteroaryl group, and an unsubstituted heterocycloalkyl group, or 1-6Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C 1-6 Alkanoyl group, ester group, nitro group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 The fused nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group; X 1 are O, S and NR A 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R A 4 N and R linked to itself 1 together with each other to form a non-condensed or condensed nitrogen-containing heterocycloalkyl group, the condensed nitrogen-containing heterocycloalkyl group being condensed with an aromatic hydrocarbon group or a heteroaryl group; X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group, or C 1-4 Alkoxy C 1-4 is an alkyl group, or R B 4 is N and R linked to itself 3together with a nitrogen-containing heterocycloalkyl group fused thereto; the nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group; L is optionally 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 C substituted with one or more substituents selected from alkynyl groups 1-8 is an alkylene group, and L is C 3 It is specified that the alkylene group is not an alkylene group. S 1 , S 2 each independently represents a bond and C 1-6 alkylene groups, and S 1 and S. 2 are not chemical bonds at the same time, 1-6 The backbone of the alkylene group optionally contains one heteroatom, which may be O, S or NR 5 (However, R 5 is hydrogen or deuterium; Y - represents a pharma- ceutically acceptable anion. or a stereoisomer or solvate thereof.

[0017] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 1 Optionally, C 1-6 Alkyl group, C 1-6 Alkoxy group, cyano group, halogen, hydroxyl group, amino group, nitro group, ester group, mono C 1-6Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 Alkynyl group, C 1-6 Haloalkyl groups and C 1-6 It is a phenyl or naphthyl group substituted with one or more substituents selected from haloalkoxy groups.

[0018] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 1 is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, methyl ester group (CH 3 OC(O)-), ethyl ester group (CH 3 CH 2 A phenyl group substituted with one or more substituents selected from the group consisting of OC(O)-.

[0019] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 1 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-hydroxyphenyl 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, or a 2,4,6-trifluorophenyl group, preferably a 2,6-dimethylphenyl group.

[0020] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate 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-hydroxyphenyl group, a 2,6-dimethylphenyl group, a 2,6-diethylphenyl group, a 2,6-dimethoxyphenyl group, a 3-nitrophenyl group, a 2,6-difluorophenyl group, a 2,6-dibromophenyl 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 2-methylphenyl group, a 4-fluorophenyl group, a 2,6-dibromophenyl group, a 2,6-diethylphenyl group, or a 2,6-dimethylphenyl group, more preferably a 2,6-dimethylphenyl group.

[0021] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 2 Optionally, C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 3-6 C substituted with one or more substituents selected from a cycloalkoxy group, a halogen, a hydroxyl group, a cyano group, and an amino group 1-8 Alkyl group or C 3-8 It is a cycloalkyl group.

[0022] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 2is 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 cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl 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.

[0023] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 2 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, a 4-methylpentyl group, an n-hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, an n-octyl group, or an n-heptyl group, preferably an ethyl group, an n-propyl group, an n-butyl group, an isobutyl group, an n-pentyl group, a 4-methylpentyl group, an n-hexyl group, an n-octyl group, or an n-heptyl group, more preferably an n-butyl group, an isobutyl group, or a 4-methylpentyl group, and particularly preferably an n-butyl group.

[0024] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a 3- to 8-membered heterocycloalkyl group, or X 2 and forming a condensed nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the 3- to 8-membered heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group are optionally selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-4 Alkyl group, C 1-6Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, sulfonyl groups, mercapto groups, 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, wherein the optionally substituted phenyl group is an unsubstituted phenyl group, or 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 The fused nitrogen-containing heterocycloalkyl group is fused with a phenyl group or a heteroaryl group.

[0025] According to one embodiment, in the compound represented by the general formula (I) of the present application, or a stereoisomer or a solvate thereof, R 3 is an aromatic hydrocarbon group, a heteroaryl group, or a 3- to 8-membered heterocycloalkyl group, or X 2 and forming a condensed nitrogen-containing heterocycloalkyl group, wherein the aromatic hydrocarbon group, the heteroaryl group, the 3- to 8-membered heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group are optionally selected from the group consisting of C 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Alkoxy C 1-4 Alkyl group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C 1-6 Alkanoyl group, ester group, nitro group, sulfonyl group, mercapto group, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl group, C 2-4 alkynyl group, an optionally substituted phenyl group, optionally wherein two adjacent substituents and the atoms connected thereto together form a ring, wherein the optionally substituted phenyl group is an unsubstituted phenyl group, or 1-6 Alkyl group, C 1-6 Alkoxy group, C 1-6 Haloalkyl group, C 1-6 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 The fused nitrogen-containing heterocycloalkyl group is fused with one or more substituents selected from alkynyl groups, and the fused nitrogen-containing heterocycloalkyl group is fused with a phenyl group or a heteroaryl group.

[0026] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, R 3are phenyl, 4-fluorobenzyl, 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-hydroxyphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-trifluoromethylphenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4-dihydroxyphenyl, 3 ,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dihydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl, 2-amino-5-fluorophenyl, 2-isopropyl-5-methylphenyl, 4-cyanophenyl, 4-ethoxycarbonylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 4-nitrophenyl, 4-sulfonylphenyl, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl, naphthyl, or 6-acetylnaphthalen-2-yl; 3 isX 2forms a fused piperidinyl group, a fused piperazinyl group, or a fused pyrrolidinyl group, wherein the fused piperidinyl group, the fused piperazinyl group, or the fused pyrrolidinyl group is a group in which a phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group is fused, and the fused piperidinyl group, the fused piperazinyl group, or the fused pyrrolidinyl group is optionally substituted with one or more substituents 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, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a methyl ester group, an ethyl ester group, a phenyl group, and a substituted phenyl group. Preferably, R 3 is a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 4-fluorophenyl group, a 2-amino-5-fluorophenyl group, a 2-isopropyl-5-methylphenyl group, a 4-cyanophenyl group, a 4-ethoxycarbonylphenyl group, a 2,6-di-tert-butyl-4-methylphenyl group, a 4-nitrophenyl group, a 4-sulfonic acid phenyl group, a 4-hydroxyphenyl group, or R 3 is X 2 forms an imidazolylpiperazinyl group, a thienylpiperazinyl group, or a pyrrolopyperazinyl group together with X, and the imidazolylpiperazinyl group, the thienylpiperazinyl group, or the pyrrolopyperazinyl group is optionally substituted with one or more substituents 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, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a methyl ester group, an ethyl ester group, and a phenyl group.

[0027] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or a solvate thereof, R 3are phenyl, 4-fluorobenzyl, 2-methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-hydroxyphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-bromophenyl, 3-hydroxyphenyl, 3-cyanophenyl, 3-trifluoromethylphenyl, 4-methylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-hydroxyphenyl, 4-trifluoromethylphenyl, 2,4-dimethylphenyl, 2,4-dimethoxyphenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4-dihydroxyphenyl, 3 ,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-difluorophenyl, 2,6-dimethylphenyl, 2,6-dimethoxyphenyl, 2,6-difluorophenyl, 2,6-dichlorophenyl, 2,6-dihydroxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2,4,6-trifluorophenyl, 2-amino-5-fluorophenyl, 2-isopropyl-5-methylphenyl, 4-cyanophenyl, 4-ethoxycarbonylphenyl, 2,6-di-tert-butyl-4-methylphenyl, 4-nitrophenyl, 4-sulfonylphenyl, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl, naphthyl or 6-acetylnaphthalen-2-yl, or X is 2and R form a condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group, wherein the condensed piperidinyl group, the condensed piperazine group, or the condensed pyrrolidinyl group is a condensed phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group, and the condensed piperidinyl group, the condensed piperazine group, or the condensed pyrrolidinyl group is optionally substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, ethyl ester, phenyl, and substituted phenyl. 3 is a phenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 4-fluorophenyl group, a 3-cyanophenyl group, a 3-trifluoromethylphenyl group, a 3,4-difluorophenyl group, a 3,4-dichlorophenyl group, a 3,5-difluorophenyl group, a 2-amino-5-fluorophenyl group, a 2-isopropyl-5-methylphenyl group, a 4-cyanophenyl group, a 4-ethoxycarbonylphenyl group, a 2,6-di-tert-butyl-4-methylphenyl group, a 4-nitrophenyl group, a 4-sulfonylphenyl group, a 4-hydroxyphenyl group, a 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl group, or a 6-acetylnaphthalen-2-yl group, or X 2 together form an imidazolipiperazinyl, thienopiperazinyl, or pyrrolopiperazinyl group, which is optionally substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, ethyl ester, and phenyl.

[0028] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, L is optionally C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkoxy 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 groups, and C 2-4 C substituted with one or more substituents selected from alkynyl groups 3-6 It is an alkylene group.

[0029] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, L is optionally C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Haloalkyl group, C 1-4 Haloalkoxy group, C 3-6 Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono C 1-6 Alkylamino group, diC 1-6 Alkylamino group, C 2-4 Alkenyl groups, and C 2-4 C substituted with one or more substituents selected from alkynyl groups 3-6 is an alkylene group, and L is C 3 It is specified that it is not an alkylene group.

[0030] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, L is -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6- and -(CH 2 ) 2 CHCH 3 (CH 2 ) 2 -, preferably -(CH 2 ) 4 -or-(CH 2 ) 5 -It is.

[0031] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, L is -(CH 2 ) 4 -, -(CH 2 ) 5 -, -(CH 2 ) 6 - and -(CH 2 ) 2 CHCH 3 (CH 2 ) 2 -, preferably -(CH 2 ) 4 -or-(CH 2 ) 5 -It is.

[0032] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, X 1 is O, NH, NCH 3 , N.C.H. 2 CH 3 or N(CH 2 ) 2 CH 3 and preferably NH.

[0033] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, X 2 is O, NH, NCH 3 , N.C.H. 2 CH 3 or N(CH 2 ) 2 CH 3 or X 2 is R 3and form a condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group, wherein the condensed piperidinyl group, the condensed piperazine group, or the condensed pyrrolidinyl group is a condensed phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group, and the condensed piperidinyl group, the condensed piperazine group, or the condensed pyrrolidinyl group is optionally substituted with one or more substituents selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, methyl ester group, ethyl ester group, phenyl group, and substituted phenyl group. 2 is O or NH, or X 2 is R 3 together form an imidazolipiperazinyl, thienopiperazinyl, or pyrrolopiperazinyl group, which is optionally substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, ethyl ester, and phenyl.

[0034] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, S 1 , S 2 If one of the is a chemical bond, the other is -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) 5 -or-(CH 2 ) 6 -It is.

[0035] According to one embodiment, in the compound represented by the general formula (I) according to the present invention, or a stereoisomer or solvate thereof, Y - is a halogen anion, sulfate, acetate, tartrate, p-toluenesulfonate, methanesulfonate or citrate, preferably Cl - , Br - , C.H. 3 COO - and more preferably Br - It is.

[0036] According to one embodiment, the present invention provides a compound of formula (IV): [ka] [In the formula, X 1 is NR A 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably NH; X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably O, NH, NCH 3 , N.C.H. 2 CH 3 or N(CH 2 ) 2 CH 3 is more preferably O or NH, R 6 , R 7 , R 8 , R 9 , R 10are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups and C 1-4 Alkoxy C 1-4 selected from alkyl groups, R 1 , R 2 , L and Y - is defined in formula (I) above.], or a stereoisomer or solvate thereof is provided.

[0037] According to one embodiment, in the compound represented by the above formula (I) according to the present invention, or a stereoisomer or solvate thereof, the compound is represented by the formula (IV) (wherein R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups and C 1-4 Alkoxy C 1-4 alkyl groups, optionally with two adjacent substituents and the atoms connected thereto joining together to form a ring.

[0038] According to one embodiment, the present invention provides a compound of formula (V): [ka] [In the formula, X 1 is NR A 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably NH; X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably O, NH, NCH 3 , N.C.H. 2 CH 3 or N(CH 2 ) 2 CH 3 and more preferably O or NH. R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups, and C 1-4 Alkoxy C 1-4 selected from alkyl groups, R 1 , R 2 , L and Y - is defined in formula (I) above. The compound represented by the above formula (I) has the structural feature represented by:

[0039] According to one embodiment, in the compound represented by the above formula (I) according to the present invention, or a stereoisomer or solvate thereof, the compound is represented by the formula (V) (wherein R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups, and C 1-4 Alkoxy C1-4 alkyl groups, optionally with two adjacent substituents and the atoms connected thereto joining together to form a ring.

[0040] According to one embodiment, the present invention provides a compound of formula (VI): [ka] [In the formula, X 1 is NR A 4 (However, R A 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably NH; X 3 is C or N, R 10 is hydrogen, C 1-4 Alkyl group, C 1-4 Alkoxy group, C 1-4 Alkoxy C 1-4 alkyl groups, aromatic hydrocarbon groups, wherein the aromatic hydrocarbon groups are optionally selected from fluorine, chlorine, bromine, iodine, hydroxyl groups, cyano groups, nitro groups, amino groups, ester groups, C 1-4 Alkyl group, C 1-4 Alkoxy groups, and C 1-4 Alkoxy C 1-4 It is substituted with one or more substituents selected from alkyl groups, R 1 , R 2 , L and Y - is defined in formula (I) above. The compound represented by the above formula (I) has the structural feature represented by:

[0041] According to one embodiment, the present invention provides a compound of formula (VII): [ka] [In the formula, X 2 are O, S and NR B 4 (However, R B 4 are hydrogen, deuterium, and C 1-8 Alkyl group, C 3-8 Cycloalkyl group or C 1-4 Alkoxy C 1-4 is an alkyl group), preferably O, NH, NCH 3 , N.C.H. 2 CH 3 or N(CH 2 ) 2 CH 3 is more preferably O or NH, R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups, and C 1-4 Alkoxy C 1-4 selected from alkyl groups, L and Y - is defined in formula (I) above. The compound represented by the above formula (I) has the structural feature represented by:

[0042] According to one embodiment, in the compound represented by the above formula (I) according to the present invention, or a stereoisomer or solvate thereof, the compound is represented by the formula (VII) (wherein R 6 , R 7 , R 8 , R 9 , R 10 are each independently hydrogen, fluorine, chlorine, bromine, iodine, a hydroxyl group, a cyano group, a nitro group, an amino group, an ester group, C 1-4 Alkyl group, C 1-4 Alkoxy groups, and C 1-4 Alkoxy C1-4 alkyl groups, optionally with two adjacent substituents and the atoms connected thereto joining together to form a ring.

[0043] In one specific embodiment, the compound is selected from those having the structure shown below: [ka] [ka] [ka] TIFF2025515874000013.tif81166

[0044] In another specific embodiment, the compound is selected from those having the structure shown below: [ka] [ka] [ka] [ka]

[0045] A second aspect of the present application relates to a method for preparing a compound of general formula (I) according to any one of the first aspects of the present application, or a stereoisomer or solvate thereof, comprising the steps of: [ka] The method includes a step of reacting a compound represented by formula (II) with a compound represented by formula (III) to obtain compound (I), Here, Z in formula (II) is an electron-withdrawing leaving group such as bromine, chlorine or sulfonate, and the definitions of the groups in formulas (II) and (III) are the same as in formula (I).

[0046] In the preparation process according to the present application, the compound of formula (II) may be prepared by the method shown below. [ka] Here, the definitions of each group in formula (II-1) and formula (II-2) are the same as above.

[0047] A third aspect of the present application relates to a pharmaceutical composition comprising a compound of general formula (I) as defined in any one of the first aspects of the present application, or a stereoisomer or solvate thereof, and a pharma- ceutically acceptable carrier excipient or diluent.

[0048] A fourth aspect of the present application relates to the use of a compound of general formula (I) as defined in any one of the first aspect of the present application, or a stereoisomer or solvate thereof, or a pharmaceutical composition according to the third aspect of the present application, in the preparation of a local anesthetic or analgesic medicament.

[0049] In the use according to any one of the fourth aspects of the present application, the local anesthesia is a conduction anesthesia, a topical anesthesia or an infiltration anesthesia, and the analgesic is suitably used for chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain or idiopathic pain.

[0050] In any one of the uses according to the fourth aspect of the present application, the method of administration for anesthesia or analgesia is local administration via a mucosal route, such as transdermal, subcutaneous, intradermal, intramuscular, paraneural, intrapulpal, intraspinal, epidural, intravenous or ophthalmic.

[0051] A fifth aspect of the present application relates to a method for local anesthesia or analgesia, comprising administering to an individual in need thereof an effective amount of a compound of formula (I) as described in any one of the first aspect of the present application, or a stereoisomer or solvate thereof, or a pharmaceutical composition according to the third aspect of the present application, said administration being local via a mucosal route, such as transdermal, subcutaneous, intradermal, intramuscular, paraneural, intrapulpal, intraspinal, epidural, intravenous or ophthalmic.

[0052] (Beneficial Effects of the Present Application) According to the present application, a cyclic quaternary ammonium salt compound with a novel structure is provided. Experiments have demonstrated that the compound according to the present application has a long-lasting local anesthetic effect after a single administration, and has the advantages of not causing damage to motor nerves, being highly safe, having a fast onset of effect, and having low skin irritation. According to the present application, in order to eliminate the short duration of local anesthetics that have been used clinically up to now, and the occurrence of tissue and neurotoxicity and skin irritation, a long-acting local anesthetic with a novel structure is provided, and a new medical strategy is proposed for the treatment of anesthesia and analgesia.

[0053] Here, the terms used to describe the present invention in the specification and claims are defined as follows. For a particular term, if the meaning defined in this application does not match the meaning commonly understood by those skilled in the art, the meaning defined in this application shall prevail. If not defined in this application, the term shall have the meaning commonly understood by those skilled in the art.

[0054] The compound names in this application correspond to their structural formulas. If the compound names and structural formulas are not consistent, the structural formulas shall prevail or may be deduced in accordance with the specific circumstances of the present invention in conjunction with the knowledge of those skilled in the art.

[0055] The term "alkyl group" as used in this application refers to a linear or branched monovalent saturated hydrocarbon group.

[0056] "C 1-8The term "alkyl group" refers to straight or branched alkyl groups having from 1 to 8 carbon atoms, i.e., 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms, and typically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, neopentyl, pentyl and hexyl groups, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2 ... butyl group, 1,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 2,3-dimethylbutyl group, n-heptyl group, 2-methylhexyl group, 3-methylhexyl group, 4-methylhexyl group, 5-methylhexyl group, 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, etc. 1-4 The term "alkyl group" refers to a straight or branched alkyl group having 1, 2, 3 or 4 carbon atoms, i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. The alkyl group in this application is preferably 1-6 is an alkyl group, more preferably C 1-4 It is an alkyl group.

[0057] The term "alkylene group" as used herein refers to a saturated linear or branched aliphatic hydrocarbon group having 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 linear or branched group having 1 to 16 carbon atoms, preferably an alkylene group having 1 to 6 carbon atoms. Non-limiting examples of "alkylene groups" include -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 )5 -, -(CH 2 ) 6 - but are not limited to these.

[0058] As used herein, the term "alkenylene group" refers to a group formed formally by removing two hydrogen atoms from an alkene. Non-limiting examples of "alkenylene groups" include -CH=CH-, [ka] These include, but are not limited to:

[0059] As used herein, the term "alkynylene group" refers to a group formed formally by removing two hydrogen atoms from an alkyne. Non-limiting examples of "alkynylene groups" include: [ka] These include, but are not limited to:

[0060] The term "alkoxy group" as used in this application refers to -O-(alkyl group) and -O-(unsubstituted cycloalkyl group), where alkyl group is defined above. Non-limiting examples of "alkoxy group" include, but are not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy groups.

[0061] As used in this application, 2-4 The term "alkenyl group" refers to an alkenyl group having 2 to 4 carbon atoms and having one or two carbon-carbon double bonds. When there is more than one carbon-carbon double bond, the carbon-carbon double bonds may be conjugated or non-conjugated. 2-4 Non-limiting examples of "alkenyl groups" include, but are not limited to, vinyl groups and ethylene groups.

[0062] As used in this application,2-4 The term "alkynyl group" refers to an alkynyl group having 2 to 4 carbon atoms and one or two carbon-carbon triple bonds. When one or more carbon-carbon triple bonds are present, the carbon-carbon triple bonds may be conjugated or non-conjugated. 2-4 Non-limiting examples of an "alkynyl group" include, but are not limited to, an ethynyl group.

[0063] The term "cycloalkyl group" as used herein refers to a saturated carbocyclic group having 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 groups" include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

[0064] The term "halogen" as used in this application refers to fluorine, chlorine, bromine and iodine atoms.

[0065] The term "aromatic hydrocarbon group" as used herein refers to a monocyclic or bicyclic aromatic system containing at least one unsaturated aromatic ring, preferably an aryl group having from 6 to 10 carbon atoms, i.e., 6, 7, 8, 9 or 10. Non-limiting examples of "aromatic hydrocarbon groups" include, but are not limited to, phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and indenyl groups.

[0066] 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, 0 and S, preferably an aromatic heterocyclic group having 5 to 10 carbon atoms, i.e., 5, 6, 7, 8, 9 or 10. Non-limiting examples of "heteroaryl groups" include, but are not limited to, thienyl, 2-pyridyl, 3-pyridyl, thiazolyl, isothiazolyl, furyl, pyrrole, triazolyl, imidazolyl, and the like.

[0067] The term "heterocycloalkyl group" as used herein refers to a monocyclic or bicyclic saturated ring system optionally substituted with at least one and up to four heteroatoms independently selected from N, O and S, preferably a heterocyclic group having 4 to 10 atoms, i.e., 4, 5, 6, 7, 8, 9 or 10 atoms (provided that the heterocyclic ring does not include two adjacent O or S atoms). Non-limiting examples of "heterocycloalkyl groups" include, but are not limited to, pyrrolidinyl, piperidinyl, morpholinyl or piperazinyl groups.

[0068] The term "haloalkyl group," as used herein, refers to an alkyl group substituted with one or more halogens, where alkyl group is defined above.

[0069] The term "haloalkoxy group," as used herein, refers to an alkoxy group substituted with one or more halogens, where alkoxy group is defined above.

[0070] The term "solvate" as used herein refers to a physical combination of the compound of the present invention with one or more solvent molecules. Representative solvates include organic solvents such as methanolates, ethanolates, and acetonitriles, and hydrates such as monohydrates, sesquihydrates, and dihydrates.

[0071] As used herein, the term "hydroxyl group" refers to --OH.

[0072] The term "amino group" as used herein means -NH 2 This refers to:

[0073] As used herein, the term "cyano" refers to --CN.

[0074] As used herein, the term "nitro group" refers to -NO 2 This refers to:

[0075] The term "sulfonyl group" as used herein means -SO 3 It refers to H.

[0076] The term "ethoxycarbonyl group" as used herein refers to -COOEt.

[0077] The term "ester group" as used herein refers to a -C(O)O(alkyl group) or -C(O)O(cycloalkyl group), where alkyl and cycloalkyl groups are defined above.

[0078] The term "acyl group" as used herein refers to -C(O)(alkyl group), -C(O)H or -C(O)O(cycloalkyl group), where alkyl and cycloalkyl groups are defined above.

[0079] As used herein, the term "two adjacent substituents and the atoms connected thereto together form a ring" refers to the formation of a carbocyclic or heterocyclic ring selected from O, N and S. Optionally, the ring may be substituted with an alkyl or alkoxy group.

[0080] The term "long-acting" as used herein refers to a drug being considered long-acting if its duration of anesthetic action is longer than that of a standard concentration of levobupivacaine hydrochloride alone.

[0081] "Optionally" or "optionally" means that the event or circumstance described below may, but does not necessarily, occur, i.e., it includes cases where the event or circumstance occurs and cases where it does not occur. For example, "an aryl group optionally substituted with an alkyl group" means that the alkyl group may, but does not necessarily, be present, i.e., it 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.

[0082] Other features and advantages of the present application will be set forth in the specification which follows, and in part will be obvious from the specification, or will be learned by the practice of the present application. Other advantages of the present application may be realized and obtained by the aspects described herein. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0083] The implementation process and beneficial effects of the present invention will be described in detail below with reference to specific examples, but these are merely for the purpose of helping to better understand the gist and characteristics of the present invention, and are not intended to limit the scope of the present invention. In addition, the following examples are only used to explain the present application, and should not be considered as limiting the scope of the present application.

[0084] The structures of the compounds are determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR displacements (δ) are 10 -6 The unit of NMR is 1.5. TM 400 MHz Plus was used, and the measurement solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) and tetramethylsilane (TMS) was used as the internal standard.

[0085] For MS measurements, a Waters Qda MS KAD 3195 portable mass spectrometer was used.

[0086] For HPLC measurements, a Waters 2545-2767-2489 high performance liquid chromatography (column: Epic Polar 5u 120A 25 cm x 30 mm) was used.

[0087] As the silica gel plate for thin layer chromatography, GF254 silica gel plate manufactured by Seia Reagents was used.

[0088] In the column chromatography, 200-300 mesh silica gel manufactured by Qingdao Marine Chemical Co., Ltd. was used as a carrier.

[0089] Starting materials known in the present application may be synthesized by methods known in the art or purchased from commercial reagent manufacturers such as Aladdin, Bidepharm, and WuXi AppTec.

[0090] Explanation of chemical synthesis abbreviations: TLC: Thin Layer Chromatography HPLC: High-performance liquid chromatography MS: Mass spectrometry 1 H NMR: Proton nuclear magnetic resonance spectrum 13 C NMR: Carbon nuclear magnetic resonance spectrum V / m: The previous equivalent (eq) stands for volume-to-mass ratio, which is the ratio of volume to mass. m / m: The previous equivalent (eq) indicates a mass ratio, which is the ratio of mass to mass.

[0091] Example 1 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(phenylamino)butyl)piperidine bromide [ka]

[0092] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0093] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and aniline (1.34mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 1 (0.10g, yield 15.85%, HPLC>98%). MS m / z=436.40[M] + . 1 H NMR (400MHz, CD 3OD):δ12.26(s,1H),10.09(s,1H),7.12-6.97(m,5H),6.72-6.53(m,3H),6.42(s,1H),4.56(t,1H),3.38-3.11(m,8H) ),2.21-2.13(m,6H),1.98-1.92(m,2H),1.78-1.69(m,6H),1.58-1.45(m,2H),1.43-1.25(m,4H),0.97-0.82(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.5,17.4,18.1,19.0,19.4,22.4,23.9,26.9,29.0,50.8,52.7,55.9, 79.3,114.5,121.7,128.1,128.9,129.6,131.8,137.6,144.9,161.8,172.3.

[0094] Example 2 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(p-tolueneamino)butyl)piperidine bromide [ka]

[0095] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0096] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and stirred to dissolve, then analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and p-methylaniline (1.34mmol, 1.2eq, 0.14g) were added, and the reaction was carried out by heating to 80°C, and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 2 (0.11g, yield 17.06%, HPLC>98%). MS m / z (ESI) = 450.34 [M] + . 1 H NMR (400MHz, CD 3 OD):δ12.29(s,1H),10.11(s,1H),7.16-6.99(m,5H),6.55-6.43(m,3H),4.58(t,1H),3.35-3.14(m,8H),2.36(s,3H) ),2.21-2.11(m,6H),1.97-1.91(m,2H),1.70-1.61(m,6H),1.51-1.49(m,2H),1.41-1.21(m,4H),0.99-0.85(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ 14.1,17.6,18.3,19.0,19.4, 21.0,22.8, 23.7, 26.9,29.0,50.9,51.9,56.2,79.9,113.3,113.5,121.7,127.1,128.0,129.6,129.8,131.9,137.8,144.5,162.0,172.5.

[0097] Example 3 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(p-fluorophenylamino)butyl)piperidine bromide [ka]

[0098] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0099] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and p-fluoroaniline (1.34mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 3 (0.11g, yield 16.96%, HPLC>98%). MS m / z (ESI) = 454.30 [M] + . 1 H NMR (400MHz, CD 3OD):δ12.22(s,1H),10.09(s,1H),7.09-6.97(m,7H),6.43(s,1H),4.51(t,1H),3.35-3.17(m,8H),2.33-2 .10(m,6H),1.92-1.80(m,2H),1.71-1.62(m,6H),1.52-1.45(m,2H),1.32-1.21(m,4H),0.97-0.82(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ14.0,17.5,18.3,19.0,19.5,22.3,23.5,26.5,28.9,50.9,52.2,55.8,79. 6,114.8,116.7,119.1,126.9,127.9,131.0,137.9,144.0,155.9,162.8,172.1.

[0100] Example 4 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(phenoxy)butyl)piperidine bromide [ka]

[0101] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0102] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and phenol (1.34mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 4 (0.12g, yield 19.04%, HPLC>98%). MS m / z=437.50[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.23(s,1H),10.02(s,1H),7.27-7.20(m,2H),7.12-7.05(m,3H),6.98-6.93(m,3H),4.51-4.58(t,1H),4.07-4.01 (t,1H),3.41-3.20(m,6H),2.25-2.10(m,6H),1.97-1.90(m,2H),1.78-1.61(m,8H),1.46-1.31(m,4H),0.94-0.88(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.9,17.3,17.9,19.1,19.5,22.3,23.4,26.5,28.6,51.3,56.7,56.9,68.8, 79.9,113.5,114.3,120.7,126.9,127.9,129.9,130.9,137.3,159.3,161.6,172.2.

[0103] Example 5 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(m-tolyloxy)butyl)piperidine bromide [ka]

[0104] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0105] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and 3-methylphenol (1.34mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 5 (0.13g, yield 20.17%, HPLC>98%). MS m / z=451.60[M] + . 1 H NMR (400MHz, CD 3OD):δ12.22(s,1H),10.06(s,1H),7.18-7.15(t,1H),7.05(s,3H),6.79-6.72(m,3H),4.56(t,1H),4.09-4.05(m,2H),3 .39-3.12(m,6H),2.30(s,3H),2.28-2.06(m,6H),1.96-1.91(m,2H),1.75-1.59(m,8H),1.45-1.23(m,4H),0.93(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.9,17.5,17.9,19.1,19.6,21.8,22.5,23.5,26.4,28.5,51.9,56.9 ,57.2,68.9,79.9,111.3,113.5,113.9,120.7,126.9,128.2,129.5,130.8, 137.9,139.8,157.9,161.8,172.8.

[0106] Example 6 (2S)-1-(4-(2-amino-5-fluorophenoxy)butyl)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0107] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,4-dibromobutane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100 °C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1b (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 423.34[M] + ,425.34[M+2H] + .

[0108] Step 2 Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and 2-amino-5-fluorophenol (1.34mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain yellow solid compound 6 (0.10g, yield 15.79%, HPLC>98%). MS m / z=470.36[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.25(s,1H),10.06(s,1H),10.03(s,1H),7.09(s,3H),6.89-6.82 (m,1H),6.79(s,1H),6.57-6.51(m,1H),6.49-6.42(m,1H),4.57(t,1H), 3.38-3.16(m,8H),2.25-2.08(m,6H),1.99-1.80(m,2H),1.74-1.56(m,6 H),1.55-1.45(m,2H),1.45-1.19(m,4H),1.45-1.23(m,4H),0.88(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.2,17.8,18.5,19.3,19.6,22.5,23.3,26.5,28.8,51.5,52.0,56.8,79.8,1 04.9,109.1,113.8,116.7,126.8,127.9,130.9,135.7,137.3,143.5,161.6,172.2.

[0109] Example 7 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(phenylamino)pentyl)piperidine bromide [ka]

[0110] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0111] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and aniline (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 7 (0.12g, yield 18.61%, HPLC>98%). MS m / z=450.60[M] + . 1 H NMR (400MHz, CD 3OD):δ12.24(s,1H),10.04(s,1H),7.09-7.03(m,5H),6.68-6.54(m,3H),6.45(s,1H),4.60(t,1H),3.40 -3.05(m,8H),2.23-2.11(m,6H),1.96-1.90(m,2H),1.79-1.56(m,8H),1.38-1.20(m,6H),0.91(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.0,17.8,19.2,19.5,22.4,23.3,25.5,25.7,31.6,44.1,51.8,56.9,56.7, 79.9,113.5,113.6,121.0,129.0,128.7,129.7,130.9,137.3,145.2,161.5,172.2.

[0112] Example 8 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(methyl(phenyl)amino)pentyl)piperidine bromide [ka]

[0113] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0114] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and N-methylaniline (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 8 (0.11g, yield 16.70%, HPLC>98%). MS m / z=464.50[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.20(s,1H),10.01(s,1H),7.29-7.20(m,2H),7.09-7.01(m,3H),6.98-6.92(m,2H),6.86-6.80(m,1H),4.60-4.54(m,1H),3.39 -3.10(m,8H),2.75(s,3H),2.25-2.10(m,6H),1.93-1.88(m,2H),1.79-1.60(m,6H),1.58-1.45(m,2H),1.41-1.25(m,6H),0.90(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.6,19.0,19.3,22.2,23.1,25.3,25.8,26.3,29.0 ,41.7,51.8,55.9,56.5,56.8,79.7,114.3,121.9,127.7,129.6,130.6,137.1,149.5,172.0.

[0115] Example 9 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(p-tolueneamino)pentyl)piperidine bromide [ka]

[0116] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0117] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and p-toluidine (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 9 (0.13g, yield 19.73%, HPLC>98%). MS m / z=464.70[M] + . 1 H NMR (400MHz, CD 3OD):δ12.26(s,1H),10.03(s,1H),7.10-7.01(m,5H),6.49-6.43(m,3H),4.60-4.56(s,1H),3.30-3.05(m,8H) ,2.33(s,3H),2.20-2.11(m,6H),1.98-1.90(m,2H),1.79-1.53(m,8H),1.42-1.16(m,6H),0.94-0.83(m,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.6,19.5,19.8,22.0,22.6,23.5,25.5,25.7,26.5,31.6,43.9,51.7 ,56.8,56.9,79.8,113.8,114.9,126.9,127.8,129.7,129.9,130.5,137.6,172.5.

[0118] Example 10 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(p-fluorophenylamino)pentyl)piperidine bromide [ka]

[0119] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0120] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and p-fluoroaniline (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain yellow powdery solid compound 10 (0.13g, yield 19.61%, HPLC>98%). MS m / z=468.50[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.26(s,1H),10.09(s,1H),7.12-6.97(m,5H),6.72-6.53(m,3H),6.42(s,1H),4.56(t,1H),3.38-3.11(m,8H) ),2.21-2.13(m,6H),1.98-1.92(m,2H),1.78-1.69(m,6H),1.58-1.45(m,2H),1.43-1.25(m,4H),0.97-0.82(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.5,17.4,18.1,19.0,19.4,22.4,23.9,26.9,29.0,50.8,52.7,55.9, 79.3,114.5,121.7,128.1,128.9,129.6,131.8,137.6,144.9,161.8,172.3.

[0121] Example 11 (2S)-1-Butyl-1-(5-(5,6-dihydroimidazole[1,2-a]pyrazin-7(8H)-yl)pentyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0122] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0123] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 5,6,7,8-tetrahydroimidazole[1,2-a]pyrazine (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain yellow powdery solid compound 11 (0.12g, yield 21.40%, HPLC>98%). MS m / z=480.55[M] + . 1 H NMR (400MHz, CD 3OD):δ12.20(s,1H),10.01(s,1H),7.08-7.02(m,3H),6.93-6.90(m,1H),6.76-6.72(m,1H),4.59(t,1H),4.10(t,2H),3.63(s,1H),3 .39-3.10(m,6H),2.85(t,2H),2.49(t,2H),2.25-2.13(m,6H),1.99-1.88(m,2H),1.78-1.60(m,6H),1.43-1.17(m,8H),0.90(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.1,17.9,19.5,19.6,22.5,23.6,25.4,25.6,26.3,28.3,39.4,56.7,56.7 ,56.9,57.1,57.3,79.9,118.6,126.4,126.9,127.8,130.9,137.3,152.9,172.5.

[0124] Example 12 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(1-methyl-3,4-dihydropyrrolid[1,2-a]pyrazin-2(1H)-yl)pentyl)piperidine bromide [ka]

[0125] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H]+ .

[0126] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and stirred to dissolve, then analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 1-methyl-1,2,3,4-tetrahydropyrro[1,2-a]pyrazine (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was heated to 80°C, and HPLC detection was performed until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain yellow powdery solid compound 12 (0.11g, yield 20.88%, HPLC>98%). MS m / z=493.48[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.23(s,1H),10.06(s,1H),7.09-7.01(m,4H),5.98-6.03(m,1H),5.76-5.70(m,1H),4.59(t,1H),4.06-3.93(m,3H),3.35-3.19(m, 6H),2.75-2.53(m,2H),2.46-2.39(m,2H),2.25-2.07(m,6H),1.97-1 .90(m,2H),1.82-1.59(m,6H),1.47-1.16(m,11H),0.92-0.86(m,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.9,17.6,18.6,19.4,19.7,22.6,23.4,25.4,25.7,26.7,28.6,43.4,51.7,54.1,54 .9,56.7,56.9,63.7,79.4,108.4,108.6,122.8,126.6,127.2,130.4,132.8,137.4,172.9.

[0127] Example 13 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(1-phenyl-3,4-dihydropyrrolid[1,2-a]pyrazin-2(1H)-yl)pentyl)piperidine bromide [ka]

[0128] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0129] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain yellow powdery solid compound 13 (0.14g, yield 21.98%, HPLC>98%). MS m / z=555.70[M] + . 1 H NMR (400MHz, CD3 OD):δ12.30(s,1H),10.13(s,1H),7.45-7.18(m,5H),7.01-7.09(m,4H),5.98- 6.02(m,1H),5.74-5.71(m,1H),5.19(s,1H),4.62-4.47(m,1H),3.99-3.96(m, 2H),3.38-3.10(m,6H),2.74-2.61(m,2H),2.48-2.41(m,2H),2.25-2.08(m,6H ),1.99-1.90(m,2H),1.77-1.59(m,6H),1.45-1.13(m,8H),0.96-0.87(m,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.7,17.1,19.4,19.4,22.9,23.4,25.7,26.4,28.4,43.7,51.7,51.7,53.1,54.7,56.4,56.7,7 1.6,79.0,107.9,108.6,119.4,122.7,126.6,127.0,127.4,128.1,130.5,134.9,137.5,138.4,173.2.

[0130] Example 14 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(phenoxy)pentyl)piperidine bromide [ka]

[0131] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0132] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and phenol (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 14 (0.13g, yield 20.17%, HPLC>98%). MS m / z=451.50[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.26(s,1H),10.09(s,1H),7.12-6.97(m,5H),6.72-6.53(m,3H),6.42(s,1H),4.56(t,1H),3.38-3.11(m,8H) ),2.21-2.13(m,6H),1.98-1.92(m,2H),1.78-1.69(m,6H),1.58-1.45(m,2H),1.43-1.25(m,4H),0.97-0.82(t,3H).

[0133] Example 15 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-(m-tolyloxy)pentyl)piperidine bromide [ka]

[0134] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0135] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 3-methylphenol (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 15 (0.12g, yield 18.22%, HPLC>98%). MS m / z=465.80[M] + . 1 H NMR (400MHz, CD 3OD):δ12.26(s,1H),10.09(s,1H),7.12-6.97(m,5H),6.72-6.53(m,3H),6.42(s,1H),4.56(t,1H),3.38-3.11(m,8H) ),2.21-2.13(m,6H),1.98-1.92(m,2H),1.78-1.69(m,6H),1.58-1.45(m,2H),1.43-1.25(m,4H),0.97-0.82(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.5,17.4,18.1,19.0,19.4,22.4,23.9,26.9,29.0,50.8,52.7,55.9, 79.3,114.5,121.7,128.1,128.9,129.6,131.8,137.6,144.9,161.8,172.3.

[0136] Example 16 (2S)-1-(5-(2-amino-5-fluorophenoxy)pentyl)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide TIFF2025515874000037.tif49161

[0137] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromopentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. TLC detection was performed. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 20:1 MeOH / 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1c (4.5 g, yield 59.13%, HPLC>90%). ESI-MS m / z: 437.30[M] + ,439.30[M+2H] + .

[0138] Step 2 Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 2-amino-5-fluorophenol (1.34mmol, 1.2eq, 0.13g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain yellow powdery solid compound 16 (0.12g, yield 17.71%, HPLC>98%). MS m / z=484.56[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.26(s,1H),10.09(s,1H),7.12-6.97(m,5H),6.72-6.53(m,3H),6.42(s,1H),4.56(t,1H),3.38-3.11(m,8H) ),2.21-2.13(m,6H),1.98-1.92(m,2H),1.78-1.69(m,6H),1.58-1.45(m,2H),1.43-1.25(m,4H),0.97-0.82(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.5,17.4,18.1,19.0,19.4,22.4,23.9,26.9,29.0,50.8,52.7,55.9, 79.3,114.5,121.7,128.1,128.9,129.6,131.8,137.6,144.9,161.8,172.3.

[0139] Example 17 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-((4-(trifluoromethyl)phenyl)amino)pentyl)piperidine bromide [ka]

[0140] Compound 1c (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1c, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1c, m / m, 0.50g) and 4-trifluoromethylaniline (1.34mmol, 1.2eq, 0.14g) were added, and the reaction was carried out by heating to 80°C. HPLC detection was performed until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1c, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 17 (0.18g, yield 26.47%, HPLC>98%). MS m / z=518.41[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.21(s,1H),11.92(s,1H),10.06(s,1H),7.23-7.15(m,2H),7.03-6.93(m,2H),6.88-6.78(m,3H),4.63-4.56(t,1H),4.1 9-4.04(t,1H),3.41-3.27(m,8H),2.35-2.19(m,6H),1.96-1.88(m,2H),1.76-1.59(m,8H),1.45-1.33(m,4H),0.96-0.87(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ14.2,16.7,17.6,18.3,19.6,22.4,23.8,26.2,28.5,43.1,51.9,56.4,56.3,68.4,7 9.7,113.2,114.7,120.1,124.1,126.7,127.1,129.5,130.6,137.3,159.1,161.8,172.7.

[0141] Example 18 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(5-((4-fluorophenyl)amino)-3-methylpentyl)piperidine bromide [ka]

[0142] Step 1 Levobupivacaine 1a (17.36 mmol, 1.0 eq, 5 g) was weighed out, 1,5-dibromo-3-methylpentane (2.0 eq of levobupivacaine 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 The eluent collected by silica gel column chromatography under the conditions of 2:MeOH=20:1 was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 2d (4.3 g, yield 46.74%, HPLC>90%). ESI-MS m / z: 451.33 [M] + ,453.33[M+2H] + .

[0143] Step 2 Compound 2d (0.94 mmol, 1 eq, 0.50 g) was weighed, and analytical grade acetonitrile (10 eq of 2d, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1 eq of 2d, m / m, 0.50 g) and 4-fluoroaniline (1.13 mmol, 1.2 eq, 0.13 g) were added, and the temperature was raised to 80 °C to react, and HPLC detection was performed until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30 eq of 2d, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 18 (0.19 g, yield 36.05%, HPLC>98%). MS m / z=482.41[M] + . 1 H NMR (400MHz, CD 3OD):δ12.16(s,1H),11.75(s,1H),10.05(s,1H),7.21-7.18(m,2H),7.04-6.94(m,2H),6.91-6.82(m,3H),4.68-4.59(t,1H),4.1 6-4.09(t,1H),3.46-3.29(m,8H),2.39-2.28(m,6H),1.96-1.90(m,2H),1.74-1.58(m,8H),1.43-1.29(m,3H),0.93-0.80(m,6H). 13 C NMR (400 MHz, CD 3 OD):δ14,1,16.6,17.5,18.3,19.7,20.6,22.4,23.8,26.1,28.6,43.4,52.1,56.8,57.3, 69.1,78.2,113.1,113.5,121.1,126.3,127.2,129.8,130.6,136.1,158.1,161.8,172.7.

[0144] Example 19 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(homotrimethylamino)butyl)piperidine bromide [ka]

[0145] Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and 2,4,6-trimethylaniline (1.34mmol, 1.2eq, 0.18g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 19 (0.16g, yield 24.75%, HPLC>98%). MS m / z (ESI) = 478.48 [M]+ . 1 H NMR (400MHz, CD 3 OD): δ12.23(s,1H),10.11(s,1H),7.20-7.12(m,2H),6.92-6.86(m,4H),4.55-4.49(t,1H),4.15-4.03(t,1H),3. 38-3.21(m,6H),2.22-2.13(m,6H),1.99-1.91(m,2H),1.79-1.60(m,8H),1.43-1.30(m,4H),0.99-0.80(t,12H). 13 C NMR (400 MHz, CD 3 OD): δ13.7,17.6,17.9,18.3,18.6,19.1,19.6,21.9,23.1,23.4,26.6,28.9,51.4,56.3,56. 8,68.6,79.9,113.4,114.3,120.2,126.7,127.6,129.5,130.3,137.9,158.6,161.3,172.7.

[0146] Example 20 (2S)-1-Butyl-1-(4-((4-chlorophenyl)amino)butyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0147] Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and 4-fluoroaniline (1.34mmol, 1.2eq, 0.17g) were added, and the mixture was heated to 80°C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white powdery solid compound 20 (0.10g, yield 16%, HPLC>98%). MS m / z (ESI) = 470.39 [M] + . 1 H NMR (400MHz, CD 3 OD):δ12.01(s,1H),10.19(s,1H),7.29-7.21(m,2H),7.16-7.07(m,2H),6.99-6.92(m,3H),6.43(s,1H),4.55-4.50(t,1H),4.06 -4.00(t,1H),3.40-3.23(m,6H),2.27-2.13(m,6H),1.98-1.90(m,2H),1.79-1.63(m,8H),1.44-1.32(m,4H),0.96-0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.5,17.6,17.7,19.3,19.2,22.6,23.9,26.3,29.4,51.3,56.7,57.9,66.8, 78.9,113.7,114.3,120.6,126.4,127.3,129.7,130.9,136.3,158.3,160.4,170.5.

[0148] Example 21 (2S)-1-Butyl-1-(4-((3,4-difluorophenyl)amino)butyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0149] Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1b, m / m, 0.50g) and 3,4-difluoroaniline (1.34mmol, 1.2eq, 0.17g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 21 (0.13g, yield 21.18%, HPLC>98%). MS m / z (ESI) = 472.31 [M] + . 1 H NMR (400MHz, CD 3 OD):δ12.09(s,1H),10.33(s,1H),7.28-7.20(m,2H),7.15-7.09(m,1H),6.98-6.90(m,3H),6.42(s,1H),4.51-4.45(t,1H),4.31 -4.26(t,1H),3.43-3.26(m,6H),2.28-2.16(m,6H),1.96-1.91(m,2H),1.79-1.60(m,8H),1.43-1.30(m,4H),0.95-0.87(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.4,15.9,16.3,18.9,19.5,23.6,25.9,27.3,28.7,51.3,56.8,57.4,66.3, 78.7,113.6,114.6,122.8,124.4,125.3,129.6,130.9,136.3,158.3,160.4,170.5.

[0150] Example 22 (2S)-1-Butyl-2-((4-fluorophenyl)carbamoyl)-1-(4-(m-tolyloxy)butyl)piperidine bromide [ka]

[0151] Step 1 (L) 2-Piperidine acid 1d (7.75 mmol, 1 eq, 1 g) was weighed out, and HCl ethanol solution (20 eq of 1d, V / m, 20 ml) was added and stirred to dissolve. The reaction was then heated to 30° C. and stirred for 2 h. The solvent was then spin-dried to give 1.28 g of a white solid 1e.

[0152] Step 2 1.28 g of the white solid 1e was weighed out, and dichlorosulfoxide (10 eq of 1e, V / m, 10 ml) was added and stirred. Five drops of DMF solution were added to completely dissolve the white solid. The reaction was then heated to 40°C and stirred for 3.5 h. The solvent was then spin-dried to obtain 1.41 g of a brown solid 1f.

[0153] Step 3 4-Fluoroaniline (15.5 mmol, 2 eq, 2.09 g) was dissolved in 10 ml of toluene, 1f (7.75 mmol, 1 eq, 1.41 g) was weighed, toluene (10 eq of 1f, V / m, 20.0 ml) was added and stirred to dissolve, and the toluene solution in which 4-fluoroaniline was dissolved was added dropwise within 5 min. Detection was performed by thin layer chromatography until the reaction was completed. The reaction solution was extracted with 50 ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected and spin-dried, and the eluent was changed to CH. 2 Cl 2 The eluent collected by silica gel column chromatography in a 20:1 mixture of MeOH and toluene was evaporated and concentrated on a rotary evaporator to give 1 g of a tan solid (0.83 g, 43.73% yield, HPLC>98%). ESI-MS m / z: 223.13 [M+1] + .

[0154] Step 4 Weigh out 1g (3.73mmol, 1eq, 0.83g), add analytical grade acetonitrile (10eq per 1g, V / m, 8.0ml) and stir to dissolve, then add analytical grade potassium carbonate (4.48mmol, 1.2eq, 0.57g) and bromobutane (4.48mmol, 1.2eq, 0.61g), heat to 80°C and react, and perform thin layer chromatography detection until the reaction is complete. Then, filter the reaction solution, wash the filter cake with 15ml of acetonitrile three times, collect the filtrate and spin dry to obtain a tan solid 1h (0.94g, yield 90.6%, HPLC>98%). ESI-MS m / z: 279.3[M+1] + .

[0155] Step 5 The tan solid 1h (0.94 g) was dissolved in 1,4-dibromobutane (20 eq of 1h, V / m, 3 ml) and the reaction was carried out at 100 °C. The reaction was monitored by thin layer chromatography until completion. The eluent was changed to CH 2 Cl 2 The eluent collected by silica gel column chromatography in a 20:1 mixture of 1,2-dichlorophenyl ether (MeOH) and 1,2-dichlorophenyl ether (MeOH) was evaporated and concentrated using a rotary evaporator to give a tan solid 1i (450 mg, 13.25% yield, HPLC>98%). MS m / z=413.3[M] + ,415.3[M+2] + .

[0156] Step 6 1i (0.37mmol, 1eq, 0.15g) was weighed, and analytical grade acetonitrile (10eq of 1i, V / m, 5.0ml) was added and dissolved by stirring. Then, analytical grade potassium carbonate (0.44mmol, 1.2eq, 0.06g) and 4-fluoroaniline (0.74mmol, 2eq, 0.07g) were added, and the mixture was heated to 80°C for reaction. The reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1i, V / m, 10ml, in three portions), and the collected filtrate was separated to obtain white solid compound 22 (16.06mg, yield 9.33%, HPLC>98%). MS m / z=444.36[M] + . 1 H NMR (400MHz, CD 3 OD): δ9.97(s,1H),7.60(d,2H),7.17-7.15(m,3H),6.78(s,3H),4.06(t,2 H),2.34-2.28(m,9H),1.75-1.74(m,4H),1.36-1.30(m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,20.4,21.6,23.0,24.5,27.3,30.4,35.0,36.5,51.0,53.0,68.4, 111.4,113.2,115.7,120.6,126.1,129.2,131.5,139.0,157.3,161.0,162.9.

[0157] Example 23 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(2-isopropyl-5-methylphenoxy)butyl)piperidine bromide [ka]

[0158] Compound 1b (1.14mmol, 1eq, 0.50g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2eq of 1b, m / m, 0.50g) and thymol (1.34mmol, 1.2eq, 0.14g) were added, and the reaction was carried out by heating to 80°C. The reaction was then detected by thin layer chromatography until the reaction was complete. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 23 (0.02g, yield 2.92%, HPLC>98%). MS m / z=493.45[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.23(m,1H),7.05-6.87(m,4H),6.71(d,1H),4.58-4.42(m,1H),4.06-3.91(m,2H),3.22-3.0 5(m,7H),2.23(s,3H),2.13-1.92(m,6H),1.90-1.81(m,2H),1.78-1.45(m,8H),1.30-1.20(m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.2,19.0,19.3,21.6,22.2,23.1,23.6,26.3,27.6,28.1,51.8,56.5,56 .8,68.7,79.7,111.5,126.8,127.7,128.6,129.7,130.7,137.1,137.7,149.5,172.0.

[0159] Example 24 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(4-fluorophenoxy)butyl)piperidine bromide [ka]

[0160] Compound 1b (0.71 mmol, 1 eq, 0.30 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and p-fluorophenol (1.42 mmol, 2 eq, 0.2 g) were added, and the mixture was heated to 80 °C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white solid compound 24 (123.5 mg, yield 23.29%, HPLC>98%). MS m / z=455.43[M] + . 1 H NMR (400MHz, CD 3 OD):δ9.70(s,1H),7.59(d,2H),7.19-7.09(m,6H),4.06(t,2H),3.04(t ,1H),2.34(t,4H),1.99-1.72(m,6H),1.55-1.30(m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,20.7,21.5,22.0,23.3,25.7,27.6,27.9,59.1,60.1,60.4,68.4,78.5,116.0,116.1,120.6, 134.1,154.5,155.0,162.9,172.0.

[0161] Example 25 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(homotrimethylphenoxy)butyl)piperidine bromide [ka]

[0162] Compound 1b (0.83 mmol, 1 eq, 0.35 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and 2,4,6-trimethylphenol (1.66 mmol, 2 eq, 0.22 g) were added, and the mixture was heated to 80 °C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white solid compound 25 (176.87 mg, yield 31.8%, HPLC>98%). MS m / z=479.47[M] + . 1 H NMR (400MHz, CD 3 OD):δ9.70(s,1H),7.59(dd,2H),7.14 (t,2H),6.97(s,2H),4.06(t,2H),3.04(t,1H),2.34(t,4H),2.18-2.15(m,9H),1.99-1.72(m,6H),1.55-1.30(m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,16.0,20.7,21.9,22.0,23.3,25.7,27.6,27.9,59.1,60.1,60.4,69.0,78.5,115.7,120.6, 122.0,129.8,131.2,134.1,151.5,162.9,172.0.

[0163] Example 26 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(3-fluorophenoxy)butyl)piperidine bromide [ka]

[0164] Compound 1b (0.83 mmol, 1 eq, 0.35 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and m-fluorophenol (1.66 mmol, 2 eq, 0.15 g) were added, and the mixture was heated to 80 °C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white solid compound 26 (164.81 mg, yield 30.7%, HPLC>98%). MS m / z=455.44[M] + . 1 H NMR (400MHz, CD 3 OD): δ9.70(s,1H),7.72(d,1H),7.59 (d,2H),7.44(td,1H),7.14-7.13 (m,3H),6.71(d,1H),4.06(t,2H),3.04(t,1H),2.34(t,4H),1.99-1.72(m,6H),1.55-1.30(m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.8,20.7,21.5,22.0,23.3,25.7,27.6,27.9,59.1,60.1,60.4,68.4,78. 5,102.5,107.1,110.0,115.7,120.6,129.6,134.1,159.0,159.7,162.9,172.0.

[0165] Example 27 (2S)-1-Butyl-1-(4-(3-cyanophenoxy)butyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0166] Compound 1b (0.71 mmol, 1 eq, 0.3 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and 3-hydroxybenzonitrile (1.42 mmol, 2 eq, 0.17 g) were added, and the temperature was raised to 80 °C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white solid compound 27 (101.52 mg, yield 22.1%, HPLC>98%). MS m / z=462.40[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.72(s,1H),7.60-7.53 (m,2H),7.22(d,1H),7.05 (s,3H),4.58(t,1H),4.06(t,2H),3.27-3.17(m,6H),2.17-1.92(m,8H),1.75-1.70(m,8H),1.30 -1.20(m,4H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.2,17.6,19.0,19.3,22.2,23.1,26.3,28.1,51.8,56.5,56.8,68.4, 79.7,113.2,118.6,118.7,123.8,126.8,127.7,130.0,130.7,137.1,158.1,172.0.

[0167] Example 28 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(3-(trifluoromethyl)phenoxy)butyl)piperidine bromide [ka]

[0168] Compound 1b (0.71 mmol, 1 eq, 0.3 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and m-trifluoromethylphenol (1.42 mmol, 2 eq, 0.26 g) were added, and the mixture was heated to 80 °C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated to obtain white solid compound 28 (173.34 mg, yield 36.01%, HPLC>98%). MS m / z=505.40[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.25(d,1H),7.16-7.15 (m,2H),7.05(s,3H),6.88 (d,1H),4.06(t,2H),3.04(t,1H),2.34(t,4H),2.13(s,6H),1.99-1.89(m,3H),1.75-1. 72 (m,3H),1.55 -1. 30 (m,10H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.8,17.6,20.7,21.5,22.0,23.3,25.7,27.6,27.9,59.1,60.1,60.4,68.4,78. 5,109.3,116.7,117.7,124.4,126.8,127.7,129.6,130.7,131.6,137.1,157.7,172.0.

[0169] Example 29 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(m-tolyloxy)butyl)piperidine chloride [ka]

[0170] A chloride ion exchange resin was prepared and washed with pure water (20 eq of chloride ion exchange resin, V / m, 20 ml, three times) until the pH of the liquid phase became alkaline, and then 1 g of prepared chloride ion exchange resin was obtained. Then, compound 5 (0.19 mmol, 1 eq, 0.1 g) was dissolved in a solvent (10 mL) of acetonitrile:water = 1:1, and prepared chloride ion exchange resin (4 eq of compound 5, m / m, 0.4 g) was added to the solution in the first time, stirred at room temperature for 0.5 h, filtered, and the filtrate was collected. Then, prepared chloride ion exchange resin (4 eq of compound 2, m / m, 0.4 g) was added to the filtrate in the second time, stirred at room temperature for 0.5 h, filtered, and the filtrate was collected. Then, the prepared chloride ion exchange resin (4 eq, m / m, 0.4 g of compound 5) was added to the filtrate for the third time, and the collected filtrate was spun dry to give white solid compound 29 (0.39 g, 20.17% yield, HPLC>98%). MS m / z=451.46[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.22(s,1H),10.06(s,1H),7.18-7.15(t,1H),7.05(s,3H),6.79-6.72(m,3H),4.56(t,1H),4.09-4.05(m,2H),3 .39-3.12(m,6H),2.30(s,3H),2.28-2.06(m,6H),1.96-1.91(m,2H),1.75-1.59(m,8H),1.45-1.23(m,4H),0.93(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.9,17.5,17.9,19.1,19.6,21.8,22.5,23.5,26.4,28.5,51.9,56.9 ,57.2,68.9,79.9,111.3,113.5,113.9,120.7,126.9,128.2,129.5,130.8, 137.9,139.8,157.9,161.8,172.8.

[0171] Example 30 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(o-tolyloxy)butyl)piperidine bromide [ka]

[0172] Compound 1b (0.70mmol, 1eq, 0.30g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade potassium carbonate (0.84mmol, 1.2eq, 0.12g of 1b) and 2-methylphenol (0.84mmol, 1.2eq, 0.09g) were added, and the mixture was heated to 80°C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 30 (67.55mg, yield 21.3%, HPLC>98%). MS m / z=451.44[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.16(d,1H),7.05(s,3H),6.93-6.85(m,3H),4.58 (t,1H),4.06(t,2H),3.27-3.17(m,6H),2.17-1.92(m,11H),1.75-1.71(m,8H),1.30-1.20(m,4H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.8,15.4,17.2,17.6,19.0,19.3,22.2,23.1,26.3,28.1,51.8,56.5,56.8,68. 7,79.7,112.3,120.0,126.3,126.7,126.8,127.7,130.7,131.2,137.1,155.4,172.0.

[0173] Example 31 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-(p-tolyloxy)butyl)piperidine bromide [ka]

[0174] Compound 1b (0.70mmol, 1eq, 0.30g) was weighed, and analytical grade acetonitrile (10eq of 1b, V / m, 5.0ml) was added and stirred to dissolve, then analytical grade potassium carbonate (0.84mmol of 1b, 1.2eq, 0.12g) and 4-methylphenol (0.84mmol, 1.2eq, 0.09g) were added, and the reaction was carried out by heating to 80°C, and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1b, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 31 (55.12mg, yield 17.4%, HPLC>98%). MS m / z=451.44[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.10-7.05(m,5H),6.81(d,2H),4.58 (t,1H),4.06(t,2H),3.27-3.17(m,6H),2.25-1.92(m,11H),1.75-1.70(m,8H),1.30-1.20(m,4H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.2,17.6,19.0,19.3,21.3,22.2,23.1,26.3,28.1,51.8,56.5,56 .8,68.4,79.7,114.3,126.8,127.7,129.6,130.0,130.7,137.1,156.4,172.0.

[0175] Using the same preparation method as in Example 4, the compounds according to the following Examples 32 and 33 were synthesized. [ka]

[0176] Example 34 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(3-phenoxypropyl)piperidine bromide [ka]

[0177] Step 1 Levobupivacaine 1a (14.35 mmol, 1.0 eq, 3.0 g) was weighed, 1,3-dibromopropane (2.0 eq of 1a, V / m, 10 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of toluene, MeOH = 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 1r (2.8 g, yield 59.9%, HPLC>90%). ESI-MS m / z: 409.18[M] + ,411.28[M+2H] + .

[0178] Step 2 Compound 1r (0.68mmol, 1eq, 0.28g) was weighed, and analytical grade acetonitrile (10eq of 1r, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1r, m / m, 0.50g) and phenol (1.36mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1r, V / m, 15ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 34 (0.33g, yield 45%, HPLC>98%). MS m / z=423.46[M] + . 1 H NMR (400MHz, CD 3 OD):δ11.32(s,1H),10.03(s,1H),7.28-7.21(m,2H),7.19-7.09(m,3H),6.99-6.98(m,3H),4.51-4.58(t,1H),4.01-3.97 (t,1H),3.49-3.11(m,4H),2.25-2.10(m,6H),1.98-1.91(m,2H),1.79-1.68(m,8H),1.49-1.36(m,4H),0.94-0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.7,17.4,17.9,19.4,19.9,22.7,23.4,26.5,28.8,54.3,55.9,69.8,78. 9,113.1,114.7,121.7,125.4,127.5,129.5,130.3,136.3,158.3,162.6,173.2.

[0179] Example 35 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(3-(m-tolyloxy)propyl)piperidine bromide [ka]

[0180] Compound 1r (0.68mmol, 1eq, 0.28g) was weighed, and analytical grade acetonitrile (10eq of 1r, V / m, 5.0ml) was added and dissolved by stirring. Analytical grade sodium bicarbonate (1eq of 1r, m / m, 0.50g) and m-cresol (1.36mmol, 1.2eq, 0.14g) were added, and the temperature was raised to 80°C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 1r, V / m, 15ml, in three portions), and the collected filtrate was separated to obtain white solid compound 35 (14.5mg, yield 6%, HPLC>98%). MS m / z=437.43[M]+ . 1 H NMR (400MHz, CD 3 OD):δ11.49(s,1H),10.11(s,1H),7.32-7.27(m,2H),7.22-7.09(m,2H),6.99-6.98(m,3H),4.51-4.58(t,1H),4.23-3.99(t,1H),3 .50-3.28(m,4H),2.25-2.10(m,6H),2.01-1.99(m,3H),1.95-1.90(m,2H),1.77-1.66(m,8H),1.44-1.33(m,4H),0.99-0.87(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.5,17.8,19.5,19.8,21.5,22.8,23.5,26.7,28.4,54.5,55.2,69.6, 78.2,113.8,114.7,121.7,125.8,127.3,129.8,130.1,136.9,158.2,162.8,173.6.

[0181] Example 36 (2S)-1-(Cyclopentylmethyl)-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-phenoxybutyl)piperidine bromide [ka]

[0182] Step 1 (L) 2-Piperidine acid 1d (7.75 mmol, 1 eq, 1 g) was weighed out and ethanolic HCl solution (20 eq of 1d, V / m, 20 ml) was added. The reaction was warmed to 30° C. and stirred for 2 h. The solvent was then spun off to give 1.28 g of a white solid, 1e.

[0183] Step 2 1.28 g of the white solid 1e was weighed out, and dichlorosulfoxide (10 eq of 1e, V / m, 10 ml) was added and stirred. Five drops of DMF solution were added to completely dissolve the white solid. The reaction was then heated to 40°C and stirred for 3.5 h. The solvent was then spin-dried to obtain 1.41 g of a brown solid 1f.

[0184] Step 3 2,6-Dimethylaniline (15.5mmol, 2eq, 2.09g) was dissolved in 10ml of toluene, 1f (7.75mmol, 1eq, 1.41g) was weighed, toluene (10eq of 1f, V / m, 20.0ml) was added and stirred to dissolve, and within 5min, the toluene solution in which 2,6-dimethylaniline had been dissolved was added dropwise. Detection was performed by thin layer chromatography until the reaction was completed. The reaction solution was extracted with 50ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected and spin-dried, and the eluent was changed to CH. 2 Cl 2 Silica gel column chromatography was performed under the condition of MeOH=20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 1j (0.83 g, yield 43.73%, HPLC>98%). ESI-MS m / z: 233.2 [M+1] + .

[0185] Step 4 1j (3.73 mmol, 1 eq, 0.83 g) was weighed, and analytical grade acetonitrile (10 eq of 1j, V / m, 8.0 ml) was added and stirred to dissolve, then analytical grade potassium carbonate (4.48 mmol, 1.2 eq, 0.57 g) and bromomethylcyclopentane (4.48 mmol, 1.2 eq, 0.61 g) were added, and the reaction was carried out by heating to 80 ° C., and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, the filter cake was washed three times with 15 ml of acetonitrile, and the filtrate was collected and spun dry to obtain a tan solid 1k (1.35 g, yield 90.6%, HPLC>98%). ESI-MS m / z: 315.2 [M+1] + .

[0186] Step 5 1.35 g of the tan solid 1k was dissolved in 1,4-dibromobutane (20 eq of 1h, V / m, 3 ml) and the reaction was carried out by heating to 100 °C. Thin layer chromatography was performed until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 The eluent collected by silica gel column chromatography in a 20:1 mixture of ethyl acetate and MeOH was concentrated in a rotary evaporator to give a tan solid 1l (1.33 g, 13.25% yield, HPLC>98%). MS m / z=449.35[M] + ,451.32[M+2] + .

[0187] Step 6 Weigh out 1L (0.7mmol, 1eq, 0.33g), add analytical grade acetonitrile (10eq in 1L, V / m, 5.0ml) and stir to dissolve, then add analytical grade potassium carbonate (0.84mmol, 1.2eq, 0.12g) and phenol (1.4mmol, 2eq, 0.13g), heat to 80℃, and perform reaction. Then, perform detection by thin layer chromatography until the reaction is completed. Then, filter the reaction solution, wash the filter cake with acetonitrile (30eq in 1L, V / m, 10ml, 3 times), and separate the collected filtrate to obtain white solid compound 36 (41.47mg, yield 10.63%, HPLC>98%). MS m / z=463.33[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.27(dd,2H),7.05(s,3H),6.93-6.92(m,3H),4.58 (t,1H),4.06(t,2H),3.27-3.16(m,6H),2.13-1.92(m,9H),1.90-1.63(m,14H),1.30-1. 13 C NMR (400 MHz, CD 3OD):δ17.2,17.6,19.3,22.2,24.8,26.3,28.1,29.1,34.9,52.1,57.2,62.2 ,68.4,80.0,114.4,120.3,126.8,127.7,129.3,130.7,137.1,159.4,172.0.

[0188] Example 37 (2S)-1-(isobutylmethyl)-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-phenoxybutyl)piperidine bromide [ka]

[0189] Step 1 1j (4.3 mmol, 1 eq, 1 g) was weighed, 10.0 ml of analytical grade acetonitrile was added and stirred to dissolve, then analytical grade potassium carbonate (5.16 mmol, 1.2 eq, 0.71 g) and 1-bromo-2-methylpropane (8.6 mmol, 2 eq, 1.16 g) were added, and the mixture was heated to 80°C to carry out the reaction, followed by detection by thin layer chromatography until the reaction was complete. The reaction solution was then filtered, the filter cake was washed three times with 15 ml of acetonitrile, and the filtrate was collected and spin-dried to obtain a tan solid 1s (1.23 g, 97% yield, HPLC>98%). ESI-MS m / z: 289.32 [M+1] + .

[0190] Step 2 1.23 g of the yellowish brown solid 1s was dissolved in 3 ml of 1,4-dibromobutane, and the reaction was carried out by heating to 100 °C. The reaction was detected by thin layer chromatography until the reaction was completed. Then, the eluent was changed to CH 2 Cl 2 The eluent collected by silica gel column chromatography under the conditions of 20:1 MeOH was evaporated and concentrated using a rotary evaporator to obtain a tan solid 1t (0.18 g, 10% yield, HPLC>98%). ESI-MS m / z: 423.35 [M] + ,423.32[M+2]+

[0191] Step 6 Weigh out 1t (0.43mmol, 1eq, 0.18g), add analytical grade acetonitrile (10eq of 1t, V / m, 3.0ml) and stir to dissolve, then add analytical grade potassium carbonate (0.51mmol, 1.2eq, 0.07g) and phenol (0.86mmol, 2eq, 0.7g), heat to 80℃, and perform reaction. Then, perform detection by thin layer chromatography until the reaction is completed. Then, filter the reaction solution, wash the filter cake with acetonitrile (30eq of 1t, V / m, 10ml, in three portions), and separate the collected filtrate to obtain white solid compound 37 (47.97mg, yield 12.3%, HPLC>98%). MS m / z=437.42 [M] + 1 H NMR (400MHz, CD 3 OD):δ11.33(s,1H),10.02(s,1H),7.33-7.26(m,2H),7.19-7.05(m,3H),6.99-6.90(m,3H),4.57-4.50(t,1H),4.19-4.09 (t,1H),3.46-3.21(m,5H),2.24-2.19(m,6H),1.99-1.88(m,2H),1.76-1.65(m,8H),1.47-1.33(m,4H),0.98-0.87(t,3H). 13 C NMR (400 MHz,CD3OD):δ14.2,16.9,18.9,19.4,19.9,23.5,23.9,25.9,27.6,52.2,55.9,57.8,67 .6,78.5,114.6,114.9,121.6,125.9,128.5,129.9,131.9,139.3,158.6,161.1,171.1.

[0192] Example 38 (2S)-2-((2,6-dimethylphenyl)carbamoyl)-1-(4-methylpentyl)-1-(4-phenoxybutyl)piperidine bromide [ka]

[0193] Step 1 1j (1.8 mmol, 1 eq, 0.42 g) was weighed, and analytical grade acetonitrile (10 eq of 1j, V / m, 8.0 ml) was added and stirred to dissolve, then analytical grade potassium carbonate (2.16 mmol, 1.2 eq, 0.3 g) and bromoisopentane (4.48 mmol, 1.2 eq, 1.41 g) were added, and the reaction was carried out by heating to 80 ° C., and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, the filter cake was washed three times with 15 ml of acetonitrile, and the filtrate was collected and spun dry to obtain a tan solid 1m (569 mg, yield 59.6%, HPLC>98%). ESI-MS m / z: 317.34 [M+1] + .

[0194] Step 2 569 mg of the tan solid 1m was dissolved in 1,4-dibromobutane (20 eq of 1m, V / m, 3 ml), heated to 100 °C, and monitored by thin layer chromatography until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 1:MeOH=20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to obtain a tan solid 1n (0.51 g, yield 62.96%, HPLC>98%). 451.35[M] + ,453.35[M+2] + .

[0195] Step 3 1n (0.55mmol, 1eq, 0.25g) was weighed out, and analytical grade acetonitrile (10eq of 1n, V / m, 5.0ml) was added and stirred to dissolve, then analytical grade potassium carbonate (1.1mmol, 1.2eq, 0.15g) and phenol (1.1mmol, 2eq, 0.1g) were added, and the mixture was heated to 80°C to react, and the reaction was detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1n, V / m, 10ml, in three portions), and the collected filtrate was separated to obtain white solid compound 38 (62.69mg, yield 20.42%, HPLC>98%). MS m / z=465.48[M] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.27(dd,2H),7.05(s,3H),6.93-6.92(m,3H),4.58 (t,1H),4.06(t,2H),3.27-3.17(m,6H),2.17-1.92(m,8H),1.75-1.62(m,9H),1.30-1.19 (m,4H),0.91(d,6H). 13 C NMR (400 MHz, CD 3 OD):δ17.2,17.6,18.1,19.3,22.2,23.2,26.3,27.8,28.1,38.1,51.8,56.8,57 .1,68.4,79.7,114.4,120.3,126.8,127.7,129.3,130.7,137.1,159.4,172.0.

[0196] Example 39 (2S)-1-Butyl-2-((4-fluorophenyl)carbamoyl)-1-(4-phenoxybutyl)piperidine bromide [ka]

[0197] Step 1 4-Fluoroaniline (15.5 mmol, 2 eq, 2.09 g) was dissolved in 10 ml of toluene, 1f (7.75 mmol, 1 eq, 1.41 g) was weighed, toluene (10 eq of 1f, V / m, 20.0 ml) was added and stirred to dissolve, and the toluene solution in which 4-fluoroaniline was dissolved was added dropwise within 5 min. Detection was performed by thin layer chromatography until the reaction was completed. The reaction solution was extracted with 50 ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected and spin-dried, and the eluent was changed to CH. 2 Cl 2 The eluent collected by silica gel column chromatography in a 20:1 mixture of MeOH and toluene was evaporated and concentrated using a rotary evaporator to give 1 g of a tan solid (0.83 g, 43.73% yield, HPLC>98%). ESI-MS m / z: 222.3 [M+1] + .

[0198] Step 2 Weigh out 1g (3.73mmol, 1eq, 0.83g), add analytical grade acetonitrile (10eq per 1g, V / m, 8.0ml) and stir to dissolve, then add analytical grade potassium carbonate (4.48mmol, 1.2eq, 0.57g) and bromobutane (4.48mmol, 1.2eq, 0.61g), heat to 80°C and react, and perform thin layer chromatography detection until the reaction is complete. Then, filter the reaction solution, wash the filter cake with 15ml of acetonitrile three times, collect the filtrate and spin dry to obtain a tan solid 1h (0.94g, yield 90.6%, HPLC>98%). ESI-MS m / z: 279.3[M+1] + .

[0199] Step 3 0.94 g of the tan solid 1h was dissolved in 1,4-dibromobutane (20 eq per 1 g, V / m, 3 ml), heated to 100 °C, and monitored by thin layer chromatography until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2The eluent collected by silica gel column chromatography in a 20:1 mixture of 1,2-dichlorophenyl ether (MeOH) and 1,2-dichlorophenyl ether (MeOH) was evaporated and concentrated using a rotary evaporator to give a tan solid 1i (450 mg, 13.25% yield, HPLC>98%). MS m / z=413.3[M] + ,415.3[M+2] + .

[0200] Step 4 1i (0.37mmol, 1eq, 0.15g) was weighed, and analytical grade acetonitrile (10eq of 1i, V / m, 5.0ml) was added and dissolved by stirring. Then, analytical grade potassium carbonate (0.44mmol, 1.2eq, 0.06g) and phenol (0.74mmol, 2eq, 0.07g) were added, and the reaction was carried out by heating to 80°C. The reaction was then detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1i, V / m, 10ml, in three portions), and the collected filtrate was separated to obtain white solid compound 39 (33.48mg, yield 2.92%, HPLC>98%). MS m / z=427.41[M] + . 1 H NMR (101 MHz, CD 3 OD):δ7.66-7.54(m,2H),7.33-7.19(m,2H),7.17-7.02(m,2H),7.02-6.79(m,3H),4.33-4.21(m,1H),4.20-3.98(m,3H) ),3.94-3.40(m,5H),2.48-2.34(m,1H),2.32-2.17(m,1H),2.11-1.69(m,10H),1.53-1.23(m,3H),1.10-0.86(m,3H). 13 C NMR (101 MHz, CD 3OD):δ 11.8,12.4,18.5,19.0,19.3, 23.2, 23.4, 23.7, 25.6, 47.1, 47.3, 47.6, 47.8, 48.0, 48.2, 56.7, 66.3, 67.9, 114.0, 115.1,115.3,120.5, 120.6, 121.9, 122.0, 129.0, 129.1, 133.4, 158.6, 164.7.

[0201] Example 40 (2S)-1-Butyl-2-((2,6-dibromophenyl)carbamoyl)-1-(4-phenoxybutyl)piperidine bromide [ka]

[0202] Step 1 2,6-Dibromoaniline (43.6mmol, 2eq, 1.89g) was dissolved in 10ml of toluene, 1f (21.8mmol, 1eq, 3.32g) was weighed, toluene (10eq of 1f, V / m, 20.0ml) was added and stirred to dissolve, and the toluene solution in which 2,6-dibromoaniline was dissolved was added dropwise within 5min. Detection was performed by thin layer chromatography until the reaction was completed. The reaction solution was extracted with 50ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected, spin-dried, and the eluent was changed to CH. 2 Cl 2 Silica gel column chromatography was performed under the condition of MeOH=20:1, and the collected eluent was evaporated and concentrated on a rotary evaporator to give a tan solid 1o (3.2 g, 74% yield, HPLC>98%). ESI-MS m / z: 363.04 [M+4] + .

[0203] Step 2 1o (8.81 mmol, 1 eq, 3.2 g) was weighed, and analytical grade acetonitrile (10 eq of 1o, V / m, 30 ml) was added and stirred to dissolve, then analytical grade potassium carbonate (2.16 mmol, 1.2 eq, 0.3 g) and n-butyl bromide (4.48 mmol, 1.2 eq, 1.41 g) were added, and the reaction was carried out by heating to 80 ° C., and detection by thin layer chromatography was carried out until the reaction was completed. The reaction solution was then filtered, the filter cake was washed three times with 15 ml of acetonitrile, the filtrate was collected, and spin-dried to obtain a tan solid 1p (3.6 g, 97% yield, HPLC>98%). ESI-MS m / z: 418.01 [M+2] + .

[0204] Step 3 The tan solid 1p (8.65 mmol, 1 eq, 3.6 g) was dissolved in 1,4-dibromobutane (18 mmol, 20 eq, 9 ml), heated to 100 °C, and detected by thin layer chromatography until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed using MeOH = 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 1q (1.5 g, 16% yield, HPLC>98%). 554.99 [M+4] + .

[0205] Step 4 Weigh out 1q (0.79mmol, 1eq, 0.5g), add analytical grade acetonitrile (10eq of 1q, V / m, 5.0ml) and stir to dissolve, then add analytical grade potassium carbonate (0.95mmol, 1.2eq, 0.13g) and phenol (1.58mmol, 2eq, 0.14g), heat to 80℃, and perform reaction. Then, perform detection by thin layer chromatography until the reaction is completed. Then, filter the reaction solution, wash the filter cake with acetonitrile (30eq of 1q, V / m, 10ml, in three portions), and separate the collected filtrate to obtain white solid compound 40 (44.91mg, yield 8.72%, HPLC>98%). MS m / z=567.13[M+2] + . 1 H NMR (400MHz, CD 3 OD):δ10.02(s,1H),7.74(d,2H),7.27(t,2H),6.93-6.92 (m,3H),6.79(t,1H),4.58(t,1H),4.06(t,2H),3.27-3.17(m,6H),2.17-1.92 (m,2H),1.75-1.70 (m,8H),1.30-1.20 (m,4H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.8,17.2,19.0,19.3,22.2,23.1,26.3,28.1,51.8,56.5,56.8,68.4,79.7,114.3,120.3,124.8,129.3,130.8,147.4,159.4,172.0.

[0206] Example 41 (2S)-1-Butyl-2-(o-tolylcarbamoyl)-1-(4-(m-tolyloxy)butyl)piperidine bromide [ka]

[0207] Step 1 2-Methylaniline (36.2 mmol, 2 eq, 3.8 g) was dissolved in 10 ml of toluene, 1f (18.1 mmol, 1 eq, 3.32 g) was weighed, toluene (10 eq of 1f, V / m, 20.0 ml) was added and stirred to dissolve, and the toluene solution in which 2-methylaniline was dissolved was added dropwise within 5 min. Detection was performed by thin layer chromatography until the reaction was completed. The reaction solution was extracted with 50 ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected, spin-dried, and the eluent was changed to CH. 2 Cl 2Silica gel column chromatography was performed using MeOH = 20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 1x (1.11 g, 28.02% yield, HPLC>98%). ESI-MS m / z: 219.35 [M+1] + .

[0208] Step 2 1x (5.06mmol, 1eq, 1.11g) was weighed out, and analytical grade acetonitrile (10eq of 1x, V / m, 11.0ml) was added and stirred to dissolve, then analytical grade potassium carbonate (6.07mmol, 1.2eq, 1g) and n-butyl bromide (6.07mmol, 1.2eq, 1g) were added, and the reaction was carried out by heating to 80°C, and detection by thin layer chromatography was carried out until the reaction was completed. The reaction solution was then filtered, the filter cake was washed three times with 15ml of acetonitrile, and the filtrate was collected and spin-dried to obtain a tan solid 1y (1.39g, 99% yield, HPLC>98%). ESI-MS m / z: 275.28[M+1] + .

[0209] Step 3 1.39 g of the tan solid 1y was dissolved in 1,4-dibromobutane (20 eq of 1y, V / m, 3 ml), heated to 100 °C, and detected by thin layer chromatography until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 Silica gel column chromatography was performed under the condition of 1:MeOH=20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 1z (1.14 g, yield 21.8%, HPLC>98%). ESI-MS m / z: 409.34 [M] + ,411.35[M+2] + .

[0210] Step 4 1z (0.9mmol, 1eq, 0.38g) was weighed, and analytical grade acetonitrile (10eq of 1z, V / m, 4.0ml) was added and dissolved by stirring. Then, analytical grade potassium carbonate (1.08mmol, 1.2eq, 0.14g) and m-cresol (1.8mmol, 2eq, 0.16g) were added, and the reaction was carried out by heating to 80°C. The reaction was then detected by thin layer chromatography until the reaction was completed. The reaction solution was then filtered, and the filter cake was washed with acetonitrile (30eq of 1z, V / m, 10ml, in three portions), and the collected filtrate was separated to obtain white solid compound 41 (84.9mg, yield 17.65%, HPLC>98%). MS m / z=437.47 [M] + 1 H NMR (400MHz, CD 3 OD):δ12.10(s,1H),10.31(s,1H),7.19-7.19(m,2H),7.16-7.11(m,3H),6.98-6.89(m,3H),4.59-4.50(t,1H),4.09-3.98 (t,1H),3.45-3.28(m,6H),2.23-2.12(m,6H),1.99-1.88(m,2H),1.81-1.67(m,8H),1.49-1.39(m,4H),0.96-0.84(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.,7,17.2,17.6,19.4,19.9,22.6,23.8,26.4,28.0,51.5,56.6,56.1,68.1, 79.6,113.7,114.6,120.1,126.3,127.3,129.6,130.1,137.7,159.1,161.7,171.5.

[0211] Example 42 (2S)-1-Butyl-2-((2,6-diethylphenyl)carbamoyl)-1-(4-(m-tolyloxy)butyl)piperidine bromide [ka]

[0212] Step 1 2,6-Diethylaniline (36.2mmol, 2eq, 3.8g) was dissolved in 10ml of toluene, 1f (18.1mmol, 1eq, 3.32g) was weighed, toluene (10eq of 1f, V / m, 20.0ml) was added and stirred to dissolve, and within 5min, a toluene solution containing 2-methylaniline was added dropwise. Thin layer chromatography was performed until the reaction was complete. The reaction solution was extracted with 50ml of saturated sodium bicarbonate solution, the pH was adjusted to 10, the organic phase was collected, spin-dried, and the eluent was changed to CH. 2 Cl 2 Silica gel column chromatography was performed under the condition of 2:MeOH=20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 2a (2.02 g, 70.9% yield, HPLC>98%). ESI-MS m / z: 261.35 [M+1] + .

[0213] Step 2 2a (6.36 mmol, 1 eq, 1.66 g) was weighed out, and analytical grade acetonitrile (10 eq of 2a, V / m, 17.0 ml) was added and stirred to dissolve, then analytical grade potassium carbonate (7.63 mmol, 1.2 eq, 1.05 g) and n-butyl bromide (7.63 mmol, 1.2 eq, 1.05 g) were added, and the reaction was carried out by heating to 80 ° C., and detection by thin layer chromatography was carried out until the reaction was completed. The reaction solution was then filtered, the filter cake was washed three times with 15 ml of acetonitrile, and the filtrate was collected and spun dry to obtain a tan solid 2b (2.02 g, 99% yield, HPLC>98%). ESI-MS m / z: 317.33 [M+1] + .

[0214] Step 3 2.02 g of the tan solid 2b was dissolved in 1,4-dibromobutane (20 eq of 2b, V / m, 4 ml), heated to 100 °C, and monitored by thin layer chromatography until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2Silica gel column chromatography was performed under the condition of 2H:MeOH=20:1, and the collected eluent was evaporated and concentrated using a rotary evaporator to give a tan solid 2c (0.86 g, 8% yield, HPLC>98%). ESI-MS m / z: 451.37 [M] + ,453.37[M+2] + .

[0215] Step 4 2c (0.8mmol, 1eq, 0.43g) was weighed, and analytical grade acetonitrile (10eq of 2c, V / m, 4.0ml) was added and stirred to dissolve, then analytical grade potassium carbonate (0.96mmol, 1.2eq, 0.12g) and m-cresol (1.6mmol, 2eq, 0.14g) were added, and the reaction was carried out by heating to 80°C, and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 2c, V / m, 10ml, in three portions), and the collected filtrate was separated to obtain white solid compound 42 (63.67mg, yield 9.75%, HPLC>98%). MS m / z=479.15 [M] + 1 H NMR (400MHz, CD 3 OD):δ12.05(s,1H),10.46(s,1H),7.22-7.16(m,2H),7.11-7.02(m,3H),6.99-6.88(m,3H),4.58-4.49(t,1H),4.11-3.99(t,1H),3 .46-3.29(m,6H),2.26-2.19(m,6H),1.98-1.88(m,2H),1.83-1.67(m,8H),1.49-1.37(m,4H),1.28-1.16(m,4H),0.96-0.84(t,3H). 13 C NMR (400 MHz, CD 3OD):δ13.6,17.2,17.6,19.4,19.9,22.6,23.6,23.6,23.8,26.4,28.9,51.5,56.8,56.1, 68.5,79.3,113.8,114.1,120.1,126.9,126.5,128.9,130.3,137.3,159.6,161.9,171.5.

[0216] Example 43 (2S)-1-(4-((6-acetylnaphthalen-2-yl)oxy)butyl)-1-butyl-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0217] Compound 1b (0.71 mmol, 1 eq, 0.30 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and 6-acetyl-2-naphthol (1.42 mmol, 2 eq, 0.27 g) were added, and the temperature was raised to 80 °C to react, and detection was performed by thin layer chromatography until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 43 (116.9 mg, yield 18.3%, HPLC>98%). MS m / z=529.43[M] + . 1 H NMR (400MHz, CD 3 OD): δ9.70(s,1H),8.40(s,1H),8.15(d,1H),7.82(d,1H),7.69(d,1H),7.59(d, 2H),7.36(s,1H),7.14-7.21(m,3H),4.16(t,2H),3.63(t,1H),2.50(s,3H),2.34 (t,4H),1.83-1.55(m,4H),1.4-1.3(m,10H),0.89(t,3H). 13C NMR (400 MHz, CD 3 OD):δ13.8,20.4,24.5,26.0,26.6,27.3,30.4,33.2,35.0,51.0,68.4,73.0,108.0,115.7,117 .7,120.6,124.7,127.1,129.6,131.0,131.3,132.0,134.1,138.2,157.9,162.9,172.0,197.0.

[0218] Example 44 (2S)-1-Butyl-1-(4-((2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)oxy)butyl)-2-((2,6-dimethylphenyl)carbamoyl)piperidine bromide [ka]

[0219] Compound 1b (0.71 mmol, 1 eq, 0.30 g) was weighed, and analytical grade acetonitrile (10 eq of 1b, V / m, 5.0 ml) was added and dissolved by stirring. Analytical grade potassium carbonate (1.2 eq of 1b, m / m, 0.50 g) and 2,3-dimethyl-7-hydroxy-benzofuran (1.42 mmol, 2 eq, 0.17 g) were added, and the reaction was carried out by heating to 80 °C, and detection by thin layer chromatography was carried out until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30 eq of 1b, V / m, 15 ml, in three portions), and the collected filtrate was separated and separated to obtain white solid compound 44 (210.38 mg, yield 42.3%, HPLC>98%). MS m / z=507.46[M] + . 1 H NMR (400MHz, CD 3OD):δ10.02(s,1H),7.05(s,3H),6.90-6.84 (m,3H),4.58(t,1H),4.06(t,2H),3.27-3.17(m,6H),2.85(s,2H),2.17-1.92(m,8H),1.75-1.70(m,8H),1.47(s,6H),1.30 -1.20(m,4H),0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD): δ13.8,17.2,17.6,19.0,19.3,22.2,23.1,26.3,28.1,28.4,42.2,51.8,56.5,56.8,68. 7,79.7,94.5,111.8,120.0,122.2,126.8,127.7,128.8,130.7,137.1,145.8,146.6,172.0.

[0220] Comparison 1 (2S)-1-Butyl-2-((2,6-dimethylphenyl)carbamoyl)-1-(2-(2-phenoxyethoxy)ethyl)piperidine bromide [ka]

[0221] Step 1 Levobupivacaine 1a (3.67 mmol, 1.0 eq, 1.06 g) was weighed, bis-(2-bromoethyl)ether (4.25 eq of levobupivacaine 1a, V / m, 3 ml) was added, and the mixture was heated to 100°C with stirring until the reaction was complete. Then, the eluent was changed to CH 2 Cl 2 The eluent collected by silica gel column chromatography under the conditions of 2:MeOH=20:1 was evaporated and concentrated using a rotary evaporator to obtain orange oily liquid compound 2e (1.0 g, yield 30%, HPLC>90%). ESI-MS m / z: 439.36 [M] + ,441.48[M+2H] + .

[0222] Step 2 Compound 2e (1mmol, 1eq, 0.51g) was weighed out, and analytical grade acetonitrile (10eq of 2e, V / m, 5.0ml) was added and stirred to dissolve, then analytical grade sodium bicarbonate (1eq of 2e, m / m, 0.50g) and phenol (1.2mmol, 1.2eq, 0.12g) were added, and the reaction was carried out by heating to 80°C, and detection by HPLC was carried out until the reaction was completed. Then, the reaction solution was filtered, and the filter cake was washed with acetonitrile (30eq of 2e, V / m, 15ml, divided into three portions), and the collected filtrate was separated and separated to obtain a white powdery solid compound (0.21g, yield 39.62%, HPLC>98%) of Comparative Example 1. MS m / z=453.38[M] + . 1 H NMR (400MHz, CD 3 OD):δ12.09(s,1H),10.13(s,1H),7.20-7.23(m,2H),7.19-7.09(m,2H),6.98-6.91(m,3H),6.42(s,1H),4.51-4.56(t,1H),4.08 -4.01(t,1H),3.49-3.29(m,6H),2.26-2.18(m,6H),1.93-1.88(m,2H),1.73-1.66(m,8H),1.44-1.32(m,4H),0.98-0.89(t,3H). 13 C NMR (400 MHz, CD 3 OD):δ13.8,17.8,17.8,19.6,19.8,22.9,24.3,28.2,29.6,51.4,56.7,57.3,66.6, 78.5,113.2,114.1,120.7,126.3,127.6,129.5,130.3,136.6,158.8,160.7,170.4.

[0223] Bio Test The experimental methods in the following test examples are general experimental methods unless otherwise specified. All experimental animals used in the following test examples are SD rats, purchased from Hunan SJA Laboratory Animal Co., Ltd. Other test materials are purchased from general biochemical reagent manufacturers unless otherwise specified.

[0224] Test Example 1. Local anesthetic effect test of the compound according to the present application Testing Method: The compound of the Example shown in Table 1 below, levobupivacaine hydrochloride (positive control group), was administered to three groups of fully adapted rats (one rat in each group).

[0225] Preparation of solutions: Preparation of 2 mg / ml levobupivacaine hydrochloride injection formulation: 2.670 ml of 7.5 mg / ml levobupivacaine hydrochloride injection (lot number: 92S0702) was pipetted into a 10 ml measuring flask, 0.9% NaCl solution was added so that the liquid level was level with the graduation line, and the mixture was inverted and mixed until homogenous to prepare a 2 mg / ml levobupivacaine hydrochloride injection formulation. Preparation of 2 mg / ml solution of example compound: 6.6 mg of the compound of the present example, which was precisely weighed, was added to 3.3 ml of 0.9% NaCl solution to prepare a 2 mg / ml solution of the example compound.

[0226] The administration concentration per rat was 2 mg / ml for the positive control group and 2 mg / ml for the compound of the present example, and the administration volume was 5 ml / kg. The administration site and administration method were a single administration around the sciatic nerve of the rat. After administration, the rat was placed on a hot plate with an intelligent thermometer that had been preheated to 50 ± 0.1 ° C., and the time required for the rat to show an escape reaction to heat stimuli such as a clear paw shake or paw licking on the side of the drug administration was recorded as the latency. The maximum acceptable latency was controlled to 60 s. If the rat did not show a paw licking phenomenon even after 60 s, the rat's hind paw was manually lifted and the latency of the rat was set to 60 s to avoid the occurrence of phenomena such as tissue damage and hyperalgesia. After each measurement, urine and feces that may be left on the hot plate were wiped off and dried in a timely manner for use in subsequent tests.

[0227] The latency results were expressed as maximum proportionality effect (MPE) and were calculated by the following equation: MPE(%)=(CB) / (PB)×100% Here, B represents the basal latency of the rat, P represents the maximum latency that can be tolerated, and C represents the latency at the time of detection.

[0228] If the measurement time was less than 50% of the maximum proportional effect, it was judged to be invalid, and if the maximum proportional effect was less than 50% even after two consecutive measurements, the measurement was stopped. The specific experimental results are shown in Table 1 below.

[0229] Test results: [Table 1-1] [Table 1-2]

[0230] From the experimental results, it was revealed that the compounds of the present application examples, when the concentration was 2 mg / ml (equivalent molar concentration: 3.0 mmol / L to 4.0 mmol / L), could basically exert a local anesthetic effect for more than 24 hours (individually more than 17 hours) in a sciatic nerve block model, and the effect of action was fast, and some of the compounds could exert a local anesthetic effect for more than 48 hours, and the duration of the local anesthetic effect was significantly longer than that of the bupivacaine control group at 2 mg / ml (equivalent molar concentration: 6.9 mmol / L), and the nerve block process effect was restored. On the other hand, the comparative compound obtained by introducing a heteroatom into the L chain of the compound represented by the general formula of the present application did not have a local anesthetic effect and was clearly toxic to rats. In addition, when L was C 3 Compounds with alkylene groups also had no local anesthetic effect.

[0231] Test Example 2. Local anesthetic effect by subcutaneous infiltration of the compound according to the present application Testing Method: After shaving and disinfecting the backs of SD rats (half male and half female) weighing 190 to 210 g, a circle with a diameter of about 1.5 cm was drawn on one side of the naked back, and a drug-containing solution: a 2 mg / ml bupivacaine hydrochloride preparation with saline as a solvent and a 1 mg / ml preparation of the compound according to the present application shown in Table 2 below was subcutaneously injected into the center of the circle (10 rats per group). Then, 100 g of filament in the Von Frey filament was bound to the needle to perform local skin stimulation. One minute after the drug injection, the rats were measured for pain stimulation response at six different points within the circle drawn at the administration site as test sites, and it was observed whether or not reactions such as skin contraction or escape occurred after stimulation. After stimulation was given to three points in the center of the circle and three points on the circumference, the number of occurrences of skin contraction and escape behavior was recorded as N / 6. In terms of judgment, if escape or skin contraction behavior appeared at four or more points, it was considered that the effect was no longer effective. If there was a response at the points on the circumference (≦3) and no response at the center point (≧1), the drug was considered to still be effective. If there was a response only at the center point, it was considered to have lost its effect. Ten rats were used for each compound in the experiment. Specific experimental results are shown in Table 2 below.

[0232] Test Results: [Table 2]

[0233] The experimental results showed that the compounds of the present invention in the examples shown in Table 2 above, when at a concentration of 1 mg / ml (equivalent molar concentration: 1.5 mmol / L-2.0 mmol / L), were able to exert a local anesthetic effect for more than 48 hours in a rat subcutaneous infiltration model, and some of the compounds were able to exert a local anesthetic effect for more than 72 hours, which was significantly longer than the anesthetic effect of the bupivacaine control group at 2 mg / ml (equivalent molar concentration: 6.9 mmol / L), and the agonistic effect was faster.

[0234] Because local anesthetic times longer than 72 hours can cause irreversible nerve damage, in subsequent studies, some compounds with durations of action greater than 72 hours were tested for activity at lower dose concentrations to determine whether the local anesthetic effect could be reversed in the skin infiltration model.

[0235] [Table 3]

[0236] The experimental results showed that the compound of the present invention showed a significant dose-response relationship in the rat subcutaneous infiltration nerve block model, and the duration of the anesthetic effect was gradually extended with an increase in the drug dose. Furthermore, when the concentration of the compound of the present application was 0.3 mmol / L, it could still exert a local anesthetic effect for more than 24 hours in the rat subcutaneous infiltration model, and the local anesthetic effect could be recovered even after the procedure.

[0237] Test Example 3. Evaluation of neuropathological damage caused by the compound according to the present application Selected Example Compounds 3, 4, 5, 24, 25, 26, 28, 30, 36, 38, 39, levobupivacaine hydrochloride (positive control group), and vehicle (control group) were each administered to test SD rats (half male and half female) weighing 190-210 g that had fully adapted to the experimental environment (8 rats per group).

[0238] Administration concentration: saline was used as a solvent, levobupivacaine hydrochloride was used as a 2 mg / mL formulation, and the concentrations of the compound according to the present application were 0.6 mg / mL and 0.2 mg / mL, respectively, and saline was used in the solvent control group.

[0239] 1.0 mL of the solution was injected around the sciatic nerve per rat. On the 7th and 14th days after the sciatic nerve injection, the rats were euthanized by intracardiac injection of levobupivacaine hydrochloride under isofluoroether anesthesia. Approximately 1.5 cm of the sciatic nerve was then harvested from the injection site and preserved in 10% formaldehyde solution for 48 h. It was then stained with HE and cut into 5 μm thick slices.

[0240] Compounds 3, 4, 5, 24, 25, 26, 28, 30, 36, 38, and 39 prepared in the examples, levobupivacaine hydrochloride (positive control group), and the solvent (control group) were each administered to test SD rats (half male and half female) weighing 190 to 210 g that had fully adapted to the experimental environment (8 rats in each group).

[0241] Administration concentrations: physiological saline as a solvent, levobupivacaine hydrochloride 2 mg / mL, the compounds according to the present application at concentrations of 0.6 mg / mL and 0.2 mg / mL, respectively, and physiological saline as a solvent control group.

[0242] Each rat was subcutaneously injected with 0.5 mL of the drug into the dorsal region. On the 7th and 14th days after subcutaneous injection, the rats were euthanized by intracardiac injection of levobupivacaine hydrochloride under isofluoroether anesthesia. Skin tissues from the injection sites were then collected and stored in 10% formaldehyde solution for 48 h, after which they were stained with HE and cut into 5 μm-thick slices.

[0243] As a result of the evaluation of neuropathological damage, it was revealed that the example compounds showed no significant differences in terms of nerve damage, vascular proliferation, demyelinating disease, muscle inflammation, connective tissue inflammation, etc., compared to the levobupivacaine hydrochloride positive control group and the solvent control group, and therefore showed good safety.

[0244] Test Example 4. Toxicity study of single doses of the compound according to the present application Selected Example compounds 3, 4 and 5 were administered to SD test rats (4 rats per group) weighing 190-210 g, which were fully adapted to the experimental environment.

[0245] Dose: Physiological saline was used as a solvent, and the dose of Compounds 3, 4, and 5 according to the present application was 6 mg / kg.

[0246] Administration method: The compound was administered via the tail vein at a volume of 1 mL / kg per rat.

[0247] Selected Example Compounds 3, 4, 5 and levobupivacaine hydrochloride (positive control group) were administered to SD test rats (4 rats per group) weighing 190-210 g that had fully adapted to the experimental environment.

[0248] Dose: Physiological saline was used as a solvent, and the dose of Compounds 3, 4, and 5 according to the present application was 100 mg / kg.

[0249] Administration method: Subcutaneous injection was performed at a dose volume of 5 mL / kg per rat.

[0250] As a result, after the compound of the present application was administered at a dose of 6 mg / kg via the tail vein and at a dose of 100 mg / kg subcutaneously, no obvious abnormalities were observed in the rats, and they exhibited active behavior, which was not significantly different from that of normal rats.

[0251] The embodiments disclosed in this application are as above, but the above contents are merely embodiments for convenient understanding of this application and are not intended to limit this application. Those skilled in the art may make any modifications and changes to the embodiments and detailed contents without departing from the spirit and scope of this application. However, the scope of protection of this application must comply with the scope defined by the appended claims.

Claims

1. Formula (I) below: 【Chemistry 1】 [In the formula, R １ is an aromatic hydrocarbon group or a heteroaryl group, or X １ Together, they form an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group. R ２ is C １－８ Alkyl or C ３－１２ It is a cycloalkyl group, R ３ is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group, or X ２ It forms a nitrogen-containing heterocycloalkyl group through condensation, X １ is O, S and NR Ａ ４ (where R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ cycloalkyl group, or C １－４ alkoxy C １－４ alkyl group, or R Ａ ４ is N and R linked to itself １ together form an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group), and is selected from X ２ O, S and NR Ｂ ４ (However, R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups, or C １－４ Alkoxy C １－４ It is an alkyl group, or R Ｂ ４ N and R are linked to themselves ３ Selected from those that form a nitrogen-containing heterocycloalkyl group when condensed together, L is C １－８ Selected from alkylene groups, S １ S ２ Each is independently a chemical bond and C １－６ Selected alkylene group, and S １ and S ２ It is defined that both are not chemical bonds at the same time. Y － [This represents a pharmaceutically acceptable anion.] A cyclic quaternary ammonium salt compound represented by the same, or its stereoisomer or solvate.

2. R １ is an aromatic hydrocarbon group or a heteroaryl group, or X １ Together with the, it forms an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group, where the aromatic hydrocarbon group, the heteroaryl group, the uncondensed nitrogen-containing heterocycloalkyl group, or the condensed nitrogen-containing heterocycloalkyl group are optionally C １－６ alkyl group, C １－６ Alkoxy groups, cyano groups, halogens, hydroxyl groups, amino groups, nitro groups, ester groups, 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 groups and CC １－６ The group is substituted with one or more substituents selected from haloalkoxy groups, and the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group. And / or, R ２ is C １－８ Alkyl or C ３－１２ It is a cycloalkyl group, and here, the C １－８ Alkyl or C ３－１２ Cycloalkyl groups are optionally 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 substituents selected from cycloalkyl groups, halogens, hydroxyl groups, cyano groups, and amino groups. And / or, R ３ is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group, or X ２ It forms a nitrogen-containing heterocycloalkyl group by condensation with the aromatic hydrocarbon group, the heteroaryl group, the heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group, C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy C １－４ alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, sulfonyl groups, mercapto groups, mono-C １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, C ２－４ It is substituted with one or more substituents selected from an alkynyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group, and further, here, the optionally substituted aromatic hydrocarbon group, the optionally substituted heteroaryl group, and the optionally substituted heterocycloalkyl group are, respectively, an unsubstituted aromatic hydrocarbon group, an unsubstituted heteroaryl group, or an unsubstituted heterocycloalkyl group, or C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono-C １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, and C ２－４ This refers to being substituted with one or more substituents selected from the alkynyl group, and the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group. And / or, X １ is O, S, and NR Ａ ４ (where R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ cycloalkyl group, or C １－４ alkoxy C １－４ alkyl group, or R Ａ ４ is N and R linked to itself １ and together form an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group), and is selected from Here, the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group. And / or, X ２ is O, S and NR Ｂ ４ (where R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ cycloalkyl group, or C １－４ alkoxy C １－４ alkyl group, or R Ｂ ４ is N and R linked to itself ３ together form a nitrogen-containing heterocycloalkyl group fused with), where the fused nitrogen-containing heterocycloalkyl group is fused with an aromatic hydrocarbon group or a heteroaryl group, And / or, L is C １－８ Selected from alkylene groups, where the C １－８ The alkylene group can be optionally C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Haloalkyl group, C １－４ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono-C1-4 alkylamino groups, di-C1-4 alkylamino groups, C ２－４ Alkenyl group, and C ２－４ It is substituted with one or more substituents selected from the alkynyl group. And / or, S １ S ２ Each is independently a chemical bond and C １－６ Selected alkylene group, and S １ and S ２ It is defined that both are not chemical bonds at the same time, and here, the C １－６ The main chain of the alkylene group optionally contains one heteroatom, and the heteroatom is O, S, and NR ５ (However, R ５ The compound according to claim 1, or a stereoisomer or solvate thereof, selected from (where is hydrogen or deuterium).

3. R １ C is optional. １－６ alkyl group, C １－６ Alkoxy groups, cyano groups, halogens, hydroxyl groups, amino groups, nitro groups, ester groups, 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 groups and C １－６ A phenyl group or naphthyl group substituted with one or more substituents selected from haloalkoxy groups, Or, R １ This is a phenyl group that is optionally substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, and ethyl ester groups. Or, R １ The group 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-hydroxyphenyl 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, or a 2,4,6-trifluorophenyl group, preferably a 2,6-dimethylphenyl group; Or, R1 is a phenyl or naphthyl group that is optionally substituted with one or more substituents selected from C1-6 alkyl groups, C1-6 alkoxy groups, cyano groups, halogens, hydroxyl groups, amino groups, nitro groups, ester groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C2-4 alkenyl groups, C2-4 alkynyl groups, C1-6 haloalkyl groups, and C1-6 haloalkoxy groups. Alternatively, R1 is a phenyl group that is optionally substituted with one or more substituents selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, fluorine, chlorine, bromine, iodine, hydroxyl, amino, nitro, methyl ester, and ethyl ester groups. Alternatively, R 1 The group 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-hydroxyphenyl group, a 2,6-dimethylphenyl group, a 2,6-diethylphenyl group, a 2,6-dimethoxyphenyl group, a 3-nitrophenyl group, a 2,6-difluorophenyl group, a 2,6-dibromophenyl 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 2-methylphenyl group, a 4-fluorophenyl group, a 2,6-dibromophenyl group, a 2,6-diethylphenyl group, or a 2,6-dimethylphenyl group, more preferably a 2,6-dimethylphenyl group. The compound according to claim 1, or its stereoisomer or solvate.

4. R ２ C is optional. １－６ alkyl group, C １－６ Alkoxy group, C １－６ C is substituted with one or more substituents selected from haloalkyl groups, C3-6 cycloalkyl groups, halogens, hydroxyl groups, cyano groups, and amino groups. １－８ Alkyl or C ３－８ It is a cycloalkyl group, Or, R ２ The group is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, n-octyl group, or n-heptyl group, preferably an ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-octyl group, or n-heptyl group, and more preferably an n-butyl group; Or, R2 is a C1-8 alkyl group or C3-8 cycloalkyl group that is optionally substituted with one or more substituents selected from C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 haloalkyl groups, C3-6 cycloalkyl groups, halogens, hydroxyl groups, cyano groups, and amino groups. Alternatively, R2 is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, 4-methylpentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, n-octyl group, or n-heptyl group, preferably an ethyl group, n-propyl group, n-butyl group, isobutyl group, n-pentyl group, 4-methylpentyl group, n-hexyl group, n-octyl group, or n-heptyl group, more preferably an n-butyl group, isobutyl group, or 4-methylpentyl group, and particularly preferably an n-butyl group. The compound according to claim 1, or its stereoisomer or solvate.

5. R ３ is an aromatic hydrocarbon group, a heteroaryl group, a 3- to 8-membered heterocycloalkyl group, or X ２ It forms a nitrogen-containing heterocycloalkyl group by condensation with the aromatic hydrocarbon group, heteroaryl group, 3-8 member heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group are optionally C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy C １－４ alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, sulfonyl groups, mercapto groups, mono-C １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, C ２－４ The alkynyl group is substituted with one or more substituents selected from phenyl groups which may be optionally substituted, and furthermore, the phenyl group which may be optionally substituted is an unsubstituted phenyl group, or C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono-C １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, and C ２－４ This refers to being substituted with one or more substituents selected from the alkynyl group, and the condensed nitrogen-containing heterocycloalkyl group is condensed with a phenyl group or a heteroaryl group. Or, R ３ phenyl group, 4-fluorobenzyl group, 2-methylphenyl 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, 4-bromophenyl group, 4-hydroxyphenyl group, 4-trifluoromethylphenyl group, 2,4-dimethylphenyl group, 2,4-dimethoxyphenyl group, 2,4-difluorophenyl The group is 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, a 2,4,6-trifluorophenyl group, a 2-amino-5-fluorophenyl group, a 2-isopropyl-5-methylphenyl group, a 4-cyanophenyl group, a 4-ethoxycarbonylphenyl group, a 2,6-di-tert-butyl-4-methylphenyl group, a 4-nitrophenyl group, or a 4-phenyl sulfonate group, or R ３ is X ２ A piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is formed together with the above, and here, the condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is formed by the condensation of a phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group, and the condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is optionally substituted with one or more substituents 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, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a methyl ester group, an ethyl ester group, a phenyl group, and a substituted phenyl group. Or, R ３ is a phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-fluorophenyl group, 2-amino-5-fluorophenyl group, 2-isopropyl-5-methylphenyl group, 4-cyanophenyl group, 4-ethoxycarbonylphenyl group, 2,6-di-tert-butyl-4-methylphenyl group, 4-nitrophenyl group, 4-phenyl sulfonate group, or 4-hydroxyphenyl group, or R ３ is X ２ Together with the imidazolipperazinyl group, thienopiperazinyl group, or pyrrolopiperarzinyl group, the imidazolipperazinyl group, thienopiperazinyl group, or pyrrolopiperarzinyl group is optionally substituted with one or more substituents selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, methyl ester group, ethyl ester group, and phenyl group; Or, R3 is an aromatic hydrocarbon group, a heteroaryl group, a 3- to 8-membered heterocycloalkyl group, or a nitrogen-containing heterocycloalkyl group formed by condensation with X2. Here, the aromatic hydrocarbon group, heteroaryl group, 3- to 8-membered heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group are optionally C1-6 alkyl groups, C1-6 alkoxy groups, C1-6 alkoxyC1-4 alkyl groups, C1-6 haloalkyl groups, C1-6 haloalkoxy groups, C3-6 cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C1-6 alkanoyl groups, ester groups, nitro groups, sulfonyl groups, mercapto groups, mono-C1-6 alkylamino groups, di-C1-6 alkylamino groups, C2-4 alkenyl groups, C2-4 The fused nitrogen-containing heterocycloalkyl group is fused with one or more substituents selected from an alkynyl group or a phenyl group which may be optionally substituted, and optionally, two adjacent substituents and the atoms linked to them form a ring together, and further, the optionally substituted phenyl group is an unsubstituted phenyl group, or is substituted with one or more substituents selected from a C1-6 alkyl group, a C1-6 alkoxy group, a C1-6 haloalkyl group, a C1-6 haloalkoxy group, a C3-6 cycloalkyl group, a halogen, a hydroxyl group, a cyano group, an amino group, an ester group, a nitro group, a mono-C1-6 alkylamino group, a di-C1-6 alkylamino group, a C2-4 alkenyl group, and a C2-4 alkynyl group, and the fused nitrogen-containing heterocycloalkyl group is fused with a phenyl group or a heteroaryl group. Alternatively, R3 is a phenyl group, 4-fluorobenzyl group, 2-methylphenyl 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, 3-cyanophenyl group, 3-trifluoromethylphenyl group, 4-methylphenyl group, 4-methoxyphenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-bromophenyl group, 4-hydroxyphenyl group, 4-trifluoromethylphenyl group, 2,4-dimethylphenyl group, 2,4-dimethoxyphenyl group, 2,4-difluorophenyl group, 2,4-di Chlorophenyl group, 2,4-dihydroxyphenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 2,6-dimethylphenyl group, 2,6-dimethoxyphenyl group, 2,6-difluorophenyl group, 2,6-dichlorophenyl group, 2,6-dihydroxyphenyl group, 2,4,6-trimethylphenyl group, 2,4,6-trimethoxyphenyl group, 2,4,6-trifluorophenyl group, 2-amino-5-fluorophenyl group, 2-isopropyl-5-methylphenyl group, 4-cyanophenyl group, 4-ethoxycarbonylphenyl group, 2,6-di-tert-butyl-4-methylphenyl group, 4-nitrophenyl group, 4-phenyl sulfonate group, 2,2-dimethyl-2,It is a 3-dihydrobenzofuran-7-yl group, a naphthyl group, or 6-acetylnaphthalene-2-yl, or R3 is X2 It forms a piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group, where the condensed piperidinyl group, condensed piperazine group, or condensed pyrrolidinyl group is formed by the condensation of a phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group, and the condensed piperidinyl group, condensed piperazine group, or condensed pyrrolidinyl group is optionally substituted with one or more substituents 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, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a methyl ester group, an ethyl ester group, a phenyl group, and a substituted phenyl group. Alternatively, R3 is a phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-fluorophenyl group, 3-cyanophenyl group, 3-trifluoromethylphenyl group, 3,4-difluorophenyl group, 3,4-dichlorophenyl group, 3,5-difluorophenyl group, 2-amino-5-fluorophenyl group, 2-isopropyl-5-methylphenyl group, 4-cyanophenyl group, 4-ethoxycarbonylphenyl group, 2,6-di-tert-butyl-4-methylphenyl group, 4-nitrophenyl group, 4-phenyl sulfonate group, 4-hydroxyphenyl group, 2,2-dimethyl-2,3-dihydrobenzofuran-7-yl group, or 6-acetylnaphthalene-2-yl group, or R3 is X2 Together with, it forms an imidazolipeperajinyl group, a thienopiperajinyl group, or a pyrrolopiperarzinyl group, where the imidazolipeperajinyl group, thienopiperajinyl group, or pyrrolopiperarzinyl group is optionally substituted with one or more substituents selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, methyl ester group, ethyl ester group, and phenyl group. The compound according to claim 1, or its stereoisomer or solvate.

6. L is optional, C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Haloalkyl group, C １－４ Haloalkoxy group, C3-6 cycloalkyl group, halogen, hydroxyl group, cyano group, amino group, ester group, nitro group, mono-C1-4 alkylamino group, di-C1-4 alkylamino group, C ２－４ Alkenyl group, and C ２－４ C substituted with one or more substituents selected from the alkynyl group ３－６ It is an alkylene group, Alternatively, L is - (CH ２ ) ３ -, - (CH ２ ) ４ -, - (CH ２ ) ５ -, - (CH ２ ) ６ -, and - (CH ２ ) ２ CHCH ３ (CH ２ ) ２ - Selected from, preferably - (CH ２ ) ４ - or - (CH ２ ) ５ - and; Or, L is a C3-6 alkylene group that is optionally substituted with one or more substituents selected from C1-4 alkyl groups, C1-4 alkoxy groups, C1-4 haloalkyl groups, C1-4 haloalkoxy groups, C3-6 cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono-C1-4 alkylamino groups, di-C1-4 alkylamino groups, C2-4 alkenyl groups, and C2-4 alkynyl groups, and L is not a C3 alkylene group. Alternatively, the compound according to claim 1, or a stereoisomer or solvate thereof, wherein L is selected from -(CH2)4-, -(CH2)5-, -(CH2)6-, and -(CH2)2CHCH3(CH2)2-, preferably -(CH2)4- or -(CH2)5-.

7. L is C ３ The compound according to claim 1, which is not an alkylene group, or a stereoisomer or solvate thereof.

8. R １ is an aromatic hydrocarbon group or a heteroaryl group, or X １ Together with the, it forms an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group, where the aromatic hydrocarbon group, the heteroaryl group, the uncondensed nitrogen-containing heterocycloalkyl group, or the condensed nitrogen-containing heterocycloalkyl group are optionally C １－６ alkyl group, C １－６ Alkoxy groups, cyano groups, halogens, hydroxyl groups, amino groups, nitro groups, ester groups, 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 groups and CC １－６ It is substituted with one or more substituents selected from haloalkoxy groups, and the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group. And / or, R ２ is C １－８ Alkyl or C ３－１２ It is a cycloalkyl group, and here, the C １－８ Alkyl or C ３－１２ Cycloalkyl groups are optionally 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 substituents selected from cycloalkyl groups, halogens, hydroxyl groups, cyano groups, and amino groups. And / or, R ３ is an aromatic hydrocarbon group, a heteroaryl group, or a heterocycloalkyl group, or X ２ It forms a nitrogen-containing heterocycloalkyl group by condensation with the aromatic hydrocarbon group, the heteroaryl group, the heterocycloalkyl group, and the condensed nitrogen-containing heterocycloalkyl group, C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Alkoxy C １－４ alkyl group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C １－６ Alkanoyl group, ester group, nitro group, sulfonyl group, mercapto group, monoC １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, C ２－４ It is substituted with one or more substituents selected from an alkynyl group, an optionally substituted aromatic hydrocarbon group, an optionally substituted heteroaryl group, or an optionally substituted heterocycloalkyl group, wherein optionally, two adjacent substituents and the atoms linked to them form a ring together, and further, the optionally substituted aromatic hydrocarbon group, the optionally substituted heteroaryl group, and the optionally substituted heterocycloalkyl group are, respectively, an unsubstituted aromatic hydrocarbon group, an unsubstituted heteroaryl group, and an unsubstituted heterocycloalkyl group, or C １－６ alkyl group, C １－６ Alkoxy group, C １－６ Haloalkyl group, C １－６ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, C １－６ Alkanoyl group, ester group, nitro group, monoC １－６ Alkylamino group, diC １－６ Alkylamino group, C ２－４ Alkenyl group, and C ２－４ This refers to being substituted with one or more substituents selected from the alkynyl group, and the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group. And / or, X １ O, S and NR Ａ ４ (However, R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups, or C １－４ Alkoxy C １－４ It is an alkyl group, or R Ａ ４ N and R are linked to themselves １ Selected from (forming an uncondensed nitrogen-containing heterocycloalkyl group or a condensed nitrogen-containing heterocycloalkyl group together with), the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group, And / or, X ２ O, S and NR Ｂ ４ (However, R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups, or C １－４ Alkoxy C １－４ It is an alkyl group, or R Ｂ ４ N and R are connected to themselves ３ (which forms a nitrogen-containing heterocycloalkyl group by condensation together with) is selected from, and the condensed nitrogen-containing heterocycloalkyl group is condensed with an aromatic hydrocarbon group or a heteroaryl group, And / or, L is optional, C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Haloalkyl group, C １－４ Haloalkoxy group, C ３－６ Cycloalkyl groups, halogens, hydroxyl groups, cyano groups, amino groups, ester groups, nitro groups, mono-C1-4 alkylamino groups, di-C1-4 alkylamino groups, C ２－４ Alkenyl group, and C ２－４ C substituted with one or more substituents selected from the alkynyl group １－８ It is an alkylene group and L is C ３ It is defined as not being an alkylene group. And / or, S １ S ２ Each is independently a chemical bond and C １－６ Selected alkylene group, and S １ and S ２ It is defined that both are not chemical bonds at the same time, and here, the C １－６ The main chain of the alkylene group optionally contains one heteroatom, and the heteroatom is O, S, and NR ５ (However, R ５ The compound according to claim 1, or a stereoisomer or solvate thereof, selected from (where is hydrogen or deuterium).

9. X １ O, NH, NCH ３ NCH ２ CH ３ , or N(CH ２ ) ２ CH ３ It is preferably NH, or X ２ O, NH, NCH ３ NCH ２ CH ３ , or N(CH ２ ) ２ CH ３ is, or X ２ is R ３ A piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is formed together with the above, and here the condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is formed by the condensation of a phenyl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an isothiazolyl group, an imidazolyl group, a triazolyl group, a pyridyl group, or a pyrimidine group, and the condensed piperidinyl group, a condensed piperazine group, or a condensed pyrrolidinyl group is optionally substituted with one or more substituents 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, fluorine, chlorine, bromine, iodine, a hydroxyl group, an amino group, a nitro group, a methyl ester group, an ethyl ester group, a phenyl group, and a substituted phenyl group, preferably X ２ is O or NH, or X ２ is R ３ Together with, it forms an imidazolipeperajinyl group, a thienopiperajinyl group, or a pyrrolopiperadinyl group, where the imidazolipeperajinyl group, thienopiperajinyl group, or pyrrolopiperadinyl group is optionally substituted with one or more substituents selected from methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-butyl group, fluorine, chlorine, bromine, iodine, hydroxyl group, amino group, nitro group, methyl ester group, ethyl ester group, and phenyl group, or S １ S ２ If one of them is a chemical bond, the other is -(CH ２ ) ２ -, - (CH ２ ) ３ -, - (CH ２ ) ４ -, - (CH ２ ) ５ - or - (CH ２ ) ６ - or Y － The root is a halogen anion, sulfate root, acetate root, tartaric acid root, p-toluenesulfonic acid root, methanesulfonic acid root, or citrate root, preferably Cl － , Br － ,CH ３ COO － And more preferably Br － The compound according to claim 1, or its stereoisomer or solvate.

10. The compound represented by the above formula (I) is the following formula (IV): 【Chemistry 2】 [In the formula, X １ NR Ａ ４ (However, R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups, or C １－４ Alkoxy C １－４ It is an alkyl group, preferably NH, X ２ O, S and NR Ｂ ４ (However, R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups or C １－４ Alkoxy C １－４ Selected from alkyl groups, preferably O, NH, NCH ３ NCH ２ CH ３ , or N(CH ２ ) ２ CH ３ It is, and more preferably O or NH, R ６ , R ７ , R ８ , R ９ , R １０ Each of these independently consists of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, and C. １－４ alkyl group, C １－４ Alkoxy groups, and C １－４ Alkoxy C １－４ Selected from alkyl groups, R １ , R ２ , L and Y － [is defined as formula (I) in claim 1] Is it a compound represented by; Or, The compound represented by the above formula (I) is given by the following formula (V): 【Transformation 3】 [In the formula, X １ NR Ａ ４ (However, R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups or C １－４ Alkoxy C １－４ It is an alkyl group, preferably NH, X ２ O, S and NR Ｂ ４ (However, R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups or C １－４ Alkoxy C １－４ Selected from alkyl groups, preferably O, NH, NCH ３ NCH ２ CH ３ or N(CH ２ ) ２ CH ３ It is more O, NH, R ６ , R ７ , R ８ , R ９ , R １０ Each of these independently consists of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, and C. １－４ alkyl group, C １－４ Alkoxy group, and C １－４ Alkoxy C １－４ Selected from alkyl groups, R １ , R ２ , L and Y － [is defined as formula (I) in claim 1] Is it the compound represented? Or, The compound represented by the above formula (I) is the following formula (VI): 【Chemistry 4】 [In the formula, X １ NR Ａ ４ (However, R Ａ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups, or C １－４ Alkoxy C １－４ It is an alkyl group, preferably NH, X ３ is C or N, R １０ is hydrogen, C １－４ alkyl group, C １－４ Alkoxy group, C １－４ Alkoxy C １－４ Selected from alkyl groups and aromatic hydrocarbon groups, where the aromatic hydrocarbon group is optionally fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, C １－４ alkyl group, C １－４ Alkoxy group, and C １－４ Alkoxy C １－４ It is substituted with one or more substituents selected from alkyl groups. R １ , R ２ , L and Y － [is defined as formula (I) in claim 1] Is it a compound represented by; Or, The compound represented by the above formula (I) is the one shown in the following formula (VII): 【Transformation 5】 [In the formula, X ２ O, S and NR Ｂ ４ (However, R Ｂ ４ is hydrogen, deuterium, C １－８ alkyl group, C ３－８ Cycloalkyl groups or C １－４ Alkoxy C １－４ Selected from alkyl groups, preferably O, NH, NCH ３ NCH ２ CH ３ , or N(CH ２ ) ２ CH ３ It is, and more preferably O or NH, R ６ , R ７ , R ８ , R ９ , R １０ Each of these independently consists of hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, and C. １－４ alkyl group, C １－４ Alkoxy group, and C １－４ Alkoxy C １－４ Selected from alkyl groups, L and Y － [is defined as formula (I) in claim 1] The compound represented by the compound in claim 1, or its stereoisomer or solvate.

11. The compound represented by formula (I) above is the following formula (IV): 【Transformation 6】 [In the formula, X1 is NR A4 (where R A4 is hydrogen, deuterium, C1-8 alkyl group, C3-8 cycloalkyl group, or C1-4 alkoxy C1-4 alkyl group), preferably NH. X2 is selected from O, S and NR B4 (where R B4 is hydrogen, deuterium, C1-8 alkyl group, C3-8 cycloalkyl group or C1-4 alkoxy C1-4 alkyl group), preferably O, NH, NCH3, NCH2CH3 or N(CH2)2CH3, more preferably O or NH. R6, R7, R8, R9, and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, C1-4 alkyl group, C1-4 alkoxy group, and C1-4 alkoxy C1-4 alkyl group, and optionally, two adjacent substituents and the atoms linked to them form a ring together. R1, R2, L, and Y are defined as in formula (I) of claim 7. Is it a compound represented by; Or, The compound represented by the above formula (I) is given by the following formula (V): 【Transformation 7】 [In the formula, X1 is NR A4 (where R A4 is hydrogen, deuterium, C1-8 alkyl group, C3-8 cycloalkyl group, or C1-4 alkoxy C1-4 alkyl group), preferably NH. X2 is selected from O, S and NR B4 (where R B4 is hydrogen, deuterium, C1-8 alkyl group, C3-8 cycloalkyl group or C1-4 alkoxy C1-4 alkyl group), preferably O, NH, NCH3, NCH2CH3 or N(CH2)2CH3, more preferably O, NH. R6, R7, R8, R9, and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, C1-4 alkyl group, C1-4 alkoxy group, and C1-4 alkoxy C1-4 alkyl group, and optionally, two adjacent substituents and the atoms linked to them form a ring together. R1, R2, L, and Y are defined as in formula (I) in claim 7. Is it a compound represented by; Or, The compound represented by the above formula (I) is the one shown in the following formula (VII): 【Transformation 8】 [In the formula, X2 is selected from O, S and NR B4 (where R B4 is hydrogen, deuterium, C1-8 alkyl group, C3-8 cycloalkyl group or C1-4 alkoxy C1-4 alkyl group), preferably O, NH, NCH3, NCH2CH3, or N(CH2)2CH3, more preferably O or NH. R6, R7, R8, R9, and R10 are each independently selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl group, cyano group, nitro group, amino group, ester group, C1-4 alkyl group, C1-4 alkoxy group, and C1-4 alkoxy C1-4 alkyl group, and optionally, two adjacent substituents and the atoms linked to them form a ring together. L and Y are defined as in formula (I) in claim 7. The compound represented by The compound according to claim 7, or its stereoisomer or solvate. 【Request Item 12】 【Chemistry 9】 【Chemistry 10】 【Chemistry 11】 【change】 Selected from, Preferably, 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 A compound according to claim 1, or a stereoisomer or solvate thereof, selected from the above. 【Request Item 13】 【Chemistry 16】 A method for preparing the compound according to claim 1, or a stereoisomer or solvate thereof, comprising the step of reacting a compound represented by formula (II) with a compound represented by formula (III) to obtain compound (I) (wherein Z in formula (II) is an electron-withdrawing leaving group, and the definitions of the groups in formula (II) and formula (III) are the same as in formula (I)).

14. A pharmaceutical composition comprising the compound described in claim 1, or a stereoisomer thereof, or a solvate thereof, and a pharmaceutically acceptable carrier excipient or diluent.

15. A local anesthetic or analgesic comprising a compound according to any one of claims 1 to 12, a stereoisomer thereof, or a solvate thereof, or the pharmaceutical composition according to claim 14. Preferably, the local anesthetic is nerve block anesthesia, surface anesthesia, or infiltration anesthesia. The aforementioned analgesic is suitably used for chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain, or idiopathic pain. Preferably, the method of administration of the drug is local administration via transdermal, subcutaneous, intradermal, intramuscular, near-nerve, intrapulp, intraspinal, epidural space, intravenous, or mucosal routes such as eye drops, for a local anesthetic or analgesic.

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