N-substituted arylamine derivative, and preparation method therefor and use thereof

Abstract

The present invention relates to a compound having a structure of formula I, formula II, formula III, formula IV or formula V, or a stereoisomer, pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, a preparation method therefor, and a pharmaceutical composition containing same and the use thereof.

Description

N-substituted aromatic amine derivatives, their preparation methods and uses Technical Field

[0001] This invention belongs to the field of pharmaceuticals, specifically a novel class of N-substituted aromatic amine derivatives, their preparation methods, and their uses in related pharmaceutical fields. Background Technology

[0002] Based on the duration of pain, it can generally be divided into acute pain and chronic pain. Treatment of acute pain mainly includes postoperative analgesia, treatment of post-traumatic pain, and management of painless childbirth and induced abortion. Clinically, the main drugs for postoperative analgesia are opioid analgesics, amide local anesthetics (such as lidocaine, bupivacaine, and ropivacaine), and nonsteroidal anti-inflammatory drugs (NSAIDs). Opioid analgesics can effectively suppress pain, but they are addictive and dependent, and produce many side effects on the central nervous system, gastrointestinal tract, urinary system, cardiovascular system, endocrine system, and immune system. Amide local anesthetics such as lidocaine and bupivacaine have short durations of action, making it difficult to meet the need for prolonged postoperative pain suppression, and they also have central nervous system toxicity and cardiovascular toxicity. The analgesic effect of NSAIDs has significant limitations, making it difficult to effectively suppress acute pain, and they are accompanied by multi-systemic side effects. In recent years, several postoperative analgesics based on bupivacaine multicyst liposomes have been launched (such as Expareel and Aihengping), claiming an analgesic duration of up to 72 hours. However, this claim is highly controversial in the literature, with some arguing that their analgesic effect is not superior to bupivacaine hydrochloride and does not offer a greater clinical advantage (Anesthesiology 2021, 134:147-64; Chinese Journal of Pain Medicine, October 2022, Vol. 18, No. 5, pp. 698-700). These bupivacaine liposomes contain high concentrations of bupivacaine (e.g., Expareel and Aihengping average 46.1 mM), which have significant central nervous system and cardiotoxicity, posing a high safety risk. WO 2024 / 012397 discloses a compound B250 with a dual bupivacaine composite structure, which exhibits a longer duration of analgesia, but its efficacy and safety in analgesia remain significant shortcomings. Therefore, the development of safer and more effective new long-acting postoperative analgesics remains an unmet clinical need. Summary of the Invention

[0003] The present invention aims to provide a new class of N-substituted aromatic amine derivatives with longer duration of analgesia, higher analgesic efficacy and safety.

[0004] In one aspect of the invention, compounds having the structure of formula I, II, III, IV or V, or stereoisomers thereof, or pharmaceutically acceptable salts or solvates thereof, or polymorphs thereof are provided.

[0005] in,

[0006] X and Y are independently represented by O, S, and NR. 3 ;

[0007] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0008] n = 0-7;

[0009] m = 0 - 8;

[0010] R 1 and R 2 Each independently

[0011] x and y are each independently 0 or 1;

[0012] G and E are independently O, S, and NR. 3 ;

[0013] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0014] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0015] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0016] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0017] According to another aspect of the present invention, a pharmaceutical composition is provided comprising a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0018] According to another aspect of the invention, use is provided of a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for analgesia or local anesthetic.

[0019] According to another aspect of the invention, a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, or a pharmaceutical composition thereof, is provided for use as an analgesic or local anesthetic.

[0020] According to another aspect of the invention, a method for analgesia or local anesthesia is provided, comprising the step of administering to an individual in need an effective dose of a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, or a pharmaceutical composition according to the present disclosure.

[0021] In this disclosure, the analgesia or local anesthesia is administered by means of surface application, tissue infiltration, nerve block, subarachnoid block, epidural block, dorsal root nerve block, and application to the wound, including application to the wound intramuscularly, subcutaneously, or to the surrounding nerves by dripping or smearing before suturing the surgical site. Detailed Implementation

[0022] definition

[0023] Unless otherwise defined below, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0024] In this invention, combinations of substituents and variables are permitted only if such combinations result in chemically stable compounds. When a substituent is replaced by two or more groups, these multiple groups can exist on the same or different carbon atoms, provided a stable structure is produced.

[0025] As used herein, the terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0026] In this invention, the subscript number of the carbon atom "C" indicates the number of carbon atoms. For example, C1 represents 1 carbon atom, C2 represents 2 carbon atoms, and C... p -C q This represents pq (0 < p < q) carbon atoms. The group name following the carbon atom "C" indicates the type of group; for example, C1 alkyl represents methyl, C2 alkenyl represents vinyl, and C... p -C q The hydrocarbon group represents a hydrocarbon group with pq carbon atoms.

[0027] As used herein, the term "hydrocarbon group" refers to a saturated or unsaturated group composed of carbon and hydrogen atoms, including straight-chain or branched aliphatic saturated or unsaturated hydrocarbon groups, alicyclic hydrocarbon groups, heterocyclic hydrocarbon groups, aromatic hydrocarbon groups, or aromatic heterocyclic hydrocarbon groups. The term "C1-C7 hydrocarbon group" refers to a hydrocarbon group having 1 to 7 carbon atoms, including C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, C3-C7 cycloalkyl, C5-C7 cycloalkenyl, C6-C7 aryl, benzyl, etc. Preferred C1-C7 hydrocarbon groups are C1-C7 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, p-pentyl, n-hexyl, 2-hexyl, 3-hexyl, n-heptyl, 2-heptyl, 3-heptyl, 4-heptyl, etc. The term "C2-C7 alkenyl" includes, for example, vinyl, propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl, 2,4-butadienyl, pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, etc. The term "C2-C7 ynyl" includes, for example, ethynyl, propynyl, propynyl, 2-butynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, 1-hepynyl, 2-hepynyl, 3-hepynyl, 4-hepynyl, 5-hepynyl, 6-hepynyl, etc. The term "C3-C7 cycloalkyl" includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc. The term "C5-C7 cycloalkenyl" includes, for example, cyclobutenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl, cycloheptanetrienyl, etc. The term "C6-C7 aryl" includes, for example, phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, etc.

[0028] This invention also includes all pharmaceutically acceptable isotopically labeled compounds that are identical to the compounds of this invention, except that one or more atoms are replaced by atoms having the same atomic number but with an atomic mass or mass number different from the dominant atomic mass or mass number in nature. Examples of isotopes suitable for inclusion in the compounds of this invention include (but are not limited to) isotopes of hydrogen (e.g., 2 H, 3 H, preferred 2 H); carbon isotopes (e.g., H); 11 C 13 C and 14 C); isotopes of chlorine (e.g.) 36 Cl); isotopes of fluorine (e.g., Cl); 18 F); isotopes of iodine (e.g., F); 123 I and 125I); nitrogen isotopes (e.g.) 13 N and 15 N); isotopes of oxygen (e.g., N); 15 O、 17 O and 18 O); isotopes of phosphorus (e.g., O); phosphorus isotopes (e.g., O); 32 P); and isotopes of sulfur (e.g., ... 35 S). Certain isotope-labeled compounds of the present invention (e.g., those doped with radioactive isotopes) can be used in drug and / or substrate tissue distribution studies (e.g., analysis). Radioactive isotope tritium (i.e. 3 H) and carbon-14 (i.e. 14 C) It is particularly suitable for this purpose due to its ease of incorporation and detection. Using positron-emitting isotopes (e.g.) 11 C 18 F, 15 O and 13 Substitution of N) can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. The isotopically labeled compounds of the present invention can be prepared by methods similar to those described in the accompanying routes and / or examples and preparations, by using a suitable isotopically labeled reagent instead of the previously used unlabeled reagent. Pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be isotopically substituted, for example, D2O, acetone-d6, or DMSO-d6.

[0029] Solid lines (—) and wavy lines can be used in this article. solid wedge Or virtual wedge Depicting the chemical bonds of the compounds of the present invention. Solid lines are used to depict bonds to asymmetric atoms, indicating all possible stereoisomers at that atom (e.g., specific enantiomers, racemic mixtures, etc.). Wavy lines are used to depict bonds to asymmetric atoms, indicating that the bond is a solid wedge. Or virtual wedge Any of the following types of bonds. The use of real or imaginary wedges to depict bonds connecting to asymmetric atoms indicates the presence of the stereoisomers shown. When present in racemic mixtures, real and imaginary wedges are used to define relative stereochemistry, not absolute stereochemistry. Unless otherwise specified, the compounds of the present invention are intended to exist as stereoisomers (including cis and trans isomers, optical isomers (e.g., R and S enantiomers), diastereomers, geometric isomers, rotational isomers, conformational isomers, trans-blocking isomers, and mixtures thereof). The compounds of the present invention may exhibit more than one type of isomerism and consist of mixtures thereof (e.g., racemic mixtures and diastereomer pairs).

[0030] The compounds of the present invention contain one or more asymmetric centers, thereby enabling them to exist in the form of racemic derivatives, racemic mixtures, single enantiomers, diastereomer mixtures, and single diastereomers.

[0031] This invention covers all possible crystalline forms or polymorphs of the compounds of this invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.

[0032] It should also be understood that certain compounds of the present invention may exist in their free form for therapeutic purposes, or, where appropriate, in their pharmaceutically acceptable derivative forms. In the present invention, pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, metabolites, or prodrugs, which, upon administration to a patient in need, can directly or indirectly provide the compounds of the present invention or their metabolites or residues. Therefore, when referring to "compounds of the present invention" herein, it is also intended to encompass the various derivative forms of the compounds described above.

[0033] The term "pharmaceutically acceptable salt" refers to an acid addition salt or base addition salt that is suitable for or compatible with the individual's treatment. For example, a pharmaceutically acceptable salt may be a salt formed by a free base of a compound according to this disclosure and one of pharmaceutically acceptable inorganic and organic acids, or two or more acids in any combination. The pharmaceutically acceptable inorganic acid salts include, for example, salts formed with hydrochloric acid, hydrobromic acid, phosphoric acid, and sulfuric acid; the pharmaceutically acceptable organic acid salts include, for example, salts formed with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxyethanesulfonic acid, formic acid, acetic acid, chloroacetic acid, glycolic acid, trifluoroacetic acid, propionic acid, acrylic acid, butyric acid, isobutyric acid, valeric acid, pteropenic acid, hexanoic acid, benzoic acid, phenylacetic acid, oxalic acid, malonic acid, succinic acid, maleic acid, trans-butenic acid, d-tartaric acid, l-tartaric acid, dl-tartaric acid, glutaric acid, adipic acid, phthalic acid, isophthalic acid, terephthalic acid, and citric acid. In the addition salts, the free base of the compound of the present invention may exist in a stoichiometric or non-stoichiometric ratio with the inorganic and organic acids.

[0034] The compounds of the present invention can exist in the form of solvates (preferably hydrates), wherein the compounds of the present invention contain a polar solvent as a structural element of the lattice of the compound, such as water, alcohols, acids, esters, ethers, ketones, nitriles, and halogenated hydrocarbons and combinations thereof, and the amount of solvent may be stoichiometric or non-stoichiometric. According to one embodiment, the solvent in the solvate is selected from water, C1-C6 alcohols, C1-C6 acids, C3-C6 esters, C4-C6 ethers, C3-C6 ketones, C1-C6 nitriles, and C1-C6 halogenated hydrocarbons and combinations thereof. Preferably, the solvent in the solvate is selected from water, methanol, ethanol, propanol, isopropanol, n-butanol, tert-butanol, ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, acetic acid, propionic acid, butyric acid, ethyl acetate, methyl acetate, isopropyl acetate, methyl propionate, ethyl propionate, diethyl ether, methyl tert-butyl ether, tetrahydrofuran, acetone, butanone, acetonitrile, dichloromethane, and chloroform and combinations thereof.

[0035] The scope of this invention also includes metabolites of the compounds of this invention, i.e., substances formed in the body when the compounds of this invention are administered. Such products can be generated, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic hydrolysis, etc., of the administered compound. Therefore, this invention includes metabolites of the compounds of this invention, including compounds obtained by methods that expose the compounds of this invention to mammals for a time sufficient to produce their metabolites.

[0036] This invention further includes, within its scope, prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention that may themselves have little or no pharmacological activity, which, when administered to or onto the body, can be converted, for example, by hydrolysis and cleavage into the compounds of the invention having the desired activity. Typically, such prodrugs are functional group derivatives of the compounds that readily convert in vivo into the compounds with the desired therapeutic activity. Further information regarding the use of prodrugs can be found in “Pro-drugs as Novel Delivery Systems,” Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and “Bioreversible Carriers in Drug Design,” Pergamon Press, 1987 (EB Roche, editor, American Pharmaceutical Association). The prodrugs of the invention can be prepared, for example, by replacing suitable functional groups present in the compounds of the invention with certain portions known to those skilled in the art as “pro-moiety” (e.g., as described in “Design of Prodrugs,” H. Bundgaard (Elsevier, 1985)).

[0037] This invention also covers compounds of the invention containing protecting groups. In any process of preparing the compounds of the invention, protection of sensitive or reactive groups on any relevant molecule may be necessary and / or desired, thereby forming a form of chemical protection for the compounds of the invention. This can be achieved by conventional protecting groups, for example, those described in *Protective Groups in Organic Chemistry*, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P. ​​G.W. Uts, *Protective Groups in Organic Synthesis*, John Wiley & Sons, 1991, which are incorporated herein by reference. Protecting groups can be removed at appropriate subsequent stages using methods known in the art.

[0038] The term “about” means within ±10% of the stated value, preferably within ±5%, and more preferably within ±2%.

[0039] compound

[0040] According to one aspect of this application, a compound having the structure of Formula I, Formula II, Formula III or Formula IV, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, is provided:

[0041] in,

[0042] X and Y are independently represented by O, S, and NR. 3 ;

[0043] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0044] n = 0 - 3;

[0045] m = 0 - 8;

[0046] R 1 and R 2 Each independently

[0047] in,

[0048] G and E are independently represented as O, S, and NR, respectively. 3 ;

[0049] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0050] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0051] The carbon atom indicated by “*” can be in the R or S configuration alone, or a mixture thereof in any proportion.

[0052] According to one aspect of this application, a compound having the structure of formula I, II, III, IV or V, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, is provided:

[0053] in,

[0054] X and Y are independently represented by O, S, and NR. 3 ;

[0055] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0056] n = 0-7;

[0057] m = 0 - 8;

[0058] R 1 and R 2 Each independently

[0059] in,

[0060] x and y are each independently 0 or 1;

[0061] G and E are independently represented as O, S, and NR, respectively. 3 ;

[0062] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0063] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0064] exist In the figure, the carbon atom indicated by "*" can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0065] exist In the middle, mark This indicates the position where the corresponding group is attached to other parts of the compound.

[0066] According to one aspect of this application, a compound having the structure of formula I, II, III, IV or V, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, is provided:

[0067] in,

[0068] X and Y are independently represented by O, S, and NR. 3 ;

[0069] n = 0-7;

[0070] m = 0 - 8;

[0071] R 1 and R 2 Each independently

[0072] x and y are each independently 0 or 1;

[0073] G and E are independently O, S, and NR. 3 ;

[0074] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0075] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0076] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0077] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0078] In some implementation schemes, R 3 It is hydrogen or C1-C7 alkyl.

[0079] In some implementation schemes, R 3 It can be hydrogen, methyl, or ethyl.

[0080] In some implementation schemes, R E It is hydrogen or C1-C7 alkyl.

[0081] In some implementation schemes, R E It can be hydrogen, methyl, or ethyl.

[0082] In some implementations, X and Y are each independently O, S, NH, or N-CH3.

[0083] In some implementations, G and E are each independently O, S, NH, or N-CH3.

[0084] In some embodiments, the compounds of the present invention have the structure of formula VI:

[0085] in,

[0086] n = 0-7;

[0087] R 1 and R 2 Each independently

[0088] x and y are each independently 0 or 1;

[0089] G and E are independently O, S, and NR. 3 ;

[0090] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0091] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0092] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0093] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0094] In some embodiments, the compounds of the present invention have the structure of formula VII:

[0095] in,

[0096] n = 0-7;

[0097] R 1 and R 2 Each independently in,

[0098] x and y are each independently 0 or 1;

[0099] G and E are independently O, S, and NR. 3 ;

[0100] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0101] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0102] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0103] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0104] In some embodiments, the compounds of the present invention have the structure of formula VIII:

[0105] in,

[0106] n = 0-7;

[0107] R 1 and R 2 Each independently

[0108] x and y are each independently 0 or 1;

[0109] G and E are independently O, S, and NR. 3 ;

[0110] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0111] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0112] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0113] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0114] In some embodiments, the compounds of the present invention have the structure of formula IX:

[0115] in,

[0116] n = 0-7;

[0117] R 1 and R 2 Each independently

[0118] x and y are each independently 0 or 1;

[0119] G and E are independently O, S, and NR. 3 ;

[0120] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0121] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0122] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0123] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0124] In some embodiments, the compounds of the present invention have the structure of formula X:

[0125] in,

[0126] n = 0-7;

[0127] R 1 and R 2 Each independently in,

[0128] x and y are each independently 0 or 1;

[0129] G and E are independently O, S, and NR. 3 ;

[0130] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0131] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0132] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0133] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0134] In some embodiments, the compounds of the present invention have the structure of formula XI:

[0135] in,

[0136] n = 0-7;

[0137] R 1 and R 2 Each independently in,

[0138] x and y are each independently 0 or 1;

[0139] G and E are independently O, S, and NR. 3 ;

[0140] R 3 It is hydrogen or a C1-C7 hydrocarbon group;

[0141] R E It is hydrogen or a C1-C7 hydrocarbon group;

[0142] The carbon atom indicated by “*” can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion;

[0143] exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound.

[0144] In some embodiments, the compounds of the present invention have the structure of formula XII:

[0145] in,

[0146] M is either O or CH2;

[0147] n = 0-7;

[0148] R 5 It can be methyl, ethyl, n-propyl, or n-butyl;

[0149] x and y are each independently 0 or 1.

[0150] In some embodiments, the compounds of the present invention have the structure of formula XIII:

[0151] in,

[0152] M is either O or CH2;

[0153] m = 0 - 8;

[0154] R 5 It can be methyl, ethyl, n-propyl, or n-butyl;

[0155] x and y are each independently 0 or 1.

[0156] In the above formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, and XIII, n = 0-7 refers to n being an integer between 0 and 7, that is, n is 0, 1, 2, 3, 4, 5, 6, or 7.

[0157] In the above formulas I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII, m = 0-8 means that m is an integer between 0 and 8, that is, m is 0, 1, 2, 3, 4, 5, 6, 7 or 8.

[0158] This invention covers any combination of the above embodiments. The group definitions applicable to one general formula compound also apply to other general formula compounds.

[0159] In some embodiments, the compounds of the present invention are selected from the compounds in the following table:

[0160] Preparation method

[0161] According to another aspect of this application, a method for preparing a compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph according to this disclosure is provided.

[0162] In one embodiment, a method is provided for preparing a compound having the structure of formula VI or VII, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, wherein the compound is prepared via route 1-1 or route 1-2 as follows:

[0163] As shown in route 1-1, the preparation method includes reacting compound A(1) with compound B(1) in the presence of an acid-binding agent to obtain compound VI.

[0164] Alternatively, as shown in route 1-2, compound A(1) and compound B(1) are reacted in the presence of an acid-binding agent to generate intermediate compound VII-M-1, and then compound VII-M-1 is reacted with compound A(2) in the presence of an acid-binding agent to generate compound VII.

[0165] In either Route 1-1 or Route 1-2 above,

[0166] n, R 1 and R 2 Each is as defined above for compounds of formula VII;

[0167] Z represents a group that is easily removed;

[0168] Z, as a group that is easily removed, includes, but is not limited to, chlorine, bromine, iodine, sulfonic acid group, carboxylic acid group, or substituted carboxylic acid group. The sulfonic acid group includes, for example, methanesulfonic acid group, benzenesulfonic acid group, p-toluenesulfonic acid group, trifluoromethanesulfonic acid group, etc. The carboxylic acid group or substituted carboxylic acid group includes, for example, acetic acid group, trifluoroacetic acid group, trichloroacetic acid group, pivalic acid group, etc.

[0169] The acid-binding agent is an inorganic or organic base. The inorganic base includes, but is not limited to, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and potassium sodium hydrogen phosphate. The organic bases include, but are not limited to, sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amino, methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium iodide, dimethyl magnesium, diethyl magnesium, diisopropyl magnesium, etc., LDA, NaHMDS, KHMDS, LiHMDS, etc.

[0170] In another embodiment, a method is provided for preparing a compound having the structure of formula VIII or formula IX, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, wherein the compound is prepared via route 2-1 or route 2-2 as follows:

[0171] As shown in route 2-1, the preparation method includes: reacting compound A(1) with compound B(2) in the presence of an acid-binding agent to obtain compound VIII-M-1, then deprotecting to obtain compound VIII-M-2, and then carrying out a methylation reaction in the presence of an acid-binding agent to obtain compound VIII.

[0172] Alternatively, as shown in route 2-2, compound A(1) is reacted with an excess of compound B(2) in the presence of an acid-binding agent to obtain compound IX-M-1, which is then reacted with compound A(2) in the presence of an acid-binding agent to generate compound IX-M-2. Subsequently, deprotection and methylation reactions are carried out to obtain compound IX.

[0173] In either Route 2-1 or Route 2-2 above,

[0174] n, R 1 and R 2 Each is as defined above for compounds of formula IX;

[0175] Z is a departing group as defined in routes 1-1 or 1-2, for example, Z as a departing group includes, but is not limited to, chlorine, bromine, iodine, sulfonic acid, etc.

[0176] P is an amino protecting group, including but not limited to Boc, Cbz, benzyl, trifluoroacetyl, Fmoc, etc.;

[0177] The deprotecting agent is a common deprotecting agent for the corresponding amino protecting group, such as, but not limited to, TFA, HCl, Pd / C-H2, HBr, TMSBr, TMSI, Na-NH3 (liq.), K2CO3, NaOH, piperidine, DBU, TBAF, CsF, etc.;

[0178] The reagents used in the methylation reaction include, but are not limited to, iodomethane, bromomethane, chloromethane, dimethyl sulfate, methyl benzenesulfonate, methyl p-toluenesulfonate, methyl trifluoromethanesulfonate, dimethyl carbonate, trimethyloxonium tetrafluoroborate, and formaldehyde or paraformaldehyde.

[0179] The acid-binding agent is as defined in route 1-1 or 1-2.

[0180] In another embodiment, a method is provided for preparing a compound having the structure of formula X or formula XI, or a stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof, or a polymorph thereof, wherein the compound is prepared via route 3-1 or route 3-2 as follows:

[0181] As shown in route 3-1, the method includes: reacting compound A(1) with compound B(3) in the presence of an acid-binding agent to obtain compound XM-1, and then reacting it with sodium sulfide to obtain compound X.

[0182] Alternatively, as shown in route 3-2, compound A(1) is reacted with compound B(3) in the presence of an acid-binding agent to obtain compound XI-M-1, which is then reacted with sodium hydrosulfide to generate compound XI-M-2, and then reacted with compound XI-M-3 generated from the reaction of compound A(2) and compound B(3) to generate compound XI.

[0183] In either Route 3-1 or Route 3-2 above,

[0184] R 1 and R 2 Each is as defined above for compounds of formula X and formula XI;

[0185] Z is a departing group as defined in route 1-1 or 1-2;

[0186] The acid-binding agent is as defined in route 1-1 or 1-2.

[0187] In another embodiment, a method is provided for preparing a compound having the structure of formula XII or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, wherein the compound is prepared by route 4-1 or route 4-2 as follows:

[0188] Route 4-1

[0189] As shown in route 4-1, the method includes: condensing a compound of formula XII-0 with an aniline compound to obtain an amide compound of formula XII-1, then reacting it with compound B(1) in the presence of an acid-binding agent to obtain a compound of formula XII-1-1, subsequently performing a deprotection reaction under the action of a deprotecting agent to obtain a compound of XII-1-2, and finally reacting it with compound B(4) under the action of an acid-binding agent to obtain the final product XII.

[0190] Route 4-2

[0191] As shown in route 4-2, the method includes: condensing a compound of formula XII-0 with an aniline compound to obtain an amide compound of formula XII-1, then performing a deprotection reaction under the action of a deprotection agent to obtain a compound of formula XII-2, subsequently reacting it with compound B(4) under the action of an acid-binding agent to obtain a compound of XII-2-1, and finally reacting it with compound B(1) under the action of an acid-binding agent to obtain the final product XII.

[0192] In routes 4-1 and 4-2 above,

[0193] n, M, R 5 x and y are each defined above for compounds of formula XII;

[0194] Z is a departing group as defined in route 1-1 or 1-2;

[0195] R 4 Amino protecting groups, such as Boc, Cbz, Bn, Fmoc, trifluoroacetyl, etc.

[0196] The condensation reaction can be carried out under conditions including but not limited to reagents such as DCC, EDCI, carbonyl diimidazole, DIC, HATU, BOP, DPPA, and various acid anhydrides and acyl chlorides.

[0197] The acid-binding agent is as defined in route 1-1 or 1-2;

[0198] The deprotection reagent is as defined in route 2-1 or 2-2.

[0199] In another embodiment, a method is provided for preparing a compound having the structure of formula XIII or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, wherein the compound is prepared by route 5-1 or route 5-2 as follows:

[0200] Route 5-1

[0201] As shown in route 5-1, the method includes: condensing a compound of formula XII-0 with an aniline compound to obtain an amide compound of formula XII-1, then reacting it with compound B(5) in the presence of an acid-binding agent to obtain a compound of formula XIII-1-1, subsequently performing a deprotection reaction under the action of a deprotecting agent to obtain a compound of XIII-1-2, and finally reacting it with compound B(4) under the action of an acid-binding agent to obtain the final product XIII.

[0202] Route 5-2

[0203] As shown in route 5-2, the method includes: condensing a compound of formula XII-0 with an aniline compound to obtain an amide compound of formula XII-1, then performing a deprotection reaction under the action of a deprotection agent to obtain a compound of formula XII-2, subsequently reacting it with compound B(4) under the action of an acid-binding agent to obtain a compound of XII-2-1, and finally reacting it with compound B(5) under the action of an acid-binding agent to obtain the final product XIII.

[0204] In routes 5-1 and 5-2 above:

[0205] m, M, R 5 x and y are each defined above for compounds of formula XII;

[0206] Z is a departing group as defined in route 1-1 or 1-2;

[0207] R 4 Amino protecting groups, such as Boc, Cbz, Bn, Fmoc, trifluoroacetyl, etc.

[0208] The condensation reaction can be carried out under conditions including but not limited to reagents such as DCC, EDCI, carbonyl diimidazole, DIC, HATU, BOP, DPPA, and various acid anhydrides and acyl chlorides.

[0209] The acid-binding agent is as defined in route 1-1 or 1-2;

[0210] The deprotection reagent is as defined in route 2-1 or 2-2.

[0211] Pharmaceutical Compositions and Uses

[0212] According to another aspect of this application, a pharmaceutical composition is provided comprising a compound according to this disclosure or a stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, and a pharmaceutically acceptable carrier or excipient.

[0213] The term "pharmaceuticalally acceptable carrier" refers to a non-toxic solvent, dispersant, excipient, adjuvant, or other material that is mixed with the active ingredient to form a pharmaceutical composition (i.e., a dosage form capable of being administered to an individual). In one embodiment, the pharmaceutically acceptable carrier or excipient is physiological saline or an aqueous solution or saline solution containing a thickener (such as sodium carboxymethyl cellulose and povidone).

[0214] In some embodiments, the compounds or compositions of this disclosure are intended for parenteral administration. For example, the parenteral route may be selected from inhalation, intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, dorsal root nerve region, mucosa and deep tissue, or via the eye, skin, or surface, or a combination thereof, or application to a wound, including application to the wound intramuscularly, subcutaneously, or around the nerves by dripping or smearing before surgical site closure. For example, solutions of the compounds of this disclosure in aqueous or saline solutions containing thickeners (such as sodium carboxymethyl cellulose and povidone) may be administered intraperitoneally, intramuscularly, subcutaneously, subarachnoid, epidural, or via dorsal root nerve injection or infusion, or instilled into the eye, or applied to a wound, including application to the wound intramuscularly, subcutaneously, or around the nerves by dripping or smearing before surgical site closure.

[0215] Those skilled in the art will know how to prepare suitable formulations according to specific analgesic or local anesthetic requirements. For parenteral administration, a sterile solution of the compound of the present invention is typically prepared, and the pH of the solution is appropriately adjusted and buffered, wherein the pH is 5-7, preferably 6-7. For intravenous administration, the total concentration of the solute should be controlled to make the formulation isotonic. For ocular administration, the instillable liquid can be administered, for example, via ocular administration systems known in the art (e.g., applicators or droppers). For intrapulmonary administration, a diluent or carrier suitable for forming an aerosol will be selected.

[0216] In some embodiments, the compounds and / or compositions described herein are formulated for parenteral administration by injection, including using conventional catheter insertion or infusion. For example, injectable formulations are present in unit dosage forms, such as in ampoules or multi-dose containers, with added preservatives. In some embodiments, the compositions or combinations are in the form of sterile suspensions, solutions, or emulsions in an oily or aqueous carrier and contain formulations such as suspending agents, stabilizers, and / or dispersants. In all cases, the dosage form must be sterile and must be fluid for easy injection. Alternatively, the compounds of this disclosure may suitably be in sterile powder form for reconstitution with a suitable carrier (e.g., sterile pyrogen-free water) prior to use.

[0217] In some embodiments, the composition or combination for inhalation (optionally administered via the nasal cavity) is conveniently formulated as an aerosol. For intranasal or inhalation administration, the compounds described herein can be conveniently delivered in the form of a solution, dry powder, granule formulation, or suspension from a pump-operated spray container squeezed or pumped by a patient, or in the form of an aerosol spray from a pressurized container or nebulizer. Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are typically present in a sterile, single- or multiple-dose form in a sealed container, such as a cartridge or filler used with a nebulizer. Alternatively, the sealed container may be a single dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve for post-use disposal. In the case of an aerosol dispenser, it may contain a propellant, such as a compressed gas (e.g., compressed air) or an organic propellant (e.g., chlorofluorocarbons). Suitable propellants include, but are not limited to, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, heptafluoroalkane, carbon dioxide, or other suitable gases. In the case of pressurized aerosols, the dosage unit is appropriately determined by providing a valve for delivering the metering.

[0218] According to another aspect of this application, the use of compounds or stereoisomers thereof or pharmaceutically acceptable salts or solvates thereof or polymorphs thereof, as well as pharmaceutical compositions thereof, according to this disclosure in the preparation of medicaments for analgesia or local anesthetic is provided.

[0219] According to another aspect of this application, compounds or stereoisomers thereof or pharmaceutically acceptable salts or solvates thereof or polymorphs thereof, as well as pharmaceutical compositions thereof, are provided for analgesia or local anesthesia.

[0220] According to another aspect of this application, a method for analgesia or local anesthesia is provided, comprising the step of administering to an individual in need an effective dose of a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof, or a pharmaceutical composition thereof, according to this disclosure.

[0221] In this disclosure, the analgesia or local anesthesia is achieved by methods including topical application, tissue infiltration, nerve block, subarachnoid block, epidural block, dorsal root nerve block, and application to the wound, including application to the wound intramuscularly, subcutaneously, or to the surrounding nerves by dripping or smearing before suturing the surgical site.

[0222] Depending on the administration site and clinical needs, the compounds of this application can be administered using different dosage ranges. For example, when administering to subjects requiring local anesthesia or analgesia via topical application, tissue infiltration, nerve block, subarachnoid block, epidural block, dorsal root nerve block, or wound application, including intramuscular, subcutaneous, or peripheral nerve application to the wound via dripping or smearing before surgical site suturing, the compound or its stereoisomers or pharmaceutically acceptable salts or solvates or their polymorphs may be administered at dosages of 0.01%–0.05%, 0.05%–0.1%, 0.1%–0.5%, 0.5%–1%, 1%–2%, 2%–4%, 4%–6%, 6%–8%, respectively. The drug can be administered once or repeatedly at a concentration range of 0.05-1 mg, 1-50 mg, 50-100 mg, 100-200 mg, 20-40 mg, 40-60 mg, 60-80 mg, or 80-100 mM (the pH of the solution is 5-7, preferably 6-7) to achieve good local anesthetic or analgesic effects.

[0223] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for surface anesthesia or analgesia, wherein the compound or pharmaceutical composition is a solution that can be directly dripped, applied or sprayed onto the mucosal surface to paralyze the sensory nerve endings under the mucosa, and is used for surgery on the mucosa of the mouth, nose, pharynx, larynx, eyes and urethra.

[0224] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for infiltration anesthesia or analgesia, wherein the compound or pharmaceutical composition is a solution that can be injected intradermally, subcutaneously or deep into the surgical field, or applied to a wound, including application to the wound intramuscularly, subcutaneously or peripherally to nerves by dripping or smearing before suturing the surgical site to block nerve conduction at the application site.

[0225] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for blocking anesthesia or analgesia, wherein the compound or pharmaceutical composition is in the form of a solution that can be injected near a peripheral nerve trunk to block nerve conduction and produce an anesthetic or analgesic effect in the area innervated by the nerve, commonly used in surgeries on the body, limbs, face, mouth and other parts of the body.

[0226] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for subarachnoid block anesthesia or analgesia, wherein the compound or pharmaceutical composition is in the form of a solution that can be injected into the subarachnoid space from the lower lumbar intervertebral space to anesthetize the spinal nerve roots in that area, commonly used for lower abdominal and lower limb analgesia or surgery.

[0227] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for epidural anesthesia or analgesia, wherein the compound or pharmaceutical composition is a solution that can be injected into the epidural space to diffuse along the spinal nerve roots and enter the intervertebral foramen, blocking the nerve trunk within the intervertebral foramen to achieve anesthesia or analgesia of a segment of the trunk. It can be used for analgesia or surgery from the neck to the lower limbs, and is particularly suitable for abdominal analgesia or surgery.

[0228] According to one embodiment, the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph or pharmaceutical composition is used for dorsal root nerve block, wherein the compound or pharmaceutical composition is a solution that can be injected into one or more dorsal root nerve regions to achieve anesthesia or analgesia at one or more sites of the body.

[0229] Unless otherwise stated, all contents and percentages in this application are by weight.

[0230] Example

[0231] To make the objectives and technical solutions of this invention clearer, preferred embodiments of this invention are described in detail below. It should be noted that the following embodiments are only used to further illustrate this invention and should not be construed as limiting the scope of protection of this invention. Any non-essential improvements and adjustments made by those skilled in the art based on the above description of this invention are within the scope of protection of this invention.

[0232] In this application, when the chemical name and structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred from the context to be correct.

[0233] abbreviation

[0234] The abbreviations used in this article have the following meanings:

[0235] In the following examples, unless otherwise specified, the reaction temperature is room temperature (15-30°C).

[0236] All reagents used in this application are commercially available.

[0237] Example 1: Preparation of compound B31 hydrochloride

[0238] Bupivacaine (500 mg) was dissolved in anhydrous tetrahydrofuran (10 ml), dried in a drying tube, and placed in an ice bath at 0 °C for 5 min. Sodium hydride (100 mg) was added, and the mixture was stirred at this temperature for 0.5 h. Then, 0.2 g of 2,2'-dibromodiethyl ether was added, and the mixture was heated to room temperature and stirred overnight after 3 h. The reaction solution was filtered through diatomaceous earth and anhydrous sodium sulfate. The concentrated filtrate was purified by preparative liquid chromatography to obtain 294 mg of the title compound as an oily substance with a purity of 99.2%. ESI-MS m / z [M+H] + =647.3.

[0239] The title compound, which was an oily substance, was subjected to preparative liquid chromatography with a mobile phase containing hydrochloric acid to obtain compound B31 hydrochloride as a glassy solid with a purity of 99.1%. 1 ¹H-NMR (JNM-ECZ400S 400MHz): D₂O solvent, 0.75–0.84 (m, 6H, carbon chain CH₃), 1.03–1.34 (m, 6H), 1.43–1.85 (m, 14H), 1.89–2.24 (m, 12H, Ar-CH₃), 2.31–3.18 (m, 6H), 3.24–3.68 (m, 8H), 3.84–4.31 (m, 2H), 4.57–4.75 (m, 2H, partially overlapping with D₂O water peak, -CH-C=O), 7.04–7.32 (m, 6H, Ar-H).

[0240] Following the method of Example 1, using the corresponding dibromide as the alkylating agent, and with mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, ropivacaine, bupivacaine, and other corresponding compounds as raw materials, hydrochlorides of compounds with the following structures were prepared:

[0241] Example 2: Preparation of compound B11 hydrochloride

[0242] Bupivacaine (500 mg) was dissolved in anhydrous tetrahydrofuran (15 ml), dried in a drying tube, and kept at -10°C for 5 min. Sodium hydride (100 mg) was added, and the mixture was stirred at this temperature for 0.5 h. Then, 2,2'-dibromodiethyl ether (4 g) was added, and the mixture was stirred overnight at room temperature. The reaction solution was filtered through diatomaceous earth and anhydrous sodium sulfate. The filtrate was concentrated and purified by preparative liquid chromatography to obtain 650 mg of the monobrominated intermediate with a purity of 99.5%. ESI-MS m / z [M+H] + =439.1.

[0243] Dissolve 0.35 g of lidocaine in 10 ml of anhydrous tetrahydrofuran, dry in a drying tube, and maintain at -10°C for five minutes. Add sodium hydride (90 mg) and stir for 0.5 h. Dissolve the monobrominated intermediate in 10 ml of anhydrous THF and add it to the lidocaine-sodium hydride reaction solution. Stir at room temperature for 2-3 days.

[0244] The reaction solution was filtered through diatomaceous earth and anhydrous sodium sulfate. The concentrated filtrate was then separated by preparative liquid chromatography, followed by salt transfer using a mobile phase containing hydrochloric acid to obtain 530 mg of the title compound B11 hydrochloride solid with a purity of 99.1%, ESI-MS m / z [MH-2Cl]. + =593.3.

[0245] Referring to the method of Example 2, using the corresponding dibromide as the alkylating agent, and using mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, ropivacaine, bupivacaine, and other corresponding compounds as raw materials, hydrochlorides of the following structural compounds were prepared:

[0246] Example 3: Preparation of compound D5 hydrochloride

[0247] Method 1:

[0248] Step 1: Synthesis of intermediate D5-1-1

[0249] 4-tert-Butoxycarbonyl-3-morpholinic acid (4.395 g), EDCI (9.7 g), and 2,6-dimethylaniline (2 g) were dissolved in anhydrous dichloromethane (50 ml). The solution was dried in a drying tube and stirred at room temperature. The reaction was monitored by LCMS until no significant progress was observed. The reaction solution was then filtered directly through a silica gel pad, and the silica gel was washed with dichloromethane (600 ml). The filtrate was evaporated under reduced pressure to obtain 3.269 g of D5-1-1 as a white solid with a purity of 97%.

[0250] Step 2: Synthesis of intermediate D5-1-2

[0251] Take intermediate D5-1-1 (2.016 g), add ethyl acetate hydrochloride solution (4 M, 20 ml), stir at room temperature, monitor the reaction until complete by LCMS, and then evaporate the solvent to obtain 1.513 g of D5-1-2 as a foamy solid.

[0252] Step 3: Synthesis of intermediate D5-1-3

[0253] Intermediate D5-1-2 (1.513 g), potassium carbonate (2.335 g), and iodobutane (1.9 ml) were added to acetonitrile (30 ml). The mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The reaction solution was then diluted with dichloromethane, filtered, and the filtrate was evaporated to dryness using a 50°C water bath oil pump. The filtrate was then dissolved in dichloromethane, filtered, and evaporated to dryness again, yielding 1.442 g of D5-1-3 as a pale yellow solid with a purity of 95.4% and a melting point of 88-116°C.

[0254] Step 4: Synthesis of D5

[0255] Intermediate D5-1-3 (512 mg) was placed in anhydrous THF (30 ml) and kept in an ice bath at -10°C under drying protection. Sodium hydride (106 mg) was added, and the mixture was kept at this temperature with stirring for 1 hour. Then, 1,4-dibromobutane (205 mg) was added, and the mixture was heated to 30°C with stirring. LC-MS was monitored until no significant progress was observed in the reaction. The mixture was then filtered, the filtrate was evaporated to dryness, dissolved in hydrochloric acid solution (0.4 M, 100 ml), extracted with PE (100 ml x 3), and the pH was adjusted to alkaline with sodium hydroxide (3.9 g). The mixture was then extracted with EA (100 ml). x2) Extraction, combined EA phases, washed once with saturated brine (150 ml), dried over anhydrous sodium sulfate for 1 h, filtered, and the filtrate was evaporated to dryness. The crude product was first separated by preparative liquid chromatography, and then converted to salt using a mobile phase containing hydrochloric acid to obtain 258 mg of the title compound hydrochloride as a white solid, with a purity of 99.45%, melting point 163.8-170℃, ESI-MS m / z [MH-2Cl]. + =635.3.

[0256] Method 2:

[0257] Step 1: Synthesis of intermediate D5-2-1

[0258] Intermediate D5-2-1 was prepared according to the synthesis method in step 1 of Method 1.

[0259] Step 2: Synthesis of intermediate D5-2-2

[0260] Dissolve intermediate D5-2-1 (298 mg) in anhydrous THF (15 ml), dry in an ice bath at 0 °C, add sodium hydride (56 mg), keep warm and stir for 1 h, then add 1,4-dibromobutane, heat to room temperature, stir overnight, then gradually heat to 60 °C and stir. After no significant progress is observed in the reaction monitored by LCMS, evaporate the solvent and directly add the crude product to the next step.

[0261] Step 3: Synthesis of intermediate D5-2-3

[0262] Add ethyl acetate hydrochloride solution (4M, 20ml) to the crude intermediate D5-2-2, stir overnight at room temperature, monitor the reaction until complete by LCMS, evaporate the solvent, wash with saturated sodium bicarbonate solution (50ml*1) and pure water (20ml*2), combine the pure aqueous phases, extract twice with EA (20ml*2), combine the EA phases, wash once with saturated brine (20ml*1), dry with anhydrous sodium sulfate for 1h, filter, and evaporate to dryness to obtain 276mg of intermediate D5-2-3 as a yellow oil.

[0263] Step 4: Synthesis of D5

[0264] Intermediate D5-2-3 (276 mg) was dissolved in acetonitrile (15 ml), followed by the addition of potassium carbonate (261 mg) and iodobutane (1.2 ml). The mixture was stirred at room temperature and monitored by LC-MS until complete. The mixture was then filtered, and the filtrate was evaporated to dryness. The crude product was first separated by preparative HPLC, and then converted to salt using a mobile phase containing hydrochloric acid to obtain 56 mg of the title compound hydrochloride as white crystals with a purity of 99.8%. ESI-MS m / z [MH-2Cl] + =635.3.

[0265] Following method one or method two above, prepare the corresponding oxygen-containing derivative intermediates of mepivacaine, 1-ethyl-2-(2,6-dimethylaminoformyl)piperidine, ropivacaine, and bupivacaine, and then react them with the corresponding dibromides as alkylating agents as described in step 2) above to obtain hydrochloride salts of the following compounds:

[0266] The following compounds were synthesized using a method similar to that in Example 3:

[0267] Example 4: Preparation of compound D7 hydrochloride

[0268] The title compound hydrochloride was prepared according to the method in Example 3, yielding 145 mg as a white solid with a purity of 99.9%. ESI-MS m / z [MH-2Cl] + =651.4.

[0269] Example 5: Preparation of compound D15 hydrochloride

[0270] The title compound hydrochloride was prepared according to the method in Example 3, yielding 221 mg as a white solid with a purity of 99.08% and a melting point of 143-146 °C. ESI-MS m / z [MH-2Cl] + =695.5.

[0271] The following compounds were prepared according to the method in Example 3:

[0272] Example 6: Preparation of compound D13 hydrochloride

[0273] Step 1: Synthesis of intermediate 3-3

[0274] Following the synthesis method in steps 1-3 of Example 3, 1.602 g of intermediate 3-3, a white waxy solid, was prepared with a purity of 97.4% and a melting point of 88.5-93℃.

[0275] Step 2: Synthesis of the title compound

[0276] Dissolve intermediate 3-3 (401 mg) in anhydrous THF (30 ml), dry in an ice bath at -5°C using a drying tube, add sodium hydride (89 mg), and stir for 1 h. Then add 1,2-bis(2-bromoethoxy)ethane (208 mg), heat to room temperature, and stir. Monitor the reaction progress by HPLC until it exceeds 60%, then filter and concentrate the filtrate to remove the solvent. The residue was dissolved in hydrochloric acid solution (2M, 15ml), diluted with pure water (200ml), and extracted with MTBE (150ml x 2). Sodium hydroxide (3.2g) was added to the aqueous phase, and the mixture was extracted with EA (150ml). The EA phase was washed with saturated brine (150ml), dried overnight with anhydrous sodium sulfate, filtered, and concentrated. The crude product was first separated by a preparative liquid phase, then converted to salt using a mobile phase containing hydrochloric acid, yielding 247mg of the title compound hydrochloride as a white solid with a purity of 99.12% and a melting point of 136-146℃. ESI-MS m / z [MH-2Cl] + =667.4.1 ¹H-NMR (Bruker-AVANCE III HD 600MHz): D₂O solvent, 0.88–0.93 (m, 6H, carbon chain CH₃), 1.65 (s, br 2H), 1.78 (s, br 2H), 1.96–2.29 (m, 12H, Ar-CH₃), 3.20–3.21 (m, 4H), 2.96–4.41 (m, 24H), 4.29–4.65 (m, 2H, partially overlapping with D₂O water peak, -CH-C=O), 7.03–7.25 (m, 6H, Ar-H).

[0277] Example 7: Preparation of compound D3 hydrochloride

[0278] The title compound hydrochloride was prepared according to the method in Example 6, yielding 227 mg as a white solid with a purity of 99.6% and a melting point of 178-193 °C. ESI-MS m / z [MH-2Cl] + =607.4.

[0279] The following compounds were prepared according to the method in Example 6:

[0280] Example 8: Preparation of compound D47 hydrochloride

[0281] The preparation was carried out according to the method of Example 6, yielding 227 mg of the title compound hydrochloride as a colorless, glassy solid with a purity of 99.6%, ESI-MS m / z [MH-2Cl]. + =611.4.

[0282] Example 9: Preparation of compound D48 hydrochloride

[0283] The preparation was carried out according to the method of Example 6, yielding 256 mg of the title compound hydrochloride as a colorless, glassy solid with a purity of 97.7%, ESI-MS m / z [MH-2Cl]. + =639.3.

[0284] The following compounds were prepared according to the method in Example 6:

[0285] Example 10: Preparation of compound C31 hydrochloride

[0286] Step 1: Synthesis of C31-1-1:

[0287] In a reaction flask, bupivacaine (0.576 g) was added to DMF (10 ml), and the mixture was cooled to 0 °C under nitrogen protection. Sodium hydride (240 mg) was added in portions, and the mixture was stirred for 30 min. Bromoethoxybenzyl ether (0.5 ml) was then added, and the mixture was allowed to warm to room temperature naturally and stirred overnight. A new product was generated. After the starting material was completely converted, the mixture was concentrated under reduced pressure, and the residue was column-chromatographically analyzed to obtain 840 mg of the oily intermediate C31-1-1, which was directly added to the next step.

[0288] Step 2: Synthesis of C31-1-2

[0289] In a reaction flask, C31-1-1 (840 mg) was added to methanol (10 ml), followed by palladium on carbon (10%, 100 mg). The mixture was evacuated under reduced pressure and purged with hydrogen. This process was repeated three times. After no change was observed on LC, the mixture was heated to 50°C. No product was observed. The reactants were recovered, concentrated under reduced pressure, and ethyl acetate was added to the residue. The residue was washed twice with water, dried over sodium sulfate, filtered, and concentrated under reduced pressure. Methanol (10 ml) and 0.5 ml concentrated HCl were added to the residue. The mixture was then evacuated under pressure and purged with hydrogen. The reaction was allowed to proceed overnight at room temperature. After LC-MS confirmed the conversion was complete, the mixture was filtered and concentrated under reduced pressure to obtain 530 mg of the yellow oily intermediate C31-1-2, which was directly added to the next step.

[0290] Step 3: Synthesis of C31-2-1

[0291] In a reaction flask, bupivacaine (0.576 g) was added to DMF (10 ml). Under nitrogen protection, the mixture was cooled to 0°C, and sodium hydride (240 mg) was added in portions. The mixture was stirred for 30 min, followed by the addition of tert-butyl chloroacetate (450 mg) and potassium iodide (100 mg). After the addition was complete, the mixture was allowed to warm to room temperature naturally and stirred overnight. A new product was formed. Stirring was continued, and LC monitoring showed little change. Ethyl bromoacetate (1 ml) was added. The mixture was stirred overnight, and LC monitoring showed that 40% of the new product had formed. Ethyl bromoacetate (1 ml) was added, and LC monitoring showed that approximately 60% of the new product had formed. The mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The ethyl acetate phase was separated, washed twice with water, and once with sodium chloride solution. The residue was dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain intermediate C31-2-1, a yellow oily substance, which was used directly in the next reaction.

[0292] Step 4: Synthesis of C31-2-2

[0293] In a reaction flask, C31-2-1 (840 mg) was added to methanol / THF / H2O (5 ml / 5 ml / 5 ml). Under nitrogen protection, an aqueous sodium hydroxide solution (1 g dissolved in 10 ml of water) was added. The mixture was stirred overnight at room temperature. LC monitoring showed little change. Ethyl bromoacetate (1 ml) was added. After stirring overnight, LC monitoring showed the formation of a new product. The mixture was concentrated under reduced pressure. Water and dichloromethane were added to the residue for extraction. The dichloromethane phase contained bupivacaine. The pH of the aqueous phase was adjusted to 2, and the mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane to remove inorganic salts. Concentration under reduced pressure yielded approximately 401 mg of the yellow oily intermediate C31-2-2, which was directly added to the next step.

[0294] Step 5: Synthesis of C31

[0295] In a reaction flask, C31-1-2 (200 mg) and DIEA (0.5 mL) were added to dichloromethane (5 mL). The mixture was cooled to 0 °C under nitrogen protection, and then C31-2-2 (250 mg) was added. The mixture was allowed to rise naturally to room temperature and stirred overnight. LC monitoring showed approximately 50% product formation and a small amount of reactant remaining. The mixture was purified by preparative chromatography. Concentration under reduced pressure yielded 113 mg of a pale yellow solid. After secondary purification, 53 mg of the title compound was obtained as a white solid with a purity >98%. ESI-MS m / z [MH-2Cl] + =661.5.

[0296] The following compounds were prepared according to the method of Example 10:

[0297] Example 11: Preparation of compound K31 hydrochloride

[0298] Step 1: Synthesis of Intermediate 1

[0299] 4-tert-Butoxycarbonyl-3-piperidinic acid (1.002 g) and triethylamine (790 μl) were dissolved in anhydrous dichloromethane (30 ml), dried with anhydrous calcium chloride in a drying tube, stirred for 5 min in an ice bath at -5 °C, then isobutyl chloroformate (738 mg) was added, and the mixture was kept warm and stirred for 2 h. Then aniline (600 μl) was added, the mixture was heated to room temperature and stirred, and the reaction was monitored by LCMS until no significant progress was observed. The reaction solution was diluted with dichloromethane, extracted with saturated sodium bicarbonate solution (100 ml x 3) and saturated brine (100 ml), dried with anhydrous sodium sulfate for 1 h, filtered, and evaporated to dryness. The mixture was then sonicated with petroleum ether (50 ml) for 10 min, filtered, washed with petroleum ether, and the filter cake was evaporated to dryness to obtain 954 mg of white solid intermediate 1 with a purity of 85%, which was directly used in the next reaction.

[0300] Step 2: Synthesis of Intermediate 2

[0301] Add ethyl hydrochloride solution (4M, 30ml) to intermediate 1 (954mg), stir overnight at room temperature, monitor the reaction until complete by LCMS, evaporate the solvent, add ethyl acetate (30ml), sonicate for 2min, filter, and evaporate the filter cake to obtain 689mg of white solid intermediate 2 with a purity of 99.9%.

[0302] Step 3: Synthesis of Intermediate 3

[0303] Intermediate 2 (400 mg), potassium carbonate (499 mg), and iodobutane (410 μl) were dissolved in acetonitrile (30 ml). The mixture was stirred at room temperature and monitored by HPLC until the reaction was complete. The solvent was then evaporated to dryness, and dichloromethane (100 ml) was added to dissolve the mixture. The mixture was then sonicated for 5 min, filtered, and evaporated to dryness to obtain 361 mg of intermediate 3 as a white solid with a purity of 98.22%.

[0304] Step 4: Synthesis of the target product

[0305] Following method 1 of Example 3, the title compound, present as a colorless, glassy solid, with a purity of 99.58%, was synthesized from intermediate 3 and 1,4-dibromobutane. ESIMS m / z [MH-2Cl] + =575.4. 1 H-NMR (Bruker-AVANCE III HD 600MHz): CD3OD solvent, 0.81-0.85(m,6H,CH3), 1.08-1.15(m,2H), 1.19-1.32(m,4H), 1.47(s,br 4H), 1.49-1.76(m,12H), 1.94(m,2H), 2.70-2.74(m,2H), 2.82-2.87(m,2H), 2.92-2.98(m,2H), 3.50-3.52(d,br 2H), 3.57-3.76(m,6H), 7.22-7.24(m,4H,Ar-H), 7.48-7.52(m,6H,Ar-H).

[0306] The following compounds were prepared according to the methods of Examples 11 and 2:

[0307] Test Example 1: Subcutaneous analgesia test in rats (median duration of action)

[0308] Experimental animals: SD rats, purchased from the Experimental Animal Center of Chongqing Medical University.

[0309] Compounds B31 hydrochloride, D5 hydrochloride, and compound B250 hydrochloride (prepared according to the method disclosed in WO 2024 / 012397) were each prepared into 2.8 mM solutions (pH 5-6) with physiological saline. Each test compound was administered subcutaneously to SD rats (n=4 per group, one compound per group), with 0.6 mL injected at a single point on the back of each rat. Wheals formed after administration, and their edges were marked. Acupuncture needles were then attached to 60-26 g Von Frey fibers (Touch). A sensory evaluator was used to insert one needle into each of the five areas marked (upper, lower, left, right, and center). The number of times no response was observed at different times after drug administration was recorded. Three or more instances of no response out of five were considered effective analgesia. The results are shown in Table 1 below, indicating that the analgesic / local anesthetic effects of compounds B31 and D5 of this invention last for a significantly longer duration than those of the prior art compound B250.

[0310] Table 1

[0311] Test Example 2: Subcutaneous analgesia test in rats (median duration of action)

[0312] Referring to Test Example 1 above, the D13 hydrochloride and D15 hydrochloride of the present invention and compound B250 hydrochloride were each prepared into a 2.8 mM solution (pH 5-6) with physiological saline. These solutions were then administered subcutaneously to SD rats along with the commercially available bupivacaine liposome preparation Aihengping (46.1 mM) (2.8 mM). The duration of analgesia at the injection site was observed, and the results are shown in Table 2 below.

[0313] Table 2

[0314] In another test conducted with reference to the above test, compounds I2, I33, and I34 all showed a duration of sustained pain inhibition in half of the animals that was comparable to or longer than that of compound D5.

[0315] Test Example 3: Subcutaneous Drug Administration Analgesia Test in Rats (Analgesia Rate)

[0316] Compounds D15 hydrochloride, D3 hydrochloride, D8 hydrochloride, D13 hydrochloride, D47 hydrochloride, and D48 hydrochloride were each prepared into solutions with physiological saline at concentrations of 2 mM, 1.4 mM, or 1 mM (pH 5-6), respectively, according to requirements. These solutions, along with compound B250 hydrochloride (2.5 mM, pH 5-6) from WO 2024 / 012397 and the commercially available bupivacaine liposome formulation Aihengping (46.1 mM), were administered to SD rats according to the method described in Test Example 1. The number of times no response to acupuncture was observed at different time points after administration was observed. The analgesic rate at each time point from 1 to 72 hours was calculated using the following formula, and the average value for each group was obtained:

[0317] Analgesia rate = Number of times no response to acupuncture ÷ 5 × 100%

[0318] The analgesia rate-time ratio was integrated to calculate its AUC. 1-72h The results are listed in Tables 3 and 4 below.

[0319] Table 3: Comparison of analgesic rates after subcutaneous administration in rats (1):

[0320] Table 4: Comparison of analgesic rates after subcutaneous administration in rats (2)

[0321] The above results show that the compounds of the present invention, at lower concentration levels (2 mM, 1.4 mM and 1 mM), have analgesic rates (AUC) within 1-72 hours after administration. 1-72h It was significantly superior to compound B250 (2.5 mM) and bupivacaine liposome acehengping (46.1 mM).

[0322] In additional tests conducted with reference to the above tests, compounds D11, D12, K31, K10, K32, and K33 also showed comparable or better analgesic efficacy and duration than compound D3.

[0323] Test Example 4: Rat Back Incision Analgesia Test

[0324] Compounds D5 hydrochloride, D8 hydrochloride, and D13 hydrochloride, along with compound B250 hydrochloride from WO 2024 / 012397, were each prepared into solutions using a 1% sodium carboxymethyl cellulose solution. The pH was adjusted to 6-7 with a small amount of sodium hydroxide solution and hydrochloric acid solution, resulting in a solution concentration of 6 mM. Compounds D5 hydrochloride, D8 hydrochloride, and D13 hydrochloride, along with compound B250 hydrochloride from WO 2024 / 012397, were each prepared into solutions using a 3% povidone solution. The pH was adjusted to 6-7 with a small amount of sodium hydroxide solution and hydrochloric acid solution, resulting in a solution concentration of 12 mM. These solutions were then set aside for use.

[0325] SD rats were randomly divided into groups of four. After intravenous anesthesia with propofol-dexmedetomidine, the hair on the back area was shaved, and the area was disinfected with povidone-iodine. A longitudinal incision of about 2 cm was made in the back skin, and about 0.1 ml of the corresponding compound solution was dripped into the incision to thoroughly moisten it before suturing. A blunt-tipped acupuncture needle was attached to a 60g Von frey fiber and used to stimulate the left and right sides of the incision at different time points (the contact point was about 2 mm from the incision). The needles were inserted once at the upper, middle, and lower parts of each side of the incision, for a total of six times. The response was observed, and the median duration of analgesia was compared between the groups.

[0326] Table 5: Comparison of the half-maximal time of analgesia of different compounds in rat dorsal incision test

[0327] The above results show that the compounds of the present invention have significantly better analgesic effects than compound B250 in the rat dorsal incision test.

[0328] Test Example 5: Testing of Sodium Ion Channels Nav1.5 and Nav1.7

[0329] In cell lines that stably express Nav1.5 and Nav1.7 ion channels, the effect of the test substance on the corresponding ion channel current was tested using manual patch-clamp technique.

[0330] Electrophysiological testing equipment:

[0331] Positive controls and test substances:

[0332] Human NaV1.5 ion channels were stably expressed in HEK293 cells, and human NaV1.7 ion channels were stably expressed in CHO cells. All experiments were performed at room temperature. Each cell served as a self-control. Positive controls and test compounds were perfused using a gravity-fed perfusion system. At least three cells were tested for each compound concentration. After current stabilization, the change in current before and after compound use was compared to calculate the inhibitory effect of the compound. Cells were transferred to perfusion tanks and perfused with extracellular fluid. Electrodes were fabricated using PC-10 (Narishige, Japan). Whole-cell patch-clamp recordings were performed, with noise filtered at one-fifth of the sampling frequency. Cells were clamped at -80 mV, then hyperpolarized to -120 mV with a 20 ms square wave, then depolarized to -10 mV with a 20 ms square wave, then depolarized to Vhalf with a square wave for 8 seconds, then hyperpolarized to -120 mV with a 20 ms square wave, and finally depolarized to -10 mV with a 20 ms square wave. This yielded two sodium ion channel currents. This procedure was repeated every 30 seconds. The maximum current induced by the square wave was detected, and after stabilization, the test compound was perfused. Once the reaction stabilized, the blocking strength was calculated. Data acquisition and analysis were performed using pCLAMP 10 (Molecular Devices, Union City, CA). The results are as follows:

[0333] Data comparison shows that compound B31 of this invention exhibits significantly better Nav1.7 inhibitory activity than compound B250 in WO 2024 / 012397, demonstrating superior analgesic activity. Simultaneously, its inhibitory activity against Nav1.5 is lower than that against Nav1.7, exhibiting a significant Nav1.7 inhibitory effect. 50 and Nav1.5 IC 50 The ratio advantage suggests better sodium channel selectivity and higher cardiac safety.

[0334] Test Example 6: Acute Toxicity Test

[0335] Experimental animals: KM mice, purchased from the Experimental Animal Center of Chongqing Medical University.

[0336] A sequential method was used, with the drug administered via a uniform injection into the tail vein of mice over a period of approximately 2-3 seconds. Mice mortality was observed and recorded, and the LD50 was calculated. 50 The values ​​were compared with the literature values ​​for compound B250 in WO 2024 / 012397:

[0337] In additional tests conducted in accordance with the above-described tests, compounds I2 and I33 both exhibited lower acute toxicity than compound B250. It can be seen from the above that the compounds of the present invention have lower acute toxicity and higher safety.

Claims

Compounds having the structure of Formula I, II, III, IV or V, or their stereoisomers, pharmaceutically acceptable salts or solvates, or their polymorphs: in, X and Y are independently represented by O, S, and NR. 3 ; n＝0-7； m＝0-8； R 1 and R 2 Each independently x and y are each independently 0 or 1; G and E are independently O, S, and NR. 3 ; R 3 It is hydrogen or a C1-C7 hydrocarbon group; R E It is hydrogen or a C1-C7 hydrocarbon group; The carbon atom indicated by "*" can be in the R configuration or the S configuration, or a mixture of the R and S configurations in any proportion; exist The mark in This indicates the position where the corresponding group is attached to other parts of the compound. According to claim 1, the compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph, wherein, R 3 It is hydrogen or C1-C7 alkyl, preferably hydrogen, methyl or ethyl. According to claim 1, the compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph, wherein, R E It is hydrogen or C1-C7 alkyl, preferably hydrogen, methyl or ethyl. According to claim 1, the compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph, wherein, X and Y can be independently O, S, NH or N-CH3. According to claim 1, the compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph, wherein, G and E can be independently O, S, NH, or N-CH3. The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound has the structure of formula IX: The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound has the structure of formula XI: The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound has the structure of formula XII: in, M is either O or CH2; n＝0-7； R 5 It can be methyl, ethyl, n-propyl, or n-butyl; x and y are each independently 0 or 1. The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound has the structure of formula XIII: in, M is either O or CH2; m＝0-8； R 5 It can be methyl, ethyl, n-propyl, or n-butyl; x and y are each independently 0 or 1. The compound according to claim 1, or its stereoisomer, pharmaceutically acceptable salt, solvate, or polymorph thereof, wherein the compound is selected from: The compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph according to any one of claims 1-10, wherein the pharmaceutically acceptable salt is a hydrochloride salt. A pharmaceutical composition comprising a compound or stereoisomer thereof or a pharmaceutically acceptable salt or solvate thereof or a polymorph thereof according to any one of claims 1-10, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition according to claim 12, wherein the pharmaceutically acceptable carrier or excipient is physiological saline or an aqueous solution or aqueous solution of physiological saline containing a thickener, wherein the thickener is, for example, sodium carboxymethyl cellulose or povidone. The pharmaceutical composition according to claim 12 or 13 is a dosage form for parenteral administration. The pharmaceutical composition according to claim 14, wherein the parenteral route is selected from inhalation, intraperitoneal, intramuscular, subcutaneous, subarachnoid, epidural, dorsal root nerve region, mucosa and deep tissue, or via the eye, percutaneous or surface, and combinations thereof. The pharmaceutical composition according to claim 15, wherein the compound or its stereoisomer or its pharmaceutically acceptable salt or solvate or its polymorph is formulated into a solution with a concentration range of 0.01% to 0.05%, 0.05% to 0.1%, 0.1% to 0.5%, 0.5% to 1%, 1% to 2%, 2% to 4%, 4% to 6%, 6% to 8%, 8% to 10%, or a solution with a concentration range of 0.1% to 0.5 mM, 0.5% to 1 mM, 1% to 5 mM, 5% to 10 mM, 10% to 20 mM, 20% to 40 mM, 40% to 60 mM, 60% to 80 mM, or 80% to 100 mM, wherein the pH of the solution is 5-7, preferably 6-7, and the solution can be administered once or repeatedly. Use of the compound or its stereoisomer or pharmaceutically acceptable salt or solvate or its polymorph according to any one of claims 1-10 in the preparation of a medicament for analgesia or local anesthetic. According to the use of claim 17, the analgesia or local anesthetic is used for topical application, tissue infiltration, nerve block, subarachnoid block, epidural block, dorsal root nerve block, and wound application, including application to the wound intramuscularly, subcutaneously, or to the surrounding nerves by dripping or smearing before suturing the surgical site. The method for preparing the compound according to claim 8 is carried out via route 4-1 or route 4-2 as follows: Route 4-1 In route 4-1, the compound of formula XII-0 undergoes a condensation reaction with an aniline compound to obtain an amide compound of formula XII-1, which then reacts with compound B(1) in the presence of an acid-binding agent to obtain a compound of formula XII-1-1. Subsequently, a deprotection reaction is carried out in the presence of a deprotecting agent to obtain a compound of formula XII-1-2. Finally, the compound reacts with compound B(4) in the presence of an acid-binding agent to obtain the final product XII. Route 4-2 In route 4-2, the compound of formula XII-0 undergoes a condensation reaction with an aniline compound to obtain an amide compound of formula XII-1. Then, under the action of a deprotecting agent, a deprotection reaction is carried out to obtain a compound of formula XII-2. Subsequently, under the action of an acid-binding agent, it reacts with compound B(4) to obtain compound XII-2-1. Finally, under the action of an acid-binding agent, it reacts with compound B(1) to obtain the final product XII. In the compounds involved in routes 4-1 and 4-2, Z represents a group that is easily removed; R 4 It is an amino protecting group, such as Boc, Cbz, Bn, Fmoc or trifluoroacetyl; The condensation reaction can be carried out with reagents such as DCC, EDCI, carbonyl diimidazole, DIC, HATU, BOP or DPPA, as well as acid anhydrides and acyl chlorides. The acid-binding agent is an inorganic or organic base, wherein the inorganic base is, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, or potassium sodium hydrogen phosphate; the organic base is, for example, sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, tert-butoxide, etc. Magnesium alkoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amino, methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium iodide, dimethyl magnesium, diethyl magnesium, diisopropyl magnesium, LDA, NaHMDS, KHMDS or LiHMDS. The method for preparing the compound according to claim 9 is carried out via route 5-1 or route 5-2 as follows: Route 5-1 In route 5-1, the compound of formula XII-0 undergoes a condensation reaction with an aniline compound to obtain an amide compound of formula XII-1, which then reacts with compound B(5) in the presence of an acid-binding agent to obtain a compound of formula XIII-1-1. Subsequently, a deprotection reaction is carried out in the presence of a deprotecting agent to obtain a compound of XIII-1-2. Finally, the compound reacts with compound B(4) in the presence of an acid-binding agent to obtain the final product XIII. Route 5-2 In route 5-2, the compound of formula XII-0 undergoes a condensation reaction with an aniline compound to obtain an amide compound of formula XII-1. Then, under the action of a deprotecting agent, a deprotection reaction is carried out to obtain a compound of formula XII-2. Subsequently, under the action of an acid-binding agent, it reacts with compound B(4) to obtain compound XII-2-1. Finally, under the action of an acid-binding agent, it reacts with compound B(5) to obtain the final product XIII. In the compounds involved in routes 5-1 and 5-2, Z represents a group that is easily removed; R 4 It is an amino protecting group, such as Boc, Cbz, Bn, Fmoc or trifluoroacetyl; The condensation reaction can be carried out with reagents such as DCC, EDCI, carbonyl diimidazole, DIC, HATU, BOP or DPPA, as well as under various acid anhydrides and acyl chlorides. The acid-binding agent is an inorganic or organic base, wherein the inorganic base is, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, lithium hydride, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, magnesium carbonate, calcium carbonate, sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, and sodium potassium hydrogen phosphate; the organic base is, for example, sodium acetate, sodium propionate, sodium butyrate, sodium methoxide, sodium ethoxide, sodium tert-butoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, and tert-butoxide. Magnesium alkoxide, trimethylamine, triethylamine, tributylamine, diisopropylamine, diisopropylethylamine, tert-butylamine, N,N-dimethylaniline, tetramethylethylenediamine, DABCO, DBU, DBN, pyridine, DMAP, N-methylmorpholine, tetramethylguanidine, n-butyllithium, tert-butyllithium, phenyllithium, sodium amino, methyl magnesium chloride, methyl magnesium bromide, methyl magnesium iodide, ethyl magnesium chloride, ethyl magnesium bromide, ethyl magnesium iodide, isopropyl magnesium chloride, isopropyl magnesium bromide, isopropyl magnesium iodide, dimethyl magnesium, diethyl magnesium, diisopropyl magnesium, LDA, NaHMDS, KHMDS or LiHMDS.

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