Bisazacyclic compounds and uses thereof

Abstract

The application provides a kind of diazacyclic compound and its use. Specifically provided is a compound V, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof, a tautomer thereof or a prodrug thereof;The compound V comprises a compound shown in formula I and a pharmaceutically acceptable anion. The compound V provided by the application is simple in structure, can be used to prepare muscle relaxant, and has good application prospect.

Description

[0001] This application claims priority to Chinese patent application 2025101034130, filed January 22, 2025; Chinese patent application 2025113544191, filed September 22, 2025; and Chinese patent application 202610030739X, filed January 9, 2026. The full text of the aforementioned Chinese patent applications is incorporated herein by reference. Technical Field

[0002] This invention relates to the pharmaceutical and chemical industry, specifically to a class of dinitrogen heterocyclic compounds and their uses. Background Technology

[0003] Anesthetic drugs are mainly classified into five categories: general anesthetics, local anesthetics, muscle relaxants, anesthetic analgesics, and sedative-hypnotic drugs. Muscle relaxants, as essential drugs in surgical anesthesia, were first introduced clinically in 1942 by a Canadian anesthesiologist using tubocurarine. The advent of muscle relaxants ended the era of deep anesthesia and ushered in a new era of deep muscle relaxation and light anesthesia, greatly improving the feasibility and safety of clinical anesthesia and promoting the development of clinical anesthesiology.

[0004] Currently, the most commonly used and mature muscle relaxants in clinical practice are mainly of two categories: intermediate- and long-acting benzyl isoquinolines and aminosteroids. Among them, benzyl isoquinoline muscle relaxants, such as micuronium chloride, atracurium, and tubocurarine, often cause histamine release as a side effect. Furthermore, these muscle relaxants have relatively complex molecular structures, are expensive to obtain, and have long muscle recovery times, usually requiring the use of muscle relaxant antagonists such as neostigmine or sugan glucose to ensure their safety.

[0005] Therefore, it is essential to find new muscle relaxants with simpler structures, better muscle relaxation activity, and more ideal and controllable onset and recovery times. Summary of the Invention

[0006] The technical problem to be solved by this invention is to overcome the deficiency of the single structure of existing non-depolarizing muscle relaxants and to develop non-depolarizing muscle relaxants with simple and abundant structures. To this end, this application provides a class of diazapyridine heterocyclic compounds and their uses. The compounds provided in this application have better efficacy and promising application prospects.

[0007] The present invention solves the above-mentioned technical problems through the following solution.

[0008] This invention provides a class of compounds V, pharmaceutically acceptable salts thereof, solvates thereof, metabolites thereof, tautomers thereof, or prodrugs thereof;

[0009] Compound V comprises the compound shown in Formula I and a pharmaceutically acceptable anion;

[0010] ;

[0011] in,

[0012] L is or ;

[0013] R 3 and R 4 Independently H, C1-6 alkyl, C 6-10 Aryl or halogen;

[0014] Ring B and ring C are independently 3-12-membered heterocyclic alkyl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl and 5-12-membered heteroaryl are optionally separated by one or more R b In the substituted 5-12-membered heteroaryl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; in the 3-12-membered heterocycloalkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4.

[0015] R b Independent of halogens and oxo groups ( C 1-6 Alkoxy or C 1-6 alkyl;

[0016] n and q are independently 0, 1, or 2;

[0017] R 1 C 6-10 aryl, with one or more R 1-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0018] R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0019] R 1-1 R 1-2 R 2-1 and R 2-2 Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-carbonyl, 3-6 membered heterocyclic alkyl or In the 3-6 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0020] L1 is a single bond independently, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, O, or S; ring A is C 6-10 Aryl;

[0021] R a Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl;

[0022] n1 can be 0, 1, 2 or 3.

[0023] In certain preferred embodiments of the present invention, certain groups in the compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug are defined as follows, and groups not mentioned are as described in any embodiment of the present invention (hereinafter referred to as "a certain embodiment").

[0024] In one embodiment, the compound represented by Formula I has the following structure:

[0025] ;

[0026] Wherein, X1 and X2 are independently S, CH2, O or NH;

[0027] n is 1 or 2;

[0028] R 1 C 6-10 aryl, with one or more R 1-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0029] R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 2-2The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0030] R 1-1 R 1-2 R 2-1 and R 2-2 Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 alkyl-carbonyl, 3-6 membered heterocyclic alkyl or In the 3-6 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0031] L1 is a single bond independently, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, O, or S; ring A is C 6-10 Aryl;

[0032] R a Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl;

[0033] n1 can be 0, 1, 2 or 3.

[0034] In one scheme, the C 6-10 The aryl group can be phenyl or naphthyl, for example, phenyl.

[0035] In one embodiment, the heteroatom in the 5-12 membered heteroaryl group is independently N, O, or S, and the number of heteroatoms is independently one or two, such as thienyl, furanyl, or benzodioxanepentyl. The 5-12 membered heteroaryl group is preferably a 5- or 6-membered heteroaryl group. The 5-12 membered heteroaryl group is preferably a 5, 6, or 9-membered heteroaryl group, such as thienyl, furanyl, benzodioxanepentyl, or benzomonazinepentyl.

[0036] In one embodiment, the halogenated C 1-6 Alkyl groups are C3 groups independently substituted with one or more (e.g., 1, 2, or 3) halogens. 1-6 Alkyl groups, such as trifluoromethyl.

[0037] In one embodiment, the halogen is independently fluorine, chlorine, bromine, or iodine, such as chlorine.

[0038] In one scheme, the C 1-6The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or isobutyl, such as methyl.

[0039] In one embodiment, the halogenated C 1-6 An alkoxy group is independently a C group substituted with one or more (e.g., 1, 2, or 3) halogens. 1-6 Alkyl group.

[0040] In one scheme, the C 1-6 Alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy, such as methoxy.

[0041] In one embodiment, the 3-6 membered heterocyclic alkyl group is a saturated group, the heteroatom is selected from N, S and O, and the number of heteroatoms is preferably 1 or 2; the 3-6 membered heterocyclic alkyl group may be a 6 membered heterocyclic alkyl group.

[0042] In one embodiment, the 3-12 membered heterocyclic alkyl group is a monocyclic, fused, spirocyclic, or bridged ring, preferably a monocyclic.

[0043] In one embodiment, the 3-12 membered heterocyclic alkyl group is a 5-9 membered heterocyclic alkyl group, and the heteroatom can be one or two of N, S, and O, and the number of heteroatoms can be one or two (preferably a 3-6 membered heterocyclic alkyl group). Examples include monoazacyclopentyl, monoazacyclohexyl, morpholinyl, etc. , , , , , or ( This indicates the presence of substituents; multiple substitution sites may exist when the structure allows.

[0044] In one embodiment, compound V is a salt formed from a compound of formula I and a pharmaceutically acceptable anion.

[0045] In one embodiment, the pharmaceutically acceptable anion is independently a halide ion, acetate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheponicate, glucuronate, glucuronate, hydroxyethanesulfonate, lactate, lacturonic acid, dodecyl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, dihydroxynaphthalate, phosphate, hydrogen phosphate, dihydrogen phosphate, polygalacturonic acid, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, or trifluoroacetate, preferably I. - ,Br - Cl - F- , , or Further preferred is I - ,Br - or Cl - .

[0046] In one embodiment, the pharmaceutically acceptable anion is a monovalent anion.

[0047] In the compound V, the molar ratio of the compound represented by Formula I to the pharmaceutically acceptable anion is a conventional molar ratio for such compounds in the art. For example, the molar ratio of the compound represented by Formula I to the pharmaceutically acceptable anion is 1:(0.1-10), or 1:2.

[0048] In one scheme, L is .

[0049] In one of the schemes, R 3 For H, R 4 For H.

[0050] In one of the schemes, R 3 For H, R 4 C1-6 alkyl, C 6-10 Aryl or halogen.

[0051] In one of the schemes, R 3 H, C1-6 alkyl, or halogen, R 4 C1-6 alkyl, C 6-10 Aryl or halogen.

[0052] In a certain scheme, X1 and X2 are independently CH2 or O, for example, X1 is CH2 and X2 is O.

[0053] In one of the schemes, R 1 For one or more R 1-1 Replacement C 6-10 Aryl (e.g., phenyl) or by one or more R 1-2 The substituted 5-12-membered heteroaryl group (e.g., a 5-membered heteroaryl group), wherein the heteroatom is selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, 3, or 4; preferably, R 1 For one or more R 1-1 Replacement C 6-10 Aryl (e.g., phenyl).

[0054] In one of the schemes, R 1 For one or more R 1-2The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4.

[0055] In one of the schemes, R 1 In this context, the 5-12-membered heteroaryl group is a benzo5-6-membered heterocyclic alkyl group. In the 5-6-membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3. The 5-6-membered heterocyclic alkyl group is, for example, 1,3-dioxane.

[0056] In one of the schemes, R 2 C 6-10 Aryl (e.g., phenyl) or by one or more R 2-1 Replacement C 6-10 Aryl (e.g., phenyl); preferably, R 2 For one or more R 2-1 Replacement C 6-10 Aryl (e.g., phenyl).

[0057] In one of the schemes, R 2 C 6-10 Aryl (e.g., phenyl), with one or more R 2-1 Replacement C 6-10 Aryl (e.g., phenyl) or by one or more R 2-2 Substituted 5-12 heteroaryl groups.

[0058] In one of the schemes, R 2 For one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4.

[0059] In one of the schemes, R 2 In this context, the 5-12-membered heteroaryl group is a benzo5-6-membered heterocyclic alkyl group. In the 5-6-membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3. The 5-6-membered heterocyclic alkyl group is, for example, 1,3-dioxane.

[0060] In one of the schemes, R 1-1 R 1-2 and R 2-1 Independently halogens (e.g., chlorine), C 1-6 Alkyl (e.g., methyl) or C 1-6 Alkyl groups (e.g., methoxy groups); preferably, R 1-1 and R 2-1 Independently halogen or C 1-6 Alkoxy, more preferably, R 1-1For halogens (e.g., chlorine); R 2-1 C 1-6 Alkyl groups (e.g., methoxy groups).

[0061] In one of the schemes, R 1-1 R 1-2 R 2-1 and R 2-2 Independently halogens (e.g., chlorine), C 1-6 Alkyl (e.g., methyl) or C 1-6 Alkyl groups (e.g., methoxy groups). Preferably, R 1-1 R 1-2 R 2-1 and R 2-2 Independently for C 1-6 Alkyl groups (e.g., methoxy groups).

[0062] In one of the schemes, R 1 C 6-10 aryl or aryl with one or more R 1-1 Replacement C 6-10 Aryl; R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 Aryl.

[0063] In one of the schemes, R 1-1 It is a halogen; R 2-1 C 1-6 Alkyl group.

[0064] In one of the schemes, R 3 and R 4 For H.

[0065] In one embodiment, ring B and ring C are independently 3-12-membered heterocyclic alkyl groups (e.g., 5-12-membered heterocyclic alkyl groups, which may be 6-membered heterocyclic alkyl groups), wherein the 5-12-membered heterocyclic alkyl group is optionally surrounded by one or more R groups. b Replacement. Preferably, ring B is... Ring C is X1 and X2 are as described in any one of the present invention.

[0066] In one scheme, q is 1 and n is 2.

[0067] In one scheme, q is 0 (representing a single bond with no carbon atoms) and n is 1.

[0068] In one embodiment, the compound represented by Formula I;

[0069] X1 and X2 are independently CH2 or O;

[0070] n is 1 or 2;

[0071] R 1 For one or more R 1-1 Replacement C 6-10 Aryl (e.g., phenyl) or by one or more R 1-2 The substituted 5-12-membered heteroaryl group (e.g., a 5-membered heteroaryl group), wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0072] R 2 C 6-10 Aryl (e.g., phenyl) or by one or more R 2-1 Replacement C 6-10 Aryl (e.g., phenyl);

[0073] R 1-1 R 1-2 and R 2-1 Independently halogens (e.g., chlorine), C 1-6 Alkyl (e.g., methyl) or C 1-6 Alkyl groups (e.g., methoxy groups).

[0074] In one scheme, L is or ;

[0075] R 3 and R 4 H is independent;

[0076] Ring B and ring C are independently 3-12-membered heterocyclic alkyl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl and 5-12-membered heteroaryl are optionally separated by one or more R b In the substituted 5-12-membered heteroaryl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; in the 3-12-membered heterocycloalkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4.

[0077] R b Independently halogen, oxo group, C 1-6 Alkoxy or C 1-6 alkyl;

[0078] n and q are independently 0, 1, or 2;

[0079] R 1 For one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-2The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0080] R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl or aryl with one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0081] R 1-1 R 1-2 R 2-1 and R 2-2 Independent of halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

[0082] In one embodiment, the compound represented by Formula I;

[0083] L is or ;

[0084] R 3 and R 4 H is independent;

[0085] Ring B and ring C are independently 3-12 membered heterocyclic alkyl groups (e.g., 6-9 membered heterocyclic alkyl groups), and the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0086] n is 1 or 2;

[0087] q is 0 or 1;

[0088] R 1 For one or more R 1-1 Replacement C 6-10 Aryl (e.g., phenyl) or by one or more R 1-2 The substituted 5-12-membered heteroaryl group (e.g., 5-9-membered heteroaryl group), wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0089] R 2 C 6-10 Aryl (e.g., phenyl), with one or more R 2-1 Replacement C 6-10 Aryl (e.g., phenyl), with one or more R 2-2The substituted 5-12-membered heteroaryl group (e.g., a 9-membered heteroaryl group), wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4;

[0090] R 1-1 R 1-2 and R 2-1 Independently halogens (e.g., chlorine), C 1-6 Alkyl (e.g., methyl) or C 1-6 Alkyl groups (e.g., methoxy groups).

[0091] In one embodiment, the compound represented by Formula I is the compound represented by Formula I-1;

[0092] ;

[0093] Where k1 and k2 are independently 0, 1, 2 or 3;

[0094] X1, X2, R 1-1 and R 2-1 As described in any one of the present invention.

[0095] Preferably, in the compound shown in Formula I-1,

[0096] k1 and k2 are independently 0, 1 or 2;

[0097] X1 and X2 are CH2 or O;

[0098] R 1-1 and R 2-1 Independently halogen or C 1-6 Alkyl group.

[0099] In one embodiment, the compound represented by Formula I is a compound represented by Formula I-2 or I-3;

[0100] ; ;

[0101] X1, X2, R 1-1 and R 2-1 As described in any one of the present invention.

[0102] Preferably, X1 is CH2 and X2 is O;

[0103] R 1-1 It is a halogen; R 2-1 C 1-6 Alkyl group.

[0104] In one embodiment, the compound represented by Formula I is the compound represented by Formula I-4;

[0105] ;

[0106] L, n, q, ring B, and ring C are as described in any one of the present invention.

[0107] In one scheme, L is , , , , or In one particular scheme, R 1 and R 2 Each can be independently one of the following structures:

[0108] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

[0109] Preferably, R 1 for , , or .

[0110] Preferably, R 1 for , , , , or .

[0111] Preferably, R 2 for , , , , or .

[0112] Preferably, R 1 for , , , , , , or .

[0113] In one scheme, ring B and ring C are independently... , , , , , , , , , , , , , , , or .

[0114] In one embodiment, the compound represented by Formula I is any of the following compounds:

[0115] ;

[0116] ;

[0117] ;

[0118] ;

[0119] ;

[0120] ;

[0121] ；

[0122] ；

[0123] ；

[0124] ；

[0125] ；

[0126] ；

[0127] ；

[0128] ；

[0129] ；

[0130] ；

[0131] ；

[0132] ；

[0133] ；

[0134] ；

[0135] ；

[0136] ；

[0137] ；

[0138] ；

[0139] ；

[0140] ；

[0141] ；

[0142] ；

[0143] ；

[0144] ；

[0145] ；

[0146] ;

[0147] ;

[0148] ;

[0149] ;

[0150] ;

[0151] .

[0152] In one embodiment, compound V is any of the following compounds:

[0153] ;

[0154] ;

[0155] ;

[0156] ;

[0157] ;

[0158] ;

[0159] ;

[0160] ;

[0161] ;

[0162] ;

[0163] ;

[0164] ;

[0165] ;

[0166] ;

[0167] ;

[0168] ;

[0169] ;

[0170] ;

[0171] ;

[0172] ;

[0173] ;

[0174] ;

[0175] ;

[0176] ;

[0177] ;

[0178] ;

[0179] ;

[0180] ;

[0181] ;

[0182] ;

[0183] ;

[0184] ;

[0185] ;

[0186] ;

[0187] ;

[0188] ;

[0189] .

[0190] This invention provides a pharmaceutical composition comprising the above-described compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or a prodrug, and pharmaceutical excipients. Preferably, the above-described compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or a prodrug are the active ingredients.

[0191] The present invention provides the use of the above-mentioned compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug, and the above-mentioned pharmaceutical composition in the preparation of a muscle relaxant.

[0192] The present invention provides a method for preparing the above-mentioned compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug, comprising the following steps: reacting compound Va with compound Vb in an organic solvent to obtain compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug;

[0193] ;

[0194] Among them, M1 and M2 are pharmaceutically acceptable anions;

[0195] Ring C, Ring B, q, n, L, R 1 R 2 Each of the pharmaceutically acceptable anions is independently described as in any embodiment of the present invention.

[0196] The present invention provides a method for preparing the above-mentioned compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug, comprising the following steps: reacting compound Va with compound Vb in an organic solvent to obtain compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug;

[0197] ;

[0198] Among them, M1 and M2 are pharmaceutically acceptable anions;

[0199] X1, X2, R 1 R 2 The anions, n, and pharmaceutically acceptable anions are each independently as described in any embodiment of the present invention.

[0200] This invention provides a compound Va or a pharmaceutically acceptable salt thereof;

[0201] ;

[0202] Among them, M1, R 1 Rings C, q, and L are each independently as described in any embodiment of the present invention.

[0203] Preferably, the compound Va has the following structure:

[0204] ;

[0205] Among them, M1, R 1 X1 and X2 are independently described as in any embodiment of the present invention.

[0206] In one embodiment, the compound Va is any of the following compounds:

[0207] ; ;

[0208] ; ; .

[0209] The terms used in this invention are explained as follows; terms not specifically explained are interpreted according to the conventional understanding and knowledge in the art:

[0210] Those skilled in the art will understand that, according to convention in the art, the use of "" in the structural formula describing the functional group in this invention is... " "" refers to the fact that the corresponding group is connected to other fragments or groups in the compound through this site. When the structure allows, multiple connection sites can exist.

[0211] The term "pharmaceutical acceptable" means that something is relatively non-toxic, safe, and suitable for patient use.

[0212] The term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0213] The terms "substituted" or "replaced by" refer to the substitution of one or more hydrogen atoms on a particular atom by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the particular atom is normal and the substituted compound is stable. When multiple substituents are present, the substituents may be different or the same. The terms "optionally substituted" or "optionally replaced by" mean that substitution may or may not be made, unless otherwise specified. The type and number of substituents can be arbitrary on a chemically feasible basis, and the substituents may be different or the same.

[0214] In this invention, the compound represented by Formula I above, or its pharmaceutically acceptable salt, may exist in the form of an isotope derivative, such as a deuterated derivative.

[0215] The term "alkyl" refers to a saturated aliphatic hydrocarbon group comprising a branched or straight chain with a specified number of carbon atoms. For example, "C1-C6 alkyl" is defined as a group comprising 1, 2, 3, 4, 5, or 6 carbon atoms in a straight or branched structure, including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, tert-hexyl, etc.

[0216] The term "alkoxy" refers to an alkyl group with the stated number of carbon atoms connected by an oxygen bridge in the parent structure. Alkyl groups are defined as described above.

[0217] The term "halogen" refers to fluorine, chlorine, bromine or iodine, with fluorine, chlorine or bromine being preferred in this invention, and chlorine being more preferred.

[0218] The term "aryl" refers to a substituent having a specified number of carbon atoms and possessing aromatic ring structural properties. Examples of aryl units include phenyl, substituted phenyl, or naphthyl. It is understood that in an aryl group, the connection to the parent structure occurs through the aromatic ring.

[0219] The term "heteroaryl" refers to a monocyclic or polycyclic group (preferably monocyclic, but also fused ring) having 5-12 ring atoms, each ring containing 1-4 heteroatoms (e.g., 1 or 2), of which one or more heteroatoms are selected from N, O, and S, and the remainder are carbon. At least one ring in a "heteroaryl" group is aromatic. For example, "5-12-membered heteroaryl" refers to heteroaryl groups having 5-12 ring atoms, including but not limited to furan, substituted furan, benzofuran, substituted benzofuran, thiophene, substituted thiophene, benzothiophene, substituted benzothiophene, indole, substituted indole, isoindole, substituted isoindole, pyrrole, substituted pyrrole, thiazole, substituted thiazole, oxazole, substituted oxazole, pyrazole, substituted pyrazole, imidazole, substituted imidazole, pyran, substituted pyran, pyridazine, substituted pyridazine, pyrazine, substituted pyrazine, pyrimidine, substituted pyrimidine, pyridine, substituted pyridine, quinoline, substituted quinoline, isoquinoline, substituted isoquinoline, carbazole, substituted carbazole, etc.

[0220] The term "halogenated" refers to a group that has been substituted with a halogen. There can be one or more halogens, and the substitution can occur at any position. If multiple halogens are substituted, the halogens can be the same or different. For example, "halogenated C1-C6 alkyl" refers to a group formed by replacing any number and position of hydrogen atoms in a C1-C6 alkyl group with a halogen.

[0221] The term "heterocyclic alkyl" refers to a saturated or partially saturated cyclic group (preferably saturated) that is non-aromatic, preferably consisting of a single ring with 3-6 atoms, including one or more (e.g., 1, 2, or 3, preferably 1-2) heteroatoms selected from N, O, and S. It can also be a polycyclic heterocyclic alkyl group, including fused, spirocyclic, or bridged rings, having 3-12 ring atoms (e.g., 5-6 or 5-9 members), including one or more (preferably 1, 2, or 3) heteroatoms selected from N, O, and S. For example, "3-6 membered heterocyclic alkyl" includes, but is not limited to, oxazolinyl, dihydropyrrolyl, tetrahydropyridyl, tetrahydrofuranyl, morpholinyl, pyrrololinyl, piperazine, piperidinyl, and imidazolinyl.

[0222] The term "alkyl-carbonyl" refers to a group of the formula -C(O)-R, where R is an alkyl group as described above.

[0223] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0224] The reagents and raw materials used in this invention are all commercially available.

[0225] The positive and progressive effects of this invention are as follows: the compound provided by this invention has one or more of the following advantages:

[0226] (1) The compounds of the present invention have good target affinity, cell activity and / or enzyme activity;

[0227] (2) The compounds of the present invention have a good muscle blocking effect;

[0228] (3) The compounds of the present invention can achieve controllable blocking time by reversing neuromuscular blockade through the application of cysteine ​​or related compounds;

[0229] (4) The compounds of the present invention have good metabolic performance, which helps to exert the drug efficacy and / or reduce side effects. Detailed Implementation

[0230] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0231] The structure of the compound was determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶. NMR measurements were performed using a Bruker Avance Neo 600 MHz NMR spectrometer with deuterated dimethyl sulfoxide (DMSO-d₆) as the solvent and tetramethylsilane (TMS) as the internal standard.

[0232] LCMS was determined using Waters ACQUITY UPLC.

[0233] Thin-layer chromatography silica gel plates were prepared using West Asia Reagent GF254 silica gel plates.

[0234] Column chromatography used 200-300 mesh silica gel from Qingdao Ocean Chemical Co., Ltd. as the carrier.

[0235] The known starting materials of this application can be obtained through conventional procurement channels in the art, such as Aladdin, Bidex Pharmaceuticals, WuXi AppTec, and other reagent companies, or synthesized according to methods known in the art.

[0236] The abbreviations used in this article have the following meanings:

[0237] LCMS: Liquid Chromatography-Mass Spectrometry

[0238] 1 H NMR: Hydrogen nuclear magnetic resonance spectrum

[0239] TCFH: Tetramethylchlorourea hexafluorophosphate

[0240] NMI: N-methylimidazole

[0241] DCM: Dichloromethane

[0242] MeOH: Methanol

[0243] Example 1: Preparation of Compound 1

[0244] ;

[0245] 3.48 g (40 mmol) of morpholine and 3.32 g (20 mmol) of 3,4-dimethoxybenzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then, the reaction was moved to an ice bath and stirred continuously. 1.14 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the mixture was stirred for another hour. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.6 g of intermediate 1-1, with a yield of 76%.

[0246] 3.0 g (12.7 mmol) of intermediate 1-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was stirred at 80 °C for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The reaction solution was then heated to 80 °C and stirred continuously. After the reaction solution was completely clear, it was cooled to room temperature, concentrated, and the reactants were extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of intermediate 1-2, which was a white oily liquid, was collected, and the yield was 2.9 g, which was 81.1%.

[0247] 1.85 g (6.1 mmol) of intermediate 1-2 was dissolved in 20 mL of acetonitrile. Then, 1.2 g (12.2 mmol) of maleic anhydride and 1.73 g (12.5 mmol) of anhydrous potassium carbonate were added to the solution. The mixture was stirred at room temperature for 2 h. The filtrate was collected by filtration and concentrated to obtain 2.26 g of intermediate 1-3, with a crude yield of 91.9%.

[0248] 2.24 g (26.35 mmol) of piperidine and 3.0 g (17.1 mmol) of 3,4-dichlorobenzaldehyde were dissolved in 30 mL of methanol. 1.0 g (26.3 mmol) of sodium borohydride was slowly added to the system, and the mixture was stirred at room temperature for 4 h. The reaction solvent was concentrated, and the reaction residue was extracted with water and ethyl acetate. The ethyl acetate phase was collected, and the solvent was concentrated to obtain 3.68 g of crude intermediate 1-4, with a yield of 88.0%.

[0249] 2.44 g (10 mmol) of intermediate 1-4 and 3.45 g (25 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was stirred at room temperature for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The mixture was then heated to 80 °C and stirred continuously. The reaction mixture was extracted with ethyl acetate and water. The aqueous phase was collected and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the white oily intermediate 1-5 collected was 2.9 g, with a yield of 81.1%.

[0250] 1.7 g (4.0 mmol) of intermediates 1-3 and 1.3 g (4.0 mmol) of intermediate 1-5 were dissolved in 15 mL of acetonitrile, along with 1.3 g (4.8 mmol) of TCFH and 0.3 g (4.0 mmol) of NMI. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solvent was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluent was used to elute with DCM / MeOH at a volume ratio of 20:1. 0.4 g of product was collected, with a yield of 13%. LC-MS m / z: 527.38 (M-151.15+H) +

[0251] 1 H NMR (600 MHz, CDCl3) δ 7.61 – 7.53 (m, 2H), 7.40 (d, J = 8.2 Hz,1H), 7.01 (d, J = 9.8 Hz, 2H), 6.93 (d, J = 8.1 Hz, 1H), 6.84 (s, 1H), 6.30(s, 1H), 4.61 (dd, J = 23.8, 9.5 Hz, 4H), 4.34 (dd, J = 12.7, 5.2 Hz, 4H), 4.08 – 4.02 (m, 2H), 4.01 – 3.96 (m, 2H), 3.92 (s, 3H), 3.88 (s, 3H), 3.59(dd, J = 25.1, 12.0 Hz, 6H), 3.45 (t, J = 9.8 Hz, 2H), 3.25 – 3.17 (m, 2H), 2.32 (dd, J = 24.8, 6.1 Hz, 4H), 1.98 – 1.89 (m, 4H), 1.34 – 1.23 (m, 4H).

[0252] Example 2: Preparation of Compound 2

[0253] ;

[0254] 3.4 g (40 mmol) of piperidine and 3.32 g (20 mmol) of 3,4-dimethoxybenzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then, the reaction was moved to an ice bath and stirred continuously. 1.14 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the mixture was stirred for another hour. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.4 g of intermediate 2-1, with a yield of 72.34%.

[0255] 3.3 g (14 mmol) of intermediate 2-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The mixture was then heated to 80 °C and stirred continuously. After the solution became completely clear, the reaction solution was concentrated. The reaction residue was extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the white oily crude intermediate 2-2 was 2.8 g, with a yield of 68%.

[0256] 1.5 g (4.5 mmol) of intermediate 2-2 was dissolved in 20 mL of acetonitrile. Then, 1.2 g (13.5 mmol) of maleic anhydride and 1.2 g (9 mmol) of anhydrous potassium carbonate were added to the solution. The mixture was stirred at room temperature for 2 h. The filtrate was collected by filtration and concentrated to obtain 1.5 g of crude intermediate 2-3, with a yield of 80%.

[0257] 1.31 g (10 mmol) of 2-morpholine ethanol and 1.84 g (10 mmol) of 3-methylbenzyl bromide were dissolved in 10 mL of acetonitrile and stirred under reflux at 80 °C for 8 h. After the reaction was stopped, the solvent was removed by concentration. The residue was extracted with water and ethyl acetate. The aqueous phase was collected and concentrated to give 2 g of crude intermediate 2-4, with a yield of 93%.

[0258] 1.5 g (3.5 mmol) of intermediates 2-3 and 1.1 g (3.5 mmol) of intermediate 2-4 were dissolved in 15 mL of acetonitrile, along with 1.2 g (4.2 mmol) of TCFH and 0.3 g (3.5 mmol) of NMI. The reaction mixture was reacted at room temperature for 5 h. After the reaction was complete, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The organic phase was collected, concentrated, and eluent was used to elute with DCM / MeOH at a volume ratio of 20:1. 0.5 g of compound 2 was collected, yielding 20%. LC-MS m / z: 298.35 (M / 2)

[0259] Example 3: Preparation of Compound 3

[0260] ;

[0261] 1.7 g (20 mmol) of piperidine and 2.8 g (20 mmol) of 4-chlorobenzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then the reaction was moved to an ice bath and stirred. 1.14 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the reaction was stirred for another hour. After the reaction was stopped, the reaction solvent was concentrated. The reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.55 g of intermediate 3-1, with a yield of 85%.

[0262] 2.09 g (10 mmol) of intermediate 3-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The reaction was then heated to 80 °C and stirred continuously. The reaction was stopped after the reaction solution was completely clear. The solvent was concentrated and the reactants were extracted with ethyl acetate and water. The aqueous phase was collected and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the crude white oily intermediate 3-2 was 2 g, with a yield of 75%.

[0263] 1.5 g (3.5 mmol) of intermediate 2-3 and 1.0 g (3.3 mmol) of intermediate 3-2 were dissolved in 15 mL of acetonitrile, along with 1.1 g (4.0 mmol) of TCFH and 0.3 g (3.5 mmol) of NMI. The reaction mixture was reacted at room temperature for 5 h. After the reaction was complete, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The organic phase was collected, concentrated, and eluent was used to elute with DCM / MeOH at a volume ratio of 20:1. 0.2 g of compound 3 was collected, yielding 8.3%. LC-MS m / z: 493.40 (M-151.12).

[0264] 1 H NMR (600 MHz, CD3CN) δ 7.53 – 7.50 (m, 2H), 7.49 – 7.45 (m, 2H), 7.07 – 6.97 (m, 3H), 6.84 (s, 1H), 4.45 (s, 2H), 4.40 (s, 2H), 4.33 – 4.29(m, 2H), 4.02 – 3.94 (m, 4H), 3.84 (d, J = 2.9 Hz, 6H), 3.46 – 3.39 (m, 4H), 3.35 – 3.23 (m, 8H), 2.28 – 2.20 (m, 4H), 1.94 (dt, J = 4.9, 2.5 Hz, 2H),1.90 – 1.87 (m, 4H).

[0265] Example 4: Preparation of Compound 4

[0266] ;

[0267] 2.6 g (30 mmol) of morpholine and 3.5 g (25 mmol) of 4-chlorobenzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then the reaction was moved to an ice bath and stirred. 1.1 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the reaction was stirred for another hour. After the reaction was stopped, the reaction solvent was concentrated. The reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.9 g of intermediate 4-1, with a yield of 74%.

[0268] 3.0 g (14.2 mmol) of intermediate 4-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The reaction was continued to be heated at 80 °C and stirred until the reaction solution was completely clear. The reaction solution was concentrated, and the reactants were extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the crude white oily intermediate 4-2 was 2.9 g, with a yield of 75%.

[0269] 1.6 g (5.2 mmol) of intermediate 4-2 was dissolved in 20 mL of acetonitrile. Then, 1.5 g (15.6 mmol) of maleic anhydride and 1.7 g (10.4 mmol) of anhydrous potassium carbonate were added to the solution sequentially. The mixture was stirred at room temperature for 2 h. The filtrate was collected by filtration and concentrated to obtain 1.9 g of crude product of intermediate 4-3, with a yield of 90%.

[0270] 1.4 g (3.5 mmol) of intermediate 4-3 and 1.0 g (3.3 mmol) of intermediate 3-2 were dissolved in 15 mL of acetonitrile, along with 1.2 g (4.2 mmol) of TCFH and 0.3 g (3.5 mmol) of NMI. The reaction mixture was reacted at room temperature for 5 h. After the reaction was complete, the reaction solution was concentrated and extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluent was used to elute with DCM / MeOH at a volume ratio of 20:1. 0.3 g of compound 4 was collected, yielding 13%. LC-MS m / z: 309.44 (M / 2)

[0271] Example 5: Preparation of Compound 5

[0272] ;

[0273] 1.7 g (20 mmol) of piperidine and 2.2 g (20 mmol) of 5-methylfurfural were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then the reaction was moved to an ice bath and stirred continuously. 1.2 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the mixture was stirred for another hour. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.3 g of crude intermediate 5-1, with a yield of 91%.

[0274] 3.2 g (18 mmol) of intermediate 5-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The reaction was then heated to 80 °C and stirred continuously until the reaction solution was completely clear. The reaction solution was concentrated, and the reactants were extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the crude white oily product intermediate 5-2 was 3.2 g, with a yield of 75%.

[0275] 2.5 g (8.4 mmol) of intermediate 1-3 and 1.9 g (8 mmol) of intermediate 5-2 were dissolved in 15 mL of acetonitrile, along with 2.8 g (10 mmol) of TCFH and 1.4 g (16.8 mmol) of NMI. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and purified by column chromatography. 0.66 g of the product was collected using a dichloromethane to methanol eluent at a volume ratio of 20:1, yielding 12%. LC-MS m / z: 463.41 (M -151.14)

[0276] Example 6: Preparation of Compound 6

[0277] ;

[0278] 1.1 g (3.3 mmol) of intermediates 1-2 and 1.4 g (3.3 mmol) of intermediates 2-3 were dissolved in 15 mL of acetonitrile, and TCFH (1.1 g, 4.0 mmol) and NMI (9.9 mmol) were added simultaneously. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solution was concentrated, and the reaction product was extracted with water and dichloromethane. The organic phase was collected, concentrated, and passed through a column. The product was collected with dichloromethane and water in a volume ratio of 20:1 to give 0.72 g of compound 6, with a yield of 13%.

[0279] 1H NMR (600 MHz, CD3CN) δ 7.07 – 6.96 (m, 6H), 6.84 (s, 1H), 4.46 (s,2H), 4.34 (s, 2H), 4.32 – 4.19 (m, 4H), 4.02 – 3.92 (m, 4H), 3.84 (t, J = 4.0Hz, 12H), 3.46 – 3.39 (m, 4H), 3.35 – 3.21 (m, 8H), 1.94 (dt, J = 4.9, 2.4Hz, 6H), 1.91 – 1.85 (m, 4H). LC-MS m / z: 519.40 (M -151.15)

[0280] Example 7: Preparation of Compound 7

[0281] ;

[0282] 1.2 g (3.6 mmol) of intermediate 2-2 and 1.5 g (3.5 mmol) of intermediate 2-3 were dissolved in 15 mL of acetonitrile, along with 1.2 g (4.3 mmol) of TCFH and 0.9 g (10 mmol) of NMI. The reaction was carried out at room temperature for 5 h. After the reaction was completed, the reaction solvent was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluent was obtained by column chromatography using a 20:1 (v / v) mixture of dichloromethane and methanol to collect 0.5 g of compound 7, yielding 19%. LC-MS m / z: 322.88 (M / 2)

[0283] Example 8: Preparation of Compound 8

[0284] ;

[0285] 1.7 g (20 mmol) of piperidine and 2.1 g (20 mmol) of benzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then the reaction was moved to an ice bath and stirred. 1.2 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the mixture was stirred for another hour. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 2.8 g of intermediate 8-1, with a yield of 80%.

[0286] 2.8 g (16 mmol) of intermediate 8-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The mixture was then heated to 80 °C and stirred continuously. After the reaction solution was completely clear, the reaction solvent was concentrated. The reactants were extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the white oily intermediate 8-2 collected was 2.96 g, with a yield of 79%.

[0287] 1.7 g (4.0 mmol) of intermediates 1-3 and 1.1 g (4.0 mmol) of intermediate 8-2 were dissolved in 15 mL of acetonitrile, and TCFH (1.3 g, 4.8 mmol) and NMI (1.0 g, 12.0 mmol) were added simultaneously. The mixture was stirred at room temperature until complete. After the reaction was completed, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and purified by column chromatography. 0.5 g of compound 8 was collected using a 20:1 (v / v) dichloromethane and methanol eluent, yielding 18.5%. LC-MS m / z: 459.45 (M-151.12)

[0288] 1 H NMR (600 MHz, CD3CN) δ 7.57 – 7.46 (m, 5H), 7.07 – 6.95 (m, 3H), 6.84 (s, 1H), 4.45 (s, 2H), 4.42 (s, 2H), 4.32 – 4.28 (m, 2H), 4.02 – 3.92(m, 4H), 3.84 (d, J = 3.4 Hz, 6H), 3.42 (dd, J = 10.0, 6.1 Hz, 4H), 3.34 –3.19 (m, 8H), 2.24 (dd, J = 9.5, 4.9 Hz, 4H), 1.94 (dd, J = 4.9, 2.5 Hz, 4H),1.88 (dd, J = 9.0, 4.6 Hz, 4H).

[0289] Example 9: Preparation of Compound 9

[0290] ;

[0291] 1.3 g (3.8 mmol) of intermediates 1-5 and 1.6 g (3.8 mmol) of intermediates 2-3 were dissolved in 15 mL of acetonitrile, and TCFH (1.4 g, 4.6 mmol) and NMI (11.4 mmol) were added simultaneously. The reaction was carried out at room temperature. After the reaction was complete, the reaction solvent was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and purified by column chromatography. 0.8 g of compound 9 was collected using a dichloromethane and methanol eluent at a volume ratio of 20:1, with a yield of 28.6%. LC-MS m / z: 338.42 (M / 2)

[0292] Example 10: Preparation of Compound 10

[0293] ;

[0294] 2.6 g (30 mmol) of morpholine and 3.5 g (20 mmol) of 3,4-dichlorobenzaldehyde were dissolved in 20 mL of methanol in a 50 mL single-necked flask. The mixture was stirred at room temperature for 4 hours. Then, the reaction was moved to an ice bath and stirred continuously. 1.1 g (30 mmol) of sodium borohydride was slowly added to the reaction solution in batches. After the sodium borohydride was added, the mixture was stirred for another hour. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The ethyl acetate phase was collected and concentrated to obtain 3.7 g of crude intermediate 10-1, with a yield of 76%.

[0295] 3.2 g (13 mmol) of intermediate 10-1 and 3.5 g (25.4 mmol) of trimethylene sulfate were dissolved in 15 mL of acetonitrile. The mixture was heated at 80 °C and stirred for 6 hours. Then, 6 M hydrochloric acid was added to the reaction solution to adjust the pH to 1-2. The reaction solution was then heated to 80 °C and stirred until the reaction solution was completely clear. The reaction solvent was concentrated, and the reactants were extracted with ethyl acetate and water. The aqueous phase was collected, and the solvent water was removed by rotary evaporation under reduced pressure. The mass of the white oily intermediate 10-2 collected was 2.7 g, with a yield of 72%.

[0296] 2 g (5.9 mmol) of intermediate 10-2 was dissolved in 20 mL of acetonitrile, and 1.7 g (17.7 mmol) of maleic anhydride and 1.6 g (11.8 mmol) of anhydrous potassium carbonate were added sequentially. The mixture was stirred at room temperature for 2 h, filtered, and the filtrate was collected. After concentration, 1.7 g of crude product intermediate 10-3 was obtained, with a yield of 70.8%.

[0297] 1.5 g (4.4 mmol) of intermediate 10⁻² and 2 g (4.6 mmol) of intermediate 10⁻³ were dissolved in 15 mL of acetonitrile, along with 1.5 g (5.3 mmol) of TCFH and 1.1 g (13.2 mmol) of NMI. The reaction was carried out at room temperature. After the reaction was complete, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluented with a 20:1 (v / v) mixture of dichloromethane and methanol to obtain 0.5 g of compound 10, with a yield of 15.2%. LC-MS m / z: 521.36 (M-151.14)

[0298] Example 11: Preparation of Compound 11

[0299] ;

[0300] 1.5 g (4.4 mmol) of intermediate 10-2 and 1.8 g (4.2 mmol) of intermediate 1-3 were dissolved in 15 mL of acetonitrile, and TCFH (1.4 g, 5.0 mmol) and NMI (1.0 g, 12.6 mmol) were added simultaneously. The reaction was carried out at room temperature. After the reaction was completed, the reaction solution was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluent was obtained by column chromatography with a dichloromethane / methanol ratio of 20:1 (v / v) to collect 0.8 g of compound 11, with a yield of 24.2%. LC-MS m / z: 529.24 (M-151.08)

[0301] Example 12: Preparation of Compound 12

[0302] ;

[0303] 1.31 g (10 mmol) of 2-morpholine ethanol and 1.89 g (10 mmol) of 2-fluorobenzyl bromide were dissolved in 10 mL of acetonitrile. The mixture was heated and stirred at 80 °C for 8 h. After the reaction was stopped, the reaction solution was concentrated to obtain 2 g of intermediate 12-1, with a yield of 84%.

[0304] 2 g (4.6 mmol) of intermediate 10-3 and 1.5 g (4.6 mmol) of intermediate 12-1 were dissolved in 15 mL of acetonitrile, and TCFH (1.5 g, 5.5 mmol) and NMI (13.8 mmol) were added simultaneously. The reaction was carried out at room temperature. After the reaction was completed, the reaction solvent was concentrated, and the reactants were extracted with dichloromethane and water. The dichloromethane phase was collected, concentrated, and eluented with dichloromethane and methanol in a volume ratio of 20:1 to give 0.7 g of compound 12, with a yield of 20.6%. LC-MS m / z: 311.35 (M / 2)

[0305] Example 13: Preparation of Compound 13

[0306] ;

[0307] Piperidine (2.6 g, 30 mmol) was dissolved in 15 mL of dichloroethane, and myristaldehyde (1.8 g, 10 mmol) was added simultaneously. Sodium triacetoxyborohydride (2.5 g, 12 mmol) was added under stirring at room temperature. The reaction was continued until the reactants were completely consumed as detected by LC-MS. The reaction solution was concentrated, water was added to the reactants, and the mixture was extracted three times with dichloromethane. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. After concentration, 2.1 g of the yellow oily product 13-1 was obtained, with a yield of 84%.

[0308] Compound 13-1 (2.0 g, 8 mmol) and compound 1,3,2-dioxothiacyclohexane-2,2-dioxide (3.3 g, 24 mmol) were dissolved in 20 mL of acetonitrile. The mixture was heated and stirred at 80 °C until a large amount of white solid precipitated out. LC-MS showed that the reaction was complete. The amount of white solid product 13-2 collected after filtration was 2.9 g, with a yield of 97%.

[0309] Compound 13-2 (2.8 g, 7.2 mmol) was dissolved in 15 mL of acetonitrile solvent, and 1 mL of 3M hydrochloric acid solution was added simultaneously. The mixture was heated to reflux at 80 °C with stirring. The reaction was stopped when the reaction solution became clear and transparent. The reaction solution was concentrated to obtain a colorless oily product 13-3 with a mass of 2.1 g and a yield of 91%.

[0310] Compound 13-3 (2.0 g, 6.1 mmol) and maleic anhydride (1.8 g, 18.3 mmol) were dissolved in 20 mL of acetonitrile solvent, and potassium carbonate (1.0 g, 7.3 mmol) was added simultaneously. The mixture was stirred at room temperature and the reaction was stopped after LC-MS detection showed that the reaction was complete. The mixture was filtered, and the filtrate was collected and concentrated to give 2.5 g of white oily crude product 13-4, with a yield of 93%.

[0311] Intermediate 13-4 (200 mg, 0.45 mmol) was dissolved in 10 mL of dichloromethane in a dry single-necked flask. Under nitrogen protection, oxalyl chloride (300 mg, 2.4 mmol) was added. After stirring in an ice bath for 20 min, a dichloromethane solution of compound 13-3 (154 mg, 0.45 mmol) was added. The reaction was continued until the reaction was complete as monitored by LC-MS. The reaction solution was evaporated to dryness and then rotary evaporated three times with dichloromethane to obtain 0.2 g of a yellow oily crude product, with a yield of 67%. MS (ESI) m / z: 348.38 (M / 2).

[0312] 1H NMR (600 MHz, D2O) δ 6.62 (s, 2H), 6.59 (s, 2H), 6.57 (s, 2H), 5.80 (s, 4H), 4.28 – 4.25 (m, 8H), 3.65 (s, 6H), 3.24 (d, J = 12.0 Hz, 8H), 3.19 –3.15 (m, 4H), 2.18 (td, J = 8.6, 4.1 Hz, 4H), 1.83 – 1.74 (m, 8H), 1.66 –1.59 (m, 2H), 1.53 – 1.44 (m, 2H).

[0313] Example 14: Preparation of Compound 14

[0314] ;

[0315] Compound 13-3 (3.4 g, 10 mmol) and fumarate chloride (1.8 g, 12 mmol) were dissolved in acetonitrile, respectively. Triethylamine (1.2 g, 12 mmol) was added to the solution of compound 13-3. The fumarate chloride solution in acetonitrile was slowly added dropwise to the reaction solution under stirring at room temperature. After the reaction was completed, the reaction was stirred until the reaction was complete as detected by LC-MS. The insoluble solids were removed by filtration, the filtrate was collected, and the crude product of compound 14 was obtained after concentration. The amount obtained was 2.8 g, and the yield was 37%.

[0316] 1 H NMR (600 MHz, D2O) δ 6.62 (s, 2H), 6.59 (s, 2H), 6.57 (s, 2H), 5.80 (s, 4H), 4.28 – 4.25 (m, 8H), 3.65 (s, 6H), 3.24 (d, J = 12.0 Hz, 8H), 3.19 –3.15 (m, 4H), 2.18 (td, J = 8.6, 4.1 Hz, 4H), 1.83 – 1.74 (m, 8H), 1.66 –1.59 (m, 2H), 1.53 – 1.44 (m, 2H).

[0317] Example 15: Preparation of Compound 15

[0318] ;

[0319] 2-morpholinoethanol (1.3 g, 10 mmol) and 3-methylbenzyl bromide (1.8 g, 10 mmol) were dissolved in acetonitrile and reacted under stirring at room temperature. After the reaction was complete as detected by LC-MS, the reaction solution was concentrated to obtain 2.1 g of product 15-1, with a yield of 68%.

[0320] Intermediate 1-3 (278 mg, 0.65 mmol) was dissolved in 10 mL of dichloromethane in a dry single-necked flask. Under nitrogen protection, oxalyl chloride (96 mg, 0.76 mmol) was added. After stirring in an ice bath for 20 min, a dichloromethane solution of compound 15-1 (199 mg, 0.63 mmol) was added. The reaction was continued until the reaction was complete as monitored by LC-MS. The reaction solution was evaporated to dryness, and dichloromethane was added and evaporated three times to obtain 200 mg of a yellow oily crude product, with a yield of 43%. MS (ESI) m / z: 299.82 (M / 2).

[0321] 1 H NMR (600 MHz, CD3CN) δ 7.48 (t, J = 7.5 Hz, 1H), 7.42 (t, J = 6.5Hz, 2H), 7.36 (t, J = 7.7 Hz, 1H), 7.03 (t, J = 7.7 Hz, 2H), 6.98 (d, J = 1.7Hz, 1H), 6.88 (s, 1H), 4.71 – 4.57 (m, 4H), 4.44 (d, J = 3.4 Hz, 2H), 4.29(t, J = 5.7 Hz, 2H), 4.04 – 3.90 (m, 10H), 3.85 (d, J = 4.4 Hz, 6H), 3.41(dd, J = 11.3, 7.7 Hz, 8H), 3.31 (d, J = 13.2 Hz, 2H), 2.45 (d, J = 5.5 Hz, 3H), 2.22 (dd, J = 11.9, 5.2 Hz, 4H).

[0322] Experimental Example 1: Evaluation of an isolated bullfrog sciatic nerve-gastrocnemius muscle tone testing model

[0323] 1. Test drug

[0324] Solvent: 5% acetonitrile aqueous solution;

[0325] Control compound: 5% aqueous solution of acetonitrile of compound CW1759-50.

[0326] (Recorded in the document Preclinical Pharmacology in the RhesusMonkey of CW 1759-50, a New Ultra-short Acting Nondepolarizing NeuromuscularBlocking Agent, Degraded and Antagonized by L-Cysteine).

[0327] Test sample: 5% aqueous solution of the compound in the examples;

[0328] 2. Laboratory animals

[0329] Bullfrogs, both male and female, should weigh 180-220 g before the experiment.

[0330] 3. Experimental Procedure

[0331] 1) Preparation of sciatic nerve-gastrocnemius muscle specimen: The bullfrog was weighed and euthanized using the double medullary destruction method. The head and upper limbs were removed. After peeling off the skin, both lower limbs were cut open for later use. The sciatic nerve and gastrocnemius muscle of one of the lower limbs were separated and exposed to obtain one sciatic nerve-gastrocnemius muscle specimen.

[0332] 2) Sciatic nerve-gastrocnemius connection device: Connect the gastrocnemius muscle to the tension transducer and place stimulation electrodes at the sciatic nerve.

[0333] 3) Apply single stimulation to the sciatic nerve to induce muscle contraction of the gastrocnemius muscle. After stabilizing for a period of time, record a normal muscle contraction curve.

[0334] 4) After the signal stabilizes, different concentrations of the test compound are injected intramuscularly, and the inhibition of muscle tone after administration is recorded.

[0335] Experimental indicators: Compare the degree of muscle contraction (twitch) and the rate of muscle twitching inhibition of each compound.

[0336] Note: The average muscle tone within 1 minute before drug administration was used as the muscle tone of the gastrocnemius muscle at 0 minutes to calculate the muscle contraction duration.

[0337] Table 1

[0338] ;

[0339] The results are shown in Table 1. The compounds of the present invention have an inhibitory effect on muscle twitching in bullfrog muscle tone experiments. The inhibitory effect of the above compounds is comparable to or better than that of CW1759-50, indicating that the compounds of the present invention have a better nerve blockade effect.

[0340] Experiment Example 2: Evaluation of the Mouse Net Climbing Experiment Model

[0341] 1. Test drug

[0342] Solvent: 5% acetonitrile aqueous solution;

[0343] Test sample: 5% aqueous solution of the compound in the examples;

[0344] Positive reagent: 5% acetonitrile aqueous solution of compound CW1759-50.

[0345] 2. Laboratory animals

[0346] Male KM mice (source: Hunan Slack Jingda Experimental Animal Co., Ltd.), weighing 30-40g during the formal test;

[0347] 3. Experimental Procedure

[0348] Weigh the mice and inject the corresponding volume of the positive compound or the test compound into the hind limb muscles. Immediately after injection, place the mice on a wire mesh and observe their fall and recovery from climbing back up the mesh.

[0349] Experimental indicators: Compare the fall rate, net dwell time, and recovery time of mice after injection of the compound.

[0350] Remark:

[0351] The drop rate refers to the percentage of mice that fall off the wire mesh after being injected with the test sample, out of the total number of mice in the group.

[0352] The net duration refers to the time required for a mouse to fall off the wire mesh after being injected with the test sample.

[0353] The criterion for complete muscle relaxation is a 100% fall rate from the wire mesh in mice.

[0354] The recovery criterion was a 0% drop rate when mice were placed on a wire mesh for 15 minutes.

[0355] The dosage is the effective dose for complete muscle relaxation in mice. This is a non-quantitative comparison model. The smaller the dose required for complete muscle relaxation, the better the efficacy.

[0356] Table 2

[0357] ;

[0358] The results in Table 2 show that the compounds of this invention have good muscle relaxant activity in mice and have a faster onset of action than CW1759-50.

[0359] Experimental Example 3: Evaluation of a Rat Muscle Tone Testing Model

[0360] 1. Test drug

[0361] Solvent: 5% acetonitrile aqueous solution;

[0362] Test sample: 5% aqueous solution of the compound in the examples;

[0363] Positive reagent: 5% acetonitrile aqueous solution of compound CW1759-50.

[0364] D-cysteine, with a purity of 99%.

[0365] 3. Experimental Procedure

[0366] Rats were randomly divided into a solvent control group, a positive control group, and a test compound group based on their body weight. Anesthesia was induced with isoflurane, the rats were shaved, and tracheostomized for intubation and mechanical ventilation. A cannula was inserted into one jugular vein. The sciatic nerve and tibialis anterior muscle were isolated and connected to a biosignal acquisition system. Electrical stimulation of the sciatic nerve was administered. After the tibialis anterior muscle tone stabilized for 2 minutes, the corresponding volume (2 mL / kg) of solvent, positive control, or test compound was injected via the jugular vein. Changes in muscle tone were recorded.

[0367] Note: Dosage refers to the maximum effective dose, which is the dose administered when the muscle tone inhibition rate reaches 100%. The dosage of cysteine ​​is 5 times the maximum effective dose.

[0368] Calculate the maximum inhibition rate of myofascial response:

[0369] Maximum muscle twitching response inhibition rate = 100% - minimum muscle tone after administration / mean muscle tone within 1 minute before administration * 100%.

[0370] Table 3

[0371] ;

[0372] Table 3 shows that the compound of the present invention not only has good muscle relaxant efficacy in rats, but its muscle relaxant activity can also be antagonized by cysteine, which significantly shortens the muscle relaxation recovery time and increases the safety of the muscle relaxant.

Claims

1. A compound V, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof, a tautomer thereof, or a prodrug thereof; Compound V comprises the compound shown in Formula I and a pharmaceutically acceptable anion; ； in, L is or ; R 3 and R 4 Independently H, C1-6 alkyl, C 6-10 Aryl or halogen; Ring B and ring C are independently 3-12-membered heterocyclic alkyl or 5-12-membered heteroaryl, wherein the 3-12-membered heterocyclic alkyl and 5-12-membered heteroaryl are optionally separated by one or more R b In the substituted 5-12-membered heteroaryl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; in the 3-12-membered heterocycloalkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4. R b Independently halogen, oxo group, C 1-6 Alkoxy or C 1-6 alkyl; n and q are independently 0, 1, or 2; R 1 C 6-10 aryl, with one or more R 1-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 1-1 R 1-2 R 2-1 and R 2-2 Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-carbonyl, 3-6 membered heterocyclic alkyl or In the 3-6 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; L1 is a single bond independently, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, O, or S; ring A is C 6-10 Aryl; R a Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl; n1 can be 0, 1, 2 or 3.

2. The compound V as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It is any of the following schemes: Option 1: The compound shown in Formula I is: ； Wherein, X1 and X2 are independently S, CH2, O or NH; n is 1 or 2; R 1 C 6-10 aryl, with one or more R 1-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl, 5-12 heteroaryl, or with one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 1-1 R 1-2 R 2-1 and R 2-2 Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkyl, Halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Alkoxy, C 1-6 Alkyl-carbonyl, 3-6 membered heterocyclic alkyl or In the 3-6 membered heterocyclic alkyl group, the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; L1 is a single bond independently, C 1-6 Alkyl, -OC 1-6 Alkyl, -SC 1-6 Alkyl, O, or S; ring A is C 6-10 Aryl; R a Independently halogen, nitro, cyano, hydroxyl, C 1-6 Alkoxy or C 1-6 alkyl; n1 is 0, 1, 2 or 3; Option 2: The compound shown in Formula I is: ； X1 and X2 are independently CH2 or O; n is 1 or 2; R 1 For one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 2 C 6-10 aryl or aryl with one or more R 2-1 Replacement C 6-10 Aryl; R 1-1 R 1-2 and R 2-1 Independent of halogen, C 1-6 Alkyl or C 1-6 Alkoxy; Option 3: L is or ; R 3 and R 4 H is independent; Ring B and ring C are independently 3-12 membered heterocyclic alkyl groups, and the heteroatoms are selected from one or more of N, S and O, with the number of heteroatoms being 1, 2, 3 or 4; n is 1 or 2; q is 0 or 1; R 1 For one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl, with one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; R 1-1 R 1-2 R 2-1 and R 2-2 Independent of halogen, C 1-6 Alkyl or C 1-6 Alkyl group.

3. The compound V as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It satisfies one or more of the following conditions: (1) The C 6-10 The aryl group can be phenyl or naphthyl, for example, phenyl; (2) In the 5-12 member heteroaryl group, the heteroatom is independently N, O or S, and the number of heteroatoms is independently 1 or 2, such as thienyl, furanyl or benzodioxanepentyl, and the 5-12 member heteroaryl group is preferably 5, 6 or 9 member heteroaryl group; (3) The halogenated C 1-6 Alkyl groups are C atoms that are independently substituted with one or more halogens. 1-6 Alkyl groups, such as trifluoromethyl groups; (4) The halogen is independently fluorine, chlorine, bromine or iodine, for example chlorine; (5) The C 1-6 The alkyl group is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, or isobutyl, for example, methyl; (6) The C mentioned 1-6 The alkoxy group is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, or isobutoxy, such as methoxy; (7) The 3-6 membered heterocyclic alkyl group is a saturated group, and the heteroatom is selected from N, S and O, and the number of heteroatoms is preferably 1 or 2; the 3-6 membered heterocyclic alkyl group is preferably a 6 membered heterocyclic alkyl group; (8) The compound V is a salt formed from the compound of formula I and a pharmaceutically acceptable anion; (9) The pharmaceutically acceptable anions are, independently, halide ions, acetate, benzoate, benzenesulfonate, camphorsulfonate, citrate, ethanedisulfonate, fumarate, glucoheponicate, glucuronate, glucuronate, hydroxyethanesulfonate, lactate, lacturonic acid, dodecyl sulfate, malate, maleate, methanesulfonate, naphthoate, naphthalenesulfonate, nitrate, stearate, oleate, oxalate, dihydroxynaphthalate, phosphate, hydrogen phosphate, dihydrogen phosphate, polygalacturonic acid, succinate, sulfate, sulfosalicylate, tartrate, toluenesulfonate, or trifluoroacetate, preferably I. - ,Br - Cl - F - , , or Further preferred is I - ,Br - or Cl - ; (10) The pharmaceutically acceptable anion is a monovalent anion; (11) The molar ratio of the compound shown in Formula I to the pharmaceutically acceptable anion is 1:(0.1-10), preferably 1:2; (12) The 3-12 membered heterocyclic alkyl group is a 5-9 membered heterocyclic alkyl group, and the heteroatom can be one or two of N, S and O, and the number of heteroatoms can be 1 or 2, such as monoazacyclopentyl, monoazacyclohexyl, morpholinyl, etc. , , , , , or ; (13) The halogenated C 1-6 Alkyl groups are C atoms that are independently substituted with one or more halogens. 1-6 Alkyl group.

4. The compound V as described in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It satisfies one or more of the following conditions: (1) X1 and X2 are independently CH2 or O, for example, X1 is CH2 and X2 is O; (2) R 1 For one or more R 1-1 Replacement C 6-10 aryl or aryl with one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S, and O, and the number of heteroatoms is 1, 2, 3, or 4; preferably, R 1 For one or more R 1-1 Replacement C 6-10 Aryl; (3) R 2 C 6-10 aryl or aryl with one or more R 2-1 Replacement C 6-10 Aryl; preferably, R 2 For one or more R 2-1 Replacement C 6-10 Aryl; more preferably, R 1 C 6-10 aryl or aryl with one or more R 1-1 Replacement C 6-10 Aryl; R 2 C 6-10 aryl or aryl with one or more R 2-1 Replacement C 6-10 Aryl; (4) R 1-1 R 1-2 and R 2-1 Independent of halogen, C 1-6 Alkyl or C 1-6 Alkoxy; preferably, R 1-1 and R 2-1 Independently halogen or C 1-6 Alkoxy, more preferably, R 1-1 It is a halogen; R 2-1 C 1-6 Alkyl group.

5. The compound V as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It satisfies one or more of the following conditions: (1) R 1 and R 2 In this context, the 5-12-membered heteroaryl group is independently a benzo5-6-membered heterocyclic alkyl group, wherein the heteroatom in the 5-6-membered heterocyclic alkyl group is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2 or 3; (2) R 2 C 6-10 aryl, with one or more R 2-1 Replacement C 6-10 aryl or aryl with one or more R 2-2 Substituted 5-12-membered heteroaryl groups; preferably, R 2 For one or more R 2-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; (3) R 3 and R 4 For H; (4) Cycle B and cycle C are independently 3-12 membered heterocyclic alkyl groups, wherein the 5-12 membered heterocyclic alkyl group is optionally surrounded by one or more R groups. b Replacement; preferably, ring B is Ring C is X1 and X2 are as described in claim 1 or 2; (5) q is 1, n is 2; Alternatively, q is 0 and n is 1; (6) R 1 For one or more R 1-2 The substituted 5-12-membered heteroaryl group, wherein the heteroatom is selected from one or more of N, S and O, and the number of heteroatoms is 1, 2, 3 or 4; (7) R 1-1 R 1-2 R 2-1 and R 2-2 Independent of halogen, C 1-6 Alkyl or C 1-6 Alkoxy, preferably, R 1-1 R 1-2 R 2-1 and R 2 -2 Independently for C 1-6 Alkoxy; (8) L is .

6. The compound V as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, The compound represented by Formula I is either the compound represented by Formula I-1 or the compound represented by Formula I-4; ; Where k1 and k2 are independently 0, 1, 2 or 3; X1, X2, R 1-1 and R 2-1 Independently as described in any one of claims 1-4; ; L, n, q, ring B, and ring C are independently as described in any one of claims 1-4; Preferably, k1 and k2 are independently 0, 1, or 2; X1 and X2 are CH2 or O; R 1-1 and R 2-1 Independently halogen or C 1-6 Alkoxy; More preferably, the compound represented by Formula I is a compound represented by Formula I-2 or I-3; ; ; X1, X2, R 1-1 and R 2-1 As described in any one of claims 1-4; For example, X1 is CH2, X2 is O; R 1-1 It is a halogen; R 2-1 C 1-6 Alkyl group.

7. The compound V as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It satisfies one or more of the following conditions: (1) R 1 and R 2 Each can be independently one of the following structures: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; Preferably, R 1 for , , , , or ; Preferably, R 2 for , , , , , , or ; (2) Ring B and ring C are independently... , , , , , , , , , , , , , , , or ; (3) L is , , , , or .

8. The compound V as claimed in claim 1 or 2, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, The compound represented by Formula I is any of the following compounds: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； Alternatively, compound V can be any of the following compounds: ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； ； 。 9. A pharmaceutical composition, characterized in that, It comprises compound V as described in any one of claims 1-8, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug and pharmaceutical excipient.

10. The use of a compound V as described in any one of claims 1-8, a pharmaceutically acceptable salt thereof, a solvate thereof, a metabolite thereof, a tautomer thereof, or a prodrug thereof, or a pharmaceutical composition as described in claim 9, in the preparation of a muscle relaxant.

11. A method for preparing compound V as described in any one of claims 1-8, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer, or its prodrug, characterized in that, It comprises the following steps: in an organic solvent, compound Va reacts with compound Vb to give compound V, its pharmaceutically acceptable salt, its solvate, its metabolite, its tautomer or its prodrug; ； Among them, M1 and M2 are pharmaceutically acceptable anions; Ring C, Ring B, q, n, L, R 1 R 2 The pharmaceutically acceptable anions are each independently described in any one of claims 1-8.

12. A compound Va or a pharmaceutically acceptable salt thereof; ； in, M1, R 1 Rings C, q, and L are each as described in claim 11 independently; Preferably, the compound Va is any of the following compounds: ； ； ； ； 。

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