Cucurbituril compound and medical application thereof

Abstract

The invention relates to a cucurbituril compound and medical application thereof. Specifically, the invention relates to a compound as shown in a formula (I) and a pharmaceutically acceptable salt thereof, a preparation method thereof, a pharmaceutical composition containing the compound and application thereof as a therapeutic agent, especially application in treatment or prevention of proliferative diseases, cardiovascular related diseases or hematologic cancers, use in reversing drug-induced neuromuscular block and / or anesthesia. I) # imgabs0 #

Description

Cucurbituril compounds and their medical uses Technical Field

[0001] The present disclosure belongs to the field of medicine, and particularly relates to cucurbituril compounds and their medical uses. Background Art

[0002] Muscle relaxation is one of the three essential elements of general anesthesia. While muscle relaxants meet the needs of endotracheal intubation and surgery, they also pose a safety risk: residual muscle relaxation, which can lead to subjective discomfort in patients and a series of pulmonary complications such as hypoxemia, regurgitation, and aspiration. To reduce the incidence of residual muscle relaxation, measures such as the use of intermediate- and short-acting muscle relaxants, optimized intraoperative muscle relaxation management, postoperative antagonism of the effects of muscle relaxants, and objective perioperative muscle relaxation monitoring are often used. These measures have resulted in progress in addressing this clinical challenge.

[0003] Postoperative muscle relaxant antagonism refers to the use of muscle relaxant antagonists to reverse the residual effects of non-depolarizing muscle relaxants. Currently, commonly used muscle relaxant antagonists can be roughly divided into two categories: one is competitive muscle relaxant antagonists, including neostigmine, an acetylcholine inhibitor; the other is selective muscle relaxant antagonists, including sugammadex sodium, an antagonist for steroid muscle relaxants, and cysteine, an antagonist for benzylisoquinoline muscle relaxants.

[0004] The prior art WO2012051407A discloses a class of non-closed-ring CB[n]-type molecular containers with a cucurbituril structure, namely Calabadion2, which can efficiently bind to benzylisoquinoline and steroidal muscle relaxants, and by covering the quaternary ammonium sites of benzylisoquinoline and steroidal muscle relaxants, prevent the binding of muscle relaxants to neuromuscular cholinergic receptors, thereby rapidly reversing the muscle relaxant effect.

[0005] Summary of the Invention

[0006] The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,

[0007] in,

[0008] R 1 Each independently selected from C 2-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 1 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 1 Optionally one or more R 1A replace;

[0009] R2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 2 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 2 Optionally one or more R 2A replace;

[0010] Ring A is independently selected from a 5- to 12-membered aromatic group or a 5- to 12-membered heteroaryl group;

[0011] R 3 are each independently selected from halogen, C 1-6 alkyl, hydroxy, nitro, cyano, -C(O)2R', NR'(R"), R'-(O)-alkylene-, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl or And at least one of them is , the R 3 Optionally one or more R 3A replace;

[0012] R 4 for A + is a monovalent or divalent cation;

[0013] R 1A 、R 2A 、R 3A Each independently selected from halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 alkoxy;

[0014] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl;

[0015] m and n are each independently selected from 1, 2, 3, 4 or 5;

[0016] p is each independently selected from 1, 2, 3, 4, 5 or 6.

[0017] In an optional embodiment, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring A is phenyl or naphthyl.

[0018] In an optional embodiment, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein the ring A is naphthyl.

[0019] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof,

[0020] Among them, R 1 、R 2 , p, m and A + As defined in the compound represented by formula (I).

[0021] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group.

[0022] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 4- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclic group.

[0023] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 5- to 6-membered cycloalkyl group or a 5- to 6-membered heterocyclic group.

[0024] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 6-membered cycloalkyl group.

[0025] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 5- to 6-membered heterocyclic group in which the heteroatom is nitrogen or oxygen.

[0026] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 5- to 6-membered heterocyclic group in which the heteroatom is oxygen.

[0027] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is C2-6 alkyl.

[0028] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently ethyl.

[0029] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is C 1-6 Halogenated alkyl.

[0030] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is C 1-3 Halogenated alkyl.

[0031] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently one, two or three fluorine-substituted methyl groups.

[0032] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently -C(O)2R', wherein R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl.

[0033] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is -C(O)2R', wherein R' is selected from H or C 1-6 alkyl.

[0034] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently -C(O)2R', wherein R' is selected from methyl or ethyl.

[0035] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is C 1-6 Hydroxyalkyl or C 1-6 Alkyl-OC 1-6 Alkylene-.

[0036] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is C 1-3 Hydroxyalkyl or C 1-3 Alkyl-OC 1-3 Alkylene-.

[0037] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently hydroxymethyl or methyl-O-methylene-.

[0038] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each is independently R'-(O)-alkylene-, wherein R' is selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 haloalkyl, 3- to 7-membered cycloalkyl, and 3- to 7-membered heterocyclic group.

[0039] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is R'-(O)-alkylene-, wherein R' is C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0040] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 1 Each independently is R'-(O)-alkylene-, wherein R' is C 1-3 alkyl.

[0041] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently hydrogen.

[0042] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation selected from H + 、Na + , K + 、H4N + 、Et3NH + 、(HOCH2CH2)3NH + or cationic forms of ethylenediamine, piperazine, or triphenylmethylaminomethane.

[0043] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation selected from H + 、Na + or K + .

[0044] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation, wherein the monovalent cation is Na + .

[0045] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein A + is a divalent cation selected from Ca 2+ Mg 2+ or Zn 2+ .

[0046] In some embodiments, the present disclosure provides compounds represented by formula (I) or (I-1) or pharmaceutically acceptable salts thereof, wherein p is independently selected from 2, 3 or 4.

[0047] In some embodiments, the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein p is 3.

[0048] In some embodiments, the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein m is independently selected from 2, 3 or 4.

[0049] In some embodiments, the present disclosure provides a compound represented by formula (I) or (I-1) or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0050] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 together to form a 5-membered cycloalkyl group, a 6-membered cycloalkyl group or a 7-membered cycloalkyl group, for example

[0051] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 Together they form a 6-membered heterocycloalkyl group, for example

[0052] In some embodiments, the present disclosure provides a compound of formula (I), (I-1) or a pharmaceutically acceptable salt thereof, wherein the two R 1 together to form a 5-membered heterocycloalkyl group, for example

[0053] In an optional embodiment, the compound of formula (I) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E) or a pharmaceutically acceptable salt thereof,

[0054] wherein X3 are each independently selected from O, S, and NH;

[0055] d is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0056] e is each independently selected from 0, 1, 2, 3, 4, 5, 6, 7, 8;

[0057] f are each independently selected from 0, 1, and 2;

[0058] g are each independently selected from 0, 1, 2;

[0059] R 1A , p are as defined above.

[0060] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E), or a pharmaceutically acceptable salt thereof, wherein R 1A Each independently selected from halogen, cyano, amino, C 1-6 Alkyl or C 1-6 Alkoxy.

[0061] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E), or a pharmaceutically acceptable salt thereof, wherein R 1A are each independently selected from halogen, C 1-6 Alkyl or C 1-6 Alkoxy.

[0062] In some embodiments, the present disclosure provides a compound of formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D) or formula (I-1-E), or a pharmaceutically acceptable salt thereof, wherein R 1AEach is independently selected from fluorine, chlorine, methyl, ethyl, methoxy, and ethoxy.

[0063] The present disclosure provides a compound represented by Formula (I), Formula (I-1), Formula (I-1-A), Formula (I-1-B), Formula (I-1-C), Formula (I-1-D) or Formula (I-1-E), or a pharmaceutically acceptable salt thereof, which is selected from:

[0064] Another aspect of the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,

[0065] wherein X1 and X2 are each independently selected from O, S, and -NH-, provided that X1 and X2 are not O at the same time;

[0066] R 5 Each independently selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 5 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 5 Optionally one or more R 5A replace;

[0067] R 6 Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 6 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 6 Optionally one or more R 6A replace;

[0068] Ring B is selected from a 5- to 12-membered aromatic group or a 5- to 12-membered heteroaryl group;

[0069] R 7 are each independently selected from halogen, C 1-6 alkyl, hydroxy, nitro, cyano, -C(O)2R', NR'(R"), R'-(O)-alkylene-, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl or And at least one of them is The R7 Optionally one or more R 7A replace;

[0070] R 8 for The A + is a monovalent or divalent cation;

[0071] R 5A 、R 6A 、R 7A Each independently selected from halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 alkoxy;

[0072] R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl;

[0073] wherein y and z are each independently selected from 1, 2, 3, 4 or 5;

[0074] w is selected from 1, 2, 3, 4, 5 or 6.

[0075] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is selected from phenyl or naphthyl.

[0076] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein ring B is naphthyl.

[0077] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-1) or a pharmaceutically acceptable salt thereof,

[0078] Among them, the R 5 、R 6 ,w,z,A + are respectively as defined in the compound represented by formula (II).

[0079] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-2) or a pharmaceutically acceptable salt thereof,

[0080] Among them, the R 5 、R 6 ,w,z,A + are respectively as defined in the compound represented by formula (II).

[0081] In some embodiments, the compound of formula (II) or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound of formula (II-3) or a pharmaceutically acceptable salt thereof,

[0082] Among them, the R 5 、R 6 ,w,z,A + are respectively as defined in the compound represented by formula (II).

[0083] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein R 5 Each independently is C 1-6 Alkyl or C 1-6 Halogenated alkyl.

[0084] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein R 5 Each independently is C 1-3 alkyl.

[0085] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein R 5 are each independently methyl.

[0086] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein the R 6 are each independently hydrogen.

[0087] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + Selected from monovalent cations, the monovalent cations selected from H + 、Na + , K + 、H4N + 、Et3NH + 、(HOCH2CH2)3NH + or cationic forms of ethylenediamine, piperazine, or triphenylmethylaminomethane.

[0088] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + is a monovalent cation selected from H+ 、Na + or K + .

[0089] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein A + is a divalent cation selected from Ca 2+ Mg 2+ or Zn 2+ .

[0090] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein w is independently selected from 2, 3 or 4.

[0091] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein w is each independently 3.

[0092] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein z is independently selected from 2, 3 or 4.

[0093] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, wherein z is independently 2.

[0094] In some embodiments, the present disclosure provides compounds represented by formula (II), (II-1), (II-2), (II-3) or pharmaceutically acceptable salts thereof, which are selected from:

[0095] Another aspect of the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,

[0096] in:

[0097] X C1 、X C2 Each is independently selected from O, S, -NH-;

[0098] R C2 Selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms C2 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R C2 Optionally substituted with one or more halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0099] Ring C is selected from 6- to 18-membered aromatic groups or 5- to 18-membered heteroaryl groups;

[0100] R C3 Each independently

[0101] R C4 Each independently Carboxylic acid group, -carboxylate-cation, phosphate group, -phosphate-cation, sulfonic acid group, -sulfonate-cation;

[0102] L, L 1 、L 2 The same or different, each independently an alkylene or heteroalkylene, the alkylene, heteroalkylene optionally substituted by one or more halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution;

[0103] R c are independently selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 alkoxy;

[0104] R a 、R b are the same or different, each independently selected from carboxylic acid, -carboxylate-cation, phosphate, -phosphate-cation, sulfonic acid, -sulfonate-cation;

[0105] R', R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl;

[0106] x is selected from 1, 2, 3, 4 or 5;

[0107] v is each independently selected from 1, 2, 3, 4 or 5;

[0108] q is each independently selected from 1, 2, 3, 4, 5 or 6.

[0109] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein X C1 、X C2 are the same and are selected from O, S, -NH-. In certain embodiments, wherein X C1 、X C2 All are O.

[0110] In some embodiments, the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein each L is independently C 1-6 Alkylene.

[0111] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a benzene ring, a naphthalene ring, or an anthracene ring, preferably a naphthalene ring or anthracene ring.

[0112] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof,

[0113] in:

[0114] R D Each independently selected from a carboxylate group, a -carboxylate-cation, a phosphate group, a -phosphate-cation;

[0115] R E Each is independently selected from the group consisting of a carboxylate group, a -carboxylate-cation, a phosphate group, a -phosphate-cation, a sulfonic acid group, and a -sulfonate-cation;

[0116] r is selected from 1, 2, 3;

[0117] R C2 ,q,x,L 1 、L 2 、R a 、R b 、R c As defined above.

[0118] In some embodiments, the present disclosure provides a compound represented by formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, wherein L1 and L2 are the same or different and are each independently C 1-6 Alkylene.

[0119] In some embodiments, the present disclosure provides a compound of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, wherein R D Each is independently selected from a carboxylic acid group, a -carboxylate-cation.

[0120] In some embodiments, the present disclosure provides a compound of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, wherein R E Each is independently selected from a carboxylic acid group, a -carboxylate-cation, a sulfonic acid group, and a -sulfonate-cation.

[0121] In some embodiments, the present disclosure provides a compound of formula (III), formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, wherein R a 、R b The same or different, each independently selected from a carboxylic acid group, a -carboxylate-cation, a sulfonic acid group, a -sulfonate-cation.

[0122] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, which is selected from the compound of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or a pharmaceutically acceptable salt thereof,

[0123] in:

[0124] a are each independently selected from 1, 2, 3, and 4;

[0125] b is selected from 1, 2, 3, and 4;

[0126] c is selected from 1, 2, 3, 4;

[0127] A1 + or A2 + the same or different, each independently selected from a monovalent cation or a divalent cation;

[0128] When A1 + When it is a monovalent cation, s is 4;

[0129] When A1 + When it is a divalent cation, s is 2;

[0130] When A2 + When it is a monovalent cation, t is 8;

[0131] When A2 + When it is a divalent cation, t is 4;

[0132] R C2 , q, x, and r are as defined above.

[0133] In some embodiments, the present disclosure provides a compound of formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, wherein R C2 are each independently hydrogen.

[0134] In some embodiments, the present disclosure provides a compound of Formula (III), Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-D), Formula (III-A-1), Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), Formula (III-C-3), Formula (III-D-1), Formula (III-D-2) or Formula (III-D-3), or a pharmaceutically acceptable salt thereof, wherein x is selected from 2, 3 or 4. In certain embodiments, x is selected from 2 and 3. In certain embodiments, x is 2.

[0135] In some embodiments, the present disclosure provides compounds of Formula (III-A), (III-B), (III-C), (III-D), (III-A-1), (III-B-1), (III-B-2), (III-C-1), (III-C-2), (III-C-3), (III-D-1), (III-D-2), or (III-D-3), or pharmaceutically acceptable salts thereof, wherein q is independently selected from 2, 3, or 4. In certain embodiments, q is selected from 3 and 4. In certain embodiments, q is 3.

[0136] In some embodiments, the present disclosure provides a compound of formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, wherein r is selected from 2 or 3. In certain embodiments, r is 2.

[0137] In some embodiments, the present disclosure provides compounds of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3) or pharmaceutically acceptable salts thereof, wherein a, b, and c are the same or different and are each independently selected from 1, 2, or 3. Preferably, a, b, and c are all 1.

[0138] In some embodiments, the present disclosure provides a compound of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, wherein A1 + 、A2 + Each independently is a monovalent cation selected from H + 、Na + , K + 、H4N + 、Et3NH + 、(HOCH2CH2)3NH + Or ethylenediamine, piperazine, triphenylmethylaminomethane cationic form. In certain embodiments, the monovalent cation is selected from H + 、Na + or K + In certain embodiments, the monovalent cation is Na + .

[0139] In some embodiments, the present disclosure provides a compound of formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, wherein A1 + 、A2 + are each independently a divalent cation selected from the group consisting of Ca 2+ Mg 2+ or Zn 2+ .

[0140] In some embodiments, the present disclosure provides a compound represented by Formula (III), Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-D), Formula (III-A-1), Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), Formula (III-C-3), Formula (III-D-1), Formula (III-D-2) or Formula (III-D-3), or a pharmaceutically acceptable salt thereof, which is selected from:

[0141] Another aspect of the present disclosure provides a compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,

[0142] wherein X4 are each independently selected from O, S, and NH;

[0143] X5 is each independently selected from O, S, NH;

[0144] R 9A Each is independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, thiol, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl, and mercapto groups;

[0145] R 9B Each is independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, thiol, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl, and mercapto groups;

[0146] R 10 Each is independently selected from hydrogen, halogen, cyano, nitro, amino, carboxyl, thiol, C 1-6 Alkyl or C 1-6 Alkoxy, wherein the alkyl and alkoxy groups are optionally substituted with one or more halogen, cyano, nitro, amino, carboxyl, and mercapto groups;

[0147] h is independently selected from 1, 2, 3, and 4;

[0148] R 1A , d, e, f, g, and p are as defined above.

[0149] In some embodiments, X4 is simultaneously O. Alternatively, in some embodiments, X4 is simultaneously S. Alternatively, in some embodiments, X4 is simultaneously NH.

[0150] In some embodiments, X5 is simultaneously O. Alternatively, in some embodiments, X5 is simultaneously S. Alternatively, in some embodiments, X5 is simultaneously NH.

[0151] In some embodiments, the present disclosure provides a compound of formula (IV) or a pharmaceutically acceptable salt thereof, which is selected from a compound of formula (IV-A), formula (IV-B) or formula (IV-C) or a pharmaceutically acceptable salt thereof,

[0152] where R 9A 、R 9B 、R 10 , h, and p are as defined above.

[0153] In some embodiments, R 9A are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 In certain specific embodiments, R 9AEach is independently selected from hydrogen, methyl, ethyl, methoxy, and ethoxy.

[0154] In some embodiments, R 9B are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 In certain specific embodiments, R 9B Each is independently selected from hydrogen, methyl, ethyl, methoxy, and ethoxy.

[0155] In some embodiments, R 10 are each independently selected from hydrogen, C 1-6 Alkyl or C 1-6 In certain specific embodiments, R 10 Each is independently selected from hydrogen, methyl, ethyl, methoxy, and ethoxy.

[0156] In some embodiments, the present disclosure provides a compound represented by formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or a pharmaceutically acceptable salt thereof, which is selected from:

[0157] Another aspect of the present disclosure provides a method for preparing a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula (C) with a compound of formula (B) in an acidic environment.

[0158] Another aspect of the present disclosure provides a method for preparing a compound of formula (II-1) or a pharmaceutically acceptable salt thereof, comprising the steps of reacting a compound of formula (D) with a compound of formula (B) in an acidic environment.

[0159] The reagent for providing an acidic environment in the present disclosure may be an organic acid or an inorganic acid, such as trifluoroacetic acid.

[0160] On the other hand, the present disclosure provides a composition comprising a compound represented by Formula (I), (I-1), (II), (II-1), (II-2), (II-3), Formula (III), Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-D), Formula (III-A-1), Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), Formula (III-C-3), Formula (III-D-1), Formula (III-D-2) or Formula (III-D-3), or a pharmaceutically acceptable salt thereof, an isotopic substitute, and a pharmaceutically acceptable excipient.

[0161] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.

[0162] In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution. In certain embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compound or its pharmaceutically acceptable salt or its isotopic substitution.

[0163] In certain embodiments, the pharmaceutical composition comprises 0.01% to 99.99% of a pharmaceutically acceptable excipient, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition comprises 0.1% to 99.9% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 0.5% to 99.5% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 1% to 99% of a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition comprises 2% to 98% of a pharmaceutically acceptable excipient.

[0164] On the other hand, the present disclosure provides the use of the compounds represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or their pharmaceutically acceptable salts, isotopic substitutions, and compositions in the preparation of drugs for treating or preventing diseases or conditions, wherein the diseases or conditions are selected from proliferative diseases, blood cancers, cardiovascular-related diseases or infectious diseases.

[0165] On the other hand, the present disclosure provides a method for treating or preventing a disease or condition selected from a proliferative disease, a blood cancer, a cardiovascular-related disease or an infectious disease, by administering to a patient a compound represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or a pharmaceutically acceptable salt, isotope substituted product, or composition thereof.

[0166] On the other hand, the present disclosure provides the use of the compounds represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C) or their pharmaceutically acceptable salts, isotope-substituted products, and compositions in the preparation of drugs for reversing drug-induced neuromuscular blockade and / or anesthesia.

[0167] On the other hand, the present disclosure provides a method for reversing drug-induced neuromuscular blockade and / or anesthesia, by administering to a patient a compound represented by the above-mentioned formula (I), formula (I-1), formula (I-1-A), formula (I-1-B), formula (I-1-C), formula (I-1-D), formula (I-1-E), formula (II), formula (II-1), formula (II-2), formula (II-3), formula (III), formula (III-A), formula (III-B), formula (III-C), formula (III-D), formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2), formula (III-D-3), formula (IV), formula (IV-A), formula (IV-B) or formula (IV-C), or a pharmaceutically acceptable salt, isotope substituted product, or composition thereof.

[0168] The proliferative diseases described in the present disclosure are selected from fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, pseudomyxoma peritoneum, lymphangioendothelial sarcoma, synovioma, synovial sarcoma, colon sarcoma, mesothelioma, mesothelioma, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, head and neck cancer, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystic adenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma , liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonal carcinoma, Wells' tumor, cervical cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma, leukemia, lymphoma, multiple myeloma, thymoma, Waldenstrom's macroglobulinemia, and heavy chain disease.

[0169] The blood cancer described in the present disclosure is selected from the group consisting of leukemia, lymphoma and myeloma.

[0170] On the other hand, the present disclosure provides a compound represented by Formula (I), Formula (I-1), Formula (I-1-A), Formula (I-1-B), Formula (I-1-C), Formula (I-1-D), Formula (I-1-E), Formula (II), Formula (II-1), Formula (II-2), Formula (II-3), Formula (III), Formula (III-A), Formula (III-B), Formula (III-C), Formula (III-D), Formula (III-A-1), Formula (III-B-1), Formula (III-B-2), Formula (III-C-1), Formula (III-C-2), Formula (III-C-3), Formula (III-D-1), Formula (III-D-2), Formula (III-D-3), Formula (IV), Formula (IV-A), Formula (IV-B) or Formula (IV-C), or a pharmaceutically acceptable salt or isotope thereof, or the use of the compound prepared by the aforementioned method as a medicine.

[0171] The pharmaceutically acceptable salts of the compounds disclosed herein may be selected from inorganic salts or organic salts, the inorganic salts including but not limited to Na + , K + , Ca 2+ Mg 2+ 、Zn 2+ ; The organic salt includes but is not limited to H4N + 、Et3NH + 、(HOCH2CH2)3NH + or cationic forms of ethylenediamine, piperazine, or triphenylmethylaminomethane.

[0172] The compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. The present disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All of these isomers and their mixtures are included within the scope of the present disclosure. The compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure form or in racemic form. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

[0173] Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is typically accomplished using chromatography, which employs a chiral stationary phase and is optionally combined with a chemical derivatization method (e.g., carbamate formation from an amine).

[0174] In the chemical structures of the compounds disclosed herein, the bond Indicates that the configuration is not specified, that is, if chiral isomers exist in the chemical structure, the bond Can be or include both Two configurations.

[0175] Compounds and intermediates of the present disclosure can also exist in different tautomeric forms, and all such forms are included in the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also referred to as prototransfer tautomers) include interconversions via proton migration, such as keto-enol and imine-enamine, lactam-lactim isomerization. The lactam-lactim equilibrium example is between A and B as shown below.

[0176] All compounds in this disclosure can be drawn as either Form A or Form B. All tautomeric forms are within the scope of the present invention. The naming of the compounds does not exclude any tautomers.

[0177] The present disclosure also includes isotopically labeled compounds of the present disclosure that are identical to those described herein, but where one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 15 O. 17 O. 18 O. 31 P. 32 P. 35 S. 18 F. 123 I. 125 I and 36 Cl et al.

[0178] Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have at least 1000 times the abundance of deuterium greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10% deuterium incorporation). In the example, the compound has a natural abundance greater than deuterium that can be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times the abundance of deuterium, at least 6000 times the abundance of deuterium or more abundant deuterium. The disclosure also includes various deuterated forms of formula (I) compounds. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize deuterated forms of formula (I) compounds with reference to relevant literature. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds of formula (I), or they may be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0179] "Optionally" or "optionally" means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur. For example, "optionally substituted C 1-6The term "alkyl" means that halogen or cyano may but need not be present, and the description includes both the case where the alkyl is substituted by halogen or cyano and the case where the alkyl is not substituted by halogen and cyano.

[0180] Explanation of terms:

[0181] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredients and thereby exerting their biological activity.

[0182] "Pharmaceutically acceptable excipients" include, but are not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent or emulsifier approved by the U.S. Food and Drug Administration (FDA) for use by humans or domestic animals.

[0183] As used herein, an "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent the symptoms or conditions of a medical condition. An effective amount also refers to an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on factors such as the condition to be treated, the patient's overall health, the route and dosage of administration, and the severity of side effects. An effective amount can be the maximum dose or dosage regimen that avoids significant side effects or toxic effects.

[0184] The prefix "C u-v " indicates that the following group has from u to v carbon atoms. For example, "C 1-6 The term "alkyl" refers to an alkyl group having 1 to 6 carbon atoms, and specifically may be an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms.

[0185] The term "alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group has 1 to 20 carbon atoms (i.e., C 1-20 alkyl), 1 to 8 carbon atoms (i.e., C 1-8 alkyl), 1 to 6 carbon atoms (i.e., C 1-6 alkyl), or 1 to 4 carbon atoms (i.e., C 1-4Alkyl). Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl. When an alkyl residue having a specific number of carbon atoms is named by chemical name or determined by molecular formula, all isomers having that number of carbon atoms are included; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0186] The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic ring (including fused, bridged, and spirocyclic ring systems). The term "cycloalkyl" includes cycloalkenyl groups (i.e., the cyclic group has at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, cyclohexenyl, and cyclohexadienyl. The cycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, and the like.

[0187] The term "heterocyclyl" or "heterocycloalkyl" refers to a saturated or unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, sulfur and phosphorus. The term "heterocyclylalkane" includes heterocycloalkenyl (i.e., a heterocyclyl group having at least one double bond), bridged heterocyclyl, fused heterocyclyl and spiro-heterocyclyl. A heterocyclyl group can be monocyclic or polycyclic, wherein the polycyclic rings can be fused, bridged or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of connection (i.e., it can be bound by carbon atoms or heteroatoms). In addition, the term heterocyclyl is intended to include any non-aromatic ring containing at least one heteroatom, which ring can be fused to an aryl or heteroaryl ring, regardless of connection to the rest of the molecule. As used herein, the heterocyclyl group has 3 to 20 ring atoms (i.e., 3- to 20-membered heterocyclyl), 3 to 12 ring atoms (i.e., 3- to 12-membered heterocyclyl), 3 to 10 ring atoms (i.e., 3- to 10-membered heterocyclyl), 3 to 8 ring atoms (i.e., 3- to 8-membered heterocyclyl), 3 to 7 ring atoms (i.e., 3- to 7-membered heterocyclyl), 3 to 6 ring atoms (i.e., 3- to 6-membered heterocyclyl); 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, the ring heteroatoms being independently selected from nitrogen, sulfur, phosphorus, or oxygen. Examples of heterocyclic groups include pyrrolidinyl, imidazolidinyl, oxetanyl, dioxolanyl, azetidinyl, tetrahydrofuranyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl.

[0188] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12-membered, more preferably 5-membered or 6-membered. For example, non-limiting examples include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazine, etc.

[0189] The heteroaryl ring may be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0190] The term "alkoxy" refers to the group "alkyl-O-," wherein alkyl is as defined above. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0191] The term "haloalkyl" refers to an unbranched or branched alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. For example, when a residue is substituted with more than one halogen, it may be referred to using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl groups substituted with two or three halogen groups, which may be, but not necessarily, the same halogen. Examples of haloalkyl include difluoromethyl (-CHF2) and trifluoromethyl (-CF3).

[0192] The term "haloalkoxy" refers to an alkoxy group as defined above wherein one or more hydrogen atoms are replaced by a halogen.

[0193] The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxy groups, wherein alkyl is as defined above.

[0194] A "monovalent group" is a compound formed by formally eliminating a monovalent atom or group. A "subunit" is a compound formed by formally eliminating two monovalent or one divalent atom or group.

[0195] The term "alkylene" refers to the portion remaining after removing two hydrogen atoms from an alkane molecule, including straight and branched subgroups of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH2-), ethylene (such as -CH2CH2- or -CH(CH3)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted. Alkylene groups used in any context herein are optionally substituted in the same manner as alkyl groups.

[0196] The term "heteroalkylene" refers to an alkylene group in which one or more -CH2- atoms are replaced by a heteroatom selected from N, O, and S; wherein the alkylene group is as defined above; the heteroalkylene group may be substituted or unsubstituted. Unless otherwise specified, the heteroalkylene group may be substituted or unsubstituted. As used herein, heteroalkylene groups are optionally substituted in the same manner as alkyl groups.

[0197] The term "hydroxy" refers to an -OH group.

[0198] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0199] The term "cyano" refers to -CN.

[0200] The term "nitro" refers to -NO2.

[0201] The term "oxo" refers to a =0 substituent.

[0202] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) whether substitution is possible or not without undue effort. BRIEF DESCRIPTION OF THE DRAWINGS

[0203] Figure 1. Comparison of TOF0.9 after cisatracurium antagonism and antagonist administration;

[0204] Figure 2. Comparison of TOF0.9 of compounds at 20 mpk. * represents p = 0.05;

[0205] Figure 3. TOF0.9 time of cisatracurium administration and muscle relaxant antagonist, where *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION

[0206] The present disclosure is further described below with reference to embodiments, but these embodiments do not limit the scope of the present disclosure.

[0207] Experimental methods in the examples disclosed herein that do not specify specific conditions are generally performed under conventional conditions or according to the conditions recommended by the raw material or product manufacturers. Reagents that do not specify their specific sources are conventional reagents purchased from the market.

[0208] The structures of the compounds were determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). -6 The unit of ppm is given. NMR measurements were performed using a Bruker AVANCE-400 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), deuterated methanol (CD3OD), and tetramethylsilane (TMS) as the internal standard.

[0209] MS was measured using a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer.

[0210] HPLC determination was performed using a Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200LC high-pressure liquid chromatograph (Ultimate XB-C18 3.0*150 mm column or Xtimate C18 2.1*30 mm column).

[0211] Chiral HPLC analysis was performed using Chiralpak IC-3 100×4.6mm ID, 3um, Chiralpak AD-3 150×4.6mm ID, 3um, Chiralpak AD-3 50×4.6mm ID, 3um, Chiralpak AS-3 150×4.6mm ID, 3um, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3um, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5um, Chiralcel OJ-3 150×4.6mm ID, 3um columns;

[0212] The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm~0.2mm, and the specification used for thin layer chromatography separation and purification products is 0.4mm~0.5mm.

[0213] Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.

[0214] The chiral preparative column used was DAICEL CHIRALPAK IC (250 mm*30 mm, 10 um) or Phenomenex-Amylose-1 (250 mm*30 mm, 5 um).

[0215] The CombiFlash rapid preparation instrument used was Combiflash Rf150 (TELEDYNE ISCO).

[0216] The known starting materials disclosed herein can be synthesized by methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc, Darui Chemicals, and other companies.

[0217] Unless otherwise specified in the examples, all reactions can be carried out under an argon atmosphere or a nitrogen atmosphere.

[0218] Argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a capacity of about 1 L.

[0219] Hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.

[0220] The pressurized hydrogenation reaction uses a Parr 3916EKX hydrogenator and a Qinglan QL-500 hydrogen generator or an HC2-SS hydrogenator.

[0221] The hydrogenation reaction is usually carried out by evacuating the chamber and filling it with hydrogen, and the operation is repeated three times.

[0222] A CEM Discover-S 908860 microwave reactor was used for the microwave reaction.

[0223] Unless otherwise specified in the examples, the solution refers to an aqueous solution.

[0224] Unless otherwise specified in the examples, the reaction temperature is room temperature, 20°C to 30°C.

[0225] The reaction progress in the examples was monitored by thin layer chromatography (TLC). The developing solvent used in the reaction, the column chromatography eluent system used to purify the compound, and the developing solvent system for thin layer chromatography, the volume ratio of the solvent were adjusted according to the polarity of the compound, and a small amount of alkaline or acidic reagents such as triethylamine and acetic acid could be added for adjustment.

[0226] Example 1. Preparation of Compound 2

[0227] Step 1: To a 500 mL three-necked flask, add urea (38.89 g, 647.46 mmol), 0.3 M dilute hydrochloric acid (80 mL), and 1,2-cyclohexanedione 2a (22.0 g, 196.20 mmol). Heat to 50°C and stir for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 100 mL of water and 100 mL of anhydrous ethanol and dried to obtain compound 2b (pale yellow solid, 27.4 g, yield: 71%).

[0228] MS m / z(ESI):197.1[M+1] + .

[0229] 1 H NMR (400MHz, DMSO-d6): δ7.02(s,4H),1.72-1.68(m,4H),1.42-1.35(m,4H).

[0230] Step 2: To a 1-L three-necked flask, compound 2b (27.4 g, 139.65 mmol), 140 mL of 9 M hydrochloric acid, and paraformaldehyde (20.9 g, 698.23 mmol) were added. The reaction solution was stirred at room temperature for 24 hours. 500 mL of water was added to the reaction system, and stirring was continued at room temperature for 16 hours. The reaction solution was filtered, washed, and dried to obtain compound 2c (white solid, 20.2 g, yield: 52%).

[0231] MS(ESI):281.1[M+1] + .

[0232] 1 H NMR (400MHz, DMSO-d6): δ5.20(d,4H,J=11.6), 4.91(d,4H,J=11.2), 2.25-2.18(m,4H), 1.56-1.50(m,4H).

[0233] Step 3: Compound 2c (2.73 g, 9.73 mmol) was weighed into a dry three-necked flask, the atmosphere was replaced with argon, and methanesulfonic acid (10 mL) was added to dissolve the mixture. Compound 1a (1 g, 3.24 mmol, prepared using the known method of WO2012 / 051407A) was added and stirred at room temperature for 24 hours. The reaction mixture was slowly added to 100 mL of water (cooled in an ice-water bath) and allowed to return to room temperature. Filter and dry to obtain 1.77 g of the crude product. This crude product was dissolved in 4 mL of TFA with heating, followed by the addition of 16 mL of water, stirring, filtering, and vacuum drying to obtain compound 2d (1.21 g, 44.9% yield).

[0234] MS(ESI):837.3[M+1] + .

[0235] 1 H NMR (400MHz, CDCl3): δ5.72~5.37(m,10H),5.15(d,4H),4.75(d,4H),4.15~4.11(m,6H),2.28(br,4H),2.05(br,4H),1.45(br,8H).

[0236] Step 4: Compound 2d (1.06 g, 1.27 mmol) was weighed into a dry three-necked flask. The atmosphere was replaced with argon, and TFA (10 mL) was added to dissolve the mixture. Compound 1b (1.42 g, 3.17 mmol, prepared according to the known method of WO2012 / 051407A) was then added. After the addition, the reaction mixture was heated to 60°C and stirred for 3 hours. The TFA was evaporated under reduced pressure, and 20 mL of ethanol was added to the resulting solid, which was heated under reflux for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The resulting solid was dissolved in 10 mL of water by heating, followed by the addition of 30 mL of ethanol and filtration. The filter cake was then purified by HPLC (SharpSil-T column, 30 x 150 mm, 5 μm; mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25% to 42%). Finally, the salt was formed with sodium hydroxide to afford compound 2 (0.27 g, yield: 12.6%).

[0237] MS m / z(ESI):1605.2[M-4Na+5H] + .

[0238] 1 H NMR (400MHz, D2O): δ7.68~7.65(m,4H),7.07~7.05(m,4H),5.50~5.45(m,6H),5.26~5.16(m,8H),4 .39(d,4H),4.17~4.05(m,8H),3.94~3.82(m,6H),3.20~3.04(m,8H),2.26~2.07(m,16H),1.46(br s,8H).

[0239] Example 2. Preparation of Compound 3

[0240] Step 1: Urea (12 g, 0.2 mol) was dissolved in 0.3 M HCl (30 mL), and compound 3a (6.97 g, 0.061 mol) was added at room temperature, followed by stirring at room temperature for 24 hours; filtered, washed, and dried to obtain the title product 3b (6.8 g, yield: 56.2%).

[0241] Step 2: Substrate 3b (3.4 g, 17.2 mmol) was weighed into a dry three-necked flask, and 2.54 g of paraformaldehyde and 9 M HCl (15 mL) were added. The mixture was stirred at room temperature for 24 h. The reaction was continued to stir at room temperature for 24 h, filtered, washed, and dried to obtain the title product 3c (2.1 g, yield: 43.2%).

[0242] MS m / z(ESI):283.1[M+1]+.

[0243] 1 H NMR (400MHz, DMSO-d6): δ5.21(d,4H), 4.93(d,4H), 2.33(q,4H), 0.91(d,6H).

[0244] Step 3: Dissolve compound 3c (2.75 g, 9.73 mmol) in methanesulfonic acid (10 mL), add compound 1a (1 g, 3.24 mmol), and stir at room temperature for 18 hours. Slowly add the reaction solution to 100 mL of water (cooled in an ice-water bath) and return to room temperature after addition. Filter and dry to obtain 1.67 g of crude product. This crude product was dissolved in TFA (4 mL) with heating, followed by the addition of 16 mL of water. Stir, filter, and dry in vacuo to obtain the title product 3d (off-white solid, 1.56 g, yield: 57.3%).

[0245] MS m / z(ESI):833.2[M+1]+.

[0246] 1 H NMR (400MHz, DMSO-d6): δ5.68(d,2H),5.53(t,6H),5.38(d,2H),5.15(d,4H),4.77( d,4H), 4.20~4.15(m,6H), 2.35~2.32(m,4H), 2.20~2.15(m,4H), 0.88~0.80(m,12H).

[0247] Step 4: 3d (0.89 g, 1.06 mmol) was weighed into a dry three-necked flask. The atmosphere was replaced with argon. TFA (10 mL) was added to dissolve the compound. Compound 1b (1.19 g, 2.66 mmol) was then added. The reaction mixture was heated to 70°C with stirring for 3 hours. The TFA was evaporated under reduced pressure. 20 mL of ethanol was added to the resulting solid, which was heated under reflux for 2 hours. The mixture was cooled to room temperature, filtered, and dried. The resulting solid was dissolved in 6.6 mL of water by heating. 19.8 mL of ethanol was then added, filtered, washed, and the filter cake was purified by HPLC (SharpSil-T column, 30 x 150 mm, 5 μm; mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25% to 42%). The title product 3 (0.28 g, yield: 15.5%) was obtained by salification with sodium hydroxide.

[0248] MS (ESI): 1607.4 [M-4Na+3H] - .

[0249] 1H NMR (400MHz, D2O): δ7.41~7.39(m,4H),6.81~6.80(m,4H),5.46(d,4H),5.38(d,2H),5.30(d,4H),5.20(d,2H),5.08(d,2 H), 4.38(d,4H), 4.09~4.01(m,8H), 3.84~3.76(m,6H), 3.19~3.02(m,8H), 2.36~2.18(m,16H), 0.88(t,6H), 0.82(t,6H).

[0250] Example 3. Preparation of Compound 1

[0251] Example 4. Preparation of Compound 4

[0252] Example 5. Preparation of Compound 5

[0253] Example 6. Preparation of Compound 6

[0254] Example 7. Preparation of Compound 7

[0255] Example 8. Preparation of Compound 8

[0256] Example 9. Preparation of Compound 9

[0257] Example 10. Preparation of Compound 10

[0258] Example 11. Preparation of Compound 11

[0259] Step 1: Dissolve 1,4-dihydroxynaphthalene (1 g, 6.24 mmol) in 10% aqueous NaOH (8 mL). After nitrogen replacement, add a solution of compound 11a (2.14 g, 15.6 mmol) in dioxane (12 mL) dropwise. Stir the reaction mixture at room temperature overnight. The reaction mixture was dried and purified by reverse phase preparative purification to afford compound 11b (0.8 g, 26% yield) as a white solid.

[0260] MS m / z(ESI):433.1[M-2Na+3H] + .

[0261] 1H NMR (400MHz, DMSO-d6): δ8.12~8.10(m,2H),7.53~7.51(m,2H),6.84(s,2H),4.07(t,4H),2.55~2.49(m,4H),1.91~1.79(m,8H).

[0262] Step 2: Compound 11b (520 mg, 1.09 mmol) was dissolved in TFA (10 mL), followed by the addition of compound 2d (364 mg, 0.44 mmol). After complete addition, the reaction system was heated to 70°C with stirring for 2 hours. The TFA was evaporated under reduced pressure, and the resulting solid was purified by column chromatography (SharpSil-T, 30×150 mm, 5 μm; mobile phase: water and acetonitrile, gradient ratio: water 25%-42%) to afford 192 mg of a white solid. This solid was dissolved in 2 mL of water, and the pH was adjusted to 5-8 with 0.5 M sodium hydroxide solution. 10 mL of ethanol was added to precipitate the solid, which was then filtered to afford compound 11 (120 mg, 16.5% yield) as a white solid.

[0263] MS m / z(ESI):1678.3[(M-4Na+4H+18)] + .

[0264] 1 H NMR (400MHz, D2O): δ7.87~7.81(m,4H),7.44~7.36(m,4H),5.53~5.46(m,7H),5.31~5.23(m,9H),4.30( d,3H),4.12~3.94(m,9H),3.78~3.76(m,4H),2.87~2.82(m,8H),2.05~1.80(m,24H),1.38~1.25(m,8H).

[0265] Example 12. Preparation of Compound 12

[0266] Step 1: Compound 12a (10.85 g, 51.6 mmol, prepared using the same method as for compound 2b in Example 1) was weighed into a dry three-necked flask. 7.75 g of paraformaldehyde and 45 mL of 9M HCl were added and stirred at room temperature for 24 hours. 163 mL of water was added and the reaction was stirred at room temperature for another 24 hours. The mixture was filtered, and the filter cake was washed with water (60 mL) and ethanol (60 mL), and dried to afford 10.84 g of compound 12b as an off-white solid (yield: 71.4%).

[0267] MS m / z(ESI):295.1[M+1] + .

[0268] 1 H NMR (400MHz, DMSO-d6): δ5.21(d,4H,J=11.3Hz), 4.93(d,4H,J=11.3Hz), 2.34(br,4H), 1.48(br,6H).

[0269] Step 2: Compound 12b (2.00 g, 6.80 mmol) was weighed into a dry three-necked flask, the atmosphere was replaced with argon, and methanesulfonic acid (7 mL) was added to dissolve the mixture. Compound 1a (0.70 g, 2.27 mmol, prepared using the known method of WO2012 / 051407A2) was added at room temperature (23°C). After stirring at room temperature for 18 hours, the reaction mixture was slowly added to 70 mL of water (cooled in an ice-water bath) and allowed to return to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. Drying afforded 1.97 g of crude product. The crude product was dissolved in TFA (6 mL, 23°C), followed by the addition of 24 mL of water and stirring at 23°C for 30 minutes. The mixture was filtered, the filter cake was washed with a small amount of water, and vacuum dried to afford 1.75 g of an off-white solid, Compound 12c (yield: 81.7%).

[0270] MS m / z(ESI):861.3[M+1] + .

[0271] 1 H NMR (400MHz, DMSO-d6): δ5.50~5.41(m,10H),5.16(d,4H,J=10.7Hz), 4.76(d,4H , J=10.6Hz), 4.22~4.15(m,6H), 2.40(br,4H), 2.22(br,4H), 1.45~1.26(m,12H).

[0272] Step 3: Compound 12c (1.00 g, 1.16 mmol) was weighed into a dry three-necked flask, the argon atmosphere was replaced, and TFA (10 mL) was added to dissolve the mixture. Compound 1b was then added. After the addition was complete, the reaction was heated to 60°C and stirred for 3 hours. The TFA was evaporated under reduced pressure, and 20 mL of ethanol was added to the resulting solid, which was heated under reflux for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The resulting solid was purified by HPLC (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25%-42%) and finally salted with sodium hydroxide to yield 0.12 g of compound 12 as a white solid.

[0273] MS m / z(ESI):1649.1[M-4Na+4H+NH4] + .

[0274] 1H NMR (400MHz, D2O): δ8.04(br,4H),7.64(br,4H),5.68~5.59(m,7H),5.42~5.39(m,4H),5.30~5.26(m,4H),4.44~ 4.39(m,3H),4.22~4.07(m,10H),3.93~3.91(m,4H),3.28~3.13(m,8H),2.44~2.22(m,16H),1.61~1.34(m,12H).

[0275] Example 13. Preparation of Compound 13

[0276] Step 1: Add DMSO (50 mL) and KOH (8.75 g, 156 mmol) to a three-necked flask. Ultrasonicate the mixture to disperse the KOH in the DMSO. Then, displace the air with nitrogen and stir at room temperature for one hour. Compound 13a (5 g, 31.25 mmol) and compound 13b (24.3 g, 125 mmol) were slowly added to the reaction mixture. Heat the reaction mixture to 60°C and stir for 2 hours. After cooling to room temperature, add 200 mL of water and extract with dichloromethane (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain 4.56 g of compound 13c as a red solid (yield: 38%).

[0277] MS m / z(ESI):389.2[M+1] + .

[0278] 1 H NMR (400MHz, CDCl3): δ8.20(q,2H),7.49(q,2H),6.67(s,2H),4.18-4.12(m,8H),2.61(t,4H),2.27-2.20(m,4H),1.25(t,6H).

[0279] Step 2: Compound 13c (3.50 g, 9.02 mmol) was weighed into a dry three-necked flask, the atmosphere was replaced with nitrogen, and TFA (20 mL) was added to dissolve the mixture. Compound 2d (3.00 g, 3.61 mmol) and acetic anhydride (918 mg, 9.02 mmol) were then added. After the additions were complete, the reaction mixture was heated to 70°C and stirred for 4 hours. The TFA was evaporated under reduced pressure, and 50 mL of methyl tert-butyl ether was added to the resulting solid. The mixture was heated to 50°C and stirred for half an hour. The mixture was cooled to room temperature and filtered. The filter cake was washed with methyl tert-butyl ether and dried to yield 4.2 g of compound 13d as a brown solid.

[0280] MS m / z(ESI):1590.3[M+18] + .

[0281] Step 3: Compound 13d (2.0 g, 1.27 mmol) was added to a 50 mL single-necked bottle, methanol and water (1:1, 30 mL), LiOH . H2O (534 mg, 12.7 mmol) was added to dissolve it. After the addition, the reaction was heated to 80°C and stirred for 3 hours. The solvent was evaporated under reduced pressure, and ethanol and water (10:1, 20 mL) were added and stirred at room temperature for half an hour, and filtered. The filter cake was washed with ethanol and dried. The obtained solid was dissolved with water and NaOH (1 M), then purified by high performance liquid chromatography (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25%-42%), and finally salified with sodium hydroxide to obtain 114 mg of white solid compound 14 (yield: 6.15%).

[0282] MS m / z(ESI):1478.2[M-4Na+4H+NH4] + .

[0283] 1 H NMR (400MHz, D2O): δ7.87(br,4H),7.46(br,4H),5.55~5.44(m,6H),5.29~5.1 3(m,8H),4.20-3.92(m,14H),3.69(br,4H),2.19~1.90(m,24H),1.34(br,8H).

[0284] Example 14. Preparation of Compound 14

[0285] Step 1: Compound E1 (25 g, 96 mmol) and anhydrous THF (70 mL) were added to a three-necked flask. The atmosphere was replaced with nitrogen and the mixture was cooled to -78°C in a dry ice-acetone bath. DIBAL-H (135 mL, 202 mmol, 1.5 M in toluene) was then slowly added dropwise. After completion of the dropwise addition, the temperature was raised to 0°C and the reaction was stirred at 0°C for 45 minutes. The reaction was then quenched by the dropwise addition of 1 M HCl (500 mL) at 0°C. 200 mL of ethyl acetate was added and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine (100 mL), dried, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (PE:EA = 5:1) to afford 15.8 g of Compound E2 as a pale yellow oil (yield: 71.5%).

[0286] 1H NMR (400MHz, CDCl3): δ3.77-3.75(m,2H), 3.62-3.53(m,4H), 2.46(br,1H), 2.29-2.22(m,1H).

[0287] Step 2: Compound E2 (7 g, 30.4 mmol), compound 13a (1.62 g, 10.1 mmol), and MeSO₃H (1.4 mL) were weighed into a dry three-necked flask. The atmosphere was replaced with nitrogen and the reaction mixture was heated to 100°C with stirring for 3 hours. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed sequentially with NaHCO₃ solution and saturated brine, dried, filtered, and the solvent was evaporated to dryness. The crude product was purified by column chromatography (PE:EA = 50:1) to obtain 2.74 g of compound E3 as a pale yellow solid (yield: 46%).

[0288] 1 H NMR (400MHz, CDCl3): δ8.16(q,2H),7.54(q,2H),6.74(s,2H),4.23(d,4H),3.81-3.71(m,8H),2.73-2.70(m,2H).

[0289] Step 3: Compound E3 (5.0 g, 8.56 mmol) was weighed into a dry, one-necked flask. The atmosphere was replaced with nitrogen. DMSO (60 mL) was added to dissolve the mixture, followed by the addition of NaCN (4.2 g, 85.6 mmol). After the addition, the reaction mixture was heated to 75°C and stirred for 1 hour. The reaction mixture was poured into ice water, whereupon a large amount of solid precipitated. This solid was filtered. Ethyl acetate was added to the resulting solid, stirred at room temperature for half an hour, filtered, and dried to yield 2.33 g of Compound E as a white solid (yield: 73.5%).

[0290] MS m / z(ESI):390[M+18] + .

[0291] Step 4: Compound E (2.1 g, 5.64 mmol) was weighed into a sealed tube. HCl / EtOH (75 mL, 10 M) was added. If the solution did not dissolve completely, the reaction mixture was heated to 90°C and stirred for 24 hours. The solvent was evaporated to dryness. The crude product was purified by column chromatography (PE:EA = 5:1) to afford 1.08 g of compound 14a as a colorless oil (yield: 34.2%).

[0292] MS m / z(ESI):561[M+1] + .

[0293] 1H NMR (400MHz, CDCl3): δ8.16(q,2H), 7.50(q,2H), 6.67(s,2H), 4.16-4.11(m,12H), 3.00-2.95(m,2H), 2.72-2.54(m,8H), 1.23(t,12H).

[0294] Step 5: Compound 14a (1.4 g, 2.50 mmol) was weighed into a dry three-necked flask, the atmosphere was replaced with nitrogen, and TFA (5 mL) was added to dissolve the mixture. Compound 2d (520 mg, 0.625 mmol) and acetic anhydride (5 mL) were then added. After the additions were complete, the reaction mixture was heated to 90°C and stirred for 4 hours. The TFA was evaporated under reduced pressure, and 50 mL of methyl tert-butyl ether was added to the resulting solid. The mixture was heated to 50°C and stirred for half an hour. The mixture was cooled to room temperature and filtered. The filter cake was washed with methyl tert-butyl ether and dried to yield 1.2 g of a brown solid. The resulting solid was dissolved in acetonitrile. The mixture was then purified by HPLC (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25%-42%) to yield 170 mg of compound 14b as a white solid (yield: 3.55%).

[0295] MS m / z(ESI):1934[M+18] + .

[0296] Step 6: Compound 14b (150 mg, 0.078 mmol) was weighed into a 25 mL single-necked bottle and methanol and water (1:1, 10 mL) were added until it could not dissolve. Then, LiOH was added. . H2O (534 mg, 12.7 mmol). After addition, the reaction mixture was heated to 80°C and stirred for 3 hours. The reaction solution was purified by HPLC (mobile phase: water and acetonitrile, gradient ratio: water 25%-42%) and finally salted with sodium hydroxide to obtain 53 mg of compound 14 as a white solid (yield: 40%).

[0297] MS m / z(ESI):1710[M-8Na+8H+NH4] + .

[0298] 1 H NMR (400MHz, D2O): δ7.80-7.97(m,4H),7.39-7.38(m,4H),5.50-5.46(m,6H),5.34(s,4H),4.96(d,4H),4.50(d,4H), 4.11-3.95(m,10H),3.69-3.67(m,4H),2.69-2.47(m,12H),2.37-2.32(m,8H),2.18(s,4H),1.94(s,4H),1.44(s,8H).

[0299] Example 15. Preparation of Compound 15

[0300] Step 1: Compound E3 (2.25 g, 3.83 mmol) and sodium sulfite (4.91 g, 38.9 mmol) were added to a three-necked flask. The air was replaced with nitrogen, followed by the addition of 42 mL of isopropanol and 42 mL of water. The reaction mixture was heated to 100°C and stirred for 24 hours. The reaction mixture was cooled to room temperature and concentrated to obtain the crude product. 83 mL of methanol was then added, and the mixture was stirred for 1 hour. The resulting solid was collected by filtration and submitted to HPLC to yield 1.62 g of compound 15a as a white solid (yield: 64%).

[0301] MS m / z(ESI):331.8[M / 2+1] + .

[0302] 1 H NMR (400MHz, D2O): δ8.23~8.22(m,2H), 8.57~7.55(m,2H), 6.90~6.88(m,2H), 4.40~4.39(m,4H), 3.33~3.31(m,8H), 2.94~2.92(m,2H).

[0303] Step 2: Compound 15a (1.57 g, 2.37 mmol) was weighed into a dry three-necked flask. The atmosphere was replaced with argon. TFA (15 mL) was added to dissolve the mixture, followed by the addition of compound 2d (0.79 g, 0.95 mmol). After complete addition, the reaction was heated to 70°C with stirring for 3 hours. The TFA was evaporated under reduced pressure, and 40 mL of ethanol was added to the resulting solid, which was heated under reflux for 2 hours. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The resulting solid was dissolved in 12 mL of water, and the pH was adjusted to approximately 7 with 1 M sodium hydroxide solution. 50 mL of ethanol was added to allow a viscous solution to precipitate. The supernatant was discarded, and the residue was spin-dried to dryness. The mixture was then purified by HPLC (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25%-42%). Finally, the mixture was salted with sodium hydroxide to afford 299 mg of compound 15 as a white solid (yield: 12%).

[0304] MS m / z(ESI):990.6[(M-8Na+8H) / 2] + .

[0305] 1H NMR (400MHz, D2O): δ7.96~7.93(m,4H), 7.32~7.33(m,4H), 5.57~5.44(m,6H), 5.35~5.31(m,4H), 5.09~5.05(m,4H), 4.54~4.50(m,4H), 4.27~4.23(m,4H),4.10~4.01(m,10H),3.52~3.31(m,16H),2.98~2.92(m,4H),2.19~2.17(m,4H),2.01~1.98(m,4H),1.47~1.45(m,8H).

[0306] Example 16. Preparation of Compound 16

[0307] Step 1: Dissolve 1,4-dihydroxynaphthalene (2.00 g, 12.49 mmol), 1,2-dibromoethane (23.46 g, 124.87 mmol, 10.76 mL), and 18-crown-6 (165.02 mg, 624.34 μmol) in acetonitrile (40 mL). The reaction mixture was purged with nitrogen three times and heated to 70°C for two days. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated to obtain the crude product, which was then purified by column chromatography (PE:PA = 50:1) to afford compound 16a (1.6 g, 34.25% yield).

[0308] 1 H NMR (400MHz, CDCl3): δ8.27~8.25(m,2H), 7.55~7.52(m,2H), 6.69(s,2H), 4.42(t,4H), 3.76(t,4H).

[0309] Step 2: Compound 16a (800 mg, 2.14 mmol) and sodium sulfite (593 mg, 4.70 mmol) were added to a three-necked flask. The air was replaced with nitrogen, and then 6 mL of DMF and 6 mL of water were added. The reaction was heated to 100°C and stirred for 24 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was poured into 60 mL of acetone. A precipitate was precipitated, which was filtered to obtain 880 mg of a light yellow solid. The crude product was dissolved in 2 mL of water, and ethanol (10 mL) was slowly added dropwise. A large amount of solid precipitated. The solid was filtered and drained to obtain 570 mg of compound 16b as a white solid (yield: 63%).

[0310] MS m / z(ESI):393.8[M-2Na+2H+18] + .

[0311] Step 3: Compound 16b (570 mg, 1.36 mmol) was weighed into a dry three-necked flask. The atmosphere was replaced with argon. TFA / AcO (1:1, 10 mL) was added to dissolve the mixture, followed by the addition of compound 2d (452 ​​mg, 0.54 mmol). After complete addition, the reaction mixture was heated to 70°C and stirred for 2 hours. The mixture was concentrated under reduced pressure and purified by column chromatography (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25%-42%) to afford 157 mg of a white solid. This was dissolved in 2 mL of water, and the pH was adjusted to approximately 7 with 0.5 M sodium hydroxide solution. 10 mL of ethanol was added, and the mixture was filtered to afford 116 mg of compound 16 as a white solid (yield: 13.8%).

[0312] MS m / z(ESI):774.4[M / 2-4Na+5H] + .

[0313] 1 H NMR (400MHz, D2O): δ7.76~7.74(m,4H),7.01~6.99(m,4H),5.52~5.46(m, 6H),5.29~5.17(m,8H),4.48-4.36(m,8H),4.18~4.06(m,8H),3.95(d,2H),3.46(t,8H),2.15~2.07(m,8H),1.52~1.39(m,8H).

[0314] Example 17. Preparation of Compound 17

[0315] Step 1: Zinc powder (3.720 g, 56.9 mmol) and acetic acid (20 mL) were added sequentially to a 100 mL three-necked flask. The atmosphere was replaced with nitrogen three times, followed by the addition of compound 17a (0.980 g, 5.69 mmol) all at once. Stir at room temperature for 5-10 minutes. When the central control panel indicated completion of the reaction, the reaction mixture was filtered, the filter cake rinsed with 15 mL of acetic acid, and the filtrate concentrated under reduced pressure. The resulting solid was dissolved in 50 mL of ethyl acetate, washed with 20 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 0.982 g of compound 17b (yield: 99%, purity: 95.8%).

[0316] MS-ESI: m / z 175.1[M+H] + .

[0317] Step 2: Sodium hydroxide (0.370 g, 9.24 mmol) and water (3.3 mL) were added sequentially to a 50 mL three-necked flask. The atmosphere was replaced with nitrogen three times. After stirring and dissolution, compound 17b (0.7 g, 4.02 mmol) was added and cooled in an ice-water bath. A solution of 1,3-propane sultone (1.030 g, 9.24 mmol) in dioxane (8.4 mL) was then added dropwise. After returning to room temperature, stirring was continued for 19 h. The central control indicated that the starting material had reacted completely. The reaction mixture was filtered, and the filter cake was rinsed sequentially with a dioxane / water (5 mL / 1 mL) mixture and then with dioxane (5 mL). The filter cake was then concentrated with toluene (15 mL x 3) to obtain 0.830 g of compound 17c (yield: 44.6%, purity: 99.7%).

[0318] MS-ESI: m / z 418.9[M-2Na+3H] + .

[0319] 1 H NMR (400MHz, D2O): δ8.01(d,J=8.4Hz,1H),7.89(s,1H),7.37-7.35(m, 1H),6.80-6.73(m,2H),4.16-4.13(m,4H),3.10-3.06(m,4H),2.42(s,3H)2.25-2.17(m,4H).

[0320] Step 3: Compound 17c (0.416 g, 0.9 mmol), TFA (6 mL), and compound 2d (0.3 g, 0.36 mmol) were added sequentially to a 50 mL single-necked flask. The atmosphere was replaced with nitrogen three times, and the mixture was heated in an oil bath to 70°C for 3 h. The reaction was stopped when the central control panel indicated completion. The reaction mixture was cooled to room temperature and concentrated to a solid. 15 mL of ethanol was added and stirred for 10 min. The solid was filtered, and the filter cake was rinsed with 10 mL of ethanol to obtain 822 mg of crude compound 17d (yield: 35.7%, purity: 97.7%).

[0321] MS-ESI: m / z 1650.4[M+18] + .

[0322] Step 4: Compound 17d (0.210 g, 0.128 mmol) and THF (4 mL) were added sequentially to a 100 mL single-necked flask. The pH of the solution was adjusted to 7 with 0.5 N aqueous sodium hydroxide solution. Ethanol (12 mL) was then added dropwise to precipitate a solid. The solid was filtered, and the filter cake was rinsed with ethanol (5 mL). The resulting filter cake was lyophilized to obtain 0.153 g of compound 17 (yield: 69.2%, purity: 98.02%).

[0323] MS-ESI: m / z 1650.3[M-4Na+18] + .

[0324] 1 H NMR (400MHz, DMSO-d6): δ7.78-7.71(m,4H),7.53-7.52(m,2H),5.59-5.24(m,14H) ),4.33-3.72(m,18H),2.78-2.62(m,14H),2.44-1.86(m,17H),1.46-1.23(m,9H).

[0325] Example 18. Preparation of Compound 18

[0326] Step 1: Compound 18a (338 mg, 3.43 mmol, prepared by a known method, Journal of the American Chemical Society, 1996, vol. 118, #34, pp. 7946–7968) was added to 2 mL of tert-butanol and stirred to dissolve. N-methylmorpholine oxide (803.4 mg, 6.86 mmol) and potassium osmate dihydrate (25.3 mg, 68.6 μmol) were then added. The mixture was allowed to react at room temperature for 16 hours until the central control panel indicated completion. The reaction was quenched by the addition of 5 mL of aqueous sodium sulfite solution. The mixture was extracted with ethyl acetate (20 mL x 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was isolated by column chromatography (PE:EA = 1:1) to afford 197 mg of compound 18b (yield: 40%).

[0327] 1 H NMR (400MHz, CDCl3): δ3.83(s,2H), 2.89(s,2H), 1.97~1.90(m,2H), 1.77~1.72(m,2H), 1.51~1.45(m,2H), 0.87~0.82(m,6H).

[0328] Step 2: DMSO (12.22 g, 156.41 mmol) and DCM (310 mL) were added to a 500 mL three-necked reaction flask. Under nitrogen protection, the temperature was lowered to -60°C, and trifluoroacetic anhydride (29.15 g, 138.77 mmol) was added dropwise. The addition was completed over about 25 minutes. After stirring for 20 minutes, a solution of compound 18b (5.1 g, 35.36 mmol) in DCM (15 mL) was added. After stirring for 1.5 hours, triethylamine (32.67 g, 322.86 mmol) was added. After stirring at -60°C for 1 hour, the mixture was heated to room temperature and stirred. The central control panel indicated that the reaction was complete. 324 mL of 10% hydrochloric acid was added to the reaction system, and the layers were separated. The aqueous phase was extracted with DCM (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was separated by column chromatography (PE:EA = 10:1) to obtain 3.715 g of compound 18c (yield: 75%).

[0329] MS m / z(ESI):141.1[M+H] + .

[0330] 1 H NMR (400MHz, CDCl3): δ6.06(d,1H),5.90(s,1H),2.65-2.57(m,1H),2.47-2.34(m,3H),1.06(d,3H),1.00(d,3H).

[0331] Step 3: To a 100 mL reaction flask, add urea (5.25 g, 87.35 mmol), 0.3 M dilute hydrochloric acid (13.4 mL), and compound 18c (3.71 g, 26.47 mmol). Heat to 50°C and stir for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 10 mL of water and 12 mL of anhydrous ethanol and dried to afford 2.34 g of compound 18d (yield: 39%).

[0332] MS m / z(ESI):225.1[M+H] + .

[0333] 1 H NMR (400MHz, DMSO-d6): δ7.10(s,2H),7.02(s,2H),1.75-1.71(m,4H),1.57-1.51(m,2H),0.84(s,3H),0.82(s,3H).

[0334] Step 4: To a 50 mL reaction flask, compound 18d (1.12 g, 5.0 mmol), 5 mL of 9 M hydrochloric acid, and paraformaldehyde (751 mg, 25.0 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. 18 mL of water was added to the reaction system, and stirring was continued at room temperature for 22 hours. The reaction mixture was filtered, and the filter cake was rinsed with 5 mL of water and 5 mL of ethanol, and dried to obtain 0.54 g of compound 18e (yield: 35%).

[0335] MS m / z(ESI):309.1[M+H] + .

[0336] 1 H NMR (400MHz, DMSO-d6): δ5.21-5.17(m,4H),,4.97-4.88(m,4H),2.64-2.6 0(m,2H),1.87-1.75(m,2H),1.66-1.56(m,2H),0.92(s,3H),0.90(s,3H).

[0337] Step 5: Compound 18e (0.54 g, 1.75 mmol) was weighed into a dry reaction flask, the atmosphere was replaced with argon, and methanesulfonic acid (1.8 mL) was added to dissolve the mixture. Compound 1a (0.18 g, 0.584 mmol) was added and stirred at room temperature for 24 hours. The reaction mixture was slowly added to 18 mL of water (cooled in an ice-water bath). After complete addition, the mixture was returned to room temperature and stirred for 10 minutes. Filter the mixture, rinse the filter cake with a small amount of water, and dissolve the crude product in TFA (0.72 mL). 2.88 mL of water was then added and stirred at room temperature for 10 minutes. Filter the mixture, rinse the filter cake with a small amount of water, and dry under vacuum to obtain 0.518 g of compound 18f (yield: 99%).

[0338] MS m / z(ESI):889.3[M+H] + .

[0339] 1 H NMR (400MHz, DMSO-d6): δ5.74~5.35(m,10H),5.21-5.08(m,4H),4.86-4.69(m,4H),4.29-4.05(m,4H),1.80-1.43(m,10H),0.98-0.74(m,16H).

[0340] Step 6: Compound 18f (502 mg, 0.565 mmol) was weighed into a dry three-necked flask, the argon atmosphere was replaced, trifluoroacetic acid (5 mL) was added to dissolve, and then compound 1b (637 mg, 1.42 mmol) was added. After the addition, the reaction was heated to 70°C and stirred for 3 hours. TFA was evaporated under reduced pressure, and 7.5 mL of ethanol was added to the resulting solid, heated under reflux for 1 hour, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dried. The resulting solid was purified by preparative HPLC (mobile phase: water and acetonitrile, gradient ratio: aqueous phase 25%-42%) and then salified with sodium hydroxide to obtain 0.12 g of compound 18 (yield: 12%).

[0341] MS m / z(ESI):1678.5[M-4Na+4H+18] + .

[0342] 1 H NMR (400MHz, DMSO-d6): δ8.00-7.89(m,4H),7.75-7.63(m,4H),7.35-6.99((m,7H),5.63-5.19(m,14H),4.42-4.00(m,1 2H),3.92-3.78(m,3H),2.88-2.77(m,7H),2.66-2.56(m,1H),2.19-1.94(m,8H),1.83-1.62(m,8H),1.01-0.82(m,12H).

[0343] Example 19. Preparation of Compound 19

[0344] Step 1: Compound 19a (4 g, 41.59 mmol) was added to tert-butanol (1.4 mL) and stirred to dissolve. N-methylmorpholine oxide (5.43 g, 46.35 mmol) and potassium osmate dihydrate (172 mg, 467 μmol) were then added. The mixture was reacted at room temperature for 16 hours. The central control panel indicated that the reaction was complete. 30 mL of aqueous sodium sulfite solution was added to quench the mixture. The mixture was extracted with ethyl acetate (3×30 ml). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated to obtain a crude product. 3 g of compound 19b (yield: 55%) was isolated by column chromatography (PE:EA=1:1).

[0345] 1 H NMR (400MHz, CDCl3): δ3.99-3.91(m,1H), 3.66-3.54(m,1H), 2.43-2.11(m,2H), 1.97-1.61(m,4H), 1.50-1.09(m,3H), 0.97-0.85(m,3H).

[0346] Step 2: To a 500 mL three-necked reaction flask, add DMSO (9.82 g, 125.69 mmol) and DCM (200 mL). Under nitrogen, cool to -60°C and add trifluoroacetic anhydride (24.24 g, 115.40 mmol) dropwise over 20 minutes. After stirring for 20 minutes, add a solution of compound 19b (3 g, 23.04 mmol) in DCM (8 mL). After stirring for 1.5 hours, add triethylamine (26.50 g, 261.87 mmol). Stir at -60°C for 1 hour and then warm to room temperature. When the central control panel indicates the reaction is complete, add approximately 216 mL of 10% hydrochloric acid to the reaction system. Extract with DCM (60 mL x 3), dry over anhydrous sodium sulfate, and concentrate. The crude product is then separated by column chromatography (PE:EA = 10:1) to afford 2.01 g of compound 19c (yield: 69%).

[0347] MS m / z(ESI):127.1[M+H] + .

[0348] 1 H NMR (400MHz, CDCl3): δ6.13-6.09(m,1H), 2.64-2.37(m,3H), 2.29-2.06(m,3H), 1.09(d,3H).

[0349] Step 3: To a 100 mL reaction flask, urea (3.17 g, 52.78 mmol), 0.3 M dilute hydrochloric acid (7.24 mL), and compound 19c (2.01 g, 15.93 mmol) were added and heated to 50°C with stirring for 16 hours. The reaction mixture was cooled to room temperature and filtered. The filter cake was rinsed with 10 mL of water and 10 mL of anhydrous ethanol and dried to afford 1.52 g of compound 19d (yield: 45%).

[0350] MS m / z(ESI):211.1[M+H] + .

[0351] 1 H NMR (400MHz, DMSO-d6): δ7.11-6.98(m,4H), 2.00-1.86(m,2H), 1.59-1.44(m,3H), 1.26-1.10(m,1H), 1.00-0.86(m,4H).

[0352] Step 4: To a 50 mL reaction flask, compound 19d (1.02 g, 4.85 mmol), 4.85 mL of 9 M hydrochloric acid, and paraformaldehyde (730 mg, 24.31 mmol) were added. The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated, and the residue was separated by column chromatography (dichloromethane:acetonitrile = 10:1) to afford 191 mg of compound 19e (yield: 13%).

[0353] MS m / z(ESI):295.1[M+H] + .

[0354] 1 H NMR (400MHz, DMSO-d6): δ5.21-5.17(m,4H),,4.96-4.88(m,4H),2.62-2.57(m,1H),1.96-1.61(m,3H),1.25-1.17(m,3H),1.00(d,3H).

[0355] Step 5: Compound 19e (66 mg, 0.21 mmol) was weighed into a dry three-necked flask, the atmosphere was replaced with argon, and methanesulfonic acid (0.5 mL) was added to dissolve the mixture. Compound 1a (189 mg, 0.64 mmol) was then added at room temperature. After stirring at room temperature for 18 hours, the reaction mixture was slowly added to 5 mL of water (cooled in an ice-water bath) and allowed to return to room temperature. The mixture was filtered and the filter cake was washed with a small amount of water. The dried crude product was dissolved in TFA (0.26 mL), followed by the addition of 1 mL of water and stirring at room temperature for 10 minutes. The mixture was filtered, the filter cake was washed with a small amount of water, and vacuum dried to obtain 185 mg of compound 19f (yield: 100%).

[0356] MS m / z(ESI):878.1[M+18] + .

[0357] 1 H NMR (400MHz, DMSO-d6): δ5.68~5.42(m,10H), 5.16~5.14(m,4H), 4.80~4.74(m,4H), 4.20~4.16(m,6H), 2.08~1.99(m,2H), 1.55~1.47(m,6H), 1.24~0.97(m,12H).

[0358] Step 6: Compound 19f (204 mg, 0.24 mmol) was weighed into a dry three-necked flask, the argon atmosphere was replaced, and TFA (2 mL) was added to dissolve the mixture. Compound 1b (266 mg, 0.59 mmol) was then added. After the addition, the reaction mixture was heated to 70°C with stirring for 3 hours. The TFA was evaporated under reduced pressure, and 3 mL of ethanol was added to the resulting solid, heated under reflux (80°C) for 40 minutes, cooled to room temperature, and filtered. The filter cake was washed with ethanol and dried to obtain a crude product. The product was purified by preparative HPLC (mobile phase: water and acetonitrile, gradient ratio: aqueous phase 25%-42%) and then salted with sodium hydroxide to obtain 0.15 g of compound 19 (yield: 36%).

[0359] MS m / z(ESI):1650.4[M-4Na+4H+18] + .

[0360] 1 H NMR (400MHz, D2O): δ7.99~7.55(m,4H), 7.47~7.04(m,4H), 5.43~4.81(m,14H), 4.20~3.52(m,18H), 3.07~2.66(m,8H), 2.20~0.90(m,28H).

[0361] Test Example 1. Test on the antagonistic effect of the disclosed compound on muscle relaxants

[0362] 1. Experimental Purpose

[0363] The compounds provided in the present disclosure were tested for their reversal effects on the muscle relaxant effect of the gastrocnemius muscle in a rat neuromuscular model, and the onset time, TOF and other indicators were evaluated, and compared with CB2 and neostigmine.

[0364] 2. Experimental Materials

[0365] SPF-grade SD male rats, BL-420A biofunctional experimental system (main unit, stimulator, tension transducer), ventilator, electronic scale, surgical instruments, syringe, hair clipper, electronic scale, iron stand, foam board, ethyl carbamate, sodium chloride, CB2, compound 2, compound 3, cisatracurium, succinylcholine, neostigmine, sterile water, and 95% alcohol.

[0366] 3. Experimental Methods

[0367] Quarantine-qualified SPF male Sprague-Dawley rats were housed at a room temperature of 22 ± 0.5°C, with a ventilation rate of 20–50 / h and an airflow velocity of 0.05–0.18 m / s, and a 12 / 12-hour light / dark cycle. Acclimate to the animal facility for at least three days, housing six rats per cage. Experiments were initiated when rats weighed between 220 and 250 g.

[0368] Reconstitute the test sample in 0.9% sodium chloride. Weigh the required amount of test sample after conversion based on the content. Dissolve it in 0.9% sodium chloride injection (within 30 minutes), then mix thoroughly using a vortex mixer. Reconstitute CB2 in purified water.

[0369] Actual weighed drug weight (mg) = dosage preparation concentration A (mg / mL) × solvent volume (mL) / content (%)

[0370] Rats were randomly divided into CB2, compound 2, compound 3, and neostigmine groups, with 4 rats in each group (based on the actual number of rats in each group), and the administration volume was 2 mL / kg.

[0371] CB2 (prepared using the known method "WO2012051407A2") has the following structure:

[0372] After anesthesia, the rats were isolated from the sciatic nerve and gastrocnemius muscle. The sciatic nerve was stimulated and muscle tension signals were recorded using a tension transducer. Endotracheal intubation was performed and mechanical ventilation was administered using a small animal ventilator. After a period of stable muscle tension signal recording, medication was administered: the initial dose was 2 times the ED. 90 A dose of 0.8 mg / kg of muscle relaxant (cisatracurium) is given. The muscle tension curve should decrease at this time. Antagonists (test substance and neostigmine) are injected 30-60 seconds after administration. When the muscle tension curve recovers to more than 95%, ED is given. 90 A muscle relaxant (succinylcholine) dose (0.9 mg / kg) should be administered. A decrease in muscle tone should be observed, and the experiment can be stopped when muscle tone naturally recovers to above 95%. Muscle tone signals should be continuously recorded during this period, and statistical analysis should be conducted on indicators such as onset time and clinical efficacy. The reversal of the muscle relaxant effect of the antagonist should be determined and compared by comparing muscle tone signals after administration.

[0373] IV. Experimental Procedure

[0374] 4.1 Weighing and anesthesia of rats

[0375] The rats were weighed, and after their emotions were stable, 25% urethane was prepared with ethyl carbamate and anesthetized by intraperitoneal injection at a rate of 1 mL / 100 g. After the pain reflex disappeared, the rats were fixed in a prone position on a foam board, and the buttocks and outer right thigh area were depilated.

[0376] 4.2 Isolation of the sciatic nerve

[0377] Behind the hip joint, make an incision in the skin at the outer edge of the femur in the middle of the thigh. Lift the skin and superficial fascia, and bluntly dissect the muscles to expose the sciatic nerve. Use a glass needle during dissection to prevent damage to the nerve with metal instruments.

[0378] 4.3 Isolation of the gastrocnemius muscle

[0379] Cut the calf skin from the ankle joint, cut the anterior ankle ligament, separate the gastrocnemius muscle, tie a ligature at the gastrocnemius tendon at the ankle, and cut the tendon at the distal end of the ligature.

[0380] 4.4 Collecting Signals

[0381] Connect the gastrocnemius ligature to the tension transducer and the sciatic nerve stimulator. Set the input signal to tension, and the parameters to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms pulse width, 2 Hz frequency, 0.225 ± 0.025 V intensity, 0 intensity increment, 4 train lengths, 12 s main cycle, 30,000 pauses, and record muscle contraction curves. Maintain the muscle and nerve moist with saline solution throughout the measurement, rehydrating every 3-5 minutes.

[0382] 4.5 Connect to ventilator, inject muscle relaxants and antagonists

[0383] Wipe the ventilator tube port with alcohol, cut the neck skin, find the jugular vein and trachea, cut the trachea, connect the ventilator, and set the parameters to tidal volume 6mL, respiratory time ratio 5:4, and respiratory rate 80 times / min. After stabilizing for about 5 minutes, administer the drug through the jugular vein. According to the reference settings, give 2 times the ED for the first time. 90 Doses of muscle relaxant (cisatracurium) are given. The muscle tension curve should decrease at this time. Antagonist (test substance or neostigmine) is injected 30-60s after administration. When the muscle tension curve recovers to more than 95%, ED is given. 90 The experiment can be stopped after the muscle tension curve recovers to more than 95%. The muscle tension curve is continuously recorded during this period.

[0384] Table 1.

[0385] 4.6 Timeliness Index Statistics

[0386] The biofunctional experimental system was used to calculate the onset time, secondary muscle relaxation onset time and other indicators. The statistical standards are as follows.

[0387] 1) TOF recovery 90% time (TOF0.9): time from the T4 / T1 value of TOF train stimulation to about 90% - antagonist administration time

[0388] 2) Duration of succinylcholine muscle relaxant effect: the time when muscle tension drops to the lowest value minus the time of succinylcholine administration

[0389] 5. Experimental Conclusion

[0390] As shown in Figures 1 and 2, compounds 2 and 3 can achieve the same efficacy level as neostigmine at 20 mg / kg, which is better than CB2.

[0391] Test Example 2. Test of the in vitro binding activity of the disclosed compounds to muscle relaxants

[0392] 1. Purpose of the test:

[0393] The in vitro binding activity of the disclosed compounds with muscle relaxants was tested by isothermal titration calorimetry (ITC) to evaluate the binding K d value.

[0394] 2. Test materials:

[0395] Isothermal titration calorimeter (including computer host and supporting software), CB2, compound 2, compound 3, compound 7, compound 12, compound 13, compound 15, cisatracurium, and deionized water.

[0396] 3. Test methods and steps:

[0397] Using the pre-set wash program, wash the tubing, sample cell, and titration needle of the isothermal titration calorimeter system with deionized water. Prepare an aqueous solution of cisatracurium and an aqueous solution of the test compound at a ratio of cisatracurium to test compound of 10:1 to 20:1. Use the sample pipette to fill the sample cell with CB2 and the test compound. Using the sample pipette, draw cisatracurium into the titration needle using the sample pipette program. Place the titration needle in the sample cell, start stirring, and equilibrate the system for 5–10 minutes. Set the titration parameters: 2.5 μL per drop, 20 drops total, and 150-second intervals. Start the titration and record the thermal curve.

[0398] After the titration is completed, the K of the compound to be tested and cisatracurium is calculated by the thermal curve. d value, use the washing program to wash the pipeline, sample cell and titration needle, and then test the next compound.

[0399] 4. Test results:

[0400] The ITC method was used to detect the binding ability of CB2, compound 2, compound 3, compound 7, compound 12, compound 13, and compound 15 to cisatracurium in vitro. The dissociation constants K d The values ​​are shown in Table 2. The results show that the ability of compound 2, compound 13 and compound 15 to bind to cisatracurium in vitro is stronger than that of CB2.

[0401] Table 2: In vitro binding affinity of test compounds to cisatracurium

[0402] Test Example 3. Test on the antagonistic effect of the disclosed compounds on muscle relaxants

[0403] 1. Experimental Purpose

[0404] The compounds provided in the present disclosure were tested for their reversal effects on the muscle relaxant effect of the gastrocnemius muscle in a rat neuromuscular model, and the onset time, TOF and other indicators were evaluated, and compared with CB2 and neostigmine.

[0405] 2. Experimental Materials

[0406] SPF-grade SD male rats, BL-420A biofunctional experimental system (main unit, stimulator, tension transducer), ventilator, electronic scale, surgical instruments, syringe, hair clipper, electronic scale, iron stand, foam board, ethyl carbamate, sodium chloride, CB2, compound 2, compound 3, cisatracurium, succinylcholine, neostigmine, sterile water, and 95% alcohol.

[0407] 3. Experimental Methods

[0408] Quarantine-qualified SPF male Sprague-Dawley rats were housed at a room temperature of 22 ± 0.5°C, with a ventilation rate of 20–50 / h and an airflow velocity of 0.05–0.18 m / s, and a 12 / 12-hour light / dark cycle. Acclimate to the animal facility for at least three days, housing six rats per cage. Experiments were initiated when rats weighed between 220 and 250 g.

[0409] Reconstitute the test sample in 0.9% sodium chloride. Weigh the required amount of test sample after conversion based on the content. Dissolve it in 0.9% sodium chloride injection (within 30 minutes), then mix thoroughly using a vortex mixer. Reconstitute CB2 in purified water.

[0410] Actual weighed drug weight (mg) = dosage preparation concentration A (mg / mL) × solvent volume (mL) / content (%)

[0411] Rats were randomly divided into CB2, compound 2, compound 15, and neostigmine groups, with 5 rats in each group (based on the actual number of rats in each group), and the administration volume was 2 mL / kg.

[0412] CB2 (prepared using the known method "WO2012051407A2") has the following structure:

[0413] After anesthesia, the rats were isolated from the sciatic nerve and gastrocnemius muscle. The sciatic nerve was stimulated and muscle tension signals were recorded using a tension transducer. Endotracheal intubation was performed and mechanical ventilation was administered using a small animal ventilator. After a period of stable muscle tension signal recording, medication was administered: the initial dose was 2 times the ED. 90 A dose of 0.8 mg / kg of muscle relaxant (cisatracurium) is given. The muscle tension curve should decrease at this time. Antagonists (test substance and neostigmine) are injected 30-60 seconds after administration. When the muscle tension curve recovers to more than 95%, ED is given. 90A muscle relaxant (succinylcholine) dose (0.9 mg / kg) should be administered. A decrease in muscle tone should be observed, and the experiment can be stopped when muscle tone naturally recovers to above 95%. Muscle tone signals should be continuously recorded during this period, and statistical analysis should be conducted on indicators such as onset time and clinical efficacy. The reversal of the muscle relaxant effect of the antagonist should be determined and compared by comparing muscle tone signals after administration.

[0414] IV. Experimental Procedure

[0415] 4.1 Weighing and anesthesia of rats

[0416] The rats were weighed, and after their emotions were stable, 25% urethane was prepared with ethyl carbamate and anesthetized by intraperitoneal injection at a rate of 1 mL / 100 g. After the pain reflex disappeared, the rats were fixed in a prone position on a foam board, and the buttocks and outer right thigh area were depilated.

[0417] 4.2 Isolation of the sciatic nerve

[0418] Behind the hip joint, make an incision in the skin at the outer edge of the femur in the middle of the thigh. Lift the skin and superficial fascia, and bluntly dissect the muscles to expose the sciatic nerve. Use a glass needle during dissection to prevent damage to the nerve with metal instruments.

[0419] 4.3 Isolation of the gastrocnemius muscle

[0420] Cut the calf skin from the ankle joint, cut the anterior ankle ligament, separate the gastrocnemius muscle, tie a ligature at the gastrocnemius tendon at the ankle, and cut the tendon at the distal end of the ligature.

[0421] 4.4 Collecting Signals

[0422] Connect the gastrocnemius ligature to the tension transducer and the sciatic nerve stimulator. Set the input signal to tension, and the parameters to square wave, fine voltage, train stimulation, 0.05 ms delay, 0.2 ms pulse width, 2 Hz frequency, 0.225 ± 0.025 V intensity, 0 intensity increment, 4 train lengths, 12 s main cycle, 30,000 pauses, and record muscle contraction curves. Maintain the muscle and nerve moist with saline solution throughout the measurement, rehydrating every 3-5 minutes.

[0423] 4.5 Connect to ventilator, inject muscle relaxants and antagonists

[0424] Wipe the ventilator tube port with alcohol, cut the neck skin, find the jugular vein and trachea, cut the trachea, connect the ventilator, and set the parameters to tidal volume 6mL, respiratory time ratio 5:4, and respiratory rate 80 times / min. After stabilizing for about 5 minutes, administer the drug through the jugular vein. According to the reference settings, give 2 times the ED for the first time. 90Doses of muscle relaxant (cisatracurium) are given. The muscle tension curve should decrease at this time. Antagonist (test substance or neostigmine) is injected 30-60s after administration. When the muscle tension curve recovers to more than 95%, ED is given. 90 The experiment can be stopped after the muscle tension curve recovers to more than 95%. The muscle tension curve is continuously recorded during this period.

[0425] Table 3.

[0426] 4.6 Timeliness Index Statistics

[0427] The biofunctional experimental system was used to calculate the onset time, secondary muscle relaxation onset time and other indicators. The statistical standards are as follows.

[0428] 1) TOF recovery 90% time (TOF0.9): time from the T4 / T1 value of TOF train stimulation to about 90% - antagonist administration time

[0429] 2) Duration of succinylcholine muscle relaxant effect: the time when muscle tension drops to the lowest value minus the time of succinylcholine administration

[0430] 5. Experimental Conclusion

[0431] As shown in Figure 3, compounds 2 and 15 can reach the efficacy level of neostigmine at 20 mg / kg, which is better than CB2.

[0432] Test Example 4. Test of the in vitro binding activity of the disclosed compounds to muscle relaxants

[0433] 1. Purpose of the test:

[0434] The in vitro binding activity of the disclosed compounds with muscle relaxants was tested by isothermal titration calorimetry (ITC) to evaluate the binding K d value.

[0435] 2. Test materials:

[0436] Isothermal titration calorimeter (including computer host and supporting software), CB2, compound 2, compound 11, compound 15, compound 16, cisatracurium, and deionized water.

[0437] 3. Test methods and steps:

[0438] Using the pre-set wash program, wash the tubing, sample cell, and titration needle of the isothermal titration calorimeter system with deionized water. Prepare an aqueous solution of cisatracurium and an aqueous solution of the test compound at a ratio of cisatracurium to test compound of 10:1 to 20:1. Use the sample pipette to fill the sample cell with CB2 and the test compound. Using the sample pipette, draw cisatracurium into the titration needle using the sample pipette program. Place the titration needle in the sample cell, start stirring, and equilibrate the system for 5–10 minutes. Set the titration parameters: 2.5 μL per drop, 20 drops total, and 150-second intervals. Start the titration and record the thermal curve.

[0439] After the titration is completed, the K of the compound to be tested and cisatracurium is calculated by the thermal curve. d value, use the washing program to wash the pipeline, sample cell and titration needle, and then test the next compound.

[0440] 4. Test results:

[0441] The ITC method was used to detect the binding ability of CB2, compound 2, compound 11, compound 15, and compound 16 to cisatracurium in vitro. The dissociation constants K d The values ​​are shown in Table 4. The results show that the ability of compound 2, compound 11, compound 15 and compound 16 to bind to cisatracurium in vitro is stronger than that of CB2.

[0442] Table 4: In vitro binding affinity of test compounds to cisatracurium

Claims

1. A compound represented by formula (I) or a pharmaceutically acceptable salt thereof, in, R 1 Each independently selected from C 2-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 1 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 1 Optionally one or more R 1A replace; R 2 are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms 2 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R 2 Optionally one or more R 2A replace; Ring A is independently selected from a 5- to 12-membered aromatic group or a 5- to 12-membered heteroaryl group; R 3 are each independently selected from halogen, C 1-6 alkyl, hydroxy, nitro, cyano, -C(O)2R', NR'(R"), R'-(O)-alkylene-, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl or And at least one of them is The R 3 Optionally one or more R 3A replace; R 4 for A + is a monovalent or divalent cation; R 1A 、R 2A 、R 3A Each independently selected from halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 alkoxy; R' and R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl; m and n are each independently selected from 1, 2, 3, 4 or 5; p is each independently selected from 1, 2, 3, 4, 5 or 6.

2. The compound represented by formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, wherein The ring A is phenyl or naphthyl, preferably naphthyl.

3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or 2, which is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof, in, R 1 、R 2 , p, m and A + As defined in claim 1.

4. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein Two R's connected to adjacent carbon atoms 1 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; preferably, the two R 1 More preferably, the two R 1 Together they form a 5- to 6-membered heterocyclic group, wherein the heteroatom is selected from nitrogen or oxygen, preferably oxygen.

5. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 Each independently is C 2-6 Alkyl, preferably ethyl; or, R 1 Each independently is C 1-6 Halogenated alkyl, preferably C 1-3 Haloalkyl, more preferably one, two or three fluorine-substituted methyl; or R 1 are each independently -C(O)2R', wherein R' is each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, preferably, said R' is H or C 1-6 Alkyl, more preferably methyl or ethyl; or, R 1 Each independently is C 1-6 Hydroxyalkyl or C 1-6 Alkyl-OC 1-6 Alkylene-, preferably C 1-3 Hydroxyalkyl or C 1-3 Alkyl-OC 1-3 Alkylene-, more preferably hydroxymethyl or methyl-O-methylene-; or, R 1 Each is independently R'-(O)-alkylene-, wherein R' is selected from C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Halogenated alkyl, 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclic group, preferably, R' is C 1-6 Alkyl or C 1-6 More preferably, the R' is C 1-3 alkyl.

6. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 2 are each independently hydrogen.

7. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein A + is a monovalent cation selected from H + 、Na + , K + 、H4N + 、Et3NH + 、(HOCH2CH2)3NH + Or cation forms of ethylenediamine, piperazine, triphenylmethylaminomethane, preferably H + 、Na + or K + , more preferably Na + or, A + is a divalent cation selected from Ca 2+ Mg 2+ or Zn 2+ .

8. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, wherein p is each independently selected from 2, 3 or 4, preferably 3.

9. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein m is each independently selected from 2, 3 or 4, preferably 2.

10. The compound represented by formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 9, which is selected from:

11. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof, in: X C1 、X C2 Each is independently selected from O, S, -NH-; R C2 Each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, -C(O)2R', R'-(O)-alkylene-, hydroxyl, NR'(R"), 3 to 7 membered cycloalkyl, 3 to 7 membered heterocyclyl; or two R attached to adjacent carbon atoms C2 Together form a 3- to 10-membered cycloalkyl or a 3- to 10-membered heterocyclic group; said R C2 Optionally substituted with one or more halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution; Ring C is selected from 6- to 18-membered aromatic groups or 5- to 18-membered heteroaryl groups; R C3 Each independently R C4 Each independently Carboxylic acid group, -carboxylate-cation, phosphate group, -phosphate-cation, sulfonic acid group, -sulfonate-cation; L, L 1 , L 2 The same or different, each independently an alkylene or heteroalkylene, the alkylene, heteroalkylene optionally substituted by one or more halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 Alkoxy substitution; R c are each independently selected from hydrogen, halogen, cyano, nitro, amino, C 1-6 Alkyl or C 1-6 alkoxy; R a 、R b are the same or different, each independently selected from carboxylic acid, -carboxylate-cation, phosphate, -phosphate-cation, sulfonic acid, -sulfonate-cation; R', R" are each independently selected from hydrogen, C 1-6 Alkyl, C 1-6 Hydroxyalkyl, C 1-6 Haloalkyl, 3- to 7-membered cycloalkyl, 3- to 7-membered heterocyclyl; x is selected from 1, 2, 3, 4 or 5; v is each independently selected from 1, 2, 3, 4 or 5; q is each independently selected from 1, 2, 3, 4, 5 or 6.

12. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 11, wherein X C1 、X C2 are the same and selected from O, S, -NH-, preferably O.

13. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 11 or 12, wherein each L is independently C 1-6 Alkylene.

14. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 11 to 13, wherein ring C is selected from a benzene ring, a naphthalene ring or an anthracene ring, preferably a naphthalene ring or anthracene ring.

15. A compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 11 to 14, which is selected from a compound represented by formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, in: R D Each independently selected from a carboxylate group, a -carboxylate-cation, a phosphate group, a -phosphate-cation; R E Each is independently selected from the group consisting of a carboxylate group, a -carboxylate-cation, a phosphate group, a -phosphate-cation, a sulfonic acid group, and a -sulfonate-cation; r is selected from 1, 2, 3; R C2 ,q,x,L 1 , L 2 、R a 、R b 、R c As defined in claim 11.

16. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 11 to 15, wherein L1 and L2 are the same or different and are each independently C 1-6 Alkylene.

17. A compound represented by formula (III) according to any one of claims 11 to 16, or a pharmaceutically acceptable salt thereof, selected from a compound represented by formula (III-A-1), formula (III-B-1), formula (III-B-2), formula (III-C-1), formula (III-C-2), formula (III-C-3), formula (III-D-1), formula (III-D-2) or formula (III-D-3), or a pharmaceutically acceptable salt thereof, in: a are each independently selected from 1, 2, 3, and 4; b are each independently selected from 1, 2, 3, and 4; c are each independently selected from 1, 2, 3, and 4; A1 + or A2 + the same or different, each independently a monovalent cation or a divalent cation; When A1 + When it is a monovalent cation, s is 4; When A1 + When it is a divalent cation, s is 2; When A2 + When it is a monovalent cation, t is 8; When A2 + When it is a divalent cation, t is 4; R C2 , q, x as defined in claim 11, and r as defined in claim 15.

18. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 17, wherein R C2 are each independently hydrogen.

19. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to claim 17 or 18, wherein r is 2 or 3, preferably 2.

20. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 19, wherein a, b, and c are the same or different and are independently selected from 1, 2, or 3. Preferably, a, b, and c are all 1.

21. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 20, wherein q is independently selected from 2, 3 or 4, preferably 3, 4, and more preferably 3.

22. The compound of formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 21, wherein x is selected from 2, 3 or 4, preferably 2, 3, and more preferably 2.

23. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 22, wherein A1 + 、A2 + Each independently is a monovalent cation selected from H + 、Na + , K + 、H4N + 、Et3NH + 、(HOCH2CH2)3NH + Or cation forms of ethylenediamine, piperazine, triphenylmethylaminomethane, preferably H + 、Na + or K + , more preferably Na + .

24. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 23, wherein A1 + 、A2 + are each independently a divalent cation selected from the group consisting of Ca 2+ Mg 2+ or Zn 2+ .

25. The compound represented by formula (III) or a pharmaceutically acceptable salt thereof according to any one of claims 17 to 24, which is selected from 26. An isotope substitution of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, preferably, the isotope substitution is a deuterium atom substitution.

27. A pharmaceutical composition comprising at least one therapeutically effective amount of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, the isotope substitute according to claim 26, and a pharmaceutically acceptable excipient.

28. Use of the compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, the isotopic substitution according to claim 26 or the pharmaceutical composition according to claim 27 in the preparation of a medicament for treating or preventing a disease or condition selected from a proliferative disease, a cardiovascular-related disease or a blood cancer.

29. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, Use of the isotope substitution according to claim 26 or the pharmaceutical composition according to claim 27 in the preparation of a medicament for reversing drug-induced neuromuscular blockade and / or anesthesia.

Images