Cucurbituril compounds and their medicinal uses

Abstract

The present disclosure relates to cucurbituril compounds and their pharmaceutical uses. Specifically, the present disclosure relates to a compound of formula (I) and its pharmaceutically acceptable salts, each of the substituents defined in the specification, a method for preparing the compound, and a pharmaceutical composition containing the compound, as well as its use as a therapeutic agent, particularly in the preparation of a medicament for reversing drug-induced neuromuscular blockade and / or anesthesia in the treatment or prevention of proliferative diseases, cardiovascular-related diseases, or hematological cancers. JPEG2025541968000084.jpg41170

Description

[Technical Field]

[0001] The present disclosure is in the field of medicine, and specifically relates to cucurbituril compounds and their medicinal uses. [Background technology]

[0002] Neuromuscular blockade is one of the three fundamental elements of general anesthesia. While neuromuscular blocking agents fulfill the requirements of tracheal intubation and surgery, they also pose a safety risk, resulting in residual neuromuscular blockade, which can lead to subjective patient discomfort and a series of pulmonary complications, such as hypoxemia and reflux aspiration. To reduce the incidence of residual neuromuscular blockade, steady progress has been made in resolving the clinical issue of residual neuromuscular blockade through measures such as the use of short- and medium-acting neuromuscular blocking agents, optimization of intraoperative neuromuscular blockade management, postoperative reversal of neuromuscular blockade, and objective perioperative neuromuscular monitoring.

[0003] "Postoperative reversal of muscle relaxant blockade" refers to the use of a muscle relaxant antagonist to reverse the residual effects of non-depolarizing muscle relaxants. Currently, commonly used muscle relaxant antagonists are broadly divided into two types: competitive muscle relaxant antagonists, such as the acetylcholinesterase inhibitor neostigmine, and selective muscle relaxant antagonists, such as the steroid muscle relaxant antagonist sugammadex sodium and the benzylisoquinoline muscle relaxant antagonist cysteine.

[0004] Prior art WO2012051407A discloses a non-closed ring CB[n] type molecular container having a cucurbituril structure, i.e., Calabadion2, which binds highly efficiently to benzylisoquinoline and steroidal muscle relaxants and blocks their binding to neuromuscular cholinergic receptors by covering the quaternary ammonium moiety of the benzylisoquinoline and steroidal muscle relaxants, thereby achieving rapid reversal of muscle relaxant activity. Summary of the Invention

[0005] The present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof: [ka] Among them, R 1 are each independently C 2-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a hydroxyalkyl group, —C(O)R′, R′—(O)-alkylene-, a hydroxy group, NR′(R″), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R linked on adjacent carbon atoms; 1 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and the R 1 optionally, one or more R 1A is replaced by R 2 are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a hydroxyalkyl group, —C(O)R′, R′—(O)-alkylene-, a hydroxy group, NR′(R″), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R linked on adjacent carbon atoms; 2 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and the R 2 optionally, one or more R 2A is replaced by each ring A is independently selected from a 5- to 12-membered aryl group or a 5- to 12-membered heteroaryl group; R 3 are each independently a halogen, C 1-6 an alkyl group, a hydroxy group, a nitro group, a cyano group, -C(O)2R', NR'(R''), R'-(O)-alkylene-, a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or [ka] At least one of [ka] and the above R 3 optionally, one or more R 3A is replaced by R 4 teeth [ka] and A + is a monovalent or divalent cation, R 1A , R 2A , R 3A are each independently a halogen, a cyano group, a nitro group, an amino group, or C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, R' and R'' are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group, C 1-6 selected from a haloalkyl group, a 3- to 7-membered cycloalkyl group, and a 3- to 7-membered heterocyclyl group; m and n are each independently selected from 1, 2, 3, 4, or 5; Each p is independently selected from 1, 2, 3, 4, 5, or 6.

[0006] In an alternative embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a phenyl group or a naphthyl group.

[0007] In an alternative embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein ring A is a naphthyl group.

[0008] In an alternative embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (I-1) or a pharmaceutically acceptable salt thereof: [ka] Among them, R 1 , R 2 , p, m and A + is as defined for compounds of formula (I).

[0009] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group.

[0010] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 4- to 8-membered cycloalkyl group or a 4- to 8-membered heterocyclyl group.

[0011] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 5- or 6-membered cycloalkyl group or a 5- or 6-membered heterocyclyl group.

[0012] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 6-membered cycloalkyl group.

[0013] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 5- to 6-membered heterocyclyl group, in which the heteroatom is nitrogen or oxygen.

[0014] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 5- to 6-membered heterocyclyl group, of which the heteroatom is oxygen.

[0015] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently C 2-6 It is an alkyl group.

[0016] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently an ethyl group.

[0017] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently C 1-6 It is a haloalkyl group.

[0018] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently C 1-3 It is a haloalkyl group.

[0019] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently an alkyl group substituted with 1, 2 or 3 fluorines.

[0020] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1are each independently —C(O)R′, and R′ and R″ are each independently hydrogen, C 1-6 Alkyl group, C 1-6 It is selected from haloalkyl groups.

[0021] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently —C(O)R′, where R′ is H or C 1-6 It is selected from alkyl groups.

[0022] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently —C(O)2R′, where R′ is selected from a methyl group or an ethyl group.

[0023] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently C 1-6 Hydroxyalkyl group or C 1-6 Alkyl-OC 1-6 It is alkylene.

[0024] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently C 1-3 Hydroxyalkyl group or C 1-3 Alkyl-OC 1-3 It is alkylene.

[0025] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently a hydroxymethyl group or methyl-O-methylene-.

[0026] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently R'-(O)-alkylene-, and R' is C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group, C 1-6 It is selected from a haloalkyl group, a 3- to 7-membered cycloalkyl group, and a 3- to 7-membered heterocyclyl group.

[0027] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently R'-(O)-alkylene-, and R' is C 1-6 Alkyl group or C 1-6 It is a haloalkyl group.

[0028] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 1 are each independently R'-(O)-alkylene-, and R' is C 1-3 It is an alkyl group.

[0029] In some embodiments, the present disclosure provides a compound of formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein R 2 are each independently hydrogen.

[0030] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, + is a monovalent cation, and the monovalent cation is H + , Na + , K. + , H4N + , Et3NH + , (HOCH2CH2)3NH + or the cationic forms of ethylenediamine, piperazine, and triphenylmethylaminomethane.

[0031] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, + is a monovalent cation, and the monovalent cation is H + , Na + , or K + Selected from.

[0032] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, + is a monovalent cation, and the monovalent cation is Na + is.

[0033] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, + is a divalent cation, and the divalent cation is Ca 2+ , Mg 2+ , or Zn 2+ Selected from.

[0034] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein each p is independently selected from 2, 3, or 4.

[0035] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein p is 3.

[0036] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein each m is independently selected from 2, 3, or 4.

[0037] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein m is 2.

[0038] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 5-membered, 6-membered or 7-membered cycloalkyl group, for example [ka] is.

[0039] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 6-membered heterocycloalkyl group, e.g. [ka] is.

[0040] In some embodiments, the present disclosure provides a compound represented by formula (I), (I-1), or a pharmaceutically acceptable salt thereof, wherein two R 1 together form a 5-membered heterocycloalkyl group, e.g. [ka] is.

[0041] In an alternative embodiment, the present disclosure provides a compound of formula (I) or a pharmaceutically acceptable salt thereof, which is a compound of formula (I-1-A), (I-1-B), (I-1-C), (I-1-D) or (I-1-E) or a pharmaceutically acceptable salt thereof, [ka] wherein X3 is independently selected from O, S, and NH; d is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; e is independently selected from 0, 1, 2, 3, 4, 5, 6, 7, and 8; f is independently selected from 0, 1, and 2; g are independently selected from 0, 1, and 2; R 1A , p is as defined above.

[0042] 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 a halogen, a cyano group, an amino group, or C 1-6 Alkyl group or C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0043] 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 a halogen, C 1-6 Alkyl group or C 1-6 The alkoxy group is selected from the group consisting of alkoxy groups.

[0044] 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 fluorine, chlorine, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0045] 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 [ka] [ka] Selected from.

[0046] In another aspect of the present disclosure, there is provided a compound of formula (II) or a pharmaceutically acceptable salt thereof: [ka] wherein X1 and X2 are each independently selected from O, S, and -NH-, provided that X1 and X2 are not both O; R 5 are each independently C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a hydroxyalkyl group, —C(O)R′, R′—(O)-alkylene-, a hydroxy group, NR′(R″), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R linked on adjacent carbon atoms; 5 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and the R 5 optionally, one or more R 5A is replaced by R 6 are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a hydroxyalkyl group, —C(O)R′, R′—(O)-alkylene-, a hydroxy group, NR′(R″), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R linked on adjacent carbon atoms; 6 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and the R 6 optionally, one or more R 6A is replaced by Ring B is selected from a 5- to 12-membered aryl group or a 5- to 12-membered heteroaryl group; R 7 are each independently a halogen, C 1-6an alkyl group, a hydroxy group, a nitro group, a cyano group, —C(O)2R′, NR′(R″), R′—(O)-alkylene-, a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or [ka] At least one of [ka] and the above R 7 optionally, one or more R 7A is replaced by R 8 teeth [ka] and the above A + is a monovalent or divalent cation, R 5A , R 6A , R 7A are each independently a halogen, a cyano group, a nitro group, an amino group, or C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, R' and R'' are each independently hydrogen, C 1-6 Alkyl group, C 1-6 Hydroxyalkyl group, C 1-6 selected from a haloalkyl group, a 3- to 7-membered cycloalkyl group, and a 3- to 7-membered heterocyclyl group; wherein y and z are each independently selected from 1, 2, 3, 4, or 5; w is selected from 1, 2, 3, 4, 5 or 6;

[0047] In some embodiments, the present disclosure provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from a phenyl group or a naphthyl group.

[0048] In some embodiments, the present disclosure provides a compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein Ring B is a naphthyl group.

[0049] In some embodiments, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (II-1) or a pharmaceutically acceptable salt thereof: [ka] Among them, the above R 5 , R 6 , w, z, A + are as defined in the compound of formula (II).

[0050] In some embodiments, the present disclosure provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof: [ka] Among them, the above R 5 , R 6 , w, z, A + are as defined in the compound of formula (II).

[0051] In some embodiments, the present disclosure provides a compound of formula (II) or a pharmaceutically acceptable salt thereof, which is a compound of formula (II-3) or a pharmaceutically acceptable salt thereof: [ka] Among them, the above R 5 , R 6 , w, z, A + are as defined in the compound of formula (II).

[0052] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 5 are each independently C 1-6 Alkyl group or C 1-6It is a haloalkyl group.

[0053] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 5 are each independently C 1-3 It is an alkyl group.

[0054] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 5 are each independently a methyl group.

[0055] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein R 6 are each independently hydrogen.

[0056] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein A + is selected from monovalent cations, and the monovalent cations are selected from H + , Na + , K. + , H4N + , Et3NH + , (HOCH2CH2)3NH + or the cationic forms of ethylenediamine, piperazine, and triphenylmethylaminomethane.

[0057] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein A + is a monovalent cation, and the monovalent cation is H + , Na + , or K + Selected from.

[0058] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3) or a pharmaceutically acceptable salt thereof, wherein A + is a divalent cation, and the divalent cation is Ca 2+ , Mg 2+ , or Zn 2+ Selected from.

[0059] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt thereof, wherein each w is independently selected from 2, 3, or 4.

[0060] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt thereof, wherein each w is independently 3.

[0061] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt thereof, wherein each z is independently selected from 2, 3, or 4.

[0062] In some embodiments, the present disclosure provides a compound represented by formula (II), (II-1), (II-2), or (II-3), or a pharmaceutically acceptable salt thereof, wherein each z is independently 2.

[0063] In some embodiments, the present disclosure provides a compound of formula (II), (II-1), (II-2), (II-3), or a pharmaceutically acceptable salt thereof, which is [ka] Selected from.

[0064] In another aspect of the present disclosure, there is provided a compound of formula (III) or a pharmaceutically acceptable salt thereof: [ka] Among them, X C1 , X C2 are each independently selected from O, S, and —NH—; R C2 is hydrogen, C 1-6 Alkyl group, C 1-6 Haloalkyl group, C 1-6 a hydroxyalkyl group, —C(O)R′, R′—(O)-alkylene-, a hydroxy group, NR′(R″), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R linked on adjacent carbon atoms; C2 together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and the R C2 optionally one or more halogens, cyano groups, nitro groups, amino groups, C 1-6 Alkyl group or C 1-6 substituted with an alkoxy group, Ring C is selected from a 6- to 18-membered aryl group or a 5- to 18-membered heteroaryl group; R C3 are each independently [ka] That is, R C4 are each independently [ka] , a carboxy group, a -carboxylate-cation; a phosphate group, a -phosphate-cation; a sulfonic acid group, a -sulfonate-cation; L, L 1 , L 2 are the same or different and each independently represent an alkylene group or a heteroalkylene group, and the alkylene group or heteroalkylene group may optionally contain one or more halogen atoms, cyano groups, nitro groups, amino groups, C 1-6 Alkyl group or C 1-6 substituted with an alkoxy group, Rc are each independently hydrogen, halogen, cyano group, nitro group, amino group, C 1-6 Alkyl group or C 1-6 selected from alkoxy groups, R a , R b are the same or different and are each independently selected from a carboxy group, a carboxylate cation, a phosphate group, a phosphate cation, a sulfonic acid group, and a sulfonate cation; x is selected from 1, 2, 3, 4 or 5; v is independently selected from 1, 2, 3, 4, or 5; Each q is independently selected from 1, 2, 3, 4, 5, or 6.

[0065] 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, and —NH—. C1 , X C2 are both O.

[0066] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein each L is independently C 1-6 It is an alkylene group.

[0067] In some embodiments, the present disclosure provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof, wherein ring C is selected from a benzene ring, a naphthalene ring, or an anthracene ring, and is preferably a naphthalene ring or an anthracene ring.

[0068] 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; [ka] Among them, R D are each independently selected from a carboxy group, a -carboxylate-cation, a phosphate group, and a -phosphate-cation; R E are each independently selected from a carboxy group, a carboxylate cation, a phosphate group, a phosphate cation, a sulfonic acid group, and a sulfonate cation; r is selected from 1, 2, and 3, R C2 , q, x, L 1 , L 2 , R a , R b , R c is as defined above.

[0069] 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 L and L are the same or different and each independently represent C 1-6 It is an alkylene group.

[0070] 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 are each independently selected from a carboxy group and a -carboxylate-cation.

[0071] 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 are each independently selected from a carboxy group, a -carboxylate-cation, a sulfonic acid group, and a -sulfonate-cation.

[0072] 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 are the same or different and are each independently selected from a carboxy group, a -carboxylate-cation, a sulfonic acid group, and a -sulfonate-cation.

[0073] In some embodiments, the present disclosure provides a compound of formula (III) or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of a compound of formula (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 a pharmaceutically acceptable salt thereof; [ka] [ka] Among them, each a is independently selected from 1, 2, 3, and 4; b is selected from 1, 2, 3, and 4; c is selected from 1, 2, 3, and 4; A1 + or A2 + are the same or different and are each independently selected from monovalent or divalent cations; A1 + is a monovalent cation, s is 4, A1 + is a divalent cation, s is 2, A2 + is a monovalent cation, t is 8, A2 + is a divalent cation, t is 4, R C2 , q, x, r are as defined above.

[0074] In some embodiments, the present disclosure provides a compound of Formula (III), (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 a pharmaceutically acceptable salt thereof, wherein R C2 are each independently hydrogen.

[0075] 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.

[0076] In some embodiments, the present disclosure provides a compound represented by 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 each q is independently selected from 2, 3, or 4. In some embodiments, q is selected from 3 and 4. In some embodiments, q is 3.

[0077] 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.

[0078] In some embodiments, the present disclosure provides 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, wherein a, b, and c are the same or different and independently selected from 1, 2, or 3; preferably, a, b, and c are all 1.

[0079] In some embodiments, the present disclosure provides a compound represented by formula (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 a pharmaceutically acceptable salt thereof, wherein A1 + , A2 + are each independently a monovalent cation, and the monovalent cation is H + , Na + , K. + , H4N + , Et3NH + , (HOCH2CH2)3NH + or the cationic forms of ethylenediamine, piperazine, and triphenylmethylaminomethane. In one embodiment, the monovalent cation is selected from H + , Na + , or K + In one embodiment, the monovalent cation is selected from Na + is.

[0080] In some embodiments, the present disclosure provides a compound represented by formula (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 a pharmaceutically acceptable salt thereof, wherein A1 + , A2 + are each independently a divalent cation, and the divalent cation is Ca 2+ , Mg 2+ , or Zn 2+ Selected from.

[0081] In some embodiments, the present disclosure provides a compound of Formula (III), (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 a pharmaceutically acceptable salt thereof, which is [ka] [ka] Selected from.

[0082] In another aspect of the present disclosure, there is provided a compound of formula (IV) or a pharmaceutically acceptable salt thereof: [ka] wherein X4 is independently selected from O, S, and NH; X5 are each independently selected from O, S, and NH; R 9A are each independently hydrogen, halogen, cyano group, nitro group, amino group, carboxy group, mercapto group, C 1-6 Alkyl group or C 1-6an alkoxy group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more halogens, cyano groups, nitro groups, amino groups, carboxy groups, and mercapto groups; R 9B are each independently hydrogen, halogen, cyano group, nitro group, amino group, carboxy group, mercapto group, C 1-6 Alkyl group or C 1-6 an alkoxy group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more halogens, cyano groups, nitro groups, amino groups, carboxy groups, and mercapto groups; R 10 are each independently hydrogen, halogen, cyano group, nitro group, amino group, carboxy group, mercapto group, C 1-6 Alkyl group or C 1-6 an alkoxy group, wherein the alkyl group and the alkoxy group are optionally substituted with one or more halogens, cyano groups, nitro groups, amino groups, carboxy groups, and mercapto groups; h is independently selected from 1, 2, 3, and 4; R 1A , d, e, f, g, p are as defined above.

[0083] In some embodiments, X4 are simultaneously O. Alternatively, in some embodiments, X4 are simultaneously S. Alternatively, in some embodiments, X4 are simultaneously NH.

[0084] In some embodiments, X5 are simultaneously O. Alternatively, in some embodiments, X5 are simultaneously S. Alternatively, in some embodiments, X5 are simultaneously NH.

[0085] 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: [ka] Among them, R 9A , R 9B , R 10 , h, p are as defined above.

[0086] In some embodiments, R 9A are each independently hydrogen, C 1-6 Alkyl group or C 1-6 In a specific embodiment, R 9A are each independently selected from hydrogen, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0087] In some embodiments, R 9B are each independently hydrogen, C 1-6 Alkyl group or C 1-6 In a specific embodiment, R 9B are each independently selected from hydrogen, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0088] In some embodiments, R 10 are each independently hydrogen, C 1-6 Alkyl group or C 1-6 In a specific embodiment, R 10 are each independently selected from hydrogen, a methyl group, an ethyl group, a methoxy group, and an ethoxy group.

[0089] In some embodiments, the present disclosure provides a compound of formula (IV), formula (IV-A), formula (IV-B), or formula (IV-C), or a pharmaceutically acceptable salt thereof, which is [ka] Selected from.

[0090] In another aspect of the present disclosure, there is provided 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; [ka] Includes.

[0091] In another aspect of the present disclosure, there is provided 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; [ka] Includes.

[0092] In the present disclosure, the reagent that provides the acidic environment can be either an organic acid or an inorganic acid, for example, trifluoroacetic acid.

[0093] Another aspect of 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 pharmaceutical salt thereof, an isotopic derivative thereof, and a pharmaceutically acceptable excipient.

[0094] In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg to 1000 mg.

[0095] In one embodiment, the pharmaceutical composition contains, based on the total weight of the composition, 0.01 to 99.99% of the compound, its medicinal salt, or its isotopic derivative. In one embodiment, the pharmaceutical composition contains 0.1 to 99.9% of the compound, its medicinal salt, or its isotopic derivative. In one embodiment, the pharmaceutical composition contains 0.5 to 99.5% of the compound, its medicinal salt, or its isotopic derivative. In one embodiment, the pharmaceutical composition contains 1 to 99% of the compound, its medicinal salt, or its isotopic derivative. In one embodiment, the pharmaceutical composition contains 2 to 98% of the compound, its medicinal salt, or its isotopic derivative.

[0096] In some embodiments, the pharmaceutical composition contains 0.01% to 99.99% pharmaceutically acceptable excipients, based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1% to 99.9% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 0.5% to 99.5% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 1% to 99% pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition contains 2% to 98% pharmaceutically acceptable excipients.

[0097] In another aspect of the present disclosure, 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) The present invention provides use of a compound represented by 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 medicament salt, isotopic substitution, or composition thereof in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, a blood cancer, a cardiovascular-related disease, or an infectious disease.

[0098] In another aspect of the present disclosure, there is provided a method for treating or preventing a disease or condition, wherein the disease or condition is selected from a proliferative disease, a blood cancer, a cardiovascular-related disease, or an infectious disease, and the method comprises administering to a patient a compound represented by any one of 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-E), Formula (III-F), Formula (III-G), Formula (III-H), Formula (III-I ... A compound represented by 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, isotopic substitution, or composition thereof, is administered.

[0099] In another aspect of the present disclosure, 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 medicamentable salt, isotopic substitution, or composition thereof, is used in the preparation of a medicament for reversing drug-induced neuromuscular blockade and / or anesthesia.

[0100] In another aspect of the present disclosure, there is provided a method for reversing drug-induced neuromuscular blockade and / or anesthesia, comprising administering to a patient a compound of 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-E), Formula (III-F), Formula (III-G), Formula (III-H), Formula (III-I ... A compound represented by 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, isotopic substitution, or composition thereof, is administered.

[0101] Proliferative diseases described in this disclosure include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, pseudomyxoma peritonei, lymphangioendosarcoma, synovioma, synovial sarcoma, colon sarcoma, 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, cystadenocarcinoma, medullary carcinoma, bronchial carcinoma, renal cell carcinoma, hepatocellular carcinoma, The tumor is selected from cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, urothelioma, oligodendroglioma, meningioma, melanoma, neuroblastoma, leukemia, lymphoma, multiple myeloma, thymoma, Waldenstrom's macroglobulinemia, and heavy chain disease.

[0102] The hematological cancers described in this disclosure are selected from leukemia, lymphoma, and myeloma.

[0103] In another aspect of the present disclosure, 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), The present invention provides a use of a compound represented by formula (III-B-2), (III-C-1), (III-C-2), (III-C-3), (III-D-1), (III-D-2), (III-D-3), (IV), (IV-A), (IV-B) or (IV-C), or a medicamentable salt or isotopically substituted derivative thereof, or a compound prepared by the above method, as a medicine.

[0104] Pharmaceutically acceptable salts of the compounds described in the present disclosure may be selected from inorganic salts or organic salts, with the inorganic salts being Na + , K. + , Ca 2+ , Mg 2+ , Zn 2+ The organic salts include, but are not limited to, H4N + , Et3NH + , (HOCH2CH2)3NH + , or cationic forms of ethylenediamine, piperazine, triphenylmethylaminomethane, but are not limited to these.

[0105] Compounds of the present disclosure may exist in particular geometric or stereoisomeric forms. The present disclosure includes cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures. All such compounds are intended to be within the scope of the present disclosure. Substituents such as alkyl groups may contain other asymmetric carbon atoms. All such isomers and mixtures thereof are within the scope of the present disclosure. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic form. Optically pure forms may be resolved from racemic mixtures or synthesized using chiral starting materials or chiral reagents.

[0106] Optically active (R)- and (S)-isomers and D- and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. Single enantiomers of certain compounds of the present disclosure can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, whereby the resulting diastereomeric mixture is isolated and the resulting diastereomeric mixture is cleaved to provide the desired enantiomer in pure form by cleavage of the corresponding groups. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxy) functional group, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by diastereomeric separation and recovery using conventional methods well known in the art to obtain the enantiomers in pure form. Separation of enantiomers and diastereomers is typically accomplished using chromatography, employing a chiral stationary phase and optionally combined with chemical derivatization (e.g., forming a carbamate from an amine).

[0107] In the chemical structures of the compounds described in this disclosure, [ka] indicates that the configuration is not specified, i.e., chiral isomers exist in the chemical structure, [ka] The bond [ka] or [ka] or [ka] and [ka] The two arrangements may be included at the same time.

[0108] The compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also called protolytic tautomers) include interconversions via protolysis, such as keto-enol and imine-enamine, lactam-lactim isomerizations. An example of a lactam-lactim equilibrium is between A and B as follows:

[0109] [ka] All of the compounds in this disclosure can be depicted as Form A or Form B. All tautomeric forms are within the scope of the invention. The naming of a compound does not exclude any tautomeric form.

[0110] The present disclosure further includes some isotopically labeled compounds of the present disclosure that are the same as those described herein, except that one or more atoms have been replaced with an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Illustrative isotopes that can be attached to compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, for example, 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, etc.

[0111] Unless otherwise specified, when a position is specifically designated as deuterium (D), it should be understood that the position is deuterium (i.e., at least 10% deuterium incorporated) with an abundance at least 1000 times greater than the natural abundance of deuterium (which is 0.015%). For example, a compound having an abundance greater than the natural abundance of deuterium may be at least 1000 times more abundant, at least 2000 times more abundant, at least 3000 times more abundant, at least 4000 times more abundant, at least 5000 times more abundant, at least 6000 times more abundant, or even greater. The present disclosure further includes various deuterated forms of the compound of formula (I). Each available hydrogen atom connected to a carbon atom may be independently replaced with a deuterium atom. Those skilled in the art can synthesize deuterated forms of the compound of formula (I) by referring to relevant literature. Deuterated forms of compounds of formula (I), when prepared, may use commercially available deuterated starting materials or may be synthesized by conventional techniques with deuterated reagents, including, but not limited to, deuterated borane, tritiated borane in tetrahydrofuran, lithium aluminum deuterated hydride, deuterated iodoethane, deuterated iodomethane, and the like.

[0112] "Optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not occur. For example, "C optionally substituted with a halogen or cyano group" 1-6 By "alkyl group" is meant that a halogen or cyano group may or may not be present, and this description includes cases where the alkyl group is substituted with a halogen or cyano group and cases where the alkyl group is not substituted with a halogen or cyano group.

[0113] Explanation of terms: A "pharmaceutical composition" is intended to include a mixture of one or more compounds described herein or physiologically acceptable salts or prodrugs thereof with other chemical components, and other components such as physiologically acceptable carriers and excipients, to facilitate administration to a living body and contribute to the absorption of the active ingredients, thereby further exerting biological activity.

[0114] A "medicinal excipient" includes, but is not limited to, any adjuvant, carrier, glidant, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, or emulsifier approved by the U.S. Food and Drug Administration (FDA) and acceptable for use in humans or domestic animals.

[0115] As used herein, an "effective amount" or "therapeutically effective amount" includes 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 enable or facilitate diagnosis. The effective amount used in a particular patient or veterinary subject can vary depending on factors such as the condition being treated, the patient's overall health, the route and dose of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.

[0116] Prefix “C” u-v " indicates that the following group has u to v carbon atoms. For example, "C 1-6 "Alkyl group" refers to an alkyl group having from 1 to 6 carbon atoms, specifically an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms.

[0117] The term "alkyl group" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, an alkyl group is a group having 1 to 20 carbon atoms (i.e., C 1-20 alkyl group), 1 to 8 carbon atoms (i.e., C 1-8 alkyl group), 1 to 6 carbon atoms (i.e., C 1-6 alkyl group), or 1 to 4 carbon atoms (i.e., C 1-4Examples 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 groups. When an alkyl group residue having a specific number of carbon atoms is named by a chemical name or determined by a molecular formula, all positional isomers having that number of carbon atoms may be included; thus, for example, a "butyl group" includes an n-butyl group (i.e., -(CH2)3CH3), a sec-butyl group (i.e., -CH(CH3)CH2CH3), an isobutyl group (i.e., -CH2CH(CH3)2), and a tert-butyl group (i.e., -C(CH3)3), and a "propyl group" includes an n-propyl group (i.e., -(CH2)2CH3) and an isopropyl group (i.e., -CH(CH3)2).

[0118] The term "cycloalkyl group" or "carbocycle" refers to a saturated or partially unsaturated cyclic alkyl group having a monocyclic or polycyclic (including fused, bridged, and spiro ring systems). The term "cycloalkyl group" includes cycloalkenyl groups (i.e., the cycloalkenyl group has at least one double bond). As used herein, a cyclic alkyl group is a group having 3 to 20 ring carbon atoms (i.e., C 3-20 cycloalkyl groups), 3 to 12 ring carbon atoms (i.e., C 3-12 cycloalkyl groups), 3 to 10 ring carbon atoms (i.e., C 3-10 cycloalkyl groups), 3 to 8 ring carbon atoms (i.e., C 3-8 cycloalkyl groups), or 3 to 7 ring carbon atoms (i.e., C 3-7 cycloalkyl groups), or 3 to 6 ring carbon atoms (i.e., C 3-6cycloalkyl groups). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, and cyclohexadienyl. The cycloalkyl ring may be fused to an aryl or heteroaryl group, where the ring connected to the parent structure is a cycloalkyl group; non-limiting examples include indanyl, tetrahydronaphthyl, and benzocycloheptanyl.

[0119] The term "heterocyclyl group" 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 "heterocycloalkyl group" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiro-heterocyclyl groups. Heterocyclyl groups can be monocyclic or polycyclic, and polycyclic rings can be fused, bridged, or spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl group regardless of connectivity (i.e., it can be bonded via a carbon atom or a heteroatom). The term heterocyclyl group is also intended to include any non-aromatic ring containing at least one heteroatom, which may be fused to an aryl or heteroaryl ring, regardless of connectivity to the rest of the molecule. As used herein, a heterocyclyl group has 3 to 20 ring atoms (i.e., a 3-20-membered heterocyclyl group), 3 to 12 ring atoms (i.e., a 3-12-membered heterocyclyl group), 3 to 10 ring atoms (i.e., a 3-10-membered heterocyclyl group), 3 to 8 ring atoms (i.e., a 3-8-membered heterocyclyl group), 3 to 7 ring atoms (i.e., a 3-7-membered heterocyclyl group), or 3 to 6 ring atoms (i.e., a 3-6-membered heterocyclyl group), and has 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom, wherein the ring heteroatoms are independently selected from nitrogen, sulfur, phosphorus, or oxygen. Examples of heterocyclyl groups include pyrrolidinyl, imidazolidinyl, oxetane, dioxolane, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and homopiperazinyl groups.

[0120] The term "heteroaryl group" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 6 to 12-membered, more preferably 5 or 6-membered. Non-limiting examples include imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like. [ka] Includes:

[0121] The heteroaryl ring may be fused to an aryl group, a heterocyclyl group, or a cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0122] The term "alkoxy" refers to the group "alkyl-O-," in which alkyl is defined above. Examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy, and 1,2-dimethylbutoxy.

[0123] The term "haloalkyl group" refers to an unbranched or branched alkyl group as defined above, in which one or more hydrogen atoms are replaced with halogen. For example, if one residue is substituted with multiple halogens, it may be referred to by using a prefix corresponding to the number of halogen moieties connected. Dihaloalkyl and trihaloalkyl groups refer to alkyl groups substituted with two or three halogen groups, which may be, but are not necessarily, the same halogen. Illustrative examples of haloalkyl groups include difluoromethyl (-CHF) or trifluoromethyl (-CF).

[0124] The term "haloalkoxy" refers to an alkoxy group, as defined above, in which one or more hydrogen atoms are replaced with a halogen.

[0125] The term "hydroxyalkyl group" refers to an alkyl group substituted with one or more hydroxy groups, where alkyl is as defined above.

[0126] A "monovalent group" is an atom or group that has one monovalent removed from a compound "in form." A "subunit" is an atom or group of atoms that has two monovalents or one divalent removed from a compound "in form."

[0127] The term "alkylene group" refers to the moiety remaining after removing two hydrogen atoms from an alkane molecule, and includes straight-chain and branched-chain subunits of 1 to 20 carbon atoms. Non-limiting examples of alkylene groups containing 1 to 6 carbon atoms include methylene (-CH-), ethylidene (e.g., -CHCH- or -CH(CH)-). Unless otherwise specified, alkylene groups may be substituted or unsubstituted. As used in any context herein, alkylene groups are optionally substituted in the same manner as alkyl groups.

[0128] The term "heteroalkylene group" refers to an alkylene group in which one or more -CH2- groups are replaced with a heteroatom selected from N, O, and S, wherein the alkylene group is as defined above, and the heteroalkylene group may be substituted or unsubstituted. Unless otherwise specified, the heteroalkylene group may be substituted or unsubstituted. As used in any context herein, the heteroalkylene group is optionally substituted in the same manner as an alkyl group.

[0129] The term "hydroxy" refers to an -OH group.

[0130] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0131] The term "cyano" refers to -CN.

[0132] The term "nitro group" refers to -NO2.

[0133] The term "oxo" refers to a =O substituent.

[0134] The term "substituted" refers to one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, being independently replaced with a corresponding number of substituents. Of course, the substituents are located only at their chemically feasible positions, and a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without much effort. [Brief explanation of the drawings]

[0135] [Figure 1] This is a comparison of TOF0.9 of antagonists administered after reversal of cisatracurium. [Figure 2] Comparison of TOF0.9 of compounds at 20mpk, where * indicates p=0.05. [Figure 3] The TOF was 0.9 hours when a muscle relaxant antagonist was administered to cisatracurium, of which *p<0.05, **p<0.01, ***p<0.001. DETAILED DESCRIPTION OF THE INVENTION

[0136] The present disclosure will be further described below in conjunction with examples, but these examples are not intended to limit the scope of the present disclosure.

[0137] Experimental methods for which specific conditions are not specified in the examples of this disclosure generally follow conventional conditions or conditions suggested by the manufacturers of raw materials or products. Reagents for which specific sources are not specified are conventional commercially available reagents.

[0138] The structure of the compound is determined by nuclear magnetic resonance (NMR) and / or mass spectrometry (MS). The NMR shifts (δ) are 10-6 The values ​​are shown in units of ppm. A Bruker AVANCE-400 nuclear magnetic resonance spectrometer was used for NMR measurements, and the measurement solvents were deuterated dimethyl sulfoxide (DMSO-6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0139] For MS measurements, a Shimadzu 2010 Mass Spectrometer or an Agilent 6110A MSD mass spectrometer was used.

[0140] For HPLC measurements, Shimadzu LC-20A systems, Shimadzu LC-2010HT series, or Agilent 1200 LC high performance liquid chromatograph (Ultimate XB-C18 3.0 x 150 mm column or Xtimate C18 2.1 x 30 mm column) was used.

[0141] For chiral HPLC analysis and measurements, Chiralpak IC-3 100×4.6mm ID, 3μm, Chiralpak AD-3 150×4.6mm ID, 3μm, Chiralpak AD-3 50×4.6mm ID, 3μm, Chiralpak AS-3 150×4.6mm ID, 3μm, Chiralpak AS-3 100×4.6mm ID, 3μm, ChiralCel OD-3 150×4.6mm ID, 3μm, Chiralcel OD-3 100×4.6mm ID, 3μm, ChiralCel OJ-H 150×4.6mm ID, 5μm, Chiralcel OJ-3 150×4.6mm ID, 3μm column was used; Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plates are used for thin layer chromatography. The silica gel plate specifications used for thin layer chromatography (TLC) are 0.15 mm to 0.2 mm, and the specifications for separating and purifying products by thin layer chromatography are 0.4 mm to 0.5 mm.

[0142] For column chromatography, Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh, or 300-400 mesh silica gel was generally used as the vector.

[0143] The chiral preparative column used was a DAICEL CHIRALPAK IC (250 x 30 mm, 10 µm) or Phenomenex-Amylose-1 (250 x 30 mm, 5 µm).

[0144] Combiflash Rf150 (TELEDYNE ISCO) was used as the CombiFlash high-speed preparative chromatograph.

[0145] Known starting materials according to the present disclosure may be synthesized by or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc.), and Darui Chemical.

[0146] In the examples, unless otherwise stated, all reactions can be carried out under an argon or nitrogen atmosphere.

[0147] An argon or nitrogen atmosphere refers to an argon or nitrogen gas balloon with a volume of approximately 1 L connected to the reaction flask.

[0148] A hydrogen atmosphere refers to a hydrogen gas balloon with a volume of approximately 1 L connected to the reaction flask.

[0149] For the pressurized hydrogenation reaction, a Parr 3916EKX hydrogenation apparatus and a Seiran QL-500 hydrogen generator or an HC2-SS hydrogenation apparatus were used.

[0150] The hydrogenation reaction was generally carried out by repeating the process of evacuating and filling with hydrogen gas three times.

[0151] A CEM Discover-S 908860 microwave reactor was used for the microwave reactions.

[0152] In the examples, unless otherwise specified, the solution refers to an aqueous solution.

[0153] In the examples, unless otherwise specified, the reaction temperature is room temperature, 20°C to 30°C.

[0154] In the examples, thin layer chromatography (TLC) was used to monitor the progress of the reaction. The volume ratio of the developing solvent used in the reaction, the eluent system for column chromatography used to purify the compound, and the developing solvent system for thin layer chromatography was adjusted according to the polarity of the compound, and may be adjusted by adding a small amount of a basic or acidic reagent such as triethylamine and acetic acid.

[0155] Example 1. Preparation of Compound 2 [ka] Step 1: 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) were added to a 500 mL three-neck flask, heated to 50 °C, and stirred for 16 h. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 100 mL of water, 100 mL of absolute ethanol, and dried to give compound 2b (pale yellow solid, 27.4 g, 71% yield). MS m / z (ESI): 197.1[M+1] + . 1 H NMR (400MHz, DMSO-d6): δ7.02 (s, 4H), 1.72-1.68 (m, 4H), 1.42-1.35 (m, 4H).

[0156] Step 2: 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 to a 1 L three-neck flask, and the reaction mixture was stirred at room temperature for 24 hours. 500 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered, washed, and dried to obtain compound 2c (white solid, 20.2 g, yield: 52%). MS(ESI): 281.1[M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ 5.20 (d, 4 H, J = 11.6), 4.91 (d, 4 H, J = 11.2), 2.25-2.18 (m, 4H), 1.56-1.50 (m, 4H).

[0157] Step 3: Compound 2c (2.73 g, 9.73 mmol) was weighed and placed in a dry three-neck flask. The flask was purged with argon gas, and methanesulfonic acid (10 mL) was added to dissolve the compound. Compound 1a (1 g, 3.24 mmol, prepared according to the known method "WO2012 / 051407A") was added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was gradually added to 100 mL of water (cooled in an ice-water bath), and the mixture was allowed to cool to room temperature after addition. The mixture was filtered and dried to obtain 1.77 g of crude product. The crude product was dissolved in TFA (4 mL) by heating, and then 16 mL of water was added, stirred, filtered, and dried under vacuum to obtain compound 2d (1.21 g, yield: 44.9%). MS(ESI): 837.3[M+1] + . 1 H NMR (400 MHz, CDCl3): δ5.72~5.37(m, 10 H), 5.15 (d, 4 H), 4.75 (d, 4 H), 4.15~4.11 (m, 6 H), 2.28 (br, 4 H), 2.05 (br, 4 H), 1.45 (br, 8 H).

[0158] Step 4: Compound 2d (1.06 g, 1.27 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in TFA (10 mL). Compound 1b (1.42 g, 3.17 mmol, prepared according to the known method in WO2012 / 051407A) was then added. After addition was complete, the reaction mixture was heated to 60°C and stirred for 3 hours. The TFA was evaporated under reduced pressure, and the resulting solid was added with 20 mL of ethanol and heated to reflux for 2 hours, 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, and then 30 mL of ethanol was added and filtered. The filter cake was purified by high-performance liquid chromatography (column: SharpSil-T, 30 × 150 mm, 5 μm, mobile phase: aqueous phase and acetonitrile, gradient blending ratio: aqueous phase 25% to 42%), and finally salted with sodium hydroxide to obtain compound 2 (0.27 g, yield: 12.6%). MS m / z (ESI): 1605.2[M-4Na+5H] + . 1 H NMR (400 MHz, D2O): δ 7.68~7.65 (m, 4 H), 7.07~7.05 (m, 4 H), 5.50~5.45 (m, 6 H), 5.26~5.16 (m, 8 H), 4.39 (d, 4 H), 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).

[0159] Example 2. Preparation of Compound 3 [ka] 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 h, filtering, washing, and drying to give the title product 3b (6.8 g, yield: 56.2%).

[0160] Step 2: Substrate 3b (3.4 g, 17.2 mmol) was weighed into a dry three-neck flask, 2.54 grams of paraformaldehyde and 9 M HCl (15 mL) were added, and the mixture was stirred at room temperature for 24 hours. The reaction mixture was then stirred at room temperature for 24 hours, filtered, washed, and dried to give the title product 3c (2.1 g, yield: 43.2%). MS m / z (ESI): 283.1 [M+1]+. 1 H NMR (400 MHz, DMSO-d6): δ5.21 (d, 4H), 4.93 (d, 4H), 2.33 (q, 4H), 0.91 (d, 6H).

[0161] Step 3: Compound 3c (2.75 g, 9.73 mmol) was dissolved in methanesulfonic acid (10 mL), and compound 1a (1 g, 3.24 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was slowly added to 100 mL of water (cooled in an ice-water bath). After addition, the mixture was allowed to cool to room temperature. The mixture was filtered and dried to give 1.67 g of crude product. The crude product was dissolved in TFA (4 mL) by heating, and then 16 mL of water was added. The mixture was stirred, filtered, and dried under vacuum to give the title product 3d (off-white solid, 1.56 g, yield: 57.3%). MS m / z (ESI): 833.2[M+1]+. 1 H NMR (400 MHz, DMSO-d6): δ5.68 (d, 2 H), 5.53 (t, 6 H),5.38 (d, 2 H), 5.15(d, 4 H), 4.77 (d, 4 H), 4.20 ~ 4.15 (m, 6 H), 2.35 ~2.32 (m, 4 H), 2.20~2.15 (m, 4 H), 0.88 ~0.80 (m, 12 H).

[0162] Step 4: 3d (0.89 g, 1.06 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in 10 mL of TFA. Compound 1b (1.19 g, 2.66 mmol) was then added. After addition, the reaction was heated to 70 °C and stirred for 3 h. The TFA was evaporated under reduced pressure. The resulting solid was added to 20 mL of ethanol and heated to reflux for 2 h. The solid was cooled to room temperature, filtered, and dried. The resulting solid was dissolved in 6.6 mL of water and then added to 19.8 mL of ethanol. The solid was filtered, washed, and the filter cake was purified by high-performance liquid chromatography (SharpSil-T, 30 x 150 mm, 5 μm column, mobile phase: aqueous and acetonitrile, gradient ratio: aqueous 25% to 42%). Finally, the title product 3 was salted with sodium hydroxide to give 0.28 g (yield: 15.5%). MS (ESI): 1607.4 [M-4Na+3H] - . 1 H NMR (400 MHz, D2O): δ7.41~7.39 (m, 4 H), 6.81~6.80 (m, 4 H), 5.46 (d, 4 H), 5.38 (d, 2 H),5.30 (d, 4 H), 5.20 (d, 2 H), 5.08 (d, 2 H), 4.38 (d, 4 H), 4.09~4.01 (m, 8 H), 3.84~3.76 (m,6 H), 3.19~3.02 (m, 8 H), 2.36~2.18 (m, 16 H), 0.88 (t, 6 H), 0.82 (t, 6 H).

[0163] Example 3. Preparation of Compound 1 [ka]

[0164] Example 4. Preparation of Compound 4 [ka]

[0165] Example 5. Preparation of Compound 5 [ka]

[0166] Example 6. Preparation of Compound 6 [ka]

[0167] Example 7. Preparation of Compound 7 [ka]

[0168] Example 8. Preparation of Compound 8 [ka]

[0169] Example 9. Preparation of Compound 9 [ka]

[0170] Example 10. Preparation of Compound 10 [ka]

[0171] Example 11. Preparation of Compound 11 [ka] Step 1: 1,4-Dihydroxynaphthalene (1 g, 6.24 mmol) was dissolved in 10% aqueous NaOH (8 mL). After purging with nitrogen, a solution of compound 11a (2.14 g, 15.6 mmol) in dioxane (12 mL) was added dropwise. The reaction was stirred overnight at room temperature. The reaction mixture was evaporated to dryness and purified by reverse-phase preparative separation to give compound 11b (0.8 g, 26% yield) as a white solid. MS m / z (ESI): 433.1[M-2Na +3H]+ . 1 H NMR (400 MHz, DMSO-d6): δ 8.12~8.10 (m, 2 H), 7.53~7.51 (m, 2 H), 6.84 (s, 2 H), 4.07 (t, 4 H), 2.55~2.49 (m, 4 H), 1.91~1.79 (m, 8 H).

[0172] 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 the addition was complete, the reaction mixture was heated to 70 °C and stirred for 2 h. TFA was evaporated under reduced pressure, and the resulting solid was purified by column chromatography (Column: SharpSil-T, 30 × 150 mm, 5 μm; Mobile phase: aqueous and acetonitrile; Gradient blending ratio: aqueous phase 25% to 42%) to obtain 192 mg of a white solid. The solid was dissolved in 2 mL of water, and the pH of the system was adjusted to 5-8 with 0.5 M aqueous sodium hydroxide. 10 mL of ethanol was added to precipitate the solid, which was then filtered to obtain compound 11 (120 mg, yield: 16.5%) as a white solid. MS m / z (ESI): 1678.3[(M-4Na+4H+18HH)] + . 1 H NMR (400 MHz, D2O): δ7.87~7.81 (m, 4 H), 7.44~7.36 (m, 4 H), 5.53~5.46(m, 7 H), 5.31~5.23(m, 9 H), 4.30(d, 3 H), 4.12~3.94 (m, 9 H), 3.78~3.76 (m, 4 H), 2.87~2.82 (m, 8 H), 2.05~1.80 (m, 24 H), 1.38~1.25 (m, 8 H).

[0173] Example 12. Preparation of Compound 12 [ka] Step 1: Compound 12a (10.85 g, 51.6 mmol, prepared in the same manner as compound 2b in Example 1) was weighed into a dry three-neck flask, and 7.75 grams of paraformaldehyde and 9 M HCl (45 mL) were added and stirred at room temperature for 24 hours. 163 mL of water was added, and the reaction mixture was stirred at room temperature for 24 hours. The mixture was filtered, and the filter cake was washed with water (60 mL) and ethanol (60 mL), and dried to give 10.84 g of compound 12b as a beige solid (71.4% yield). MS m / z (ESI): 295.1 [M+1] + . 1 H NMR (400 MHz, DMSO-d6): δ5.21 (d, 4 H, J = 11.3 Hz), 4.93 (d, 4 H, J = 11.3 Hz), 2.34 (br, 4 H), 1.48 (br, 6 H).

[0174] Step 2: Compound 12b (2.00 g, 6.80 mmol) was weighed and placed in a dry three-neck flask. The flask was purged with argon gas, and methanesulfonic acid (7 mL) was added to dissolve the compound. Compound 1a (0.70 g, 2.27 mmol, prepared according to the known method "WO2012 / 051407 A2") was then 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). After addition, the mixture was allowed to cool to room temperature. The mixture was filtered, and the filter cake was washed with a small amount of water. After drying, 1.97 g of crude product was obtained. 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 filter cake was filtered, washed with a small amount of water, and dried under vacuum to obtain 1.75 g of compound 12c as an off-white solid (yield: 81.7%). MS m / z (ESI): 861.3 [M+1] + . 1H NMR (400 MHz, DMSO-d6): δ5.50 ~ 5.41 (m, 10 H), 5.16 (d, 4 H, J = 10.7 Hz),4.76 (d, 4 H, J = 10.6 Hz), 4.22 ~ 4.15(m, 6 H), 2.40 (br, 4 H), 2.22 (br, 4 H), 1.45 ~1.26 (m, 12 H).

[0175] Step 3: Compound 12c (1.00 g, 1.16 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in TFA (10 mL). Compound 1b was then added. After the addition was complete, the reaction mixture was heated to 60 °C and stirred for 3 h. The TFA was evaporated under reduced pressure, and the resulting solid was added to 20 mL of ethanol and heated to reflux for 2 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The resulting solid was purified by high-performance liquid chromatography (mobile phase: aqueous and acetonitrile, gradient ratio: aqueous 25% to 42%) and finally salted with sodium hydroxide to give 0.12 g of compound 12 as a white solid. MS m / z (ESI): 1649.1 [M-4Na+4H + NH4] + . 1 H NMR (400 MHz, D2O): δ8.04(br, 4 H), 7.64(br, 4 H),5.68 ~ 5.59 (m, 7 H), 5.42 ~ 5.39 (m, 4 H), 5.30 ~ 5.26 (m, 4 H), 4.44 ~ 4.39 (m, 3 H), 4.22 ~ 4.07 (m, 10 H), 3.93 ~ 3.91 (m, 4 H), 3.28 ~ 3.13 (m, 8 H), 2.44 ~ 2.22 (m, 16 H), 1.61 ~ 1.34 (m, 12 H).

[0176] Example 13. Preparation of Compound 13 [ka] Step 1: DMSO (50 mL) was added to a three-neck flask, followed by KOH (8.75 g, 156 mmol). The mixture was ultrasonically mixed to disperse the KOH in the DMSO. The air was then purged with nitrogen gas and the mixture was stirred at room temperature for 1 hour. Compound 13a (5 g, 31.25 mmol) and compound 13b (24.3 g, 125 mmol) were added slowly to the reaction mixture. The reaction mixture was heated to 60 °C and stirred for 2 hours. After the reaction mixture cooled to room temperature, 200 mL of water was added and the mixture was extracted with dichloromethane (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried, filtered, and the solvent was removed by rotary evaporation. The crude product was column-coated (PE:EA = 5:1) to give 4.56 g of compound 13c as a red solid (38% yield). MS m / z (ESI): 389.2[M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.20 (q, 2 H), 7.49 (q, 2 H),6.67 (s,2 H),4.18-4.12 (m,8 H), 2.61 (t, 4 H), 2.27-2.20 (m, 4 H), 1.25 (t, 6 H).

[0177] Step 2: Compound 13c (3.50 g, 9.02 mmol) was weighed into a dry three-neck flask, purged with nitrogen, and dissolved in TFA (20 mL). Compound 2d (3.00 g, 3.61 mmol) and acetic anhydride (918 mg, 9.02 mmol) were then added. After the addition was complete, the reaction was heated to 70 °C and stirred for 4 hours. The TFA was evaporated under reduced pressure, and the resulting solid was added with 50 mL of methyl tert-butyl ether. The mixture was heated to 50 °C and stirred for 0.5 hours, cooled to room temperature, and filtered. The filter cake was washed with methyl tert-butyl ether and dried to give 4.2 g of compound 13d as a brown solid. MS m / z (ESI): 1590.3[M+18] + .

[0178] Step 3: Compound 13d (2.0 g, 1.27 mmol) was added to a 50 mL single-neck flask and mixed with methanol and water (1:1, 30 mL), LiOH . HO (534 mg, 12.7 mmol) was added to dissolve it. After the addition was complete, the reaction was heated to 80 °C and stirred for 3 h. The solvent was evaporated under reduced pressure, and ethanol and water (10:1, 20 mL) were added. The mixture was stirred at room temperature for 0.5 h and then filtered. The filter cake was washed with ethanol and dried. The resulting solid was dissolved in water and NaOH (1 M) and then purified by high-performance liquid chromatography (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25% to 42%). Finally, the salt was formed with sodium hydroxide to give 114 mg of compound 14 as a white solid (yield 6.15%). MS m / z (ESI): 1478.2[M-4Na+4H+NH4] + . 1 H NMR (400 MHz, D2O): δ7.87 (br, 4 H), 7.46 (br, 4 H), 5.55~5.44(m, 6 H), 5.29~5.13 (m, 8 H), 4.20-3.92 (m, 14 H), 3.69 (br, 4 H), 2.19~1.90 (m, 24 H), 1.34 (br, 8 H).

[0179] Example 14. Preparation of Compound 14 [ka] Step 1: Compound E1 (25 g, 96 mmol) and anhydrous THF (70 mL) were added to a three-neck flask, which was then purged with nitrogen gas and cooled to -78 °C in a dry ice acetone bath. DIBAL-H (135 mL, 202 mmol, 1.5 M toluene) was slowly added dropwise. After the addition was complete, the temperature was raised to 0 °C and the reaction was stirred at 0 °C for 45 min. The reaction was then quenched by the dropwise addition of HCl (1 M, 500 mL) at 0 °C, 200 mL of ethyl acetate was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed with saturated brine (100 mL), dried, filtered, and the solvent was removed by rotary evaporation. The crude product was column-coated (PE:EA = 5:1) to obtain 15.8 g of compound E2 as a pale yellow oil (yield: 71.5%). 1 H NMR (400 MHz, CDCl3): δ 3.77-3.75 (m, 2 H), 3.62-3.53 (m, 4 H), 2.46 (br,1 H), 2.29-2.22 (m,1 H).

[0180] 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-neck flask. The flask was purged with nitrogen and the reaction mixture was heated to 100 °C and stirred for 3 h. After cooling to room temperature, the reaction mixture was poured into ice water and extracted with ethyl acetate (50 mL × 3). The combined organic phase was washed sequentially with NaHCO3 solution and saturated brine, dried, filtered, and the solvent was removed by rotary evaporation. The crude product was column-coated (PE:EA = 50:1) to give 2.74 g of compound E3 as a pale yellow solid (46% yield). 1 H NMR (400 MHz, CDCl3): δ 8.16 (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).

[0181] Step 3: Compound E3 (5.0 g, 8.56 mmol) was weighed into a dry three-neck flask, purged with nitrogen, and dissolved in DMSO (60 mL). NaCN (4.2 g, 85.6 mmol) was then added. After the addition was complete, the reaction mixture was heated to 75°C and stirred for 1 hour. The reaction mixture was poured into ice water, and a large amount of solid precipitated, which was filtered. Ethyl acetate was added to the resulting solid, and the mixture was stirred at room temperature for 0.5 hours. The solid was filtered and dried to give 2.33 g of compound E (73.5% yield) as a white solid. MS m / z (ESI): 390[M+18] + .

[0182] Step 4: Compound E (2.1 g, 5.64 mmol) was weighed into a sealed tube and HCl / EtOH (75 mL, 10 M) was added. Although it did not completely dissolve, the reaction was heated to 90 °C and stirred for 24 h. The solvent was evaporated. The crude product was columned (PE:EA = 5:1) to give 1.08 g of compound 14a as a colorless oil (yield: 34.2%). MS m / z (ESI): 561[M+1] + . 1 H NMR (400 MHz, CDCl3): δ 8.16 (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).

[0183] Step 5: Compound 14a (1.4 g, 2.50 mmol) was weighed into a dry three-neck flask, purged with nitrogen, and dissolved in TFA (5 mL). Compound 2d (520 mg, 0.625 mmol) and acetic anhydride (5 mL) were then added. After the addition was complete, the reaction mixture was heated to 90 °C and stirred for 4 h. The TFA was evaporated under reduced pressure, and the resulting solid was added with 50 mL of methyl tert-butyl ether. The mixture was heated to 50 °C and stirred for 0.5 h, cooled to room temperature, and filtered. The filter cake was washed with methyl tert-butyl ether and dried to give 1.2 g of a brown solid. Acetonitrile was added to the resulting solid to dissolve it. The solid was then purified by high-performance liquid chromatography (mobile phase: aqueous and acetonitrile, gradient blend ratio: aqueous 25% to 42%) to give 170 mg of compound 14b as a white solid (yield: 3.55%). MS m / z (ESI): 1934[M+18] + .

[0184] Step 6: Compound 14b (150 mg, 0.078 mmol) was weighed into a 25 mL single-neck flask, and methanol and water (1:1, 10 mL) were added to dissolve it, followed by LiOH . HO (534 mg, 12.7 mmol) was added. After the addition was complete, the reaction mixture was heated to 80 °C and stirred for 3 h. The reaction mixture was purified by high-performance liquid chromatography (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25% to 42%) and finally salted with sodium hydroxide to give 53 mg of compound 14 as a white solid (yield: 40%). MS m / z (ESI): 1710[M-8Na+8H+NH4] + . 1H NMR (400 MHz, D2O): δ7.80-7.97 (m, 4 H), 7.39-7.38 (m, 4 H), 5.50-5.46(m, 6 H), 5.34 (s, 4 H), 4.96(d, 4 H),4.50 (d, 4 H), 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).

[0185] Example 15. Preparation of Compound 15 [ka] Step 1: Compound E3 (2.25 g, 3.83 mmol) and sodium sulfite (4.91 g, 38.9 mmol) were added to a three-neck flask, and the air was purged with nitrogen. Then, 42 mL of isopropanol and 42 mL of water were added. The reaction mixture was heated to 100 °C and stirred for 24 hours. The reaction mixture was cooled to room temperature and concentrated to give the crude product. An additional 83 mL of methanol was added, and the mixture was slurried and stirred for 1 hour. The solid was collected by filtration and purified by HPLC to give 1.62 g of compound 15a as a white solid (yield: 64%). MS m / z (ESI): 331.8[M / 2+1] + . 1 H NMR (400 MHz, D2O): δ 8.23~8.22 (m, 2 H), 8.57~7.55 (m, 2 H), 6.90~6.88 (m, 2 H),4.40~4.39 (m, 4 H), 3.33~3.31 (m, 8 H), 2.94~2.92 (m, 2H).

[0186] Step 2: Compound 15a (1.57 g, 2.37 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in TFA (15 mL). Compound 2d (0.79 g, 0.95 mmol) was then added. After the addition was complete, the reaction was heated to 70 °C and stirred for 3 h. The TFA was evaporated under reduced pressure, and the resulting solid was added to 40 mL of ethanol and heated to reflux for 2 h, 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 then the pH of the system was adjusted to approximately 7 with 1 M aqueous sodium hydroxide solution. 50 mL of ethanol was added to precipitate the viscous substance. The supernatant was discarded, and the residue was dried by rotation. It was then purified by high-performance liquid chromatography (mobile phase: aqueous phase and acetonitrile, gradient ratio: aqueous phase 25% to 42%), and finally salted with sodium hydroxide to obtain 299 mg of compound 15 as a white solid (yield: 12%). MS m / z (ESI): 990.6[(M-8Na+8HHH) / 2] + . 1 H NMR (400 MHz, D2O): δ7.96~7.93 (m, 4 H), 7.32~7.33 (m, 4 H), 5.57~5.44(m, 6 H), 5.35~5.31(m, 4 H), 5.09~5.05(m, 4 H), 4.54~4.50 (m, 4 H), 4.27~4.23 (m, 4 H), 4.10~4.01 (m, 10 H), 3.52~3.31 (m, 16 H), 2.98~2.92 (m, 4 H), 2.19~2.17 (m, 4 H), 2.01~1.98 (m, 4 H), 1.47~1.45 (m, 8H).

[0187] Example 16. Preparation of Compound 16 [ka] Step 1: 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) were dissolved in acetonitrile (40 mL). The reaction mixture was purged with nitrogen gas three times, heated to 70 °C, and reacted for 2 days. After cooling to room temperature, the reaction mixture was filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by column chromatography (PE:PA = 50:1) to give compound 16a (1.6 g, yield: 34.25%). 1 H NMR (400 MHz, CDCl3): δ 8.27~8.25 (m, 2 H), 7.55~7.52 (m, 2 H), 6.69 (s, 2 H), 4.42 (t, 4 H), 3.76 (t, 4 H).

[0188] Step 2: Compound 16a (800 mg, 2.14 mmol) and sodium sulfite (593 mg, 4.70 mmol) were added to a three-neck flask, and the air was purged with nitrogen. Then, 6 mL of DMF and 6 mL of water were added. The reaction mixture was heated to 100 °C and stirred for 24 hours. The reaction mixture was cooled to room temperature and filtered. The filtrate was poured into 60 mL of acetone, and a precipitate formed. The resulting mixture was filtered to give 880 mg of a pale 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 dried under vacuum to give 570 mg of compound 16b as a white solid (63% yield). MS m / z (ESI): 393.8[M-2Na+2H+18] + .

[0189] Step 3: Compound 16b (570 mg, 1.36 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in TFA / AcO (1:1, 10 mL). Compound 2d (452 ​​mg, 0.54 mmol) was then added. After the addition was complete, 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 and acetonitrile, gradient ratio: aqueous 25% to 42%) to give 157 mg of a white solid. This was dissolved in 2 mL of water, adjusted to a pH of approximately 7 with 0.5 M aqueous sodium hydroxide, added with 10 mL of ethanol, and filtered to give 116 mg of compound 16 as a white solid (yield: 13.8%). MS m / z (ESI): 774.4[M / 2-4Na+5HHH] + . 1 H NMR (400 MHz, D2O): δ7.76~7.74 (m, 4 H), 7.01~6.99 (m, 4 H), 5.52~5.46(m, 6 H), 5.29~5.17(m, 8 H), 4.48~4.36(m, 8 H), 4.18~4.06 (m, 8 H), 3.95 (d, 2 H), 3.46 (t, 8 H), 2.15~2.07 (m, 8 H), 1.52~1.39 (m, 8 H).

[0190] Example 17. Preparation of Compound 17 [ka] Step 1: A 100 mL three-neck flask was charged with zinc powder (3.720 g, 56.9 mmol) and acetic acid (20 mL), and the mixture was flushed with nitrogen three times. Compound 17a (0.980 g, 5.69 mmol) was then added in one portion and stirred at room temperature for 5–10 min. When in-process control showed the reaction was complete, the reaction mixture was filtered, the filter cake was rinsed with 15 mL of acetic acid, and the filtrate was 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 give 0.982 g of compound 17b (yield: 99%, purity: 95.8%). MS-ESI: m / z 175.1 [M+H] + .

[0191] Step 2: A 50 mL three-neck flask was charged with sodium hydroxide (0.370 g, 9.24 mmol) and water (3.3 mL), followed by flushing with nitrogen three times. After stirring to dissolve, 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 the addition was complete, the temperature was returned to room temperature and stirring continued for 19 h. In-process control confirmed the complete reaction of the starting materials. The reaction mixture was filtered, and the filter cake was rinsed 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 × 3) to give 0.830 g of compound 17c (yield: 44.6%, purity: 99.7%). MS-ESI: m / z 418.9 [M-2Na+3H] + . 1 H NMR (400 MHz, D2O):δ 8.01 (d, J = 8.4 Hz, 1 H), 7.89 (s, 1 H), 7.37-7.35 (m, 1 H), 6.80-6.73 (m, 2 H), 4.16-4.13 (m, 4 H), 3.10-3.06 (m, 4 H), 2.42 (s, 3 H) 2.25-2.17 (m, 4 H).

[0192] Step 3: Compound 17c (0.416 g, 0.9 mmol), TFA (6 mL), and compound 2d (0.3 g, 0.36 mmol) were added to a 50 mL single-neck flask, purged with nitrogen gas three times, and heated to 70 °C in an oil bath for 3 h. When in-process control indicated the reaction was complete, the reaction was stopped. The reaction mixture was cooled to room temperature and concentrated to a solid. 15 mL of ethanol was added, stirred for 10 min, filtered, and the filter cake was rinsed with ethanol (10 mL) to give 822 mg of crude compound 17d (yield: 35.7%, purity: 97.7%). MS-ESI: m / z 1650.4 [M+18] + .

[0193] Step 4: Compound 17d (0.210 g, 0.128 mmol) and THF (4 mL) were added to a 100 mL single-neck flask. The pH of the solution was adjusted to 7 with 0.5 N aqueous sodium hydroxide solution, and then ethanol (12 mL) was added dropwise to precipitate a solid. After filtration, the filter cake was rinsed with ethanol (5 mL). The resulting filter cake was freeze-dried to give 0.153 g of compound 17 (yield: 69.2%, purity: 98.02%). MS-ESI: m / z 1650.3 [M-4Na+18] + . 1 H NMR (400 MHz, DMSO-d6):δ 7.78-7.71 (m, 4 H), 7.53-7.52 (m, 2 H), 5.59-5.24 (m, 14 H), 4.33-3.72 (m, 18 H), 2.78-2.62 (m, 14 H), 2.44-1.86 (m, 17 H), 1.46-1.23 (m, 9 H).

[0194] Example 18. Preparation of Compound 18 [ka] 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 dissolved in 2 mL of tert-butyl alcohol and stirred. N-methylmorpholinodioxide (803.4 mg, 6.86 mmol) and potassium osmate dihydrate (25.3 mg, 68.6 μmol) were added. After addition was complete, the reaction was allowed to proceed at room temperature for 16 h. In-process control indicated completion. The reaction was quenched by adding 5 mL of aqueous sodium sulfite solution, 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 then separated by column chromatography (PE:EA = 1:1) to give 197 mg of compound 18b (40% yield). 1 H NMR (400 MHz, CDCl3): δ 3.83 (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).

[0195] Step 2: A 500 mL three-necked reaction flask was charged with DMSO (12.22 g, 156.41 mmol) and DCM (310 mL), protected with nitrogen gas, and cooled to -60 °C. Trifluoroacetic anhydride (29.15 g, 138.77 mmol) was added dropwise, and after approximately 25 minutes of dropwise addition, the mixture was kept warm and stirred for 20 minutes. Then, a solution of compound 18b (5.1 g, 35.36 mmol) in DCM (15 mL) was added, and the mixture was kept warm and stirred for 1.5 hours. Triethylamine (32.67 g, 322.86 mmol) was added, and the mixture was stirred at -60 °C for 1 hour, and then the mixture was warmed to room temperature and stirred. When the in-process control showed that the reaction was complete, 324 mL of 10% hydrochloric acid was added to the reaction mixture, 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 then separated by column chromatography (PE:EA = 10:1) to give 3.715 g of compound 18c (yield: 75%). MS m / z (ESI): 141.1[M+H] + . 1 H NMR (400 MHz, CDCl3): δ 6.06 (d, 1 H), 5.90 (s, 1 H), 2.65-2.57 (m, 1H), 2.47-2.34 (m, 3H), 1.06 (d, 3 H), 1.00 (d, 3 H).

[0196] Step 3: A 100 mL reaction flask was charged with 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), heated to 50 °C, and stirred for 16 h. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 10 mL of water, 12 mL of absolute ethanol, and dried to give 2.34 g of compound 18d (yield: 39%). MS m / z (ESI): 225.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.10 (s, 2 H), 7.02 (s, 2 H) ,1.75-1.71 (m, 4H), 1.57-1.51 (m, 2H) ,0.84 (s, 3 H) ,0.82 (s, 3 H).

[0197] Step 4: Compound 18d (1.12 g, 5.0 mmol), 5 mL of 9 M hydrochloric acid, and paraformaldehyde (751 mg, 25.0 mmol) were added to a 50 mL reaction flask, and the reaction mixture was stirred at room temperature for 24 hours. 18 mL of water was added to the reaction mixture, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was filtered, and the filter cake was rinsed with 5 mL of water, 5 mL of ethanol, and dried to give 0.54 g of compound 18e (yield: 35%). MS m / z (ESI): 309.1[M+H] + . 1H NMR (400 MHz, DMSO-d6): δ 5.21-5.17 (m, 4H),,4.97-4.88 (m, 4H), 2.64-2.60 (m, 2H), 1.87-1.75 (m, 2H), 1.66-1.56 (m, 2H),0.92 (s, 3H) ,0.90 (s, 3H).

[0198] Step 5: Compound 18e (0.54 g, 1.75 mmol) was weighed into a dry reaction flask, purged with argon gas, and dissolved in methanesulfonic acid (1.8 mL). Compound 1a (0.18 g, 0.584 mmol) was added at room temperature and allowed to react with stirring for 24 hours. The reaction mixture was then slowly added to 18 mL of water (cooled in an ice-water bath). After addition, the mixture was allowed to warm to room temperature and stirred for 10 min. After filtration, the filter cake was washed with a small amount of water. The crude product was dissolved in TFA (0.72 mL), followed by addition of 2.88 mL of water and stirring at room temperature for 10 min. After filtration, the filter cake was washed with a small amount of water and dried under vacuum to give 0.518 g of compound 18f (yield: 99%). MS m / z (ESI): 889.3[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 5.74~5.35(m, 10 H), 5.21-5.08 (m, 4 H), 4.86-4.69 (m, 4 H), 4.29-4.05 (m, 4 H), 1.80-1.43 (m, 10 H), 0.98-0.74 (m, 16H).

[0199] Step 6: Compound 18f (502 mg, 0.565 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in trifluoroacetic acid (5 mL). Compound 1b (637 mg, 1.42 mmol) was then added. After the addition was complete, the reaction mixture was heated to 70 °C and stirred for 3 h. TFA was evaporated under reduced pressure, and the resulting solid was added to 7.5 mL of ethanol and heated to reflux for 1 h. The mixture was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The resulting solid was purified by high-performance liquid chromatography (mobile phase: aqueous and acetonitrile, gradient ratio: aqueous 25% to 42%) and further salted with sodium hydroxide to give 0.12 g of compound 18 (yield: 12%). MS m / z (ESI): 1678.5 [M-4Na+4H+18] + . 1 H NMR (400 MHz, DMSO-d6): δ 8.00-7.89 (m, 4 H), 7.75-7.63 (m, 4 H), 7.35-6.99((m, 7 H), 5.63-5.19 (m, 14 H), 4.42-4.00 (m, 12 H), 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).

[0200] Example 19. Preparation of Compound 19 [ka] Step 1: Compound 19a (4 g, 41.59 mmol) was dissolved in tert-butyl alcohol (1.4 mL) and stirred. N-methylmorpholinodioxide (5.43 g, 46.35 mmol) and potassium osmate dihydrate (172 mg, 467 μmol) were then added. After the addition was complete, the reaction was allowed to proceed at room temperature for 16 hours. When the reaction was complete as indicated by in-process control, the reaction was quenched by adding 30 mL of aqueous sodium sulfite solution and extracted with ethyl acetate (3 × 30 mL). The organic phases were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was separated by column chromatography (PE:EA = 1:1) to give 3 g of compound 19b (yield: 55%). 1 H NMR (400 MHz, CDCl3): δ 3.99-3.91(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).

[0201] Step 2: A 500 mL three-necked reaction flask was charged with DMSO (9.82 g, 125.69 mmol) and DCM (200 mL), protected with nitrogen gas, and cooled to -60 °C. Trifluoroacetic anhydride (24.24 g, 115.40 mmol) was added dropwise, and after 20 minutes of addition, the mixture was kept warm and stirred for 20 minutes. Then, a solution of compound 19b (3 g, 23.04 mmol) in DCM (8 mL) was added, and the mixture was kept warm and stirred for 1.5 hours. Then, triethylamine (26.50 g, 261.87 mmol) was added, and the mixture was stirred at -60 °C for 1 hour, and then the mixture was warmed to room temperature and stirred. When the in-process control showed that the reaction was complete, approximately 216 mL of 10% hydrochloric acid was added to the reaction system, which was then extracted with DCM (60 mL × 3), dried over anhydrous sodium sulfate, and concentrated. After that, the crude product was separated by column chromatography (PE:EA = 10:1) to give 2.01 g of compound 19c (yield: 69%). MS m / z (ESI): 127.1[M+H] + . 1H NMR (400 MHz, CDCl3): δ 6.13-6.09 (m, 1H), 2.64-2.37 (m, 3H), 2.29-2.06 (m, 3H), 1.09 (d, 3H).

[0202] Step 3: A 100 mL reaction flask was charged with 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), heated to 50 °C, and stirred for 16 h. The reaction was cooled to room temperature, filtered, and the filter cake was rinsed with 10 mL of water, 10 mL of absolute ethanol, and dried to give 1.52 g of compound 19d (45% yield). MS m / z (ESI): 211.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 7.11-6.98 (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).

[0203] Step 4: 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 to a 50 mL reaction flask, and the mixture was stirred at room temperature for 24 h. The mixture was concentrated, and the residue was separated by column chromatography (dichloromethane:acetonitrile = 10:1) to give 191 mg of compound 19e (yield: 13%). MS m / z (ESI): 295.1[M+H] + . 1 H NMR (400 MHz, DMSO-d6): δ 5.21-5.17 (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).

[0204] Step 5: Compound 19e (66 mg, 0.21 mmol) was weighed and placed in a dry three-neck flask. The flask was purged with argon gas, and methanesulfonic acid (0.5 mL) was added to dissolve the compound. 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). After addition, the mixture was allowed to cool to room temperature. After filtration, the filter cake was washed with a small amount of water and dried. The 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. After filtration, the filter cake was washed with a small amount of water and dried under vacuum to give 185 mg of compound 19f (yield: 100%). MS m / z (ESI): 878.1[M+18] + . 1 H NMR (400 MHz, DMSO-d6): δ5.68~5.42(m, 10 H), 5.16~5.14 (m, 4 H), 4.80~4.74 (m, 4 H), 4.20~4.16 (m, 6 H), 2.08~1.99 (m, 2 H), 1.55~1.47 (m, 6H), 1.24~0.97 (m, 12H).

[0205] Step 6: Compound 19f (204 mg, 0.24 mmol) was weighed into a dry three-neck flask, purged with argon gas, and dissolved in TFA (2 mL). Compound 1b (266 mg, 0.59 mmol) was then added. After the addition was complete, the reaction mixture was heated to 70 °C and stirred for 3 h. The TFA was evaporated under reduced pressure, and the resulting solid was added with 3 mL of ethanol and heated to reflux (80 °C) for 40 min. The solid was cooled to room temperature and filtered. The filter cake was washed with ethanol and dried. The crude product was purified by high-performance liquid chromatography (HPLC) (mobile phase: aqueous and acetonitrile, gradient ratio: aqueous 25% to 42%) and further salted with sodium hydroxide to give 0.15 g of compound 19 (yield: 36%). MS m / z (ESI): 1650.4[M-4Na+4H+18] + . 1H NMR (400 MHz, D2O): δ 7.99~7.55 (m, 4 H), 7.47~7.04 (m, 4 H), 5.43~4.81 (m, 14 H), 4.20~3.52 (m, 18H), 3.07~2.66 (m, 8 H), 2.20~0.90 (m, 28H).

[0206] Test Example 1: Test of antagonistic effect of compounds according to the present disclosure against muscle relaxants 1. Purpose of the experiment The compounds provided by the present disclosure are tested for their ability to reverse muscle relaxant effects on the gastrocnemius muscle in a rat neuromuscular model, evaluating indicators such as time to onset of action and TOF, and comparing them with CB2 and neostigmine.

[0207] 2. Experimental materials SPF-grade SD male rats, BL-420A biological function 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, suxamethonium, neostigmine, sterile water, 95% alcohol.

[0208] 3. Experimental Method SPF-grade SD male rats that had passed quarantine were selected and housed in a room temperature of 22±0.5°C, with a ventilation rate of 20-50 / h, an air velocity of 0.05-0.18 m / s, and a 12 / 12-hour light / dark cycle. They were allowed to adapt for at least three days in the animal facility, housed six rats per cage, and the study began when they reached a body weight of 220-250 g.

[0209] The test sample was reconstituted in 0.9% sodium chloride. After calculating the content, the required amount of test sample was weighed and dissolved in 0.9% sodium chloride injection (within 30 minutes). After that, the mixture was mixed uniformly in a vortex mixer and shaken. CB2 was reconstituted in purified water.

[0210] Actual weighed drug weight (mg) = administered formulation concentration A (mg / mL) × solvent volume (mL) / content (%) The rats were randomly divided into CB2 group, compound 2 group, compound 3 group, and neostigmine group, with 4 rats in each group (according to the actual number of rats in each group), and the administration volume was 2 mL / kg for all groups.

[0211] The structure of CB2 (prepared by the known method "WO2012051407A2") is as follows:

[0212] [ka] After anesthetizing the rat, the sciatic nerve and gastrocnemius muscle were isolated, and muscle tension signals were recorded using a tension transducer while stimulating the sciatic nerve. The trachea was intubated and mechanical ventilation was performed using a small animal ventilator. After a period of stable muscle tension recording, drugs were administered, initially at a dose of 2x ED1. 90 A muscle relaxant (cisatracurium) was administered at a dose of 0.8 mg / kg. At this point, the muscle tension curve should decrease. After 30 to 60 seconds, the antagonist (test product and neostigmine) was injected. When the muscle tension curve recovered to 95% or more, ED was initiated. 90 A dose (0.9 mg / kg) of muscle relaxant (suxamethonium) was administered, at which point a decrease in muscle tension was observed. The experiment was stopped when muscle tension spontaneously recovered to more than 95%. During this time, muscle tension signals were continuously recorded, and indicators such as the onset of action time and clinical time effect were statistically analyzed. By comparing the muscle tension signals after administration, the effect of the antagonist on reversing muscle relaxation was determined and compared.

[0213] 4. Experimental Procedure 4.1 Weighing and anesthetizing rats The rats were weighed, and once their emotions had stabilized, they were anesthetized by intraperitoneal injection of 25% ethyl carbamate in urethane at 1 mL / 100 g. Once the pain reflex had disappeared, the rats were fixed prone on a foam board and their buttocks and right lateral thighs were depilated.

[0214] 4.2 Isolation of the sciatic nerve The skin was incised at the lateral edge of the femur behind the hip joint, and the skin and superficial fascia were removed. The muscles were bluntly separated to expose the sciatic nerve. Care was taken to avoid nerve damage with metal instruments during the separation using a glass probe.

[0215] 4.3 Isolation of the gastrocnemius muscle The skin of the lower leg was incised at the ankle joint, the ligament at the anterior part of the ankle joint was cut, the gastrocnemius muscle was separated, a ligature was placed around the gastrocnemius tendon at the ankle joint, and the tendon was cut at the distal end of the ligature.

[0216] 4.4 Signal Collection The gastrocnemius muscle ligature was connected to a tension transducer, and the stimulator was connected to the sciatic nerve. The input signal was tension, and the parameters were square wave, microvoltage, train-of-four, delay 0.05 ms, amplitude 0.2 ms, frequency 2 Hz, intensity 0.225 ± 0.025 V, intensity increment 0, string length 4, main period 12 s, and pause count 30,000. Muscle contraction curves were recorded. During the measurement, the muscle nerve was moistened with saline every 3–5 minutes to maintain a constant state.

[0217] 4.5 Ventilator connection, muscle relaxant and antagonist injection The ventilator tube opening was wiped with alcohol, the neck skin was incised, the jugular vein and trachea were located, the trachea was incised, and the ventilator was connected. The parameters were set to a tidal volume of 6 mL, an inspiratory-expiratory ratio of 5:4, and a respiratory rate of 80 breaths / min. After 5 minutes of stabilization, the ventilator was administered via the jugular vein. The settings were adjusted according to the reference, and the initial ED was doubled. 90 A muscle relaxant (cisatracurium) is administered at a dose of 100mg / kg, at which point the muscle tension curve should decrease. After 30-60 seconds of administration, the antagonist (test product and neostigmine) is injected. When the muscle tension curve has recovered to 95% or more, ED is initiated. 90 A muscle relaxant (suxamethonium) was administered at a dose of 100 mg / kg, and the experiment was stopped when the muscle tension curve recovered to 95% or more again. During this time, the muscle tension curve was continuously recorded.

[0218] [Table 1]

[0219] 4.6 Statistics for indicators of time effects Using the biological function experiment system, indicators such as the onset time of action and the onset time of secondary muscle relaxation were statistically calculated, and the statistical standards were as follows:

[0220] 1) Time for TOF to recover to 90% (TOF0.9): Time for the T4 / T1 value of TOF train-of-four stimulation to recover to approximately 90% - Administration time of antagonist 2) Duration of muscle relaxant action of suxamethonium: Time until muscle tension reaches its lowest value - Time of administration of suxamethonium

[0221] 5. Conclusion of the experiment As can be seen from Figures 1 and 2, Compounds 2 and 3 can reach the pharmacological effect level of neostigmine at 20 mg / kg, and are superior to CB2.

[0222] Test Example 2: Test of in vitro binding activity of compounds according to the present disclosure to muscle relaxants 1. Test Objectives: The in vitro binding activity of the compounds of the present disclosure with muscle relaxants was tested by isothermal titration calorimetry (ITC), and the binding K d Evaluate the value.

[0223] 2. Test materials: Isothermal titration calorimeter (including computer and software), CB2, Compound 2, Compound 3, Compound 7, Compound 12, Compound 13, Compound 15, cisatracurium, deionized water.

[0224] 3. Testing methods and procedures: The tubing, sample cell, and titration needle of the isothermal titration calorimetry system were cleaned with deionized water using a pre-set cleaning program. An aqueous solution of cisatracurium and the test compound were prepared in a ratio of cisatracurium:test compound = 10:1 to 20:1. The sample cell was filled with CB2 and the test compound using a sampling needle, and the cisatracurium was drawn into the titration needle using the sampling program. The titration needle was placed in the sample cell, stirring was started, and the system was allowed to equilibrate for 5 to 10 min. The titration parameters were set to 2.5 μL per drop of sample, 20 drops in total, and a titration interval of 150 s. The titration was started, and the thermal curve was recorded.

[0225] After the titration is complete, the K binding between the test compound and cisatracurium is measured by the thermal curve. d The values ​​were calculated, the tubing, sample cell and titration needle were cleaned using a cleaning program, and the next compound was tested.

[0226] 4. Test results: The ITC method was used to detect the ability of CB2, Compound 2, Compound 3, Compound 7, Compound 12, Compound 13, and Compound 15 to bind to cisatracurium in vitro and their dissociation constants, K d The values ​​are shown in Table 2, and the results show that Compound 2, Compound 13 and Compound 15 have stronger binding ability to cisatracurium in vitro than CB2.

[0227] [Table 2]

[0228] Test Example 3. Testing the Muscle Relaxant Antagonistic Effect of Compounds According to the Present Disclosure 1. Purpose of the experiment The compounds provided by the present disclosure are tested for their ability to reverse muscle relaxant effects on the gastrocnemius muscle in a rat neuromuscular model, evaluating indicators such as time to onset of action and TOF, and comparing them with CB2 and neostigmine.

[0229] 2. Experimental materials SPF-grade SD male rats, BL-420A biological function 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, suxamethonium, neostigmine, sterile water, 95% alcohol.

[0230] 3. Experimental Method SPF-grade SD male rats that had passed quarantine were selected and housed in a room temperature of 22±0.5°C, with a ventilation rate of 20-50 / h, an air velocity of 0.05-0.18 m / s, and a 12 / 12-hour light / dark cycle. They were allowed to adapt for at least three days in the animal facility, housed six rats per cage, and the study began when they reached a body weight of 220-250 g.

[0231] The test sample was reconstituted in 0.9% sodium chloride. After calculating the content, the required amount of test sample was weighed and dissolved in 0.9% sodium chloride injection (within 30 minutes). After that, the mixture was mixed uniformly in a vortex mixer and shaken. CB2 was reconstituted in purified water.

[0232] Actual weighed drug weight (mg) = administered formulation concentration A (mg / mL) × solvent volume (mL) / content (%) The rats were randomly divided into CB2 group, Compound 2 group, Compound 15 group, and neostigmine group, with 5 rats in each group (based on the actual number of rats in each group), and the administration volume was 2 mL / kg for all groups.

[0233] The structure of CB2 (prepared by the known method "WO2012051407A2") is as follows:

[0234] [ka] After anesthetizing the rat, the sciatic nerve and gastrocnemius muscle were isolated, and muscle tension signals were recorded using a tension transducer while stimulating the sciatic nerve. The trachea was intubated and mechanical ventilation was performed using a small animal ventilator. After a period of stable muscle tension recording, drugs were administered, initially at a dose of 2x ED1. 90 A muscle relaxant (cisatracurium) was administered at a dose of 0.8 mg / kg. At this point, the muscle tension curve should decrease. After 30 to 60 seconds, the antagonist (test product and neostigmine) was injected. When the muscle tension curve recovered to 95% or more, ED was initiated. 90 A dose (0.9 mg / kg) of muscle relaxant (suxamethonium) was administered, at which point a decrease in muscle tension was observed. The experiment was stopped when muscle tension spontaneously recovered to more than 95%. During this time, muscle tension signals were continuously recorded, and indicators such as the onset of action time and clinical time effect were statistically analyzed. By comparing the muscle tension signals after administration, the effect of the antagonist on reversing muscle relaxation was determined and compared.

[0235] 4. Experimental Procedure 4.1 Weighing and anesthetizing rats The rats were weighed, and once their emotions had stabilized, they were anesthetized by intraperitoneal injection of 25% ethyl carbamate in urethane at 1 mL / 100 g. Once the pain reflex had disappeared, the rats were fixed prone on a foam board and their buttocks and right lateral thighs were depilated.

[0236] 4.2 Isolation of the sciatic nerve The skin was incised at the lateral edge of the femur behind the hip joint, and the skin and superficial fascia were removed. The muscles were bluntly separated to expose the sciatic nerve. Care was taken to avoid nerve damage with metal instruments during the separation using a glass probe.

[0237] 4.3 Isolation of the gastrocnemius muscle The skin of the lower leg was incised at the ankle joint, the ligament at the anterior part of the ankle joint was cut, the gastrocnemius muscle was separated, a ligature was placed around the gastrocnemius tendon at the ankle joint, and the tendon was cut at the distal end of the ligature.

[0238] 4.4 Signal Collection The gastrocnemius muscle ligature was connected to a tension transducer, and the stimulator was connected to the sciatic nerve. The input signal was tension, and the parameters were square wave, microvoltage, train-of-four, delay 0.05 ms, amplitude 0.2 ms, frequency 2 Hz, intensity 0.225 ± 0.025 V, intensity increment 0, string length 4, main period 12 s, and pause count 30,000. Muscle contraction curves were recorded. During the measurement, the muscle nerve was moistened with saline every 3–5 minutes to maintain a constant state.

[0239] 4.5 Ventilator connection, muscle relaxant and antagonist injection The ventilator tube opening was wiped with alcohol, the neck skin was incised, the jugular vein and trachea were located, the trachea was incised, and the ventilator was connected. The parameters were set to a tidal volume of 6 mL, an inspiratory-expiratory ratio of 5:4, and a respiratory rate of 80 breaths / min. After 5 minutes of stabilization, the ventilator was administered via the jugular vein. The settings were adjusted according to the reference, and the initial ED was doubled. 90 A muscle relaxant (cisatracurium) is administered at a dose of 100mg / kg, at which point the muscle tension curve should decrease. After 30-60 seconds of administration, the antagonist (test product and neostigmine) is injected. When the muscle tension curve has recovered to 95% or more, ED is initiated. 90 A muscle relaxant (suxamethonium) was administered at a dose of 100 mg / kg, and the experiment was stopped when the muscle tension curve recovered to 95% or more again. During this time, the muscle tension curve was continuously recorded.

[0240] [Table 3]

[0241] 4.6 Statistics for indicators of time effects Using the biological function experiment system, indicators such as the onset time of action and the onset time of secondary muscle relaxation were statistically calculated, and the statistical standards were as follows:

[0242] 1) Time for TOF to recover to 90% (TOF0.9): Time for the T4 / T1 value of TOF train-of-four stimulation to recover to approximately 90% - Administration time of antagonist 2) Duration of muscle relaxant action of suxamethonium: Time until muscle tension reaches its lowest value - Time of administration of suxamethonium

[0243] 5. Conclusion of the experiment As can be seen from Figure 3, compounds 2 and 15 can reach the pharmacological effect level of neostigmine at 20 mg / kg, which is superior to CB2.

[0244] Test Example 4: Test of in vitro binding activity of compounds according to the present disclosure to muscle relaxants 1. Test Objectives: The in vitro binding activity of the compounds of the present disclosure with muscle relaxants was tested by isothermal titration calorimetry (ITC), and the binding K d Evaluate the value.

[0245] 2. Test materials: Isothermal titration calorimeter (including computer and software), CB2, compound 2, compound 11, compound 15, compound 16, cisatracurium, deionized water.

[0246] 3. Testing methods and procedures: The tubing, sample cell, and titration needle of the isothermal titration calorimetry system were cleaned with deionized water using a pre-set cleaning program. An aqueous solution of cisatracurium and the test compound were prepared in a ratio of cisatracurium:test compound = 10:1 to 20:1. The sample cell was filled with CB2 and the test compound using a sampling needle, and the cisatracurium was drawn into the titration needle using the sampling program. The titration needle was placed in the sample cell, stirring was started, and the system was allowed to equilibrate for 5 to 10 min. The titration parameters were set to 2.5 μL per drop of sample, 20 drops in total, and a titration interval of 150 s. The titration was started, and the thermal curve was recorded.

[0247] After the titration is complete, the K binding between the test compound and cisatracurium is measured by the thermal curve. d The values ​​were calculated, the tubing, sample cell and titration needle were cleaned using a cleaning program, and the next compound was tested.

[0248] 4. Test results: The ITC method was used to detect the ability of CB2, Compound 2, Compound 11, Compound 15, and Compound 16 to bind to cisatracurium in vitro and their dissociation constants, K d The values ​​are shown in Table 4, and the results show that Compound 2, Compound 11, Compound 15 and Compound 16 have stronger binding ability to cisatracurium in vitro than CB2.

[0249] [Table 4]

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, 【Chemistry 1】 Among them, R １ are each independently C ２－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, —C(O) ２ R', R'-(O)-alkylene-, a hydroxy group, NR'(R''), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R's linked on adjacent carbon atoms. １ together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, １ optionally, one or more R １Ａ is replaced by R ２ are each independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, —C(O) ２ R', R'-(O)-alkylene-, a hydroxy group, NR'(R''), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R's linked on adjacent carbon atoms. ２ together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, ２ optionally, one or more R ２Ａ is replaced by each ring A is independently selected from a 5- to 12-membered aryl group or a 5- to 12-membered heteroaryl group; R ３ are each independently a halogen, C １－６ Alkyl group, hydroxy group, nitro group, cyano group, —C(O) ２ R', NR'(R"), R'-(O)-alkylene-, a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or 【Chemistry 2】 and at least one is selected from 【Transformation 3】 and R ３ optionally, one or more R ３Ａ is replaced by R ４ teeth 【Chemistry 4】 and A ＋ is a monovalent or divalent cation, R １Ａ , R ２Ａ , R ３Ａ are each independently a halogen, a cyano group, a nitro group, an amino group, C １－６ Alkyl group or C １－６ selected from alkoxy groups, R′ and R″ are each independently hydrogen, C １－６ Alkyl group, C １－６ Hydroxyalkyl group, C １－６ selected from haloalkyl groups, 3- to 7-membered cycloalkyl groups, and 3- to 7-membered heterocyclyl groups; m and n are each independently selected from 1, 2, 3, 4, or 5; p is independently selected from 1, 2, 3, 4, 5, or 6; A compound of formula (I) or a pharmaceutically acceptable salt thereof.

2. the ring A is a phenyl group or a naphthyl group, preferably naphthyl; 2. A compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. A compound represented by general formula (I-1) or a medicamentable salt thereof, 【Transformation 5】 Among them, R １ , R ２ , p, m and A ＋ is as defined in claim 1 3. A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Two R's linked on adjacent carbon atoms １ together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, and preferably, two R １ together form a 6-membered cycloalkyl group, and more preferably, two R １ together form a 5- to 6-membered heterocyclyl group, in which the heteroatom is selected from nitrogen or oxygen, preferably oxygen; A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

5. R １ are each independently C ２－６ an alkyl group, preferably an ethyl group, or R １ are each independently C １－６ haloalkyl group, preferably C １－３ haloalkyl groups, more preferably alkyl groups substituted with one, two or three fluorines, or R １ are each independently —C(O) ２ R', each R' independently represents hydrogen, C １－６ Alkyl group, C １－６ haloalkyl groups, preferably R' is H or C １－６ is an alkyl group, more preferably a methyl group or an ethyl group, or R １ are each independently C １－６ Hydroxyalkyl group or C １－６ Alkyl-O-C １－６ alkylene-, preferably C １－３ Hydroxyalkyl group or C １－３ Alkyl-O-C １－３ alkylene-, more preferably a hydroxymethyl group or a methyl-O-methylene-, or R １ are each independently R'-(O)-alkylene-, and said R' is C １－６ Alkyl group, C １－６ Hydroxyalkyl group, C １－６ haloalkyl group, 3- to 7-membered cycloalkyl group, 3- to 7-membered heterocyclyl group, preferably, said R' is C １－６ Alkyl group or C １－６ haloalkyl group, more preferably, R' is C １－３ is an alkyl group, A compound of formula (I) according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

6. R ２ are each independently hydrogen; A compound of formula (I) according to any one of claims 1 to 5 or a medicamentable salt thereof.

7. A ＋ is a monovalent cation, and the monovalent cation is H ＋ , Na ＋ , K. ＋ , H ４ N ＋ , Et ３ NH ＋ , (HOCH ２ CH ２ ) ３ NH ＋ or the cationic forms of ethylenediamine, piperazine, triphenylmethylaminomethane, preferably H ＋ , Na ＋ , or K ＋ and more preferably Na ＋ Or, A ＋ is a divalent cation, and the divalent cation is Ca ２＋ , Mg ２＋ , or Zn ２＋ Selected from A compound of formula (I) according to any one of claims 1 to 6 or a medicamentable salt thereof.

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

9. m is independently selected from 2, 3, or 4, preferably 2; A compound of formula (I) according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof. 【Request Item 10】 【Chemistry 6-1】 【Chemistry 6-2】 Selected from A compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. A compound of formula (III) or a pharmaceutically acceptable salt thereof, 【Transformation 7】 Among them, X Ｃ１ , X Ｃ２ are each independently selected from O, S, and —NH—; R Ｃ２ are each independently hydrogen, C １－６ Alkyl group, C １－６ Haloalkyl group, C １－６ Hydroxyalkyl group, —C(O) ２ R', R'-(O)-alkylene-, a hydroxy group, NR'(R''), a 3- to 7-membered cycloalkyl group, a 3- to 7-membered heterocyclyl group, or two R's linked on adjacent carbon atoms. Ｃ２ together form a 3- to 10-membered cycloalkyl group or a 3- to 10-membered heterocyclyl group, Ｃ２ optionally one or more halogens, cyano groups, nitro groups, amino groups, C １－６ Alkyl group or C １－６ substituted with an alkoxy group, Ring C is selected from a 6- to 18-membered aryl group or a 5- to 18-membered heteroaryl group; R Ｃ３ are each independently 【Transformation 8】 That is, R Ｃ４ are each independently 【Chemistry 9】 , a carboxy group, a carboxylate cation; a phosphate group, a phosphate cation; a sulfonic acid group, a sulfonate cation; L, L １ , L ２ are the same or different and each independently represent an alkylene group or a heteroalkylene group, and the alkylene group or heteroalkylene group may optionally contain one or more halogen atoms, cyano groups, nitro groups, amino groups, C １－６ Alkyl group, or C １－６ substituted with an alkoxy group, R ｃ are each independently hydrogen, halogen, a cyano group, a nitro group, an amino group, C １－６ Alkyl group or C １－６ selected from alkoxy groups, R ａ , R ｂ are the same or different and are each independently selected from a carboxy group, a carboxylate cation, a phosphate group, a phosphate cation, a sulfonic acid group, and a sulfonate cation; R′ and R″ are each independently hydrogen, C １－６ Alkyl group, C １－６ Hydroxyalkyl group, C １－６ selected from haloalkyl groups, 3- to 7-membered cycloalkyl groups, and 3- to 7-membered heterocyclyl groups; x is selected from 1, 2, 3, 4 or 5; v is independently selected from 1, 2, 3, 4, or 5; q is independently selected from 1, 2, 3, 4, 5, or 6; A compound of formula (III) or a pharmaceutically acceptable salt thereof:

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

13. L is independently C １－６ is an alkylene group, 13. A compound of formula (III) or a medicament salt thereof according to claim 11 or 12.

14. Ring C is selected from a benzene ring, a naphthalene ring, or an anthracene ring, and is preferably a naphthalene ring or an anthracene ring. A compound of formula (III) or a medicament salt thereof according to any one of claims 11 to 13.

15. A compound of formula (III-A), formula (III-B), formula (III-C) or formula (III-D) or a pharmaceutically acceptable salt thereof, 【Chemistry 10】 Among them, R Ｄ are each independently selected from a carboxy group, a carboxylate cation, a phosphate group, and a phosphate cation; R Ｅ are each independently selected from a carboxy group, a carboxylate cation, a phosphate group, a phosphate cation, a sulfonic acid group, and a sulfonate cation; r is selected from 1, 2, and 3; R Ｃ２ , q, x, L １ , L ２ , R ａ , R ｂ , R ｃ is as defined in claim 11 A compound of formula (III) or a medicament salt thereof according to any one of claims 11 to 14.

16. L １ , L ２ are the same or different, and each independently represents C １－６ is an alkylene group, A compound of formula (III) or a medicament salt thereof according to any one of claims 11 to 15.

17. selected from compounds 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 medicinal salts thereof; 【Chemistry 11-1】 【Chemistry 11-2】 Among them, each a is independently selected from 1, 2, 3, and 4; b's are independently selected from 1, 2, 3, and 4; c is independently selected from 1, 2, 3, and 4; A １ ＋ or A ２ ＋ are the same or different and are each independently a monovalent cation or a divalent cation; A １ ＋ is a monovalent cation, s is 4; A １ ＋ is a divalent cation, s is 2; A ２ ＋ is a monovalent cation, t is 8; A ２ ＋ is a divalent cation, t is 4; R Ｃ２ , q, x are as defined in claim 11 and r is as defined in claim 15; A compound of formula (III) or a medicament salt thereof according to any one of claims 11 to 16.

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

19. r is 2 or 3, preferably 2; 19. A compound of formula (III) or a medicament salt thereof according to claim 17 or 18.

20. a, b, and c are the same or different and each independently selected from 1, 2, or 3, preferably a, b, and c are all 1; A compound of formula (III) or a medicament salt thereof according to any one of claims 17 to 19.

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

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

23. A １ ＋ , A ２ ＋ are each independently a monovalent cation, and the monovalent cation is H ＋ , Na ＋ , K. ＋ , H ４ N ＋ , Et ３ NH ＋ , (HOCH ２ CH ２ ) ３ NH ＋ or the cationic forms of ethylenediamine, piperazine, triphenylmethylaminomethane, preferably H ＋ , Na ＋ , or K ＋ and more preferably Na ＋ That is, A compound of formula (III) or a medicament salt thereof according to any one of claims 17 to 22.

24. A １ ＋ , A ２ ＋ are each independently a divalent cation, and the divalent cation is Ca ２＋ , Mg ２＋ or Zn ２＋ Choose from A compound of formula (III) or a medicament salt thereof according to any one of claims 17 to 23. 【Request Item 25】 【Chemistry 12-1】 【Chemistry 12-2】 【Chemistry 12-3】 Selected from A compound of formula (III) or a medicamentable salt thereof according to any one of claims 17 to 24.

26. An isotopic substitution of the compound or a medicament salt thereof according to any one of claims 1 to 25, wherein the isotopic substitution is preferably a deuterium atom substitution. Isotopically substituted compounds.

27. 26. A method for treating a rheumatoid arthritis comprising administering to a patient a therapeutically effective amount of at least one compound according to claim 1 or a pharmaceutically acceptable salt thereof, an isotopic derivative according to claim 26, and a pharmaceutically acceptable excipient. Pharmaceutical compositions.

28. Use of the compound according to any one of claims 1 to 25 or a medicament salt thereof, the isotope-substituted compound 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, wherein the disease or condition is selected from a proliferative disease, a cardiovascular-related disease, or a blood cancer. use.

29. In preparing a medicament for reversing drug-induced neuromuscular blockade and / or anesthesia, the compound according to any one of claims 1 to 25 or a medicament salt thereof, the isotope-substituted compound according to claim 26 or the pharmaceutical composition according to claim 27, use.

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